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Congenital malformations of individual organ systems

3  Atlas of fetal pathology

3.3  Congenital malformations of individual organ systems

3.3.1  Congenital malformations of the central nervous system

Sylva Hotárková

Introduction:

Nervous and cardiovascular systems are the first functional organ systems during embryonal development. During the first month differentiation and cell division is going on. The process of formation of new neurons propably stops quite early and does not continue after the birth. The prenatal overall growth of the nervous system continues postnatally, especially during the first 3 years of life. It is characterised by growth of the neurons as well as glial cells and myelinization. The frequency of congenital malformations of the central nervous system (i.e. brain and spinal cord) is 1 : 500 – 1 : 3000. More often it affects female fetuses.

Clinical signs:

Congenital malformations of the CNS are often present in fetuses with chromosomal aberrations (Edward's or Patau syndromes to name a few), but there is no specific anomaly associated with a certain chromosomal abnormality. Meckel syndrome is a rare example of a single gene disorder characterised by major CNS malformations. Teratogens are important in the etiology as well  — radiation, chemical teratogens like isotretinoin or methyl-mercury, alcohol; viral infections. Other teratogenic etiological factors are hypoxic-ischemic episodes and some maternal diseases (diabetes, poor controled phenylketonuria or hypotermia). Amniotic bands cause severe mutilations of the face and head.

3.3.1.1  Congenital malformations of the spinal cord

Neral tube defects are the most common congenital malformations of the CNS. There is a failure of closure of the neural tube during the 1 st trimestr. The closure involves the neural plate, meninges, vertebral arches, soft tissues and epidermis. Spina bifida, rachischisis and as for the brain anencephaly and encephalocele are classified with the neural tube defects. Neural tube defects can be recognised prenatally by detection of high levels of alphafetoprotein (AFP)in the maternal blood. This test is routinely done at 16 – 18 weeks (triple test). Elevated AFP is seen in open defects uncovered by skin. Prenatal diagnosis is also done by ultrasound examination.

3.3.1.1.1  Spina bifida

Introduction:

Neural tube defect involving mostly the lumbosacral region of the spine.

Macroscopic appearance:

Various subtypes exist:

  • Spina bifida occulta:
    • incidence is 1 : 500
    • one or more vertebral arches failed to close, spinal cord and meninges are normal
    • intact skin over the defect may be hairy and hyperpigmented
    • does not cause symptoms, spina bifida occulta is usually diagnosed accidentally
  • Spina bifida cystica:
    • incidence is 1 : 1000.
    • there is a cyst protruding through the defect in the vertebral arches
    • according to the contents of the cystic protrusion these variants can be recognized:
      • Meningocele: cystic sac contains dura mater, arachnoid and cerebrospinal fluid. Neither the spinal cord nor the spinal nerves are malformed.This occurs in 15% of cases.
      • Meningomyelocele: the cystic sac also contains the spinal cord and the spinal nerves (in addition to the meninges), which adhere to the sides of the sack. This occurs in 85% of cases. Hzdrocephalus (Arnold Chiari malformation) is invariably associted. Symptomatology corresponds with localisation of the defect, for example if the defect is in the sacral area, there is loss of bladder and bowel function. The sac can become infected and there is a risk of ascendent meningitis. Surgery is necessary right after the birth.
3.3.1.1.2  Myeloschisis (rachischisis posterior)

Clinical signs:

  • severe open defect, the neural tissue is bare with no dermal or meningeal covering.
  • always associated with serious functional disorders of the spinal cord
  • the most severe form of spina bifida, affected newborns die very soon
  • craniorachischisis totalis is a complete neural tube defect with missing neurocranium and rachischisis.

Pictures

Lumbosacral rachischisis, 22-week fetus:
Rhachischisis, Macro, autopsy (72524)

Rhachischisis posterior:
Rhachischisis posterior, Macro, autopsy (73333)
Rhachischisis posterior, Macro, autopsy (73334)
Rhachischisis posterior, Macro, autopsy (73335)

Atypical shape of the occipital region (Arnold Chiari malformation), together with lumbosacral rachischisis, 22-week fetus:
Rhachischisis, Macro, autopsy (72523)

Spina bifida aperta, US video:
Spina bifida aperta, Ultrasound, video (74030)

3.3.1.2  Congenital malformations of the brain
3.3.1.2.1  Anencephaly

Clinical signs:

  • severe malformation which occurs when the cephalic end of the neural tube fails to close and major parts of the brain and the cranial vault fail to develop
  • incidence is 1 : 1000 (therefore not very rare)
  • anencephaly can often be associated with rachischisis and other congenital defects
  • incompatible with survival
  • diagnosis is made by ultrasound: missing skull and polyhydramnion

Macroscopic appearance:

  • absent cranial vault
  • the base of the skull is small with absent or decreased anterior and middle cranial fossa
  • the cranial base is covered by a vascular mass, so-called area cerebrovasculosa, structurally close to chorioid plexus, with remnants of immature nervous tissue; area cerebrovasculosa merges into skin at the edges.
  • eyes are prominent no optical nerves usually.
  • hypophysis is present, but usually hypoplastic

Histology:

Area cerebrovasculosa consists of dilated blood vessels and variable amount of immature nervous tissue, glial in particular.

Pictures

Area cerebrovasculosa:
Area neurovasculosa, HE 20x (73002)

3.3.1.2.2  Iniencephaly

Introduction:

Neural tube defect involving the occiput combined with rachischisis of the cervical and thoracic spine with extreme retroflexion of the head.

Inion  —  greek word for occiput.

Clinical signs:

Fatal condition, consistent with anencephaly.

Macroscopic appearance:

  • extreme retroflexion of the head, fusion of the skin of the face and thorax because of absent neck
  • overall shortening of the fetus
  • variable deficit of the occipital bones, enlarged foramen magnum
  • malformed cervical and thoracic spine:
    • cervical lordosis
    • partial or total absence of vertebrae
    • fusion of the vertebrae
    • imcomplete closure of the vertebral arches
  • open neural tube defect, rarely closed defect
  • can be asocciated with acrania

Pictures

16 week male fetus, iniencephaly and craniorhachischisis; karyotype 46XY:
Ineincephaly, Macro, autopsy (72742)
Ineincephaly, Macro, autopsy (72743)

The same case, US examination:
Iniencephaly, Ultrasound (72980)

3.3.1.2.3  Encephalocele

Clinical signs:

  • a herniation of brain tissue and meninges outside the cranial cavity, most often found in the occipital area
  • infarction and hemorrhage is frequent in the encephalocele (due to pressure on the vessels)
  • the sac may contain cerebral cortex, which has abnormal histological structure
  • encephalocele is not as common as anencephaly
  • large encephalocele is incompatible with survival
  • a herniation of the meninges only is better classified as cranial meningocele
3.3.1.2.4  Arnold-Chiari malformation

Clinical signs:

  • abnormally shaped bone structures in the posterior cranial fossa (small posterior fossa, low attachement of the tentorium cerebelli)
  • the inferior vermis, cerebellar tonsils and distal brain stem are displaced down through the foramen occipitale magnum into the upper cervical canal, where they are damaged due to high pressure
  • hydrocephalus is a rule
  • Arnold Chiari malformation is almost always associated with lumbosacral meningomyelocele
  • additional malformations of the brain, such as cerebral heterotopy, corpus callosum agenesis, abnormal gyrification can be found
3.3.1.2.5  Disorders of formation of the structures derived from the mediobasal prosencephalon

Introduction:

The prosencephalon is the anterior end of the neural tube. It consists of the telencephalon which gives rise to the cerebral hemispheres and striatum and the diencephalonwhich gives rise to thalamus, hypothalamus globus pallidus and eye. The term midline field defects is also used for this group of defects.

Classification:

Several malformations belong to this category:

Holoprosencephaly

  • the most serious defect from this group of anomalies; prosencephalon has not divided into two parts supposed to become the hemispheres
  • 3 forms (according to the degree of division):
    • alobar:very small spherical brain undivided into hemispheres or lobes
    • semilobar: two hemispheres partially separated by shallow interhemispheric fissure which is best seen occipitally
    • lobar: almost complete separation of the hemispheres except for small parts of anterior lobes or gyrus cinguli which is fused
  • other CNS anomalies are also often present, depending on the severity of the original defect:
    • absence of bulbus and tractus olphactorius
    • absence of corpus striatum and corpus callosum
    • fused thalamus
    • anomalies of the cortex
    • glioneural heterotopy
    • anomalies of the circle of Willis
  • crainofacial dysmorphology is always found, the rule is the face predicts the brain
    • cyclopia: single eye, absent nose, supraorbital proboscis
    • ethmocephaly: closely set eyes, absent nose, interorbital proboscis
    • cebocephaly: closely set eyes, flattened nose with single nostril
    • median cleft lip, closely set eyes, small flattened nose
    • hypertelorism, microphtalmy, unilateral or bilateral cleft lip can be seen as well
  • etiology: often is associated with these chromosomal aberrations: trisomies and abnormalities of chromosomes 13 and 18; it is also associated with chemical teratogens (for example alcohol)
  • most of the affected fetuses are stillborn or die right after the birth

Corpus callosum agenesis

It is a common malformation. The agenesis can be complete or partial. Agenesis corpus callosum is either an isolated malformation or associated with other CNS defects (holoprosencephaly, Arnold Chiari) and a wide range of variable human malformations. Clinical symptomatology largely depends on associated anomalies. Psychomotoric delay is frequent but isolated cases can be asymptomatic. Occipital horns of the lateral ventricles are dilated. This sign is also usefull in prenatal diagnosis.

Arhinencephaly

  • the least serious from this group
  • means the mere absence of olfactory bulbs and tracts, usually bilateral
  • either isolated or associated with other CNS malformations

Pictures

Holoprosencephaly:
Holoprosencephaly, Macro, autopsy (72104)
Holoprosencephaly, Macro, autopsy (72059)

Holoprosencephaly:
Holoprosencephaly, Macro, autopsy (73293)
Holoprosencephaly, Macro, autopsy (73294)
Holoprosencephaly, Macro, autopsy (73295)
Holoprosencephaly, Macro, autopsy (73296)
Holoprosencephaly, Macro, autopsy (73297)

Holoprosencephaly, macro and US video:
Holoprosencephaly, Macro, autopsy (73298)
Holoprosencephaly, Macro, autopsy (73299)
Holoprosencephaly, Macro, autopsy (73300)
Holoprosencephaly, Macro, autopsy (73301)
Holoprosencephaly, Macro, autopsy (73302)
Holoprosencephaly, Macro, autopsy (73303)
Holoprosencephaly, Macro, autopsy (73304)
Holoprosencephaly, Macro, autopsy (73305)
Holoprosencephaly, Ultrasound, video (74017)

Holoprosencephaly, semilobar:
Holoprosencephaly, semilobar, Macro, autopsy (73673)
Holoprosencephaly, semilobar, Macro, autopsy (73674)
Holoprosencephaly, semilobar, Macro, autopsy (73675)

Corpus callosum agenesis:
Agenesis corporis callosi, Macro, autopsy (72036)
Agenesis corporis callosi, Macro, autopsy (72037)
Agenesis corporis callosi, Macro, autopsy (72035)

Normal corpus callosum (for comparison):
Corpus callosum, normal, Macro, autopsy (72082)

Another case of corpus callosum agenesis, macro and US video:
Agenesis of the corpus callosum, Macro, autopsy (73264)
Agenesis of the corpus callosum, Macro, autopsy (73265)
Agenesis corporis callosi, Ultrasound, video (74028)

Agenesis corporis callosi:
Agenesis corporis callosi, Macro, autopsy (74336)
Agenesis corporis callosi, Macro, autopsy (74337)
Agenesis corporis callosi, Macro, autopsy (74338)

Agenesis corporis callosi:
Agenesis corporis callosi, Macro, autopsy (74339)
Agenesis corporis callosi, Macro, autopsy (74340)

3.3.1.2.6  Migration disorders

Introduction:

Abnormal migration of neurons to the cortex can be easily recognised by abnormal gyrification.

Classification:

  • Agyria: very rare defect, brain surface is almost completely smooth, gyri are absent. On sectioning the cortex is very thick and white matter thin. There is an abnormal four-layer cortex.
  • Pachygyria: gyri are wide, thick and reduced in number. Both agyria and pachygyria are etiologically often associated with chromosomal aberrations, gene mutations and teratogens.
  • Polymicrogyria: very small gyri, sometimes with little central dimples caused by mechanisms of disruption.
  • Heterotopic gray matter: small foci of unmigrated gray matter can be found under the ependyma of the lateral ventricles or between the ventricle and the cortex. This is seen in many different conditions: agyria and pachygyria, Arnold-Chiari malformation.
3.3.1.2.7  Destructive lesions of fetal brain (disruptions)

Introduction:

Ischemia occuring as early as 26 weeks of gestation results in necrosis which heals without obvious reactive astrocytosis. A smooth-walled porencephallic cavity develops this way. An insult timed in the second trimestr also disturbs the neuronal migration resulting in polymicrogyria. Lesions arising later in the third trimestr and perinatal period heal with gliosis but without abnormal gyral pattern.

Etiology:

  • vascular occlusion
  • diffuse hypoxic-ischemic brain necrosis
  • pathology of twinning (intrauterine demise of the monochorionic co-twin produces an episode of severe hypotension in the surviving twin)
  • prenatal infections (toxoplasmosis, CMV, herpes simplex)

Classification:

The lesions differ in the extent of cerebral destruction.

  1. Porencephaly
  2. Hydranancephaly
  3. Basket brain is a term used for extensive bilateral porencephalic defects
  4. Multicystic encephalopathy
3.3.1.2.7.1  Porencephaly

Introduction:

Fluid  —  filled cavity (pseudocyst) originating during fetal life.

Clinical signs:

Clinical presentation depends on the extent and location of the defect: cerebral palsy, developemental delay, epilepsy, blindness.

Macroscopic appearance:

  • smooth walled cavity in a hemispere
  • unilateral or bilateral
  • deep defects allow communacation between the ventricle and the surface covered only by a thin external membrane
  • the cortex at the edge of the cavity may show polymicrogyria
  • polymicrogyria is frequently seen in the contralateral hemispere in unilateral porencephaly
3.3.1.2.7.2  Hydranencephaly

Macroscopic appearance:

The major part of fetal cerebrum supplied by internal carotis arteries are destroyed. Hemispheres are reduced to a thin membranous sac filled with abundant cerebrospinal fluid (bubble brain). There is variable preservation of inferior frontal, temporal, occipital lobes (depends on the collateral vascular supply) basal ganglia and diencephalon. The brain stem and cerebellum in the posterior fossa are always intact. Falx cerebri is absent or hypoplastic.

Clinical signs:

  • normal head circumference at birth, normal face
  • seizures, deafness, blindness, hyperreflexia, poor body temperature control, respiratory problems, spastic quadruparesis
  • the condition is uniformly fatal, affected infants die in the first year of life
  • differential diagnosis: extreme hydrocephalus, holoprosencephaly and porencephaly

Pictures

Hydranencefalie (basket brain), plod; mistaken for holoprosencephaly of lobar type at prenatal examination:
Hydranencephaly, Macro, autopsy (73306)
Hydranencephaly, Macro, autopsy (73307)
Hydranencephaly, Macro, autopsy (73308)

3.3.1.2.8  Hydrocephalus

Clinical signs:

  • hydrocephalus can occur during the fetal period
  • refers to an increase volume of cerebrospinal fluid within the cranium
  • manifestation:
    • head enlargement with wide fontanels and sutures in neonate and child, fetus up to 24 – 30 weeks rarely presents with increased head circumference
    • the ventricular system is widely dilated
    • brain tissue atrophies, first the white matter, than the cortex
    • irreversible damage can be prevented by shunting

Classification:

There are 2 types of hydrocephalus:

  • obstructive hydrocephalusis a result of a space occupying lesion which impedes free passage of the cerebrospinal fluid, this occurs mostly in the aqueduct
  • communicating (hyporesorptive) hydrocephalusis caused by failure of resorption of cerebrospinal fluid and has no obstruction. Hydrocephalus due to excess of cerebrospinal fluid secretion is very rarely seen in papillomas of choroid plexus.
  • congenital hydrocephalusis obstructive in majority of cases. The main causes are aqueductal stenosis or atresia, Arnold Chiari malformation, Dandy Walker malformation, corpus callosum agenesis.
  • ultrasound measurement of ventricular width is easily done prenatally
    • mild ventriculomegaly (ventricular width 10 – 15 mm)is associated with abnormal karyotype. Otherwise the prognosis of isolated mild ventriculomegaly and normal karyotype is favourable, intelligence normal
    • severe ventriculomegaly or hydrocephalus (ventricular width more than 15 mm)
  • aquired hydrocephalushemorrhage, inflammation and tumours are the most common causes
3.3.1.2.9  Dandy-Walker malformation

Clinical signs:

Clinically it resembles the hydrocephalus. Affected persons can live up to their twenties.

Macroscopic appearance:

  • agenesis or hypoplasia of the cerebellar vermis
  • cystic dilatation of the 4th ventricle
  • obstruction of the foramina rhombencephali
  • larger posterior cranial fossa
  • hydrocephalus
  • sometimes even agenesis of the corpus callosum and gyrification disorders

Pictures

Dandy-Walker malformation, agenesis of the corpus callosum, child 2 years old, hydrocephalus:
Dandy Walker, hydrocephalus, Macro, autopsy (72357)

Dandy-Walker malformation, cerebellum:
Dandy Walker, cerebellum, Macro, autopsy (72358)
Dandy Walker, cerebellum, Macro, autopsy (72359)

Agyria, agenesis of the corpus callosum, Dandy-Walker syndrome, child 2 years old:
Dandy Walker, agyria, agenesis of the corpus callossum, Macro, autopsy (72360)

Cystic dilatation of the 4th ventricle:
Dandy Walker, cystic dilatation of the 4th ventricle, Macro, autopsy (72361)
Dandy Walker, cystic dilatation of the 4th ventricle, Macro, autopsy (72362)

3.3.1.2.10  Intracranial non-neoplastic cysts

Introduction:

Intracranial cysts are rare and make up only 1 % of intracranial lesions in childhood. There are very rare cases reported in a fetus.

Classification:

Classification and terminology is disunited.

Basic classification

  • arachoid cyst
  • neuroepithelial cyst

Final diagnosis can be achieved only by use of histology and immunohistology.

Clinical signs:

The prognosis of intracranial cysts identified prenatally during the 1st or 2nd trimestr is not good. The cyst may present with obstructive hydrocephalus in utero. They are often associated with additional CNS malformations, corpus callosum dysgenesis and grey matter heterotopia in particular. The affected individuals often suffer from epilepsy and psychomotoric impairment.

Cysts identified accidentally during the 3rd trimestr or during childhood tend to be asymptomatic and the prognosis is generally good. Some cysts expand, increase intracranial pressure and thus became symptomatic.

3.3.1.2.10.1  Arachnoid cyst

Etiology:

Congenital developement anomaly of arachonoid membrane.

The cysts are formed from splitting or the arachnoid membrane, the cysts are intra-arachnoid to be exact.

Aquired arachnoid cysts are different. These cysts develope following meningitis, hemorrhage, trauma or neurosurgary.

Macroscopic appearance:

  • Smooth thin walled unilocular or septate cyst containing clear fluid
  • Approximately 50% are localized supratentorial in the Sylvian fissure 25% are infratentorial
  • spinal cysts are also common

Histology:

Discontinuited meningotelial layer, connective tissue.

3.3.1.2.10.2  Neuroepithelial cyst

Etiology:

Developemental cyst lined with neuroepithelium (ependymal, choroid plexus cells or mix of both). An outer layer of glial cells may be present.

Macroscopic appearance:

  • smooth thin walled unilocular or septate cyst containing clear fluid
  • most often found supratentorial in the midline (interhemispheric cysts), but inftratentorial or intraventricular locations were also described
  • interhemispheric cysts associated with complete or partial corpus callosum agenesis have been reported

Histology:

Ependymal cells (ciliated), choriod plexus cells, glial elements, connective tissue.

Case study:

Intracranial cyst
Marta Ježová

History:

31 – year woman, second gravidity.

Prenatal ultrasound examination (23 weeks): a cyst 20×13 mm between the cerebellum and the left cereberal hemisphere. Arachnoid origin ot the cyst was supposed. Ventricular system was normal.

Fetal karyotype: 46 XX

Final diagnosis (based on histology and imunohistochemical staining): intehemispheric neuroepithelial (glioependymal) cyst.

Macroscopic appearance:

24 – week female fetus.

Large thin walled cyst 25 mm in diameter was detected supratentorial in the midline. The cyst had no continuity with the leptomeninges and contained clear fluid.

3.3.2  Congenital malformations of the respiratory system

Sylva Hotárková

Introduction:

The development of the respiratory system, especially of the pulmonary tissue, is very important for a child to survive in case of premature birth. These problems are described in the chapter Patology of the newborn and infancy. The development of the respiratory system starts in the 4th week of intrauterine development and continues throughout the whole intrauterine development and postnatally till the 8th year of life. The nubmber and size of alveoli increases during late gravidity and during the childhood.

Congenital malformations of the respiratory tract are rather rare, the overall incidence is about 1 : 10 000.

Etiology:

Etiology of congenital malformations of the respiratory tract is variable and in most cases unknown.

Congenital malformations of the larynx, trachea, lung and diaphragm will be described.

Classification:

Larynx:

  • atresia
    • rare fatal condition
    • associated with pulmonary hyperplasia
    • laryngeal atresia is often a part of the VACTERL

Trachea:

  • agenesis
    • rare fatal malformation
    • classification: 7 types
    • tracheo or bronchoesophageal connection in most cases
    • in 75% of cases other congenital malformations are present, including annular pancreas, duodenal atresia or VACTERL
  • tracheoesophageal fistulae are described in the chapter Patology of the GIT and in detail in the chapter Congenital malformations of the esophagus (not yet available in English)

The lungs, congenital malformations:

  • variability of lobation are common and are not associated with any other pathology
  • Agenesis
    • unilateral (more common)
    • bilateral (rare)
  • Pulmonary isomerism
    • Condition, where the number of lobar bronchi is the same in both sides. If 3 bronchi on both sides are present, it is right-sided isomerism, which is more common and occurrs more often in males. In left-sided isomerism 2 bronchi are present; this condition is more common in females.
    • Isomerism is often associated with congenital heart malformations
  • Bronchogenic cysts
    • located from the hypopharynx to the diaphragm, within the mediastinum or the lungs
    • the cysts are lined by pseudostratified ciliated epithelium, their wall may contain cartilage, connective tissue, smooth mucle and submucosal glands
    • clinical presentation in pulmonary localization:
      • respiratory distress syndrome
      • lobar emphysema
3.3.2.1  Congenital cystic adenomatoid malformation (CCAM)

Etiology:

Unclear, perhaps abnormal blood supply or abnormal proliferation of bronchioli.

Clinical signs:

  • more common in males
  • clinical presentation:
    • prenatally often hydrops of the fetus and intrauterine death
    • respiratory distress syndrome perinatally
    • usually one lobe is affected
    • the finding may mimic congenital lobar emphysema
  • 20% of affected (usualy CCAM of type 2) have other congenital malformations, e.g. agenesis of the kindeys

Pictures

Cystic adenomatoid malformation of the right lung, newborn:
Cystic adenomatoid malformation of the lung, Macro, autopsy (72050)

Another case, CCAM, lower lobe of the right lung, 21-week fetus, compared with normal lung:
CCAM, lower left lobe, fetus 21th week, Macro, autopsy (72502)
CCAM, lower left lobe, fetus 21th week, Macro, autopsy (72503)

Histology:

Cystic malformation of the pulmonary tissue; according to the size and histological structure of the wall and lining of the cysts (thickness, presence of the cartilage and striated muscle, mucin producing cells) 3 types of CCAM can be recognized: CCAM I – III.

Case study:

Congenital cystic adenomatoid malformation of lung
Marta Ježová

History:

Abortus imminens in 1st trimester. Ultrasound examination in 20 w.g. reveals bilateral macrocystic malformation of lungs with hydrops, ascites.

Macroscopic appearance:

  • 21-week fetus
  • congenital cystic adenomatoid malformation of inferior and middle lobe of the right lung
  • mediastinal shift
  • hypoplastic left lung
  • ascites
3.3.2.2  Lobar sequestration

Macroscopic appearance:

  • unusual condition, characterized by separation of a focus of pulmonary tissue from the tracheobronchial tree
  • extralobar and intralobar types can be distinguished:
    • Extralobar sequestration: mass of pulmonary tissue is located outside the pleura and is not connected to the tracheobronchial tree. Left hemithorax is affected more often. Histology corresponds to immature pulmonary tissue with dilated bronchi.
    • Intralobar sequestration: this condition is mentioned just for the sake of completeness, because it does not occur in prenatal or perinatal period. Affected are adult persons suffering of repeated bronchopulmonary infections. Intralobar sequestration is a part of pulmonary tissue covered by pleura, with systemic blood supply without any evident connection to the bronchi, often with acute or chronic inflammation.
3.3.2.3  Congenital lobar emphysema

Introduction:

Hyperinflation most commonly affecting the upper left lobe.

Etiology:

Variable, the most common factors are:

  • external compression of the bronchus by anomal blood vessels
  • bronchogenic cysts
  • mucosal valves
  • insufficiently formed bronchial cartilage

Clinical signs:

  • quickly developing respiratory distress syndrome after the birth, shift of the mediastinum and compression of the rest of the lungs
  • other congenital anomalies are often present, namely heart defects

Histology:

Broad dilatation of interalveolar ducts and alveoli without any destruction of the pulmonary tissue, sometimes with some fibrosis.

3.3.2.4  Pulmonary hyperplasia

Etiology:

  • laryngeal or tracheal atresia with pharyngotracheal communication

Clinical signs:

  • hydrops
  • endlarged lungs

Histology:

Histologic appearance of the lung is normal, but the lungs are more mature. In non-communicating forms histology resembles rather CAM, type III.

Case study:

Laryngeal atresia
Marta Ježová

History:

20-week fetus with hydrops fetalis, enlarged abdomen, striking edema of the head.

Pictures

20-week fetus with hydrops fetalis, enlarged abdomen, striking edema of the head
Laryngeal atresia, hydrops, Macro, autopsy (73040)

Enlarged lungs:
Laryngeal atresia, situs viscerum, Macro, autopsy (73041)

Hyperplastic lung (detail):
Hyperplastic lung, laryngeal atresia, Macro, autopsy (73042)

Laryngeal atresia, lumen occluded by cartilage:
Laryngeal atresia, Macro, autopsy (73043)

Hyperplastic lung, agenesis of the larynx:
Hypoplastic lung in laryngeal atresia, HE 40x (72968)

3.3.2.5  Pulmonary hypoplasia

Etiology:

Variable etiology:

  • compression of the lung in congenital diaphragmatic hernia
  • prolonged oligohydramnion in congenital renal malformations of urinary tract obstructions
  • prolonged oligohydramnion in chronic leakage of amniotic fluid
  • pleural effusions usually associated with hydrops fetus universalis
  • abnormalities of the thoracic cage in lethal osteochochondrodysplasias e.g. thanatophoric dysplasia, short rib polydactyly, osteogenesis imperfecta
  • anencephaly, neuromuscular disorders, fetal akinesis
  • trisomy 13,18,21
  • large defects of the abdominal wall

Clinical signs:

Newborn infant with severe pulmonary hypoplasia presents shorly after birth with respiratory distress and need of ventilatory support. The distress is often worsened by pneumothorax.

Macroscopic appearance:

The lungs are small with decreased number of alveoli, bronchi and bronchioli. Pulmonary hypoplasia is evaluated autoptically; gestational age, weight of the lungs and body weight are taken into account. Normal values of lung to body weight ratio matches 0.012 or more in infants of 28 weeks gestation and 0.015 for those of lower gestational age.

3.3.2.6  Congenital pulmonary lymphangiectasia

Clinical signs:

  • rare disease
  • the pleura rupture and chylothorax may develop
  • the occurence is isolated or combined with other congenital malformations, mostly heart defects

Histology:

The lymfatic dilatation is sometimes cystic in pleura, subpleura and within the septa.

3.3.2.7  Diaphragm and congenital malformations

Introduction:

The diaphragm is formed from the structures of septum transversum, body wall and pleuroperitoneal membranes.

The most important and most frequent defect is congenital posterolateral hernia located on the left. The occurence is 1 : 2000 – 3000 liveborns.

Associated congenital malformations of other organs are found in about one quarter of the affected individuals. Cardiovascular, urogenital or central nervous system malformations are associated.

Classification:

  • posterolateral hernia (Bochdalek)occurs in 95% of the cases, located on the left in nine of ten cases. The defect is on the right or even bilateral in a small proportion of cases. The defect is a result of persistence of a pleuropulmonal canal.
  • anterolateral hernia (Morgagni)is retrosternal, usually a small and asymptomatic defect
  • diaphragmatic eventrationintact but very thin, hypoplastic diaphragm bulges into the thoracic cavity. There is an abnormal muscularization of the diaphragm. Severe involvement has the same detrimental sequelae as congenital diaphragmatic hernia.
  • diaphragmatic agenesis

Etiology:

Often occurs with chromosomal aberrations (trisomy 18,21) Nevertheless most cases are sporadic, the condition commonly presents as the sole abnormality in wellgrown term infant. Familial cases are very rare and comprise less than 2% of the cases.

Clinical signs:

Through the defect of the diaphragm the abdominal organs herniate into the thoracic cavity and compress the lung. Sometimes the mediastinum is shifted. The lung on the side of the hernia is always hypoplastic but the contralateral lung may be also involved. An infant with a large hernia presents in the first minutes to hours of life with severe respiratory distress. Surgical correction of the defect is performed immediately. Survival rates are low even nowadays in infants with large or bilateral diaphragmatic defets, severe pulmonary hypoplasia and persistent pulmonary hypertension.

3.3.3  Congenital malformations of kidneys and efferent urinary tracts

Marta Ježová

Introduction:

The urine production in the fetal kidneys is substantial for keeping the optimal volume of the amniotic fluid.

Oligohydramnion (reduced volume of amniotic fluid) or anhydramion (nearly absent amniotic fluid) is a common consequence of congenital malformations of kidneys and urinary tract. It may be caused either by insufficient urine production or by urinary tract obstruction.

In case of oligo/anhydramnion the following sequence develops (called as Potter sequence):

External compression of the fetus against uterus walls constrains its mobility, the lower extremities are deformed(club feet), the face has characteristic deformities caused by the pressure (beaked nose, low-set ears, recessive chin). The respiratory movements which are since the end of the second trimester necessary for the growth and maturing of the pulmonary tissue are also restricted. The lungs have normal appearance but are markedly reduced in size — pulmonary hypoplasia (ratio of lung weight to body weight is lower). The surface for the exchange of blood gases is too small and the newborn dies shortly after the birth of severe respiratory insufficiency.

Congenital renal malformations are nowadays exactly and early diagnosed by sonographic screening, often as early as 16 week of gestation. The most frequent anomalies in our autopsy group are lower urinary tract obstructions, multicystic renal dysplasia and bilateral renal agenesis. Simultaneous occurence of congenital malformations of reproductive and urinary system is common.

Case study:

Congenital kidney malformation, Potter's sequence
Marta Ježová

History:

35-week infant born after a prolonged period of oligohydramnion.

Intraterine growth restriction is a cardinal sign of Potter sequence:
Potter's sequention, newborn, 35th week, Macro, autopsy (72528)

Facies Potteri (backwards rotated flat auricles, flattened nose, recessive chin):
Potter's sequention, newborn, 35th week, Macro, autopsy (72531)

Facies Potteri (flattened nose, broad nasal bridge):
Potter's sequention, newborn, 35th week, Macro, autopsy (72529)

Deformities of the lower limbs (pedes equinovares):
Potter's sequention, newborn, 35th week, Macro, autopsy (72530)

Pulmonary hypoplasia:
Potter's sequention, newborn, 35th week, Macro, autopsy (72532)

Bilateral multicystic renal dysplasia is a cause of Potter sequence in this case:
Potter's sequention, newborn, 35th week, Macro, autopsy (72533)

Histology:

Immature kidney (of a fetus or immature newborn) has glomeruli in different stages of maturation. Typical are proglomeruli benath the renal capsule which disappear between 32 to 36 weeks.

Pictures

Fetal kidney, 22-week fetus:
Normal fetal kidney, HE 40x (72658)

3.3.3.1  Renal agenesis

Classification:

Bilateral:the kidneys are not founded, ureters are missing, the bladder is insufficiently developed (hypoplastic) and empty. Amniotic fluid is absent. Bilateral renal agenesis is not compatible with survival. The affected newborn dies several hours after birth of respiratory failure due to pulmonary hypoplasia. The incidence is 1 : 6000.

Most cases of bilateral renal agensis are sporadic. The minority of bilateral renal agenesis, and also bilateral dysplasia and combination of agenesis and dysplasia cases are familial, transimitted as an autosomal dominant trait (hereditary renal adysplasia or agenesis/dysplasia syndrom). The sydnrom has an incomplete penetrance and variable expression. There is an increas incidence of subtle genitourinary anomalies (solitary kidney, ureter duplex, uterine anomalies) among the family members of the proband. In suspicion of familial occurence the family members must be thoroughly examined even if asymptomatic.

Unilateral: rather common (1 : 1000) and has no serious consequences.

Pictures

Right kidney agenesis, multicystic dysplasia of the left kidney, 23-week fetus:
Agenesis of the right kidney, multicystic dysplasia of the left kidney, Macro, autopsy (72135)

Renal agenesis, discoid adrenal, 23-week fetus:
Agenesis of the kidney, discoid adrenal, Macro, autopsy (72136)

Agenesis of both kidneys:
Bilateral agenesis of the kidneys, Macro, autopsy (73266)

Unilateral agenesis of one kidney in a newborn, accidental autoptic finding:
Unilateral agenesis of the kidney, Macro, autopsy (73965)

3.3.3.2  Variations of shape and position of the kidneys

Classification:

Horseshoe kidney: the kidneys are fused at the lower pole and placed close the midline. The anomaly itself is generally inconsequential. Also common in trisomy 18 and Turner syndrome.

Ectopic kidney: the kidney is not in the normal position, commonly located in the small pelvis. Ectopic kidney can be mistaken for renal agenesis at sonographic examination.

Pictures

Horseshoe kidney (ren arcuatus) at trisomy 18, 26-week fetus:
Ren arcuatus, Macro, autopsy (72083)

3.3.3.3  Renal cystic disease

Introduction:

There are several entities which differ in etiology, heredity and clinical symptoms.

Classification:

Potter classification:

  • type I: autosomal recessive polycystic kidney disease, infantile
  • type II: renal dysplasia
    • type IIA: multicystic dysplasia, the kidney is enlarged and cystic
    • type IIB: solid dysplasia, the kidney is small, cysts scarse
  • type III: autosomal dominant polycystic kidney disease, adult
  • type IV: cystic dysplasia with lower urinary tract obstruction
    • subcapsular cysts predominate

note: many authors point out that cystic dysplasia Potter type II and IV result from a similar defect i.e. obstruction. They are seen as variants on a continuum rather then separate entities.

Minor cortical or glomerular microcysts are associated with miscellaneous sydromes and metabolic disorders e.g. trisomy 13, trisomy 18, Zellweger syndrome, several subtypes of chondrodysplasias. Renal cystic dysplasia is a cardial feature of autosomal recessive Meckel syndrome (characteristic trias: polydactyly, encephalocele, polycystic kidneys).

3.3.3.3.1  Infantile polycystic kidneys (ARKPD)

Etiology:

  • transmitted as an autosomal recessive trait
  • incidence 1 : 20 000

Clinical signs:

Beside polycystic kidneys liver disease is present in every patient with ARPKD. As a rule those with less severe renal involvement have more severe hepatic disease and vice versa. There is a periportal fibrosis, intrahepatal biliary duct ectasia (those signs are not pronounced in fetus). Significant liver involvement which is complicated by portal hypertension is reffered to as congenital hepatic fibrosis.

Classification is based on the onset of clinical manifestations. The categories are perinatal, neonatal, infantile and juvenile disease. Perinatal manifestation which is seen in 75% of all cases of ARPKD has poor prognosis.

  • perinatal form manifestations include oligohydramnion, Potter sequence with pulmonary hypoplasia
  • progressive renal failure is seen in neonatal and infantile form
  • major hepatic involvement with portal hypertension occurs in juvenile form

Macroscopic appearance:

The kidneys are of normal shape but markedly enlarged, the cut surface shows a large number of minute cysts.

Pictures

Polycystic kidneys, 19-week fetus:
Polycystic kidney, Macro, autopsy (72080)

Polycystic kidneys, detail:
Polycystic kidney, Macro, autopsy (72079)

Histology:

Cysts are formed by dilated collecting tubules.

3.3.3.3.2  Renal dysplasia

Etiology:

Renal dysplasia is the result of complete obstruction at either renal pelvis or proximal ureter prior to the 10 th week of gestation and inhibition of ureteral bud branching. There is no continuity between the lower urinary tract and the dysplastic nephronic elements.

Most cases are sporadic, the minority is familiar (see the text bilateral renal agenesis).

Macroscopic appearance:

The kidney looks grossly abnormal, renculisation is absent. Numerous cysts of several centimeters in diameter are seen in the most common type (multicystic dysplasia), small kidney with only a few or no cysts at all is reffered to as an solid or aplastic dysplasia.

Ureters are filiform, atretic partially or all of its lenght.

The dysplastic kidney does not produce any urine. In bilateral dysplasia the prognosis is as bad as in bilateral renal agenesis, death occurs due to respiratory failure.

Pictures

Multicystic renal dysplasia, bilateral, 20-week fetus:
Multicystic renal dysplasia, Macro, autopsy (72070)

Multicystic renal dysplasia, detail:
Multicystic renal dysplasia, Macro, autopsy (72069)

Multicystic renal dysplasia, 23-week fetus:
Multicystic dysplasia of the kidney, Macro, autopsy (72141)
Multicystic dysplasia of the kidney, Macro, autopsy (72140)

Histology:

The structure is disorganized. There is considerable increase in connective tissue and multiple large cysts. Cartilage, thich nervous trunks, hematopoetic islands which are not seen in normal kidney are frequently found in dysplastic kidney. The glomeruli and proglomeruli are sparse. The histological hallmark of renal dysplasia is presence of so called primitive tubules which are lined by cubical or cylindrical epithelium and surrounded by concentric fibromuscular connective tissue. Large cysts are derived from from uteteral bud branches that failed to induce nephron formation.

3.3.3.3.3  Adult polycystic kidneys (ADPKD)

Etiology:

  • inherited as an autosomal dominant trait
  • in 90% of cases the affected gen is located on the chromosome 16
  • frequency of disease is 1 : 1000
  • most patients present in adulthood with hypertension and progressive renal failure at the age of 30 to 40 years
  • extrarenal symptoms inculde hepatic and pancreatic cysts and intracranial berry aneurysms, hemorrhage from ruptured aneurysm can be a cause of death in patients with ADPKD.

Macroscopic appearance:

Both kidneys are deformed by large cysts of several centimetres in size, which compress the intervening parenchyma.

Histology:

Cysts arise in any portion of the nephron and collecting system, although they show predilection for Henles loop and collecting tubules.

3.3.3.3.3.1  Autosomal dominant polycystic kidney disease in infant and fetus

Introduction:

ADPKD is typically diagnosed in adults but may be rarely recognized in an infant or even fetus (early-onset disease). Involvement of glomeruli and formation of glomerulal cysts predominante which is in contrast with histological findings in late-onset disease.

Etiology:

  • Early-onset form of ADPKD is associated with mutations in gen PKD 1 (chromosome 16).
  • The pattern of inheritance is autosomal dominant.

Clinical signs:

  • The manifestation of early onset disease includes oligohydramnion, Potter sequence, end-stage renal failure and early-onset hypertension.
  • The prognosis of early-onset disease is poor. Nearly 45% of cases presenting in utero or in the early postnatal period die before 1 year of age. The survivors develope hypertension at a mean age of 3 years and some of them rapidly progress to end-stage renal failure.
  • The recognition of the dominant polycystic kidneys in a newborn or fetus may antedate the clinical onset of the disease in a parent.

Macroscopic appearance:

  • Nephromegaly.
  • Sonograpic findings: moderately enlarged kidneys, increased corticomedullar difference (hyperechogenic cortex, hypoechogenic medulla). Less often obvious cysts.

Pictures

21-week fetus, nephromegaly (double the normal size), early onset ADPKD:
Polycystic kidney, fetus, Macro, autopsy (72880)
Polycystic kidney, fetus, Macro, autopsy (72881)

Polycystic kidney, cross section:
Polycystic kidney, fetus, Macro, autopsy (72882)

Histology:

Plentiful cysts wich represent dilated Bowmans spaces of glomeruli. Glomerulal tufts clearly seen in some of the cyst walls.

3.3.3.3.4  Lower urinary tract obstruction

Classification:

  • posterior urethral valves
  • urethral stenosis and atresia
  • prune belly syndrome

Etiology, pathogenesis:

  • common consequence of the obstruction is dilation of the urinary tract above the occlusion (enlarged bladder, hydronephrosis)
  • the kidneys are commonly dysplastic, the cysts form predominantely beneath the renal capsule(Potter type IV).
  • the prognosis of these malformations depends on the presence and severity of oligohydramnion, lung hypoplasia and renal dysplasia.

Clinical signs:

prune belly syndromeis characterized by the trias: deficient abdominal wall musculature, cryptorchidism and urinary tract anomalies (megavesica, hydronephrosis, renal dysplasia). Smooth distended abdomen is seen in a fetus, flank abdomen with wrinkled redundant skin is seen in a newborn. Anatomic obstruction (urethral atresia, stenosis, kinking) can be identified in some cases. In the rest functional or transient obstruction is suspected. Prostatic maldevelopment is also typical. Prune belly syndrom was initially described in males only but similar phenotype can be seen in females with urethral agenesis.

3.3.3.3.4.1  Posterior urethral valves

Introduction:

Posterior urethral valves are the most common cause of lower urinary tract obstruction. Only males are affected. The valves are in fact hypertrophic mucosal folds in th prostatic urethra. The severity of obstruction varies. The most serious forms manifest prenatally as hydronephrosis and oligohydramnion. Less serious forms are diagnosed after the birth, the symptoms then include poor urine stream, recurrent urinary tract infections or renal failure.

Pictures

Posterior urethral valves, urinary bladder hypertrophy, 22-week fetus.
Urethral valve, Macro, autopsy (72443)

Hydroureters, dysplastic kidneys (the right is more distinct):
Urethral valve, hydroureter, Macro, autopsy (72444)

Right kidney with a cyst, detail:
Urethral valve, Macro, autopsy (72445)

Hydronephrosis:
Urethral valve, hydronephrosis, Macro, autopsy (72447)

Posterior urethral valves, detail (near the wire):
Urethral valve, Macro, autopsy (72446)

3.3.3.4  Congenital tubular renal dysgenesis

Introduction:

Defined by histopathologic findings of a paucity or abscence of proximal tubules in the kidney.

Clinical signs:

  • rare malformation
  • late-onset oligohydramnion
  • Potter sequence
  • persistent anuria in newborn, renal failure
  • prognosis: lethal condition
  • may be associated with hypoplastic cranium, widening of cranial sutures

Etiology, pathogenesis:

  • Familiar
    • AR inheritance
    • mutations in genes in the renin-angiotensin system
  • Sporadic
    • in utero exposure to ACE inhibitors (antihypertensive drug)
    • renal hypoperfusion in fetus: twin transfusion syndrom (RTD found in donor) etc.

Macroscopic appearance:

Kidneys are usually grossly unremarkable and normal sized.

Histology:

  • tubules cannot be differentiated into proximal and distal portion
  • crowding of glomeruli
  • all tubules are EMA positive (normally are positive only distal tubules)

Pictures

Renal tubular dysplasia, HE and EMA; monoclonal antibody EMA (for Epithelial Membrane Antigen) reacts with all tubules:
Tubular renal dysplasia, HE 40x (72648)
Tubular renal dysplasia, EMA 40x (72647)

Normal kidney, EMA (only distal tubules react, compare with images above):
Normal kidney, 18-week fetus, EMA 40x (72636)

3.3.3.5  Urinary bladder

Classification:

Agenesis: may be a part of complex defects of the urogenital system

Extrophy of the urinary bladder: The bladder is exposed through a defect in the lower abdominal wall. The mucosa of the urinary bladder verges into the skin. The pelvis is not connected by symphysis. Ureters drain into the bladder normally and drench its surface. The urethra opens onto the dorsal side of the penis — epispadia. The defect is very rare and occurs in 1 : 40000.

3.3.3.6  Hypospadia

Introduction:

Male urethra opens onto the inferior side of the penis (ventral side) or — in the most serious forms to the scrotum or perineum.

3.3.4  Congenital malformations of genital system and somatosexual congenital disorders

Marta Ježová

Introduction:

Development of the urogenital tract depends on:

  • proper development of the primordia of the organs
  • karyotype
  • hormones

Etiology, pathogenesis:

Development of the internal and external genitalia proceeds according to these basic principles:

Internal and external genitalia develops from indifferent bases common to both genders (indifferent gonad, indifferent external genitalia).

Development of gonads depends on the karyotype:

  • 46XY: testis develops from indifferent gonad
  • 46XX: ovary develops

Development of the internal and external genitalia is influenced by hormone-like substances which are produced by functional fetal testis: owing to androgens the epididymis and ductus deferens develop from the Wolffian duct. MIS (Müllerian inhibiting substance) causes degeneration of Müllerian duct.

Without influence of these substances (normal ovaria, functionless testis) the female genitalia develops. Fetal ovary is not necessary for development of the female genitalia.

External genitalia develops similarly by structure differentiation around the urogenital sinus. Differentiation of the male external genitalia depends on the androgen production in the fetal testis.

Organs derived from the Wolffian duct: tubes, uterus, superior part of vagina.

Organs derived from the Müllerian duct: epididymis, vesiculae seminales, ductus deferens.

Urogenital sinus:

  • genital tubercle: clitoris or penis
  • labioscrotal swellings: labia majora or scrotum
  • from the urogenital sinus develops the inferior part of vagina as well
3.3.4.1  Somatosexual disorders

Introduction:

Somatosexual disorders (intersex) are characterized by improper development of sexual organs.

Clinical signs:

Most obvious is the malformation of the external genitalia of the newborn (the genitalia is not typically male or female — ambiguous genitalia).

Some syndromes manifest by delay of puberty or infertility (e.g. testicular feminization syndrome).

Classification:

  1. Somatosexual disorders with normal karyotype
  2. Somatosexual disorders with abnormal karyotype
3.3.4.1.1  Somatosexual disorders with normal karyotype
3.3.4.1.1.1  Pseudohermaphroditism masculinus

Clinical signs:

  • 46XY, testis
  • external: female genitalia, ambiguous genitalia

Etiology, pathogenesis:

Absent or insufficient androgen effect on the target organs during the critical stage of the development can be caused by two mechanisms:

  • by disorder of testicular development, the testis regresses during the development and stops working (vanishing testis, dysgenetic testis)
  • by disorder of biosynthesis and androgen metabolism
3.3.4.1.1.1.1  Androgen insensitivity syndrome, testicular feminization syndrome, female XY

Clinical signs:

  • karyotype 46XY, 2 testes
  • inner genitalia: missing uterus, tubes, superior part of vagina and epididymis, ductus deferens, prostate
  • external genitalia: female, lower part of vagina is present

Etiology, pathogenesis:

In target organs the androgen receptors are missing. Derivates of the Müllerian ducts disappear due to MIS, which is produced normally by the testes.

3.3.4.1.1.2  Pseudohermaphroditism femininus

Clinical signs:

  • 46 XX, ovaria
  • external: ambiguous genitalia or developing in the male way (virilization):
    • in a mild form only clitoris hypertrophy
    • in a serious form the newborn girls can be confused with a cryptorchid boy

Etiology:

Increased level of androgens during intrauterine development.

Pictures

Masculinization of female fetus caused by continued use of oral contraception till the week 20 of gestation. Progestins included in contraceptives are responsible for the masculinization effect (pseudohermaphroditism):
External genital malformation, Macro, autopsy (73310)

3.3.4.1.1.3  Congenital adrenal hyperplasia

Etiology, pathogenesis:

  • defect of the cortisol synthesis in the adrenals
  • the precursor level increases before enzyme block; in classic form (21-hydroxylase defect) the precursors are androgens

Clinical signs:

  • AR heredity
  • incidence 1 : 10 000
  • girls: 2 ovaries, female internal genitalia, the external genitalia is virilized
  • newborn boys with this disorder have normal genitalia
  • newborns are in danger of metabolic crisis during the first days of life because of lack of the adrenal cortex hormones
3.3.4.1.2  Somatosexual disorders with pathologic karyotype

Clinical signs:

  • Turner syndrome
  • Klinefelter syndrome
  • True hermaphroditism
    • ovarial and testicular tissues are present
    • development of the internal and external genitalia depends on the function of the testicular tissue
    • external genitalia malformation is a rule
    • rare anomaly
3.3.4.2  Congenital malformations of female genitalia
3.3.4.2.1  Congenital malformations of the internal genitalia

Classification:

  • Disorder of the fusion of pairwise bases (Müller's ducts)
    • uterus septus: cavum uteri is divided by a septum
    • uterus bicornis: uterus body is parted into 2 corners
    • uterus duplex: complete uterus duplicity with 2 cervices; vagina can be duplicated as well
  • Patency disorders:
    • hymen atresia
  • Aplasia of the Müller's ducts derivates (Rokitanski-Küster-Hauser syndrome):
    • ovaries are normal
    • uterus, tubes and superior part of vagina are missing
    • external genitalia is normal female with short blindly ending vagina
3.3.4.2.2  Congenital malformations associated with congenital malformations of urinary system

Classification:

  • development of the female internal genitalia organs depends on proper development of surrounding structures (fusion of Wolffian and Müllerian ducts)
  • unilateral kidney agenesis is sometimes associated e.g. with unicornuate uterus (on the side where the kidney is missing the uterus corner is rudimental)
  • Bilateral kidney agenesis is sometimes associated with aplasia of the uterus, Fallopian tubes and upper part of the vagina
3.3.4.2.3  Congenital malformations of the vulva

Agenesis of the vulva is an extremely rare defect and usually is found in complex malformations.

Pictures

Vulva agenesis as a part of VATER association:
Agenesis vulvae, Macro, autopsy (72453)

3.3.4.3  Congenital malformations of the male genital organs
3.3.4.3.1  Cryptorchidism

Clinical signs:

  • undescended testis in a mature newborn, unilaterally or bilaterally
  • very frequent defect in healthy newborns (3 – 5% of full-term boys)
  • sometimes part of syndromes and somatosexual disorders
3.3.4.3.2  Congenital malformations of penis and scrotum

Clinical signs:

  • Hypospadia:
    • deficient closure of urethral sulcus in 11th – 12th week of gestation
    • urethra leads into any place on the lower side (ventral surface) of the penis from glans penis to perineum
    • ventral penis flexion is caused by fibrous band (chorda urethrae)
    • incidence is 1 : 350
    • more serious hypospadia (urethra leads to the scrotum, perineum) is a symptom of feminization and has to be differentiated from intersex
  • Epispadia:
    • congenital malformations of genital tubercle
    • urethra leads to the dorsum of the penis
    • see urinary bladder extrophy
  • Complete penoscrotal transposition (synonyms: prepenile scrotum, transposition of the penis)
    • abnormal development of indifferent external genitalia in 4th – 5th week of gestation
    • very rare defect, occurs sporadically
    • sometimes part of syndromes, e.g. Smith-Lemli-Opitz

Pictures

Hypospadia:
SLOS, Macro, autopsy (72456)

Penoscrotal transposition; penis is under scrotum, serious hypospadia, associated with defects of kidneys and efferent urinary tracts, 24-week fetus:
Penoscrotal transposition, Macro, autopsy (72454)

Penis transposition, perineal hypospadia:
Penoscrotal transposition, perineal hypospadia, Macro, autopsy (72455)

3.3.4.3.2.1  Smith-Lemli-Opitz syndrome (SLOS)

Introduction:

One of the most frequent AR syndromes in our population (second after the cystic fibrosis). Genetically based metabolic disorder of the cholesterol synthesis which cause wide spectrum of congenital malformations and mental retardation. Congenital malformations of the urogenital tract are characteristic.

Etiology, pathogenesis:

  • incidence: 1 : 10 000 – 1 : 40 000
  • carriers (heterozygotes): up to every 30th individual in the population
  • deficit of one of the enzymes for the cholesterol synthesis leads to its deficiency (disorders of cell membranes construction, deficit of steroid hormones, bile acids, myelinisation disorder) and causes structural defects and disorders of the fetus masculinization

Clinical signs:

Wide variability of symptomes of this syndrome:

  • phenotypic features of the face (micrognathia, eyelid ptosis, long philtrum and others) and limbs (syndactyly of the 3rd and 4th toe, simian creases and others), microcephaly and others.
  • congenital malformations of the urogenital tract (ambiguous genitalia and other serious malformations of the external genitalia, agenesis, hypoplasia and cystic renal dysplasia)
  • congenital malformations of the central nervous system, cleft palate, congenital heart defects etc.
  • growth retardation
  • Prognosis:
    • fetuses are often spontaneously aborted or stillborn
    • seriously afected newborns die during the first weeks of life, the symptoms are multiorgan failure, evetually heart defects, while less damaged (with phenotypic features, minor congenital malformation such as hypospadia, cryptorchidism, cleft palate) can live to adult age.
    • mental retardation, behavior disorders, failure to thrive

Prenatal diagnosis:

  • low estriol level in the screening triple test
  • amniotic fluid examination of cholesterol level and its precursors (metabolites such as 7-DHC are remarkably elevated) in the 2nd trimester
  • chorionic villi sampling (CVS) at the end of the 1st trimester
  • ultrasound: congenital malformation of the fetus

Postnatally the cholesterol level in the serum and its precursors is examined (cholesterol levels are low and the precursors are remarkably increased).

Case study:

Smith-Lemli-Opitz syndrome (SLOS)
Marta Ježová

Introduction:

Case of Smith-Lemli-Opitz sydrome in a male 22-week fetus.

Macroscopic appearance:

  • external features of the face:
    • microcephaly
    • long philtrum
    • lowered corners of the mouth — fish mouth
  • external genitalia malformation

Pictures

SLOS, 22-week male fetus, general view:
SLOS, stigmatisation, Macro, autopsy (72457)

SLOS, external features of the face, side view (micrognathia):
SLOS, stigmatisation, micrognathia, Macro, autopsy (72458)

SLOS, external genitalia (hypospadia, ventral penis flexion):
Hypospadia, Macro, autopsy (72459)

Skin syndactyly of 2nd and 3rd toe (fork toe):
Syndactylia (fork-toe), Macro, autopsy (72460)
Syndactylia (fork-toe), Macro, autopsy (72461)

Case study:

Smith-Lemli-Opitz syndrom (SLOS)
Marta Ježová

History:

Female infant born at term with abnormal phenotypic features. Corpus callosum agenesis had been diagnosed prenatally. Prenatal karyotype was normal 46 XX. Pulmonary hypertension persisted after birth. The child required ventilation support and failured to thrive. Bilateral congenital cataract was also identified. Attacks of malign arrythmia (ventricular tachycardia, ventricular fibrilation) appeared agonally. The child demised at 1 month of age.

Final diagnosis was made post mortem by DNA analysis: Smith-Lemli-Opitz syndrome.

Direct DNA analysis was carried out in both parents and than the deceased child to search for the most common mutations in the 7- dehydrocholesterol reductase gen (in Czech population).

The childs genotype was p. W151X/ IVS 8-1G>C.

The parents are healty carriers of the mutations.

There is an entire deficiency of the enzym with p. W151X mutation, the affected individuals do not survive 1 month.

Macroscopic appearance:

  • external features: postnatal growth retardation, microcephaly, receding forehead, flat occiput, deep-set eyes, broad nasal bridge, low set ears, micrognathia, small tongue, short upper limbs, postaxial polydactyly of the left lower limb, deformed feet (turned outward)
  • brain malformation: microencephaly, partial corpus callosum agenesis, dilated occipital horns of the lateral ventricles
  • heart defect: patent ductus arteriosus, right ventricle hypertrophy
  • abnormal lobation of lungs (there was no lobation at all)
  • icterus, hepatomegaly, intrahepatal cholestasis

Pictures

Icterus, microcephaly, short upper limbs, feet deformity:
SLOS, Macro, autopsy (73066)

Microcephaly, flat occiput, receding forehead, low-set ears, mild micrognathia:
SLOS, Macro, autopsy (73067)

Hexadactyly:
SLOS, Macro, autopsy (73068)

Broad nasal bridge, deep set eyes:
SLOS, Macro, autopsy (73069)

3.3.5  Congenital tumors

Marta Ježová

Introduction:

Congenital tumors are very rare. The definition includes benign and malignant tumors diagnosed in utero, in a newborn or during the first months of life. The most common congenital tumors except for hemangioma are the teratoma, various soft tissue neoplasms, leukemia, brain tumors and renal neoplasms.

Clinical signs:

Common symptoms of congenital tumors:

  • many congenital tumors have benign biological behavior
  • the tumors grow fast because they are formed by immature tissues
  • malignant tumors are less agressive than expected and may undergo a spontaneous regression
  • prognosis of a congenital malignant tumor is better than for the identical tumor in an older child
  • tumors can be large enough to prevent the vaginal delivery
  • fatal prognosis can be a result of the tumor localisation or size, not its malignant behavior (e.g. brain teratoma resulting in obstructive hydrocephalus and compression of important brain centers)
  • congenital tumors are associated with hydrops

Classification:

  • Teratomas:mixed germinal cells neoplasms
  • Hamartomas: benign lesions composed of excess of tissues that are normally found in the site of origin (congenital hemangioma, melanocytic nevi)
  • Blastomas:neoplasm imitating embryonic or fetal tissues (neuroblastoma, hepatoblastoma)

Etiology:

  • genetic: known in some cases (congenital leukemia at trisomy 21, familiar retinoblastoma)
  • unknown:e.g. teratomas
3.3.5.1  Sacrococcygeal teratoma

Etiology:

The most frequent site of congenital teratomas is the sacrococcygeal region. The tumor arises from totipotential cells of the primitive node (Hensens node) located near the coccyx.

Clinical signs:

  • incidence: 1 : 30 000 – 70 000, more frequent in females
  • the prognosis in a fetus correlates inversely with the tumor size and rate of tumor growth, the prognosis is worsened with the presence of hydrops fetalis and placental edema
  • hydrops is a result of high output cardiac failure and precedes the intrauterine demise
  • teratoma is often large and obstructs the delivery (caesarean section or punction of the cystic part of the tumor before the delivery are inevitable)
  • significant mortality and morbidity is due to premature delivery
  • survivors undergo a surgical resection of the tumor and the coccyx as well, otherwise there is a risk of local reccurence
  • the tumor is behaves benignly, the risk of malignant transformation increases if the resection is delayed or if the tumor is incompletely excised.

Macroscopic appearance:

  • large tumor deforming the sacral region
  • appearance is solid (on the cut mainly grey-white tender nervous tissue) or cystic

Classification:

  • type 1: predominantly external, minimal intrapelvic component
  • type 2: predominantly external, significant intrapelvic component
  • type 3: minor external component, predominantly internal component extending into the abdomen
  • type 4: only intrapelvic component

Type 1 and 2 common and include 80% of the cases.

Histology:

Tumor consists of different somatic tissues of all germ layers. The largest part is made of immature nervous tissue (represents the ectoderm).

Pictures

Sacrococcygeal teratoma, fetus:
Sacrococcygeal teratoma, HE 40x (72158)

3.3.5.2  Congenital cardiac rhabdomyoma

Introduction:

Rhabdomyoma is the most common pediatric tumor arising in the heart. It is commonly associated with tuberous sclerosis.

Clinical signs:

  • bening hamartomatous neoplasm
  • occurs in fetus and neonate
  • tend to regress spontaneously after birth
  • frequent in patients with tuberous sclerosis (50 – 85%)
  • patiens are usually asymptomatic
  • complications with multiple large tumors:
    • fetal hydrops
    • conduction abnormalities
    • outflow obstruction
    • congestive heart failure
    • sudden death
  • single or commonly multiple
  • firm pale mass
  • arising anywhere within the myocardium

Histology:

Sharply circumscribed but unencapsulated nodule with characteristic spider cells. These are quite large vacuolated cells rich in glykogen with central nucleus and cytoplasmic strands extending to the plasma membrane.

3.3.6  Congenital heart defects

Marta Ježová

Introduction:

Congenital heart defects are congenital anomalies of the heart and big vessels. Prevalence is 6 – 8 for 1000 live-born children, but total occurence is higher.

Nowadays, these defects are mostly seen by fetal pathologist who autoptically examines spontaneous and induced abortions. Many of the heart defects are recognised and exactly diagnosed by the ultrasound screening during the 2nd trimester and are the reason for pregnancy termination between 20th – and 24th week. Suspicion for a congenital malformation can be already get at the ultrasound examination at the turn of the 1st and 2nd trimester (11th – 13th week).

Classification:

Most frequent congenital heart defects:

  • isolated ventricular septal defect
  • isolated atrial septal defect
  • aortic and pulmonary stenosis
  • coarctation of the aorta
  • transposition of the great vessels
  • patent ductus arteriosus

Critical heart defects:

  • life threatening early after birth
  • demand urgent surgery
  • these are:
    • hypoplastic left heart
    • pulmonary atresia
    • transposition of the great vessels
    • tight coarctation of the aorta
    • interruption of the aortic arch

Etiology:

  • Genetic: trisomy 21, 18, 13, Turner syndrome, Di George syndrome (microdeletion of the 22nd chromosome)
  • Enviromental: alcohol (fetal alcoholic syndrome), infection (German measles), mother's diseases (phenylketonuria at breaking the diet by the mother, poorly compensated diabetes mellitus).
  • In most cases the etiology isunknown, probably multifactorial.

Clinical signs:

  • Cyanotic defects: cyanosis is caused by right-to-left shunt, e.g.transposition of the great vessels  — deoxygenated blood flows into the aorta
  • Noncyanotic defects: left-to-right shunt leads to increased pulmonary blood flow and pulmonary hypertension envolves gradually, e.g. the large defect of the ventricular septum. Eisenmengers complex is a complex of clinical symptoms in congenital heart defects with significant pulmonary hypertension. In the defects with initial left-to-right shunting the direction of the shunt gets reversed to right-to-left and late cyanosis appears. The patients are week, dyspnoic, often present with syncopas or hemoptysis, ictus, sudden death. Eisenmenger syndrome is irreversible. The prevention is early surgical therapy of congential heart defects prior to the developement of pulmonary arterial hypertension.
  • Defects with obstruction: left heart or right heart insufficiency (left heart insufficiency in coarctation of the aorta)
  • Heart failure in infants manifests by tiring with feeding, excessive sweating on the head, tachypnea
  • Failure to thrive
  • Murmurs, precordial whirl
  • Arythmias, changes in ECG
  • Increased risk of infective endocarditis
  • Hydrops fetalis is not a constant feature of cardiovascular malformations. It is seen in some cases of hypoplastic left heart syndrome, AV septal defects, hypoplastic right heart, prenatal closure of foramen ovale, Ebstein malformation

The clasification of congenital heart defects is possible from several points of view (functional, anatomical...). Following classification respects especially the anatomy of the heart defects. The defects may be either isolated or complex.

3.3.6.1  Defects of heart septum
3.3.6.1.1  Atrial septal defects

Introduction:

The foramen ovale is patent till delivery. With fall in the pulmonary resistence thereafter the foramen ovale gets close by the valve. The closure is functional at first, the valve gets firmly attached to the edges of the foramen at the end of the 1st year of life.

Classification:

Atrial septal defects according to the localisation:

  • ostium secundum defect: the valve covering the foramen ovale is insufficiently developed or is completely missing; the isolated defect manifests is asymptomatic till adulthood. It is the most frequent type of the atrial defects.
  • sinus venosus defect: a defect near the opening of the superior or inferior vena cava; asocciated with partial anomalous venous return, very rare
  • ostium primum defect: is classified among defects of AV septum (see below)
  • aplasia of the atrial septum: total absence of the atrial septum; usually in complex heart malformations and malformation of situs
3.3.6.1.2  Ventricular septal defects

Clinical signs:

Defects of the ventricular septum are the most frequent heart defects (they form 40% of all heart defects). The defects are isolated or a part of complex heart malformations.

The defect leads to left-to-right shunt and its severity of the clinical symptoms is directly proportional to the size of the defect. Small defects, muscular in particular, are well tolerated. Spontaneous closure is quite common in these small defects.

Classification:

Ventricular septal defects according to localisation:

  • Perimembranous: viewed from the left ventricle they are located inferior to the aorta, obscured by the septal leaflet of the tricuspid valve in the right ventricle. The most common type of defect.
  • Muscular: in the septal trabeculisation, often multiple
  • Subarterial (infundibular): in the outlet tract of the ventricles

Macroscopic appearance:

Perimembranous ventricular septal defect, trisomy 18, 26-week fetus:
Defect of the interventricular septum, trisomy 18, Macro, autopsy (72054)

Perimembranous ventricular septal defect, 28-week fetus, view from the left atrium:
Defect of the interventricular perimembranous septum, viewed from the left ventricle, Macro, autopsy (72051)

Perimembranous ventricular septal defect, 28-week fetus, view form the right atrium:
Defect of the interventricular perimembranous septum, viewed from the right ventricle, Macro, autopsy (72052)

Infundibular septal defect in tricuspid atresia, 24-week fetus:
Defect of ventricular septum, infundibular atresia of the tricuspid valve, Macro, autopsy (72053)

3.3.6.1.3  AV septal defects

Classification:

Partial AV canal (equals to the ostium primum defect): an opening in the lower part of the atrial septum, right and left ventriculare orifices remain separate. There is a cleft in the anterior leaflet of the mitral valve, which causes mitral regurgitation.

Complete AV canal: the blood from all four chambers of the heart is mixed in the large defect in the lower part of the atrial septum and upper part of the interventricular septum. There is a single atrioventricular valve with five leaflets. Abnormal anterior and posterior leaflets of the common valve bridge the septal defect.

Clinical signs:

The defect is typically associated with trisomy 21: one quarter of children with Down's syndrome has the AV septal defect and vice versa 60% of the patients with complete AV canal has Down syndrome.

Symptomes of heart failure occur during the first months of life and half of the nontreated pacients die within six months.

Pictures

Complete defect of AV septum, 22-week fetus, atrial part of the defect, view from the right atrium:
AV canal, Macro, autopsy (72437)

Complete defect of AV septum, 22-week fetus, shared AV valve, view from the left ventricle:
AV canal, Macro, autopsy (72438)
AV canal, Macro, autopsy (72439)

Incomplete defect of AV septum in adult male, 50 years old, without clinical symptoms:
Incomplete defect of the AV septum, Macro, autopsy (73993)
Incomplete defect of the AV septum, Macro, autopsy (73994)
Incomplete defect of the AV septum, Macro, autopsy (73995)

3.3.6.2  Anomalies of the great arteries

Introduction:

During the autopsy we assess the position of the great arteries on the heart base. Normally the pulmonary artery arises anterior to the left and the aorta posterior to the right relative to the pulmonary artery.

3.3.6.2.1  Transposition of the great arteries

Macroscopic appearance:

  • incorrect connection of ventricles and great vessels: the aorta arises from the morphologic right ventricle, the pulmonary artery from the morphologic left ventricle
  • the great arteries arise in an unusual position from the base of the heart, the aorta in front of the pulmonary artery, aorta slightly to the right
  • ventricular septal defect is found in 40% of affected hearts

Clinical signs:

  • the most common congenital cyanotic heart defect in the newborns
  • the infants present with severe and progressive cyanosis within hours after birth with closure of the ductus
  • the systemic and pulmonary circulations are separated
  • oxygenation of systemic blood is totally dependent on mixing of pulmonary and systemic blood flow at arterial level (patent ductus arteriosus) and the cardiac level (foramen ovale, atrial septal defect, ventricular septal defect)
  • palliation: prostaglandin E infusion to maintain patency of the ductus, balloon atrial septostomy is performed as soon as possible after delivery
  • corrective surgary: arterial switch procedure (anatomical correction) is strongly preferred. The aorta and pulmonary artery are transected and removed in their normal position. Coronary arteries must be transferred as well. After the surgery the left ventricle works as the systemic ventricle.

Pictures

Transposition of the great arteries, view of the heart base, newborn:
Transposition of the great arteries, Macro, autopsy (72094)

Transposition of the great arteries, aorta arises from the right ventricle, newborn (the same case):
Transposition of the great arteries, Macro, autopsy (72095)

Transposition of the great arteries, ventricular septal defect:
Transposition of great arteries, VSD, Macro, autopsy (73338)
Transposition of great arteries, VSD, Macro, autopsy (73339)
Transposition of great arteries, VSD, Macro, autopsy (73340)
Transposition of great arteries, VSD, Macro, autopsy (73341)

3.3.6.2.2  Truncus arteriosus

Macroscopic appearance:

  • a single arterial trunk arises from the base of the heart supplying the pulmonary, systemic and coronary arteries
  • the truncus overrides a large ventricular septal defect
  • truncal valve is tricuspid, the cusps are often thickened and dysplastic

Clinical signs:

  • mixing of the systemic and pulmonary venous blood flow at the level of the truncus during systole
  • affected infants present in the first two months of life with heart failure, cyanosis is mild
  • truncal insufficiency is seen in 15% of the cases, its presence worsens the outcome of the surgical correction
  • rare defect, typical of Di George syndrome
3.3.6.2.3  Double-outlet right ventricle

Macroscopic appearance:

  • the pulmonary artery and the aorta arise both from the morphologic right ventricle
  • there is a ventricular septal defect, its location is used to define the subcategory of the defect
  • various malformations are commonly associated: pulmonary stenosis is frequent, mitral atresia, dextrocardia or AV septal defect are less common
  • the hemodynamics is complicated and depends on the associated defects and localisation of the ventricular septal defect
  • rare malformation
  • double outlet left ventricle is the analogous malformation on the left side, extremely rare
3.3.6.3  Malformations of the valves

Introduction:

There are two variants of valvular defects: stenosis (narrowing) and atresia (absent connection).

Heart chambers proximal to the site of obstruction show marked hypertrophy (increased preload) and there is congestion proximal to obstruction. Right sided obstructions produce decreased pulmonary flow, left sided obstrucions produce decreased systemic blood flow. In addition heart chambers distal to atresia are hypoplastic (insufficiently developed because of absent blood flow).

Dysplastic valves: anomalies of shape and insertion anomalies

Polyvalvular dysplasia: atriventricular and seminular valves are dysplastic in 90% of the cases of trisomy 18, less often in the other aneuploidias (trisomy 13 etc.) The leaflets and cusps are redudant, myxomatously thickened or nodular not infrequently with minute blood cysts at the valve margins. Aortic and pulmonary valves are often bicuspid. The most severe changes are present in mitral and tricuspid valves.

3.3.6.3.1  Tricuspid atresia

Macroscopic appearance:

Tricupis atresia:

  • there is a dimple at the usual site of the valve or the valve forms an imperforate membrane
  • right ventricle is hypoplastic, represented only by the outlet portion of the ventricle,so called the outlet chamber
  • ventricular septal defect is invariably present

Ebstein malformation of the tricuspid valve: the septal and posterior leaflets adhere to the right ventricular wall. The inlet portion of the ventricle in thus included functionally within the right atrium. The malformed tricuspid valve is insufficient.

Classification:

Further classification of tricupis atresia is based on the great vesells position:

  • tricuspid atresia with normally related great arteries, 70% of case
  • tricuspid atresia with transposition of great arteries
  • pulmonary stenosis, pulmonary atresia are common, coarctation of the aorta is seen in tricuspid atresia with transposition of great vessels

Clinical signs:

  • tricuspid atresia is a rare cyanotic defect
  • the diagnosis of an isolated Ebstein malformation is often late during childhood or early adulthood. Infants with severe regurgitation are severely cyanotic

Case study:

Tricuspid atresia
Marta Ježová

History:

23-week fetus, tricuspid atresia:

Pictures

Tricuspid atresia, base of the heart:
Atresia valvae tricuspidalis, Macro, autopsy (72041)

Tricuspid atresia, view from the right atrium:
Atresia valvae tricuspidalis, Macro, autopsy (72042)

Tricuspid atresia, right ventricle hypoplasia:
Atresia valvae tricuspidalis, Macro, autopsy (72043)

Tricuspid atresia, ventricular septal defect, view from the left ventricle:
Atresia valvae tricuspidalis, Macro, autopsy (72045)

Tricuspid atresia, ventricular septal defect, view from the right ventricle:
Atresia valvae tricuspidalis, Macro, autopsy (72044)

3.3.6.3.2  Stenosis and atresia of the mitral valve, the hypoplastic left heart syndrome

Introduction:

Mitral stenosis: the annulus is narrow, hypoplastic. The leaflets are thickend or fused with short chordae.

Mitral atresia:> the valve is completely absent with a dimple in the usual site of the valve, less common there is an imperforate membrane.

Stenosis or atresia of the mitral valve is the part of the hypoplastic left heart syndrome.

Hypoplastic left heart syndrome is a critical congenital heart defect with a small left ventricle and stenosis or atresia of the aortic and the mitral valve.

Macroscopic appearance:

  • there is a wide spectrum of changes of the mitral valve, left ventricle and aorta
  • the combinations of the mitral stenosis and aortic atresia and combination of mitral and aortic stenosis are the most frequent
  • the whole aortic arch is strongly hypoplastic (the aorta is filiform)
  • the coronary arteries are supplied by reverse flow from the patent ductus arteriosus; the pulmonary artery is dilated
  • the left ventricle is always hypoplastic. With mitral atreis the left ventricle is extremely hypoplastic with thick walls and slitlike cavity or no cavity is present
  • with mitral stenosis a cavity in the small left ventricle is developed, the endocardium is fibrously thickened (fibroelastosis)
  • the right ventricle is hypertrophic pumping all the blood flow

Clinical signs:

  • this critical defect manifests in the first days of life as the ductus closes by severe heart failure or shock
  • the affected infants uniformly die within few days without urgnet surgery
  • the defect is corrected in several steps (Norwood surgery)
  • after reconstruction the right ventricle works as the systemic ventricle but it cannot fully compensate the the normal left ventricle (right ventricle is a low-pressure pump)
  • in some cases this defect is inoperabile or could be corrected only by neonatal heart transplantation
  • individuals with hypoplastic left heart usually do not have any other congenital defects; hypoplastic left heart syndrome is not a typical part of other syndromes

Classification:

Hypoplastic left heart syndrome is associated with premature (fetal) closure of foramen ovale in approximately 10% of the cases. The presence of intact atrial septum or highly restrictive (small) foramen ovale is a predictor of poor outcome in infants with hypoplastic left heart. Premature closure of foramen ovale is associated with coarctation of the aorta, an isolated form without any heart malformation is quite rare.

Pictures

Hypoplastic left heart syndrome, fibroelastosis of the left ventricle endocardium, fetus:
Hypoplasia of the left ventricle, fibroelastosis, Macro, autopsy (72063)

Hypoplastic left heart with fetal closure of the foramen ovale:
Hypoplastic left heart syndrome, Macro, autopsy (73189)
Hypoplastic left heart syndrome, Macro, autopsy (73190)
Hypoplastic left heart syndrome, Macro, autopsy (73191)
Hypoplastic left heart syndrome, Macro, autopsy (73192)
Hypoplastic left heart syndrome, Macro, autopsy (73193)

Another case of hypoplastic left heart with fetal closure of the foramen ovale:
Hypoplastic left heart syndrome, Macro, autopsy (73194)
Hypoplastic left heart syndrome, Macro, autopsy (73195)
Hypoplastic left heart syndrome, Macro, autopsy (73196)
Hypoplastic left heart syndrome, Macro, autopsy (73197)
Hypoplastic left heart syndrome, Macro, autopsy (73198)
Hypoplastic left heart syndrome, Macro, autopsy (73199)

Hypoplastic left heart:
Hypoplastic left heart syndrome, Macro, autopsy (73292)

Hypoplastic left heart syndrome, ultrasound video:
Hypoplastic left heart syndrome, Macro, autopsy (73664)
Hypoplastic left heart syndrome, 1st trimester, Ultrasound, video (74011)

Hypoplastic left heart syndrome:
Hypoplastic left heart syndrome, Macro, autopsy (73665)
Hypoplastic left heart syndrome, Macro, autopsy (73666)
Hypoplastic left heart syndrome, Macro, autopsy (73667)
Hypoplastic left heart syndrome, Macro, autopsy (73668)
Hypoplastic left heart syndrome, Macro, autopsy (73669)
Hypoplastic left heart syndrome, Macro, autopsy (73670)
Hypoplastic left heart syndrome, Macro, autopsy (73671)
Hypoplastic left heart syndrome, Macro, autopsy (73672)

Case study:

Hypoplastic left heart syndrome 1
Marta Ježová

History:

24-week fetus, mitral atresia, aortic atresia, hypoplastic left heart syndrome.

Pictures

Hypoplastic left heart syndrome, base of the heart:
Hypoplastic left ventricle, Macro, autopsy (72065)

Hypoplastic left heart syndrome, atresia of the mitral valve, left ventricle:
Hypoplastic left ventricle, mitral atresia, Macro, autopsy (72062)

Hypoplastic left heart syndrome, hypertrophy of the right ventricle:
Right ventricle in left heart hypoplasia, Macro, autopsy (72064)

Hypoplastic left heart syndrome, slit-like left ventricle at mitral atresia:
Hypoplastic left heart, Macro, autopsy (72144)

Case study:

Hypoplastic left heart syndrome 2
Marta Ježová

History:

Immature 31-week newborn from twin pregnancy, mitral stenosis, aortic stenosis, hypoplastic left heart syndrome.

3.3.6.3.3  Stenosis of the pulmonary artery

Classification:

  • valvular: stenosis of the vessel at the site of the valve
  • subvalvular (infuncibular): stenosis in the outlet tract of the right ventricle
  • supravalvular: localized stenosis of the main pulmonary arteries or peripheral segmental arteries, these often multiple
3.3.6.3.3.1  Pulmonary atresia with intact ventricular septum

Macroscopic appearance:

  • pulmonary atresia is usually valvular in origin
  • the infundibulum may be stenotic or atretic as well
  • no defect in the ventricular septum
  • the tricuspid valve is rarely normal
  • two types are desribed according to the size of the right ventricle:
    • type 1 with small ventricle: tricuspid annulus is hypoplastic, the right ventricle has thick walls with a slit like cavity and thickened endocardium. Intramyocardial sinusoids are seen in approximately 50% of type I. The hypoplastic right ventricle feeds into the intramyocardial sinusoids which communicate with with torturous coronary arteries, coronary veins and sinus coronarius draining ultimately into the right atrium.
    • type 2 with normal or large right ventricle: the tricuspid valve is always insufficient. The tricupid leaflets are dysplastic, fused or present frank Ebstein malformation. The right ventricle is of normal size or enlarged, the right atrium is massively dilated. Intramyocardial sinusoids are not found.

Clinical signs:

  • pulmonary blood flow is ductus dependent, the infants are severely cyanosed
3.3.6.3.3.2  Tetralogy of Fallot

Macroscopic appearance:

  • complex heart defect:
    • infundibular pulmonic stenosis
    • ventricular septal defect
    • dextroposition of the aorta overriding the septal defect
    • right ventricle hypertrophy
  • 75% of affected children have a combination of infundibular and pulmonary valve stenosis
  • pulmonary valve is often abnormal: in most cases bicuspid, with thickened valves
  • pulmonary arteries often show localized stenosis or diffuse hypoplasia
  • the defect of the ventricular septum is often large

Clinical signs:

  • the degree of pulmonary obstruction at the infundibulum or secondarily at the pulmonary valve or peripheral arteries is quite variable ranging from mild stenosis to complete atresia and account for the variability of clinical symptoms
  • those with severe pulmonic obstrucion present in the first days of life as the ductus closes with extreme cyanosis and hypoxemia due to right to left shunting
  • in milder stenosis the infants are initially acyanotic and typically have progressive cyanosis in the first 6 months of life
  • the stenotic infundibulum is prone to spasms which acute episodes of extreme cyanosis, dyspnea, convulsions. They often appear during feeding, crying or in the morning.

Classification:

Pulmonary atresia with ventricular septal defect is an extreme form of tetralogy of Fallot. There is no flow through the pulmonic valve. The mediastinal portions of the pulmonary arteries may be hypoplastic or atretic as well. As the ductus closes in the first days of life the infant is dependent on blood flow through the aortopulmonary collateral arteries. These usually arise from the thoracic aorta. If the collateral arteries are small the infant is markedly cyanotic.

Syndrom of absence of the pulmonary valve is a rare anomaly associated with tetralogy of Fallot. There is a narrow annulus, no valve and marked poststenotic dilatation of the pulmonary arteries. The dilated arteries compress the bronchi, the affected children present with major respiratory problems. Absent pulmonary valve is associated with Di George syndrome.

3.3.6.3.4  Aortic stenosis

Classification:

Aortic stenosis leads to left heart failure, the severity of the symptoms and the age of presentation depend on the severity of the stenosis

  • valvular: at the site of the semilunar valve
    • bicuspid aortic valve: very common malformation, asymptomatic until late adulthood; the bicuspid valve wears sooner, stenosis and its symptomes appear due to degenerative changes at about the age of 60
    • at unicuspid valve the stenosis is usually symptomatic in early childhood
  • subvalvular: stenosis in the left ventricular outflow tract
  • supravalvular: stenosis of the ascending aorta above the valve lunules; also in a form of the entire aortic arch hypoplasia

Aortic atresia: see The hypoplastic left heart syndrome

3.3.6.4  Malformations of the aortic arch system
3.3.6.4.1  Persistence of ductus arteriosus

Clinical signs:

Ductus arteriosus connects the aorta and the pulmonary artery during the fetal circulation. Functional closure occurs in the first hours of life by contraction of the walls, true anatomic closure occurs at 10th – 20th day after birth by adhesion of the walls and obliteration of the lumen.

In the very premature newborns the closure of the ductus is delayed because of the immaturity of the duct wall.

On the other hand the patent ductus in a full term infant is probably caused by a structural wall abnormity. Through the ductus the blood flows from the aorta to the pulmonary artery (left-to-right shunt). Clinical symptomes and the risk of pulmonary hypertension depend on the width of the ductus.

In immature infants the closure can be affected pharmacologically  — indometacin). In the other cases catatherization techniques or surgical ligation of the ductus are performed.

3.3.6.4.2  Coarctation of the aorta

Classification:

Coarctation is congenital narrowing of the aorta just distal to the origin of the left subclavian artery

  • two variants:
    • true coarctation: local, short narrowing of the aortic arch. According to the relationship between the coarctation and the inserction of the ductus arteriosus or ligamentum arteriosum preductal, juxtaductal and postductal variants are distinguished.
    • tubular hypoplasia: narrowing of the long preductal segment of the aortic arch between the left subclavian artery and the ductus (the aortic isthmus). In extreme coarctation the entire trasverse aortic arch may be hypoplastic. Tubular hypoplasia is the variant seen commonly in fetuses

Coarctation of the aorta may be an isolated defect but is frequenly associated with other cardiac malformations: bicuspid aortic valve, patent ductus arteriosus, ventricular septal defect, mitral valve anomalies, tricuspid atresia etc.

Clinical signs:

  • symptoms of severe and progressive left heart failure occur in first days of life with closure of the ductus (there is an acute increse in afterload to the left ventricle)
  • in less severe obstruction there is time for compensatory mechanisms to develope: left ventricle hypertrophy, collateral vessels bypassing the obstruction
  • typical finding is diminished blood pressure and pulses in femoral arteries compared to upper extremities. Note: the pulse in lower extremities is palpable in infants with patent ductus.
  • surgical therapy: resection of the narrowed segment and end to end anastomosis. Subclavian flap aortoplasty is used in tubular hypoplasia
  • coarctation of the aorta is often associated with Turner syndrome

Pictures

Scheme of coarctation of the aorta:
Coarctation of the aorta, Macro, autopsy (72718)

3.3.6.4.3  Interruption of the aortic arch

Macroscopic appearance:

  • the aorta is totally disconnected:
    • type A: interruption distal to the left subclavian artery
    • type B: interruption distal to the left common carotid, the most common type
    • type C: interruption distal to the innominate artery
  • rare defect, almost always associated with ventricular septal defect or some other defect
  • Di George syndrome is found in 70% of patients with interruption of the aortic arch, this marked association is true for the type B
3.3.6.4.4  Right-sided aortic arch

Clinical signs:

The aorta descends on the right of the spine. The defect itself has no clinical importance, usually it is part of complex heart defects (disorders of right-left organ symmetry, Fallot tetralogy). Ductus arteriosus is usually missing.

3.3.6.5  Malformations of the venous system

Clinical signs:

Systemic venous anomalies:

Relatively often the left superior vena cava persists and leads into the principal heart vein (sinus coronarius). It is an asymptomatic anomaly. Remark: left superior vena cava is always founded but disappears normally during the development.

Pulmonary venous anomalies:>

  • total anomalous pulmonary venous connection:
    • all pulmonary veins join into one venous trunk which anomally drain into the system veins above the diaphragm (v. brachiocefalica, superior vena cava) or under the diaphragm (inferior vena cava, portal vein)
    • obstrucion of the common venous drainage is especially common in infradiaphragmatic variant
    • rare serious malformation
  • partial anomalous pulmonary venous connection:
    • in the most common form the right sided pulmonary veins drain directly into the right heart (into the superior vena cava or directly into the right atrium); there is a sinus venosus type of atrial septal defect

Pictures

Persistent left superior vena cava, heart base, fetus:
Persisting left superior vena cava, Macro, autopsy (72071)

Total anomalous pulmonary venous return:
Total anomalous pulmonary venous return, Macro, autopsy (73200)

3.3.6.6  Anomalies of situs and heart position

Classification:

Situs describes the posision of the cardiac atria and viscera. Morphological right atrium has a blunt atrial appendage with a wide orificium, morphological left atrium had a finger like appendage with a narrow orificium. POsition of the atria corresponds to the position bronchi and lungs.

Normal position of the inner organs is called situs solitus (usual position).

In situs inversus the position of cardiac atria and viscera is mirror image of the normal position: morphologic right atrium is on the left and morphologic left atrium is on the right. Pulmonary anatomy is reversed. Gallbladder is on the left, spleen and stomach are on the right. Situs inversus is present in 0.01% of the population. Kartagener syndrome of ciliary dyskinesis affects about 20% of individuls with situs inversus.

Direction of the cardiac apex in situs inversus:

  • situs inversus with dextrocardia (situs inversus totalis): more common variant, heart malformations are observed in 5%, usually transpositon of the great vessels.
  • situs inversus with levocardia: very rare, always associated with congenital heart defects

The most complicated situation is observedn in situs ambiguus (undetermined position). The right-left organ symmetry is disturbed. Right symmetry predominates in dextroisomerism, left symmetry in levoisomerism. Both atria are morphologically right atria in dextroisomerism. Both atria are morphologically left atria in levoisomerism. Severe complex heart anomalies are almost always associated. The incidence is 1 : 6 000 – 20 000.

Dexteroisomerism: bilateral trilobed lungs, symmetric liver, spleen is missing, heart defects (mostly AV septal defect, aplasia of the atrial septum, total anomalous pulmonary venous connection, systemic venous anomalies, transposition of the great arteries, dextrocardia). Also called the asplenia syndrome.

Levoisomerism: both lungs are bilobed, symmetric liver, more spleens are present (polysplenia), heart defects (atrial septal defect, atrioventricular or ventricular septal defects, systemic venous anomalies). Also called the polysplenia syndrome.

Dextrocardia:heart position on the right side of the thorax, cardiac apex points to the right. Various heart defects are frequently associated. Dextrocardia is observed in situs solitus, situs inversus and situs ambiguus as well.

Ectopia cordis: heart located partially or totally outside the thoracic cavity. The most common forms is thoracic ectopie with the sternum completelly split or absent, and thoracoabdominal ectopia seen as a part of pentalogy of Cantrell. Ectopia is seen in abdominal wall defects and amniotic bands syndrome. There are intracardiac malformations associated in the majority. Ectopia cordis is quite rare and has poor prognosis.

3.3.6.7  Di George syndrome

Marta Ježová

Introduction:

This syndrome occurs relatively often. Characteristic are serious congenital heart defects and immunodeficiency.

Etiology, pathogenesis:

  • incidence: 1 : 6000 – 8000
  • genetics: microdeletion of the long arm of the 22nd chromosome
  • disorder of the embryonal development of the 3rd and 4th branchial arch, pouches and their derivates

Clinical signs:

  • external features of the face:
    • hypertelorism
    • small recessive chin and mouth
    • narrow philtrum
    • backwards rotated auricles
  • severe hypoplasia or agenesis of the thymus
  • T cell immudeficiency: predisposion to diseminated viral and mycotic infections
  • agenesis of the parathyreoid glands: hypocalcemia, spasms of the newborn
  • congenital malformation of the palate: cleft palate, more often incomplete, ev. only cleft uvula
  • serious congenital heart defects, conotruncal defects (related to the outlet tract):
    • tetralogy of Fallot
    • ventricular septal defect
    • interruption of the aortic arch
    • pulmonary atresia
    • truncus arteriosus
    • double outlet right ventricle
    • transposition of the great arteries
  • syndrome shortcut: CATCH 22:
    • Cardiac defects
    • Abnormal facies
    • Thymic agenesis
    • Cleft palate
    • Hypocalcemia
    • 22 del
  • mortality: because of the heart defect it is about 8%

Case study:

Syndrom Di George 1
Marta Ježová

History:

20-week fetus, Di George (tetralogy of Fallot, hypoplastic thymus, cleft palate, abnormal face — small ears, cleft lip, del 22).

Case study:

Di George syndrome 2
Marta Ježová

History:

  • by routine ultrasound examination the congenital heart defect was found and consequently confirmed by the specialized cardiologic clinic
  • congenital malformation according to the clinicians: double outlet right ventricle, defect of the ventricular septum with aorta overriding the defect
  • cordocenthesis: karyotype 46XY, microdeletion 22q11 – 13

Clinical signs:

  • Dg: Di George syndrome
  • pregnancy termination at 24 week of gestation

Macroscopic appearance:

  • male 24th – 25-week fetus, weight 750 g, length 34.5 cm
  • mild micrognathia, palate is normal
  • agenesis of the thymus
  • complex congenital heart defects:
    • dextrocardia
    • perimembranous ventricular septal defect
    • valvular stenosis of the aorta, bicuspid valve
    • interruption of the aortic arch distal to a. carotis communis sinistra
    • leftsided vena cava superior
  • congenital malformation of the urogenital tract: left sided hydronephrosis

Conclusion:

Interruption of the aortic arch is defect typical for the Di George syndrome. The ascending aorta is interruped in the arch usually distal to the a. carotis communis sin. The inflow of blood to the thoracic aorta is enabled only by patent ductus arteriosus. It is a critical heart defect with early neonatal manifestation.

3.3.7  Congenital malformations of the gastrointestinal tract

Katarína Múčková

Introduction:

Organs of the digestive system develop mostly from the endoderm. The primitive gut tube is divided into three sections. The tube growths in length and forms a U loop which later rotates counterclockwise. The foregut gives rise to esophagus, stomach, duodenum, pancreas and liver. Jejunum, ileum and colon (ascending and first 2/3 of transverse colon) develop from the midgut. The hindgut gives rise to the last third of transverse colon, descending colon, sigmoid colon and rectum. It terminates as common cloaca which is later divided by urorectal septum into ventral urinary component and dorsal rectal component. The face and the oral cavity form between 4 – 8 week of embryonal development from the branchial arches (maxillar, mandibular).

Congenital malformations of the gastrointestinal tract are quite frequent.

Etiology:

Etiology is complex, many of these malformatins are parts of chromosomal aberrations and genetic syndromes. They are ranked among symptoms of intrauterine infection or effect of teratogens. Frequent reason for intestinal discontinuity is disorder of the vascular supply and related ischemia.

3.3.7.1  Oral cavity and the palate

Classification:

  • cleft lip and palate
  • microstomia
  • macrostomia
    • parts of various congenital syndromes
  • macroglossia
    • association with trisomy 21, congenital syphilis, storage diseases etc.
3.3.7.1.1  Cleft lip and palate

Classification:

  • isolated cleft lip — cheiloschisis
  • isolated cleft palate — palatoschisis, veloschisis, uvula bifida
  • complex cleft — cheilognathopalatoschisis
  • submucouse cleft palatum — mucosal cover is developed
  • central cleft lip is less frequent (associated with holoprosencephalia)
  • oblique cleft leads from the mouth to the orbita

Clinical signs:

  • may be unilateral or bilateral
  • develop when the maxilar and mandibular branchial arch do not connect
  • frequent is association with the amniotic band syndrome
  • most frequent congenital malformation of the oral cavity, incidence 1 : 950
  • symptomes:
    • disorders of sucking, swallowing, phonation
    • frequent aspiration of the food
    • reccurent otitides and pneumonias
3.3.7.2  Congenital defects of the esophagus
3.3.7.2.1  Atresia

Clinical signs:

  • incidence 1 : 3000 – 5000
  • occurs in different variations, in 90% combined with tracheosophageal fistula
  • division:
    • both blind ends of the esophagus do not communicate with the trachea
    • oral blind end communicates with the trachea, this type is most frequent (80%)
    • aboral blind portion communicates with the trachea
    • both blind ends communicate with the trachea, they are not connected
    • tracheoesophageal fistula: lumen of the nonatretic esophagus communicates with the trachea
  • atresia of the esophagus is associated with various syndromes, e.g. VACTERL (vertebral, anal, cardiac, tracheoesophageal, renal, radial limb defects), trisomies 13, 18, 21
  • prenatally is usually polyhydramnion
  • postnatally it manifests by
    • salivation
    • attacks of dyspnoe
    • attacks of stridor with cyanosis
    • frequent aspirations
    • reccurent pneumonias

Pictures

Atresia of the esophagus, trisomy 18, 26-week fetus:
Atresia of the esophagus, trisomy 18, Macro, autopsy (72138)

Atresia of the esophagus, tracheoesophageal fistula, 26-week fetus:
Atresia of the esophagus, tracheoesophageal fistula, trisomy 18, Macro, autopsy (72137)

3.3.7.2.2  Congenital esophagus stenoses

Classification:

  • membranous (even multiple) or caused by other obstruction
  • most often in distal third of the esophagus
3.3.7.3  Congenital malformations of the stomach

Clinical signs:

  • Atresia, aplasia of the pylorus and antrum
    • less frequent is atresia associated with epidermolysis bullosa
    • prenatally is polyhydramnion
  • Congenital hypertrophic pylorostenosis
    • incidence 1 : 150 in born boys, in girls less frequent
    • circular muscle of the pylorus is hypertrophic, the stomach is dilated, on the cut the pylorus looks like cartilage
    • manifests postnatally by explosive arch vomiting in the 2nd week up to the 2nd month of life
    • surgical correction — pyloromyotomia
3.3.7.4  Congenital malformations of the intestines
3.3.7.4.1  Atresia

Classification:

Several morphologic types:

  • type I: membranous: the intestine is closed by a diaphragm formed of connective tissue
  • type II: disrupted continuity of the intestine, segments are connected by a fibrous band
  • type III: disrupted continuity of the intestine, a gap between the segments
  • type IV: multiple atresias

Clinical signs:

  • vomiting
  • dilatation of the intestine
  • disorder of the meconium passage

Macroscopic appearance:

  • atresia (mainly type I and II) or stenosis in the duodenum is more frequent than defects of other parts of the intestine and is often associated with various anomalies such as intestinal malrotation, annual pancreas, congenital volvulus, Ladd's syndrome (fibrous bands), tracheoesophageal fistula and others
    • has characteristic macroscopic appearance of hour glass (double bubble)
    • prenatally polyhydramnion is present
    • postnatally explosive vomitting
  • jejunoileal atresia (all types) is less frequently associated with other malformations
    • proximal section of the intestine is conspicuously dilated
    • perforation may complicate the condition of the patient
    • the part behind the stenosis is contracted with narrow lumen
  • atresia of the colon forms only 10% of the intestinal atresias; majority affects the intestine proximally from the lineal flexura

Pictures

Duodenal atresia:
Duodenal atresia, Macro, autopsy (73044)

3.3.7.4.2  Malrotation of the intestine

Classification:

  • disorder of the rotation of the intestine or its fixation to the dorsal abdominal wall
    • nonrotation: the whole colon is on the left side
    • incomplete rotation: caecum is above the duodenjejunal junction
    • inverted rotation: clockwise rotation
  • frequent complication is volvulus and duodenal obstruction
  • association with trisomy 12, 18, 21 or with polysplenia and asplenia syndromes
3.3.7.4.3  Remnants of the omphalomesentric duct

Classification:

  • duct persistence: connection between the ileum and the umbilicus, umbilical enterocutanous fistula
  • fibrous band or fibrous band with cysts between the ileum and abdominal wall
  • Meckel's diverticulum
    • 50 – 70 cm above the ileocecal valve
    • in 50 – 80% contains the stomach mucosa
    • may contain also ectopic tissue of the pancreas
    • complications: volvulus, intususception, bleeding, perforation
3.3.7.4.4  Anorectal malformations

Clinical signs:

  • most common congenital malformation of the intestine, more frequent in males
  • occurs isolated or in combination with other anomalies (VACTERL syndrome)
  • there are many variations of anorectal and cloacal anomalies which are high, intermedial and low according to the relation between the dead end of the intestine and the musculus levator ani
  • frequent fistulas, communication with urethra, vagina, urinary bladder, opening on the perineum

Classification:

  • rectal atresia
  • anorectal agenesis (communicating, noncommunicating)
  • stenosis of the anus
  • membranous atresia of the anus
  • anal agenesis (communicating, noncommunicating)
  • persistating cloaca: common opening of the rectum, vagina and urethra on the perineum

Pictures

High rectum aplasia at VATER association, 20-week fetus:
High atresia of the rectum, VATER association, Macro, autopsy (72151)

3.3.7.4.5  Duplicatures

Clinical signs:

  • tubular or cystic structures formed by mucosa and muscle and filled with mucus, which adhere on some part of the GI tract from the hypopharynx to the rectum
  • mostly affect the intestine (ileum)
  • are located mainly extramurally and have complete wall
  • less frequently they are connected by a duct with the intestinal lumen or located intramurally in the intestinal wall
  • can be complicated by bleeding, perforation or ileus
3.3.7.5  Defects of the abdominal wall

Classification:

  • Omphalocele
  • Gastroschisis
  • Limb-body wall complex
3.3.7.5.1  Omphalocele

Clinical signs:

  • incidence 1 : 3500
  • hernia in place of insertion of the umbilical cord
  • the sac is formed by amnial membranes and peritoneum
  • the content of the hernia depends on the size of the defect (loops of the small intestine up to liver in large defects)
  • 30 – 50% of cases are associated with other malformations (anorectal, genitourinal, malrotations etc.), frequent at trisomy 18
  • with omphalocele congenital short intestine is often associated
3.3.7.5.2  Gastroschisis

Clinical signs:

  • less frequent than omphalocele
  • complete defect of the abdominal wall (an aperture to diameter 5 mm) paraumbilically on the right with evisceration of the intestinal loops, separated from the umbilical cords insertion by a thin band of skin
  • no association with chromosomal aberrations and genetic syndromes
3.3.7.5.3  Limb-body wall complex

Clinical signs:

  • probably caused by early amniotic rupture
  • includes
    • amnial bands
    • encephalocele
    • meningomyelocele
    • reduction defects of the limbs
    • facial clefts
    • defects of abdominal and thoracic wall

Case study:

Limb body wall complex
Marta Ježová

History:

Screening triple test in 16 week of gestation — maternal serum alpha fetoprotein (AFP) was elevated. Congenital maformations involving most fetal organs were subsequently detected by ultrasound.

Macroscopic appearance:

  • 20-week fetus
  • abdominal and thoracic wall defect
  • eventration of small and large intestine, stomach, liver, spleen, adrenals, kidneys and right lung
  • exencephaly (brain is exposed through defect in cranial vault)
  • unilateral cleft lip
  • limb defects:
    • rocker bottom feet — prominující paty
    • hypodactyly in left lower limb
    • syndactyly in right lower limb
    • hypoplastic thumb in right upper limb
  • severe torsion and scoliosis of the spine, chest wall deformity
  • heart malformation:
    • ectopia cordis
    • transposition of great vessels with ventricular septal defect
    • pulmonary atresia
  • fusion of adrenals
  • intrauterine growth retardation
  • umbilical cord:
    • extremely short (5 cm long)
    • single umbilical artery
  • no amniotic bands

Pictures

Abdominal and thoracic wall defect, eventration of abdominal and thoracic organs, exencephaly, cleft lip, intrauterine growth retardation:
Abdominal and thoracic wall defect, Macro, autopsy (72700)

Lower limb malformation — rocker bottom foot:
Rocker bottom foot, Macro, autopsy (72701)

Upper limb malformation — hypoplastic thumb:
Hypoplastic thumb, Macro, autopsy (72702)

Lower limb malformation — hypodactyly:
Hypodactyly, Macro, autopsy (72704)

Protrusion of internal organs, ectopia cordis:
Protrusion of internal organs, ectopia cordis, Macro, autopsy (72703)

Fetus viewed from the dorsal aspect, curvature of body line:
Curvature of body line, Macro, autopsy (72705)

Severe scoliosis, chest wall deformity:
Severe scoliosis, Macro, autopsy (72708)

Heart defect: aorta arising from right ventricle, ventricular septal defect:
Aorta arising from right ventricle, VSD, Macro, autopsy (72707)

Heart defect: anomalous origin of great arteries seen in heart base, hypoplastic truncus pulmonalis:
Anomalous origin of great arteries, Macro, autopsy (72706)

Ultrasound examination:
Limb body wall complex, Ultrasound (72716)
Limb body wall complex, Ultrasound (72717)

3.3.7.5.4  Pentalogy of Cantrell

Introduction:

Pentalogy of Cantrell is a constellation of congenital defects involving the abdominal wall, sternum, diaphragm, pericardium and heart.

Clinical signs:

  • very rare anomaly
  • chromosomal analysis is highly recommended; associations with trisomy 13, 18 and Turner syndrome have been reported
  • associated anomalies include cleft lip and palate, limb anomalies, neural tube defects etc.
  • associated anomalies include:
    • limb anomalies
    • cleft lip and palate
    • neural tube defects etc.
  • The prognosis is dismal. Most of the affected infants are stillborn or die soon after delivery. Survival after surgical correction is limited by pulmonary and thoracic cage hypoplasia.

Macroscopic appearance:

  1. a midline, supraumbilical abdominal wall defect (usually ompalocele)
  2. a defect of the lower sternum (clefting, shortening or abscence of the sternum)
  3. a deficiency of the anterior diaphragm
  4. a defect in the diaphragmatic pericardium
  5. intracardiac defects (atrial septal defect and tetralogy of Fallot are common)

Case study:

Pentalogie Cantrell
Marta Ježová

History:

  • giant omphalocele containing the intestine, liver and heart was detected by prenatal ultrasonography in the 2nd trimestr.
  • karyotype 46XY
  • final diagnosis: Pentalogy of Cantrell

Macroscopic appearance:

  • 22-week fetus
  • omphalocele
  • herniated liver, small and large intestine, stomach, heart partially (ectopia cordis)
  • defect in the ventral part of the diaphragm, both diaphramatic cupulae were well formed
  • defect of the pericardium
  • shortening of the sternum
  • Heart defect:
    • persistence of the left superior vena cava draining to the sinus coronarius
    • atrial septal defect (sinus venosus defect)
    • anomalous drainage of the right pulmonary veins into the right atrium
  • pulmonary hypoplasia

Pictures

Fetus with omphalocele:
Pentalogy of Cantrell, Macro, autopsy (72744)

Omphalocele:
Pentalogy of Cantrell, Macro, autopsy (72745)

The omphalocele contains the liver, intestines, the stomach and the heart:
Pentalogy of Cantrell, Macro, autopsy (72746)

Defect of the ventral diaphragm, defect of the pericardium:
Pentalogy of Cantrell, Macro, autopsy (72747)

Ultrasound video of the case:
Pentalogy of Cantrell, Ultrasound, video (72948)

3.3.8  Developemental anomalies of the skeleton

Marta Ježová

Introduction:

More than 200 different developemental disorders have been defined.

Manifestation vary greatly.

Lethal and non-lethal skeletal dysplasias, lethal forms are particularly important for the pathologist.

The diagnosis is made primarily on radiological features, histological examination of cartilage and bone is recommended.

  • Osteochondrodysplasias are global involvements of cartilage and bone tissue resulting in disproportionate growth or dwarfism
    • defects of the growth of tubular bone and/or spine
    • abnormalities of density of cortical diaphyseal structure or metaphyseal modeling
    • disorganized developement or cartilage and fibrous component of skeleton
  • Dysostoses: are malformations of individual bones singly or in combination result form localized problem in migration and condensation of primitive mesenchymal cells. Affect particular bone skeletal elements with the remainder being normal.
    • craniofacial dysostoses  —  various craniosynostoses
    • Axial skeleton malformations  —  segmentation defect disorders
    • Limb malformations
3.3.8.1  Defects of growth of tubular bone and/or spine
3.3.8.1.1  Thanatophoric dysplasia

Introduction:

  • The most common form of lethal skeletal dysplasia.
  • The name is derived from Greek thanatos (death) and phorus (seeking).

Etiology, pathogenesis:

  • mutations of the fibroblastic growth factor 3 (FGFR3)
  • mutations of the same gen were also identified in achondroplasia and hypochondroplasia which are compatible with normal survival
  • sporadic dominant mutations (AD)
  • thanatophoric dysplasia common type
  • thanatophoric dysplasia with cloverleaf skull: generalized skeletal dysplasia identical to the common form and a craniosynostosis with abnormal skull configuration, severe hydrocephalus is present

Clinical signs:

  • stillbirth
  • death at birth or early after birth due to respiratory insufficiency
  • relatively large head
  • short limbs (micromelia)
  • narrow thorax
  • RTG: severe platyspondyly, short ribs, bowing of the shortened femurs (telephone receiver femur)

Histology:

Severely disturbed enchondral ossification.

3.3.8.1.2  Diastrophic dysplasia

Introduction:

  • rare autosomal recessive disorder
  • lethal as well as non-lethal and mild forms
  • short limbs
  • deformation of spine (kyphoscoliosis)
  • joint abnormalities: hitchhiker's thumb, clubfeet

Pictures

Diastrophic dysplasia:
Diastrophic dysplasia, Macro, autopsy (73644)

Myxoid changes and cystic areas in the resting cartilage.

3.3.8.2  Abnormalities of density of cortical diaphyseal structure or metaphyseal modeling
3.3.8.2.1  Osteogenesis imperfecta

Introduction:

Brittle bone disease with varying degrees of severity.

Etiology:

  • deficiency in the synthesis of type 1 collagen which is found in bone, skin, dentin, ligaments and tendons
  • decreased synthesis of normal collagen in mild forms, synthesis of abnormal collagen chains in severe and lethal types
  • inherited both in autosomal dominant and autosomal recessive trait

Clinical signs:

  • skeletal fragility, multiple fractures
  • dentinogenesis imperfecta
  • hearing loss
  • laxity of the joints
  • excessive sweating
  • fragile skin
  • certain types present with blue sclerae which may later become white

Broad range of phenotypes.

Classification according to Silence in 4 major subtypes:

Type II. is uniformly lethal, type I., III. and IV. compatible with survival.

Type II. is the most common type seen by the pathologist. Prenatal diagnosis and termination of pregnancy is possible in severe types of OI.

Clinical signs:

  • Type II.
    • the most severe form
    • extreme skeletal fragility
    • multiple fractures occur form movement in utero
    • skeletal deformity  —  limb shortening, bowing of long bones
    • small bell shaped thorax
    • the head is speherical and soft (poor osification)
    • death occurs in utero or within days after birth due to intracranial hemorrhage or respiratory insuficiency (lung hypoplasia).
    • the majority of cases are new dominant mutations
  • Type III.
    • progressive deformity of long bones and spine
    • compatible with survival
    • multiple fractures (dozens), some may be found even at birth
    • short and bowed long bones
    • progressive kyphoscoliosis
    • short stature
    • wheel-chair dependence
    • life span is shortened
  • Type I.
    • mild fragility
    • postnatal fractures
    • blue sclerae
  • Type IV.
    • moderate fragility
    • postnatal fractures
    • white sclerae
    • prognosis is much better than in type III.

Histology:

  • osteopenia  —  thin, delicate cortical and trabecular bone
  • fractures with callus formation
  • cartilage growth plate is normal
3.3.8.2.2  Limb malformations

Introduction:

The overall incidence of congenital limb malformations is 1 in 500 to 1500 live births. The manifestation vary from minor anomalies to severe crippling. The defects may be isolated or found with additional malformations. Radial and central ray maformations, amelia and rudimentary limb show a strong association with other anomalies. Severe malformations can be diagnosed prenatally. Syndactyly and polydactyly are the most common abnormalities seen in general population.

Etiology:

  • genetic
  • enviromental  —  teratogenic agents such as certain drugs, maternal diabetes, congenital varicella infection. Phocomelia is the most common limb malformation associated with teratogenic Thalidomid (note: Thalidomid was prescribed to pregnent women as a sedative releaving nauzea in the late 1950 and early 1960).
  • unknown

Important syndromes associated with limb malformations:

  • Trombocytopenia  —  absent  —  radius (TAR) syndrome: autosomal recessive, radial aplasia and bleeding disorders
  • Fanconi anemia: autosomal recessive, variable limb malformations, short stature, microcephaly, pancytopenia occurs in childhood, high risk of leukemia
  • Holt  —  Oram syndrome (hand  —  heart): autosomal dominant, variable bilateral but often assymetrical limb malformation, heart defects (atrial septal defects in particular)
  • VACTERL see VACTERL
  • Femoral hypoplasia  —  unusual facies: often associated with maternal diabetes, unusual face with recessed chin, long filtrum and small nose, short femur
  • Tibial hemimelia: autosomal dominant
  • Femur  —  ulna syndrome
  • Tibial hemimelia

Terms derived from Latin or Greek which are used in common praxis are familiar, but the meaning is innacurate and often misused.

  • Ectromelia  —  complete or almost complete absence of one or more limb. The limb is completely absent or ends in one or more imperfect digits or in a stump without any digits.
  • Phocomelia  —  seal limb (greek phoke means a seal). The hand or feet of usual size and often completely normal are attached directly to the shoulder/hip or to abbreviated arms and legs.
  • Hemimelia  —  half limb. The forearm or the leg, but particularly the hand or foot, is lacking or it represented by only some rudimentary parts. There is a stump without any sign of hand or foot or a stump ending in one or more imperfect digits
  • Peromelia  —  meaning a malformed limb (limb stump), a vague clinical term
  • Amelia  —  absence of an entire limb
  • Meromelia  —  partial absence of a limb
  • Acheiria  —  absence of one or both hands
  • Apodia  —  absence of one or both feet

The involvement of individual bone ranges from complete aplasia to partial aplasia and hypoplasia (teratogenic sequence).

Precise classification on anatomical basis (Swanson)

  • Type I.  —  failure of formation of parts
  • Type II.  —  failure of separation
  • Type III.  —  duplication
  • Type IV.  —  overgrowth
  • Type V.  —  undergrowth
  • Type VI.  —  constriction (amniotic) band syndrome

Type I., subclassificaton of defects

  • Terminal  —  absence of limb segments below a certain point with relative preservation of the more proximal segments
  • Intercalary (interposed)  —  absence of proximal or middle segments when the distal structures are present even if malformed
  • Transverse  —  involves the full width of the limb
  • Longitudinal  —  defects paralleling the long axis of the limb
    • Preaxial  —  involvement on the radial (thumb) or tibial (big toe) side
    • Postaxial  —  involvement on the ulnar (little finger) or fibular (5th toe) side
    • Central  —  involvement of the middle rays

Most limb deficiencies can be classified into one of the following groups this way:

  • Terminal transverse
  • Terminal longitudinal
  • Intercalary transverse (phocomelia)
  • Intercalary longitudinal
3.3.8.2.2.1  Terminal transverse limb defects

Introduction:

Also called reduction limb defects.

  • reduction defect resembling an amputation
  • transverse arrest is common at the upper third of forearm, wrist, metacarpal and phalangeal level
  • the upper limb is twice as commonly affected than the lower limb

Clinical signs:

Additional malformations occur rarely.

3.3.8.2.2.2  Radial ray defects

Introduction:

Anomalies of radius and thenar

  • Radial agenesis (complete, partial)
  • Radial hypoplasia
  • Triphalangeal thumb
  • Thumb agenesis
  • Thumb and thener hypoplasia
  • Anomalies of the thumb
  • Preaxial polydactyly

Clinical signs:

Radial ray anomalies (radial agenesis and hypoplasia in particular) are frequently syndromic: trisomy 18, Holt-Oram, TAR syndrome, Fanconi anemia, VACTERL.

The forearm is shortened and the wrist is radially deviated in radial aplasia/hypoplasia. The thumb is either absent or present as a rudimentary bud or nonfuncioning structure..The term radial club hand is also used.

Triphalangeal thumb  —  long thumb with three phalanges, either opposable or non-opposable because in one plane with the other fingers.

3.3.8.2.3  Finger anomalies
  • Syndactyly  —  fusion of fingers or toes, affects only skin or even a bone
  • Polydactyly  —  additional fingers or toes. The extra digit may be either a fully developed finger, an incomplete digit resulting in a broad or bifid digit or just a skin tag (appendix digitiformis).
  • Polysyndactyly  —  combination of additional digits (polydactyly) which are fused together.
  • Oligodactyly  —  reduced number of well formed fingers
  • Camptodactyly  —  permanent flexion of one or more fingers
  • Clinodactyly  —  fixed abnormal deviation of the finger. It typically affects the middle phalanx of the little finger, the distal phalanx is bent toward the fourth finger
  • Ectrodactyly (cleft hand/foot)  —  cleft in the central portion of a hand or foot due to the absence of central rays (f.e. in a hand central digits or metacarpales are absent, residual fingers usually show syndactyly). Also called a lobster claw deformity.

Polydactyly classification:

    Pre-axial  —  rare Post-axial  —  80% of cases Central  —  quite rare

Clinical signs:

Syndactyly is quite frequent and occurs in approximately 1 of every 2500 births. The most common is bilateral syndactyly of toes. The incidence of polydactyly is approximately 1 – 2 in 1000 in whites but 10 times more frequent in blacks. These minor anomalies are often inherited in autosomal dominant trait.

Severe camptodactyly is usually associated with karyotypic anomalies or contracture syndromes

3.3.8.2.4  Club foot

Introduction:

Complex deformity of the foot which consists or equinus (the foot in plantar flexion), varus, forefoot adduction and inversion, cavus deformity. From the word equinus meaning like a horse.

Clinical signs:

  • incidence in general population is 1 per 1000 live births
  • male to female ratio is 2:1
  • 20% of affected children have severe coexisting malformations  —  spina bifida, trisomy 18 and various genetic syndromes
  • idiopathic club foot in an otherwise healthy child is probably the result of multifactorial traif of inheritance. A higer incidence of club foot is noted in patiens with positive family history

Etiology, pathogenesis:

True etiology remains unknown despite several theories:

  • arrest of fetal developement
  • neurogenic factors
  • mechanical factors  —  external uterine compression in oligohydramnion
  • defective cartilaginous anlage of the talus
  • prenatal poliomyelitis-like infection
  • Postural or positional  —  f.e. due to oligohydramnion, correctable without surgary
  • True club foot (rigid)  —  surgary is required
  • Club foot associated with arthrogryposis
  • Club foot associated with syndromes and neuromuscular disorders (spina bifida)

The person walks on the outer part of the sole, the heel is upward. The foot is smaller than normal, musles of the calf are hypotrophic.

40 % cases are bilateral.

Pictures

Pedes equinovari:
Pedes equinovari, Macro, autopsy (73696)

3.3.8.2.5  Constriction (amniotic) band syndrome
  • simple ring constrictions
  • swelling of the extremities distal to the point of constriction
  • syndactyly
  • intrauterine amputations

The hands are affected in almost 90 % of cases

Syndactyly takes form of fusion of the finger tips (fenestrated syndactyly)

Intrauterine amputations occurs in the longer digits of the hands (middle, index and ring finger), the same rule holds true for the foot, where amputation most often involves the thumb.

Club foot is seen in almost 25 %. The club foot deformity may be due to tight bands around the extremity with the involvement of the peroneal nerve. In 50 % of cases no bands are found, the deformity is thus thought to arise form lack of space in oligohydramnios which occurs transiently after amnion rupture.


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