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Congenital malformations   (Sylva Hotárková)

3  Atlas of fetal pathology

3.1  Congenital malformations

Sylva Hotárková

Introduction:

Diagnosing deviations from normal intrauterine development requires a detailed knowledge of the normal developement. Here fetal pathology closely coresponds with embryology. The duration of normal gestation is 280 days (which equals 40 weeks) counted from the first day of the last menstruation. Intrauterine development is traditionally divided into the folowing stages:

Furthermore, fetal period can be theoretically divided into a prevailable> (0 to 20 w.g.) and a viable period (over 20 w.g.).

It is necessary to emphasise that this classification is only formal and does not reflect the actual ability to survive after the premature delivery. This ability depends especially on the stage of development of the respiratory tract and lung tissue in particular. Infants born before 28th w.g. suffer of serious health complications caused by insufficient production of aleveolar surfactant by aleveolar type 2 pneumocytes.

Note: gestational age of the fetus is calculated from the first day of the last menstruation. However, the actual age of the fetus as approximately 2 weeks less (due to the usual date of conception) To make things clearer, the gestational age terminology is usualy used.

3.1.1  Physiological developement of an embryo and fetus, growth and changes of the external shape

1st lunar month
Presomite stage of development: fertilized oocyte quickly develops into a blastocyst, in which the embryo itself is represented by embryoblast, which will soon turn into an embryonic disc. The disc becomes oval and from the end of the 3rd week it begins to bend in the craniocaudal and also dorsoventral axis and finally becomes the cylindrical embryo body. The somite stage of development follows. The embryo is bent, it has the shape of the letter C, the convexity is dorsal. In a very large head part, there is the forebrain with a frontal prominence, then (dorsally from from the forebrain) midbrain (mesencefalon) with a dorsal curve (flexura cephalica). Another bend forms flexura occipitalis in the hindbrain region. On the concave dorsal side of the embryo body somites are plainly visible. Caudal end of the embryo body is also ventrally bent and ends with a tail. On the ventral side of the body there are the heart and liver prominences. Face and limb prominences begin to form (the limbs resemble tiny fins). At the end of the first lunar month, the body is cca 4 mm long.
2nd lunar month
Development of the facial structures continues — eyes, ears and nose are formed. The body begins to straighten and the head rounds out. In the brain the 4th ventricle is formed. The tail is shorter. Limbs continue to develop, fingers become separate. The neck begins to form and also the insertion of the umbilical cord narrows. The genitalia prominence is being formed. Slowly embryo gains human features and becomes distinguishable from embryos of other mammals. The crown to rump length at the end of the 2nd month is approximately 28 mm. At this stage, terminology changes and the embryo becomes fetus.
3rd lunar month
The fetus continues to grow quickly, most of the internal organs are in their final positions. Its trunk lengthens, but the head still remains rather large compared to the rest of the body (the head is approx. 1/3 of body length). External genitalias are completely developed and gender can be told. Body length at the end of the 2nd month is cca 90 mm, C-R length cca 70 mm. The fetus weights approximately 20 g.
4th lunar month
Rapid growth continues, nails begin to appear and skin is covered with first (very fine) hair (lanugo). The body is about 150 mm long, C-R length is cca 130 mm, weight is approx. 120 g.
5th lunar month
Growth slows down, the head becomes smaller compared to the rest of the body. The fetus is covered with lanugo, vernix caseosa is produced. The fetus moves and its mother begins to feel its movement — primigravida around 19th w.g., multigravida aprox. 2 weeks earlier. Heartbeat can be detected with a stetoscope. Body length at the end of the month is cca 250 mm, C-R is cca 180 mm, weight is approximately 300 g
6th lunar mmonth
Because there is no subcutaneous fat, the skin is soft, transparent, purple-red with blood vessels clearly visible. The head is covered with short hair, eye lashes and eyebrows begin to grow. Body length at the end of the month is cca 300 mm, C-R is cca 230 mm, weight is approximately 600 g.
7th lunar month
Subcutaneous fat begins to form, skin stretches Eyes open; epitelial suture between eyelids reopens. Testes begin to descend into the scrotal pouch. Body length is cca 350 mm, C-R is cca 270 mm, weight approximately 1200 g.
8th lunar month
The ammount of subcutaneus fat increases, the fetus is plump, pink with hair on its head, nails reach to the ends of fingertips. There is plenty of vernix caseosa on the body surface. Body length is cca 400 mm, C-R is cca 310 mm, the fetus weights approximately 1800 g.
9th lunar month
Changes which began in the 8th lunar month continue. Descend of testes is finished. Body length is cca 450 mm, C-R is cca 340 mm, weight is approximately 2600 g.
10th lunar month
By this time a full-term baby is ready to be born: its body is plump, skin is smooth without lanugo. Nails reach over the ends of fingertips, hair is at least 10 mm long. Bones on the head are hard, cartilage is firm and fontanels are palpable. Perimeter of the chest is slightly larger than perimeter of the head. Body length is approximately 500 mm, C-R length is approximately 360 mm, average weight is 3300 g. These signs are evaluated by a neonatologist right after the delivery.

Pictures

Normal 7-week fetus:
Fetus, 7-week, Macro, autopsy (73329)
Fetus, 7-week, Macro, autopsy (73330)

Normal 10-week fetus:
Fetus, 10-week, Macro, autopsy (73325)
Fetus, 10-week, Macro, autopsy (73326)
Fetus, 10-week, Macro, autopsy (73327)
Fetus, 10-week, Macro, autopsy (73328)

Normal 14-week fetus:
Fetus, normal, 14-week, Macro, autopsy (73645)
Fetus, normal, 14-week, Macro, autopsy (73646)

Normal 15-week fetus:
Normal fetus, 15 w.g., Macro, autopsy (73053)

Normal 15-week fetus:
Normal fetus, 15-week, Macro, autopsy (73697)
Normal fetus, 15-week, Macro, autopsy (73698)

Normal 16-week fetus:
Normal fetus, 16 w.g., Macro, autopsy (73054)
Normal fetus, 16 w.g., Macro, autopsy (73055)

Normal 17-week fetus:
Normal fetus, 17th week of pregnancy, Macro, autopsy (72075)
Normal fetus, 17th week of pregnancy, Macro, autopsy (72076)
Normal fetus, 17th week of pregnancy, Macro, autopsy (72077)
Normal fetus, 17th week of pregnancy, Macro, autopsy (72078)

Normal 18-week fetus:
Normal fetus, 18-week, Macro, autopsy (73699)
Normal fetus, 18-week, Macro, autopsy (73700)

Normal 17-week fetus:
Normal fetus, 17 w.g., Macro, autopsy (73056)

Normal 19-week fetus:
Normal fetus, 19 w.g., Macro, autopsy (73057)

Normal 19-week fetus:
Normal fetus, 19-week, Macro, autopsy (73701)
Normal fetus, 19-week, Macro, autopsy (73702)
Normal fetus, 19-week, Macro, autopsy (73703)
Normal fetus, 19-week, Macro, autopsy (73704)

Normal 21-week fetus:
Normal fetus, 21 w.g., Macro, autopsy (73058)

Normal 22-week fetus:
Normal fetus, 22-week, Macro, autopsy (73705)
Normal fetus, 22-week, Macro, autopsy (73706)

Normal 24-week fetus:
Fetus, 24 week, Macro, autopsy (73998)

Normal 25-week fetus:
Normal fetus, 25 w.g., Macro, autopsy (73059)

Normální plod, 25. týden gravidity:
Fetus, 28 week, Macro, autopsy (73999)

Histology:

Tissues in various stages of embryonal development.

Pictures

Normal myocardium, 20-week fetus:
Fetus, 20th week, myocardium, HE 40x (72612)

Normal brain, radial glia, developing cortex, 20-week fetus:
Fetus, 20th week, periventricular area, HE 40x (72611)

Normal lung, canallicular, (with focal adnate pneumonia), 20-week fetus:
Fetus, 20th week, lung, pneumonia, HE 40x (72613)
Fetus, 20th week, lung, pneumonia, HE 40x (72614)

Extramedullar hemopoesis, fetus, 20-week, spleen:
Spleen, fetus, 20th week of gravidity, HE 40x (72553)

Normal kidney, fetus, 20-week:
Normal fetal kidney, HE 40x (72658)

Ovary with follicular cyst:
Follicular cyst, ovary, newborn, HE 40x (72884)

3.1.2  Congenital malformations and congenital anomalies

Introduction:

Congenital anomalies (CA) follow disorders during uterine development and can have various degrees of seriousness on a gradual scale from minor to very serious defects. Congenital anomalies can be either structural or functional.

Structural congenital anomalies vary from hypoplasia to agenesis and include also malformations, disruptions and deformations and their combinations. These congenital defects can be detected during the intrauterine development and if such a child is born the anomalies are usually recognizable at first sight.

Functional congenital anomalies usually do not manifest themselves right after the birth. The majority of them are metabolic disorders.

The science studying congenital anomalies their causes, pathogenesis, morfolology and prevention is called — teratology.

The global occurance of congenital anomalies is about 5% of stillborn infants, 2 – 3% newborn infants (anomalies detected right after birth) and another 2 – 3% are diagnosed during the first year of life.

3.1.2.1  Basic terminology

Classification:

There is a large number of morfogenesis disorders that can occur during intrauterine development. The basic terminology is given here:

Malformation
Morphological defects of organs or organ parts resulting from anomal development, which was pathologic right from the start. Malformations can occur on a genetic or evironmental basis. For example neural tube defects: neural tube fails to close, it has never formed in a normal way.
Disruption
Secondary defect in the development of an organ or its part, which was developing correctly at the beginning. The etiological factors are either external or internal, but are not hereditary. For example: amniotic bands — as a result of a amnion rupture during the fetal development, strands of the amnion are released and encircle parts of the body of the fetus, causing constrictions or even amputations.
Deformation
Deformations develop during later stages of intrauterine development as a result of mechanical powers (pressure) causing abnormal shape or position of a body part. In these cases, the development of the fetus is not much disturbed, but is diverted from the original course. There are many etiological factors, for example a small or malformed uterus, leiymyomatosis, oligoanhydramnion, abnormal positions of the fetus or multiple gravidity. Examples: limb dislocations or pes equinovarus (clubfoot).
Sequence
Term used to describe the origination of secondary congenital anomalies, which develop in cascade as a consequence of a primary malformation. For example Potter's sequence (oligohydramnial sequence), which is (in more detail) described in the congenitalia anomalies of the urogenitalia tract. It is a pathological state caused by a lack of amniotic fluid (for various reasons: chronic efflux of the amniotic fluid or kidney agenesis) leading to a sequence of secondary fetal anomalies (flattened face, limb deformations, pulmonary hypoplasia).
Syndrome
Term used to describe symptoms and anomalies present together. The collective occurence is not random, but relates to the etiology of the process. As opposed to the sequence, syndrome is nor not caused by any primary malformation. Syndromes often originate from one etiologic agent, for example some specific chromosomal aberration (as is Down syndrome — trisomy 21, described in more detail in another part of the chapter) or viral infection.
Association
Term used to describe a situation, where certain signs or abnormalities occur together more often than would be expected by chance alone, but the reasons are not yet known. The point is that if one anomaly is found, organs with an increased risk of associated anomalies should be examined carefully. Examples: VATER association —  vertebral, anal, tracheoesophageal and radial anomalies often occur together.
Agenesis
complete absence of an organ and its primordia.
Aplasia
absence of an organ resulting from damaging its primordia.
Atresia
absence of an opening of mostly visceral organs.
Hypoplasia
a not-so-serious stage of aplasia, the organ is not completely developed and the number of cells in its structure is decreased.
Hyperplasia
organ enlargment caused by an increase in the number of its cells.
Dysplasia
in the malformation context, dysplasia is defined as an abnormal organisation of cells.
3.1.2.2  Etiology of congenital anomalies (CA)

Factors participating on the congenital anomalies genesis:

  1. genetic factors: responsible for approximately 10 – 15% of CAs, are associated with chromosomal aberrations or originate in gene mutations
  2. environmental factors: so-called teratogens, cause another 10 – 15% of CAs
  3. multifactorial causes and factors not yet known: (70 – 80% VVV)

Teratogens and genetic factors can interfere with normal morphogenesis of the fetus on several levels. For example: cell migration, proliferation, interaction, apoptosis etc. can all be affected.

The sensitivity of the fetus to damage causing factors changes during its development. The first trimester of gravidity is the time, when the embryo is highly sensitive to teratogens, while in the second and third trimester (with organogenesis practically finished) the sensitivity decreases. This means that the sooner the damage occures, the more serious the consequences are. The co-called critical stage of the fetus is from the 3rd to the 9th week of gestation. Critical stages of the organs are specific for each organ and slightly vary from one another:

  • Central nervous system and cardiovascular system: cca 3 – 6th week of gestation.
  • Senses — eyes and ears — cca 4 – 9th week of gestation.
  • Limbs: from the end of 4th week to the middle of 8th week of gestation.
  • Palate and teeth: 6 – 8th week of gestation.
  • External genitalia: 7 – 9th week of gestation.

The stage of gravidity is not the only important factor. Intensity of the teratogenic agent is important as well. Strong agents usually cause death of the fetus, therefore malformations are more likely to be caused by less intensive insults. During the first 2 weeks of development, the embryo is not very sensitive to teratogens, so there is either no damage at all, or the whole conceptus dies (which is less frequent).

3.1.2.2.1  Environmental causes of congenital anomalies, congenital infections

Introduction:

Environmental factors (also called teratogens) can be divided into these groups: physical, chemical and biologic.

Classification:

Physical agents:

One of the most serious is ionizing radiation, which causes growth retardation and defects of the central nervous system. Also it is necessary to mention the negative effects of vibrations.

Chemical agents:

  • Pharmacs: cytostatics, antibiotics (especially tetracyclines and streptomycin), hormones (progesteron, androgens), antiepileptics, anticoagulants etc.
  • Drugs: alcohol — with a cca 40% probability, chronic alcohol abuse during pregnancy causes fetal alcohol syndrome (characterised by brain damage — microcephaly, hydrocephaly, leptomeningeal heterotopy, corpus callosum agenesis, arinencephaly; heart defects — especially atrio-ventricular septal defects; growth retardation, congenital malformations of eyes and joints.)
  • LSD, marijuana
  • Smoking: leads to disorders in afterbirth adaptation, lower birth weight and increases the risk of pre-term delivery. Children whose mothers smoked during pregnancy also develop asthma more often.

Biologic agents:

The fetus can be negatively affected by any illness the mother undergoes during her pregnancy. Etiologic agents with the most serious effects on the fetus are listed below (however, the listing is not complete).

  • Viruses: cytomegalovirus, herpes simplex, varicella-zoster, EBV, influenza, mumps
  • Bacteria: treponema pallidum
  • Parasites: toxoplasmosis
3.1.2.2.1.1  Rubella

Introduction:

Highly teratogenic agent, the risk of fetal damage is 60% and higher, and is extremly dangerous in case the infection occures before 16th w.g. The risk decreases as the pregnancy continues to the later stages.

Macroscopic appearance:

The infection results in a large variety of congenital malformations: triad of congenital heart defects (patent ductus arteriosus, hypoplasia or stenosis of the pulmonary artery, septal defects, tetralogy of Fallot), deafness and blindness.

Histology:

Necrosis of vascular endothelial cells, necrotic foci in the vicinity of supposed hematogenous spread in fetal tissues and the placenta.

3.1.2.2.1.2  Cytomegalovirus

Introduction:

A member of the herpesvirus family. The risk of teratogenic activity is cca 10%. Infection during pregnancy can either be primary or a reactivation of a latent virus. Fortunately the infection is asymptomatic in most cases. Maternal imunity modifies the process of the disease, but it does not prevent transplacental transmission. The risk is greatest during the second trimester. Since organogenesis is practically finished by this time, malformations are rare, but virus caused organ damage is usually serious.

Macroscopic appearance:

Inflammatory damage of the CNS which lead to microcephaly, mental retardation and deafness; hepatosplenomegaly is also present.

Histology:

Typical nuclear and cytoplasmatic cytomegalic inclusions can be found in the damaged organs as well as in the inflammed placenta and fetal membranes. Nuclear inclusions are more distinct and are surrounded by characteristic round halo. Placental changes get to be more distinct during the later stages of gestation: diffuse villitis with plasma cell infiltration, with foci of necrosis and hemorrhage. CMV inclusions are sometimes present in the stromal cells of villi.

3.1.2.2.1.3  Syphilis

Introduction:

Infection with Treponema pallidum bacterium has a well established teratogenic effect. Transmission can occur during any stage of gestation and the risk of fetal damage is high (90%). The bacterium induces vascular endothelial inflammation, which results in secondary fibrosis and tissue damage. In cases where a large number of organs is affected, stillborn rate is high.

Macroscopic appearance:

Infection manifestations also include hepatosplenomegaly, hydrops fetalis, hemolytic anemia, meningitis, pneumonia, myositis and osteochondritis. Nowadays, late congenital syphilis diagnosed after 2nd year of age is very rare and if not treated, it manifests itself typically: the so-called Hutchinson's triad (deafness, blindness, teeth damage), saddle nose, palate perforations and saber shins.

Histology:

Silver staining gives evidence of the bacteria during the 1st trimester. If the woman was treated before 16 – 18th w.g., the infection cannot be histologically detected.

3.1.2.2.1.4  Toxoplasmosis

Introduction:

Toxoplasma gondii, a mammal-borne parasite can cause serious fetal damage, especially if the infection occures during the first or second trimester (the risk is 10 – 40%).

Macroscopic appearance:

The congenital infection manifests itself through a typical triad: hydrocephalus, chorioretinitis and intracranial calcifications. Infection can also be found in other organs such as the lungs, the liver, the heart, kidneys, adrenal glands and skeletal muscle. In the CNS necroses of the cortex and basal ganglia are sometimes present.

Histology:

The inflammatory infiltrate consists of histiocytes and lymphocytes. Later calcifications are present. Cystic forms of parasite are PAS-positive. We can find them in the embryonal tissues, the placenta, membranes and the umbilical cord as well. In extraembryonal tissues microorganism can be most easily detected if infection occured during the 3rd trimester. Other manifestations include villous edema and fibrosis.

Pictures

Toxoplasmosis, congenital hydrocephalus, 4 day infant:
Toxoplasmosis, congenital hydrocephalus, HE 100x (71997)  [zoomify]

3.1.2.2.2  Diabetes mellitus (DM) and pregnancy

Introduction:

Maternal diabetes mellitus is associated with high miscarriage rate, increase in congenital malformation, neonatal morbidity and mortality.

These complications correlate with a degree of glycemic control.

Classification:

  • DM type 1
  • DM type 2
  • Gestational diabetes  —  recognized first during pregnancy usually resolves after delivery. It is the most common type of diabetes among pregnant women, being diagnosed in 3% of all pregnancies.
3.1.2.2.2.1  Diabetic embryopathy

Introduction:

The incidence of congenital malformations in infants of diabetic mothers is increased 2 to 4 times compared to general population. These malformations are frequently multiple.

Macroscopic appearance:

Typical congenital malformations reported in diabetic embryopathy:

  • heart defects: double outlet right ventricle, transposition of the great vessels, tetralogy of Fallot
  • skeletal defects: caudal regression anomaly  —  agenesis/dysgenesis of caudal vertebrae, hypoplasia of lower limbs. (see caudal regresion syndrome); caudal regression has the strongest association with diabetes (occuring more than 200 times more frequently in infants of diabetic mothers than in other infants):
    • femoral hypoplasia
    • upper limb defects
    • amelia
  • neural tube defects (anencephaly, spina bifida)
  • VACTERL association (see VACTERL)

Etiology:

Teratogenic effect of diabetes occurs during the critical 2 to 6 weeks after conception. The exact cause of the teratogenic effect is not known. Specialized preconceptional and prenatal care with strict glycemic control reduce the likelihood of congenital defects. There is close correlation between the incidence of congenital malformations and glykosylated hemoglobin HbA1c values. If optimal glycemic control is achieved prior conception and maintained during the gestation, the malformation rates decrease similar to those in the healthy population.

This risk is the same for diabetes mellitus of type 1 and 2.

Peroral antidiabetics are contraindicated during pregnancy.

Case study:

Diabetic embryopathy
Marta Ježová

History:

37 — year old woman with type 2 diabetes mellitus, obesity and hypertension. There was no preconceptional and prenatal care. The mother continued on peroral anditiabetics. Second trimestr ultrasonography revealed multiple congenital malformations of the fetus. The aborted fetus was macerated.

Final diagnosis: diabetic embryopathy.

Macroscopic appearance:

Macerated 17-week male fetus.

  • caudal regression anomaly, phocomelia of the lower limbs
  • polydactyly of the left lower rudimentary limb
  • cleft palate
  • micrognathia
  • microtia
  • heart defect: double outlet right ventricle with ventricular septal defect

It was not possible to examine the brain and kidneys because of severe maceration of the fetus.

Pictures

Macerated 17-week fetus with phocomelic diabetic embryopathy:
Diabetic embryopathy, Macro, autopsy (72753)

3.1.2.2.2.2  Diabetic fetopathy

Introduction:

Diabetic fetopathy presents as fetal macrosomia in the 3rd trimestr of gestation.

The accelerated growth (exactly fetal obesity) results from fetal hyperinsulinemia when more glucose and other nutritions reach the fetus.

Clinical signs:

The birthweight is greater than 4000g. Fat is stored preferentionally in the abdominal and interscapular region, abdominal and shoulder circumference is increased. Complications durign labor (shoulder dystocia) are common and there is an increased risk of birth injury and asphyxia.

The early postnatal period complications include:

  • transient hypoglycemia
  • transient hypertrophic cardiomyopathy with subaortic stenosis, congestive heart failure
  • polycythemia
  • hyperbilirubinemia
  • respiratory distress syndrome (pulmonary maturity in infants of diabetic mothers is achieved 3 to 4 week later)

Pancreas pathology: hyperplasia of the islet cells. This finding returns to normal within the first few days after birth.

Strict glycemic control during the pregnancy and labor prevents these complications.

Pictures

Large fetus 5900 g, gestational diabetes of the mother: Obrovský plod o hmotnosti 5900 g při gestačním diabetu matky:
Diabetic fetopathy, Macro, autopsy (73970)

3.1.2.2.3  Genetic causes of congenital malformations

Classification:

  1. chromosomal abnormalities including triploidy
  2. single gene disorders
  3. polygenic disorders
3.1.2.2.3.1  Chromosomal abnormalities

Introduction:

Chromosomal abnormalities are present in 10 – 15 % cases of liveborn infants with congenital malformations. The most frequent syndromes are described bellow (the most frequent ones come first):

  • Down syndrome
  • Klinefelter syndrome and its variants
  • Turner syndrome
  • Patau syndrome
  • Edwards syndrome
  • Triploidy
3.1.2.2.3.1.1  Down syndrome

Etiology:

Full trisomy 21 in 95% of the cases

Clinical signs:

  • incidience 1 : 700 livebirths
  • the indicence is directly related to advanced maternal age
  • increased risk of fetal demise
  • mental retardation
  • intrauterine growth retardation, short stature, obesity
  • high relative risk of acute leukemia in the first 5 years of life
  • immunodeficiency, increased risk of bacterial pneumonia in particular
  • there is a shortened life expectancy even if the the survival in individuals with Down syndrome has significantly improved, the estimated life expectancy nowadays is near 60 years
  • congenital heart diseases are major cause of early mortality, 10% of these infants die within the first year of life nowadays

Macroscopic appearance:

  • Phenotypic features in a full term infant: brachycephaly, microcephaly, flattened occiput, flat face, upslanting palpebral fissures, epicanthic folds, small nose with broad and flat nasal bridge, open mouth with protruding tongue, slightly abnormal ears, fifth finger clinodactyly, single palmar crease(simian crease).
  • Mongoloid face and brachycephaly cannot be identified in a fetus. Fifth finger clinodactyly and single palmar creases can be easily recognized even in a second trimester fetus. Nuchal edema can be seen in a small fetus, hydrops is rare.
  • Cardiovascular system malformations: in approximately 40% of the cases:
    • AV septal defect, common atrioventricular canal
    • ventricular septal defect
    • atrial septal defect
  • CNS: the brain has abnormal shape, abnormal gyri in the temporal lobe and decreased weight
  • Thymus: hypoplasia, cystic degeneration of Hassall's corpuscles; these findings are probably related to abnormal immune system
  • Gastrointestinal system malformations:duodenal atresia, umbilical hernia.
  • Ultrasonographic findings in trisomy 21:
    • 1st trimestr ultrasonography:
      • Nuchal translucency is subcutaneous accumulation of fluid behind the fetal neck. It looks like a small black space under the fetal neck skin on ultrasonound examination. All major chromosomal defects (trisomy 21, 13,18, Turner syndrome, triploidy) are associated with increased nuchal translucency thickness. The optimal gestational age for measurement of nuchal translucency (NT) is between 11  —  14 weeks. NT greater than 2,5 mm substantially increases the risk of chromosomal abnormality in the fetus. During the second trimestr the translucency usually disappears, sometimes it evolves into either nuchal edema or nuchal cystic hygroma
      • Absent nasal bone: The fetal nasal bone can be visualized by ultrasonography as early as at 11 – 14 weeks. Absent fetal bone (because of delayed ossification of the bone) is detected in approximately 70% of trisomy 21 fetuses. In chromosomally normal fetuses the prevalence of absent nasal bone is less than 1%.
      • Up to 90 % of fetuses with trisomy 21 can be detected in early gestation if the ultrasonographic and biochemical screening are combined.
    • 2nd trimestr ultrasonography
      • Nonstructural markers of chromosomal abnormality:
        • nuchal edema
        • absent nasal bone or nasal bone hypoplasia
        • short limbs (femus, humerus)
        • mild ventriculomegaly
        • mild pyelectasia
      • structural defects:
        • cardiac defects
        • omphalocele
        • duodenal atresia

Pictures

Down syndrome, 1st trimester of gravidity: absence of nasal bone, nuchal edema:
M. Down, 1st trimester, Ultrasound, video (72952)

Down syndrome, fetus 14-week:
M. Down, Macro, autopsy (73971)

15 – week fetus, trisomy 21; marked nuchal edema:
m. Down, nuchal edema, Macro, autopsy (72967)

Downův syndrom, fetus 22-week:
M. Down, Macro, autopsy (73972)
M. Down, Macro, autopsy (73973)

Down syndrome, fetus:
Down syndrome, Macro, autopsy (72097)
Down syndrome, Macro, autopsy (72098)

Down syndrome, fetus, hand with single palmar crease (simian crease), clinodactyly of the little finger:
m. Down, simian crease, Macro, autopsy (72389)
m. Down, Macro, autopsy (72390)

Down syndrome, AV septal defect (complete AV canal):
AV canal, view from the left ventricle, fetus 18th week of gestation, Macro, autopsy (72501)
AV canal, septum with the defect, Macro, autopsy (72500)
AV canal, view from the right ventricle, fetus 18th week of gestation, Macro, autopsy (72499)

Stillborn 40-week infant, trisomy 21; intrauterine growth retardation (weight 2600 g), external features  —  flat face, small nose, broad flat nasal bridge; severe maceration:
m. Down, intrauterine death, maceration, Macro, autopsy (72963)
m. Down, intrauterine death, maceration, Macro, autopsy (72964)
m. Down, intrauterine death, maceration, Macro, autopsy (72965)

Male newborn, trisomy 21. Hydroureter (extremely dilated left ureter), bilateral renal dysplasia. The child died of pulmonary hypoplasia:
m. Down, hydronephrosis, Macro, autopsy (72962)

M. Down, duodenal atresia:
m. Down, duodenal atresia, Macro, autopsy (74369)
m. Down, duodenal atresia, Macro, autopsy (74370)
m. Down, duodenal atresia, Macro, autopsy (74371)
m. Down, duodenal atresia, Macro, autopsy (74372)
m. Down, duodenal atresia, Macro, autopsy (74373)

Case study:

Morbus Down
Marta Ježová

History:

  • 46 – year-old woman, third gravidity
  • Prenatal ultrasound examination (16 weeks):
    • nuchal edema 5 mm
    • mild hydrops
    • absent nasal bone
    • normal anatomy of the heart
  • Fetal karyotype (QF-PCR): trisomy 21

Note: QF-PCR  —  quantitative fluorescence polymerase chain reaction is a method for rapid detection of the most common chromosomal abnormalities.

Pictures

17 – week female fetus, nuchal edema:
m. Down, nuchal edema, Macro, autopsy (72966)

Prenatal ultrasound, video: nasal bone is missing:
M. Down, 2nd trimester, Ultrasound, video (72953)

Histology:

Thymus may be hypoplasic with lymphocyte depletetion, large cystic Hassals corpusles with calcification seem to be characteristic for Down syndrome.

Pictures

Thymus, macerated fetus with Down syndrome:
m. Down, calcification of the thymus (abortion), HE 40x (71990)  [zoomify]

3.1.2.2.3.1.2  Klinefelter syndrome

Etiology:

  • karyotype 47 XXY and its variants (additional X and Y chromosomes — 48XXXY, 48XXYY, 49XXXXY, 49XXXYY), mosaicism in 20% of the cases.

Clinical signs:

  • incidence 1 : 500 až 1 : 1000
  • the risk correlates with advanced maternal age
  • about 60% of conceptuses with Klinefelter syndrome are spontaneously aborted
  • normal life span
  • male habitus
  • main symptoms:
    • borderline intelligence or obvious mental retardation — the severity of mental retardation is directly related to the increasing number of extranumerary X chromosomes
    • psychiatric disorders, behavioral problems, learning disabilities
    • tall stature
    • eunuchoid body proportions
    • feminine distribution of pubic hair, sparse facial and body hair
    • gynecomastia in late puberty
    • osteoporosis
    • infertility

No symptoms are present during intrauterine developmental period. Diagnosis usually occurs in adulthood due to hypogonadism and infertility. Minor skeletal and cardiac anomalies (mitral valve prolapse) may be present.

Macroscopic appearance:

  • Testicular dysgenesis: testes fail to enlarge during adolescence, azoospermia/oligospermia. Infertility is seen practically in all affected individuals with 47 XXY.
  • External genitalia: hypospadia or cryptorchidism in some cases
  • Clinodactyly

Histology:

Testes: seminiferous tubules are atrophic, hyalinized, germ cells are absent, Leydig cells are hyperplastic

3.1.2.2.3.1.3  Turner syndrome

Etiology:

Karyotype: full monosomy X (45 X), often mosaic (e.g.45X/46XX)

Clinical signs:

  • incidence 1 : 4000 livebirths
  • the incidence is not increased in advanced maternal age
  • up to 99% of 45 X conceptuses are spontaneously aborted
  • female habitus
  • normal intelligence
  • life expectancy is slightly shortened
  • clinical signs in a fetus:
    • prominent edema over the dorsum of the hands and feet
    • nuchal cystic hygroma
    • hydrops fetus universalis with effusions, pulmonary hypoplasia in some cases
  • main symptoms in late childhood and adolescence:
    • short stature
    • primary amenorrhea, sterility

Macroscopic appearance:

Dysmorphic features and phenotype: broad webbed neck, broad chest with increased internipple distance, low hairline, swollen hands and feet in a newborn

Congenital malformations of the internal organs:

  • cardiovascular system:seen in 20% of cases, mainly
    • coarctation of the aorta
    • aortic valvular stenosis
    • hypoplastic left heart syndrome
  • kidneys: horseshoe kidney
  • ovaries: gonadal dysgenesis — the follicles progressively dissappear after 16 weeks of gestation and ovaries of a term infant are completely fibrotic without follicles (streak gonads)

Case study:

Turner syndrome
Marta Ježová

History:

Ultrasound examination in 20 w.g.: hydrops, nuchal hygroma 5 cm, pleural effusion, ascites. The aortic arch not visible, aortic atresia has been suspected.

Karyotype 45X.

Macroscopic appearance:

  • 21-week fetus
  • hydrops fetus universalis
  • nuchal cystic hygroma
  • edema of dorsa of hands and feet
  • tubular hypoplasia of the aortic arch (coarctation)
  • horseshoe kidney

Pictures

Hydrops, edema over dorsum of hands and feet, nuchal cystic hygroma, hydropic face:
Edema of feet, Macro, autopsy (72709)
Edema of hands, Macro, autopsy (72710)
Hydrops, nuchal edema, Macro, autopsy (72711)
Hydrops, nuchal edema, Macro, autopsy (72712)

Coarcation of the aorta (narrowing of the aortic isthmus):
Coarcation of the aorta, Macro, autopsy (72713)

Horseshoe kidney:
Horseshoe kidney, Macro, autopsy (72714)

Coarctation of the aorta, US video:
Coarctation of the aorta, Ultrasound, video (72732)

Hydrothorax, ascites, cystic hygroma (US video):
Hydrothorax, ascites, hygroma colli, Ultrasound, video (72731)

3.1.2.2.3.1.4  Patau syndrome

Etiology:

Full trisomy 13 is found in most cases. Translocation is present in 20% of the cases, mosaicism in less than 10%.

Clinical signs:

  • incidence 1 : 4000 – 1 : 10000 live births
  • the risk of having a child with trisomy 13 is increased with advanced maternal age
  • prenatal wastage is high, up to 95% of trisomy 13 conceptuses are spontaneously aborted
  • median survival is 2,5 days and only 5% of liveborn infants with trisomy 13 survive longer than 6 months
  • longer survival is associated with mosaicism and partial trisomy, these cases also show milder phenotype
  • severe mental retardation
  • intrauterine growth retardation
  • characteristic triad: microphtalmia, cleft lip and palate, polydactyly

Macroscopic appearance:

  • External features: microcephaly, receding forhead, low-set dysmorphic ears, clef lip and/or palate, broad nose, prominent glabella, scalp defects at vertex of head (aplasia cutis), postaxial polydactyly midline facial defects associated with holoprosencephaly
  • Cardiovascular system: various malformations are seen in 80% of the cases including ventricular septal defects, atrial septal defects, dextrocardia, pulmonary stenosis etc.
  • CNS malformations: in approximately 50% of cases; arhinencephaly — holoprosecephaly, corpus callosum agenesis, cerebellar anomalies neural tube defects
  • Ocular malformation:are seen in 90% of the cases: microphtalmy, coloboma, retinal dysplasia, cataracts
  • Deafness
  • Urogenital: micromulticystic kidneys, cryptorchidism is constant in males, penis and scrotum are small, uterus bicornis is commonly seen in females
  • Omphalocele, ectopic pancreas in spleen, Meckels diverticulum
  • Single umbilical artery
3.1.2.2.3.1.5  Edwards syndrome

Etiology:

Full trisomy 18 in 90% of the cases, mosaicism in 5% and translocations in 5%.

Clinical signs:

  • incidence 1 : 7500 live births
  • the risk of having a child with trisomy 18 is increased with advanced maternal age
  • prenatal wastage is high, up to 95% of trisomy 18 conceptuses are spontaneously aborted
  • median survival is 6 days, only 5 — 10% survive beyond the first year of life
  • intrauterine growth retardation, failure to thrive
  • severe mental retardation
  • multiple congenital malformations and characteristic phenotypic features

Macroscopic appearance:

  • External features: dolichocephaly, protuberant occiput, small triangular face, short horizontal palpebral fissures, small mouth, micrognathia, low-set malformed ears, short sternum, narrow pelvis, clenched fists, index finger overlapping the middle and ring fingers, hypoplastic nails, rocker bottom feet
  • Cardiovascular malformations: are seen in more than 90% of the cases
    • polyvalvular dysplasia: atrioventricular and semilunar valves are dysplastic with gelationous or nodular appearance
    • ventricular septal defect
    • bicuspid aortic or pulmonary valve
    • double outlet right ventricle
    • hypoplastic left heart
  • CNS malformations: abnormal gyri, cerebellar anomalies, hydrocephalus, neural tube defects
  • Urogenital malformations: horseshoe kidney, micromulticystic kidneys
  • Skeletal malformaions:radial aplasia
  • Malformations of diaphragm, omphalocele, ectopic pancreas, Meckels diverticulum
  • Single umbilical artery

Pictures

Edwards syndrome, fetus, dysmorphic face:
Syndrome Edwards, Macro, autopsy (72099)

Edwards syndrome, 26 week fetus, typical phenotype:
Syndrome Edwards, Macro, autopsy (72100)
Syndrome Edwards, Macro, autopsy (72101)
Syndrome Edwards, Macro, autopsy (72102)
Syndrome Edwards, Macro, autopsy (72103)

Another case, full term infant, trisomy 18; omphalocele, growth retardation, typical phenotypic features rocker bottom feet, overlapping fingers:
Trisomy 18, Edwards, omphalocele, stigmata, Macro, autopsy (72514)
Trisomy 18, Edwards, face, Macro, autopsy (72515)

Stillborn twin, trisomy 18, growth retardation, unilateral cleft lip, bilateral radial aplasia:
Trisomy 18, Edwards, Macro, autopsy (72516)
Trisomy 18, Edwards, Macro, autopsy (72517)
Trisomy 18, Edwards (aplasia of the radium, club hand), Macro, autopsy (72518)

Fetus, trisomy 18, horseshoe kidney:
Trisomy 18, Edwards, Macro, autopsy (72513)

Edwards syndrome, nuchal edema:
Trisomy 18, Edwards, Macro, autopsy (73045)

Edwards syndrome:
Edwards syndrome, Macro, autopsy (73281)
Edwards syndrome, Macro, autopsy (73282)

Edwards syndrome:
Edwards syndrome, Macro, autopsy (73283)

Edwards syndrome, fenotype of the fetus:
Trisomy 18, Edwards, Macro, autopsy (73976)

Edwards syndrome:
Trisomy 18, Edwards, Macro, autopsy (74375)

Edwards syndrome:
Trisomy 18, Edwards, Macro, autopsy (74376)
Trisomy 18, Edwards, Macro, autopsy (74377)
Trisomy 18, Edwards, Macro, autopsy (74378)
Trisomy 18, Edwards, Macro, autopsy (74379)
Trisomy 18, Edwards, Macro, autopsy (74380)
Trisomy 18, Edwards, Macro, autopsy (74381)

Case study:

Edwards syndrome
Marta Ježová

History:

Neonate 9 days old, trisomy 18. Typical phenotype and growth retardation were found. Congenital heart defect and ivolvement of the diaphragm were revealed during the autopsy.

Pictures

Growth retardation, phenotypic features (microcephaly, small triangular face, microstomia, micrognathia, microphtalmia, skin apendix on the cheek):
Trisomy 18, Edwards, Macro, autopsy (72504)

Dysplastic low set ears, micrognathia:
Trisomy 18, Edwards, Macro, autopsy (72505)

Overlapping fingers: Trisomy 18, Edwards, Macro, autopsy (72506)

Eventration of the left diaphragm:
Trisomy 18, Edwards, Macro, autopsy (72507)
Trisomy 18, Edwards, Macro, autopsy (72508)

Bicuspid dysplastic aortic valve, ventricular septal defect:
Trisomy 18, Edwards, Macro, autopsy (72509)
Trisomy 18, Edwards, Macro, autopsy (72510)

Bicuspid dysplastic pulmonary valve:
Trisomy 18, Edwards, Macro, autopsy (72511)

Dysplastic tricuspid valve, ventricular septal defect in the place of the wire:
Trisomy 18, Edwards, Macro, autopsy (72512)

3.1.2.2.3.1.6  Triploidy

Marta Ježová

Etiology, pathogenesis:

Karyotype is 69 XXY, 69 XXX or 69XYY

3 possible mechanisms:

  • Dispermia: fertilization of haploid egg by two sperms (most common)
  • Diandria: fertilization of haploid egg by diploid sperm
  • Digynia: fertilization of diploid egg by haploid sperm

The extra chromosomal set can either be of a paternal (dispermia, diandria) or maternal (digynia) origin. The development of both the fetus and the placenta is seriously affected. Basically the extra paternal chromosome set leads to an abnormal placental overgrowth  — molar placenta (partial mola hydatidosa) the embryo becomes stunted and is aborted early in the first trimester.

In cases with extra maternal set of chromosomes the placenta is extremely small, nonmolar. The fetus with marked intrauterine growth retardation and congenital malformations is aborted late in second or third trimester.

Clinical signs:

  • Triploidy is one of the most frequent chromosomal aberrations in humans and the most frequent chromosomal abnormality in the first trimester abortions.
  • The risk does not increase with advanced maternal nor parental age
  • Triploidy is lehtal, most affected fetuses are spontaneously aborted or stillbirth
  • Livebirth is extremely rare, death occurs within a few hours after birth
  • Marked intrauterine growth retardation is a cardial feature of triploidy

Macroscopic appearance:

  • External features: macrocephaly, disproportionally large head, hypertelorism, large bulbous nose, low set malformed ears, micrognathia, talipes equinovarus, short and proximally displaced thumbs, syndactyly between the third and fourth fingers, simian crease
  • Cardiovascular malformations: in 20% of the cases namely ventricular septal defect
  • CNS malformations:hydrocephalus, Dandy Walker malformation, rarely holoprosencephaly
  • Adrenal hypoplasia, pulmonary hypoplasia, thymus hypoplasia, malrotation of colon
  • Single umbilical artery
  • Abnormal placenta see above

Prenatal diagnosis:

  • clinical features of triploidy overlap with those of the other chromosomal aberration syndromes trisomy 18 especially
  • marked intrauterine growth retardation and relative macrocephaly might be the only abnormalities detected,serious internal malformations may be absent

Pictures

Stillborn 33-week triploid (69 XXX) macerated fetus, markedly growth retarded, weight 580 g (normal weight should be 1500 g), macrocephaly, low set ears, bulbous nose:
Triploidy, face stigmatisation, Macro, autopsy (72449)
Triploidy, stigmata, Macro, autopsy (72451)

Upper limb, syndactyly of fingers 3 and 4 (the same case):
Triploidy, Macro, autopsy (72450)

Placenta is extremely small for gestational age, nonmolar (weight 58g, normal cca 300g):
Triploidy, small placenta, Macro, autopsy (72452)

Another case of a triploid fetus with growth retardation, macrocephaly, micrognathia:
Triploidy, Macro, autopsy (72984)
Triploidy, Macro, autopsy (72985)
Triploidy, Macro, autopsy (72986)

3.1.2.2.3.2  Single gene disorders

Introduction:

Single gene disorders (mendelian disorders) involve approximately 0.6 – 0.8 % of general population. They are passed from generation to generation according to the Mendel's laws. 90% are inherited in autosomal manner (dominant or recessive), 10% are inherited in X-linked manner.

Classification:

Types of heredity:

  • autosomal dominant heredity:
    • is the most frequent
    • male : female ratio is 50 : 50
    • 50% descendents are affected, 50% are healthy
    • characteristic is variable expresivity a penetration of the pathological gene
    • examples: Marfan's syndrome, tuberous sclerosis, achondroplasia
  • autosomal recessive heredity:
    • clinical symptoms are manifested only in homozygotes
    • 25% descendents are affected, 50% are carriers, 25% are healthy
    • many of the autosomal recessive disorders are enzymopathies — enzyme defects
    • examples: mucoviscidosis, phenylketonuria, Wilson's disease
  • gonosomal heredity:
    • X-linked
    • almost always recessive
    • most of the affected are males
    • examples: Duchenne's muscular dystrophy, hemophilia
3.1.2.2.3.2.1  Tuberous sclerosis

Introduction:

Tuberous sclerosis is an autosomal dominant disorder associated with a spectrum of lesions involving almost every organ in the body. It is characterized by clinical triad of epilepsy, mental retardation and facial angiofibromas.

Etiology:

It is one of neuroectodermal dysplasias with features of both maldevelopement/hamartomatous lesions of skin and nervous system and neoplasia.

  • indicence 1:100 000
  • autosomal dominant inheritance
  • high rate of spontaneous mutations
  • variable expressivity

Clinical signs:

  • mental retardation
  • seizures
  • behavioral disorders including autism
  • various skin lesions
  • Tuberous sclerosis may affect many organs, but certain lesions are not apperent until late childhood or adulthood. The most common cause of death is status epilepticus and bronchopneumonia.
Macro
  • Brain:
    • Cortical tubersare multiple, firm and pale nodules obscuring the junction between the white and grey matter. Microscopically, a tuber consists of irregular neuronal lamination with giant multinucleated cells.
    • Subependymal nodulesare seen along the walls of lateral ventricles, less often along the third and fourth ventricle. They are protuberant and resemble candle gutterings. Nodules in foramen of Monro may cause signs of obstructive hydrocephalus.
    • The subependymal giant cell tumor(or astrocytoma) presumably arise from subependymal nodules. This tumor is unique for its subependymal location, histology (giant cells with abundant pink cytoplasm that are nor clearly neuronal or astrocytic) and clinical association with tuberous sclerosis. It is a grade I. glioma.
    • Neuronal heterotopias
  • Skin:
    • Hypomelanotic maculeis the most common early finding
    • Facial angiofibromaslocated on cheeks, nose and chin
  • Heart:
    • Rhabdomyomasare usually multiple and may be seen in both ventricles and atrias. These benign tumors grow in utero but tend to regress spontaneously after birth. The clinical features include congestive heart failure, cardiac dysrythmias or sudden death.
  • Kidney:
    • Angiomyolipomais a bening renal neoplasm. Patients with tuberous sclerosis present with bilateral and multifocal lesions. Renal failure may complicate massive bilateral disease. Angiomyolipomas are composed of variable combinations of vasculature, smooth muscle and mature adipose tissue. Angiomyolipomas are common in adults with tuberous sclerosis.
    • Renal cysts
  • Lung:
    • Lymphangioleiomyomatosisis a hamartomatous lesions which develops exclusively in females
3.1.2.2.4  Miscellaneous malformation syndromes, sequences and associations, unclassified

Introduction:

Heterogenous group of disorders with complicated classification. In this chapter some examples of rare defects without detailed classification are given.

3.1.2.2.4.1  Sirenomelia (Mermaid syndrome)

Introduction:

A very rare complex congenital malformation syndrome, in which the legs are fused together (the name comes from mythical mermaids — sirens). Always accompanied by urogenital malformations with oligo/anhydramnion.

Etiology, pathogenesis:

  • sporadic occurence, incidence 1 : 60 000 – 100 000
  • patogenesis is unknown, these mechanism are possible:
    • inadequate vascular supply of the caudal end of the embryo
    • a defect in the development of caudal somites
    • effect of compression

Clinical signs:

Sirenomelia is always lethal. Congenital renal malformations with oligo/anhydramnion inevitably lead to pulmonary hypoplasia (Potter's sequence).

Macroscopic appearance:

  • single lower limb (sympus) with various degrees of involvement: from the fusion of the soft tissues of two relatively well developed limbs to an atrophic stub
  • anal and rectal atresia
  • bilateral renal agenesis, or (less frequently) cystic renal dysplasia
  • urinary bladder agenesis
  • sacral and coccygeal agenesis, rudimental pelvis
  • agenesis or malformation of external genitalia
  • internal genital organs — testes undescended in the small pelvis, or even testicular agenesis
  • congenital malformations of other organs are frequent (skeletal, pulmonary, heart, esophageal atresia etc.)
  • single umbilical artery

Case study:

Sirenomelia
Marta Ježová

History:

23-week male fetus, anhydramnion.

Pictures

Single rudimental lower limb, agenesis of the external genitalia, imperforate anus:
Sirenomelia, Macro, autopsy (72534)
Sirenomelia, Macro, autopsy (72535)

Rectal atresia, bladder agenesis:
Sirenomelia, Macro, autopsy (72536)

Bilateral renal agenesis:
Sirenomelia, Macro, autopsy (72538)

Agenesis of the right lung:
Sirenomelia, Macro, autopsy (72537)

3.1.2.2.4.2  Hydrops fetalis

Introduction:

Hydrops fetalis is defined as generalized accumulation of fluid in a fetus. Hydrops is an end-stage process for numerous fetal diseases.

Etiology, pathogenesis:

  1. increased intracapillary hydrostatic pressure
    • congestive heart failure due to severe fetal anemia, structural heart defect, arrythmia
    • obstruction of cardiac venous return
    • portal hypertension due to sinusoidal obstruction of the liver by excessive extramedullary hematopoiesis or storage material
  2. decreased intracapillary oncotic pressure
    • hepatic synthesis of albumin may be imparaired because of hepatic hypoperfusion, increased extramedullary hematopoisis, storage diseases and infectious injury
  3. increased capillary permeability, endotelial damage
    • endotelial damage in various infections
  4. obstructed lymphatic flow

Macroscopic appearance:

  • diffuse subcutaneous edema
  • pleural effusion
  • peritoneal effusion
  • pericardial effusion
  • placental edema

Classification:

  1. immune hydrops
  2. nonimmune hydrops

Clinical signs:

  • Incidence: In the past the most common cause of immune hydrops fetalis was Rh isoimmunization. Since the advent of anti-D globulin prophylaxis the incidence of immune hydrops has decreased significantly. Nowadays most cases of hydrops fetalis are nonimmune in nature. The incidence of nonimmune hydrops in Europe and the United States is approximately 1:2500 – 4000 newborns. Parvovirus B19 infection, fetomaternal transfusion and twin-to-twin transfusion are quite common. The indicence of hydrops fetalis, up to 1:500 pregnancies, is very high in the Southeast Asia as a consequence of homozygous α thalassemia.
  • Prognosis: General mortality of hydrops fetalis is 60 – 90%. Stillbirth is frequent. The cause of death of a hydropic infant is respiratory insuficiency due to pulmonary hypoplasia.
3.1.2.2.4.2.1  Immune hydrops (erythroblastosis fetalis, hemolytic disease of the newborn)

Introduction:

Hemolytic disease of the newborn is caused by specific maternal antibodies directed against red cell antigens of the fetus. These are largely Rh (D) antigens.

Etiology, pathogenesis:

  • Pre-requisite of Rh isoimmunization: Rh- mother and Rh+ fetus.
  • The mother is sensitized to Rh antigen by Rh+ fetal erythrocytes that reach the maternal circulation. The mother is thus stimulated to production of anti-Rh antibodies. Maternal IgG antibodies cross the placenta, attach to the red blood cells and lead to hemolytic anemia in the fetus. Compensatory mechanisms used by the fetus include extensive activation of the hematopoeitic tissue and increased cardiac output. Congestive heart failure and generalized edema are marks of decompensation. The sensitization occurs most often during the first childbirth, so the second and any following pregnancy are at risk of hemolytic disease. The immunization also develops following invasive examination durign pregnancy and abortion but the volume of transplacental bleed is lower than during childbirth. There is a very effective preventive program of Rh-isoimmunization. Intravenous drug abuse in young women has been reported as the most common cause of Rh isoimmunization today.

Rare causes of erythroblastosis fetalis: Isoimmunisation against other antigens of the Rh system (C, E) or antigens Kell, Lewis occurs rarely. The clinical signs are the same as for the original anti-D disease.

ABO incompatibility: Pre-requisite: Mother of group O and infant of group A or B. Hemolytic disease of the newborn in cases of ABO incompatiblity is usually mild. It presents as fetal anemia in the third trimestr of pregnancy and moderate jaundice after delivery. Hydrops fetalis is an exceptional complication.

Clinical signs:

  • Clinical stages of the hemolytic disease of the newborn:
    • anemia neonatorum
    • icterus neonatorum
    • hydrops fetus universalis: the most severe stage of the hemolytic disease; a hydropic fetus is stillborn or dies soon after birth
  • Prevention: Administration of the anti-Rh (D) immunoglobulin to Rh- women with Rh+ newborn within 72 hours of delivery, also to Rh- women following 2nd trimestr abortion, chorionic villi sampling, amniocentesis and cordocentesis

Macroscopic appearance:

  • generalized tissue edema
  • hepatosplenomegaly
  • cardiomegaly
  • the placenta is enlarged, pale and very friable

Pictures

Icterus neonatorum:
Neonatal icterus, Macro, autopsy (73047)

Histology:

Increased extramedullary hematopoiesis. Hepatic sinusoids are crowded by immature nuclated red cells precursors.

Placenta: Villous immaturity, abundance of Hofbauer cells, persistent cytotrophoblastic layer, deacreased vascularity, nucleated red blood cells within the vessels.

Pictures

Fetal erythroblastosis, spleen with extramedullar hemopoiesis, placenta with nucleated erythrocytes:
Fetal erythroblastosis, spleen, HE 100x (72722)
Fetal erythroblastosis, placenta, HE 100x (72739)

3.1.2.2.4.2.2  Nonimmune hydrops

Classification:

The main causes of nonimmune hydrops are enumerated below. However no definite cause of hydrops can be found in about 20% cases of nonimmune hydrops despite extensive investigations (so called idiopathic hydrops).

  1. Hematologic disorders:
    • Homozygous α thalassemia
    • Hemolytic disorders (glucose-6-phosphatase deficiency)
    • Twin to twin tranfusion: chronic fetofetal transfusion of the twins
    • chronic fetomaternal hemorrhage/transfusion where the fetus may bleed into maternal circulation if the fetomaternal circulation becomes disrupted. This is sometimes caused by overt trauma but the exact cause cannot be identified in most cases. This condition can be proved by Kleihauer Betke test which detects fetal erythrocytes (containing the fetal variant of hemoglobin HbF) in maternal blood smear.
  2. Cardiovascular:
    • Some congenital structural heart defects, for example hypoplastic left heart syndrome, Ebstein anomaly, premature closure of the foramen ovale
    • Vascular malformations with AV shunting in fetus or placenta (large chorangioma)
    • Nonstructural anomalies
    • Fetal supraventricular tachycardias  —  relatively common, the prognosis is excellent
    • Congenital AV block  —  this condition is found in pregnancies complicated by maternal systemic lupus erythematosus. The conduction system in the fetal heart is damaged by maternal antinuclear antibodies which cross the placental barrier.
    • Bradycardia associated with complex structural heart defects — asplenia/polysplenia syndromes, AV septal defect etc. The prognosis is very poor.
    • Acardius, see the chapter Acardius
    • Cardiac tumors (rhabdomyoma)
  3. Intrauterine infections:
    • human parvovirus B19 may be the cause of as much as one third of all cases of hydrops fetalis. This highly contagious virus is the etiological agens of the fifth disease (erythema infectiosum) and severe aplastic anemia in patients with congenital hemolytic diseases. The virus directly attacks red cells precursors. The virus is transmitted tranplacentally and causes severe fetal anemia, hydrops or miscarriage. Itranuclear eosinophilic inclusions can be found in the nuclear red cells in fetal tissues. PCR is used to confirm the diagnosis. The virus is not teratogenic.
    • congenital syphilis
    • TORCH infections
  4. Storage disorders: There is a wide range of rare metabolic conditions which have been described with fetal hydrops (Gaucher disease will be mentioned as the only example).
  5. Chromosomal syndromes:
    • Turner syndrome, see the chapter Turner syndrome
    • Trisomies
  6. Abdominal and thoracic tumors and masses:
    • congenital cystic adenomatoid malformation of lungs, see CCAM case study
    • tracheal/laryngeal atresia
    • diaphragmatic hernia
    • polycystic kidneys
    • fetal neoplasms (neuroblastoma)
  7. Genetic syndromes:
    • chondrodysplasias
    • lethal multiple pterygium syndrome
    • tuberous sclerosis
  8. Miscellaneous:
    • congenital nephrotic syndrome
    • GIT atresia and duplication
    • lower urinary tract obstruction

Pictures

28-week liveborn infant, idiopathic hydrops fetalis; The infant died 1 hour after birth of pulmonary hypoplasia:
Hydrops fetus universalis, Macro, autopsy (72539)

Hydrops; congenital hepatoblastoma:
Hydrops fetus universalis, hepatoblastoma, Macro, autopsy (70353)
Hydrops fetus universalis, hepatoblastoma, Macro, autopsy (70354)
Hydrops fetus universalis, hepatoblastoma, Macro, autopsy (70355)
Hepatoblastoma, Macro, autopsy (70462)
Hepatoblastoma, Macro, autopsy (70402)
Hepatoblastoma, Macro, autopsy (70403)

30-week liveborn infant, hydrops fetalis. Complex cardiac defect (AV septal defect, total anomalous return of pulomary veins) complicated by bradycardia in utero. Left-sided isomerism  —  polysplenia.
Fetal hydrops, Macro, autopsy (72781)

1-week stillborn infant, hydrops fetalis. Hypoplastic left heart syndrome in trisomy 13.
Fetal hydrops, trisomy 13, Macro, autopsy (72782)

21-week fetus, hydrops fetalis with prominent ascites. Congenital cystic adenomatoid lung malformation:
Fetal hydrops, Macro, autopsy (72779)

3.1.2.2.4.2.3  Hygroma colli cysticum

Introduction:

Cystic hygroma is a cystic mass localized in the nuchal region. It is a congenital malformation of the lymphatic system. Most fetuses with cystic hygroma have abnormal karyotype.

Etiology, pathogenesis:

  • A communication between the primitive lymphytic system and the jugular vein is formed in the early gestation. Failure of developement of this communication results in lymphatic stasis in distended lymphatic channels.
  • 50% of fetuses with cystic hygroma have Turner syndrome
  • 10 – 15% have trisomy 18, 13, 21
  • Cystic hygroma in normal karyotype is associated with multiple lethal pterygium syndrome, Noonan syndrome etc.

Clinical signs:

  • unilocular or multilocular cystic mass
  • usually localized in the cervical region (75%), additional 20% are found in the axilla and rare cases in the mediastinum, retroperitoneum etc.
  • hygroma colli often progress to hydrops fetalis

Pictures

21-week fetus, hydrops fetalis, nuchal cystic hygroma. Turner syndrome:
Hydrops, nuchal edema, Macro, autopsy (72712)

Hygroma colli with septa from inside, the same case:
Hygroma colli cysticum, detail, Macro, autopsy (72780)

20-week fetus, hydrops fetalis, hygroma colli cysticum. Lethal multiple pterygium syndrome:
Lethal multiple pterygium syndrome, hydrops, Macro, autopsy (72777)
Lethal multiple pterygium syndrome, hydrops, Macro, autopsy (72778)

3.1.2.2.4.3  Pierre-Robin sequence

Introduction:

A group of developmental abnormalities, which include mandibular hypoplasia (recessive chin), glossoptosis and cleft palate.

Etiology, pathogenesis:

As a isolated defect or a part of some syndrome (trisomy 18, Di George syndrome etc.)

The initial event is mandibular hypoplasia, the tongue is therefore pushed back and down, preventing the closure of the palate shelves.

Clinical signs:

  • incidence 1 : 8 500 – 1 : 30 000
  • characteristic trias:
    • marked micrognathia, i.e. small jaw
    • glossoptosis — downward displacement of the tongue
    • cleft palate
  • associated systemic anomalies are frequent, especially congenital skeletal defects
  • clinical signs: airway obstruction, feeding difficulties, recurrent otitis and hearing disorders

Case study:

Pierre Robin Sequence
Marta Ježová

History:

Marked micrognathia, upper limb malformations, 22-week fetus.

Pictures

Marked micrognathia, upper limb malformations:
Robin's sequence, Macro, autopsy (72525)

Detail of the head:
Robin's sequence, autopsy, Macro, autopsy (72526)
Robin's sequence, autopsy, Macro, autopsy (72527)

Ultrasound video of the fetus, prominent micrognathia:
Pierre-Robin sequence, Ultrasound, video (72951)

3.1.2.2.4.4  Caudal regression syndrome (sacral agenesis)

Introduction:

A congenital malformation of caudal axial skeleton.

Etiology, pathogenesis:

  • sporadic incidence
  • strong association with gestational diabetes, the risk increases 250× compared with normal population

Clinical signs:

  • sacral spine agenesis (may extend as far as lower lumbal vertebrae)
  • lower limbs are in abnormal fixed position (Buddha position), short, immovable
  • variable congenital malformations of internal organs (anorectal atresia, congenital renal malformations, genital malformations)
  • caudal regression syndrome is similar to sirenomelia; according to some authors, sirenomelia is an extreme variant of caudal regression, but in new studies these two syndromes are taken separately.
  • prognosis: depends on the severity an type of neurological malformations (caudal end of the spinal cord is not developed)

Pictures

Caudal regression, 23-week fetus:
Caudal regression, Macro, autopsy (72522)

3.1.2.2.4.5  VACTERL association

Introduction:

VACTERL is an acronym for:

  • V  —  Vertebral anomalies
  • A  —  Anal atresia
  • C  —  Cardiovascular anomalies
  • T  —  Tracheoesophageal fistula
  • E  —  Esophageal atresia
  • R  —  Renal anomalies
  • L  —  Limb anomalies

These anomalies occur together more frequent than would be expected by chance alone (see definition of association). VACTERL can be diagnosed when at least 3 organ systems are involved.

Etiology, pathogenesis:

Most cases are sporadic. More frequent in infants of diabetic mothers A common developemental pathogenesis is a defective mesodermal developement (for example a mesodermal septum between the future esophageus and trachea fails to develope). Precise etiology is unknown.

Clinical signs:

  • incidence: is approximately 1  –   2: 10 000 live births
  • lesions:
    • anorectal atresia
    • esophageal atresia, tracheoesophageal fistula (and vice versa, 50% of patients with esophageal atresia present with another VACTERL anomaly)
    • various heart defects
    • enal malformatiosn  —  dysplasia, agenesis etc.
    • skeletal anomalies  —  hemivertebrae, congenital scoliosis, caudal regression, rib anomalies
    • limb malformations  —  radial/preaxial anomalies are specific for VACTERL
    • single umbilical artery is extremely common
    • intrauterine growth retardation
    • associated anomalies except for the cardinal defects which constitute the VACTERL are frequent:
      • hydrocephalus (VACTERL-H )
      • laryngeal atresia
      • tracheal agenesis
      • pulmonary agenesis
      • duodenal atresia etc.
  • Prognosis: prognosis is poor because of multiorgan involvement; Potter sequence is a common consequence of renal anomalies

VACTERL has often similar features to sirenomely.

VACTERL has often similar feauters to another associations which belong to the range of mesodermal dysplasias (CHARGE, TACRD etc.)

Synonyms:

VATER association was described in 1973. The association has been expanded to include cardiovascular anomalies among the cardinal features and this constitute the VACTERL acronym used at present.

Pictures

21-week fetus, VACTERL association; anorectal aresia and rectovesical fistula; hypoplastic urinary blader; single umblicical artery:
VACTERL association, Macro, autopsy (72765)

Rectovesical fistula, detail:
VACTERL association, Macro, autopsy (72766)

Case study:

VACTERL association 1
Marta Ježová

History:

This pregnency was terminated because of a congenital heart defect diagnosed prenataly in the fetus. An autoptic examinaton revealed multiple anomalies associated with the heart defect.

Final diagnosis: VACTERL association.

Macroscopic appearance:

  • 22-week male fetus
  • heart defect: pulmonary atresia with vetricular septal defect, dextroposition of the dilatated aorta; persisting left superior vena cava draining into the coronary sinus.
  • anorectal atresia
  • esophageal atresia, broad tracheoesophageal fistula
  • laryngeal atresia
  • right thumb hypoplasia
  • single umbilical artery; velamentous insertion of the umbilical cord
  • intestinal malrotation

Pictures

Perineum, imperforate anus:
VACTERL association, Macro, autopsy (72760)

Intestinal malrotation, the appendix is seen in the midline, distended rectum proximal to the atresia:
VACTERL association, Macro, autopsy (72761)

Abnormal shape of the heart with right ventricular hypertrophy, right lateral displacement of the aorta:
VACTERL association, Macro, autopsy (72762)

Esophageal atresia, broad tracheoesophagela fistula:
VACTERL association, Macro, autopsy (72763)

Laryngeal atresia (occlusion by cartilage):
VACTERL association, Macro, autopsy (72764)

Case study:

VACTERL association 2 (with hydrocephalus)
Marta Ježová

History:

Ultrasonographic examination in the 2nd trimestr showed multiple congenital malformations including hydrocephalus, abnormal fused vertebrae, ambigous genitalia. Pregnancy was terminated and the VACTERL association was confirmed by fetal autopsy.

Final diagnosis: VACTERL association with hydrocephalus.

Macroscopic appearance:

  • 20-week female fetus
  • macrocephaly, low set ears, short neck
  • limb deformities due to oligohydramnion
  • hydrocephalus internus
  • esophageal atresia; tracheoesophageal fistula
  • multicystic dysplasia of the left kidney and agenesis of the right kidney
  • anorectal atresia; a skin appendage in the anal region
  • congenital scoliosis — hemivertebrae and missing ribs, fusion of vertebrae
  • thumb hypoplasia
  • cardiovascular anomaly: right-sided aortic arch, persisting left vena cava superior
  • single umbilical artery
  • agenesis of external genitalia; agenesis of the vagina and urinary bladder; uterus, fallopian tubes and ovaries were normal

Pictures

Macrocephaly, short neck, libm deformities, skin appendage in the anal region:
VACTERL association, Macro, autopsy (72767)

Thumb hypoplasia (appendix digitiformis without phalangae):
VACTERL association, Macro, autopsy (72768)

Agenesis of external genitalia, absent anus, vaginal and urethral openings:
VACTERL association, Macro, autopsy (72769)

Anorectal atresia, bowel distension proximal to atresia:
VACTERL association, Macro, autopsy (72770)

Scolisosis, hemivertebrae and missing ribs:
VACTERL association, Macro, autopsy (72771)


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