Fetopathology and developmental pathology of the embryo and fetus: Smith-Lemli-Opitz syndrome (SLOS)

+ Introduction

+ Support

+ Atlas of fetal pathology

+ Congenital malformations of individual organ systems

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

SLOS, obličej (72458)

SLOS, zevní genitál (72459)

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

SLOS, face (73067)

Hexadactyly (73068)

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)