Smith-Lemli-Opitz syndrome

Synonyms: SLO syndrome (SLOS), RSH syndrome and Rutledge lethal multiple congenital anomaly syndrome

The syndrome was first described by Smith, Lemli and Opitz in 1964.¹ The name 'RSH syndrome' is derived from the initials of the first 3 patients to be described.

Pathogenesis

It is an inherited autosomal recessive disorder caused by mutations in the sterol delta-7-reductase gene. DHCR7 is the only gene in which mutation is known to cause Smith-Lemli-Opitz syndrome (SLOS) and sequence analysis detects approximately 96% of known mutations.² It is the final enzyme in the sterol synthetic pathway that converts 7-dehydrocholesterol (7DHC) to cholesterol.

The syndrome constitutes a spectrum of disease from mild to severe. This has been called a classical 'type I' disorder (mild) and a more severe 'type II disorder in the past. The deficiency of DHCR7 produces low plasma cholesterol and reduced myelination in the cerebral hemispheres, cranial nerves and peripheral nerves.

It occurs in approximately 1 in 20,000 to 30,000 births in populations of northern and central European background.³

In a UK study of 49 cases, 35 (71%) were male.⁴ At the time of study, 24 were alive, 20 had died (including one stillbirth) and five pregnancies had been terminated.

There is a wide clinical spectrum and some individuals have been described with normal development and only minor malformations:²

• Hypospadias is frequently found and helps in the recognition of male cases. Ambiguous external genitalia are also found and, in extreme instances, there is complete failure of development of male external genitalia despite normal XY karyotype.

• Growth restriction is characteristic, both in utero and after delivery. Vomiting, feeding difficulties, constipation, toxic megacolon, electrolyte disturbances and failure to thrive are common. In some cases they are related to gastrointestinal anomalies.

• Moderate-to-severe intellectual disability is also usually seen.

• The malformations include distinctive facial features, cleft palate, cardiac defects, postaxial polydactyly and 2-3 syndactyly of the toes.

• Visual loss may occur due to cataracts, optic nerve abnormalities, or other ophthalmic problems.

• Hearing loss is fairly common.

• Microcephaly is often found.

Most studies show that low cholesterol levels are found in the most severe cases.

There are also characteristic behavioural patterns:⁵

• Cognitive delay.

• Sensory hyper-reactivity.

• Irritability.

• Language impairment.

• Sleep-cycle disturbance.

• Self-injury.

• Syndrome-specific motor movements.

• Autistic spectrum disorders.

• Ambiguous genitalia and intersexuality.

• Congenital adrenal hyperplasia.

• Edwards' syndrome (trisomy 18).

• Antenatal ultrasound may show intrauterine growth restriction and possibly other features.⁶

• Plasma total cholesterol and/or low-density lipoprotein (LDL) cholesterol levels may be low but can be normal in 10%.

• Gene testing.

• Electrolytes (and possibly cortisol and adrenocorticotropic hormone (ACTH)) may be useful in excluding adrenal insufficiency.

• Brain MRI or CT scanning may show structural brain malformations.

• Chest radiography is important in looking for congenital heart disease and/or congenital pulmonary abnormalities.

• Genitourinary ultrasonography may be important in identifying genitourinary anomalies.

Patients are often severely photosensitive and should therefore limit their exposure to the sun. Hearing aids are beneficial.⁷

Dietary

Although cholesterol supplementation leads to increased plasma cholesterol levels and variable decreases in 7DHC, well-controlled clinical trials of cholesterol supplementation showing clear clinical benefit have not yet been published. Recently, short-term cholesterol supplementation in a placebo-controlled clinical trial did not improve behaviour.⁸

Surgical

Congenital heart disease and polydactyly may require surgery. Feeding via gastrostomy tube may be helpful.

Survival is less likely where the plasma cholesterol level is very low.

• Spontaneous abortion of affected fetuses is not unusual. Stillbirths have also been reported.

• Death from multi-organ system failure during the first weeks of life is typical in the severe form.

• Cause of death can include pneumonia, lethal congenital heart defect or hepatic failure.

Measurements of amniotic fluid or chorionic villous 7DHC content can be taken. Enzyme activity can also be measured in chorionic villi.⁷

If a proband in the family has had previously identified DHCR7 gene mutation, mutation analysis could also be considered.