Smith-Lemli-Opitz syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Synonyms and keywords: SLOS, SLO Syndrome, 7-dehydrocholesterol reductase deficiency, RSH Syndrome, Rutledge Lethal Multiple Congenital Anomaly Syndrome, Polydactyly, Renal Hypoplasia and Unilobar Lung, Lethal Acrodysgenital Syndrome.

Smith-Lemli-Opitz syndrome
7-Dehydrocholesterol
ICD-10	Q87.1
ICD-9	759.89
OMIM	270400
DiseasesDB	12223
eMedicine	ped/2117
MeSH	D019082

Overview

Smith-Lemli-Opitz syndrome is an metabolic and developmental disorder that occurs due to deficiency of 7-dehydrocholesterol reductase. 7-dehydrocholesterol reductase is an enzyme required for the formation of cholesterol from 7-dehydrocholesterol.

Historical Perspective

• In 1964, David Smith, Luc Lemli and John Opitz described a malformation syndrome in 3 patients, who had common facial dysmorphic features, developmental delay, microcephaly and urogenital abnormalities.
• A more descriptive profile of SLOS was reported in 1969, and SLOS was termed as RSH syndrome after the first letters of the names of the original patients. Description of more cases of SLOS expanded its clinical presentation spectrum over the years.
• Few years later, more lethal phenotype of SLO syndrome was discovered and this phenotype was termed as type II SLOS which has significantly increased mortality in infancy. Association of defective cholesterol synthesis with SLO syndrome was described for the first time in 1993.
• On July 24th, 2007 a jury awarded a Florida couple, Daniel and Amara Estrada, whose sons are afflicted with Smith-Lemli-Opitz syndrome, 21 million dollars in damages. The Estradas claimed that Dr. Boris Kousseff failed to diagnose their first son's genetic disorder, leading to them having another son with the disorder.

Classification

• Type 1: less severe, with partial enzyme block
• Type II: Lethal, increased infant mortality, complete enzyme block

Pathophysiology

Genetics

• Smith-Lemli-Opitz syndrome affects an estimated 1 in 20,000 to 40,000 births. Its incidence is equal in both males and females. It is most common in Caucasians of European ancestry, but less common among African and Asian populations. 40 new cases per year is the reported incidence in the United States.

• This disorder is inherited in an autosomal recessive pattern. Missense mutations are the most common mutations accounting for SLOS. The gene involved is DHCR7 and it codes for 7-dehydrocholesterol enzyme. DHCR7 gene has been localized at chromosome 11q23. Mutations in the DHCR7 gene reduce or eliminate the activity of 7-dehydrocholesterol reductase, preventing cells from producing enough cholesterol.

Shown below is an image depicting the autosomal recessive pattern of inheritance of SLOS.

Pathology

DHCR7 enzyme is responsible for the final step in the production of cholesterol. How cholesterol causes dysmorphogenesis, has not been completely established. Cholesterol deficiency is detrimental for fetal development as it is an essential component for normal embryogenesis. Cholesterol is also a structural component of cell membranes and the protective substance covering nerve cells (myelin). Additionally, cholesterol plays an important role in the production of certain hormones and digestive acids. Toxic effects of cholesterol precursors accumulation in blood and other tissues in addition to cholesterol deficiency leads to defective development. As cholesterol plays an important role in neuronal differentiation and synapses formation, its deficiency results in mental retardation and learning disabilities. Additionally, disruption of intracellular pathways involving sonic hedgehog protein is currently a prime theory for defective congenital development.

Causes

A 2006 study of 14 children with Smith-Lemli-Opitz syndrome reported that most children with SLOS have an autism spectrum disorder. SLOS appears to have the most consistent relationship with autism of any single-gene disorder.

Diagnosis

Increased 7-dehydrocholesterol and low cholesterol levels in serum are generally used to diagnose SLOS in addition to presence of family history and clinical symptoms. However there are cases with normal level of biochemical markers, to diagnose these atypical cases, 7-dehydrocholesterol levels of cultured skin fibroblasts can be measured. It is increased in fibroblasts of patients with SLOS.

Physical Examination

Cases of SLOS can vary widely in their clinical presentation. It is characterized by multiple congenital anomalies, but not all features are present in all affected individuals. The most commonly observed features are:

• Dysmorphic facial features including micrognathia, V-shaped upper lip, short nose, microglossia, high arched palate
• Smaller head size (microcephaly)
• Webbed neck
• Widely spaced nipples
• Mental retardation, learning disabilities and behavior problems
• Grwoth restriction
• Syndactyly (most commonly of the second and third toes)
• Polydactyly
• Urogenital abnormalities including hypospadias, ambiguous genitilia
• Cleft palate

Common visceral findings include:

• Congenital heart defects
• Renal hypoplasia
• Malformations of gastrointestinal tracts
• Type II SLOS also presents with Hirschsprung disease, unilobar lung, pancreatic hyperplasia.

Laboratory Findings

Defective 7-dehydrocholesterol reductase leads to decreased cholesterol and increased levels of cholesterol precursors like 7-dehydrocholesterol. Low cholesterol levels result in decreased adrenal functions and decreased bile acid production.

Shown below is the normal pathway of cholesterol synthesis.

Cholesterol

DHCR7

7-Dehydrocholesterol

UVB radiation

Pre-vitamin D3

Other Diagnostic Studies

Severe cases of intrauterine growth restriction without a defined cause and pregnancies with a family history of SLOS should be screened prenatally for this syndrome. A 1995 study done retrospectively demonstrated that increased level of 7- dehydrocholestrol in amniotic fluid during second trimester can be used as a very effective screening test for SLOS. Increased ratio of 7-dehydrocholesterol/ cholesterol in amniotic fluid and chorionic villus samples is highly suggestive of SLOS. Low levels of unconjugated estriol E3 in maternal serum can also be used as a non-invasive screening procedure.

Treatment

Exogenous cholesterol supplementation is currently used to improve clinical symptoms. Increasing cholesterol levels in body helps to restore adrenal insufficiency symptoms and also to increase level of bile acids. HMG-CoA reductase inhibitors (statins) have been suggested for SLOS, however, their definite role in SLOS has not been established. Rationale behind using statins is to decrease the formation of toxic cholesterol precursors.