Smith-Lemli-Opitz syndrome


Smith-Lemli-Opitz syndrome (SLOS) is a rare autosomal recessive disorder of cholesterol synthesis caused by mutations in 3β-hydroxysterol Δ7-reductase (DHCR7) gene. The estimated incidence of SLOS is between 1 in 20,000 to 1 in 40,000 live births, but may be higher.


Last updated September 2018 by Germaine Pierre, Paediatric Metabolic Consultant, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

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What are the symptoms?

The presentation of individuals with SLOS is broad ranging from a less severe disorder with behavioural and learning difficulties to a lethal syndrome with miscarriage, stillbirth or death in the first weeks of life. Individuals often have typical facial features, including microcephaly, a small upturned nose, droopy upper eyelids and micrognathia (undersized jaw). Other abnormalities may include:

  • cleft palate (see entry Cleft Lip and/or Palate)
  • abnormalities of the fingers and toes, including polydactyly (an additional digit) and syndactyly of the second and third toes. (where two or more digits are fused together)
  • abnormalities in development of the heart, kidneys, liver and lungs
  • underdevelopment of external genitalia occurs in males.

In surviving infants, slow growth and poor weight gain is usual and feeding via a gastrostomy (a tube into the stomach) may be required. As the infant gets older, severe learning difficulties (see entry Learning Disability) usually become evident. In addition, individuals with SLOS tend to display hyperactivity, sleep disturbance, autistic-type behaviour (see entry Autism Spectrum conditions) and have a tendency to self-injure. Individuals are very rarely able to live independently.

What are the causes?

Mutations in the DHCR7 gene result in abnormal sterol metabolism. The DHCR7 gene codes for the DHCR7 enzyme which drives the conversion of 7-dehydrocholesterol to cholesterol. Reduction in the activity of the DHCR7 enzyme leads to increased 7-dehydrocholesterol levels and reduced cholesterol levels leading to the problems seen in SLOS.

How is it diagnosed?

SLOS is usually first suspected clinically from characteristic features.  High levels of 7-dehydrocholesterol in blood or other tissues confirms the diagnosis. This finding is usually specific to SLOS, though borderline cases can be confirmed by genetic studies looking for mutations in the DHCR7 gene. A normal cholesterol level does not exclude SLOS.

How is it treated?

There is no treatment for SLOS. Dietary cholesterol does not cross into the brain to correct neurodevelopmental deficits though in some individuals, supplementation has been reported to improve growth and behaviour.

In less affected cases, simvastatin has been used as it crosses into the brain and lowers 7-deyhydrocholesterol levels but study findings have not shown consistent benefit. Antioxidant supplements may be helpful.

Good supportive care remains the mainstay of management. Input is often needed for nutritional management, treatment of sleep disturbances or seizures and management of skin sensitivities and behaviour. Surgical intervention may be needed for placement of a feeding tube or correction of malformations.

Future treatment options

Gene therapy: Using mouse models for SLOS, functional copies of the DHCR7 gene have been delivered into the brain with an adeno-associated viral vector and shown to partially restore sterol levels. Further work is needed to show functional correction before translation to humans.

Substrate reduction: SLOS has been shown to secondarily affect the transport of cholesterol within the cell similar to what is seen in another disorder, Niemann Pick C disease type 1 (NPC1). In NPC1, there is a build-up of glycosphingolipids which are harmful. SLOS cells also show a build-up of glycosphingolipid which increases with disease severity. Miglustat, a substrate reducer can cross into the brain and reduces glycosphingolipid accumulation in NPC1 and also in SLOS cells. It may be a useful adjunctive therapy for SLOS in the future.

Inheritance patterns and prenatal diagnosis

Inheritance patterns
SLOS is inherited in an autosomal recessive manner which means 2 copies of the abnormal gene must be present for SLOS to develop.

Prenatal diagnosis
Prenatal testing is available through measurement of 7-dehydrocholesterol levels in tissue obtained from the pregnancy by chorionic villus sampling or by amniocentesis. Molecular genetic (DNA) tests are available if the specific gene mutations that caused the disease in an affected individual can be identified. Carriers may be identified by this method. In theory, preimplantation genetic diagnosis may be possible for some families.

Is there support?

Information and support in the UK for Smith-Lemli-Opitz syndrome is provided by Metabolic Support UK (previously CLIMB). See entry Inherited Metabolic diseases.

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