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Smith-Lemli-Opitz syndrome

Background

Smith-Lemli-Opitz syndrome (SLOS) is a rare congenital syndrome caused by deficiency of an enzyme called 7-dehydrocholesterol reductase (DHCR7). The estimated incidence of SLOS is between 1 in 20,000 to 1 in 40,000 live births, but may be higher.

Credits

Last updated August 2016 by Germaine Pierre, Paediatric Metabolic Consultant, University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

Although great care has been taken in the compilation and preparation of all entries to ensure accuracy, we cannot accept responsibility for any errors or omissions. Any medical information is provided is for education/information purposes and is not designed to replace medical advice by a qualified medical professional.

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 (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 disorders, including Asperger syndrome) and have a tendency to self-injure. Individuals are very rarely able to live independently.

What are the causes?

The enzyme DHCR7 is important in cholesterol synthesis and drives the conversion of the chemical called 7-dehydrocholesterol to cholesterol. Mutations in the DHCR7 gene reduces the activity of the DHCR7 enzyme leading to both increased 7-dehydrocholesterol levels and reduced cholesterol levels - these two factors contribute to the problems seen in SLOS.

How is it diagnosed?

SLOS is usually first suspected clinically from characteristic features including developmental delay, microcephaly, typical facial features, and syndactyly of the second and third toes. The diagnosis is confirmed by finding higher levels of 7-dehydrocholesterol in blood or other tissues. 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?

In some individuals, cholesterol supplementation results in improved growth and behaviour but with less clear benefit on development. 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.

Research into the potential for gene therapy is ongoing.

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?

Talk to other families about your child's condition

Visit our online Smith-Lemli-Opitz syndrome group

Visit our online advice and support or read all about diagnosis.


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