Smith-Lemli-Opitz Syndrome

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Smith-Lemli-Opitz syndrome (SLOS) is a metabolic disorder characterized by psychomotor and growth retardation, cleft palate, polydactyly, syndactyly, and a distinctive craniofacial appearance. SLOS is an inherited autosomal recessive disorder, which means that those with SLOS have inherited the defective gene from both parents. Couples who have one affected child have a 25% risk of having a child with SLOS in each pregnancy. For those individuals who already have a child with SLOS, prenatal testing is available for subsequent pregnancies.

The first three cases of SLOS were described in 1964 where poor growth, developmental delay, and a common pattern of malformations were seen in three boys. It wasn’t until 1993, however, that scientists discovered that children with SLOS have a metabolic disorder that prevents them from making cholesterol in amounts sufficient for normal growth and development. Studies have shown that children with SLOS typically have cholesterol levels less than 50 mg/dl (normal is greater than 100 mg/dl) and abnormally high levels of a microsomal enzyme called 7DHC-reductase.

It is now estimated that SLOS occurs in 1 out of every 10,000 to 20,000 live births. This rate may be underestimated, however, because the recognition of SLOS in mildly affected patients, where only a few abnormalities are found, can be difficult. In addition, some individuals may have separate malformations that disrupt the diagnostically important facial characteristics. It does appear, however, that there is a higher frequency of SLOS in individuals of northern European ancestry and a lower frequency in people of Asian or African background.

 

Features and Characteristics

The following characteristics have been seen in more than 50% of patients:

• Microcephaly
• Blepharoptosis (drooping of the upper eyelids)
• Cleft palate
• Postnatal growth retardation
• Syndactyly of toes (webbing between toes)
• Mental retardation
• Hypospadias (developmental anomaly involving the urethra)
• Hypotonia
• Inner epicanthal folds
• Low-set ears
• Small, upturned nose
• Small tongue
• Undescended testicles
• Micrognathia (small jaw)
• Broad maxillary alveolar ridges

The following characteristics have been seen in 10% to 50% of patients:

• Cataracts
• Postaxial polydactyly (additional fingers or toes)
• Cardiac defect
• Sexual ambiguity
• Renal cystic dysplasia
• Liver disease
• Adrenal hyperplasia
• Prenatal growth retardation
• Abnormal pulmonary lobation
• Hirschprung’s disease
• Equinovarus deformity (foot deformity with heel turned inward)
• Pyloric stenosis

 

Diagnosis

In addition to clinical findings, SLOS can be diagnosed with a biochemical blood test for the detection of an elevated serum concentration of 7DHC. (Although serum concentration of cholesterol is characteristically low in those with SLOS, it may be in the normal range in about 10% of the cases, making it an unreliable marker for screening and diagnosis.) Since the DHCR7 gene (which is found on chromosome 11q) has been identified as the SLOS gene, DNA analysis for mutations of DHCR7 is also available, however, currently on a research basis only.

Biochemical testing for diagnosis of SLOS should be considered in any child or fetus with polydactyly, 2/3 toe syndactyly, cataracts, cleft palate, ambiguous genitalia, or apparent sex reversal in a 46XY patient.

 

Treatment

With the recognition of the severe deficiency of cholesterol in individuals with SLOS, dietary therapy has been used and has been quite encouraging. Treatment plans have included providing cholesterol either in a natural form (eggs, cream, meat) or in the form of a purified food-grade cholesterol. For children with substantial growth retardation, cholesterol supplements have, in some situations, resulted in a tremendous increase in the rate of growth. In addition, parents have reported that their children are less irritable and have shown improved behavior (this, however, has not been scientifically reported). No harmful side effects of cholesterol supplementation have been documented.

In addition to dietary therapy, there are several treatments available to manage the symptoms associated with SLOS. Feeding problems are common and many children with SLOS are considered failure to thrive. Problems include difficulty sucking and swallowing, persistent vomiting, abnormally small stomach, and pyloric stenosis. For those with these types of gastrointestinal problems, a G-tube may be placed and the child may require a fundoplication if his or her reflux is not manageable. For those with congenital malformations such as cleft palate, congenital heart disease, or genital anomalies, surgery may be necessary.

 

What to Expect

The clinical spectrum for those with SLOS is wide. Some children will have remarkably good intellectual function, with developmental quotients in the moderate to mild mental retardation range. Others will be in the moderate to severe range, although they still can be very interactive children with good receptive language and communication abilities. Children with the lowest levels of cholesterol tend to have the most severe forms of the disorder.

Although some children with SLOS will learn to walk and talk, independent living as adults is unlikely. The life span of an individual with SLOS can be limited by serious internal malformations, however, with good nutrition and medical care, a normal life span is possible.

 

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Resources

If you are interested in meeting other parents and individuals who are involved in raising a child with Smith-Lemli-Opitz syndrome, the following website is available: http://www.med.unc.edu/~hwaage/SLO.html

For more information on Smith-Lemli-Opitz syndrome, please see the following references:

• Kelley, Richard, Smith-Lemli-Opitz Syndrome, Kennedy Krieger Institute http://www.med.jhu.edu/CMSL/SLOS_Web_Text.html#SLOS Summary
• Kurtzman, T.L., Cunniff, C., Smith-Lemli-Optiz Syndrome, 1998, Gene Clinics http://www.geneclinics.org/profiles/slos
• Smith-Lemli-Opitz Syndrome Advocacy and Exchange http://members.aol.com/slo97/index.html