FINAL DIAGNOSIS -- Smith-Lemli-Opitz syndrome (SLOS)
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder cause by mutation in the DHCR7 gene on chromosome 11q14 that encodes for 7-dehydrocholesterol reductase (1). This mutation inhibits appropriate cholesterol biosynthesis in the final step from 7-dehydrocholesterol to cholesterol by 7 dehydrocholesterol reductase. This leads to an elevation in 7-dehydrocholesterol and 8 dehydrocholesterol and subsequently causes anomalies including mental and growth retardation, facial abnormalities and genitourinary and gastrointestinal abnormalities (2). Adequate cholesterol synthesis is also required for testosterone production. The deficiency in SLOS leads to virilization of genitalia secondary to inadequate testosterone production. Biochemically, there is often an inverse relationship between the concentration of cholesterol and 7-dehydrocholesterol due to this mutation.
Many children with this syndrome may experience gastrointestinal difficulties and undergo a nutritional status assessment. Using standard high pressure liquid chromatographic techniques the results often include an aberrantly elevated α-tocopherol (Vitamin E) level. This elevation occurs because 7-dehydrocholesterol and α-tocopherol elute near the same time. Without adequate history or an index of suspicion, this would appear as an extremely elevated α-tocopherol level and raise concerns about supplementation. However, astute laboratory and clinical staff may recognize the coelution. Due to the frequent overlap in results, several groups have developed techniques for more accurately evaluating the α-tocopherol and 7-dehydrocholesterol levels (3, 4). In our laboratory, lengthening the retention time allowed the two substances to elute separately and clarify the results (Figure 3).
Children with SLOS may be diagnosed biochemically: elevated 7-dehydrocholesterol and abnormal testosterone synthesis. More specific testing is available via molecular studies. Currently several commercial reference laboratories perform testing for the DHCR7 mutation (5) and more than 120 mutations have been identified and described in the literature.
Contributed by Matthew A Smith, MD, Octavia Peck-Palmer, PhD and David Finegold MD, PhD.