Study of Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital
anomaly/mental retardation syndrome. Typical clinical features include a distinctive facial
appearance, mental retardation, autistic behavior, hypotonia, failure to feed, poor growth,
decreased life span, and variable structural anomalies of the heart, lungs, brain,
gastrointestinal tract, limbs, genitalia and kidneys. The SLOS phenotypic spectrum is broad
and variable. At the severe end of the spectrum SLOS is a lethal disorder with multiple major
congenital anomalies; whereas, mild cases of SLOS present with a combination of minor
physical stigmata, behavioral problems, and learning disabilities. SLOS is due to an inborn
error of cholesterol biosynthesis. Biochemically, SLOS patients have a deficiency of
3beta-hydroxysterol delta(7)-reductase activity. 3beta-hydroxysterol delta(7)-reductase is an
NADPH dependent microsomal enzyme that catalyzes the reduction of the C7(8) double bond of
7-dehydrocholesterol (7-DHC) to yield cholesterol in the last step of cholesterol
biosynthesis via the Kandutsch-Russel pathway. This inborn error of cholesterol biosynthesis
results in elevated tissue and serum 7-DHC levels and typically decreased serum and tissue
cholesterol levels. In 1998 we established that the deficiency in 3beta-hydroxysterol
delta(7)-reductase activity is due to mutation of the 3beta-hydroxysterol delta(7)-reductase
gene (DHCR7). Once the biochemical defect in SLOS was identified, dietary cholesterol
supplementation was proposed and employed as a therapeutic approach. Although developmental
malformations remain fixed, dietary cholesterol supplementation appears to improve the
overall health of these patients, and initial results have shown that dietary cholesterol
supplementation has had a positive impact on some of the behavioral manifestations of this
disorder. Although our understanding of this disorder has advanced over the last few years,
many questions remain concerning the effectiveness of cholesterol replacement therapy, the
long term prognosis for individuals on dietary cholesterol supplementation, and the need for
adjunctive measures in the clinical management of SLOS patients. We propose to answer some of
these questions by continuing our longitudinal natural history/prognosis study on patients
with SLOS. We also plan on studying very closely related disorders such as lathosterolosis
under this protocol. Lathosterolosis is caused by a deficiency in the enzyme sterol
3-beta-hydroxysteroid-delta-5-desaturase which is necessary for the conversion of lathosterol
into 7-DHC. The clinical picture is very similar to SLOS with prominent features including
microcephaly, ptosis bilateral 2,3 toe syndactyly. Lathosterolosis is also inherited in an
autosomal recessive manner. Lethosterolosis is extremely rare with only 4 cases described in
the literature so far and an estimated incidence of less than 1 in a million. The below
objectives, protocol evaluations, risks, benefits and other pertinent issues apply to SLOS
and lathosterolosis even if lathosterolosis is not explicitly named.

- INCLUSION CRITERIA:

- Any patient with biochemically confirmed SLOS will be accepted into this study.
Patients of any age, either gender, or any ethnicity will be accepted into this study.
No exclusions will be made based on race or gender. Historically, more males than
females have been diagnosed as having SLOS. This bias was likely a result of the fact
that genital hypoplasia is readily apparent in a male, and therefore the clinical
diagnosis is easier to make in a male patient. SLOS syndrome appears more commonly in
individuals of Northern European ancestry. Out of 150 biochemically proven cases, only
one was an African American and no patients of Asian descent were reported. One SLOS
mutant allele (R404C) appears to be present in individuals of French Canadian and
Creole heritage. This likely represents a founder effect. One puzzling finding is that
the carrier rate of the most common SLOS mutant allele in Black Canadians from Ontario
and African Americans from Pennsylvania appears to be approximately 0.7%. However,
clinical cases appear to be rare. The predominance of Caucasians reported in the
literature may represent a bias of ascertainment of the disorder, variable
presentation in different ethnic groups, or a founder effect in some ethnic groups.
Because we function as a referral center with respect to recruitment, the ethnic
background of our population is likely going to reflect the overall population of
diagnosed cases.

EXCLUSION CRITERIA:

- Patients will be excluded if they cannot travel to the NIH because of their medical
condition.

- Pregnant women will be excluded, and a negative urine pregnancy test will be required
of menstruating women. This protocol focuses on biosampling. Increasing blood draws
during pregnancy for research is not appropriate. Fetuses will be excluded since the
proposed evaluations are not possible during fetal life.