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A syndrome characterized by the inability to make
cholesterol. Affects the central nervous system (CNS) (white matter) and characterized
by growth retardation, developmental delay, severe dysphagia,
microcephaly, micrognathia, cleft palate, cataracts, ptosis, polysyndactyly
and syndactyly of the second and third toes, and congenital heart defects
(transposition of the great vessels is frequent). Congestive heart failure
and liver failure are not uncommon.
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RSH Syndrome; SLOS I Syndrome; 7-Dehydrocholesterol
Reductase Deficiency.
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1:20,000 to 1:60,000 live births in the United States
among white people. Smith-Lemli-Opitz syndrome is uncommon in Hispanic
population. Carrier frequency for Smith-Lemli-Opitz syndrome is
approximately 1 in 30 in individuals of northern European descent, suggesting a
disease incidence between 1:5000 and 1:18,000 in Europe. Internationally,
Smith-Lemli-Opitz syndrome has been described in patients from the United
States, Japan, South America, and Canada.
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Results from a mutation in either the DHCR7
(7-dehydrocholesterol-delta7-reductase) gene on chromosome 11 or the SLOS
gene on chromosome 7. Autosomal recessive inheritance.
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The classic paradigm is an inborn error of
metabolism, which includes the accumulation of a toxic precursor (7DHC) leading to the
deficiency in production of an essential product (cholesterol). The
absence in cholesterol can be implicated in the production of all the anomalies
described. Cholesterol is required for normal development because of its involvement in
cell and mitochondrial membranes, as well as steroid metabolism and
myelination.
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As a result of the defect in cholesterol metabolism,
serum cholesterol levels are very low and levels of 7-dehydrocholesterol (a
cholesterol precursor) are high in serum as well as any other tissue
specimens. This biochemical finding associated with the clinical
findings confirms the diagnosis of Smith-Lemli-Opitz syndrome. The
mortality/morbidity is associated with stillbirths, or spontaneous abortion,
or immediately after birth from multiorgan failure (during the first week of
life). Causes of death include pneumonia, lethal congenital heart defect
(most often transposition of the great vessels), congestive heart failure
(not uncommon), and hepatic failure.
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Prognosis is poor. Neuromuscular: initially hypotonia followed
later by hypertonia; mental deficiency can be severe (IQ as low as 20);
seizures and generalized nerve demyelination. Cardiovascular: malformations may be
present in up to 44% of cases. The incidence of atrioventricular canal defects and
anomalous pulmonary venous drainage is relatively high. Craniofacial: microcephaly,
strabismus, epicanthic folds, elfin facies, ptosis, low-set ears, and
micrognathia may be present. Genital tract: Developmental anomalies of the genital tract
(particularly male) are common. Gastrointestinal/Nutrition: feeding difficulties and
failure to thrive; Hirschsprung Disease may be more common.
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Cardiac evaluation: echocardiogram
to rule out congenital heart disease. Neurological assessment to evaluate
degree of disability. Careful airway evaluation in view of micrognathia. The
presence of frequent vomiting, feeding difficulties, electrolyte
disturbances, and failure to thrive requires complete assessment.
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The presence of muscular hypertonia raises the
concern of malignant hyperthermia. Generalized muscle rigidity and hyperthermia have been
reported following the use of halothane with and without succinylcholine. However, these
episodes ...