The diagnosis of this syndrome in females is very difficult because the most characteristic features (cryptorchidism and hypospadia) are not present. Brain and brainstem malformations may be present. Arthrogryposis is more prominent in the hands. Smith-Lemli-Opitz syndrome is due to a severe defect in cholesterol biosynthesis. The defective enzyme is 7-dehydrocholesterol reductase. This defect leads to a high level of the cholesterol precursor 7-dehydrocholesterol and low cholesterol levels. The low cholesterol levels lead to abnormalities of mitochondrial function, hormone synthesis, myelinization and bile acid and vitamin D metabolism. Smith-Lemli-Opitz syndrome can be diagnosed prenatally or postnatally by measuring 7-dehydrocholesterol using chromatographic assay. Most patients with Smith-Lemli-Opitz syndrome die during the neonatal period. Survivors are severely mentally retarded. Smith-Lemli-Opitz syndrome is an autosomal recessive condition.

Zellweger Syndrome
Zellweger syndrome or cerebrohepatorenal syndrome is characterized by severe hypotonia, brachycephaly, widely open fontanels and sutures, hepatomegaly, hypospadias and cryptorchidism in males (Figure 160.1), and clitoral hypertrophy in females. Patients with Zellweger syndrome have a prominent forehead, flat occiput, round face, micrognathia, anteverted nares, low-set dysplastic ears, hypertelorism, puffy eyelids, epicanthal folds, glaucoma, cataracts, corneal clouding, and Brushfield spots. Hepatomegaly may not be present at birth but develops during the first month of life. Arthrogryposis primarily involves distal joints. Bone radiograph may reveal calcified stippling of the patella and acetabulum. Magnetic resonance imaging may show: (1) hypomyelination, (2) perisylvian and perirolandic cortical malformation, and (3) germinolytic cysts. Zellweger syndrome is associated with increased serum concentrations of very-long-chain fatty acids in plasma.

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