Desmosterolosis

A number sign (#) is used with this entry because desmosterolosis is caused by homozygous or compound heterozygous mutation in the DHCR24 gene (606418) on chromosome 1p32.

Description

Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells (summary by Waterham et al., 2001).

Clinical Features

FitzPatrick et al. (1998) reported the case of an infant with multiple lethal congenital malformations and osteosclerosis in whom there was generalized accumulation of an abnormal neutral sterol and a relative deficiency of cholesterol. The sterol was identified by gas chromatography-mass spectrometry (GC-MS) as desmosterol, a biosynthetic precursor of cholesterol. The infant had macrocephaly, hypoplastic nasal bridge, thick alveolar ridges, gingival nodules, cleft palate, total anomalous pulmonary venous drainage, ambiguous genitalia, short limbs, and generalized osteosclerosis. FitzPatrick et al. (1998) compared the phenotype to that of Smith-Lemli-Opitz syndrome (270400), which is a defect in the synthesis of cholesterol, and Raine syndrome (259775), which is characterized by generalized osteosclerosis, nasal hypoplasia, and gingival nodules. The abnormal accumulations of desmosterol occurred in the kidney, liver, and brain. Higher than normal levels of the same sterol were detected in plasma samples obtained from both parents. The biochemical phenotype was highly suggestive of a novel inborn error of cholesterol biosynthesis caused by an autosomal recessive deficiency of 3-beta-hydroxysterol-delta-24-reductase. Because of the phenotypic overlap with Raine syndrome, postmortem tissue samples from the patient with Raine syndrome described by Kan and Kozlowski (1992) were analyzed; however, desmosterol accumulation was not found in the tissues of that case, suggesting that it represented a distinct disorder. FitzPatrick et al. (1998) stated that there are 2 general mechanisms by which aberrant cholesterol synthesis may cause malformations: a relative deficiency of cholesterol and a relative excess of sterol precursor. These are not mutually exclusive. Furthermore, the hedgehog family of proteins, mutations in which have been identified in malformations (e.g., SHH; 600725), have been shown to undergo posttranslational modification by covalent attachment of a cholesterol molecule to the biologically active N-terminal fragment of these peptides (Porter et al., 1996).

Zolotushko et al. (2011) reported a consanguineous Bedouin kindred in which 6 individuals had desmosterolosis confirmed by genetic analysis. Four living individuals were examined. All had a severe neurologic phenotype with psychomotor retardation, microcephaly, spasticity, severe convulsions, nystagmus, and strabismus. Brain MRI showed ventriculomegaly, decreased white matter, and partial or complete agenesis of the corpus callosum. Other features included failure to thrive, microretrognathia, and contractures of the hands. Dysmorphic facial features were not observed. Biochemical studies of 2 affected boys showed significantly increased desmosterol levels compared to controls. Desmosterol accounted for 3.4% and 10%, respectively, of the total sterols compared to less than 0.04% in controls. Their unaffected fathers had increased levels compared to controls (0.1%), but not as high as their affected sons.

Schaaf et al. (2011) reported a female infant with desmosterolosis confirmed by genetic analysis (606418.0005 and 606418.0006). The patient was born prematurely at 34 weeks' gestation and showed macrocephaly, hydrocephalus, hypoplasia of the corpus callosum, and generalized arthrogryposis. Dysmorphic features included prominent forehead, telecanthus, short nose with anteverted nares, retrognathia, and low-set ears. She also had rhizomesomelia, fifth finger clinodactyly, mild cutaneous 2-4 toe syndactyly, and proximal placement of the big toes. She had developmental delay associated with enlarged and abnormal ventricles and an effaced gyral pattern, and radiographs showed eventration of the right anterior medial diaphragm.

Molecular Genetics

In 2 patients with desmosterolosis described by FitzPatrick et al. (1998) and Andersson et al. (2000, 2002), Waterham et al. (2001) identified mutations in the DHCR24 gene (606418.0001-606418.0003).

Andersson et al. (2000, 2002) described a boy with desmosterolosis who was born at term with microcephaly, agenesis of the corpus callosum, downslanting palpebral fissures, bilateral epicanthal folds, submucous cleft palate, micrognathia, mild contractures of the hands, bilateral clubfeet, cutis aplasia, and persistent patent ductus arteriosus. At 40 months of age, he was severely developmentally delayed but was learning to walk, used 5 words, and followed simple commands. Height and weight were less than the 2nd centile. Radiologic examination disclosed neither rhizomelic shortness nor osteosclerosis. Plasma sterol quantification when the patient was 2 years old demonstrated a normal cholesterol level but a 100-fold increase in desmosterol. Both parents had mildly increased levels of desmosterol in plasma, consistent with heterozygosity for DHCR24 deficiency. Analysis of sterol metabolism in cultured transformed lymphoblasts showed a 100-fold increased level of desmosterol and a moderately decreased level of cholesterol in the patient's cells and a 10-fold elevation of desmosterol in the mother's cells. DNA analysis of the patient and his parents identified a homozygous and heterozygous mutation, respectively, in the DHCR24 gene that when expressed in yeast had a residual activity of 20%.

By genomewide linkage analysis followed by candidate gene sequencing of a consanguineous Bedouin family with desmosterolosis, Zolotushko et al. (2011) identified a homozygous mutation in the DHCR24 gene (R103C; 606418.0004).