Chanarin-Dorfman Syndrome

A number sign (#) is used with this entry because Chanarin-Dorfman syndrome, a rare form of nonbullous congenital ichthyosiform erythroderma (NCIE; see 242300), can be caused by homozygous mutation in the CGI58 gene (ABHD5; 604780). Another form of neutral lipid storage disease without ichthyosis but with myopathy (NLSDM; 610717) is caused by mutation in the PNPLA2 gene (609059).

Clinical Features

In a 5-year-old girl, Angelini et al. (1980) identified a syndrome, presumably inherited as an autosomal recessive, characterized by congenital ichthyosis, hepatosplenomegaly, vacuolated granulocytes (Jordans anomaly), and myopathy. Pathologic, ultrastructural and biochemical studies showed nonlysosomal, multisystem triglyceride storage. Cultured fibroblasts showed an increased uptake but decreased oxidation of labeled oleate. The patient failed to produce ketone bodies on fasting. A medium-chain triglyceride diet reversed the hepatosplenomegaly. A partial defect in the catabolism of long-chain fatty acids was postulated. The parents, of Sicilian ancestry, denied consanguinity. Jordans (1953) found fat-containing cytoplasmic vacuoles in the leukocytes of 2 brothers with progressive muscular dystrophy. (No ichthyosis was noted in these patients; they may have had carnitine deficiency, witness the finding of lipid droplets in granulocytes in the case of Markesbery et al. (1974). See 212160.) Rozenszajn et al. (1966) found cytoplasmic vacuoles in 2 sisters with ichthyosis. A follow-up of these sisters (Dorfman et al., 1974) added 2 new cases and pointed out the systemic nature of storage of triglyceride. The elder sister developed, at age 35 years, fatty degeneration of the liver, cataracts, nystagmus, decreased hearing, ataxia, areflexia, and increased cerebrospinal fluid protein. Chanarin et al. (1975) described a 22-year-old woman with congenital ichthyosis, Jordans anomaly, and triglyceride storage in the gastrointestinal epithelium, bone marrow, cultured fibroblasts, and striated muscles.

Hays et al. (1976) and Miranda et al. (1979) reported a man in his forties with congenital ichthyosis and muscle weakness beginning in his thirties. Carnitine-palmitoyltransferase II deficiency (255110) leads to accumulation of triglycerides in muscle. Triglycerides accumulate in lysosomes in Wolman disease (278000). Triglyceride storage disease does not affect the central nervous system before middle age, in contrast to the variants of Wolman disease. The lipid storage myopathies described with carnitine deficiency (212160) and carnitine-palmitoyltransferase deficiency are not associated with striking ichthyosis and hepatosplenomegaly. The cytoplasmic lipid droplets found within many cell types are not membrane-enclosed.

Williams et al. (1985) reported a family with pseudodominance: a consanguineous couple of Middle Eastern origin had affected 46-year-old father and 3 affected children aged 13, 12 and 5. The disorder could be recognized by the presence of lipid vacuoles in nearly all granulocytes and monocytes. Williams et al. (1985) showed, furthermore, that heterozygotes can be identified by the presence of similar vacuoles in circulating eosinophils. In their family, the affected father, a product of a first-cousin marriage, was a college graduate with lifelong ichthyosiform erythroderma, impaired hearing and vision in adulthood, bilateral nuclear cataracts, ptosis, and electromyographic evidence of a mild primary myopathy. He had aortic regurgitation, possibly unrelated to the metabolic defect. All 3 children likewise had cataracts and mild neurologic deficit involving cranial nerves in particular and at least 2 showed psychomotor delay.

Musumeci et al. (1988) described a case in a Sicilian family. Heterozygotes could be detected by the presence of vacuoles in circulating eosinophils. A patient with documented autosomal recessive inheritance had high serum muscle enzymes, but electromyography showed no abnormality. Hepatosplenomegaly had led to the suspicion of storage disease. Other cases have been observed in Sicilian families, and it is possible that the disorder had an Arabic origin, according to a suggestion of Musumeci et al. (1988).

El-Kabbany et al. (2003) described DCS in a 1-year-old Egyptian boy born to first-cousin parents. Generalized ichthyosis and bilateral ectropion were noted at birth. Hepatosplenomegaly was discovered at the age of 9 months. The authors stated that 29 cases of DCS had previously been reported.

Huigen et al. (2015) presented a clinical description of 2 patients with congenital ichthyosis. On suspicion of Sjogren-Larsson syndrome (SLS; 270200), single-voxel 1H-MR spectroscopy of the brain was performed; biochemical testing of fatty aldehyde dehydrogenase (see 609523) to establish this diagnosis yielded normal results. Vacuolization in peripheral blood smears had led to suspicion of Chanarin-Dorfman syndrome. In both patients, that diagnosis was confirmed by ABHD5 mutation analysis. Interestingly, a clear lipid accumulation in cerebral white matter, cortex, and basal ganglia was demonstrated in both patients with CDS. Huigen et al. (2015) concluded that their results demonstrated, for the first time, cerebral involvement in CDS and gave new insights into the complex phenotype.

Mapping

In a genomewide scan of large consanguineous families of different origins, Fischer et al. (2000) identified linkage of a form of autosomal recessive nonbullous congenital ichthyosis in 6 families to a 7.7-cM interval on chromosome 3p21. The disease locus was designated NCIE2. Lefevre et al. (2001) further refined the candidate region on 3p21.

Molecular Genetics

In 9 families from the Mediterranean basin with Chanarin-Dorfman syndrome, Lefevre et al. (2001) identified 8 different haplotypes and homozygous mutations in the ABHD5 gene (604780.0001-604780.0008).