Heimler Syndrome 1

A number sign (#) is used with this entry because of evidence that Heimler syndrome-1 (HMLR1) is caused by homozygous or compound heterozygous mutations in the PEX1 gene (602136) on chromosome 7q21.

Description

Heimler syndrome-1 (HMLR1), which represents the mildest end of the peroxisomal biogenesis disorder spectrum (see PBD1A, 214100), is a rare autosomal recessive disorder characterized by sensorineural hearing loss, enamel hyoplasia of the secondary dentition, and nail abnormalities (Ratbi et al., 2015).

Genetic Heterogeneity of Heimler Syndrome

Another form of Heimler syndrome (HMLR2; 616617) is caused by mutation in the PEX6 gene (601498) on chromosome 6p21.

Clinical Features

Heimler et al. (1991) described an 11-year-old boy and his 9-year-old sister, born of healthy, unrelated parents. Both children had severe bilateral sensorineural hearing loss which developed in the first or second year of life. Both had normal primary dentition, but the permanent teeth showed generalized enamel hypoplasia. Both children had Beau lines (transverse ridges) of the toenails and the brother had white patches in the fingernails (leukonychia). The sibs had been reported earlier by Fox et al. (1989).

Tischkowitz et al. (1999) reported a 12-year-old girl who presented at age 7 years with unilateral sensorineural hearing loss. In addition, she had hypomineralized amelogenesis imperfecta of the permanent dentition only, and Beau lines, but no leukonychia. Tischkowitz et al. (1999) pointed out that although the amelogenesis imperfecta in the original report by Heimler et al. (1991) was said to be hypoplastic in nature, this diagnosis had been made on the basis of clinical and radiographic appearances rather than on histopathologic examination of teeth, which was available in the later case.

Pollak et al. (2003) reported a pair of sibs with Heimler syndrome who had sensorineural hearing loss diagnosed after the first year of life and enamel hypoplasia with normal primary dentition. Nail findings of Beau lines and leukonychia, which were described in previously reported cases, were absent to questionable. The parents were unaffected and nonconsanguineous.

Inheritance

Heimler et al. (1991) and Pollak et al. (2003) suggested autosomal recessive inheritance of this disorder.

Molecular Genetics

Ratbi et al. (2015) performed whole-exome sequencing in 8 families with Heimler syndrome and identified biallelic mutations in the PEX1 gene in 4 of the families, including the family reported by Heimler et al. (1991) (602136.0004 and 602136.0006-602136.0009). In 2 families (see HMLR2, 616617), they identified mutations in the PEX6 gene (601498.0010-601498.0013). No mutations in any of the known PEX genes were identified in the 2 remaining families, 1 of which was the family previously studied by Tischkowitz et al. (1999). Ratbi et al. (2015) noted phenotypic differences between the affected individuals from these 2 families and those in whom PEX mutations were identified, including less severe hearing loss and minimal to no nail defects. Additionally, no fundus abnormalities were observed in the latter 2 families, whereas 3 patients with PEX1 mutations, including the 2 sibs previously reported by Heimler et al. (1991), exhibited retinal pigmentation abnormalities; the sibs reported by Heimler et al. (1991) also showed macular dystrophy. All 4 patients with PEX1 mutations had retinal pigmentation abnormalities.