Alternative titles; symbols
ORPHA: 3220; DO: 0080624;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.1 | Heimler syndrome 2 | 616617 | Autosomal recessive | 3 | PEX6 | 601498 |
A number sign (#) is used with this entry because of evidence that Heimler syndrome-2 (HMLR2) is caused by homozygous or compound heterozygous mutation in the PEX6 gene (601498) on chromosome 6p21.
Heimler syndrome, 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 hypoplasia of the secondary dentition, and nail abnormalities (Ratbi et al., 2015).
For a discussion of genetic heterogeneity of Heimler syndrome, see HMLR1 (234580).
Ong et al. (2006) reported monozygotic twin girls who both had mild clubfeet at birth that responded to orthotics. At 3 years of age, the twins underwent audiography due to concerns about indistinct speech and poor vocabulary, which revealed moderate to severe bilateral sensorineural hearing loss. Primary teeth erupted normally; however, at age 10 years, abnormalities in their secondary dentition became evident, with the enamel on all 4 first permanent molars appearing pitted, grooved, and deficient in quantity. Dental radiography showed the presence of all permanent teeth, with hypoplasia or hypocalcification of the lower canines, premolars, and molars, as well as the unerupted upper second and third molars. Maxillary molars exhibited taurodontism (abnormally enlarged pulp chambers). In addition, there was marked dental overcrowding. Examination showed transverse ridges (Beau lines) on some of the toenails and leukonychia of the fingernails of both girls. Thumbs were slightly broad, and both girls exhibited pes planus. Intellectual development was normal.
Zaki et al. (2016) described 2 Egyptian sibs, aged 20 and 9 years, with moderate/severe hearing loss, which was initially identified as mild hearing loss in the first year of life. The sibs had nystagmus at age 2 years and developed retinitis pigmentosa. They had psychomotor delay with decline in learning ability during primary school. Both had microcephaly. Brain MRI in the older sib showed a left-sided temporoparietal porencephalic cyst, a thin corpus callosum, and mild deep white matter changes; brain MRI in the younger sib showed a thin corpus callosum and deep white matter changes. Both sibs had elevated liver enzymes and hepatomegaly, and plasma phytanic acid was in the upper normal range in the older sib and elevated in the younger sib. Both sibs had yellowish incisors, dense bone trabeculae in the anterior segment of the mandible, and taurodontism of some molars. The older sib also had amelogenesis imperfecta of permanent teeth.
The transmission pattern of HMLR2 in the families studied by Ratbi et al. (2015), including the sisters reported by Ong et al. (2006), was consistent with autosomal recessive inheritance.
In 2 sisters from the UK with Heimler syndrome, Ratbi et al. (2015) performed whole-exome sequencing and identified compound heterozygosity for missense mutations in the PEX6 gene, P274L (601498.0010) and R644W (601498.0011). Sanger sequencing of the PEX1 (602136) and PEX6 genes in the monozygotic twin girls with Heimler syndrome who were originally reported by Ong et al. (2006) revealed compound heterozygosity for a frameshift (601498.0012) and a missense mutation (R601Q; 601498.0013) in the PEX6 gene. Ratbi et al. (2015) noted that, in contrast to patients with peroxisomal biogenesis disorders of the Zellweger type that are also caused by mutation in PEX6 (see PBD4A, 614862), none of the patients with PEX6-associated Heimler syndrome exhibited dysmorphism or additional neurologic features.
In 2 sibs, born of consanguineous Egyptian parents, with HMLR2, Zaki et al. (2016) identified a homozygous missense mutation (G413V; 601498.0016) in the PEX6 gene. The mutation, which was identified by genomewide linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing. The parents were heterozygous for the mutation.
Ong, K. R., Visram, S., McKaig, S., Brueton, L. A. Sensorineural deafness, enamel abnormalities and nail abnormalities: a case report of Heimler syndrome in identical twin girls. Europ. J. Med. Genet. 49: 187-193, 2006. [PubMed: 16530715] [Full Text: https://doi.org/10.1016/j.ejmg.2005.07.003]
Ratbi, I., Falkenberg, K. D., Sommen, M., Al-Sheqaih, N., Guaoua, S., Vandeweyer, G., Urquhart, J. E., Chandler, K. E., Williams, S. G., Roberts, N. A., El Alloussi, M., Black, G. C., and 19 others. Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6. Am. J. Hum. Genet. 97: 535-545, 2015. [PubMed: 26387595] [Full Text: https://doi.org/10.1016/j.ajhg.2015.08.011]
Zaki, M. S., Heller, R., Thoenes, M., Nurnberg, G., Stern-Schneider, G., Nurnberg, P., Karnati, S., Swan, D., Fateen, E., Nagel-Wolfrum, K., Mostafa, M. I., Thiele, H., Wolfrum, U., Baumgart-Vogt, E., Bolz, H. J. PEX6 is expressed in photoreceptor cilia and mutated in deafblindness with enamel dysplasia and microcephaly. Hum. Mutat. 37: 170-174, 2016. [PubMed: 26593283] [Full Text: https://doi.org/10.1002/humu.22934]