Bjornstad Syndrome

A number sign (#) is used with this entry because Bjornstad syndrome (BJS) is caused by homozygous or compound heterozygous mutation in the BCS1L gene (603647) on chromosome 2q35.

Description

Bjornstad syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss and pili torti. The hearing loss is congenital and of variable severity. Pili torti (twisted hairs), a condition in which the hair shafts are flattened at irregular intervals and twisted 180 degrees from the normal axis, making the hair very brittle, is usually recognized early in childhood (Selvaag, 2000).

Clinical Features

Bjornstad (1965) first commented on this association. Among 8 cases of pili torti, 5 had nerve deafness. Reed (1966) observed 4 additional cases, and Robinson and Johnston (1967) reported a case. Deafness was evident in the first year of life. The syndrome occurred in sibs among the cases of Bjornstad (1965) and Reed (1966). Crandall et al. (1973) described 3 male sibs with neurosensory deafness, alopecia due to pili torti, and secondary hypogonadism. This may be the same disorder. Indeed, the cases of Crandall et al. (1973) had been observed (and referred to) by Reed (1966).

Van Buggenhout et al. (1998) described severe mental retardation in association with Bjornstad syndrome. This was apparently a unique observation.

Siddiqi et al. (2013) reported a large consanguineous Pakistani family in which 5 individuals had Bjornstad syndrome. The patients had scalp hair at birth that began to fall out around age 2 to 3 months. Eyelashes also fell out. The hair fibers were twisted around their axes and were devoid of any pigment. All patients had light eye color and anhidrosis, although teeth, nails, palms, and soles were normal. Affected males had short stature. Audiometric measurements showed variable degrees of progressive sensorineural hearing loss.

Inheritance

The transmission pattern of Bjornstad syndrome in the family reported by Siddiqi et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

Lubianca Neto et al. (1998) evaluated a large kindred with Bjornstad syndrome in which 8 members inherited pili torti and prelingual sensorineural hearing loss as autosomal recessive traits. They reported that the disease gene maps to chromosome 2q34-q36. A genomewide search using polymorphic loci demonstrated linkage between the disease gene segregating in this kindred and D2S434 (maximum 2-point lod score = 4.98 at theta = 0.0). Haplotype analysis of recombination events located the disease gene in a 3-cM region between D2S1371 and D2S163.

Hinson et al. (2007) performed refined genetic mapping of the Bjornstad syndrome locus on 2q and narrowed the assignment to a 2-Mb region between D2S2210 and D2S2244.

Molecular Genetics

By DNA sequencing of 44 genes within the critical region for Bjornstad syndrome on chromosome 2q, Hinson et al. (2007) identified mutations in the BCS1L gene (e.g., 603647.0008) in affected members of families segregating for the disorder. One of the families had previously been reported by Lubianca Neto et al. (1998).

In 5 affected individuals of a consanguineous Pakistani family with Bjornstad syndrome, Siddiqi et al. (2013) identified a homozygous missense mutation in the BCS1L gene (Y301N; 603647.0013). Functional studies of the variant were not performed.

Pathogenesis

Mutations in the BCS1L gene had previously been found to cause mitochondrial complex III deficiency (124000), manifested by neonatal renal tubulopathy, encephalopathy, and liver failure, and GRACILE syndrome (603358), a severe disorder of intrauterine growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death. To understand how BCS1L mutations cause widely different clinical phenotypes, Hinson et al. (2007) reviewed the locations of defects on the BCS1L protein structure and compared the function of mutant BCS1L in yeast and in human lymphocytes. They found that all BCS1L mutations altered assembly of the mitochondrial respirasome, reduced activity of the electron transport chain, and increased the production of reactive oxygen species. The production of reactive oxygen species correlated with the clinical severity of different BCS1L mutations. The data indicated that in addition to mitochondrial heteroplasmy and variable energy requirements of tissues, tissue-specific sensitivities to reactive oxygen species contribute to the variability of the manifestations of mitochondrial defects. Hinson et al. (2007) noted that mutations that cause the Bjornstad syndrome illustrate the exquisite sensitivity of ear and hair tissues to mitochondrial function, particularly to the production of reactive oxygen species. Models of the effects of aminoglycoside antibiotics and excessive noise on hearing support a critical role for increased levels of reactive oxygen species in ototoxicity. Mitochondrial disease is often manifested by a variety of hair abnormalities (Bodemer et al., 1999).