Björnstad syndrome is a rare condition characterized by the combination of sensorineural hearing loss and pili torti (a rare hair type with fragile twisted hair) in individuals with mutations in the BCS1L gene.1-3 This syndrome is most commonly inherited as an autosomal recessive trait.1, 4, 5 The BCS1L gene encodes an AAA family ATPase needed for complex III formation in the mitochondria.3 As of 2017, an estimated 16 pathological variants in BCS1L associated with Björnstad syndrome have been reported.1, 4
In this case report, we describe a 3-year-old girl with sensorineural hearing loss and pili torti who was found to be heterozygous for two different alterations in the BCS1L gene that have not been previously associated with Björnstad syndrome. This report aims to review the clinical and genetic features of Björnstad syndrome and highlight two novel variants in BCSIL that likely cause Björnstad syndrome.
We describe a 3-year-old girl with sensorineural hearing loss and pili torti who is the first child of non-consanguineous parents of Italian, German, and Irish descent. Her mother has two older children from a previous marriage. The girl was born at 40-week gestation by an induced and uncomplicated vaginal delivery. She weighed 7 lbs 7 oz at birth. Her parents reported that she had extremely short hair at birth. Since birth, her hair had grown to only 2-3 cm in length, and she had never needed a haircut. She passed her initial newborn hearing screen and achieved all developmental milestones, but had a significant speech delay.
At 3 years of age, she was diagnosed with moderate to moderately severe sensorineural hearing loss via behavioral audiometry. Soundfield visual reinforcement audiometry was consistent with moderate to moderately severe hearing loss in both ears with her speech awareness thresholds at 25-30 dB hearing level. For conditioned play audiometry using a task in a booster chair with parental encouragement, results were also consistent with symmetric moderate to moderately severe sensorineural hearing loss for 500 – 4,000 Hz stimuli. Otoacoustic emissions revealed absent emissions from 1.5 to 6 kHz frequencies, indicating abnormal cochlear functioning. For additional audiologic data, audiometry results were available at the age of five, revealing continued moderate to moderately severe sensorineural hearing loss. An air conduction audiogram from age 5 is shown in Figure 1. Tympanometry was normal. She was subsequently fitted with hearing aids. She later presented to dermatology and genetics for further evaluation.
Of note, the patient had no prior risk factors for hearing loss, including prematurity, admission to neonatal intensive care, perinatal infections, blood transfusions, or hyperbilirubinemia. Her family history was unremarkable for hearing loss, congenital anomalies, major medical conditions, intellectual disabilities, or known heritable disorders. She has no known relatives with a reported history of similar symptoms.
The patient's physical examination at 3 years of age was notable for thin, short (approximately 2 cm in length), coarse, brittle, red hair, with few interspersed longer hairs (Fig. 2). Her eyebrows were of a similar texture to that of her scalp hair, while her nails were found to be normal. Her external ears were normal in appearance, and the external auditory canals were patent. She was not dysmorphic, and the remainder of her physical examination was normal.
BCS1L sequencing was performed at Baylor Miraca Genetics Laboratories using DNA from peripheral blood. The coding regions of the BCS1L gene (NM_004328.4) were PCR amplified and sequenced using automated sequencing methods per the laboratory's protocol. BCS1L sequence analysis revealed two missense variants in trans, c.518G>A (p.G173D) and c.551G>A (p.R184H), which were confirmed by parental testing. Variant results were analyzed by the laboratory using SIFT and PolyPhen programs. Additional analysis was performed by our institution using MutationTaster and Align GVGD. The G173D (SNP rs375876694) and R184H (SNP rs779504946) variants have been observed at low minor allele frequency in the gnomAD population database.6 G173D was reported at a frequency of 1.083e-5, and p.R184H was reported at a frequency of 8.532e-5.6 Both variants are located in exon 3 of the gene, affecting the BCS1-specific sequencing domain.1 Additional pathogenic variants associated with Björnstad syndrome have been identified in this domain.1,7 In aggregate, in silico predictive algorithms suggest that these variants adversely affect the protein function of BCS1L.
A trichogram was performed with findings consistent with Björnstad syndrome. Of note, hairs were clipped rather than pulled to minimize distortion of the hair shaft. On 10x light microscopy, mild twisting and canal-like areas of the hair shaft were noted (Fig. 3A). With polarized light, a 180-degree twisting of the hair shaft at multiple segments was noted (Fig. 3B). The triad of confirmed pili torti, sensorineural deafness, and compound heterozygous variants in BCS1L is clinically consistent with a diagnosis of Björnstad syndrome in our patient.
Our patient's speech is age-appropriate after one year of speech therapy and hearing aids, which she has been wearing since age 3; she's now 5-and-a-half years old. The patient and her mother reported getting significant benefits from the hearing aids, which she wears nearly all times when awake. Consistent with most other previous reports of Björnstad syndrome, she exhibited no evidence of cognitive impairment.1, 8
The patient was found to have two novel missense variants in the BCS1L gene. These variants are not prevalent in the general population and are located within a domain where other pathologic variants have been identified. The findings highly support that the novel variants in the BCS1L gene likely cause Björnstad syndrome.
Although, to our knowledge, these variants have not been associated with Björnstad syndrome, variants affecting the same and an adjacent amino acid residue as R184H were reported previously.3 R184C in combination with G35R was associated with Björnstad syndrome and mild mitochondrial complex III deficiency in one patient.3 The homozygous variant R183H was reported in a consanguineous family, with multiple family members exhibiting Björnstad syndrome.3 Functional studies found the R184C variant resulted in the loss of function of the BCS1L gene.3
We conducted an Online Mendelian Inheritance in Man (OMIM) review of pili torti and found it to be associated with 19 OMIM entries. Of the 19 OMIM syndromes, our patient's symptoms were only consistent with Björnstad syndrome. Other syndromes associated with BCS1L variants are characterized by more severe phenotypes and associated with comorbidities that were not present in this patient.10
The combination of sensorineural hearing loss and pili torti in Björnstad syndrome is thought to be due to the susceptibility of both the hair and the auditory system to alterations in mitochondrial metabolism, with some evidence indicating that this results in low hair tensile strength.3, 11 Specifically, it is thought that alterations in mitochondrial function due to BCS1L mutations seen in Björnstad syndrome may lead to the accumulation of reactive oxygen species and thereby oxidative stress in the inner ear.3 The exact mechanism that causes sensorineural hearing loss is not certain but it may result in cochlear damage similar to that of aminoglycoside toxicity.3, 12, 13
Understanding the phenotype of individuals with Björnstad syndrome and their prognosis is helpful in counseling individuals with this syndrome and their families. The novel variants described in this report may also be important in facilitating the diagnosis and management of other rare disorders and add to the described BCS1L variants associated with Björnstad syndrome.
Acknowledgments: The authors thank the patient's parents for their permission to publish this work. We thank Alexander Ing for his assistance with the in silico prediction tools.
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