The Genetics Of Deafness
by Beth A. Pletcher, MD, November 1999

It may be hard to believe, but almost 7% of the population of the United States is deaf or hearing impaired. This amounts to about 20 million people across the country. You might say that this makes sense when one considers the ever increasing population of senior citizens, but you may be surprised to learn that 50% of severe to profound hearing impairment is genetically determined.

There are an estimated 4 to 6 genes associated with isolated autosomal recessive deafness of the sensorineural type. These account for about half of the genetically determined cases of congenital deafness and are present in about 1/4000 newborns. Therefore, in a busy hospital with a fair number of deliveries, between one and two newborns each year will have severe to profound deafness due to an autosomal recessive gene. While we have recognized the occurrence of ototoxicity with aminogycoside use for many years, recently a mitochondrial gene change has been identified which confers aminoglycoside sensitivity. For many premature infants who receive gentamycin, this may actually be the cause for their hearing loss. Although gene testing for this susceptibility is not currently commercially available, it may become available in the very near future.

There are many other single gene causes of deafness with and without other systemic findings. There is an X-linked form of deafness that accounts for about 1 in 200 cases of profound childhood deafness called X-linked progressive mixed hearing loss with perilymphatic gusher. As the name implies, hearing loss is progressive and appears to be caused by congenital fixation of the stapedal footplate. The perilymphatic gusher occurs when stapedectomy is done. Affected males often have vestibular involvement and heterozygous females may have milder mixed hearing loss. Otosclerosis is an autosomal dominant condition and is a common cause of conductive or mixed hearing loss in adults. Hearing problems can begin in childhood, but usually are not noted until the second to third decades of life. Not everyone who inherits this gene is symptomic because of "reduced penetrance", on the order of 25-40%.

Other Mendelian disorders that have hearing loss as a frequent component include:

• Alport syndrome is an autosomal dominant or X-linked dominant condition associated with variable degrees of nephritis or even renal failure. Renal problems may be more severe or of earlier onset in males. Many carrier women may only have mild hematuria without obvious hearing problems. Careful eye exam in juvenile onset cases may reveal anterior lenticonus and there may be a predilection for leiomyomatosis of the esophagus, trachea or vulva in some families.

• Infantile renal tubular acidosis and congenital sensorineural hearing loss is an autosomal recessive condition that also ties hearing loss and renal disease together. The renal tubular acidosis may cause failure to thrive or growth retardation and this condition should be considered in any deaf child with growth failure.

• Usher syndrome is one of several autosomal recessive conditions associated with sensorineural deafness, retinitis pigmentosa and in some people, vestibular abnormalities.

• Neurofibromatosis type 2 is a dominant genetic disorder with vestibular schwannomas as a common feature. This form of NF is much less common than classic NF (NF type 1) and has fewer cutaneous findings compared to the average NF 1 patient. However, cutaneous and even deeper neurofibromas are seen with some frequency and subcapsular cataracts are common. Gliomas, ependymomas and meningiomas may be seen as well. Half of affected individuals will be symptomatic by age 25 and many cases represent new dominant mutations, so family history may not always be helpful.

• Waardenburg syndrome is seen in between 2 and 5 % of individuals with congenital deafness. The triad of pigmentation defects (heterochromia or white forelock), widely placed medial canthi and sensorineural hearing loss is often pathognomonic for this condition. However, at least one third of families with this condition do not have the typical medial canthal changes (type II) and only 20% of patients with type I and 50% of those with type II actually have hearing loss. Therefore, it is not unusual for a mother or father with normal facial proportions and normal hearing, but who has heterochromia and/or a white forelock to give birth to a child with profound sensorineural hearing loss.

• LEOPARD syndrome is an autosomal dominant condition associated with lentigines, EKG changes, ocular hypertelorism, pulmonic stenosis, abnormalities of the genitalia, retardation of growth and sensorineural deafness. Many of these patients are initially seen by a cardiologist because of the high incidence of pulmonic stenosis and/or arrhythmias. About half of affected males have hypospadias with sensorineural hearing loss of variable degree in about 25% of gene carriers.

• Treacher Collins syndrome is an autosomal dominant condition with many cases resulting from new mutations. Individuals with this condition have variable degrees of craniofacial involvement with microtia, malar hypoplasia and lower eyelid colobomas being the most common features. Intelligence is usually normal although conductive deafness, if not recognized and addressed, can lead to developmental delays in young children.

• Osteogenesis imperfecta actually represents a number of fragile bone entities with variable degrees of blue sclera, bone fractures and limb/spine deformities. The mild form designated type I is a dominant condition with the least number of fractures, blue-grey sclera and dentinogenesis imperfecta in some families. More than 50% of affected individuals with OI type I will have some degree of hearing loss which may be sensorineural, conductive or mixed. Hearing loss may be progressive and may not be clinically significant until adulthood. Types III and IV are more medically significant with hearing loss seen in many but not all individuals.

• CHARGE Association and Facio-Auriculo-Vertebral Spectrum both represent in utero events that are not primarily genetically determined. Both represent developmental defects in the fetus occurring at a critical moment in time during the first trimester. CHARGE is a multisystem condition with variable features of colobma/microphthalmia, heart defects, atresia choanae, retardation of growth and/or development, genital hypoplasia in males and ear anomalies including external ear malformations and hearing loss. FAVS also known as Goldenhar syndrome is a field defect involving the first and second branchial arches resulting in hemifacial microsomia, microtia and hemivertebrae.

In addition to these conditions, there are many more multiple anomaly, biochemical and cytogenetic disorders that have hearing loss as a common finding. For a child with congenital hearing loss a number of simple screening tools can be employed to rule out some of these conditions that have additional medical implications. A reasonable work-up for an infant or child with significant hearing loss without obvious cause would include:

• Careful family history including history about renal failure, dialysis or nephritis as well as hearing loss, white forelock or different colored eyes. Complete prenatal exposure and perinatal history including use of aminoglycosides.

• Comprehensive audiologic assessment to determine if hearing loss is conductive, sensorineural or mixed.

• Urinalysis and SMA-7 to assess renal function.

• Consider eye exam to evaluate retina and optic nerve if clinically indicated.

• Consider renal ultrasound if external ear malformation is present, even with normal renal function.

• Monitor growth and development carefully and refer to appropriate specialists and special child health services to promote early intervention and optimal school placement.