Genetics and Craniofacial Anomalies

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Genetic factors contribute to more than half of all congenital hearing losses and are also responsible for later-onset hearing losses. Understanding the factors underlying hereditary hearing loss requires locating the genes responsible for hearing loss and defining the specific mechanisms and functions of those genes. From a clinical standpoint, this information may contribute to improved management strategies for individuals with hereditary hearing loss and their families. Accurate determination of the auditory characteristics associated with various genetic abnormalities requires the use of measures sensitive to subtle aspects of auditory function.

Hereditary Hearing Loss. Congenital (hereditary) hearing loss occurs in approximately 1-2 of 1000 births, and at least 50% of all cases of hearing loss have a genetic origin (Morton, 1991). Although hereditary hearing losses may occur in conjunction with other disorders as part of a syndrome, the majority of cases are non-syndromic. Later-onset hereditary hearing loss occurs at various ages from the first decade to later in life.

Chromosomes. Human cells contain 23 pairs of chromosomes (22 pairs of autosomes and two sex chromosomes). Hereditary material in the form of DNA is carried as genes on chromosomes. Cells reproduce by mitosis (meiosis for the sex chromosomes), where chromosomes divide, resulting in two genetically similar cells. Errors can occur during mitotic or meiotic division, resulting in cells with chromosomal abnormalities and an individual with a chromosomal defect.

Genotype and Phenotype. Genotype describes an individual's genetic constitution. Phenotype relates to the physical characteristics of an individual and can include information obtained from physiological, morphological, and biochemical studies. Auditory tests contribute to the phenotypic description.

Inheritance Patterns

Hereditary hearing loss follows several patterns of inheritance. Autosomal recessive inheritance occurs in 70%-80% of individuals with nonsyndromic hearing loss. To display a recessive trait, a person must acquire one abnormal gene for the trait from each parent. Parents are heterozygous for the trait since they each carry one abnormal gene and one normal gene. Thus, recessively inherited defects appear among the offspring of phenotypically normal parents who are both carriers of a single recessive gene for the trait. When both parents are carriers, the chance of a child receiving two copies of the abnormal gene and displaying the pheno-type is 25%. The parents' chance of having a carrier child is 50%, and there is a 25% chance of having a child with no gene for the defect. In cases of nonsyndromic recessive hearing loss, a genetic source may be suspected in families with two or more occurrences of the disorder. Recessive inheritance occurs more commonly in non-syndromic than in syndromic hearing loss.

In autosomal dominant inheritance, a single copy of an abnormal gene can result in hearing loss; thus, an affected parent has a 50% chance of passing that gene to their child. Autosomal dominant hereditary hearing loss occurs in approximately 15%-20% of nonsyndromic hearing loss and is more commonly associated with syn-dromic hearing loss. Other inheritance patterns that can result in hearing loss are X-linked, at a rate of 2%-3%, and mitochondrial, which occurs in less than 1% of cases.

Variability in Hereditary Hearing Loss. Phenotypic and genetic heterogeneity is pronounced, with reports of more than 400 forms of syndromic and nonsyndromic hereditary hearing loss (Gorlin, Toriello, and Cohen, 1955). Considerable variation exists among hereditary hearing losses, between dominant and recessive hearing losses, among various forms of either recessive or dominant hearing loss, and even among persons with the same genetic mutations. Furthermore, the same genes have been found responsible for both syndromic and nonsyndromic hearing loss, and have been associated with both autosomal dominant and recessive transmission.

Hereditary hearing losses range from mild to profound (Nance and Sweeney, 1975). In subjects with autosomal recessive nonsyndromic hereditary hearing loss, onset of the hearing loss tends to be congenital, severe to profound in degree, stable over time, and af fecting all frequencies (Liu and Xu, 1994). Autosomal dominant nonsyndromic hereditary hearing loss tends to be less severe, more often delayed in onset, progressive, and affecting high frequencies. Patients with X-linked hearing loss generally have prelingual onset but are clinically diverse.

Mutations in the GJB2 (connexin 26) gene may explain greater than 50% of autosomal recessive deafness in some populations (Zelante et al., 1997). The GJB2 gene encodes the protein connexin 26 (Cx26), thought to be essential for maintenance of high potassium in the scala media of the inner ear. Several mutations in the GJB2 gene have been associated with hearing loss, and mutation sites vary among world populations. A 35delG mutation is common in some Mediterranean-based populations (Denoyelle et al., 1997), while a 167delT mutation is most common in the Ashkenazi Jewish population (Morell et al., 1998). Cx26 mutations are generally responsible for recessive deafness, although they have been observed in dominant deafness.

Hearing losses associated with Cx26 mutations are cochlear in nature but vary widely in degree, ranging from mild to profound, and stability (e.g., Cohn et al., 1999; Denoyelle et al., 1999; Mueller et al., 1999; Wilcox et al., 2000). Hearing losses resulting from the same genetic mutations show wide variability in degree and progression. Furthermore, audiometric characteristics are not directly linked to a particular type of mutation (e.g., Cohn et al., 1999; Sobe et al., 2000).

Chromosomal Defects. Down syndrome is the most common autosomal defect. The affected individual has an additional chromosome 21 (trisomy 21), for a total of 47 chromosomes, or a translocation trisomy. Down syndrome is characterized by mental retardation and a number of craniofacial and other characteristics. Hearing loss may be congenital, sensory, and there is a high incidence of middle ear disorders. Trisomy 13 and 18 syndromes, less common and with more dramatic abnormalities, are characterized by inner ear dysplasias involving the organ of Corti and stria vacularis, external and middle ear malformations, cleft lip and palate, and other defects.

Syndromes Associated with Hearing Loss

There are far too many syndromes associated with hearing loss to include in this brief entry. A useful method of classifying hearing loss was provided by Konigsmark and Gorlin (1976), where genetic and metabolic hearing losses were divided into major categories depending on the organ system or metabolic defect involved.

Usher syndrome is the most common syndrome associated with hearing loss and eye abnormalities, specifically retinitis pigmentosa. There are several types and subtypes and various genetic loci. Other syndromes involving vision are Cockayne syndrome and Alstrom disease, associated with retinal disorders. Treacher Collins syndrome, Goldenhar syndrome (hemifacial micro-

somia), Crouzon syndrome (craniofacial dysostosis), Apert syndrome, otopalatal-digital syndrome, and osteogenesis imperfecta are all associated with musculoskeletal disease.

Waardenburg syndrome, characterized by displaced medial canthi, white forelock, heterochromia, and broad nasal root, is the most prominent hearing syndrome involving the integumentary system. Alport syndrome is a combination of progressive hearing loss, progressive renal disease, and ocular lens abnormalities. Pendred syndrome, mucopolysaccharidosis, and Jervell and Lange-Nielsen syndrome are associated with metabolic and other abnormalities. The diverse syndromes associated with neurological disorders include Friedreich ataxia and acoustic neuromas and neural deafness.

Craniofacial anomalies associated with hearing loss may be sporadic, inherited, due to disturbances during embryonic development, of toxic origin, or related to chromosomal abnormalities. These maldevelopments may be of unknown origin or related to known syndromes.

Inner ear dysplasias include Michel deafness, which is rare and involves complete inner ear dysplasia, Mondini deafness, and Scheibe deafness (Schuknecht, 1974). In Mondini deafness, the bony cochlear capsule is flattened, with underdevelopment of the apical turn of the cochlea and possible saccular and endolymphatic involvement. Hearing loss is typically moderate to profound but varies widely. Scheibe deafness involves the membranous portion of the cochlea and saccule, greater in basal portions, and is the most common of the inner ear dysplasias.

External and middle ear anomalies are associated with improper development of the first and second branchial clefts and arches, which are also responsible for lower jaw and other structures. Middle ear abnormalities include absence or fusion of the ossicles or abnormalities of the eustachian tube or middle ear cavity. Middle ear anomalies may be suspected whenever other branchial arch anomalies such as external ear atresia, cleft palate, micrognathia, Treacher Collins syndrome, Pierre Robin syndrome, and low-set auricles are present. Skeletal defects, such as those associated with Apert syndrome, Klippel-Feil syndrome, and Paget disease, and connective tissue disorders, such as those related to Hunter-Hurler or Mobius syndromes, may also indicate the presence of middle ear anomalies. Maldevelopment of the external ear includes preauricular tags, microtic or deformed pinna, or partial or complete atre-sia of the external canal. The presence of external or middle ear anomalies may indicate additional malformations or reduced hearing, depending on the structures and degree of involvement.

Evaluation and Classification of Hearing Loss

The characteristics of a hearing loss are important in understanding relationships, or lack of relationships, between genotype and phenotype. The audiogram provides a general description of the degree, configuration, fre quency range, type, and progression of a hearing loss, and whether one or both ears are affected. Other, more sensitive measures (such as otoacoustic emissions, efferent reflexes, and auditory-evoked potentials) are necessary to understand the nature of a hearing loss in more detail.

The majority of hereditary hearing losses are non-syndromic, with no associated disorders that might raise the index of suspicion or aid in diagnosis. Furthermore, since the majority of nonsyndromic hearing losses are recessively inherited, parents are not affected by hearing loss. There may be no history of hearing loss in the family, so this risk factor would not be an indicator to raise suspicion of hearing loss. Thus, identification of nonsyndromic, and particularly recessively inherited, hearing loss is particularly challenging clinically.

See also speech disorders: genetic transmission.

References

Cohn, E. S., Kelley, P. M., Fowler, T. W., et al. (1999). Clinical studies of families with hearing loss attributable to mutations in the connexin 26 gene (GJB2/DFNB1). Pediatrics, 103, 546-550.

Denoyelle, F., Martin, S., Weil, D., et al. (1999). Clinical features of the prevalent form of childhood deafness, DFNB1, due to a connexin-26 gene defect: Implications for genetic counseling. Lancet, 353, 1298-1303.

Denoyelle, F., Weil, D., Maw, M. A., et al. (1997). Prelingual deafness: High prevalence of a 30delG mutation in the connexin 26 gene. Human Molecular Genetics, 6, 21732177.

Gorlin, R. J., Toriello, H. V., and Cohen, M. M. (1955). Hereditary hearing loss and its syndromes. Oxford: Oxford University Press.

Konigsmark, B. W., and Gorlin, R. J. (1976). Genetic and metabolic deafness. Philadelphia: Saunders.

Liu, X., and Xu, L. (1994). Nonsyndromic hearing loss: An analysis of audiograms. Annals of Otology, Rhinology, and Laryngology, 103, 428-433.

Morell, R., Kim, H. J., Hood, L. J., et al. (1998). Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. New England Journal of Medicine, 339, 1500-1505.

Morton, N. E. (1991). Genetic epidemiology of hearing impairment. In R. J. Ruben, T. R. van de Water, and K. P. Steel (Eds.), Genetics of hearing impairment. Annals of the New York Academy of Sciences, 630, 16-31.

Mueller, R. F., Nehammer, A., Middleton, A., et al. (1999). Congenital non-syndromal sensorineural hearing impairment due to connexin 26 gene mutations: Molecular and audiological findings. International Journal of Pediatric Otorhinolaryngology, 50, 3-13.

Nance, W. E., and Sweeney, A. (1975). Genetic factors in deafness of early life. Otolaryngolic Clinics of North America, 8, 19-48.

Schuknecht, H. F. (1974). Pathology of the ear. Cambridge, MA: Harvard University Press.

Sobe, T., Vreugde, S., Shahin, H., et al. (2000). The prevalence and expression of inherited connexin 26 mutations associated with nonsyndromic hearing loss in the Israeli population. Human Genetics, 106, 50-57.

Wilcox, S. A., Saunders, K., Osborn, A. H., et al. (2000). High frequency hearing loss correlated with mutations in the GJB2 gene. Human Genetics, 106, 399-405.

Zelante, L., Gasparini, P., Estivill, X., et al. (1997). Connexin 26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Human Molecular Genetics, 6, 1605-1609.

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