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J Am Acad Audiol 6 : 15-27 (1995)
Nosology of Deafness
John T. Jacobson*
Abstract
It is estimated that about one half of all congenital deafness and/or hearing impairment is
inherited and that approximately one third of this communicative disorder is associated with
syndromic abnormalities. The remainder of inherited deafness occurs as an isolated entity,
independent of alterations in physical status or any disease process. This latter group typically presents with no clinical signs or symptoms or other dysmorphic stigmata that might
help in the early identification of hearing loss . As contemporary advances in genetic testing
and therapy emerge, there is an ever-increasing opportunity to provide improved diagnosis
and counseling to those with inherited disorders. Over the past 3 decades, there have been
several distinct categorical systems introduced to define deafness . Most often, the nosology
of deafness is described by either origin, onset, degree and type of severity, and/or structural pathology. Therefore, understanding the cause and nature of hearing loss is the first
measure in the accurate diagnosis and management of patient care . This article describes
several classification schemata, citing examples of numerous congenital syndromes and
other disorders that contribute to deafness .
Key Words: Autosomal dominant, autosomal recessive, congenital, deafness, hearing impairment, inheritance, syndrome, X-linked
egardless of the etiology or onset, newborn and/or childhood hearing impairRment has significant long-term consequences for the affected infant and family members, as well as for society in general. Unequivocal evidence supports the relationship between
deafness and deficits in speech, language, and
cognitive development, limitations in educational and socioeconomic opportunities, and discrimination in work-related placement. As a
result, the importance of early identification
and early management has been universally
advocated. Recently, the Joint Committee on
Infant Hearing (1994) and the National Institute
of Health Consensus Development Conference
Statement on Early Identification of Hearing
Impairment in Infants and Young Children
(National Institutes of Health, 1993) have recognized and acknowledged these principles of
early identification and have recommended uni-
*Department of Otolaryngology-Head and Neck
Surgery, Division of Audiology, Eastern Virginia Medical
School, Norfolk, Virginia
Reprint requests : John T. Jacobson, Eastern Virginia
Medical School, Department of Otolaryngology-Head
and Neck Surgery, 825 Fairfax Ave ., Suite #510, Norfolk,
VA 23507
versal infant hearing screening. Recommendations include not only the hearing screening of
infants at risk for hearing loss, as determined
by a high-risk register, but also all normal
healthy, term babies . These recommendations
take into account that only about one half of all
hearing-impaired infants are identified through
the implementation of risk factors ; the remainder of infants and children identified with hearing loss result from genetic factors with a negative family history (Rose et al, 1977).
Because as many as one third of all patients
with hereditary hearing loss are associated with
other syndromic abnormalities, medical management, including newly developed genetic
techniques, is a priority in the overall health care
strategy. With recent advances in genetic mapping of the human genome and the ability to
determine its DNA sequence, there is an increasing opportunity to provide improved counseling and other available medical management
alternatives to individuals of the more than
4000 inherited diseases .
To address this formidable task, hearing
health care professionals require, in addition to
their specific area of expertise, broad-based
knowledge in such areas as genetics, craniofacial embryology, and normal growth and devel-
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
opment. Advance knowledge should lead to an
improved comprehensive service through the
recognition, diagnosis, and eventual auditory
management of the patient. The information
found within the article summarizes multidisciplinary efforts that have added to and elucidate both inherited and acquired factors associated with deafness and hearing impairment .
Several fundamental genetic concepts were discussed in the article by Smith (1995) in this issue
and are an integral part of discussions that follow in this special issue on hereditary syndromes and other childhood auditory disorders.
The following is a review of existing classification schemes of deafness and hearing impairment that also includes their diverse modes of
inheritance. For an excellent, comprehensive,
readable review of genetics, the reader is
referred to and encouraged to examine Smith's
Recognizable Patterns ofHuman Malformation
(Jones, 1988).
CLASSIFICATION
T
here are several methods of classifying
hearing impairment and/or deafness, but
most often they are described in terms of either
their origin (e .g ., hereditary, acquired), onset
(e .g ., congenital, delayed), degree and type of
severity (e .g ., mild-to-profound sensory, conductive, or mixed), and/or structural pathology
(e.g ., inner ear congenital anomaly types: Michel,
Mondini, Scheibe, etc.) . Although there are other
descriptive nomenclature, these four classifications or combinations of these four are most
commonly found in the literature .
Intrinsically, within each classification category there may be several descriptive subsets
and, as a result, interrelationships between categories and their subsets often introduce more
confusion than clarification. As an example,
McKusick (1992) has listed seven distinct methods of describing genetic disorders, suggesting
that the naming of syndromes is, at best, disorderly. He argues that the name for a genetic
trait should have some relation to the basic
defect, should be imaginative, and should present an image of the phenotype. McKusick states
that terminology should be appropriate for transmittal to patients but readily admits that there
is little sense to the use of disorder, disease,
syndrome, and anomaly. The terms association
and anomalad were proposed (Smith, 1974) for
some birth defects but, according to McKusick,
are of limited use in connection with Mendelian
phenotypes . Often, the terms malformation,
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deformation, and disruption have been used
interchangeably, but they express specific distinctions in birth defects. The term malformation refers to a basic abnormality in embryologic
development; deformation connotes intrauterine
pressure effects, whereas the effects of abnormal
vascular supply to developing structures are
best described as a disruption . In short,
Diefendorf and colleagues (1993) have correctly
pointed out that the best interests of the patient
are served when intervention strategies embrace
common goals and when a common terminology
is optimized.
The causes of deafness tend to be broadly
classified into three primary categories : genetic
(hereditary disorder), nongenetic (acquired),
and unknown causes . It is estimated that about
one half of all congenital deafness is hereditary,
that is, the genetic trait of deafness is passed
from parent(s) to offspring (Beighton, 1983 ;
NIDCD, 1989). The remainder of hearing impairment appears equally represented by either
causative (nongenetic) factors or by those of
unknown origin .
The ability to hear is a genetic predisposition and therefore is present in the majority of
live births ; however, if an inherited auditory
deficit is identified at birth, three recognized
genetic forms of inheritance may be considered
as potential contributing factors. They include
single gene abnormalities, chromosomal aberrations, and disorders due to multifactoral inheritance . Of noteworthy clinical significance, hereditary hearing loss may be congenital (present at
birth) or may manifest at a later period in life .
Importantly, regardless of the descriptive classification scheme employed, a thorough knowledge of the nosology of deafness is a prerequisite to correct medical and audiologic management of hearing impairment . This article
addresses two commonly referred classification
systems, inherited hearing loss and congenital
hearing loss . Acquired hearing loss that results
from environmental factors is described later in
this issue (by Strasnick and Jacobson, 1995).
Inherited Hearing Loss
To review, Mendelian laws describe genetic
traits (physical characteristics) of inheritance
that are passed from one generation to another.
These fundamental physical and functional
units of inheritance are called genes and consist of segments of deoxyribonucleic acid (DNA)
that encode the blueprint for every living thing.
DNA is structurally packaged within chromo-
Nosology of Deafness/Jacobson
somes. Each human cell contains 46 chromosomes in 23 pairs. Twenty-two of the pairs are
identical in the male and female and are designated as autosomes. The remaining pair are
called the sex chromosomes and are represented
by two X chromosomes in the female and one X
and one Y chromosome in the male . One chromosome of each pair is inherited from each parent and, with the exception of the XY male
chromosome, each genetic determinant is present in two doses (Jones, 1988). Pairs of genes
are called alleles and occupy the identical site
on homologous chromosomes . Unless there is a
structural anomaly, each pair of homologous
chromosomes is identical with respect to its
locus. A gene that alters normal characteristics
is referred to as a mutant gene . The full complement of genetic material in the set of chromosomes of an organism is called its genome .
One method of describing a chromosome is
by its structural morphology ; its narrowest
point is called a centromere . Each chromosome has a characteristic length and position
of the centromere, allowing each projection to
be called an arm. At metaphase, each chromosome has paired long and short arms . The
short arms are designated as "p" (petite) and
the long arms as "q." Reference to a specific arm
of chromosome 1 would be to lp or 1q, to chromosome 2 as 2p and 2q, and so forth. The designation of a + or - sign before a chromosome
number is indicative of the addition or absence
of an entire chromosome . This represents a
numeric chromosomal aberration . An example
of this is the karyotype 47, XY, +21, which is
that of a male with an extra number 21 chromosome (i .e ., trisomy 21 - Down syndrome).
In contrast, the designation of a + or - sign following a chromosome number represents an
increase or decrease in chromosome length .
This represents a structural chromosomal
anomaly. Such an example is Cri-du-chat syndrome, represented as 46,YX,5p-, meaning 46
chromosomes, in a female with deletion of the
short arm of the #5 chromosome . This basic
form of descriptive reference is referred to as
karyotype nomenclature .
Single Gene Mutation
Single gene (monogenic) mutations that
cause changes in the normal sequence of DNA
base pairs are associated forms of Mendelian
inheritance that are designated as autosomal
dominant, autosomal recessive, and sex (X)linked patterns . X-linked inherited disorders
Normal
Dominant
Heterozygous
Recessive
Homozygous
Recessive
Except for the XY, there is a pair of genes for
each function, located at the same loci on
sister chromosomes . One pair of normal genes
is represented as dots on a homologous pair of
chromosomes.
A single mutant (changed) gene is dominant if
it causes an evident abnormality. The chance
of inheritance of the mutant gene (M) is the
same as the chance of inheriting a particular
chromosome of the pair: 50 per cent .
A single mutant gene is recessive (1) if it
causes no evident abnormality, the function
being well covered by the normal partner gene
(allele) . Such an individual may be referred to
as a heterozygous carrier.
When both genes are recessive mutant ()o.) the
abnormal effect is expressed . The parents are
generally carriers, and their risk of having
another affected offspring is the chance of
receiving the mutant from one parent (50 per
cent) times the chance from the other (50 per
cent) or 25 per cent for each offspring .
An X-linked recessive will be expressed in the
male because he has no normal partner gene .
His daughters, receiving the X, will all be carriers, and his sons, receiving the Y, will all be
normal .
X-linked
Recessive
An X-linked recessive will not show overt
expression in the female because at least part
of her "active" X's will contain the normal gene .
The risk for affected sons and carrier daughters will each be 50 per cent.
Figure 1 Diagram of normal and major mutant gene
Mendelian inheritance. (Jones KL . [19881 . Smith's Recognizable Patterns ofHuman Malformations. 4th ed . Philadelphia: WB Saunders, 646. Reprinted with permission
from the publisher.)
may be either recessive or dominant (addressed
in the following discussion). A diagrammatic
representation of Mendelian inheritance is illustrated in Figure 1 . Single gene mutations may
cause about 1500 rare syndromes, diseases, and
morphologic traits that are associated with a
high risk of recurrence (Jones, 1988). The term
syndrome is used to describe a pattern of multiple anomalies that are pathogenetically related,
that is, attributable to a specific etiology. Syndromes are either known-genesis (e .g ., Turner
syndrome, a chromosomal aberration causing
external and middle ear abnormalities and sensory and mixed hearing loss) or unknown-genesis types (e .g ., Goldenhar syndrome, affecting
the development of the first and second branchial
arch derivatives, causing a multitude of facial
deformities and malformations, including inner
ear anomalies), having several subcategories
(Cohen, 1982).
Autosomal-Recessive Inheritance. Autosomal-recessive inheritance requires a pair of
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
genes for hearing loss, one recessive gene from
each parent to produce the disorder. The mutant
gene must be present in a double dose for abnormal characteristics to present. The term recessive applies only to homozygous (a condition
having similar genetic patterns at both alleles) expressed traits . Parents are heterozygous,
having one normal and one abnormal allele,
and clinically asymptomatic . Recessive inherited hearing loss is by far the largest of the single gene mutations, consisting of about 80 percent of this genetic trait. Although usually unaffected, these carriers will pass a copy of the
identical recessive gene for hearing loss to about
25 percent of their children . Infants with recessive inherited hearing deficits that are first
born to families comprise the largest percentage of neonatal hospital-discharged, unidentified, hearing-impaired babies, since there are
no associated abnormalities and generally no
other recognized familial hearing loss . With
minor exception, these otherwise healthy babies
are typically not screened for hearing loss and
are discharged with no confirmed knowledge or
even suspicion of possible auditory deficits .
Autosomal-Dominant Inheritance. About
20 percent of genetic hearing loss is attributed to autosomal-dominant inheritance (Rose
et al, 1977). The term dominant applies to a
genetic pattern that is expressed when only one
gene from either parent is dominant for hearing loss (heterozygous state) . In this condition, an affected parent need pass only a single mutant gene in a single dose to cause the
trait. Thus, the trait is manifested in every
infant who inherits the gene, irrespective of the
condition (normal) of the other allele . The
affected offspring will either be the product of
an affected parent who expresses the gene or
the result of a new mutation dominant trait
(Nora and Fraser, 1989). From this inheritance pattern, the risk for hearing impairment is 50 percent for each pregnancy. The carrier is almost always hearing impaired . The
term penetrance refers to the proportion of
individuals who have clinical expression of
the gene in some form or another and transmit it to their offspring; 100 percent penetrance suggests that all individuals with the
gene have symptoms of the disorder. The
degree of clinical manifestation varies greatly
between individuals with a specific disorder.
The term expressivity describes the degree of
clinical variability encountered from mild to
18
severe . In Waardenburg syndrome, an autosomal-dominant disorder, 50 percent of the
offspring are affected but only 20 percent have
deafness (Jones, 1988). Often in the same family, the expressivity differs substantially (e .g.,
see Treacher Collins Syndrome in this issue
[Jahrsdoerfer and Jacobson, 1995]) .
X-Linked Inheritance. X-linked inherited
hearing loss accounts for the remaining 1 to 2
percent of this genetic trait (Nance and
Sweeney, 1975). X-linked genes can be either
recessive or dominant . Because of the XX
(female)/XY (male) chromosomal relationship,
a female with a recessive gene for hearing loss
on one of her two X chromosomes will have
normal hearing. Only males are affected with
offspring having a 50 percent chance of hearing loss, whereas each daughter has a 50 percent chance of carrying the affected gene and,
in turn, transmitting the X-linked trait to 50
percent of her sons . A male with the gene cannot pass the trait on to his sons (since they will
have inherited his Y chromosome), but all of his
daughters will be carriers . Further, the potential for a new mutation in X-linked disorders
also exists . Two well-known, X-linked, recessive
gene disorders are Hunter and Alport syndromes (the latter is described in detail by
Wester [1995] in this special issue) .
In contrast, X-linked dominant disorders
are generally expressed in hemizygous males
(a condition where only one allele of a specific
gene locus is present) and is only relevant for
X-linked recessive inheritance, since the recessive allele appears because there is no corresponding allele on the Y chromosome . Therefore, since a dominant allele will be expressed
with just one "dose," it does not matter if the
individual is a heterozygous female or hemizygous male . The pedigree pattern of X-linked
dominant traits differs from that of autosomal
dominance only in that all of the daughters
and none of the sons of affected males will be
affected, since a male gives his X chromosome
only to his daughters (Nora and Fraser, 1989).
One example of an X-linked, dominant, inherited trait is otopalatodigital syndrome (Gorlin
et al, 1973). Otopalatodigital syndrome, types
I and II (a more severe skeletal manifestation
of type I, with a life expectancy of about 5
years), includes auditory abnormalities usually limited to conductive pathology due to middle ear ossicular anomalies (Dudding et al,
1967). Recently, Brunner (1991) reported nearly
Nosology of Deafness/Jacobson
30 distinct X-linked conditions that have hearing loss as an associated anomaly.
Chromosomal Aberrations
Genetic hearing loss may also be the result
of chromosomal or cytogenetic (the study of
chromosomes) abnormalities such as numeric
distribution errors that may consist of the presence (e .g., trisomy 18 [47,XX,+18] representing chromosome 18 in triplicate rather than in
duplicate) or absence (e .g., Turner syndrome ;
45,X) of an additional chromosome . Chromosomal aberrations may also present as structural
errors in which deletions, additions, duplications, translocations, and inversions may occur
(Rollnick and Smith, 1986 ; Jung, 1989). Chromosomal disorders account for about 1 percent of
the total newborn population (Jacobs, 1977).
Down syndrome (trisomy 21) is the most familiar and common chromosomal abnormality, having an incidence of about 1 :600 live births
(de Grouchy and Truleau, 1984) and producing
a high incidence of conductive hearing loss
(Balkany et al, 1979) and, to a lesser degree,
associated auditory sensory pathology. In Down
syndrome, there is evidence that sensory auditory pathology worsens with age, suggesting a
possible acquired component (Keiser et al, 1981).
For an in-depth review, see Diefendorf et al
(1995), in this special issue.
Multifactorial Inheritance
Deafness due to multifactoral (polygenic)
inheritance refers to the additive effects of several minor gene pair abnormalities in association with nongenetic environmental interactive
factors (McKusick, 1992). In these cases, genetic
inheritance is difficult to ascertain; however,
there remains a familial predisposition for a
disorder to occur at a greater incidence than
that found in the general population. In addition
to hearing loss within this category, a higher incidence of craniofacial birth defects may occur,
including cleft lip and palate . For example,
Pierre Robin sequence is a triad of micrognathia,
cleft palate, and glossoptosis (Gorlin et al, 1990).
A sequence is considered a multiple pattern of
anomalies, but unlike a syndrome, a sequence
results from a primary anomaly such as micrognathia, as in the case of Robin sequence . In this
sequence, the presence of mandibular hypoplasia has not been accurately traced and the underlying cause could be a combination of genetic factors or a secondary effect of in utero compression
of the mandible, limiting its growth and development (Jung, 1989). Robin sequence may also
be a feature of a genetic syndrome such as Beckwith-Wiedemann in rare cases, Catel-Manzke,
Donlan, Myotonic dystrophy, otopalatodigital
type II, or velocardiofacial . It may also be identified in a chromosomal syndrome such as del(4p)
or dup(llq) . Robin sequence has been reported
as the result of fetal exposure to a teratogen as
in fetal alcohol or fetal trimethadione syndromes
or in conditions of unknown etiology, such as
CHARGE association (see Toriello [1995], in this
special issue) and Moebius sequence . Auditory
abnormalities include low-set and malformed
ears and mixed hearing loss (Smith and Stowe,
1961). Its most common association, however, is
with Stickler syndrome (Turner, 1974 ; Cohen et
al, 1990 ; Gorlin et al, 1990). Stickler syndrome
is an autosomal-dominant hereditary condition
that presents with pathognomonic facial features, bone dysplasia, myopia, and auditory
deficits (Stickler et al, 1965 ; Stickler and Pugh,
1967 ; Gorlin et al, 1990). This skeletal disorder
has been linked to chromosome 12q, close to
the structural gene for type II collagen (Francomano et al, 1987). There is evidence, however, that mutations in the collagen gene itself
are the cause of the syndrome in some but not
in all cases, whereas other cases do not show
linkage to that region . These findings led to a
syndrome that produces expressive variability
and high but incomplete penetrance (Weingeist
et al, 1982 ; Suslak and Desposito, 1988). Because
such similar clinical traits are reported between
Pierre Robin sequence and Stickler syndrome,
Herrmann and colleagues (1975) have suggested
that as many as half of those with the Pierre
Robin sequence may have the inherited disorder,
Stickler syndrome . The degree and type of hearing loss has been variable in these disorders
(Jacobson et al, 1990a) .
Multifactoral risk characteristics are dependent on ethnic origin, gender, the number of
affected relatives and their relationship in any
one family, and the severity of the defect (Rollnick and Smith, 1986). Table 1 lists some common, inherited hearing disorders based on single gene abnormalities (autosomal dominant,
autosomal recessive, and X-linked), chromosomal aberrations, and disorders due to multifactoral inheritance .
The majority of inherited hearing loss occurs
as an isolated entity, independent of other
changes in physical status or disease processes.
Typically, there are no additional clinical signs
or symptoms or other dysmorphic stigmata
Journal of the American Academy of Audiology/ Volume 6, Number 1, January 1995
Table 1
Classification of Primary Categories of Common Inherited Hearing Loss
Autosomal-Recessive Inherited
Single Gene Disorders
Abert-Schonberg (type 1)
Alstrom
Bloom
Carpenter
Cockayne
Hallgren
Hurler
Jervell and Lange-Nielsen
Laurence-Moon-Biedl
Klippel-Feil sequence
Mobius
Mucopolysaccharidoses (types I-VII)
Oro-facial-digital (Mohr-type II)
Pendred
Pili torti (with deafness)
Refsum
Sanfilipo
Sickle cell anemia
Usher (types I, II)
Chromosomal Aberrations
Numerical
Trisomy (13, 18 & 21, Down)
Turner
Structural
Cri du chat
DiGeorge sequence
Prader-Willi
Wolfe-Hirshhorn
Autosomal-Dominant Inherited
X-Linked Inherited
Alport (types I, V, VI)
Apert
Branch io-oto-renal
Crouzon
Goldenhar
Klippel-Fell
Leopard
Marfan
Marshall
Myosilis ossificans
Neurofibromatosis
Nager
Noonan
Osteogenesis imperfecta (types II, III)
Otosclerosis
Paget
Pyle disease
Stickler
Symphalangism
Townes
Treacher Collins
van der Woude
Waardenburg
Alport (types II-IV)
Fabry
Fragile X
Hypogonadism
Hunter
Norrie
Oro-facial-digital (type I)
Oto-palatal-digital (types I, II)
Perilymph gusher
Zinsser-Engman-Cole
(dyskeratosis congenita)
Multifactorial Inheritance (single or
multiple gene abnormality with possible
nongenetic environmental factors)
Cornelia de Lange
DiGeorge sequence
Goldenhar
Klippel-Fell
Pierre-Robin sequence
Wildervanck
Specific syndromes may be listed in more than one category because more than one type may exist,
associated with this type of hearing loss, often
making early identification of hearing loss problematic. However, about one third of all genetic
hearing loss accompanies syndromes having
physical characteristics such as craniofacial
anomalies or multiple congenital organ system
malformations. Specific examples include hearing impairment with craniofacial and musculoskeletal disease (e .g ., Crouzon syndrome, an
autos omal-dominant disorder), eye disease
(e .g ., Alstrom syndrome, an autosomal-recessive
disorder), skin disease (e.g., Leopard syndrome,
an autosomal-dominant disorder), and metabolic abnormalities (Hurler and Hunter syndromes, autosomal recessive and X-linked,
respectively) . The most common metabolic
disorder with hearing loss is Pendred syndrome,
having an incidence of about 1:200,000 . This
autosomal-recessive endocrine-metabolic trait,
which usually presents with hypothyroidism,
20
goiter abnormality, severe sensory hearing
loss, and often defective vestibular function,
may account for up to 10 percent of all congenital deafness (Batsakis and Nishiyama, 1962 ;
McKusick, 1992)..Van Wouwe et al (1986) have
linked Pendred syndrome to duplication deficiency, that is, duplication in 10p and deficiency
in distal 8q.
This classification system, which combines
hearing loss with an organ system defect caused
by the same gene, was described by Konigsmark and Gorlin (1976) . Table 2 lists inherited
syndromes by their major physical organ abnormality, each having some degree of hearing loss
as a component of the disorder. At present, over
90 different types of hereditary deafness have
been identified and their degree of severity
varies dramatically (Konigsmark and Gorlin,
1976 ; McKusick, 1992).
Nosology of Deafness/Jacobson
Table 2
Classification of Genetic Hearing Loss Incorporating Major System Defects
No Associated Abnormalities
Dominant congenital severe sensory
Dominant progressive early-onset sensory
Dominant unilateral sensory
Otosclerosis (conductive or mixed loss)
Recessive congenital severe sensory
Recessive congenital moderate sensory
Recessive early-onset sensory
X-linked congenital sensory
X-linked early-onset sensory
X-linked moderate sensory
Atresia of auditory canal - conductive
Musculoskeletal Disease
Albers-Schonberg disease (osteopetrosis)
Apert syndrome (type I)
Cornelia de Lange
Crouzon syndrome
Forney syndrome
Goldenhar
Juvenile Paget's disease
Karmondy-Feingold
Klippel-Feil syndrome
Kniest syndrome
Mohr syndrome
Osteogenesis imperfecta (types I-IV)
Otopalatodigital syndrome
Pierre Robin sequence
Sanfilipo (type III)
Stickler syndrome
Treacher Collins syndrome
van Buchem's disease
Wildervanck syndrome
Renal Disease
Adolescent renal tubular acidosis
Alport syndrome
Branch io-oto-renal
Charcot-Marie-Tooth syndrome
Infantile renal tubular acidosis
Macrothrombocytopathia
Lemieux-Neemeh syndrome
Nephritis-Muckle-Wells syndrome
Renal, genital, and middle ear anomalies
Nervous System Disease
Ataxia
Bulbopontine paralysis
Diabetes mellitus
Mycoclonic elipepsy and sensory deafness
Neoplastics
Neurofibromatosis
Noonan syndrome
Progressive sensory neuropathy
Richards-Rundle syndrome
External Ear Abnormalities
Atresia
Otofaciocervical syndrome
Lacrimoauriculodentodigiral syndrome
Lop ears, micrognathia, and conductive hearing loss
Malformed low-set ears
Microtia
Preauricular pits, branchial fistulas
Thickened ear lobes
Integumentary (Skin) System Disease
Dominant onychodystrophy
Dominant piebald trait
Fragile X
Leopard syndrome
Pili Torti and sensory hearing loss
Recessive onychodystrophy
Recessive piebaldness
Waardenburg syndrome (types I, II)
Eye Disease
Alstrom syndrome
Cockayne syndrome
Cryptophthalmia syndrome
Hallgren syndrome
Harboyan syndrome
Laurence-Moon-Biedl syndrome
Marshall syndrome
Mobius syndrome
Norrie syndrome
Optic atrophy, juvenile diabetes
Refsum syndrome
Rosenberg-Chutorian syndrome
Usher syndrome (types I, II)
Metabolic and Other Abnormalities
Familial streptomycin ototoxicity
Pendred syndrome
Mucopolysaccaridoses
Hurler syndrome
Hunter syndrome
Scheie syndrome
Mannosidosis
Jervell Large-Nielsen syndrome
Sickle cell disease
Trisomy 13, 18, and 21
Turner syndrome
Modified from Konigsmark and Gorlin, 1976 .
Congenital Hearing Loss
The term congenital is used to describe
a condition or symptom, the onset of which
occurred at (perinatal) or before (prenatal) birth.
Congenital birth defects imply that during certain critical periods of the pregnancy, changes
in normal morphologic and functional development have occurred that are recognized at birth
or manifest and progress later in life . Importantly, there is a systematic pattern of embryologic development that exists within the human
auditory system . Consider the external ear,
which consists of the pinna and external audi-
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
tory canal (EAC). By the fourth gestational
week, the pinna begins to develop around the
first branchial groove from first (mandibular) and
second (hyoid) branchial arch mesoderm . Within
2 weeks, these arches divide into six hillocks,
each contributing to a specific structural component of the pinna. Williams (1994) reports
that the first three hillocks are formed from the
mandibular arch and the remaining three are
derived from the hyoid arch . By the twentieth
fetal week, the pinna has reached adult shape
and location (Kenna, 1990). The developmental
pattern of the EAC is similar in that by the
fourth gestational week, it begins its maturation
from the first branchial groove between the
mandibular and hyoid arches . By the eighth
week, a tube is shaped from the branchial groove,
ultimately forming the outer one third (primary
meatus) of the EAC. Simultaneously, a dense epidermal plug extends medial, reaching the primary tympanic cavity to cast the meatal plate.
Mesenchyme then begins to constitute a bridge
between the epithelial cells and the meatal
plate. Absorption of epithelial cells takes place
by the fifth month, establishing a canal and
leaving only an ectodermal plug. Eventually,
the medial bony two-thirds portion of the EAC
is derived from this ectodermal tube (Schuknecht
and Gulya, 1986). Importantly, any alteration to
normal fetal development of the external ear
within this critical time frame may result in
congenital malformations to either the pinna
or the EAC. Take, for instance, malformations
of the branchial sinus and/or cyst, which result
in defects in the resolution of the branchial cleft.
Primary causes usually occur prior to the eighth
week, resulting in preauricular malformations
(Jones, 1988). Because anatomic structures comprising the auditory system have independent
developmental archetype, congenital anomalies
may be independent, as in first and second
branchial arch disorders that directly involve the
external and middle ear, leaving the inner ear
predominantly unscathed. Therefore, in the clinical analysis of patients who present with craniofacial anomalies, an expanded knowledge of the
developmental patterns of the auditory system
may help to support and explain findings that
are associated with congenital ear abnormalities
and provide realistic management strategies in
this population base .
The incidence of total deafness represents
less than 1 percent of infants and children with
congenital auditory deficits, thus leaving the
vast majority with some degree of residual hearing. The term congenital hearing loss is often lim22
ited to that population with severe-to-profound
sensory auditory deficits . This description is
somewhat restrictive and should be expanded to
include those with conductive as well as mixed
hearing loss of all degrees of severity, since hearing loss at birth is congenital by definition.
Congenital hearing loss may result from
either genetic and/or other factors such as prenatal viral infection, anoxia, trauma, or other
perinatal insults of known or unknown origin .
Therefore, congenital hearing impairment may
not necessarily be genetically based. Further, a
congenital syndrome may also have later-onset
hearing loss . For example, congenital syphilis
(nongenetic disorder), which has shown substantial increases of occurrence over the past
decade, is present at birth because it is a prenatal event, but hearing loss is delayed, since
symptoms are usually not demonstrated until
the teenage years. Alport syndrome is a heterogenetic kidney disease often progressing to
renal failure (Barker et al, 1990). It has six
subtypes and two modes of inheritance: autosomal dominant (types I, V, and VI) and Xlinked dominant (types II, III, and IV) (Atkin
et al, 1986). With the exception of type IV (Xlinked adult, purely renal disease; McKusick
[1992]), all are reported to have deafness as a
characteristic trait. Although congenital, Alport
syndrome usually presents as a preadolescent
progressive sensory impairment affecting males
and females in successive generations (McKusick, 1992). (See Wester [1995], for a comprehensive review of Alport syndrome in this special issue.) Two examples of variable onset are
branchio-oto-renal syndrome (described in this
special issue) and Klippel-Feil sequence, a primary skeletal abnormality with fused cervical
vertebrae. Klippel-Feil sequence is considered
to be a morphologically and etiologically heterogeneous disorder with five patterns and two
modes of inheritance, autosomal recessive and
autosomal dominant . It has been reported that
between one quarter to one half present with
associated sensory and/or conductive hearing
loss that may be present at birth or delayed in
its onset (Palant and Carter, 1972 ; Helmi and
Pruzansky, 1980 ; Shaver et al, 1986 ; Stewart
and O'Reilly, 1989). Anomalies include preauricular appendages, microtia, and stenosis or
atresia of the EAC, whereas sensory pathology
is attributed to a rudimentary cochlea, although
syndromic dependent (Sando et al, 1990). The
degree, severity, and acceleration of auditory erosion vary considerably in delayed hearing
impairment, and its onset may be observed dur-
Nosology of Deafness/Jacobson
ing the neonatal or early childhood period
(Bergstrom, 1984) .
These examples of congenital conditions
with delayed onset having hearing loss are generally the exception rather than the rule . Typically, infants with congenital syndromes have
Table 3
auditory deficits that are identifiable at birth .
Such an example is Jervell and Lange-Nielsen
syndrome, an autosomal-recessive hereditary
condition that presents with cardiac abnormalities characterized by a prolonged Q-T electrocardiographic pattern. Although milder states of
Classification System of Hearing Disorders by Type and Major System Dysfunction
Craniofacial and Skeletal Disorders
Nervous System Disorders
Endocrine and Metabolic Disorders
Sensory Hearing Loss
Cleidocranial dysostosis-D
Diastrophic dwarfism-D
Marshall syndrome-D
Townes syndrome-D
Sensory Hearing Loss
Cerebral palsy-R
Muscular dystrophy-R
Myoclonic epilepsy-R
Noonan syndrome-D
Richards-Rundel syndrome-R
Sensory Hearing Loss
Alstrom-R
Hyperprolinemia I-D
Iminoglycinuria-D
Pendred syndrome-R
Sickle cell anemia-D
Conductive Hearing Loss
Apert syndrome-D
Branchio-oto-renal syndrome-D
Carpenter syndrome-R
Fanconi's anemia symdrome-R
Goldenhar symdrome-R
Madelung deformity-D
Malformed, low-set ears-R
Mohr syndrome-R
Preauricular appendages-D
Proximal symphalangism-D
Symphalangism-D
Sensory and/or Conductive
Hearing Loss
Achondroplasia-D
Crouzon syndrome-D
Karmondy-Feingold-D
Klippel-Feil syndrome-R
Marfan syndrome-D
Myositis ossificans-D
Otopalatodigital syndrome-X
Pierre Robin sequence-D
Pyle disease-D
Stickler syndrome-D
Treacher Collins syndrome-D
Progressive Sensory and
Delayed Onset
Spondyloepiphyseal dysplasia
van Buchem syndrome-R
Progressive Sensory and/or
Conductive Hearing Loss
Albers-Schonberg disease-R
Cockayne syndrome-R
Englemann syndrome-D
Osteogenesis imperfecta-D
(types I-IV)
Otosclerosis-D
Paget disease-D
Progressive Sensory and
Delayed Onset
Acoustic neuromas-D
Friedreich ataxia-R
Herrmann syndrome-D
Myoclonic seizures-D
Sensory radicular neuropathy-D
Infantile muscular dystrophy-R
Renal Disorders
Conductive Hearing Loss
Branch io-oto-renal-D
Nephrosis, urinary tract
malformations-X/R
Oto-renal-genital syndrome-R
Taylor syndrome-R
Integumentary and
Pigmentary Disorders
Sensory Hearing Loss
Albinism syndrome-R/X
Congenital atopic dermatisis-R
Ectodermal dysplasia-D
Hypopigmentation-D
Keratopachyderma-R
Leopard syndrome-D
Neurofibromatosis-D
Onychodystrophy-R
Partial albinism-X/R
Pili torti-R
Waardenburg syndrome-D
Zinesser-Engman-Cole-X
Conductive Hearing Loss
Forney syndrome-D
Miscellaneous Somatic Disorders
Cardiovascular System Disorders
Sensory Hearing Loss
Trisomy 13-C
Trisomy 18-C
Sensory Hearing Loss
Jervell and Lange-Nielsen-R
Conductive Hearing Loss
Turner syndrome-C
Modified from Bergstrom et al, 1971 .
R = autosomal recessive, D = autosomal dominant, X = X-linked, C = chromosomal .
Sensory Progressive and
Delayed Onset
Alport syndrome-D
Amyloidosis, nephritis, and
urticaria-D
Hyperprolinemia II-D
Hyperuricemia-D
Primary testicular deletion-X/R
Progressive Sensory and/or
Conductive Hearing Loss
Hunter syndrome-X
Hurler syndrome-R
Eye Disorders
Sensory Hearing Loss
CHARGE Association
Hallgren syndrome-R
Laurence-Moon-Biedl syndrome-R
Usher syndrome-R
Conductive Hearing Loss
Cryptophthalmia-R
Duane retraction syndrome-D
Okihiro syndrome-R
Sensory and/or Conductive
Hearing Loss
Mobius syndrome-R
Progressive Sensory and
Delayed Onset
Alstrom syndrome-R
Cockayne syndrome-R
Fehr corneal dystrophy-R
Flynn-Aird syndrome-D
Norrie syndrome-R
Optic atrophy and
diabetes mellitus-R
Refsum syndrome-R
Journal of the American Academy of Audiology/Volume 6, Number 1, January 1995
hearing sensitivity have been reported (Corcos
et al, 1989), infants routinely present with congenital severe-to-profound bilateral sensory
hearing loss . This disorder affects about 0.3 percent of the congenitally deaf with the cases of
deafness representing 6 percent to 30 percent of
all the patients with a prolonged Q-T pattern
(Schwartz et al, 1975 ; Moss et al, 1985). Early
identification through the use of electrocardiographic and auditory brainstem response screening has helped to identify this potentially lifethreatening condition (Jacobson et al, 1990b) . In
all cases of congenital hereditary hearing loss
that are identified, appropriate referral sources
including genetic counseling must be strongly
underscored.
As early as 1971, Bergstrom and associates
adapted a classification scheme based on congenital hearing loss, major system dysfunction,
and type of auditory deficit, that is, conductive,
sensory, mixed, and progressive. This complex
myriad is similar to that fashioned by Konigsmark and Gorlin (1976; Table 2) and provides the
added benefit of type of hearing loss as an additional descriptor. For example, a congenital "sensory" hearing loss with integumentary disorder
includes Waardenburg syndrome, type I (with
lateral displacement of the inner canthi) and type
II (without dystopia), an autosomal-dominant
pattern with variable expressivity (Arias, 1971).
About half of type I families have been linked to
chromosome 2q (Asher and Friedman, 1990 ;
Table 4
Grundfast and San Agustin, 1992) . The frequency of sensory deafness is greater in type II
(McKusick, 1992). Syndromes of congenital "conductive" hearing loss with craniofacial and skeletal disorders include Apert syndrome (autosomal
dominant) and Goldenhar syndrome, a form of
hemifacial microsomia including microtia and
preauricular tags (Rollnick and Kaye, 1985).
The latter is considered a form of heterogeneous
inheritance including teratogenic, chromosomal
anomalies and evidence that about 2 percent of
the syndrome present as autosomal-dominant
inheritance (Regenbogen et al, 1982). Finally, a
"progressive" sensory hearing loss of delayed
onset and nervous system disorder includes neurofibromatosis (autosomal dominant, types I
and II ; see Pikus [19951, in this special issue) and
Friedreich's ataxia (autosomal recessive) . This
multifaceted classification system provides a
complex yet precise method of describing auditory disorders and is illustrated in Table 3.
Another method of classifying deafness was
reported by Glasscock et al (1988) and is presented in Table 4. This eclectic approach synthesizes both onset and origin as follows: (1) congenital nongenetic, (2) congenital genetic, (3)
delayed-onset nongenetic, and (4) delayed-onset
genetic. Glasscock and colleagues reasoned that
the use of origin (genetic versus nongenetic)
descriptors independent of onset was confining since parents may not be aware of the specific familial hearing history, and only follow-
Classification of Hearing Loss by Origin and Onset
Congenital Nongenetic
Congenital Genetic
Delayed-Onset Nongenetic
Hypothyroidism
Hypoxia/anoxia
Neonatal jaundice
Ototoxicity
Pierre Robin sequence
Duane syndrome
Radiation
Rh incompatibility
Rubella
Syphilis
Alpert syndrome
Cockayne syndrome
Chromosomal deficits
Crouzon syndrome
Meniere's disease
Hallgren syndrome
Jervell Lange-Nielsen
Klippel-Feil sequence
Leopard syndrome
Mobius syndrome
Oto-palatal-digital syndrome
Noonan syndrome
Pendred syndrome
Refsum syndrome
Sickle cell anemia
Treacher Collins syndrome
Turner syndrome
Usher syndrome
Waardenburg syndrome
Wildervanck syndrome
Acoustic neuroma
Chronic otitis media
Cytomegalovirous
Fetal alcohol syndrome
Juvenile hypothyroidism
Meningitis
Neoplastic disease
Perilymph fistula
Persistent pulmonary
hypertension
Pseudohypoacusis
Trauma
Tuberculosis
Unknown
Modified from Glasscock et al, 1988 .
Delayed-Onset Genetic
Alport syndrome
Alstrom syndrome
Branch io-oto-renal
Crouzon syndrome
Freidreich ataxia
Hunter syndrome
Hurler syndrome
Laurence-Moon-Biedl
Mucopolysaccharidoses
Noorie syndrome
Neurofibromatoses II
Neurofibromatoses II
Osteogenesis imperfecta I
Otosclerosis
Pyle disease
Nosology of Deafness/Jacobson
ing the detection of family members or affected
offspring would the nature of the genetic hearing loss be accurately identified . Conversely,
using only onset as the exclusive method of
classification is also self-constraining, that is,
infants born severely physically compromised
are often too ill and/or neurologically premature
to be screened for hearing loss prior to hospital
discharge. Frequently, these same infants are
released from the hospital with potentially
unrecognized auditory deficits . In such cases in
which hearing impairment is eventually recognized, hearing loss may have been truly congenital but undetected. Thus, auditory disorders
tend to be lost in the larger picture of morbidity and, subsequently, deafness and/or hearing
loss when discovered may be misclassified as
acquired . The value of this four-component
interactive classification system is simplicity.
Finally, Jones (1988) ascribes to a genetic
classification system that uses recognizable patterns of malformation . Each anomaly includes
syndromes in which defects are listed as either
the frequent or occasional feature. Two categories pertinent to this discussion are deafness
and external ears (low-set ears, malformed auricles, and preauricular tags or pits). For a catalogue of this application, see Hall et al (1995) in
this special issue, specifically Table 2.
SUMMARY
t is beyond the expectations of any hearing
health care professional to commit to memory every auditory disorder that causes hearing loss . Suffice it to say that this article is
intended to provide only a brief introduction to
the nosology of deafness and hearing loss . The
listing of various classification schemes found
within the tables contained in this article should
not be considered inclusive but rather as a
quick reference to be used as a first, not primary, source of information. It is important to
recognize that many books and articles are
currently available that provide specific details
regarding auditory deficits, their origin, and
onset. The reader is encouraged to review several excellent sources, including Pediatric Otolaryngology (Bluestone and Stool, 1990), Syndromes of the Head and Neck (Gorlin et al,
1990), Smith's Recognizable Patterns ofHuman
Malformations (Jones, 1988), and Mendelian
Inheritance in Man (McKusick, 1992). As our
knowledge of new technology in human genetics improves, so will our ability to diagnose
and manage inherited syndromes and other
auditory deficits in infants and children .
Acknowledgment. The author would like to acknowledge Shelley Smith, Ph .D . FACMG, Boys Town National
Research Hospital and Marie T. Greally, M.D ., Eastern
Virginia Medical School for their review of and thoughtful suggestions on earlier versions of this manuscript.
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