Biology Reference
In-Depth Information
A possible pitfall to this line of associative reasoning is that a syndrome
may be caused by a contiguous gene deletion, or by linked mutations
in separate genes. In this circumstance, a hearing loss gene may be altered
in association with a separate gene(s) causing pathology in another organ
system. This was observed in a kindred originally used to identify
DFNB1
(Kelsell et al. 1997) in which autosomal dominant palmoplantar kerato-
derma (PPK) was also segregating. Clinical ascertainment of that pedigree
identified 3 individuals with PPK but without hearing loss, and linkage of
GJB2
was demonstrated with the hearing loss phenotype but not the PPK
phenotype. This kindred illustrates how contiguous gene deletions or
co-segregation of mutations have the potential to confound the linkage
analysis and any conclusions regarding shared pathogenetic mechanisms
between the affected organ systems.
Approximately 100 genes for syndromic hearing loss have now been
mapped, and over 60 of these have been identified (Table 6.5). Some of
these genes and their corresponding mutations have provided interest-
ing and novel insights into the development and function of the auditory
system. The following review will focus on six forms of syndromic hearing
loss in which at least some of the causative genes have been identified, and
the resulting molecular data has raised and/or answered important ques-
tions regarding the molecular basis of auditory function and hearing impair-
ment. A discussion of all forms of syndromic hearing loss (Gorlin et al.
1995) in which the genes have been mapped or identified would require its
own volume. Table 6.5 summarizes some of the essential features of approx-
imately 100 forms of syndromic hearing loss.
It is clinically important to identify the cause of hearing loss in families
where in auditory dysfunction is accompanied by other serious problems,
such as heart conduction problems (Jervell and Lange-Nielsen syndrome),
progressive nephritis (Alport syndrome), or progressive loss of vision
(Usher syndrome). Within the congenitally hearing impaired population,
the incidences of these three syndromes are estimated to be 0.25%, 1.0%,
and 3 to 8%, respectively (Gorlin et al. 1995; Vernon 1959). Hearing loss
may be detected before manifestation of other organ system pathologies
in all three of these syndromes. For example, the hearing loss in Jervell
and Lange-Nielsen syndrome may be evident before the onset of fainting
attacks or detection of a cardiac arrhythmia. Life-saving anti-arrhythmic
therapy may thus be initiated prophylactically (Ackerman 1998).
5.1 Stickler Syndrome
5.1.1 Phenotype
Stickler syndrome (OMIM 108300, 184840) is an autosomal-dominant dis-
order characterized by progressive sensorineural hearing loss, skeletal dys-
plasia, craniofacial dysmorphism, cataracts, and myopia. Marshall syndrome
