WFS1-Related Disorders

[Includes: DFNA6/14/38 Nonsyndromic Low-Frequency Sensorineural Hearing Loss (WFS1-Related Low-Frequency Sensory Hearing Loss); Wolfram Syndrome (DIDMOAD; Wolfram Syndrome-Like Disease)]

Clinical Diagnosis

WFS1-related disorders include a phenotypic spectrum ranging from Wolfram syndrome (WFS) to WFS1-related low-frequency sensory hearing loss (also known as DFNA6/14/38 LFSNHL).

Wolfram syndrome (WFS), sometimes referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). The following are sensitive and specific for WFS [Barrett et al 1995]:

• Juvenile-onset (before age 15 years) diabetes mellitus

• Juvenile-onset optic atrophy

• Autosomal recessive inheritance

Additional clinical features include:

• Sensorineural hearing impairment (which can sometimes be congenital and severe)

• Ataxia

• Dementia/ mental retardation (both may occur, but mental retardation is rare)

• Psychiatric disease

• Neurogenic bladder

• Other endocrine findings:

  • Diabetes insipidus

  • Delayed/absent puberty; hypogonadism in males

  • Hypothyroidism

  • Growth retardation

• Cardiomyopathy

Wolfram syndrome-like disease, described in two families with the same mutation in exon 8, includes:

• LFSNHL

• Diabetes mellitus

• Psychiatric illness

• Optic atrophy (present in the family of Eiberg et al [2006]; absent in the family of Valéro et al [2008])

• Autosomal dominant inheritance

WFS1-related low-frequency sensory hearing loss is congenital, nonsyndromic, slowly progressive, and low frequency (<2000 Hz). Because it is mild and involves the low frequencies, this hearing loss is often not diagnosed until after language is acquired. Note: This disorder has also been identified by mapping studies as DFNA6/14/38 nonsyndromic LFSNHL.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Gene. WFS1 is the only gene associated with WFS1-related disorders [Inoue et al 1998].

Clinical testing

• Sequence analysis. Most known mutations are located in the large exon 8; mutations are also found in exons 3, 4, 5, and 6 (see Table C).
  
  In 90% of individuals with findings of WFS, the diagnosis can be confirmed by the identification of at least one mutation in WFS1 [Khanim et al 2001].
  
  Only two families with WFS-like disease caused by a heterozygous WFS1 (p.Glu864Lys) mutation have been reported [Eiberg et al 2006, Valéro et al 2008].

Research testing. Deletion/duplication testing (e.g., multiplex ligation-dependent probe amplification [MLPA]) can detect larger genomic deletions/duplications, but the frequency of exonic, multiexonic, and whole-gene deletions/duplications in WFS1-related disorders is unknown [Berg et al 2007]. MLPA testing of a cohort of individuals with WFS who are negative by sequence analysis remains to be performed.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in WFS1-Related Disorders

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method and Phenotype			Test Availability
			WFS	WFS-like	DFNA6/14/38
WFS1	Sequence analysis	Sequence variants	90% 1	Two families 2	100% 3	Clinical
	Deletion/ duplication testing 4	Partial- and whole-gene deletion/ duplication	Unknown			Research

1. Khanim et al [2001]

2. Eiberg et al [2006], Valéro et al [2008]

3. Smith et al [2004]

4. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative polymerase chain reaction (PCR), long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or array CGH (see ) may be used.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Individuals with typical WFS with only one apparent de novo WFS1 missense mutation [Hansen et al 2005] remain unexplained. These two unrelated individuals may have a second undetectable mutation (e.g., promoter region) or the missense mutation, which is the same in both individuals, may not be pathologic. The development of a functional assay may address the latter possibility.

Testing Strategy

Confirming/establishing the diagnosis in a proband

• The diagnosis of WFS and Wolfram-like syndrome is based on clinical findings and confirmed by findings on molecular genetic testing.

• The diagnosis of WFS1-related LFSNHL is established by molecular genetic testing.

Carrier testing for relatives at risk for autosomal recessive WFS requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for the autosomal recessive disorder WFS and are not at risk of developing WFS.

Predictive testing for:

• Asymptomatic family members at risk for autosomal recessive WFS requires prior identification of the disease-causing mutations in the family;

• Asymptomatic family members at risk for autosomal dominant WFS-like disease require prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Genetically Related (Allelic) Disorders

Heterozygotes for WFS1 mutations. Relatives of individuals with WFS do not have increased risk of hearing impairment [Pennings et al 2004], but it is as yet unknown whether they could be at higher risk for diabetes mellitus and psychiatric disorders [Swift et al 1998].

• Although a number of WFS1 mutations have been associated with increased risk for suicide (Kresge database), causal correlation is not proven [Swift & Swift 2000, Crawford et al 2002, Martorell et al 2003, Sequeira et al 2003, Aluclu et al 2006].

• Several studies now convincingly show a strong association between sequence abnormalities of WFS1 and type 2 diabetes mellitus (OMIM 605290, OMIM 165500) in the absence of other systemic findings [Minton et al 2002, Sandhu et al 2007, Franks et al 2008, Wasson & Permutt 2008]. The implications of this association in terms of a possible risk of multiple organ involvement have not yet been studied [Payne et al 2004, Amati-Bonneau et al 2005, Sandhu et al 2007, Franks et al 2008, Wasson & Permutt 2008].

Natural History

A comprehensive review of WFS1 and its role in different clinical presentations is available [Tranebjærg 2008].

Genotype-Phenotype Correlations

Wolfram syndrome. The clinical course of WFS is highly variable, even within a family, and is not predictable from the type or location of the mutation.

Cano et al [2007a] found that two WFS1 alleles, both with inactivating mutations, predisposed to an earlier age of onset of both diabetes mellitus and optic atrophy. Moreover, the clinical expression of WFS was more complete and occurred earlier in individuals harboring no missense mutation.

Wolfram-like syndrome. Two families have been identified with WS-like features that are inherited in an autosomal dominant manner (i.e., only one WFS1 mutation segregating in the family) [Eiberg et al 2006]; in another family the same missense mutation was associated with co-segregation of hearing impairment and diabetes mellitus, but no optic atrophy [Valéro et al 2008].

Prevalence

Wolfram syndrome. More than 90 individuals from more than 60 families have been described worldwide [Khanim et al 2001, Tessa et al 2001, Domènech et al 2002, Colosimo et al 2003, Cryns et al 2003, Den Ouweland et al 2003, Simsek et al 2003, Smith et al 2004, Giuliano et al 2005, Hansen et al 2005, Cano et al 2007b].

A study from the UK estimated a prevalence of WFS of 1:550,000 children in the UK [Barrett et al 1995]. No valid estimate of prevalence is possible if atypical presentations (e.g., autosomal dominant WS-like disorder, autosomal dominant LFSNHL caused by WFS1 mutations) are included.

DFNA6/14/38 (WFS1-related LFSNHL)

• Mutations in WFS1 were identified in ten families out of 13 families with autosomal dominant LFSNHL in whom linkage studies either showed linkage or were compatible with linkage to chromosome 4p [Bespalova et al 2001, Young et al 2001, Cryns et al 2002].

• In five of 30 Danish families [Tranebjærg et al 2004] and three of nine Japanese families [Fukuoka et al 2007] with characteristic findings on audiogram and/or a positive family history that were unsuitable for linkage analysis, molecular genetic testing showed WFS1 mutations.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a WFS1-related disorder, the following evaluations are recommended:

Wolfram syndrome and Wolfram-like syndrome

• Glucose tolerance test (if not already performed)

• Eye examination, including visual acuity, color vision, and visual fields

• Audiologic examination, including auditory brain stem responses (ABRs) and evoked otoacoustic emissions

• Neurologic examination

• Neuroimaging with MRI

• Developmental assessment in young children and assessment of cognitive abilities in older children and adolescents

• Baseline psychologic assessment

• Urologic consultation with imaging studies of the urinary tract and kidneys

• Test of the concentrating ability of urine to evaluate for diabetes insipidus

Low-frequency sensorineural hearing loss (LFSNHL)

• Audiologic examination

Treatment of Manifestations

Diabetes mellitus. Treatment follows routine practices for insulin-dependent diabetes mellitus.

Optic atrophy. Treatment of decreased visual acuity is symptomatic (e.g., low-vision aids).

Hearing impairment

• WFS. Hearing loss is managed with either hearing aids or cochlear implant depending on the degree of hearing impairment and the frequencies affected.

• Low-frequency sensorineural hearing loss (LFSNHL). Hearing aids should be tried early on, but may not be necessary until later in the disease course when a broader range of frequencies is involved. Hearing should be assessed throughout childhood in order to provide hearing aids when clinically indicated.

Developmental delay/cognitive impairment. Treatment follows routine practices.

Psychiatric difficulties. Treatment follows routine practices.

Neurogenic bladder. Treatment follows routine practices. Patients with recurrent urinary infections, urodynamic abnormalities, and incomplete bladder emptying must be treated according to established protocols for these abnormalities, like clean intermittent self-catheterizations or indwelling catheter, and frequent surveillance of presence of urinary infections.

Other

• Treatment of central diabetes insipidus follows routine practices.

• Treatment of gastroparesis and celiac disease follows routine practices. (See Celiac Disease.)

Surveillance

Wolfram syndrome. Regular evaluations including the following to detect manifestations that can occur with time:

• Diabetes mellitus: tests of glucose tolerance

• Optic atrophy: ophthalmologic examination

• Sensorineural hearing loss: audiologic examination including speech discrimination testing

• Neurologic deficits: neurologic examination including assessment of memory, personality changes

• Psychiatric abnormalities: assessment for signs including depression, suicidal behavior, and changes in personal appearance and social behavior

• Urologic abnormalities: urodynamic examination and assessment of ability to empty the bladder. Regular urine cultures when bladder dysfunction or other renal tract abnormality is present.

• Diabetes insipidus: assessment of concentrating ability of the urine

• Growth delay: monitoring of linear growth in children using standard growth charts

• Hypogonadism

• Puberty: monitoring for signs of onset of puberty

Once diabetes mellitus is present, regular follow-up for complications that can occur with time, including evaluations for:

• Diabetic retinopathy

• Bowel dysfunction

Because women with WFS may develop diabetes insipidus during pregnancy [Rugolo et al 2002], monitoring for diabetes insipidus during pregnancy is warranted.

Low-frequency sensorineural hearing loss (LFSNHL). Regular audiologic examination including speech discrimination testing is appropriate.

Testing of Relatives at Risk

Wolfram syndrome. Sibs of a proband warrant either molecular genetic testing (if the family-specific mutations are known) or screening for the earliest manifestations of WFS (i.e., diabetes mellitus, optic atrophy, and sensorineural hearing loss) to allow for early diagnosis and treatment.

Low-frequency sensorineural hearing loss (LFSNHL). At-risk relatives should be encouraged to seek either molecular genetic testing (if the family-specific mutation is known) or audiologic evaluation because the earliest manifestations of low-tone hearing loss may not be appreciated clinically.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.

Mode of Inheritance

Wolfram syndrome is inherited in an autosomal recessive manner. Individuals with typical Wolfram syndrome (WFS) who have apparently only one, and in some cases, de novo mutations have been reported [Hansen et al 2005].

Wolfram syndrome-like disease is inherited in an autosomal dominant manner.

DFNA6/14/38 nonsyndromic low-frequency sensorineural hearing loss (WSF1-related LFSNHL) is inherited in an autosomal dominant manner.

Risk to Family Members –Autosomal Recessive Inheritance

Parents of a proband

• The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic although conflicting reports exist on the possibility of an increased risk of psychiatric symptoms [Pennings et al 2004].

Offspring of a proband. The offspring of an individual with WFS are obligate heterozygotes (carriers) for a disease-causing mutation in WFS1.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible once the disease-causing mutations have been identified in the family.

Risk to Family Members –Autosomal Dominant Inheritance

Parents of a proband

• Most individuals diagnosed with WFS-like disease or DFNA6/14/38 have an affected parent.

• A proband with WFS-like disease or DFNA6/14/38 may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been documented it remains a possibility, as there are reports of apparently de novo mutations in individuals with WFS.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include hearing evaluation, physical examination, and molecular genetic testing of WFS1 if the mutation has been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with WFS-like disease or DFNA6/14/38 have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband’s parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.

• When the parents are clinically unaffected and neither has a WFS1 mutation, the risk to the sibs of a proband appears to be low.

• The sibs of a proband with clinically unaffected parents are still at increased risk (for the disorder) because of the possibility of reduced penetrance in a parent.

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with WFS-like disease or DFNA6/14/38 has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele(s) of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Acknowledgments

The Audiogenetic Research Group, headed by Lisbeth Tranebjærg, receives financial support from Widex AS and other research grants.

Revision History

• 24 February 2009 (me) Review posted live

• 12 August 2008 (lt) Original submission