Wfs1 Wolfram Syndrome Spectrum Disorder

Clinical characteristics.

WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus (DM) and optic atrophy (OA) before age 16 years, and typically associated with other endocrine abnormalities, sensorineural hearing loss, and progressive neurologic abnormalities (cerebellar ataxia, peripheral neuropathy, dementia, psychiatric illness, and urinary tract atony). Although DM is mostly insulin-dependent, overall the course is milder (with lower prevalence of microvascular disease) than that seen in isolated DM. OA typically results in significantly reduced visual acuity in the first decade. Sensorineural hearing impairment ranges from congenital deafness to milder, sometimes progressive, hearing impairment.

Diagnosis / testing.

The diagnosis of WFS1-WSSD is established in a proband with suggestive findings and biallelic pathogenic variants in WFS1 by molecular genetic testing.

Management.

Treatment of manifestations: Recommendations (based on detailed clinical guidelines for Wolfram syndrome) include routine management by multidisciplinary specialists for the following: insulin-dependent DM; OA; hearing impairment; mobility and activities of daily living; dysarthria; dysphagia; endocrine disorders; developmental delay/intellectual disability; neurogenic bladder; and psychiatric/behavioral issues.

Surveillance: Routine follow up evaluations to assess effectiveness of ongoing care and to identify new disease manifestations.

Genetic counseling.

WFS1-WSSD is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for a WFS1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the WFS1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) should be suspected in individuals with the following clinical findings and family history.

Clinical findings [Barrett et al 1995, Urano 2016]:

• Diabetes mellitus (onset age <15 years)
• Optic atrophy (onset age <15 years)
• High-tone sensorineural hearing impairment (sometimes congenital and severe)
• Cerebellar ataxia
• Dementia / intellectual disability (Both may occur, but intellectual disability is rare.)
• Psychiatric disease
• Neurogenic bladder or bladder dyssynergia
• Other endocrine findings:
  • Central diabetes insipidus
  • Delayed / absent puberty; hypogonadism in males
  • Non-autoimmune hypothyroidism
  • Growth retardation
• Cardiomyopathy and structural congenital heart defects

Family history consistent with autosomal recessive inheritance

Establishing the Diagnosis

The diagnosis of WFS1-WSSD is established in a proband with biallelic pathogenic variants in WFS1 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of WFS1-WSSD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of WFS1-WSSD has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Typical autosomal recessive WFS1 Wolfram syndrome spectrum disorder (WFS1-WSSD) features are childhood-onset diabetes mellitus, optic atrophy, hearing impairment/deafness, diabetes insipidus, neurologic abnormalities, and psychiatric abnormalities (see Table 2).

Note: This GeneReview focuses on Wolfram syndrome spectrum disorder caused by biallelic WFS1 pathogenic variants. Wolfram syndrome-like disorder, caused by heterozygous WFS1 pathogenic variants and associated with a clinical spectrum overlapping that of autosomal recessive WFS1-WSSD, is addressed in Genetically Related Disorders.

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

WFS1-WSSD is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus and optic atrophy before age 15 years, and typically associated with sensorineural hearing loss, progressive neurologic abnormalities, and other endocrine abnormalities. Almost every organ system may be affected; however, because only a minority of published cases have had extensive clinical workup, the natural history of these multiorgan findings in WFS1-WSSD is largely unknown.

The natural history of Wolfram syndrome was described in 45 individuals in 29 families in the UK [Barrett et al 1995]. Hearing impairment was present in 64% by age 20 years. Sixty percent of all individuals studied (mean age 16 years, range 5-32 years) had one or more of the following: cerebellar ataxia, peripheral neuropathy, intellectual disability, dementia, psychiatric illness, and urinary tract atony. Life span was considerably shortened. In the families of British, Pakistani, and mixed Arab/African origin, WFS1 pathogenic variants were subsequently identified in 17 of 19 probands [Hardy et al 1999].

Diabetes mellitus (DM). Median age of onset of DM was before age ten years (age range <1-17 years). Almost all with DM were insulin dependent. DM may present with ketoacidosis; however, overall the course is milder than that seen in isolated DM, with lower prevalence of microvascular disease [Cano et al 2007a] and microvascular retinopathy.

Optic atrophy (OA). OA occurs eventually in all known individuals with WSSD. OA is progressive: the median age of onset is before ten years; after a median of eight years visual acuity is reduced to about 6/60 in most individuals [Barrett et al 1995]. Note: Visual acuity of 6/60, signifying that the tested person sees at six meters what an average person sees at 60 meters, is the definition of "registered blind" in the UK and "legally blind" in the US.

Other ophthalmologic findings reported in WSSD but not confirmed as part of the phenotype:

• Cataract, described in eight individuals [Hansen et al 2005]. Cataract may be a frequent, but underdiagnosed, finding. See Genetically Related Disorders for a description of isolated autosomal dominant congenital cataract due to a pathogenic missense variant in WFS1.
• Pigmentary retinopathy rather than optic atrophy in one person [Dhalla et al 2006]
• Nystagmus

Sensorineural hearing impairment, present in about 66% of individuals with WSSD, ranges from congenital deafness to a milder, sometimes progressive sensorineural hearing impairment. Median age of onset was 12.5 years [Barrett et al 1995]. Audiograms show a downsloping progressive pattern of hearing loss [Pennings et al 2004]. Among individuals with inactivating WFS1 variants, five females were significantly more hearing impaired than four males, giving rise to speculation that hormonal factors may modulate hearing loss [Pennings et al 2004]. A multicenter study confirmed the preferential involvement of high frequencies and the slowly progressive rate of hearing loss, but did not confirm any gender differences in degree of hearing loss [Plantinga et al 2008].

Deterioration in speech recognition score with increasing age is more pronounced than could be explained by age-related decline in hearing alone, suggesting that progressive central nervous system involvement may also account for difficulties with speech over time [Pennings et al 2004].

Note: Although experience is limited, abnormal vestibular function does not appear to be a prominent feature of WFS1-WSSD. Among six individuals with WFS1-WSSD who were evaluated, only one had vestibular areflexia [Pennings et al 2004]. Balance problems may be the result of neurologic movement abnormalities.

Neurologic abnormalities were present in 62% of the individuals (mean age 30 years, range 5-44 years) studied by Barrett et al [1995] before molecular confirmation of the diagnosis was possible. However, very limited data are available regarding the frequency of the types of neurologic abnormalities.

Current experience indicates the presence of neurologic findings by the fourth decade with an onset typically between the first and second decade.

Neurologic findings are progressive and result from general brain atrophy with brain stem and cranial nerve involvement [Barrett et al 1995, Pakdemirli et al 2005, Domenech et al 2006]. Abnormal cerebral MRIs found in eight of 45 individuals typically showed generalized brain atrophy most prominently of the cerebellum, medulla, and pons; and reduced signal intensity of the optic nerves and the posterior part of hypothalamus [Barrett et al 1995]. The correlation between brain atrophy on MRI and clinical findings is not always strong [Ito et al 2007].

• Truncal or gait ataxia was found in 15 of 45 individuals studied [Barrett et al 1995].
• Episodes of apnea, a serious manifestation, occurred in five of 45 individuals studied [Barrett et al 1995].
• Dementia is seen as part of the wider neurodegeneration in older patients. Intellectual disability is not common.
• A significantly increased risk of suicidal behavior and psychiatric illness requiring hospitalization has been observed [Swift et al 1998].

Other endocrine findings

• Diabetes insipidus of central origin occurred in 72% with a median age of onset of 15.5 years. The range in age of onset is broad, possibly because of delays in establishing the correct diagnosis.
• Hypogonadism is more prevalent in males than in females. It can be either hypogonadotropic (i.e., central) or hypergonadotropic (i.e., secondary to gonadal failure). The underlying pathology of either type is not understood. Females usually retain their ability to become pregnant; about six successful pregnancies are described in the literature. One female had absence of the uterus [Tranebjærg, personal observation].
• Hypothyroidism. Frequency is not known.
• Growth retardation. Most adults have normal height, but growth retardation is not infrequent. The age of onset of puberty varies.

Urinary tract. Dilated renal outflow tracts (hydroureter), urinary incontinence, and recurrent infections are common signs of neurogenic bladder. Fifty-five percent of 29 index patients had such signs with median age of onset of 22 years (age range: 10-44 years) [Barrett et al 1995]. Urodynamic examinations showed incomplete bladder emptying or complete bladder atony.

Gastrointestinal dysmotility and celiac disease. Constipation, chronic diarrhea, and other bowel dysfunction is reported in 25% of individuals with WFS1-WSSD, sometimes the result of gluten intolerance, which is 20 times more frequent in those who have had diabetes mellitus for several years [Barera et al 2002, Skovbjerg et al 2005, Liu et al 2006] (see Celiac Disease).

Cardiomyopathy. No data on frequency are available.

Causes of death. Ten of the 45 individuals reported in the study of Barrett et al [1995] had died. The median age at death was 30 years. Reports suggest 65% mortality by age 35 years. It must be kept in mind, however, that a bias toward reporting the most severe cases of WSSD in the literature may skew these figures. The causes of death were hypoglycemic coma, status epilepticus, end-stage renal disease from recurrent urinary tract infection, and suicide. Three individuals died from central respiratory failure associated with brain stem atrophy.

Neuropathology. Currently the only published reports are of clinically diagnosed individuals; neuropathology of molecularly confirmed cases has not yet been published. In two cases the findings included atrophy of the olfactory bulbs, optic nerves, pontine nuclei, inferior olive, and dentate nuclei of the cerebellum; loss of cochlear ganglion cells; and mild loss of neurons in the spinal cord [Genís et al 1997, Shannon et al 1999].

Genotype-Phenotype Correlations

The clinical course of WFS1-WSSD is highly variable, even within a family, and is not predictable from the type or location of the pathogenic variant.

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

Nomenclature

Wolfram syndrome has sometimes been referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness).

Prevalence

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, Simsek et al 2003, van den Ouweland 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 WSS of 1:550,000 children in the UK [Barrett et al 1995].