Clinical Guidance

No genotype-phenotype correlations have been identified for classic WFS1-SD or nonclassic WFS1-SD.

Source: GeneReviews — "WFS1 Spectrum Disorder"

Diagnostic Criteria

Suggestive Findings – Classic WFS1 Spectrum Disorder

Classic WFS1-SD should be suspected in individuals with any of the following clinical findings and family history. Major clinical findings :

• Diabetes mellitus (onset age usually 16 years)

• Optic atrophy (onset age usually 16 years)

Additional clinical findings may include one or more of the following:

• High-tone sensorineural hearing impairment

• Cerebellar ataxia

• Psychiatric illness

• Neurogenic bladder (overactive or underactive)

• Other endocrine findings:

• Central diabetes insipidus

• Delayed puberty, particularly in males, associated with hypogonadism

• Non-autoimmune hypothyroidism

• Structural congenital heart defects

Source: GeneReviews — "WFS1 Spectrum Disorder"

Differential Diagnosis

Wolfram syndrome type 2 (WS2) (OMIM 604928) is an autosomal recessive disorder caused by biallelic pathogenic variants in CISD2. Like classic WFS1 spectrum disorder (WFS1-SD), WS2 presents as a continuum of clinical features; however, the full clinical spectrum of WS2 abnormalities has not yet been fully established because so few affected individuals have been described. To date, the following clinical features have been reported in individuals with WS2: • Families of Palestinian Arab origin have been described with juvenile-onset diabetes mellitus, optic atrophy, high-frequency sensorineural hearing impairment, urinary tract dilatation, impaired kidney function, hypogonadism, and severe gastrointestinal ulcer and bleeding ; abnormal facial features were described in one family . • Diabetes insipidus, psychiatric abnormalities, and variable degrees of optic atrophy have been reported in individuals from Italy and Morocco . Peptic ulcers, mucocutaneous bleeding, and defective platelet aggregation were also described in a subset of these individuals. Note: A novel CISD2 pathogenic variant (c.215AG; p.Asn72Ser) was identified in an individual with clinical findings suggestive of classic WFS1-SD who did not have WFS1 pathogenic variants . Other Genetic Causes of Features Seen in WFS1 Spectrum Disorder Hearing impairment. See Genetic Hearing Loss Overview. Monogenic diabetes syndromes. See . Table 3. Monogenic Diabetes Syndromes in the Differential Diagnosis of WFS1 Spectrum Disorder

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with classic or nonclassic WFS1 spectrum disorder (WFS1-SD), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. See also Wolfram Syndrome Clinical Management Guidelines, page 5, for recommended baseline investigations.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Classic or Nonclassic WFS1 Spectrum Disorder

System/Concern | Evaluation | Comment

Diabetes mellitus

| By diabetologist |

Optic atrophy

| Ophthalmologic eval | • Assess extraocular movement, best corrected visual acuity, visual evoked potentials.

• Perform color vision testing, visual field testing, optical coherence tomography, fundus exam.

Optometry /or low-vision clinic | Assess for low-vision aids.

Sensorineural

hearing impairment | • Audiologic exam

• Eval by speech-language therapist

| Incl:

• Auditory brain stem responses to confirm pathology provide baseline

• Evoked otoacoustic emissions to identify type of hearing impairment

• Audiogram

• Speech discrimination tests

• Assessment for hearing aids; children w/profound infancy-onset deafness may require cochlear implant.

Neurologic

dysfunction | Neurologic exam incl brain MRI (if not performed previously) | Evaluate for:

Source: GeneReviews — "WFS1 Spectrum Disorder"

Therapies Under Investigation

For a review of current and future therapeutic strategies, see . Classic WFS1-SD. An ongoing multicenter randomized double-blind controlled pivotal clinical trial is evaluating the use of sodium valproate to slow the progression of neurodegeneration (EudraCT Number 2017-001215-37). Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "WFS1 Spectrum Disorder"

Surveillance Guidelines

See also Wolfram Syndrome Clinical Management Guidelines, pages 6-12, for surveillance recommendations. Classic WFS1 Spectrum Disorder To monitor existing manifestations, the response of an individual with classic WFS1-SD to supportive care, and the emergence of new manifestations, the evaluations in are recommended. Table 7. Recommended Surveillance for Individuals with Classic WFS1 Spectrum Disorder

Source: GeneReviews — "WFS1 Spectrum Disorder"