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
Gene(s)/ Genetic Mechanism | Differential Disorder | MOI | Selected Features of Differential Disorder |
|---|
Endocrine abnormalities | Eye findings | Hearing loss | Neurologic abnormalities ALMS1 |
Alstrm syndrome | AR | Insulin resistance/ type 2 DM often presents in 2nd decade. Other endocrine abnormalities incl hypogonadotropic hypogonadism in boys, polycystic ovaries in girls, hypothyroidism. Obesity common, leading to non-alcoholic fatty liver disease. | Cone-rod dystrophy presents as progressive visual impairment, photophobia, nystagmus starting between birth age 15 mos; no light perception by age 20 yrs in many persons. |
Bardet-Biedl syndrome | AR | Insulin resistance/ type 2 DM in adolescence or adulthood; male hypogonadotropic hypogonadism. Obesity is common. | Cone-rod dystrophy; night blindness usually evident by age 7-8 yrs; mean age of legal blindness is 15.5 yrs. |
DMPK | Myotonic dystrophy type 1 (DM1) | AD | DM is common in mild classic DM1. |
Source: GeneReviews — "WFS1 Spectrum Disorder"
