Clinical characteristics: WFS1 spectrum disorder (WFS1-SD) comprises classic WFS1 spectrum disorder and nonclassic WFS1 spectrum disorder.

1. Classic WFS1-SD, a progressive neurodegenerative disorder, is characterized by onset of diabetes mellitus and optic atrophy before age 16 years. Additional complications may include one or more of the following: variable hearing impairment / deafness, diabetes insipidus, neurologic abnormalities, neurogenic bladder, and psychiatric abnormalities.

2. Nonclassic WFS1-SD is less common than classic WFS1-SD. Phenotypes that appear to be milder than classic WFS1-SD include: optic atrophy and hearing impairment; neonatal diabetes, profound congenital deafness, and cataracts; isolated diabetes mellitus; isolated congenital cataracts; and isolated congenital, slowly progressive, and low-frequency (<2000 Hz) sensorineural hearing loss.

Diagnosis/testing:

1. Classic WFS1-SD. The diagnosis is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in WFS1 identified by molecular genetic testing.

2. Nonclassic WFS1-SD. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant identified by molecular genetic testing.

Management: There is no cure for WFS1-SD.

Treatment of manifestations: Supportive care (based on the manifestations of classic or nonclassic WFS1-SD) is often provided by multidisciplinary specialists in diabetic care, endocrinology, ophthalmology and low vision, audiology, speech-language therapy, neurology, pulmonology, psychiatry / psychology / mental health, urology, gastroenterology, social work, and medical genetics.

Surveillance: For both classic and nonclassic WFS1-SD, regular monitoring of existing manifestations, the response of an individual to supportive care, and the emergence of new manifestations is recommended.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment for the earliest manifestations of WFS1-SD: diabetes mellitus, optic atrophy, and sensorineural hearing loss.

Pregnancy management: Pregnant women with insulin-dependent diabetes mellitus, a characteristic of both classic and nonclassic WFS1-SD, have a two- to eightfold higher risk of having a child with a birth defect or a pattern of birth defects (diabetic embryopathy) than women who do not have diabetes. Optimizing glucose control before and during pregnancy can reduce – but not eliminate – the risk for diabetic embryopathy. Because women with classic WFS1-SD may develop diabetes insipidus during pregnancy, monitoring for diabetes insipidus during pregnancy is warranted. Consultation with a maternal fetal medicine specialist during pregnancy should be considered for all women with WFS1-SD.

Genetic counseling:

1. Classic WFS1-SD is caused by biallelic WFS1 pathogenic variants and is inherited in an autosomal recessive manner. If both parents are 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 inheriting neither of the familial pathogenic variants.

2. Nonclassic WFS1-SD is caused by a heterozygous pathogenic variant and can either be inherited in an autosomal dominant manner from an affected parent or result from a de novo WFS1 pathogenic variant. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. If the WFS1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism.

3. Both classic and nonclassic WFS1-SD. Once the WFS1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for classic and nonclassic WFS1-SD are possible.