Compound Heterozygous Mutations in WFS1 Cause Atypical Wolfram Syndrome

Compound Heterozygous Mutations in WFS1 Cause Atypical Wolfram Syndrome

Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), is a rare autosomal recessive disorder primarily caused by mutations in the WFS1 or CISD2 genes. The prevalence of WS is estimated to be between one in 160,000 to one in 770,000 individuals. This syndrome is characterized by a progressive neurodegenerative course, with patients typically presenting with insulin-dependent diabetes mellitus (DM) around the age of six, followed by optic atrophy (OA) around the age of eleven. Additional symptoms, such as diabetes insipidus, sensorineural deafness, urinary tract abnormalities, and neuropsychiatric disorders, may develop later in life. The average life expectancy for individuals with WS is between 30 to 40 years, with respiratory failure being the most common cause of death.

The genetic basis of WS is complex, with mutations in the WFS1 gene being the most common cause. WFS1 encodes wolframin, a protein involved in endoplasmic reticulum function. While WS is typically inherited in an autosomal recessive manner, some pathogenic mutations in WFS1 can exhibit a dominant inheritance pattern, leading to a milder form of the disorder known as Wolfram-like syndrome. This variant is associated with hearing impairment, OA, DM, and psychiatric problems.

This report describes a case of atypical WS in a 19-year-old Chinese male who presented with non-insulin-dependent DM and OA. The patient’s condition was attributed to compound heterozygous mutations in the WFS1 gene, including a novel nonsense mutation, c.2217C>A. This case highlights the variability in the clinical presentation of WS and underscores the importance of genetic testing in the diagnosis and management of this disorder.

The patient initially presented to a local hospital with a five-month history of DM, characterized by polydipsia, polyphagia, polyuria, and a weight loss from 58 kg to 52 kg over the course of a year. His height was 173 cm. Laboratory tests revealed a fasting serum glucose level of 14.4 mmol/L, and tests for anti-glutamic acid decarboxylase, anti-islet cell antibodies, and anti-insulin autoantibodies were negative. Based on these findings, the patient was diagnosed with type 2 DM and was initially treated with intensive insulin therapy (multiple daily insulin injections) for one month. His treatment was subsequently adjusted to include acarbose and 2 units of recombinant insulin glargine at bedtime, which effectively controlled his symptoms.

Upon referral to the endocrinology department, a 2-hour oral glucose tolerance test (OGTT) was conducted. The patient’s serum glucose, insulin, and C-peptide levels were measured at baseline (0 hours) and at 2 hours post-meal. At baseline, the serum glucose level was 5.2 mmol/L, insulin was 2.95 mIU/mL (normal range: 5.2–17.2 mIU/mL), and C-peptide was 0.57 ng/mL (normal range: 0.8–4.2 ng/mL). At 2 hours, the serum glucose level decreased to 3.2 mmol/L, insulin increased to 13.77 mIU/mL, and C-peptide increased to 2.68 ng/mL. Hemoglobin A1c (HbA1c) was 5.7%, and C-reactive protein was 0.19 mg/L. Urine albumin was negative. The patient had no siblings, and his parents were non-consanguineous and showed no signs or symptoms of DM or other related conditions. His paternal grandmother was diagnosed with type 2 DM at the age of 62.

Given the patient’s young age and lack of obesity, genetic diabetes such as maturity-onset diabetes of the young (MODY) or recessive genetic syndromes was suspected. Whole-exome sequencing was performed, and patient consent was obtained. The sequencing revealed compound heterozygous mutations in the WFS1 gene. Sanger sequencing confirmed that the patient inherited a missense variant, c.1673G>A (p.Arg558His), from his father and a nonsense variant, c.2217C>A (p.Tyr739*), from his mother. Both parents carried one mutated allele but did not exhibit hearing impairment, OA, or DM.

In light of the genetic findings, the patient underwent further evaluations, including optic nerve and hearing tests. His visual acuity, which had been normal before the age of 11, had gradually decreased to 20/40 and 20/50 in each eye. Brain magnetic resonance imaging (MRI) confirmed bilateral optic nerve atrophy. Audiometry results were normal, and no signs of urological abnormalities or psychiatric disorders were observed. The presence of DM, OA, and the identified WFS1 mutations confirmed the diagnosis of WFS1-related spectrum disorder.

WS is typically diagnosed based on the co-occurrence of insulin-dependent DM and bilateral OA before the second decade of life. However, the patient described in this case presented with non-insulin-dependent DM, which is atypical for WS. The use of next-generation sequencing technology facilitated a rapid and accurate diagnosis, allowing for appropriate evaluations and management.

Over 300 pathogenic variants in the WFS1 gene have been identified, and the severity of the disease varies depending on the type of mutation. Establishing genotype-phenotype correlations is crucial for improving diagnosis and management. In this patient, the c.1673G>A mutation results in the substitution of arginine at residue 558 for histidine, while the c.2217C>A mutation generates a premature stop codon at tyrosine 739 (p.Y739X), a novel mutation not previously reported. A previous case involving siblings with the p.R558C mutation in compound heterozygosity with a p.E864X nonsense mutation presented with DM and OA in their teens without additional complications. Based on the genetic test results, the patient in this case is likely to have a mild form of WS.

One notable aspect of this patient’s case is the early diagnosis of DM and the absence of progression to insulin-dependent DM, with good control of serum glucose levels achieved through diet and exercise. While certain dominant WFS1 mutations have been associated with type 2 DM due to relative insulin insufficiency, recessive mutations are typically linked to insulin-dependent DM. The patient’s parents did not exhibit DM, visual loss, or hearing problems. Over the next three months, the patient maintained glucose control without medication, and his HbA1c was 6.4% at the last follow-up. The long-term prognosis for this patient remains to be determined, but this case contributes to a broader understanding of the WFS1 gene’s role in DM and the genotype-phenotype correlations in WS.

In conclusion, this case report highlights the importance of genetic testing in the diagnosis of atypical presentations of WS. The identification of compound heterozygous mutations in the WFS1 gene, including a novel nonsense mutation, underscores the genetic heterogeneity of this disorder. The patient’s clinical course, characterized by non-insulin-dependent DM and OA, expands our knowledge of the phenotypic spectrum associated with WFS1 mutations. Further research into the genotype-phenotype correlations in WS will enhance our ability to diagnose and manage this complex disorder effectively.

doi.org/10.1097/CM9.0000000000000464

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