Clinical presentation

All patients diagnosed with WS at a tertiary hospital in Xinjiang, China from 2016 to 2022 were included in these case series. Eleven cases were included, and 7 out of the 11 cases were male. The age at WS diagnosis ranged from 8 to 30 years. For a summary of the genealogy, see Fig. 1.

Fig. 1

Genealogical trees of seven Wolfram syndrome families. Black-and-white striped circle or square = patients with diabetes; white circle or square = healthy individuals

Case 1

A 21-year-old female had experienced gradual dry mouth, polyuria, and fatigue over the past 14 years. At the age of 7, because fasting blood glucose was 28.0 mmol/L, the patient was diagnosed with “type 1 diabetes mellitus” and treated with insulin injection. At 19 years of age, the patient developed decreased vision in both eyes. The patient was otherwise healthy and did not take any medications. The patient’s parents denied consanguineous marriage or family history of diabetes. The patient had a BMI of 19.5 kg/m2, an HbA1c rate of 9.8%, double hydronephrosis, bilateral ureteral dilatation, diabetic retinopathy, and optic nerve papillary atrophy in both eyes. Hearing test results were normal. Diagnosis of WS was suspected. The genetic testing identified the c.1314_1317delCTTT,p.F438Lfs * 3 homozygous mutation of the WFS1 gene. Sanger sequencing of family members found both parents and the elder brother being heterozygous carriers of the WFS1 mutation.

Case 2

A 14-year-old male noticed dry mouth, polyuria for the past 4 years, and slow growth for the past 3 years. At the age of 10, because fasting blood glucose was 16.0 mmol/L, the patient was diagnosed with “type 1 diabetes mellitus” and treated with insulin. At the age of 11 years, slow growth appeared, and the patient’s height was shorter than that of the patient’s peers. Visual loss, urinary frequency, and urinary incontinence were observed within two years. The patient’s parents were consanguineous in marriage (II4, II5) and the grandfather (I1), grandmother (I2), uncle (II1), and uncle (II3) have diabetes. The patient had a BMI of 18.3 kg/m2, HbA1c 14.9%, hydronephrosis, and bilateral ureal expansion. The indirect water deprivation test result was negative, and pituitary MRI suggested a pituitary microadenoma. In addition, there were refractive errors in both eyes and sensorineural deafness in the right ear. Diagnosis of WS was suspected. The genetic testing identified the presence of a homozygous missense mutation of the WFS1 gene, the c.C529T p.R177C. Both parents, a second uncle, and a grandmother were heterozygous carries. Interestingly, the younger brother and sister carried the homozygous mutation, but no relevant clinical findings were found and the time of this study and they were still in close follow-up.

Case 3

A 17-year-old male experienced thirst and polyuria over the past 14 years. At the age of 3 years, the patient developed polyuria with a random blood glucose of 42.8 mmol/L. The patient was diagnosed with “type 1 diabetes, diabetic ketosis.” At nine age of 9 years old, the patient’s height was shorter than that of the patient’s peers, and vision and hearing loss decreased at the age of 14 years. The patient’s parents were consanguineous in marriage (III2, III3) and the grandfather (II3), grandmother (II2), and aunt (III6) have diabetes. The patient was 1.3 m tall with a weight of 27 kg, HbA1c of 10.6%, optic nerve atrophy, mild hydronephrosis in the left kidney, and expansion of the upper ureteric segment. WS was suspected and genetic testing identified two homozygous mutations of the WFS1 gene, the c.C529A p.R177S and the c.G2105A p.G702D. The patient’s parents, brother, sister, grandmother, grandfather, sister, and uncle carried homozygous or heterozygous mutations.

Case 4

A 17-year-old male noticed polydipsia and polyuria for the past 12 years. At the age of 15, the patient had a random blood glucose of 33.1 mmol/L, and was diagnosed with “type 1 diabetes, diabetic ketosis,” and was discharged after insulin treatment. In recent years, the patient experienced repeated palpitations, sweating, hunger, handshaking, and relief from eating. The parents denied consanguineous marriage or family history of diabetes. The patient was 1.55m tall with a weight of 46 kg, HbA1c level of 10.6%, and mild water accumulation in both kidneys and ureter. WS was suspected and genetic testing identified a homozygous mutation of WFS1 c.C1885T p.R629W; both parents carried heterozygous mutations.

Case 5

A 30-year-old male noticed a gradual decrease in vision in both eyes over the age of 16 years. At the age of 14, the patient was diagnosed with “optic atrophy,” and 2 years later, was diagnosed with “type 1 diabetes” due to fasting blood glucose of 18.0 mmol/L. The patient’s parents denied consanguineous marriage. The patient’s uncle (II2) has diabetes, and two sisters (III4, III6) were also clearly diagnosed with WS. The patient had fasting blood glucose of 17.8 mmol/L, 2 h postprandial blood glucose 20.28 mmol/L, HbA1c 7.9%, fasting C peptide 2.25 ng/ml, 2 h C peptide 2.76 ng/ml, and negative islet-related antibodies. A diagnosis of WS was suspected and genetic testing identified the presence of compound heterozygous mutations, the c.1859_1860del p.V620Gfs * 91 and the c.G2020A p.G674R, of the WFS1 gene; the patient’s parents and uncles carried heterozygous mutations, and both sisters carried compound heterozygous mutations.

Case 6

A 12-year-old male noticed thirst, drinking, polyuria, and wasting over the past 7 years. At the age of 5 years, the patient was diagnosed with type 1 diabetes; and blood glucose level was unknown, and was discharged after insulin treatment. The patient’s parents were consanguineous in marriage (IV3, IV4) with diabetes, and the patient’s brother (V6) was also diagnosed with WS. The patient was 1.4 m tall with a weight of 32 kg, HbA1c of 11.1%, optic nerve atrophy, and refractive error (both eyes). The patient’s brother is 8 years old, after a perfect examination, was diagnosed with WS and given insulin injection treatment. WS was suspected and genetic testing identified homozygous WFS1, c.C529A p.R177S, and c.G2105A p.G702D mutations; both parents, sister, and brother carried compound heterozygous mutations.

Case 7

A 19-year-old female noticed thirst, polydipsia, and polyuria 14 years prior to presentation. The local hospital diagnosed “type 1 diabetes” and the patient was given insulin injections. The patient had no history of menstruation. The patient’s parents were consanguineous in marriage (III3, III4) and the younger brother (IV2) was also clearly diagnosed with WS. The patient was 1.23 m tall with a weight of 25 kg and no secondary sexual characteristics. Relevant examination revealed low hypogonadism (LH 0.59IU/L, FSH4.34IU/L, E2 < 10.08Pg/ml) and central hypothyroidism (T4 FT411.02PMOL/L, TSH3.8). In addition, the patient’s anti-islet cell antibody test results were negative, and had severe hydronephrosis and ureteral dilatation. No significant hearing or eye diseases were observed. The patient’s younger brother (IV2) was diagnosed with T1DM at the age of 10 because of abnormal blood glucose levels and was treated with insulin. The patient had cleft lip and palate, and finger and toe development deformities. The patient also had severe hydronephrosis and poor vision. Diagnosis of WS was suspected and genetic testing identified the homozygous mutation of WFS1, c.G1393C p.A465P; the patient’s father carried the heterozygous mutation and did not retain the samples.

Genetic analysis

This study reported seven families with WS and 11 patients screened for a total of 10 mutations in the WFS1 gene screened. Among these, only c.G1393C showed a VUS mutation, and the rest were pathogenic/likely pathogenic (c.1314_1317delCTTT, c.C529T, c.C529A, c.G2105A, c.C1885T, c.1859_1860del, c.G2020A, c.C529A, and c.G2105A) (Table 1). Among them, except for c.C529T in family B, c.G2105A in family C, c.G2020A in family E, and c.G2105A in family F were reported (without functional verification), the remaining mutation sites have not been reported and belong to new mutations.

Table 1 WFS1 mutations in seven families with Wolfram syndrome