Patient 1 (male) presented with hyperopia and astigmatism at age 6. Shortly after, bilateral neurosensorial hearing loss was diagnosed and required the use of bilateral hearing aids. IDDM was diagnosed at age 6.7 years and treatment with multiple daily insulin injections (MDI) was initiated consisting of insulin aspart and glargine. Double heterozygous missense WFS1 gene variants (c.409_424dup16; p.Val142fs*251 and c.1628 T>G; p.Leu543Arg) were confirmed at age 7.8 years with Sanger sequencing. One year later, patient 1 developed diabetes insipidus (see Table 1). At baseline, aged 11.3 years, with a standardized body mass index (sBMI) of 0.82, insulin requirements of 1 U/kg/day, patient 1 had a C-AUC of 122 ng*min/mL, HbA1c of 8% (64 mmol/mol), and a TIR of 53% and TAR of 40%. Liraglutide was initiated at 0.6 mg/day and the maximum dose of 1.8 mg/day was progressively achieved. As shown in Figure 1, at the latest 27-month follow-up C-AUC decreased to 102 ng*min/mL. Insulin requirements decreased to 0.47 U/kg/day, HbA1c improved to 7.5% (58 mmol/mol). Glucometrics via CGM showed improvements in TIR and TAR at 71% and 21%, respectively while TBR remained stable. The total daily insulin dose (TDD) was reduced by 53%. No adverse events occurred.
Patient 2 (female) had an unremarkable medical history except for transient mild speech delay. IDDM was diagnosed at age 5.2 years and insulin therapy was started with MDI consisting of insulin aspart and glargine. At age 8.2 years, two previously unreported likely pathogenetic variants (c.316-1G>A; c.757A>T and p.Lys253Ter), a splice site disruption and premature stop codon respectively, were identified by Next Generation Sequencing (NGS), and a WS diagnosis was confirmed. At baseline, aged 10.7 years, patient 2 presented with a sBMI of -2.08, insulin requirements of 0.28 U/kg/day, C-AUC of 28 ng*min/mL, HbA1c of 6.7% (50 mmol/mol), and a TIR of 69% recorded via CGM. Liraglutide was started at a dose of 0.3 mg/day and gradually increased to 1.8 mg/day. At 20 months, C-AUC increased to 48 ng*min/mL, TDD, TIR, TAR, TBR, and HbA1c remained stable. No severe adverse events were recorded.
Patient 3 (male) was diagnosed with IDDM at age 9 years and began insulin therapy with MDI consisting of insulin lispro and glargine. Prior to being diagnosed with IDDM, the patient had been complaining of visual impairment. Past medical history was unremarkable except for a transient mild motor delay. Family history was positive for bilateral congenital hypoacusia in his biological father and sister. WS diagnosis was established by NGS which confirmed a double heterozygous missense variant (c.605A>G; p.Glu202Gly and c.1289C>T; p.Ser430Leu) at age 11.4 years. At baseline, aged 12.3 years, patient 3 had a sBMI of 1.59, C-AUC of 111 ng*min/mL, HbA1c of 7.5% (58 mmol/mol) and insulin requirements of 0.5 U/kg/day. TIR, TAR, and TBR were 70, 20, and 10% respectively. Liraglutide was started at a dose of 0.3 mg/day and progressively increased to 1.8 mg/day as tolerated. At the 16-month follow-up the patient showed sBMI of 1.92, C-AUC of 90 ng*min/mL, HbA1c of 9.4% (79 mmol/mol), insulin requirements of 0.78 U/kg/day, and a TIR of 29%. TDD remained stable. No adverse events occurred.
Patient 4 (male) was diagnosed with IDDM at age 12.3 years and started insulin therapy with MDI consisting of insulin aspart and glargine. Prior to his diabetes diagnosis, the patient had an unremarkable past medical history. At age 13.4 years the patient complained of worsening vision and heterozygous WFS1 variants revealed a premature stop condon and missense variants (c.387G>A; p.Trp129 and c.1675G>C; p.Ala559Pr respectively) was confirmed with Sanger sequencing which revealed a double heterozygous variant. At baseline, age 14, patient 4 had a C-AUC of 296 ng*min/mL, HbA1c of 8.5% (69 mmol/mol), sBMI of -0.77 and insulin requirements of 0.4 U/kg/day. Glucometrics recorded TIR, TAR and TBR were 73%, 26%, and 1% respectively. Liraglutide was started at a dose of 0.6 mg/day and progressively increased to 1.8 mg/day as tolerated. At the latest 8-month follow-up, patient 4 had a sBMI of -1.17, C-AUC measuring 313 ng*min/mL, HbA1c improved to 7.1% (54 mmol/mol) and insulin requirements decreased to 0.08 U/kg/day. Glucometrics recorded TIR and TAR at 62% and 38%. TDD was reduced by 80%. No adverse events occurred.