A Japanese infant with fulminant type 1 diabetes with disease-sensitive CSAD polymorphism and HLA haplotype

Abstract.

Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes (T1DM) with an acute onset. There are limited reports on FT1DM in pediatric patients. Here, we report the case of a Japanese female infant with FT1DM, representing the youngest female with FT1DM documented to date. The patient was referred to our hospital at 10 mo of age. Although her laboratory findings met the diagnostic criteria for severe diabetic ketoacidosis, her HbA1c level was not excessively high. Anti-glutamic acid decarboxylase and anti-insulinoma-associated protein-2 antibodies were not detected. Test results for insulin autoantibodies were positive. The glucagon stimulation-loading test revealed a C-peptide level of < 0.6 ng/mL. At 8 yr of age, the patient was diagnosed with Graves’ disease. Human leukocyte antigen typing and analysis of a single-nucleotide polymorphism (rs3782151) in CSAD/lnc-ITGB7-1 revealed that the patient was predisposed to FT1DM owing to these two factors. Her findings at the disease onset fulfilled the diagnostic criteria for FT1DM. Although rare in FT1DM, the patient developed Graves’ disease, a complication commonly associated with autoimmune T1DM. Moreover, although her condition at onset and genetic predisposition were consistent with those of FT1DM, her clinical course resembled that of autoimmune T1DM.

Highlights

● We report the youngest female with FT1DM to date.

● The patient had a disease-sensitive CSAD polymorphism and HLA haplotype.

● She also had Graves’ disease combined with FT1DM.

Introduction

Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes mellitus (T1DM) that was discovered and clinically characterized in Japan (1). FT1DM is characterized by a markedly abrupt onset and complete β-cell destruction (1,2,3,4). In 70% of patients with FT1DM, flu-like and gastrointestinal symptoms precede disease onset, suggesting an association with viral infection (2,3,4). Reports of patients with FT1DM predominantly originate from Japan, China, and Korea and are extremely rare from non-Asian countries, especially Western countries (2, 3, 5). In a nationwide Japanese survey of 161 FT1DM cases, FT1DM accounted for approximately 20% of acute-onset T1DM cases with ketosis at disease onset; the age at onset of FT1DM ranged between 1 and 80 yr, with only a few pediatric cases. Although T1DM in Japanese children is not rare, only a few cases of FT1DM have been reported in Japanese children and adolescents in a previous survey (3). In addition to this survey, reports on FT1DM in pediatric patients remain limited (5,6,7).

Regarding the genetic background of FT1DM, a relationship between class II human leukocyte antigen (HLA) and FT1DM has been reported, while the DRB1*04:05-DQB1*04:01 haplotype was associated with a strong susceptibility for FT1DM (4, 8, 9). The genetic contribution of non-HLA genes has also been explored (10, 11). The first genome-wide association study of FT1DM performed in Japanese individuals revealed a strong association between FT1DM and a single-nucleotide polymorphism (SNP) in CSAD/lnc-ITGB7-1 on chromosome 12q13.13. The strongest association was observed for rs3782151 in CSAD/lnc-ITGB7-1, with an odds ratio (OR) of 1.97 (11).

Although the association between FT1DM pathogenesis and autoimmunity remains unknown, patients with FT1DM reportedly exhibit an extremely low prevalence of islet-related and thyroid-related autoantibodies (3). Classic T1DM is frequently associated with autoimmune thyroid diseases (12). However, such associations are rare in FT1DM (13).

Herein, we report the case of a young Japanese female with FT1DM and describe her clinical characteristics, including the coexistence of Graves’ disease and the genetic background based on the analysis of a disease-susceptible SNP in CSAD/lnc-ITGB7-1 and HLA haplotypes.

Case Report

The patient was the second child of an unrelated Japanese parent. She was born at 37 wk of gestation by spontaneous vaginal delivery following an uneventful pregnancy, with a birth weight of 2602 g. She had a family history of type 2 diabetes mellitus but no family history of autoimmune disorders. At 10 mo of age, she experienced polyuria and polydipsia for 1 wk and thereafter became unwell and vomited frequently for 3 d. After consulting a local physician, she was diagnosed with gastroenteritis and was sent home. Thereafter, the patient developed dyspnea and impaired consciousness and was admitted to a local hospital. She was initially diagnosed with an unknown condition; however, critical illness was suspected, and an infusion of saline solution was initiated. At that time, her venous blood gas analysis revealed severe metabolic acidosis (pH 6.909, pCO₂ 18.2 mmHg, HCO₃ 3.4 mmol/L, and base excess −26.2 mmol/L). Subsequently, marked hyperglycemia (exceeding the limit of analysis) and positive urine ketones were detected, based on which diabetic ketoacidosis was suspected, and insulin therapy was initiated. Subsequently, the patient was referred to our hospital for further evaluation and treatment. At hospital admission, the patient was inactive, drowsy, and exhibited reduced skin turgor. Her body length and weight were 72.0 cm and 6578 g (approximately 18% of body weight loss), respectively. Venous blood gas analysis revealed severe metabolic acidosis (pH 6.941, pCO₂ 8.1 mmHg, HCO₃ 5.9 mmol/L, and base excess −28.8 mmol/L). Her laboratory findings fulfilled the diagnostic criteria for severe diabetic ketoacidosis; however, her HbA1c levels were not markedly elevated (Table 1). Anti-glutamic acid decarboxylase (GAD) and anti-insulinoma-associated protein-2 (IA2) antibodies were not detected. The test for insulin autoantibody (IAA) was positive (Table 1). Accordingly, the patient was diagnosed with T1DM, and treatment with intravenous insulin injections and fluid therapy was continued. Ketoacidosis resolved on day 2, and multiple daily insulin injections (MDIs) were administered. The intravenous glucagon stimulation-loading test revealed a C-peptide level of < 0.6 ng/mL at baseline, which remained unchanged even after glucagon loading. Her findings at the disease onset fulfilled the diagnostic criteria for FT1DM. Routine blood tests performed at the age of 8 yr and 8 mo revealed hyperthyroidism (Table 2). She also presented with an enlarged thyroid gland and tachycardia and was diagnosed with Graves’ disease. Treatment with methimazole improved her thyroid function. Currently, she is 15 yr of age and was switched to continuous subcutaneous insulin infusion for a period, but was again treated with MDIs, with her HbA1c level maintained at approximately 7–8%. She developed no obvious growth problems, and her height and weight are 161.1 cm and 58.8 kg, respectively (Fig. 1). She had no diabetes-related complications other than Graves’ disease.

Table 1. Laboratory findings at disease onset.

Table 2. Laboratory findings at 8 yr and 8 mo of age.

Fig. 1.

Growth chart of the patient.

Results

We conducted a genetic analysis of the patient after obtaining informed consent from the parents and approval from the Institutional Review Board of Tohoku University (approval number 14827; May 27, 2019).

HLA genotyping

HLA-DR and HLA-DQ genes were analyzed using a PCR-sequencing-based typing method [SRL, Inc., Tokyo, Japan] (14). Table 3 presents the HLA genotypes of the patient. The patient had DRB1*04:05-DQB1*04:01, which is known to be associated with a strong susceptibility to FT1DM (4, 9). She also had DRB1*09:01-DQB1*03:03, which is also associated with susceptibility to FT1DM (9).

Table 3. HLA typing of the patient.

CSAD analysis

Genomic DNA was extracted from the peripheral blood leukocytes of the patient. CSAD/lnc-ITGB7-1 was analyzed by PCR-direct sequencing. Using direct PCR sequencing, we evaluated an SNP (rs3782151) in CSAD/lnc-ITGB7-1, which demonstrated a strong association with FT1DM. The patient harbored a homozygous risk allele (NC_000012.12: g. 5315877 G > T) at rs3782151.

Discussion

Here, we report a case of a Japanese infant with FT1DM. To the best of our knowledge, this patient is the youngest female diagnosed with FT1DM reported to date. The incidence of FT1DM in pediatric patients with T1DM in China is 1.56%, and the average age of onset is 2 yr, which is considerably younger than that of classic T1DM (5). In Japan, Shiga et al. reported that patient age distribution was biphasic, with peaks observed in children aged < 5 and > 8 yr (7). Our patient was 10 mo at disease onset and had an abrupt onset of diabetic ketoacidosis with markedly low C-peptide and relatively low HbA1c levels, although marked hyperglycemia fulfilled the diagnostic criteria for FT1DM. She presented with nonspecific symptoms, such as vomiting and dyspnea. In a previous case of an infant slightly older than our patient, the primary complaint was also nonspecific, documented as “not doing well” (7). In the case of FT1DM in infants and young children, the symptoms are nonspecific, and if the diagnosis is delayed, the condition can progress rapidly to become severe; hence, early diagnosis is essential.

HLA genotyping revealed that the patient harbored the DRB1*04:05-DQB1*04:01 and DRB1*09:01-DQB1*03:03 haplotype. In a study exploring the contribution of HLA to FT1DM in Japan, DRB1*04:05-DQB1*04:01 was identified in 32.6% of 207 patients with FT1DM, a prevalence that was significantly higher than that in healthy controls, with an OR of 2.9 (8). DRB1*09:01-DQB1*03:03 was also associated with susceptibility to FT1DM, with an OR of 2.1 (8). Siga et al. also reported HLA genotyping of eight Japanese children with FT1DM, wherein DRB1*04:05-DQB1*04:01 was identified in four cases and DRB1*09:01-DQB1*03:03 in three cases. The remaining patient had both DRB1*04:05-DQB1*04:01 and DRB1*09:01-DQB1*03:03 haplotypes, similar to our patient (7). The involvement of certain HLA subtypes has been suggested in pediatric patients with FT1DM, similar to that in adult patients.

Analysis of an SNP (rs3782151) in CSAD/lnc-ITGB7-1 revealed that the patient harbored the homozygous adenine risk allele. The first genome-wide association study of FT1DM in Japanese individuals reported that rs3782151, CSAD/lnc-ITGB7-1 on chromosome 12q13.13, is strongly associated with susceptibility to FT1DM but not classical type 1A diabetes (11). CSAD encodes cysteine sulfonic acid decarboxylase (CSAD), a key enzyme in taurine synthesis. Taurine exerts anti-inflammatory and cytoprotective effects by attenuating apoptosis and stimulating antioxidant activity (11, 15). Taurine was shown to exert a protective effect against the destruction of pancreatic islets in T1DM (11, 16). Thus, CSAD variants may contribute to FT1DM by impairing the protective function of pancreatic islets (11). CSAD is reportedly associated with susceptibility to FT1DM independent of HLA (11). Based on these findings, we believe that this patient was predisposed to FT1DM owing to the two factors, HLA and CSAD.

Anti-GAD and IA-2 antibodies are absent in most patients with FT1D, and these antibodies were also absent in our patient, although IAA was positive. Kawasaki et al. reported the presence of IAA in 6% of the patients with FT1DM (17). Thus, the detection rate of IAA is low, and the specific characteristics of IAA-positive FT1DM have not been discussed. The patient had already started insulin therapy at a previous hospital and was transferred to our facility shortly thereafter. Given that we measured her IAA levels immediately upon arrival, it is likely that her IAA was already positive prior to the initiation of insulin therapy.

Our patient subsequently developed Graves’ disease, although her clinical characteristics at onset were consistent with those reported previously. The prevalence of thyroid-related autoantibodies in patients with FT1DM is extremely low (3). Although classic T1DM is frequently complicated by autoimmune thyroid diseases (12), such complications are rare in FT1DM (13). However, it remains unclear whether FT1DM pathogenesis is associated with autoimmunity (3). In the current case, the diagnosis of FT1DM was consistent with the condition at the time of onset and genetic predisposition; however, the patient’s clinical course was similar to that of autoimmune T1DM.

The progression of FT1D is extremely rapid, and delayed diagnosis can result in death; hence, early diagnosis is particularly important in children. Further accumulation of cases and investigations is essential.

Conclusion

Here, we report the youngest female with FT1DM who had a disease-sensitive CSAD polymorphism and an HLA haplotype. She also had Graves’ disease and FT1DM. The diagnostic criteria for FT1DM were consistent, based on the condition at the time of onset and genetic predisposition; however, the patient’s clinical course was similar to that of autoimmune T1DM.

Conflicts of interests

The authors have no conflicts of interest to declare.