Shareque T. Shaikh, DD; Swati S. Jadhav, MD; Vyankatesh K. Shivane, DD; Anurag R. Lila, DM; Tushar R. Bandgar, DM; Nalini S.

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1 Case Report CHILDHOOD ONSET OF SULFONYLUREA RESPONSIVE NEONATAL DIABETES DUE TO A NOVEL HOMOZYGOUS AUTOSOMAL RECESSIVE MUTATION IN THE ABCC8 GENE WHICH WAS PRESUMED TO BE TYPE 1B DIABETES BEFORE GENETIC ANALYSIS Shareque T. Shaikh, DD; Swati S. Jadhav, MD; Vyankatesh K. Shivane, DD; Anurag R. Lila, DM; Tushar R. Bandgar, DM; Nalini S. Shah, DM ABSTRACT Submitted for publication April 10, 2015 Accepted for publication May 27, 2015 From Seth G.S. Medical College & King Edward Memorial Hospital, Parel, Mumbai Maharashtra, India. Address correspondence to Dr. Shareque T. Shaikh, Registrar, Department of Endocrinology, OPD No. 103 (Diabetes OPD), First Floor, Registration Hall Building, Near Gate No. 2, Seth G.S. Medical College & K.E.M. Hospital Campus, Parel, Mumbai , Maharashtra, India. drshareque7@gmail.com. DOI: /EP15773.CR To purchase reprints of this article, please visit: Objective: To describe an atypical childhood onset presentation of sulfonylurea-responsive neonatal diabetes mellitus (NDM) resulting from the unusually late expression of a homozygous, novel ABCC8 gene mutation. Onset was at 9 years of age and was initially misdiagnosed as being type 1B diabetes, with subsequent treatment as insulin-dependent diabetes before a genetic analysis was performed. Methods: Genetic screening of the individual and her family was conducted due to history of her youngest brother having classic NDM with onset at 2 months of age, later confirmed to be due to an identical homozygous mutation. Results: Both siblings were successfully shifted to treatment with an oral sulfonylurea following genetic diagnosis. Conclusion: We report the first case of a childhood onset, autosomal recessive ABCC8 mutation in a homozygous state presenting as type 1B diabetes. Current recommendations are to perform genetic screening for NDM only when the age of onset is less than 1 year. Our case highlights that apparently insulin-dependent diabetes that is actually due to ABCC8 mutation can present later in childhood, with an onset even as late as 9 years, and thus can be easily confused with childhood onset type 1B diabetes, even in the homozygous state. Genetic analysis and subsequent transfer to sulfonylurea therapy if responsive can significantly change lifelong disease management in such patients. (AACE Clinical Case Rep. 2016;2:e117-e121) Abbreviations: ABCC8 = ATP binding cassette transporter subfamily C member 8; BMI = body mass index; DM = diabetes mellitus; INS = insulin gene; KATP = ATP-sensitive potassium channel; KCNJ11 = potassium channel J11; Kir6.2 = inward rectifier K+ channel; MMTT = mixed meal tolerance test; NDM = neonatal diabetes mellitus; PNDM = permanent neonatal diabetes mellitus; TNDM = transient neonatal diabetes mellitus INTRODUCTION Neonatal diabetes mellitus (NDM) is a rare form of diabetes with highest reported incidence of approximately 1 per 89,000 newborns with a usual time of onset within 6 to 9 months of age (1-3). According to the current standard of care, only patients diagnosed with diabetes within the first year of life are recommended for genetic testing (4). Nearly half (47%) of NDM cases develop permanent neonatal diabetes (PNDM), while the remainder have transient neonatal diabetes (TNDM) (2). TNDM appears before 6 months of age and remits in infancy or early adulthood, with 50% of patients relapsing later in life (5). Many genes have been associated with neonatal diabetes, including mutations in potassium channel J11 (KCNJ11), ATP binding cassette transporter subfamily C member 8 (ABCC8), insulin (INS), eukaryotic translation initiation factor 2 alpha kinase 3; insulin promotor factor 1; pancreas transcription factor 1 subunit alpha; hepatocyte nuclear AACE CLINICAL CASE REPORTS Vol 2 No. 2 Spring 2016 e117

2 e118 Neonatal Diabetes, Presumed Type 1B, AACE Clinical Case Rep. 2016;2(No. 2) factor 1 homeobox B; forkhead box P3, GLIS family zinc finger 3, and glucokinase, as well as 6q24 deletion (2). ATP-sensitive potassium channels (KATP channels) link metabolism with membrane electrical activity by responding to changes in the adenine nucleotide levels the mirror s the changes in blood glucose concentration and altering the energy status within pancreatic beta cells (7). Mutations in ABCC8 (encoding a sulfonylurea receptor 1 subunit) and KCNJ11 (encoding the Kir6.2 subunit) are involved in the etiology of both PNDM and TNDM (2). We describe the case of a patient with sulfonylurearesponsive diabetes caused by a novel homozygous ABCC8 mutation leading to diabetes onset at 9 years of age. The patient had been previously misdiagnosed as having type 1B diabetes due to persistently low serum C peptide concentration. CASE REPORT A 9 year and 6 months old girl ( Case 1 ) born of distant consanguineous marriage (birth weight 2.5 kg) was referred to our hospital as a case of antibody negative, insulin-dependent diabetes diagnosed 2 months earlier during an evaluation for lower respiratory tract infection and osmotic symptoms (Table 1). Her birth history was insignificant with no history of neonatal hyperglycemia and no developmental delay. She had a thin frame with a body mass index (BMI) of 13.8 kg/m 2 and no evidence of dysmorphism or neurological abnormality. Systemic screening was negative for the involvement of other organs. She continued a regimen of subcutaneous insulin at 0.6 U/kg/day due to persistently low serum concentrations of C-peptide. Upon enquiry, her 2-year-old, prematurely born youngest brother ( Case 2 ) had been diagnosed with diabetes at the age of 2 months when he developed diabetic ketoacidosis (Table 1). He was also treated with insulin due to subsequent persistently low serum C peptide concentrations. Her parents were recently diagnosed as being prediabetic (their father s and mother s BMI was and kg/m 2, respectively). Both patients and their parents tested negative for the antibodies usually expressed in type 1 diabetes. The 2 other siblings were both normoglycemic. Based on diabetes onset at 2 months of age with negative diabetes-associated antibodies and persistently low serum C peptide levels, Case 2 was genetically screened for mutations in KCNJ11, ABCC8, and INS. He was subsequently found to have a novel ABCC8 exon 7 E382V homozygous missense mutation. Hence, Case 1 (despite diabetes onset at 9 years) and other family members were also screened for the same mutation. Case 1 also had the same novel homozygous E382V mutation, while both parents and the 2 unaffected siblings were heterozygous for the mutation (Fig. 1). Both patients (Case 1 and Case 2) were admitted to the hospital as inpatients and were simultaneously given a trial of the oral glibenclamide therapy according to inpatient protocol (Case 1 at 10 years old and Case 2 at 2.5 years old) and were successfully shifted from insulin to oral glibenclamide therapy (6). After 3 months, both patients showed significant improvement in their serum glycosylated hemoglobin (HbA1c) concentration and their results of 90 minute mixed meal tolerance test (MMTT) stimulated serum C peptide levels (Table 1). At the last follow-up appointment, Case 1 was 14 years and 5 months old (height: 25 th percentile) on glibenclamide 0.17 mg/kg/day (HbA1C: 6.7% [50 mmol/mol]), with a 90 minute MMTT-stimulated serum C peptide concentration of 3.19 ng/ml (Table 1). She attained menarche at age 13.5 years. Case 2 was 7 years old (height: 25 th percentile) at the last follow-up appointment and on glibenclamide 0.07 mg/kg/day (HbA1C: 5.9% [41 mmol/mol]). His 90 minute MMTT-stimulated serum C peptide concentration was 3.24 ng/ml (Table 1). To the best of our knowledge, this case represents the first report of childhood onset (at 9 years), sulfonylurea-responsive neonatal diabetes presenting and behaving as type 1B diabetes (prior to genetic analysis) due to the unusually late expression of an autosomal recessive, homozygous ABCC8 gene mutation. KATP mutations involving either ABCC8 or KCNJ11 together account for a substantial proportion of TNDM (1/4th) and PNDM (half to 2/3rd) cases (7). The majority (up to 90%) of NDM cases which are caused by KATP channel related gene mutations (ABCC8 and KCNJ11) respond to sulfonylurea treatment (2,8). Activating mutations in the ABCC8 gene are reported to cause NDM (TNDM as well as PNDM) in either a heterozygous or a homozygous state (6,9). Homozygous mutations in ABCC8 are reported to have diabetes onset during their first year of life and some of these cases do respond to sulfonylurea (9). Conversely, diabetes secondary to heterozygous ABCC8 mutations have a more variable age of onset but they usually present as non-insulindependent/ type 2 diabetes if the onset occurs beyond 1 year of age (10,11). There are case reports of patients with diabetes that initiated before 1 year of age who were treated with insulin since diagnosis as type 1 diabetes, but their diagnosis shifted to NDM later in adulthood after a genetic analysis was performed due to NDM occurring in another family members and they were subsequently successfully shifted to sulfonylurea therapy (5). Compared to these reports, the present case seems novel, since our Case 1 was homozygous for an ABCC8 autosomal recessive gene mutation and was thus expected to have had diabetes onset within the first year of life. However, she presented with diabetes symptoms unusually late, with a diabetes onset at 9 years. This delay is clinically significant, since she was misdiagnosed and treated as a patient with type 1B diabetes. Only later was her diagnosis corrected and her treatment shifted to a sulfonylurea. Had

3 Neonatal Diabetes, Presumed Type 1B, AACE Clinical Case Rep. 2016;2(No. 2) e119 Table 1 Index Patient and Her Affected Brother: Presentation, Clinical Diagnosis, Genetic Report, Sulfonylurea Trial, and Parameters Before and After the Sulfonylurea Trial Initial presentation Index patient (Case 1) Affected brother (Case 2) Age 9 years, 4 months 2 months Plasma glucose, mmol/l Serum C peptide, ng/ml 0.55 NA Autoantibodies (anti-gad, anti-ia2a, and anti-insulin) Negative Negative Body mass index, kg/m Not available Clinical diagnosis prior to genetic analysis Type 1B diabetes Neonatal diabetes ABCC8 exon 7 E382V mutation in each allele E382V/E382V E382V/E382V 90 minute mixed-meal tolerance test, ng/ml a Prior to sulfonylurea trial initiation months after changing to an oral sulfonylurea Serum HbA1C, %(mmol/mol) Prior to sulfonylurea trial initiation 8.2 (66) 9.0 (75) 3 months after changing to an oral sulfonylurea 6.8 (51) 7.4 (57) Insulin dose before shifting to glibenclamide (IU/kg/day) Oral glibenclamide dose (mg/kg/day) Starting dose during shifting Maximum dose during shifting Stabilized dose after shifting Current dose Abbreviations: GAD = glutamic acid decarboxylase; HbA1C = glycosylated hemoglobin; IA2A = protein tyrosine phosphatase IA2; IU = international unit; NA = not available. a The reference range for the 90 minute mixed-meal tolerance test with stimulated serum C peptide is ng/ml Case 2 not been born, Case 1 would have continued to live as a patient with type 1B diabetes and would have received lifelong insulin therapy. Our case signifies the importance and utility of genetic analysis, even for childhood onset of presumed type 1B diabetes patients. Although largely unknown, one possible explanation for this delayed presentation could be a period of undiagnosed and asymptomatic hyperglycemia with onset during the neonatal period (or up to 6 to 9 months of age according to the definition of NDM), remitting spontaneously as with TNDM and then relapsing later at 9 years of age. Another explanation could be that the mutation can express late even in a homozygous state and that homozygosity contributed to the type 1 diabetes-like presentation (and subsequent low serum C peptide concentrations prior to initiation of sulfonylurea therapy). The variable gene expression was strong enough in one sibling to present as PNDM at 2 months of age while the other sibling remained asymptomatic until 9 years of age, despite having an identical homozygous state and the same ABCC8 mutation, and merits emphasis. One similar case report of an inherited, autosomal dominant C42R Mutation in the Kir6.2 gene (KCNJ11) also showed variable expression amongst relatives, with the proband presenting as transient neonatal diabetes, the father diagnosed with diabetes at 23 years of age, and his grandfather diagnosed at 3 years of age (12). The grandfather was treated as an insulin-dependent diabetes patient from the time of diagnosis at 3 years of age until he was 21 years of age and genetic studies indicated neonatal diabetes. That patient was later shifted successfully from insulin to sulfonylurea treatment and has maintained good glycemic control without complications on sulfonylureas alone until a reported age of 58 years old. In that family, the variable age of diabetes onset due to the presence of the same mutation may suggest a possible role for environmental factors in affecting the differential expression of these genes amongst family members from different generations. There are also reports of insulin-dependent diabetes occurring because of an INS gene mutation that presents as familial type 1B diabetes with onset at up to 4 years of age (13). The patients were insulin dependent

4 e120 Neonatal Diabetes, Presumed Type 1B, AACE Clinical Case Rep. 2016;2(No. 2) Fig. 1. Family pedigree indicating the affected members and the genotype of each genetically tested members. Solid symbol = diabetes; empty symbol = diabetes was not detected or status not known (Note: A and B have prediabetes); DM = diabetes mellitus; A = father of Case 1; B = mother of Case 1; C = Sister of Case 1; D = brother of Case 1. Individual genotypes are presented underneath each symbol. E382V/E382V = homozygous for the E382 mutation; E382V/N = heterozygous for the E382 mutation; E382V = E382V mutation; N = wild type. due to INS mutations. These cases underscore the importance of recognizing that there can be delayed expression of these mutations and a more variable onset of diabetes than the conventionally described onset within 6 to 9 months of age that leads to confusion with childhood type 1B diabetes. The ABCC8 exon 7 E382V mutation identified in this family is novel. This A>T transition at nucleotide 1145 (c.1145a>t) results in the substitution of a valine for glutamic acid at codon 382 (p.glu382val). This particular glutamic acid residue shows high conservation across species. Also, E382K, a different missense mutation, has been reported previously in 2 homozygous siblings born to unaffected heterozygous parents, with both patients presenting as PNDM (onset <6 months old) (9). No functional studies were conducted in our study. However, the pathogenicity of the mutation was established by the presence of neonatal diabetes in Case 2 and the fact that both Case 1 and 2 were successfully shifted from insulin to oral glibenclamide therapy. The development of prediabetes in both parents in the presence of the same heterozygous mutation cannot be fully attributable to the mutation in the background of a high BMI phenotype. The parents need to be followed to monitor their glycemic status. If required, sulfonylureas may be the best choice for their future disease management (10). Our case emphasizes the need to understand the frequency of these clinically significant, sulfonylurearesponsive ABCC8 mutations in patients with presumed type 1B childhood onset diabetes so that disease management can be revised as glycemic control significantly improves both in children as well as in adults after they have shifted from insulin to sulfonylureas (8). CONCLUSIONS Insulin-dependent diabetes due to sulfonylurearesponsive ABCC8 gene mutation can present late in childhood, with onset even at 9 years of age and even in homozygous state. This presentation can lead to confusion with childhood onset type 1B diabetes. Genetic analysis and subsequent transfer of therapy to a sulfonylurea if responsive can significantly change lifelong disease management in such patients. An ABCC8 mutation could be investigated in patients with presumed type 1B diabetes and disease onset even beyond the first year of childhood, especially when there is evidence of familial clustering. ACKNOWLEDGMENT We gratefully acknowledge Dr. Andrew Hattersley, Professor of Molecular Medicine, Peninsula Medical

5 Neonatal Diabetes, Presumed Type 1B, AACE Clinical Case Rep. 2016;2(No. 2) e121 School, Barrack Road, Exeter EX2 5DW, United Kingdom, for performing molecular analyses for the patient and her family. DISCLOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Grulich-Henn J, Wagner V, Thon A, et al. Entities and frequency of neonatal diabetes: data from the diabetes documentation and quality management system (DPV). Diabet Med. 2010;27: Bryan LA, Bryan J. Neonatal diabetes mellitus. Endocrine Rev. 2008;29: Rubio-Cabezas O, Flanagan SE, Damhuis A, Hattersley AT, Ellard S. KATP channel mutations in infants with permanent diabetes diagnosed after 6 months of life. Pediatric Diabetes. 2012;13: Mohamadi A, Clark LM, Lipkin PH, Mahone EM, Wodka EL, Plotnick LP. Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15-yr-old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM. Pediatr Diabetes. 2010;11: Flanagan SE, Patch A, Mackay DJ, et al. Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes. 2007;56: Stanik J, Gasperikova D, Paskova M, et al. Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. J Clin Endocrinol Metab. 2007;92: Kataria A, Gopi RP, Mally P, Shah B. Neonatal diabetes mellitus: current perspective. Res Rep Neonatol. 2014;4: Pearson ER, Flechtner I, Njølstad PR, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006;355: Ellard S, Flanagan SE, Girard CA, et al. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Human Genet. 2007;81: Babenko AP, Polak M, Cave H, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006;355: Tarasov AI, Nicolson TJ, Riveline JP, et al. A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and ß cell glucose sensing is associated with type 2 diabetes in adults. Diabetes. 2008;57: Yorifuji T, Nagashima K, Kurokawa K, et al. The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J Clin Endocrinol Metab. 2005;90: Polak M, Dechaume A, Cave H, et al. Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy. Diabetes. 2008;57: