Journal of Perinatology (2012) 32, 645–647 r 2012 Nature America, Inc. All rights reserved. 0743-8346/12 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Successful treatment of a neonate with neonatal mellitus due to a novel missense , p.P1199L, in the ABCC8

O Oztekin1, E Durmaz2, S Kalay1, SE Flanagan3, S Ellard3 and I Bircan2 1Akdeniz University Medical School, Department of Pediatrics, Division of , Antalya, Turkey; 2Akdeniz University Medical School, Department of Pediatrics, Division of Pediatric , Antalya, Turkey and 3Department of Molecular Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, UK

Case Neonatal/infancy-onset diabetes mellitus is a monogenic form of diabetes A 1-month-old girl was referred to the neonatal intensive care unit, with onset within 6 months of age. Two distinct types of neonatal diabetes with the complaints of tachpynea, respiratory distress, lethargy and mellitus have been recognized: permanent and transient. within poor feeding. The patient was born to a 34-year-old mother whose the K þ ATP channel and are found in most patients with was uneventful. A full-term female neonate weighting permanent diabetes mellitus. There have been several reports of the 3520 g (50 percentile) with a length of 52 cm (75 percentile) was successful transition from insulin to sulfonylurea agents in patients with delivered via elective cesarean section. The physical examination permanent diabetes mellitus caused by mutations in the KCNJ11 gene. We was normal and the newborn did not have any dysmorphic report on a term female neonate with a novel missense mutation, p.P1199L, abnormalities at birth. Breastfeeding was started shortly after in the ABCC8 gene that encodes the sulfonylurea receptor 1 whose birth. She was the second child of unrelated parents. There was no treatment was successfully converted from insulin to sulfonylurea. family or autoimmune diseases. On physical Journal of Perinatology (2012) 32, 645–647; doi:10.1038/jp.2012.46 examination, the was irritable, drowsy, dehydrated, Keywords: newborn; diabetes mellitus; genetic mutation; sulfonylurea tachypneic (72 breaths per min) and tachycardic (182 beats per min). Her body temperature was 37.1 1C (axillary), and blood pressure was 62/38 mm Hg. First-line laboratory analyses revealed the following results: blood chemistry: : 725 mg dlÀ1, Introduction Na: 134 mmol lÀ1, K: 5.5 mmol lÀ1, Cl: 112 mmol lÀ1, Ca: À1 À1 À1 Neonatal diabetes mellitus (NDM) is defined as diabetes diagnosed 12.4 mg dl , ammonia: 94 mgdl , lactate: 1.67 mmol l . within the first 6 months of life. This condition can either be Arterial blood gas analysis was (venous blood gas analysis), pH: À1 permanent, requiring lifelong insulin therapy, or transient, where 7.04, pO2: 90 mm Hg, pCO2: 12.4 mm Hg HCO3: 3.3 mEq l , and the condition can remit during infancy but relapse later in life. base deficit À25.1. Urinalysis showed specific gravity 1.030, glucose À1 Transient and permanent NDM (TNDM and PNDM) are rare 4 þ and 3 þ . Serum insulin level was 0.2 mUml and À1 conditions with an estimated incidence of 1 in 260 000 to 500 000 C- (0.04 ng ml (0.3 to 1.37)) was low, while blood À1 live births.1–3 PNDM is less common than the transient form, and sugar level was 432 mg dl . The glycosylated hemoglobin level in these patients insulin dependence is lifelong. (high-pressure liquid chromatography method, HPLC) was 7.23%. Here, we report on a patient with a novel missense mutation, Anti-insulin, anti-islet cell and anti-glutamic acid decarboxylase p.P1199L, in the ABCC8 gene that encodes the sulfonylurea antibodies were found to be negative. Thyroid function tests (TSH: À1 À1 receptor 1 subunit of the pancreatic ATP-sensitive 2.43 mUml , fT4: 0.98 ng dl ) were within normal ranges. (K-ATP) channel. The patient, who had PNDM accompanied by Tandem mass spectrometry and serum organic acids were normal. diabetic (DKA), was admitted to the neonatal intensive There was no clinical evidence of pancreatic exocrine insufficiency care unit and was successfully transitioned from insulin to and abdominal ultrasound showed the presence of a normal-sized sulfonylurea therapy following the genetic diagnosis. . Cranial magnetic resonance imaging was normal. Echocardiography revealed no abnormality. The parents’ fasting Correspondence: Dr O Oztekin, Akdeniz University Medical School, Department of Pediatrics, blood glucose levels were normal. Division of Neonatology, 07070-Antalya, Turkey. E-mail: [email protected] A diagnosis of DKA was made and treatment was started with À1 À1 À1 À1 Received 13 January 2012; accepted 15 March 2012 intravenous insulin (0.05 IU kg h for 2 h and 0.1 IU kg h Sulfonylurea treatment of a neonate with neonatal diabetes mellitus OOztekinet al 646 thereafter) and a rehydration solution. Insulin and glucose NDM.8,9 Our patient was misdiagnosed as having pneumonia in concentrations were subsequently adjusted according to the rate of another hospital. We think that the cause of DKA in our case was glucose fall, and no complications were observed. due to delayed diagnosis or late admission to the emergency unit. and ketoacidosis resolved by the 24th hour of treatment. Also, NDM associated with DKA may mimic sepsis or pneumonia Breastfeeding was resumed with feedings at 3-h intervals. She was and should be kept in mind in all newborns who present with discharged 3 weeks after admission with a regimen of neutral tachypnea, respiratory distress, and weight loss. protamine Hagendorn and regular insulin injections twice a day Permanent NDM is associated with defects in genes that have (0.9 U kgÀ1 per day). major roles in pancreatic development and function. Molecular genetic analysis revealed the patient was heterozygous Besides the imprinting abnormalities at 6q24 first for a novel missense mutation, p.P1199L (c.3596C>T), in the ABCC8 described for TNDM mutations in the genes, KCNJ11 and ABCC8 gene, which encodes the sulfonylurea receptor 1. Her father and mother that encode the subunits Kir6.2 and sulfonylurea receptor 1 of did not carry the mutation. The genetic analysis was performed at the KATP channel are a common cause of both transient and Peninsula Medical School, University of Exeter, UK as previously described.4 permanent forms of NDM. Mutations in the (GCK) and During the follow-up, insulin dose was decreased but serum Insulin (INS) genes have also been reported in patients with glucose level increased again, due to increment in blood glucose PNDM. Moreover, individuals with some exceedingly rare forms of levels to 150 to 450 mg dlÀ1, suggesting a diagnosis of PNDM. syndromic PNDM may bear recessive mutations in several genes, Based on this finding, we attempted to convert her treatment from including PDX1, EIF2AK3, PTF1A, GLIS3, RFX6, SLC19A2, GATA6, insulin to at the same dose (as a tablet at 5 mg NUEROG3, NEUROD1 or FOXP3.3,10 Russo et al.10 reported that a dissolved in 5 ml water) as in literature cases and proceeded as molecular genetic diagnosis can be reached in B75% of patients per the established recommendations of Dr Andrew Hattersley with diabetes onset at p6 months of age when KCNJ11, INS and (published at http://www.diabetesgenes.org).5–7 The patient was ABCC8 genes are sequenced in populations with a low 2 months old at the start of this transition. The patient was treated consanguinity rate. Flanagan et al.4 reported that a genetic with oral glibenclamide 0.2 mg kgÀ1 per day with 0.1 mg kgÀ1 pre- diagnosis was possible for up to 97% of patients with TNDM in a breakfast (0800 h) and 0.1 mg kgÀ1 pre-evening meal (1800 h). cohort collected across four continents following a request of the Dosage was increased over the next 7 days to 0.4 mg kgÀ1 per day, International Society of Paediatric and Adolescent Diabetes. The while regular insulin was concomitantly tapered off glibenclamide. majority of these patients (71%) had chromosome 6q24 imprinting Her blood sugar was regulated with that dosage. Her hyperglycemia abnormalities, while 26% of cases had a KATP channel mutation. resolved completely after her glibenclamide dose was further Heterozygous gain-of-function mutations in the KCNJ11 and increased to 0.4 mg kgÀ1 per day, divided two times daily, and she ABCC8 genes are the most common cause of NDM, which for the vast no longer required doses of regular insulin. Three months after majority of cases can be treated with oral .3,5,10 Our starting glibenclamide, the patient remained asymptomatic; her patient was heterozygous for a missense mutation, p.P1199L, in serum C-peptide level increased to 1.37 ng mlÀ1 (1.1 to 4.4) and ABCC8, allowing us to convert her treatment from insulin to HbA1c level normalized (5.8%). Only with glibenclamide treatment glibenclamide, which resulted in an improvement in glycemic control. her insulin level was 4.36 U lÀ1; meanwhile, her blood sugar was In conclusion, this is one of the youngest reported patients 105 mg dlÀ1, which may be accepted in the normal range. Her to commence oral glibenclamide therapy for treatment of NDM glibenclamide requirement slowly decreased (due to weight gain) resulting from a novel mutation in the ABCC8 gene. This case and stabilized at 0.25 mg kgÀ1 per day and her blood sugar levels illustrates safe and effective initiation of glibenclamide in PNDM reached an average of around 120 mg dlÀ1. She was found to be due to mutations in the K þ ATP channel genes. These patients gaining weight (6.9 kg at the 25th percentile) and showing normal can be successfully treated with oral sulfonylurea instead of neurodevelopmental progress. Currently, the patient is 5 months subcutaneous insulin therapy. Further genetic investigation should old and is on two doses of glibenclamide (0.2 mg kgÀ1 per day). focus on assessment in NDM for therapy options.

Discussion Conflict of interest Neonatal/infancy-onset diabetes mellitus (NDM) is a monogenic The authors declare no conflict of interest. form of diabetes. In patients with TNDM, remission of hyperglycemia usually occurs within 3 to 6 months from diagnosis. References Permanent NDM is less common than TNDM and never goes into 8 1 Slingerland AS, Shields BM, Flanagan SE, Bruining GJ, Noordam K, Gach A et al. remission. It accounts for approximately 40 to 50% of NDM cases. Referral rates for diagnostic testing support an incidence of permanent neonatal Several reviews were reported that ketonuria is usually mild or diabetes in three European countries of at least 1 in 260 000 live births. Diabetologia absent; however, DKA may develop when the diagnosis is delayed in 2009; 52: 1683–1685.

Journal of Perinatology Sulfonylurea treatment of a neonate with neonatal diabetes mellitus O Oztekin et al 647

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