A Newborn with Transient Diabetes Mellitus Accompanied by Ketoacidosis Attributable to a ZFP57 Mutation

Abstract

INTRODUCTION

Neonatal diabetes mellitus (NDM) is rare, noted in only 1 of every 300 000–500 000 live births. Both transient and permanent conditions have been described (TNDM and PNDM, respectively). TNDM develops within the first week of life and disappears after about 2 months. TNDM may recur in adolescence and adulthood, and may then persist for life. TNDM patients usually exhibit intrauterine growth retardation (IUGR), hyperglycemia, dehydration and (sometimes) mild ketonemia in the first week of life [1]. As ketoacidosis is rather rare, we present the case of an 11-day-old infant admitted with diabetic ketoacidosis, a ZFP57 mutation and TNDM.

CASE

An 11-day-old male infant was admitted because of feeding difficulties, weight loss and vomiting. He had been born at term (birth weight 2500 g) via vaginal delivery to a 38-year-old mother (gravity: four, parity: two, abortus: two, live birth: two). The mother experienced gestational diabetes that was controlled by dietary adjustments. She was taking L-thyroxine to treat hypothyroidism. The patient had a healthy 4-year-old brother and the parents were not blood relatives.

On physical examination, the infant was conscious but restless. His temperature, blood pressure, heartbeat and respiratory rate were 36 °C, 63/41 mmHg, 168/min and 68/min, respectively. He exhibited moderate dehydration (weight loss of 9%). The prolonged capillary refilling time was associated with sunken eyes and fontanels. His acidotic breath smelt of acetone.

Laboratory data on admission were a white blood cell count of 16 × 10³/µl with a normal differential count; a hemoglobin level of 13.6 g/dl; a hematocrit of 41%; a platelet count of 315 × 10³/µl; a serum glucose level of 1110 mg/dl; an Na level of 134 mEq/l; a K level of 5.5 mEq/l; a calcium level of 10.4 mg/dl; a blood urea nitrogen level of 56 mg/dl; and a creatinine level of 1.2 mg/dl. Blood gas analysis yielded the following values: pH, 7.05; HCO₃ level, 6.6 mEq/l; pO₂, 60 mmHg; and pCO₂, 24 mmHg. The urine density, glucose and ketone levels were 1.025 g/ml, 4+ and 2+, respectively. Blood and cerebrospinal fluid cultures were negative. A suprapubic urine culture yielded a Klebsiella species. The serum insulin and C-peptide levels were 0.86 µU/ml and 0.319 µU/ml, respectively. Tests for anti-insulin, anti-islet cell and anti-glutamic acid decarboxylase antibodies were all negative, but the fructosamine level was abnormally high. Echocardiographic and metabolic screens were normal.

The infant was diagnosed with diabetic ketoacidosis after exclusion of sepsis, severe dehydration, congenital heart disease and any hereditary metabolic disorder. Treatment commenced with intravenous rehydration and 0.1 unit/kg/h of intravenous short-acting (regular) insulin. The hyperglycemia and acidosis normalized by 36 h of treatment, and breast-feeding then commenced at 3 h intervals. The treatment was then changed to neutral protamine Hagedorn insulin, administered four times daily (0.8 IU/kg/day); this ceased in the fourth postnatal month, and the serum glucose levels have remained normal since this time.

Parental genetic testing was performed at the University of Exeter (Exeter, UK) and the University of Southampton (Hampshire, UK). No mutation was found on analysis of the coding and flanking intronic regions of the KCNJ11 (NM_000525.3), ABCC8 (U63421 and L78208), INS (NM_000207.2) and EIF2AK3 (AF110146.1) genes. However, the infant was heterozygous for a novel variant, p.A635T (c.1903G > A), in exon 13 of the ABCC8 gene. He had inherited this variant from his clinically unaffected father. Analysis of the 6q24 locus was then done. All maternal methylation was absent, accompanied by partial loss of methylation of the GRB10 and PEG3 loci. Such hypomethylation is consistent with mutation of ZFP57, and sequencing of ZFP57 showed that the patient was homozygous for the NM_001109809.1:c.313C > T mutation, causing truncation of the ZFP57 protein NM_001109809.1(ZFP57_i001):p.(Arg105*).

DISCUSSION

TNDM is usually sporadic and constitutes 50–60% of all NDM cases. NDM is a developmental disorder of insulin production that usually resolves within the first year of life. Children with TNDM commonly present within the first few weeks of life with parentally voiced complaints of IUGR, failure to thrive, hyperglycemia, glycosuria and dehydration. Ketonuria is usually mild or absent. Paternal transmission is evident in one-third of all cases. Some cases exhibit paternally derived partial duplication of the long arm of chromosome 6, and isodisomy. In recent years, it has been shown that methylation disorders of chromosome 6, of both the mother and father and especially of genes in the 6q24 region, play roles in TNDM development [2].

In our case, the clinical significance of the heterozygous variation in the ABCC8 gene was unclear. This was either a loss-of-function mutation associated with recessive inheritance of congenital hyperinsulinism, or was of no clinical significance. Further analysis revealed a ZFP57 mutation, associated with complete loss of maternal methylation of the TND locus and only partial methylation of the GRB10 and PEG3 loci. The mutation prematurely terminated translation, triggering nonsense-mediated mRNA decay in the absence of protein production. This finding is consistent with the reported role of the 6q24 TNDM locus [3, 4]. ZFP57 encodes a zinc-finger protein that regulates transcription and is required for the maintenance of imprinting. Boonen et al. described seven families containing 12 ZFP57 TNDM patients with IUGR, macroglossia, developmental delay and two asymptomatic ZFP57 deletions [5]. Docherty et al. studied 163 patients with 6q24-attributable TNDM and found that 12 had ZFP57 mutations [2]. Their mean birth weight, age at onset and time to remission were 2098 g, 18 days and 6 months, respectively. Boyraz et al. described a 12-day-old Turkish infant with TNDM attributable to a ZFP57 deletion; the infant did not exhibit ketoacidosis and attained remission at the age of 6 months [3]. Our patient is the first example of an infant who came to medical attention because of ketoacidosis and who was then shown to carry a ZFP57 mutation. A few cases of diabetic ketoacidosis have been described in the literature. Two were admitted with symptoms mimicking sepsis [6, 7], and no genetic predisposition was reported in these patients. Initially, we suspected that our patient exhibited persistent NDM attributable to ketoacidosis, but his clinical course and identification of the ZFP57 mutation allowed us to diagnose TNDM.

In conclusion, several diseases in newborns, including sepsis, dehydration, congenital heart disease and hereditary metabolic disorders, should be considered during the differential diagnosis of NDM. Genetic studies are required for the differential diagnosis of both TNDM and PNDM, and to aid in prognosis. Ketoacidosis may complicate the clinical course, as in our patient.

What is already known: Diabetic ketoacidosis is extremely rare among neonatal diabetes mellitus cases, and there is no obvious ketonemia or ketonuria in majority of the cases. ZFP57 gene mutations were reported in newborns with transient diabetes mellitus without ketoacidosis.

What this study adds: Our case was presented with ketoacidosis, and genetic study revealed ZFP57 gene mutation first time in the literature. On follow-up, transient diabetes mellitus diagnosis was performed. Clinical and genetic studies should be performed to differentiate transient and permanent diabetes mellitus.

References