LETTER TO JMG Major difference in aetiology and phenotypic abnormalities between transient and permanent neonatal diabetes

Neonatal diabetes (ND) is a rare entity with an estimated incidence of 1/400 000 births in Europe. Hyperglycaemia usually occurs in the first few days of life and patients require insulin treatment. Intrauterine growth retardation, low birth weight, and decreased adipose tissue are frequently associated. ND is permanent in some patients (permanent ND), and in other cases hyperglycaemia is transient (transient ND, OMIM 601410). Type 2 diabetes (T2D) frequently arises in adolescence or adulthood in transient ND patients. Chromosome 6 abnormalities are specifically associated with transient ND, with imprinting effects unmasked by uniparental disomy (UPD) of paternal chromosome 6 and duplications in 6q24. Two imprinted genes expressed from the paternal allele in various tissues, ZAC/PLAGL1 (zinc finger, apoptosis, cell cycle/pleomorphic adenoma of the salivary gland gene like 1) and HYMAI (hydatidiform mole associated and imprinted transcript), lie in the transient ND locus in 6q24. 8 The genetic causes of permanent ND forms are less known. Homozygous mutation in the glucokinase gene (GK) and in the insulin promoter factor-1 (IPF1) gene may lead to permanent ND owing to complete deficiency of the GK or IPF1 gene product. Mutations of the eukaryotic translation initiation factor-2-alpha kinase 3 (EIF2AK3) gene were found to segregate with the Wolcott-Rallison syndrome (OMIM 226980), a rare autosomal recessive disorder with early onset permanent diabetes mellitus and multiple epiphyseal dysplasia (spondyloepiphyseal dysplasia). Clinical information and a molecular genetic study of 14 patients with transient or permanent ND forms are reported. The phenotypes of ND patients from previous reports together with cases reported here provide an initial outline for further studies and molecular mechanisms. PATIENTS Fourteen patients with ND were studied. Their main clinical features are summarised in table 1. The patients were all born at term, mean birth weight was 2288 g (SD 570 g), and nine patients displayed intrauterine growth retardation (>2 SD). Diabetes was diagnosed within the first month of life in 13 of the patients. The proband referred to as O7 is a child from a multiplex family, with permanent diabetes appearing before 6 months of age. Four other members of family O in two generations were affected in a manner suggestive of an autosomal dominant pattern of inheritance. Patients I3 and I4 were brother and sister with permanent ND. All nine patients with transient ND were sporadic cases. All the patients were found to be negative for autoantibodies against islet cells (ICA) or insulin (AIA). Sequences of HLA-DRB1 and DQB1 loci were achieved for all the patients and relatives and alleles classically associated with juvenile diabetes were not found. Ultrasound scans were performed to exclude pancreatic agenesis in permanent ND patients. The patients were all white, except for patient J who originated from Guyana.