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We report a male infant with transient neonatal diabetes mellitus (TNDM; MIM 601410), macroglossia, hypertelorism, umbilical hernia, inguinoscrotal hernia and onychomycosis. Diabetes mellitus was diagnosed 10 days after birth and resolved after 6.5 months of treatment. Genetic investigation indicated the presence of paternal uniparental disomy of chromosome 6 (UPD 6). The finding of paternal UPD 6 allows prediction of a transient, rather than permanent NDM, and no increased recurrence risk of TNDM in subsequent pregnancies. Therefore, finding of NDM should be a strong indicator for genetic testing.

Transient neonatal diabetes (TND) is a rare type of diabetes that presents soon after birth, resolves by 18 months, and predisposes to diabetes later in life. A total of 30 patients were ascertained and investigated for aberrations of chromosome 6. A genotype/phenotype study was also performed. Genotypically, these patients can be classified into 4 etiologic groups. Group 1 had paternal uniparental isodisomy of chromosome 6 (11 cases, including 1 set of identical twins). Group 2 had a duplication involving chromosome band 6q24, which was paternal in origin where tested (4 sporadic cases and 7 familial cases from 2 families). Group 3 consisted of 1 patient with a loss of methylation at a CpG island within the TND critical region (1 sporadic case). Group 4 had no identifiable rearrangement of chromosome 6 (7 sporadic cases). Most patients were growth retarded at birth, presented at a median age of 3 days, and recovered at a median age of 12 weeks. In group 2, 2 relatives of the TND patients who presented with type 2 diabetes and no early history of TND had inherited an identical duplication. An abnormality of chromosome 6 was identified in approximately 70% of sporadic TND cases and in all familial cases. No significant clinical differences were found between the 4 etiological groups. The study has broadened the clinical spectrum of TND to include type 2 diabetes presenting in later life with no neonatal presentation. The findings are consistent with an imprinted gene for diabetes mapping to 6q24, which we predict will have an important function in normal pancreatic development.

Transient neonatal diabetes mellitus (TNDM) is a rare condition which presents with intrauterine growth retardation, dehydration, and failure to thrive. The condition spontaneously resolves before 1 year of age but predisposes patients to type 2 diabetes later in life. We have previously shown that, in some cases, TNDM is associated with paternal uniparental disomy (UPD) of chromosome 6 and suggested that an imprinted gene responsible for TNDM lies within a region of chromosome 6q. By analysing three families, two with duplications (family A and patient C) and one with several affected subjects with normal karyotypes (family B), we have further defined the TNDM critical region. In patient A, polymorphic microsatellite repeat analysis identified a duplicated region of chromosome 6, flanked by markers D6S472 and D6S311. This region was identified on the Sanger Centre's chromosome 6 radiation hybrid map (http://www.sanger.ac.uk/HGP/Chr6) and spanned approximately 60 cR3000. Using markers within the region, 418 unique P1 derived artificial chromosomes (PACs) have been isolated and used to localise the distal breakpoints of the two duplications. Linkage analysis of the familial case with a normal karyotype identified a recombination within the critical region. This recombination has been identified on the radiation hybrid map and defines the proximal end of the region of interest. We therefore propose that an imprinted gene for TNDM lies within an 18.72 cR3000 (approximately 5.4 Mb) interval on chromosome 6q24.1-q24.3 between markers D6S1699 and D6S1010.

Transient neonatal diabetes mellitus occurs in growth-retarded infants, has an incidence of 1 in 400000 live births and has been associated with both paternal uniparental disomy of chromosome 6 and paternal duplications of 6q. We analysed samples from our cohort of patients with transient neonatal diabetes mellitus for uniparental disomy of chromosome 6 using polymorphic microsatellite repeat analysis. We report here the fifth case of paternal uniparental disomy of chromosome 6 associated with classic transient neonatal diabetes mellitus and estimate that uniparental disomy of chromosome 6 accounts for approximately one fifth of cases of transient neonatal diabetes mellitus.

A British Paediatric Association Surveillance Unit* study of neonatal diabetes determined a national incidence of 1 in 400,000 live births. Additional cases of transient neonatal diabetes were collected retrospectively. Most cases were of low birthweight at term: none had evidence of an autoimmune aetiopathogenesis. The median requirement for exogenous insulin treatment was three months. A significant number of cases developed type 2 diabetes in later life. Three of the 11 cases were found to have paternal uniparental isodisomy of chromosome 6. A further patient carried an unbalanced duplication of 6q 22-23, inherited from the father, which localised a potentially imprinted gene for diabetes to this region. The fact that low birthweight predisposes to type 2 diabetes in later life is well established, but a genetic defect that may relate both to intrauterine growth failure and the development of type 2 diabetes in later life has now been identified.

Transient neonatal diabetes mellitus (TNDM) is a rare form of childhood diabetes which usually resolves in the first 6 months of life but which predisposes to type 2 diabetes of adult onset. We recently reported paternal uniparental isodisomy of chromosome 6 (UPD6) in two children with TNDM and proposed that there may be an imprinted gene important in the aetiology of diabetes on chromosome 6. We now describe two unrelated families which independently suggest that the gene is imprinted, is paternally expressed and maps to 6q22-q23. One family has a duplication while the other, with familial TNDM, shows linkage to a marker in this region.