Neonatal diabetes mellitus (NDM), defined as insulin-requiring hyperglycemia within the first month of life, is a rare entity, with an estimated incidence of 1 in 400,000 neonates (Shield, 2000). In about half of the neonates, diabetes is transient ... Neonatal diabetes mellitus (NDM), defined as insulin-requiring hyperglycemia within the first month of life, is a rare entity, with an estimated incidence of 1 in 400,000 neonates (Shield, 2000). In about half of the neonates, diabetes is transient and resolves at a median age of 3 months, whereas the rest have a permanent form of diabetes (606176). In a significant number of patients with transient neonatal diabetes mellitus, type II diabetes appears later in life (Arthur et al., 1997). The major cause of transient neonatal diabetes (TND) is aberrant expression of imprinted genes at chromosome 6q24, associated in 20% of cases with DNA hypomethylation at the TND differentially methylated region (DMR), which lies within the imprinted promoter of the PLAGL1 gene (603044; Mackay et al., 2005). Over 50% of individuals with TND and hypomethylation at 6q24 also show mosaic DNA hypomethylation at other imprinted loci throughout the genome and a range of additional clinical features. Mackay et al. (2008) found that mutations in the ZFP57 gene are associated with TND with hypomethylation of the TND DMR as well as hypomethylation of the PEG3 (601483) and GRB10 (601523) DMRs, and heterogeneous clinical features.
Temple et al. (1996) reviewed the manifestations of transient neonatal diabetes mellitus and the evidence for an imprinted, paternally expressed gene on chromosome 6q22-q23. They reported that TNDM occurs with a frequency of approximately 1 in 500,000 births. ... Temple et al. (1996) reviewed the manifestations of transient neonatal diabetes mellitus and the evidence for an imprinted, paternally expressed gene on chromosome 6q22-q23. They reported that TNDM occurs with a frequency of approximately 1 in 500,000 births. Patients are born with intrauterine growth retardation and present within the first 6 weeks of life with severe failure to thrive, hyperglycemia, and dehydration. Temple et al. (1996) noted that there is evidence for failure of insulin (176730) production in response to glucose feeding and that insulin therapy is usually required. The condition usually resolves within the first 6 months of life. However there is a predisposition toward type 2 (insulin resistant) diabetes (see 601283) later in life. Christian et al. (1999) reported 2 patients who presented at birth with neonatal diabetes mellitus (NMD): one with paternal uniparental disomy for chromosome 6 and one with normal, biparental inheritance. The first child presented with low birth weight, macroglossia, hypertelorism, and clubfoot in addition to NDM. In this patient hyperglycemia was transient, and insulin treatment was discontinued at 4 months of age. The second child also presented with low birth weight but was normal in appearance, and insulin dependence continued after 5 years. Genetic analysis with polymorphic DNA markers for chromosome 6 indicated the presence of paternal uniparental disomy (UPD6) in the first case and normal, biparental inheritance in the second case. Christian et al. (1999) found reports of 8 previous cases of UPD6 of which 6 showed NDM. Three cases with paternal UPD6 also included additional anomalies, such as macroglossia, not usually associated with NDM. Christian et al. (1999) suggested, therefore, that the simultaneous finding of NDM and macroglossia should be a strong indicator for genetic testing. The genetic finding of paternal UPD6 allows prediction of a transient, rather than a permanent, form of diabetes mellitus and no increased recurrence risk of transient NDM in subsequent pregnancies. Marquis et al. (2000) described 2 patients who suffered from transient neonatal diabetes mellitus (TNDM) due to paternal isodisomy of chromosome 6. One patient, 5 years old at the time of report, had severe intrauterine growth retardation, but recovered normal growth parameters. The other patient, 12 years old at the time of report, had a normal birth weight but showed impaired postnatal growth; in addition to TNDM, this patient presented with cardiac and thyroid abnormalities. Mackay et al. (2006) reported 2 unrelated TNDM patients who had loss of maternal methylation both at 6q24 and at the centromeric DMR on 11p15.5 (KCNQ1OT1; 604115), which is involved in imprinting abnormalities in Beckwith-Wiedemann syndrome. Both patients presented with intrauterine growth retardation and TNDM without features of overgrowth. However, both had moderate macroglossia and abdominal wall defects, features occasionally found in both BWS and TNDM.
In a study of 97 patients with diabetes diagnosed in the first 6 months of life whose diabetes remitted before the age of 5 years, 64 of whom had previously been reported, Flanagan et al. (2007) found that ... In a study of 97 patients with diabetes diagnosed in the first 6 months of life whose diabetes remitted before the age of 5 years, 64 of whom had previously been reported, Flanagan et al. (2007) found that 70 of 97 (72%) had an abnormality at the 6q24 locus: 27 (39%) had paternal uniparental isodisomy, 28 (40%) had a duplication of the paternal allele, and 15 (22%) had a methylation defect. Of the remaining 28 TNDM patients without 6q24 abnormalities, 13 were found to have a mutation in the ABCC8 gene (600509) and 12 in the KCNJ11 gene (600937); in 3 patients no mutation was found. There were no significant differences in clinical characteristics between patients with ABCC8 and KCNJ11 mutations, whereas patients with a 6q24 abnormality had a significantly lower birth weight and an earlier diagnosis and remission than patients with K(ATP) channel mutations (p less than 0.001 for all). Atypical phenotypes were observed in all 3 patients in whom the genetic etiology was not defined, including premature birth, epilepsy, and multiple episodes of relapse and remission. Of 16 Japanese patients with TNDM, Suzuki et al. (2007) identified the 6q24 abnormality in 11 and a KCNJ11 mutation in 2; of 15 patients with PNDM, they identified a KCNJ11 mutation in 7 and an ABCC8 mutation in 2. Compared to patients with a KCNJ11 mutation, patients with the 6q24 abnormality had earlier onset of diabetes, a lower frequency of diabetic ketoacidosis at onset, and a higher proportion of patients with macroglossia at initial presentation. Diatloff-Zito et al. (2007) reported a group of 13 sporadic transient neonatal diabetes cases, including 5 with birth defects (congenital abnormalities of heart, brain, and bone) and 8 without. Two of the patients had paternal uniparental disomy-6 (UPD6); of the remaining 11 cases, 2 had complete and 3 had partial loss of the maternal methylation signature upstream of the ZAC1-HYMAI imprinted genes in non-UPD cases. There was 1 case of hemizygous deletion among all 13 cases, in a patient with severe congenital malformations. Diatloff-Zito et al. (2007) raised the hypothesis that the deletion had an effect on regulatory elements critical for imprinting and tissue-specific gene expression in early development.
On the basis of selection under the twin criteria of involvement in DNA binding or transcription regulation and expression in mouse oocyte or early zygote, and because of its expression in undifferentiated stem cell lineages and downregulation upon ... On the basis of selection under the twin criteria of involvement in DNA binding or transcription regulation and expression in mouse oocyte or early zygote, and because of its expression in undifferentiated stem cell lineages and downregulation upon stem cell differentiation, Mackay et al. (2008) chose ZFP57 as the best candidate among the genes in the critical interval on 6p22.2-6p21.1. They identified ZFP57 mutations in 7 families with hypomethylation of multiple imprinted loci. Missense, nonsense, and frameshift mutations were identified. In addition to showing the cardinal epigenetic feature of TND, hypomethylation of the TND differentially methylated region (DMR), individuals with ZFP57 mutations were all hypomethylated at the PEG3 (601483) and GRB10 (601523) differentially methylated regions (DMRs). Hypomethylation of the KCNQ1OT1 (604115) and PEG1 (601029) DMRs was found in individuals with or without mutations in ZFP57. The diabetic presentation was typical for 6q TND in the 8 infant probands. Mackay et al. (2008) found that 6 of 9 individuals with TNDM and ZFP57 mutations had additional clinical features atypical of TNDM associated with hypomethylation at 6q24. Developmental delay was noted in 6 cases, including 2 with severe developmental delay and hypoplasia of the corpus callosum; however, ZFP57 mutation was also compatible with normal intelligence and development. Three probands were reported to have cardiac defects. These anomalies are less prevalent among individuals with hypomethylation of multiple imprinted loci but without mutations in ZFP57.