Newborns with TNDM1 show intrauterine growth restriction (IUGR), and are typically small for gestational age (Temple et al, 2000).  In a series of 163 cases, the mean birth weight was 2.0kg, significantly lower than average (Docherty et al 2013).  Most infants present with hyperglycaemia in the first days of life, and insulin treatment is required on average for 2-3 months, but in some cases for over a year.  Unlike other forms of neonatal diabetes patients with 6q24 related TND should stay on insulin during the neonatal phase of this disorder. The hyperglycaemia generally resolves spontaneously, and most children will then have normal growth and development.  However, some glycaemic problems have been described:

(i)            Some individuals may suffer brief periods of hyperglycemia during childhood, particularly during intercurrent illness (Shield et al, 2004).

(ii)           Some infants, on resolution of neonatal diabetes, develop hyperinsulinaemic hypoglycaemia of varying severity (Flanagan et al 2013).

(iii)          Some individuals with TNDM1 develop type 2 diabetes in later life. For this reason it is important that patients are made aware of this and consider regular follow up or take action if they have symptoms. If diabetes recurs it can be  managed by diet or oral drugs, or it requires insulin treatment (Temple et al 2000). The true frequency of relapse is not known, nor is it clear whether any genetic or lifestyle factors can modify the risk of diabetic relapse.

Aside from IUGR and transient diabetes, TNDM1 has no major cardinal features; however, individuals may have congenital abnormalities (Temple et al 2000, Docherty et al 2013).  Macroglossia (large tongue) affects just under half of infants with TNDM1, and about 1 in 5 individuals may also have a minor anomaly of the abdominal wall, most notably an umbilical hernia.  Other congenital problems are rare, and often connected with the genetic nature of the disease; they are mentioned below.  Approximately 10% of individuals with TNDM1 do not present with hyperglycaemia at birth (Valerio et al 2004, Boonen et al 2013).

The TNDM1 locus on 6q24 is relatively small among human imprinted loci (Iglesias Platas et al, 2012).  It contains one coding gene, PLAGL1, where only the paternally inherited allele is normally expressed in the majority of tissues, while the maternally-inherited allele is repressed (Kamiya et al 2000, Gardner et al 2000).  This differential expression is controlled by a differentially methylated region (DMR) in a promoter region which is methylated in oocytes, but not in sperm. PLAGL1 has a second promoter 55Kb upstream from the imprinted promoter, which is not imprinted and promotes biallelic expression in some tissues including blood and adult pancreas in normal individuals (Valleley et al 2007).  PLAGL1 is a zinc finger DNA binding protein with tumor suppressor activity, involved in cell cycle control and apoptosis, and with a central regulatory role in the imprinted gene network (Varrault et al 1998, Varrault et al 2006). Loss of PLAGL1 expression has been described in a number of cancers. Mice overexpressing PLAGL1 have reduced beta cell mass in fetal pancreas (Ma et al, 2004).  In a model system using the INS-1 cell line, overexpression of PLAGL1 did not influence cell growth or proliferation, but did repress insulin secretion in response to glucose (Du et al, 2012).

HYMAI is a non-coding gene transcribed in the same orientation as PLAGL1 from the imprinted promoter, whose function is not known (Arima et al, 2001).  A third transcript, Plagl1it, has been identified in mice (Iglesias-Platas et al,2012).

Unlike many other imprinting disorders, TND is caused not by loss of function but by overexpression of imprinted genes.  Three basic mechanisms are described.

(i)            paternal uniparental disomy of chromosome 6 (UPD6pat) involving 6q24 is found in approximately 35% of cases.  Some of these have additional clinical problems, caused by unmasking of recessive mutations on chromosome 6.  UPD6pat normally has an extremely low risk of recurring in families.

(ii)           genomic duplication of the paternally-inherited allele of 6q24 is found in 35% of cases.  Duplication of 6q24 only causes TND when inherited on the paternal allele; but in families with duplications, affected children can be born to asymptomatic fathers carrying the duplication on their maternal allele.  Individuals do not normally have other clinical problems besides TND, unless the duplication spans a large genomic region.

(iii)          loss of maternal methylation of the imprinted DMR (in the absence of a genomic rearrangement) is seen in 30% of cases.  Half of these maternal hypomethylation cases affect only the TNDM DMR:  they are thought to be sporadic, though local genomic mutations may be identified that predispose to DNA methylation errors.  In the other 50% of cases, hypomethylation affects other imprinted loci in addition to 6q24.  A proportion of these cases have mutations of ZFP57, a zinc finger transcription factor expressed in very early embryo development (Mackay et al 2008).  A mouse study showed that loss of zfp57 function disturbed both setting and maintenance of DNA methylation at a group of imprinted loci (Li et al 2008).  It should be noted that the majority of ZFP57 mutation cases have been identified in consanguineous pedigrees (Boonen et al 2012), and therefore, in ethnicities with high levels of consanguineous union, ZFP57 mutation may be a major cause of TND.  In other cases with loss of methylation at multiple imprinted genes, no genetic cause has yet been found.  Other factors like assisted reproduction or monozygous (identical) twinning are present among these cases at a slightly higher level than the normal population (Docherty et al 2013), but this may not be causal.

For infants presenting with growth restriction and hyperglycaemia in the first two weeks of life, TNDM1 diagnostic testing is advisable (Mackay et al, 2014).

Ratiometric determination of DNA methylation at the TNDM1 DMR detects all known causes of TNDM1.  Various methods are used across different diagnostic settings (summarised in Temple 2012)

If complete loss of methylation is detected, microsatellite inheritance of chromosome 6 markers from the patient, mother and father can identify UPD6pat.  If no UPD6pat is detected, then a DNA methylation anomaly is suggested, and to determine its cause molecular genetic testing of ZFP57 can be considered.

If partial loss of DNA methylation is detected, copy number analysis is indicated to identify paternal 6q24 duplication.  If paternal 6q24 duplication is identified, screening of wider family may be indicated.  Conventional karyotype analysis can determine whether visible chromosome translocations or insertions are causative.

[/wpex)

References: ↓

Arima T, Drewell RA, Arney KL, Inoue J, Makita Y, Hata A, Oshimura M, Wake N, Surani MA.  A conserved imprinting control region at the HYMAI/ZAC domain is implicated in transient neonatal diabetes mellitus. Hum Mol Genet. 2001 Jul 1;10(14):1475-83.

Boonen SE, Mackay DJ, Hahnemann JM, Docherty L, Grønskov K, Lehmann A, Larsen LG, Haemers AP, Kockaerts Y, Dooms L, Vu DC, Ngoc CT, Nguyen PB, Kordonouri O, Sundberg F, Dayanikli P, Puthi V, Acerini C, Massoud AF, Tümer Z, Temple IK. Transient neonatal diabetes, ZFP57 and hypomethylation of multiple imprinted loci: a detailed follow-up.  Diabetes Care. 2013 Mar;36(3):505-12.

Docherty LE, Kabwama S, Lehmann A, Hawke E, Harrison L, Flanagan SE, Ellard S, Hattersley AT, Shield JPH,Ennis S, Mackay DJ, Temple IK.  6q24 Transient Neonatal Diabetes Mellitus (6q24 TNDM) – clinical presentation and genotype phenotype correlation in an international cohort of cases.  Diabetologia 2013 Apr;56(4):758-62.

Du X, Ounissi-Benkalha H, Loder MK, Rutter GA, Polychronakos C. Overexpression of ZAC impairs glucose-stimulated insulin translation and secretion in clonal pancreatic beta-cells. Diabetes Metab Res Rev. 2012 Nov;28(8):645-53.

Flanagan SE, Patch A, Mackay DJG, Edghill EL, Gloyn AL, Robinson D, Shield JPH, Temple IK, Ellard S, Hattersley AT.   Mutations in KATP channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood.  Diabetes. 2007 Jul;56(7):1930-7.

Flanagan SE, Mackay DJ, Greeley SA, McDonald TJ, Mericq V, Hassing J, Richmond EJ, Martin WR, Acerini C, Kaulfers AM, Flynn DP, Popovic J, Sperling MA, Hussain K, Ellard S, Hattersley AT.  Hypoglycaemia following diabetes remission in patients with 6q24 methylation defects: expanding the clinical phenotype. Diabetologia. 2013 Jan;56(1):218-21.

Gardner RJ, Mackay DJG, Mungall AJ, Polychronakos C, Siebert R, Shield JP et al. (2000). An imprinted locus associated with transient neonatal diabetes mellitus. Hum Mol Genet. 9, 589-96

Kamiya M, Judson H, Okazaki Y, Kusakabe M, Muramatsu M, Takada S, Takagi N, Arima T, Wake N, Kamimura K, Satomura K, Hermann R, Bonthron DT, Hayashizaki Y.  The cell cycle control gene ZAC/PLAGL1 is imprinted–a strong candidate gene for transient neonatal diabetes.  Hum Mol Genet. 2000 Feb 12;9(3):453-60.

Iglesias-Platas I, Martin-Trujillo A, Cirillo D, Court F, Guillaumet-Adkins A, Camprubi C, Bourc’his D, Hata K, Feil R, Tartaglia G, Arnaud P, Monk D. Characterization of novel paternal ncRNAs at the Plagl1 locus, including Hymai, predicted to interact with regulators of active chromatin. PLoS One. 2012;7(6):e38907.

Iglesias-Platas I, Court F, Camprubi C, Sparago A, Guillaumet-Adkins A, Martin-Trujillo A, Riccio A, Moore GE, Monk D. Imprinting at the PLAGL1 domain is contained within a 70-kb CTCF/cohesin-mediated non-allelic chromatin loop. Nucleic Acids Res. 2013 Feb 1;41(4):2171-9.

Li X, Ito M, Zhou F, Youngson N, Zuo X, Leder P, Ferguson-Smith AC. A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Dev Cell. 2008 Oct;15(4):547-57.

Ma D, Shield JP, Dean W, Leclerc I, Knauf C, Burcelin R Ré, Rutter GA, Kelsey G.  Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM.  J Clin Invest 2004; 114:339-348

Mackay DJG, Callaway JLA, Marks SM, White HE, Acerini CL, Boonen SE, Dayanikli P, Firth HV, Goodship JA, Haemers AP, Hahnemann JMD, Kordonouri O, Masoud AF, Oestergaard E, Storr J, Ellard S, Hattersley AT, Robinson DO, Temple IK.  2008. Hypomethylation of multiple imprinted loci in patients with transient neonatal diabetes is associated with mutations in ZFP57.  Nat Genet 40:949-951.

Mackay D, Bens S, Perez de Nanclares G, Siebert R, Temple IK. Clinical utility gene card for: Transient Neonatal Diabetes Mellitus, 6q24-related.  Eur J Hum Genet. 2014 Feb 26. doi: 10.1038/ejhg.2014.27.

Polak M, Cavé H.  Neonatal diabetes mellitus: a disease linked to multiple mechanisms.  Orphanet J Rare Dis. 2007;2:12.

Polak M, Shield J. Neonatal and very-early-onset diabetes mellitus. Semin Neonatol. 2004;9:59–65

Shield JP, Gardner RJ, Wadsworth EJ, Whiteford ML, James RS, Robinson DO, Baum JD, Temple IK. Aetiopathology and genetic basis of neonatal diabetes. Arch Dis Child Fetal Neonatal Ed. 1997;76:F39–42.

Shield JP, Temple IK, Sabin M et al. An assessment of pancreatic endocrine function and insulin sensitivity in patients with transient neonatal diabetes in remission. Arch Dis Child Fetal Neonatal Ed. 2004;89:F341–343.

Stanik J, Gasperikova D, Paskova M, Barak L, Javorkova J, Jancova E, Ciljakova M, Hlava P, Michalek J, Flanagan SE, Pearson E, Hattersley AT, Ellard S, Klimes I. Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. J Clin Endocrinol Metab. 2007;92:1276–82.

Temple IK, Gardner RJ, Mackay DJG, Barber JCK, Robinson DO and Shield JPH.  (2000). Transient neonatal diabetes mellitus:  widening our understanding of the aetiopathogenesis of diabetes.  Diabetes, 49,1359-66

Temple IK, Docherty LE, Mackay DJG.  Diabetes Mellitus, 6q24-Related Transient Neonatal.  In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2005 Oct 10, updated 27 September 2012.  http://www.ncbi.nlm.nih.gov/books/NBK1534/#dmtn.Clinical_Description

Valerio G, Franzese A, Salerno M et al. Beta-cell dysfunction in classic transient neonatal diabetes is characterized by impaired insulin response to glucose but normal response to glucagon. Diabetes Care. 2004;27:2405–8.

Valleley, E. M., Cordery, S. F., Bonthron, D. T. Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters. Hum. Molec. Genet. 16: 972-981, 2007.

Varrault, A., Ciani, E., Apiou, F., Bilanges, B., Hoffmann, A., Pantaloni, C., Bockaert, J., Spengler, D., Journot, L. hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer. Proc. Nat. Acad. Sci. 95: 8835-8840, 1998.

Varrault, A., Gueydan, C., Delalbre, A., Bellmann, A., Houssami, S., Aknin, C., Severac, D., Chotard, L., Kahli, M., Le Digarcher, A., Pavlidis, P., Journot, L. Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Dev. Cell 11: 711-722, 2006.

Wiedemann B, Schober E, Waldhoer T, Koehle J, Flanagan S, Mackay DJG, Steichen E, Meraner D, Zimmerhackl L, Hattersley AT, Ellard S, Hofer S. Incidence of neonatal diabetes in Austria – Calculation based on the Austrian Diabetes Register. Pediatr Diabetes. 2010;11:18–23.