Transient Neonatal Diabetes Mellitus
(Transient neonatal diabetes mellitus 1, TNDM1, OMIM #601410)
Transient neonatal diabetes (type 1) (TNDM1) is characterised by diabetes mellitus that develops in the first six weeks of life, and resolves by the age of 18 months (Temple et al, 2012; Mackay et al 2014). It is caused by over-expression of imprinted genes at chromsome 6q24 (Kamiya et al 2000, Gardner et al, 2000). TNDM1 is distinct from transient neonatal diabetes caused by mutations of other genes (Polak & Cave 2007; Flanagan et al 2007), including TNDM2 (OMIM #610374) associated with mutation of ABCC8, and TNDM3 (OMIM #610582) caused by mutation of KCNJ11. Prevalence of TNDM in the UK was initially estimated at 1:400,000 as reported (Shield et al 1997); but more recent calculations estimate total neonatal diabetes incidence of 1:215,000 to 1:400,000 (Polak & Shield 2004, Stanik et al 2007, Wiedemann et al 2010).
Clinical characteristics: ↓
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).
Genetic background: ↓
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).
Molecular mechanisms: ↓
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.
Molecular genetic testing: ↓
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.
Tables & Graphs: ↓
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