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Diabetes Mellitus, 6q24-Related Transient Neonatal

Synonyms: Chromosome 6-Associated Transient Diabetes Mellitus, TNDM

, MD, MBChB, FRCP, , PhD, MA, and , PhD, BSc (hons).

Author Information
, MD, MBChB, FRCP
Professor of Medical Genetics, Human Genetics and Genomic Medicine
Academic Unit of Human Development and Health
Faculty of Medicine, University of Southampton
Honorary Consultant in Clinical Genetics, Wessex Clinical Genetics Service
Southampton University Hospitals NHS Trust
Southampton, Hampshire, United Kingdom
, PhD, MA
Reader of Medical Epigenetics, Epigenetics
Academic Unit of Human Development and Health
Faculty of Medicine, University of Southampton
Wessex Regional Genetics Laboratory
Salisbury NHS Foundation Trust
Salisbury, United Kingdom
, PhD, BSc (hons)
Post-doctoral Research Fellow, Epigenetics
Academic Unit of Human Development and Health
Faculty of Medicine, University of Southampton
Wessex Regional Genetics Laboratory
Salisbury NHS Foundation Trust
Salisbury, United Kingdom

Initial Posting: ; Last Update: September 27, 2012.

Summary

Disease characteristics. 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) is defined as transient neonatal diabetes mellitus caused by genetic aberrations of the imprinted locus at 6q24. The cardinal features are: severe intrauterine growth retardation, hyperglycemia that begins in the neonatal period in a term infant and resolves by age 18 months, dehydration, and absence of ketoacidosis. Macroglossia and umbilical hernia are often present. In the subset of children with ZFP57 mutations, other manifestations can include structural brain abnormalities, developmental delay, and congenital heart disease. Diabetes mellitus usually starts within the first week of life and lasts on average three months but can last over a year. Although insulin is usually required initially, the need for insulin gradually declines over time. Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Diabetes mellitus may recur in adolescence or later in adulthood. Women who have had 6q24-TNDM are at risk for relapse during pregnancy.

Diagnosis/testing. 6q24-TNDM is caused by overexpression of the imprinted genes at 6q24 (PLAGL1 [ZAC] and HYMAI). A ‘differentially methylated region’ (DMR) is present within the shared promoter of these genes. Normally, expression of the maternal alleles of PLAGL1 and HYMAI are silenced by DMR methylation and only the paternal alleles PLAGL1 and HYMAI are expressed. Three different genetic mechanisms result in twice the normal dosage of these two genes and cause 6q24-TNDM:

  • Paternal uniparental disomy of chromosome 6 (41%);
  • Duplication of 6q24 on the paternal allele (29%); and
  • Hypomethylation of the maternal DMR resulting in inappropriate expression of the maternal PLAGL1 and HYMAI alleles (30%).

Maternal PLAGL1/HYMAI DMR hypomethylation may result from an isolated imprinting mutation or as part of a more generalized defect termed ‘hypomethylation at imprinted loci’ (HIL). Homozygous or compound heterozygous ZFP57 mutations account for almost half of TNDM-HIL; the other causes of HIL are not known. Rapid testing can confirm the diagnosis of 6q24-TNDM by detecting methylation changes resulting from any of the three mechanisms of disease causation. Additional clinical testing can detect paternal UPD6 and paternal 6q24 duplication.

Management. Treatment of manifestations: Rehydration and IV insulin are usually required at the time of diagnosis; subcutaneous insulin is introduced as soon as possible and used until blood glucose levels stabilize. Later recurrence of diabetes may require diet alone, oral agents, or insulin.

Prevention of secondary complications: Prompt treatment of dehydration to avoid sequelae.

Surveillance: Periodic glucose tolerance tests; abnormalities suggest future recurrence.

Evaluation of relatives at risk: Screening for diabetes mellitus in relatives who have inherited a paternal 6q24 duplication or who are at risk of having inherited two ZFP57 mutations.

Genetic counseling. The risk to sibs and offspring of a proband of having 6q24-TNDM or of developing diabetes later in life depends on the genetic mechanism in the family. Recurrence risk counseling by a genetics professional is strongly recommended. 6q24-TNDM caused by paternal UPD6 is typically a de novo, non-recurrent event. 6q24-TNDM caused by paternal dup6q24 can occur de novo, be inherited in an autosomal dominant manner, or be inherited as a part of a complex chromosome rearrangement; TNDM caused by an inherited dup6q24 may recur in sibs and offspring of a proband if the duplication is inherited from the father. Prenatal diagnosis of paternal dup6q24 is possible in pregnancies at risk for a structural chromosome abnormality. TNDM-HIL is inherited in an autosomal recessive manner when caused by mutations in ZFP57; however, the phenotype of homozygous or compound heterozygous sibs is variable and cannot be predicted by molecular genetic testing.

Diagnosis

Clinical Diagnosis

6q24-related transient neonatal diabetes mellitus (6q24-TNDM), defined as transient neonatal diabetes mellitus caused by overexpression of imprinted genes at 6q24, is characterized by diabetes mellitus that commences in the first six weeks of life in a term infant and resolves by age 18 months.

The cardinal features are severe intrauterine growth retardation, hyperglycemia, dehydration, and absence of ketoacidosis.

To aid in the diagnosis of neonatal diabetes mellitus the following are recommended:

  • A general pregnancy history, including use of assisted reproductive technology (ART) for conception
  • Family history
  • Clinical examination including a dysmorphology and neurologic assessment. Careful growth recordings are essential.
  • An ultrasound or MRI examination of the abdomen to identify the presence or absence of the pancreas

Testing

At the time of diagnosis:

  • Plasma insulin concentrations are low in the presence of high serum glucose concentrations.
  • Ketones are usually not present in the urine.
  • Islet cell antibodies are absent.

Cytogenetic analysis. A small minority of individuals have a cytogenetically visible duplication of 6q24 [personal observation]. FISH or chromosomal microarray analysis (CMA) can be used to confirm 6q24 duplications (see Table 1).

Molecular Genetic Testing

Genes. 6q24-TNDM is caused by overexpression of the imprinted genes PLAGL1 (ZAC) and HYMAI, at 6q24. At this region, imprinting is associated with the epigenetic changes at the ‘differentially methylated region’ (DMR). The DMR, thought to function as an imprinting center (IC), regulates the imprinting program in the region by epigenetic changes in methylation. Normally, expression of the maternal alleles of PLAGL1 and HYMAI are silenced by DMR methylation and only the paternal alleles PLAGL1 and HYMAI are expressed. In 6q24-TNDM, PLAGL1 and HYMAI alleles are overexpressed through one of the three following mechanisms (Figure 1):

Figure 1

Figure

Figure 1. Three different genetic mechanisms cause 6q24-TNDM: paternal UPD (uniparental disomy) of chromosome 6 (41%); duplication of 6q24 on the paternal allele (29%); and expression of the maternal PLAGL1/HYMAI differentially methylated region (DMR) (more...)

  • Partial or complete paternal uniparental disomy of chromosome 6 (UPD6). Two chromosome 6q24 regions, each with an expressed copy of PLAGL1 and HYMAI, are inherited from the father and none are inherited from the mother. This mechanism accounts for 41% of cases.
  • Paternal duplication of 6q24. Usually a submicroscopic duplication results in the presence of two copies of PLAGL1 and HYMAI on one paternal chromosome 6. This mechanism accounts for 29% of cases.
  • Hypomethylation of the maternal PLAGL1/HYMAI DMR. Loss of normal methylation (hypomethylation) in the maternal PLAGL1/HYMAI DMR results in inappropriate expression of the maternal PLAGL1 and HYMAI alleles. This mechanism accounts for 30% of cases. Hypomethylation can result from either an isolated imprinting mutation of the DMR or a more generalized defect termed ‘hypomethylation at imprinted loci’ (HIL). Forty-five percent of TNDM-HIL results from compound heterozygous or homozygous mutations in ZFP57; the other causes of TNDM-HIL are not known.

Clinical testing

Tier 1 testing detects hypomethylation within the 6q24 DMR region, regardless of the underlying molecular mechanism.

  • Ratiometric methylated/unmethylated DNA measurement. The test is based on ratiometric measurement of methylated and unmethylated DNA within the DMR. Methylation-specific PCR (MSPCR) of bisulfited DNA produces amplicons representing the unmethylated and methylated alleles, the amounts of which are represented on an electropherogram as peak heights [Mackay et al 2005]. The presence of an equivalent abundance of methylated and unmethylated DNA is consistent with a normal 1:1 unmethylated/methylated ratio. The patient’s ratio is compared to that of at least four normal controls in the same experiment. Hypomethylation (i.e., greater peak intensity for the unmethylated than the methylated amplicon of >3 SD greater than normal) is indicative of a positive result. Further studies to differentiate between the different causes are necessary.

Tier 2 testing is necessary to differentiate the two different molecular mechanisms that cause an extra copy of the paternal DMR region (see Table 1).

  • Uniparental disomy (UPD) studies are used to detect paternal UPD6 (41% of cases).
  • Duplication of 6q24. A variety of methods may be used for deletion/duplication analysis (copy number analysis) to identify an additional paternal copy of PLAGL1/HYMAI (see Table 1, footnote 3).

Tier 3 testing is useful to identify the cause of hypomethylation within the 6q24 DMR region not attributed to an extra copy of the paternal DMR region. If ratiometric measurement of methylated and unmethylated DNA within the differentially methylated region (DMR) is abnormal and neither paternal UPD6 nor copy number change of 6q24 is detected, it is assumed that the abnormal methylated/unmethylated ratio results from an abnormality of DNA methylation (see Research testing).

Limited clinical/research testing. Hypomethylation of the maternal PLAGL1/HYMAI DMR, in the absence of paternal UPD6 or 6q24 duplication, results from either:

  • An imprinting mutation of the promoter PLAGL1 DMR (isolated)

    or
  • A generalized ‘hypomethylation at imprinted loci’ (HIL); homozygous or compound heterozygous ZFP57 mutations account for more than half of HIL cases.

Note: The other causes of HIL are not known.

Table 1. Summary of Molecular Genetic Testing Used in 6q24-Related Transient Neonatal Diabetes Mellitus

Tiered Testing Strategy 1Genetic Mechanism DetectedTest Method% of All 6q24-Related TNDM
Identified
Tier 1All Ratiometric methylated / unmethylated DNA analysis 2100%
Tier 2Uniparental disomy 6 Uniparental disomy studies ~41%
Duplication of 6q24 Deletion / duplication analysis 3~29%
Tier 3Hypomethylation of maternal DMR with normal Tier 2 testingZFP57 mutationSequence analysis9% 4
Isolated imprinting center mutation 5(By exclusion of other causes) 10%
As part of HIL but cause unknownNA11%

1. See Testing Strategy.

2. Ratio of methylated to unmethylated DNA within the differentially methylated region (DMR) [Mackay et al 2005]

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

4. Mutations in ZFP57 account for 30% of individuals with an epigenetic cause of 6q24-related TNDM (i.e., not UPD6 or 6q24 duplication).

5. Diagnosis of exclusion

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

Suggested genetic testing strategy for infants with neonatal diabetes mellitus. The two most common causes of neonatal diabetes mellitus are 6q24-TNDM and mutations in KCNJ11. Metz et al [2002] failed to demonstrate clear clinical indicators to differentiate 6q24-TNDM from other causes in a large cohort of 50 individuals presenting with neonatal diabetes.

  • For infants presenting in the first two weeks of life, test for 6q24-related TNDM aberrations first (see below), followed by testing for KCNJ11, INS, and ABCC8 mutations.
  • For infants presenting from the fourth week onwards, it may be more appropriate to test for KCNJ11 and INS mutations first, followed by testing for 6q24-related TNDM aberrations.
  • For infants with associated features or consanguineous parents, other genetic analysis may be appropriate.

To confirm the diagnosis of 6q24-TNDM in a proband, the following tests are recommended in the order shown:

  • Tier 1. Ratiometric methylated/unmethylated DNA analysis determines the ratio of methylated to unmethylated DNA at the DMR within the promoter of PLAGL1/ HYMAI, thus establishing the diagnosis of 6q24-related TNDM.
  • Tier 2. To determine if an extra copy of the paternal DMR region is present the following test(s) are required:
    • Family studies of inheritance of chromosome 6 markers from the mother and father to identify paternal UPD6
    • If paternal UPD6 is not identified, duplication analysis (see Table 1, footnote 3 for methods) to identify paternal 6q24 duplication
    • If paternal 6q24 duplication is identified, conventional karyotype analysis to determine if visible chromosome translocations or insertions are causative
  • Tier 3. To determine the cause of hypomethylation of the maternal PLAGL1/HYMAI differentially methylated region (DMR) in the absence of paternal UPD6 or 6q24 duplication, molecular genetic testing of ZFP57 can be considered.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for pregnancies at risk for:

  • Paternal duplication 6q24 requires prior identification of the structural chromosome abnormality in the family.
  • Hypomethylation of the maternal PLAGL1/HYMAI DMR as a result of compound heterozygous or homozygous ZFP57 mutations requires identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Females and males are equally likely to be affected.

Pregnancy. Growth retardation may be noted in the third trimester.

In the neonate. Intrauterine growth retardation is a key feature; the mean birth weight in a study of 30 infants was 1930 g at 39 weeks' gestation [Temple et al 2000]. This is in keeping with other studies [Metz et al 2002, Diatloff-Zito et al 2007]. Because the plasma concentration of insulin is low at the time of diagnosis, it is assumed that low birth weight is a result of low in utero levels of insulin, an important prenatal growth factor.

Diabetes mellitus tends to develop in the first week of life, although it may not be recognized until later. Hyperglycemia may be identified by chance during routine investigations in the newborn period for a sick dehydrated infant. Infants rapidly become dehydrated and usually require insulin. The diabetes may be resistant to treatment initially. Occasionally insulin is not required and neonates are treated with rehydration alone.

Macroglossia and umbilical hernia are sometimes observed. No other dysmorphic features are consistently associated with this condition. Screening for congenital hypothyroidism is prudent.

6q24-TNDM caused by generalized HIL (hypomethylation at imprinted loci) can be associated with marked hypotonia, congenital heart disease, deafness, neurologic features including epilepsy, and renal malformations.

In infancy. Diabetes mellitus lasts on average three months but has been reported to last over a year [Temple et al 2000]. The need for insulin gradually declines. This is often accompanied by a significant weight gain and catch-up growth and some infants become overweight in the first year [Metz et al 2002].

In childhood. Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Few studies have been performed during this period and so the extent of these episodes is not known. Shield et al [2004] studied seven children during this period and found low insulin secretion in four and normal insulin secretion in three.

Diabetes may recur in very early childhood.

Permanent diabetes mellitus can occur in up to 50% in some series [Temple et al 2000] but this may be higher than the actual risk because of the bias of identifying affected individuals. There is usually some residual endogenous insulin production; however, insulin therapy may be needed.

In adolescence. The average age of recurrence in the series of Temple et al [2000] was 14 years, coinciding with puberty. Some individuals require insulin; others are treated with oral drugs or diet alone.

Intelligence and growth are usually normal in this condition except in individuals with loss of methylation at multiple loci, who may have developmental delay. In a series from France, five of seven individuals developed diabetes again after age eight years [Metz et al 2002].

In adulthood. Women are at risk for relapse during pregnancy and may present with gestational diabetes mellitus.

Studies have not been performed to assess the level of diabetes-related complications that can occur in this disorder. One individual with poor compliance with treatment had persistent hyperglycemia from ages 14 to 28 years. He did not develop ketoacidosis but did develop evidence of microangiopathy [Valerio et al 2004].

Genotype-Phenotype Correlations

Diabetes mellitus. No difference in the severity, duration, or relapse rate of diabetes has been detected between the 6q24-TNDM etiologic subgroups [Temple et al 2000].

Non-diabetes manifestations vary by causative genetic mechanism:

  • UPD6. The majority of UPD6 is isodisomic, i.e., two copies of chromosome 6 are identical and therefore the affected individual is at increased risk for rare autosomal recessive disorders that may be unmasked by this unusual inheritance pattern. The most common is HFE-associated hereditary hemochromatosis, for which testing can be performed in adulthood. Methylmalonic acidemia and congenital adrenal hyperplasia caused by 21-hydroxylase deficiency have also been described as occurring through this mechanism.
  • 6q duplication. Cytogenetically visible duplication of 6q can also be associated with learning difficulties related to other genes within the duplicated region. Note: Individuals with a submicroscopic 6q24 duplication are usually of normal intelligence.
  • Hypomethylation of the maternal PLAGL1/HYMAI DMR. Non-diabetes manifestations are more likely in the subgroup with generalized hypomethylation at imprinted loci (HIL) and can include significant learning difficulties [Boonen et al 2008, Mackay et al 2008]. No correlation has been observed between clinical severity and either the degree of hypomethylation or the range of loci involved. For example, the features seen in individuals with 6q24-TNDM caused by homozygous or compound heterozygous ZFP57 mutations can vary from severe intellectual disability and early infant death to a normal phenotype. It is therefore difficult to predict the phenotype in individuals with HIL, possibly because of the inability to interrogate all imprinted loci.

Penetrance

Lack of expression of the 6q24-TNDM phenotype leading to reduced penetrance is rare but has been noted when siblings of affected individuals were found to have an identical paternal duplication of 6q24 but no history of neonatal diabetes mellitus [Valerio et al 2004].

Reduced penetrance has also been shown in an individual homozygous for ZFP57 mutations.

Anticipation

Anticipation has not been noted.

Prevalence

Prevalence of TNDM in the UK was initially estimated at 1:400,000 as reported by Shield et al [1997]. More recent calculations confirm a total neonatal diabetes incidence of 1:215,000 to 1:400,000 [Polak & Shield 2004, Stanik et al 2007, Wiedemann et al 2010]. Fifty percent of neonatal diabetes mellitus is transient rather than permanent (see Permanent Neonatal Diabetes Mellitus).

Differential Diagnosis

Transient neonatal diabetes mellitus (TNDM) was found to account for approximately 50% of diabetes mellitus presenting in the neonatal period [Cave et al 2000, Metz et al 2002, Polak & Cavé 2007]. Flanagan et al [2007] showed that 70% of TNDM was caused by 6q24 aberrations. Other genetic causes of transient neonatal diabetes mellitus include mutations in KCNJ11 and SUR1, which usually cause permanent neonatal diabetes (see also Permanent Neonatal Diabetes Mellitus.)

Other genetic causes of neonatal diabetes mellitus (isolated and syndromic, transient and permanent):

  • KCNJ11- and ABCC8-related neonatal diabetes mellitus. Mutations in KCNJ11 and ABCC8 are important causes of neonatal diabetes mellitus coding for the Kir 6.2 and SUR1 subunits, respectively, of the ATP-sensitive potassium channel of pancreatic β cells. This KATP channel is a key regulator of insulin release, coupling cell metabolism to electrical activity through the movement of potassium across the membrane [Gloyn et al 2004]. Together, heterozygous mutations in these two genes account for 33%-50% of permanent neonatal diabetes [Gloyn et al 2004] and 26% of transient neonatal diabetes [Flanagan et al 2007].

    Affected infants present with low birth weight and hyperglycemia. Compared to 6q24-TNDM, KCNJ11- and ABCC8-related neonatal diabetes usually presents slightly later, birth weight is higher, remission usually takes longer, and ketoacidosis is often present at diagnosis. Some of the children have epilepsy, hypotonia, and developmental delay in addition to diabetes mellitus (DEND syndrome). DEND syndrome has been associated with both KCNJ11 and ABCC8 mutations [Proks et al 2007]. Phenotype correlates with genotype depending on the impact of the mutation on ATP binding [Gloyn et al 2005, Gloyn et al 2006].
  • INS-related neonatal diabetes mellitus. In a recent series, 23% of probands presenting with diabetes before age six months were found to have heterozygous mutations in the insulin gene, INS [Edghill et al 2008]. This is the second most common cause of permanent neonatal diabetes, a finding supported by a national US study of early-onset diabetes [Støy et al 2008].

    Although the median age of diagnosis was 11 weeks, the range of the age of onset overlaps with neonatal diabetes; therefore, mutations in INS should be considered in the differential diagnosis of 6q24-TNDM. Presentation includes ketoacidosis in half of the infants. Clinical findings can vary among family members. In at least one family in the series neonatal diabetes was transient, becoming permanent diabetes at age two years.
  • Glucokinase-related neonatal diabetes mellitus. Homozygous missense loss-of-function mutations within GCK, the gene encoding glucokinase, have been reported as a rare cause of PNDM (4%). This condition should be considered, particularly in consanguineous families [Njolstad et al 2001, Njolstad et al 2003].
  • PDX1 (IPF-1)-related neonatal diabetes mellitus. Stoffers et al [1997] were the first to describe permanent neonatal diabetes mellitus (PNDM) in a child with pancreatic agenesis who was homozygous for a single-nucleotide deletion in IPF-1, encoding the homeodomain protein IPF-1, a critical regulator of insulin gene function in the islet cell. Imaging of the pancreas may help to differentiate such cases [Schwitzgebel et al 2003]. This is a very rare cause of pancreatic agenesis (<1%).
  • HNF1β mutations. Occasional cases of neonatal diabetes mellitus have been reported with heterozygous mutations in HNF1β [Yorifuji et al 2004, Edghill et al 2006]. The individual reported by Edghill et al [2006] had transient neonatal diabetes mellitus with recurrence at age eight years. Mutations in this gene usually cause MODY5 (maturity-onset diabetes of the young type 5) characterized by dominantly inherited adolescent-onset diabetes mellitus associated with renal cysts.
  • Wolcott-Rallison syndrome is an autosomal recessive disorder characterized by infantile-onset (often within the neonatal period) diabetes mellitus and spondyloepiphyseal dysplasia, which may develop after the neonatal period. This condition is caused by mutations in EIF2AK3 at 2p12 [Delepine et al 2000]. EIF2AK3 is highly expressed in pancreatic islet cells, acting as a regulator of protein synthesis.
  • X-linked immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) is characterized by the development of overwhelming systemic autoimmunity in the first year of life resulting in the commonly observed triad of watery diarrhea, eczematous dermatitis, and endocrinopathy, most often insulin-dependent diabetes mellitus. Most infants have other autoimmune phenomena including Coombs-positive anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy. The majority of affected males die within the first year of life of either metabolic derangements or sepsis; a few have survived into the second and third decade. FOXP3 is the only gene currently known to be associated with IPEX syndrome. Inheritance is X-linked.
  • Neonatal diabetes mellitus and cerebellar agenesis is caused by mutations in PTF1A, encoding pancreas transcription factor 1 alpha at 10p13 [Sellick et al 2004]. The disorder is characterized by the combination of cerebellar agenesis and neonatal diabetes mellitus. Infants usually die within a few months of birth.
  • Neonatal diabetes mellitus, annular pancreas, intestinal atresias, and gall bladder agenesis. A small number of affected individuals have been reported with various combinations of pancreatic hypoplasia, agenesis, or neonatal diabetes without clear evidence of abnormal pancreatic anatomy in association with gut atresias and gall bladder hypoplasia/atresia [Galán-Gómez et al 2007]. The majority have died in the first year of life; however, some individuals are still living with normal development, although the follow-up has not been long. This condition is likely to be inherited in an autosomal recessive manner in consanguineous families; affected sibs have been reported. The genetic cause is as yet unknown. It has been most recently reviewed by Chappell et al [2008].
  • Neonatal diabetes mellitus and congenital hypothyroidism caused by mutations in GLIS3. This rare autosomal recessive condition is characterized by the combination of neonatal diabetes mellitus, congenital hypothyroidism, glaucoma, polycystic kidneys, cholestasis, and hepatic fibrosis. However, the findings can be variable and not all the features are reported in all cases. Some individuals have survived infancy; mild intellectual disability has been reported [Senée et al 2006] (see also Congenital Hepatic Fibrosis Overview).
  • Neonatal diabetes mellitus and congenital heart disease. The combination of congenital heart disease (ventricular septal defect) and pancreatic hypoplasia was first reported by Gurson et al [1970]. Yorifuji et al [1994] reported a second Japanese family in which individuals in two generations had pancreatic hypoplasia, neonatal diabetes mellitus, and congenital heart disease.
  • X-linked phosphoribosylpyrophosphate synthetase I superactivity has been reported as a cause of permanent neonatal diabetes mellitus. The male siblings reported by Christen et al [1992] also had intellectual disability and a progressive axonal neuropathy.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with 6q24-related transient neonatal diabetes mellitus (6q24-TNDM), the following evaluations are recommended:

  • Birth weight, length, and head circumference and any subsequent growth parameters
  • General dysmorphology examination, preferably by a medical geneticist including evaluation of tongue size and umbilicus
  • Neurologic examination and developmental assessment
  • Investigation of the anatomy of the pancreas by ultrasound examination or MRI
  • Echocardiogram and ultrasound examination of the liver and kidneys to help identify those infants likely to have 6q24-TNDM caused by mutation of ZFP57
  • Brain MRI scan if evidence of developmental delay or hypotonia
  • Serum glucose concentration
  • C peptide measurement
  • Pancreatic beta cell autoantibody measurements
  • Liver function and thyroid function tests
  • A pediatric endocrinology consultation for follow up of diabetes
  • Medical genetics consultation

Patients with hypomethylation at imprinted loci (HIL) should be evaluated for hypotonia and other neurologic features including epilepsy, congenital heart disease, deafness, renal malformations, and pseudohypoparathyroidism with measurement of serum concentrations of calcium and phosphate and parathyroid hormone testing.

Treatment of Manifestations

Rehydration and IV insulin on a sliding scale are usually required. Some infants produce some insulin and can be treated by rehydration alone.

Subcutaneous injection of insulin is introduced as soon as possible, often within two weeks. Continuous insulin pump therapy as opposed to intermittent insulin injections has been used successfully in a number of cases in the UK and France [JP Shield, personal communication]. Successful treatment with subcutaneous insulin glargine has also been reported [Barone et al 2011].

Blood glucose concentration should be monitored and insulin doses changed accordingly as in the standard treatment for diabetes mellitus. Insulin can be discontinued when blood glucose concentrations stabilize.

Once diabetes mellitus is in remission, parents need to be alerted to the possibility of recurrence of the diabetes mellitus, particularly during periods of illness. Symptoms such as excessive thirst, polyuria, and repeated bacterial infections should prompt measurement of blood glucose concentration.

If diabetes mellitus recurs, treatment may require diet alone, oral agents, or insulin, although the doses of insulin needed tend to be less than those required in type 1 diabetes mellitus (i.e., some residual endogenous insulin remains). It should be noted that patients do not always require treatment with insulin even in the neonatal period. In several patients at relapse, sulphonylureas or diet alone is adequate [Valerio et al 2004].

Note: Macroglossia could potentially cause airway obstruction; macroglossia severe enough to require treatment has not been reported.

Prevention of Secondary Complications

The main concerns are related to failure to make the diagnosis soon enough. Dehydration secondary to hyperglycemia can cause serious long-term sequelae if not treated promptly. Therefore, rehydration is most important in the early stages of the disease.

Surveillance

Periodic glucose tolerance tests can be used to assess insulin secretion. Most children with transient neonatal diabetes mellitus in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state. Insulin response to intravenous glucose loading is often normal but suggests future recurrence if abnormal [Shield et al 2004].

Measure growth (height, weight, head circumference) at regular intervals (i.e., at least every six months)

Developmental assessment to identify any special educational needs is appropriate.

Children with HIL need to be monitored for developmental delay and special educational needs.

Agents/Circumstances to Avoid

General factors that predispose to late-onset diabetes (e.g., excessive weight gain) or risk factors for cardiovascular disorders should be avoided.

Evaluation of Relatives at Risk

Recommendations vary by underlying genetic mechanism:

  • When the proband is identified as having TNDM caused by an inherited paternal 6q24 duplication, the sibs and offspring of the proband are at increased risk of inheriting the duplication. Screening for diabetes mellitus is appropriate for those infants who have inherited the paternal 6q24 duplication.
  • For 6q24-TNDM caused by ZFP57 mutations, sibs are at a 25% risk for the same condition, although the clinical findings can be variable.
  • Although individuals reported to have 6q24-TNDM as the result of an imprinting center epimutation have been simplex cases (i.e., a single occurrence in a family), it is not clear if all cases are de novo (see also Genetic Counseling).
    • Screening the mother and sibs of these individuals for diabetes mellitus may be appropriate.
    • Offspring of female probands with 6q24-TNDM caused by a hypomethylation of the maternal PLAGL1/HYMAI differentially methylated region (DMR) may be at risk of having 6q24-TNDM or of developing diabetes mellitus later in life and should be offered testing.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There are no specific guidelines on pregnancy management for women with a history of 6q24-TNDM. However, it is important to inform health professionals during the pregnancy of a susceptibility to diabetes. Rarely some affected women with classic 6q24-TNDM genetic aberrations (for example, duplication of 6q24, paternal UPD 6, and methylation mutations) will develop gestational diabetes; therefore, pregnancy is thought to be a risk factor for recurrence of diabetes.

If prenatal diagnosis identifies an affected fetus, fetal growth is anticipated to lag during the third trimester.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

6q24-related transient neonatal diabetes mellitus (6q24-TNDM) results from overexpression of imprinted genes at 6q24 (PLAGL1 and HYMAI). Three different genetic mechanisms cause 6q24-TNDM:

  • Paternal uniparental disomy of chromosome 6 (41%);
  • Duplication of 6q24 on the paternal allele (29%); and
  • Hypomethylation of the maternal PLAGL1/HYMAI DMR thereby losing the methylation that typically silences the maternal region (30%).

Maternal PLAGL1 DMR hypomethylation can result from an imprinting mutation of the promoter PLAGL1 DMR (isolated) or as part of a generalized ‘hypomethylation at imprinted loci’ (HIL); homozygous or compound heterozygous ZFP57 mutations account for almost half of TNDM-HIL.

  • Both complete and partial paternal uniparental disomy of chromosome 6 are typically de novo events.
  • Paternal duplication of 6q24 can be occur de novo or be inherited. Occasionally the duplication can arise as part of a complex chromosomal rearrangement in a parent.
  • Hypomethylation of the maternal PLAGL1/HYMAI DMR can result from an imprinting mutation of the promoter PLAGL1 DMR (isolated) or as part of a generalized HIL. Homozygous or compound heterozygous ZFP57 mutations account for almost half of TNDM-HIL; the other causes of HIL are not known.

Risk to Family Members — Paternal Uniparental Disomy of Chromosome 6

Parents, sibs, and offspring of a proband

  • The risk to parents, sibs, and offspring of a proband with TNDM caused by paternal UPD6 is unlikely to be higher than the risk to the general population, as paternal UPD6 is a de novo, typically non-recurrent event.
  • If the proband has a chromosome abnormality in addition to paternal UPD6, the risk to parents, sibs, and offspring is related to the specific abnormality identified in the proband.

Risk to Family Members — Paternal Inherited/Derived Duplication of 6q24 — Usually Submicroscopic Tandem Duplication

Parents of a proband

  • The father of a proband may have the (submicroscopic or visible) 6q24 duplication identified in the proband and may be at risk of developing diabetes mellitus in later life (or having had a history of early diabetes mellitus) if the 6q24 duplication was inherited from his father.
  • Alternatively, the 6q24 duplication may be a de novo occurrence in the proband.
  • Recommendations for the evaluation of the father of a proband with 6q24-TNDM include routine cytogenetic analysis and molecular genetic testing to identify a 6q24 duplication if present, and to exclude a balanced/unbalanced translocation involving the 6q24 critical region.

Sibs of a proband

  • The risk to the sibs of a proband depends on the genetic status of the father.
  • If the father does not have a duplication of 6q24, the risk to the sibs depends on the possibility of germline mosaicism in the father (estimated risk: ~1%).
  • If the father has the 6q24 duplication, the risk to each sib of inheriting the duplication is 50%. Because of reduced penetrance, sibs who inherit the paternal 6q24 duplication may not develop TNDM, but they are at increased risk of developing diabetes mellitus later in life.
  • If the father has a complex chromosomal rearrangement involving 6q24, the risk to sibs is related to the specific rearrangement.

Offspring of a male proband. Each child of a male with 6q24-TNDM caused by duplication of 6q24 has a 50% chance of inheriting the duplication and is at high risk of developing 6q24-TNDM and/or diabetes mellitus later in life.

Offspring of a female proband. Each child of a female with 6q24-TNDM caused by duplication of 6q24 has a 50% chance of inheriting the duplication but is not at increased risk of developing 6q24-TNDM or diabetes mellitus later in life.

Other family members of a proband. The risk to more distant family members depends on the status of the proband's parents. Family members may be at risk if the proband has an inherited duplication of 6q24.

Risk to Family Members — Hypomethylation of the Maternal PLAGL1/HYMAI DMR

Risks depend on the underlying cause of the hypomethylation.

Proband with Isolated Hypomethylation at TNDM-DMR

Parents of a proband. Parents of a proband with 6q24-TNDM caused by isolated DMR hypomethylation have not been reported as having a similar finding, as having neonatal diabetes mellitus, or as developing it later in life.

Sibs of a proband

  • Sibs of a proband with 6q24-TNDM caused by isolated DMR hypomethylation are not reported to have an increased risk of having 6q24-TNDM or of developing diabetes mellitus.
  • Because the cause of isolated hypomethylation at the DMR (imprinting center) is not understood and it is possible that it is not de novo in all families, testing of sibs of a proband for diabetes is appropriate.

Offspring of a proband. The risk to the offspring of individuals with 6q24-TNDM caused by isolated hypomethylation of the imprinting center of developing 6q24-TNDM or diabetes mellitus later in life is unknown but may be higher in offspring of a female proband (theoretical based on the possibility of the hypomethylation being secondary to an as-yet undiscovered deletion on the maternal allele which could be inherited).

Hypomethylation at Imprinted Loci (HIL) as a Result of Two Mutations in ZFP57

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant ZFP57 allele). In highly consanguineous families a parent may also be homozygous rather than heterozygous. This finding has been reported in at least one family [Mackay et al 2008].
  • Parents heterozygous for ZFP57 mutations are not known to be at risk of developing diabetes mellitus. No phenotype has yet been reported in heterozygotes.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of inheriting two ZFP57 mutations and being at risk of developing 6q24-TNDM (although clinical findings in sibs can be variable), a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • In sibs who have inherited two ZFP57 mutations, the risk of developing 6q24-TNDM is not known but may be high. The non-diabetes manifestations are variable. Affected sibs of whom one was severely developmentally delayed and the other only mildly delayed have been reported [Boonesn et al 2008]. At least one person homozygous for ZFP57 mutations had a normal phenotype [Mackay et al 2008].

Offspring of a proband. The offspring of an individual with two mutations in ZFP57 are obligate heterozygotes (carriers) for a ZFP57 mutation.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier of a ZFP57 mutation.

Carrier detection. Carrier testing using molecular genetic techniques is not offered unless the family mutation is known.

Hypomethylation at Imprinted Loci (HIL) with No Mutations Identified in ZFP57

The risks to sibs, offspring, and parents are unknown as recurrence has not as yet been reported in this subgroup.

Note: There is an increased incidence of assisted reproductive technology used by the parents of these probands; whether a causal relationship exists between ART and hypomethylation is not clear [Mackay et al 2008].

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Consideration of prenatal diagnosis for 6q24-TNDM depends on the genetic mechanism in the family: paternal UPD6 is typically a de novo, non-recurrent event; dup6q24 may recur when the duplication is inherited from the father; and hypomethylation at imprinted loci caused by biallelic ZFP57 mutations is inherited in an autosomal recessive manner. Counseling by a genetics professional is strongly recommended.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Diabetes Association (ADA)
    ATTN: Center for Information
    1701 North Beauregard Street
    Alexandria VA 22311
    Phone: 800-342-2383 (toll-free information/support); 703-549-1500
    Email: AskADA@diabetes.org
  • Diabetes UK
    Macleod House
    10 Parkway
    London NW1 7AA
    United Kingdom
    Phone: 020 7424 1000
    Fax: 020 7424 1001
    Email: info@diabetes.org.uk
  • Transient Neonatal Diabetes Registry
    Wessex Clinical Genetics Service - Princess Anne Hospital
    Level G, Mailpoint 105
    Coxford Road
    Southampton Hampshire SO16 5YA
    United Kingdom
    Phone: +44 2380 796166
  • US Neonatal Diabetes Mellitus Registry
    University of Chicago, Kovler Diabetes Center
    5841 South Maryland Avenue
    MC1027
    Chicago IL 60637
    Phone: 773-795-4454
    Email: neonataldiabetes@uchicago.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Diabetes Mellitus, 6q24-Related Transient Neonatal: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Diabetes Mellitus, 6q24-Related Transient Neonatal (View All in OMIM)

601410DIABETES MELLITUS, TRANSIENT NEONATAL, 1
603044PLEOMORPHIC ADENOMA GENE-LIKE 1; PLAGL1
606546HYDATIDIFORM MOLE-ASSOCIATED AND IMPRINTED TRANSCRIPT; HYMAI
612192ZINC FINGER PROTEIN 57, MOUSE, HOMOLOG OF; ZFP57

Normal allelic variants. Maternal alleles are methylated within the DMR (imprinting center) of PLAGL1 (ZAC) and HYMAI, thereby silencing their expression. Paternal alleles are not methylated and are expressed. HYMAI makes an RNA transcript that does not encode a protein. Many PLAGL1 transcript variants differing in the 5' UTR and encoding two different isoforms are known for this gene.

Pathologic allelic variants. Pathologic alleles have either lost the methylation imprint that silences the maternal allele or have a rearrangement that results in duplication and overexpression of paternal alleles. See Molecular Genetic Testing for mechanisms.

Normal gene product. The minimal disease-associated region has been refined [Docherty et al 2010] excluding all but PLAGL1 and HYMAI as candidate genes for 6q24. However, the molecular pathogenesis of 6q24-TNDM is not yet understood. All mechanisms described in relation to 6q24-TNDM result in overexpression of PLAGL1. In most human fetal tissues, PLAGL1 is expressed only from the paternal allele because of the lack of paternal methylation within the differentially methylated region (DMR) of the fetal promoter of the gene [Varrault et al 2001]. No enhancers or insulators of the region have been identified. In adult tissues imprinted expression is present only in a minority of tissues such as skin fibroblasts. Biallelic expression results from an alternative non-imprinted promoter, 55 kb upstream of the imprinted promoter [Valleley et al 2007].

The mechanism whereby PLAGL1 overexpression causes early diabetes mellitus from which an individual eventually recovers is not fully understood. PLAGL1 codes for a zinc finger protein and overexpression is known to lead to cell cycle arrest and apoptosis in cell lines; PLAGL1 regulates the pituitary adenylate cyclase-activating polypeptide receptor (PACAP1) which is known to stimulate insulin secretion. Downstream targets of PLAGL1 are not fully characterized although Arima et al [2005] showed that PLAGL1 binds to the CpG island in KCNQ1OT1, which negatively regulates CDKN1C. Varrault et al [2006] showed that PLAGL1 is an important member of a cellular network of imprinted genes involved in fetal growth.

A mouse model for TNDM [Ma et al 2004] demonstrated impaired glucose homeostasis in mice with overexpression of plagl1 and showed a downregulation of pdx-1, a key transcription factor vital for normal pancreatic development. Although beta cell mass was reduced in fetal mice, it had recovered by the time of birth; nonetheless, insulin response to hyperglycemia was decreased. It is hypothesized that the beta cell mass is not sufficient to respond during times of excessive physiologic stress, resulting in ‘breakthrough’ diabetes with intercurrent illnesses and sometimes with increasing age.

In keeping with this hypothesis, Valerio et al [2004] have demonstrated in 6q24-TNDM a specific defect of insulin secretion after glucose stimulation. Furthermore, insulin secretion is possible through the stimulatory G protein pathway.

At the molecular level, the picture is complicated by HYMAI, which overlaps PLAGL1 and the 6q24-TNDM DMR, which is also only expressed paternally. HYMAI lacks an open reading frame and is not translated. It may regulate PLAGL1 expression; its relationship to PLAGL1 and 6q24-TNDM is not yet known.

Abnormal gene product. In fibroblasts from an individual with transient neonatal diabetes mellitus, the monoallelic expression of both PLAGL1 and HYMAI was found to be relaxed, providing strong supportive evidence that the presence of two unmethylated alleles of this locus is indeed associated with the inappropriate expression of neighboring genes [Mackay et al 2002].The PLAGL1 promoter is localized to the CpG island harboring the methylation imprint associated with 6q24-TNDM, and methylation of this promoter silences its activity [Varrault et al 2001].

References

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Chapter Notes

Acknowledgments

IKT, LD, and DJGM are supported by Diabetes UK and MRC for work on 6q24 transient neonatal diabetes.

Revision History

  • 27 September 2012 (me) Comprehensive update posted live
  • 23 December 2010 (cd) Revision: sequence analysis of ZFP57 available clinically on a limited basis
  • 4 February 2010 (me) Comprehensive update posted live
  • 10 October 2005 (me) Review posted to live Web site
  • 10 February 2005 (ikt) Original submission
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