 |
|
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. TNDM is caused by overexpression of two genes, PLAGL1 (ZAC) and HYMAI, found within an imprinted region on chromosome 6q24. Molecular diagnosis is based on identifying an additional paternal copy of PLAGL1 (ZAC)/ HYMAI or loss of maternal methylation within the differentially methylated region (DMR) of the promoter of PLAGL1 (ZAC) and HYMAI. Three known mechanisms cause TNDM (90% of cases): paternal uniparental disomy of chromosome 6, duplication of 6q24 on the paternal allele, and a 6q24 methylation defect. They can be detected clinically by measuring the ratio of methylated to unmethylated DNA within the DMR. Testing for uniparental disomy is also available clinically and detects an abnormality (i.e., inheritance of both number 6 chromosomes from the father) in about 35% of cases.
Management. Rehydration and IV insulin are usually required immediately at diagnosis of TNDM; a few infants have been treated by rehydration alone. Subcutaneous insulin is often introduced within two weeks and used until blood glucose levels stabilize. Children are monitored for diabetes mellitus, particularly during periods of illness; recurring diabetes is treated with diet, oral agents, or insulin.
Genetic counseling. 6q24-related TNDM is caused by one of three mechanisms involving chromosome 6: paternal uniparental isodisomy of chromosome 6, duplication of 6q24 on the paternal allele, or a 6q24 methylation defect. The risk to sibs and offspring of a proband of having TNDM or of developing diabetes later in life depends upon the genetic mechanism in the family. TNDM caused by paternal uniparental isodisomy of chromosome 6 is typically a de novo, non-recurrent event. Duplication of 6q24 (pat) can be a de novo occurrence, inherited in an autosomal dominant manner, or inherited as a part of a complex chromosome rearrangement; TNDM caused by an inherited duplication of 6q24 may recur in sibs and offspring of a proband if the duplication is inherited from the father. All reported instances of individuals with a methylation defect have been simplex cases (i.e., a single occurrence in the family). However it is possible that the offspring of individuals with TNDM caused by a methylation defect may be at risk of developing TNDM or diabetes in later life if his/her affected parent is female. Prenatal diagnosis of TNDM is possible in those individuals at risk for a structural chromosome abnormality.
6q24-related transient neonatal diabetes mellitus (TNDM) is characterized by diabetes mellitus that commences in the first six weeks of life in a term infant and resolves by 18 months of age.
The cardinal features are severe intrauterine growth retardation, dehydration and hyperglycemia, and absence of ketoacidosis.
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 About 2% of individuals have a cytogenetically visible duplication of 6q24 (personal observation).
FISH is used to confirm small rearrangements but is not used routinely to detect submicroscopic duplication.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genes. TNDM is caused by overexpression of a locus containing two imprinted genes, PLAGL1 (ZAC) and HYMAI, on chromosome 6q24. Normally the maternal copies of PLAGL1 (ZAC) and HYMAI are silent as a result of differential methylation of the promoter; thus, only one copy (the paternal copy) of PLAGL1 (ZAC) and HYMAI is expressed. In TNDM, two (or more) expressed copies of PLAGL1 (ZAC) and HYMAI are present through one of the three following mechanisms:
Paternal uniparental disomy of chromosome 6 (UPD6). Two chromosome 6 homologues, each with an expressed copy of PLAGL1 (ZAC) and HYMAI, are inherited from the father and none from the mother.
Paternal duplication of 6q24. This is usually a submicroscopic tandem duplication that results in the presence of two copies of PLAGL1 (ZAC) and HYMAI on the paternal chromosome 6.
A methylation defect in the promoter of PLAGL1 (ZAC)/ HYMAI. Loss of methylation in the maternal copy of the promoter results in expression of the maternal copy of PLAGL1 (ZAC)/ HYMAI.
Molecular genetic testing: Clinical use
Confirmatory diagnostic testing
Molecular genetic testing: Clinical methods
Uniparental disomy (UPD) studies. Uniparental disomy studies detect UPD6 in about 35% of cases.
Ratiometric methylated/unmethylated DNA measurement. Molecular diagnosis based on identifying an additional paternal copy of PLAGL1 (ZAC)/ HYMAI or loss of maternal methylation within the differentially methylated region (DMR) of the promoter of PLAGL1 (ZAC) and HYMAI is available. A diagnostic test has been developed by Mackay et al (2005) that can detect all three mechanisms based on ratiometric measurement of methylated and unmethylated DNA within the differentially methylated region (DMR).
Molecular genetic testing: Research. Further research is ongoing to identify the cause of TNDM in those individuals in whom no genetic aberration is identified.
| Mechanism | Test Methods | Mutations Detected | Mutation Detection Rate | Test Availability | |
|---|---|---|---|---|---|
| Uniparental disomy 6 | Ratio of methylated to unmethylated DNA within the differentially methylated region (DMR1) 1 | Uniparental disomy studies | NA | ~35% | Clinical
 |
| Duplication of 6q24 | NA | ~35% | |||
| Imprinting mutation | ~20% | ||||
All probands should have conventional karyotype analysis to identify visible chromosome translocations or insertions.
A single test based on a quantitative method to determine the ratio of methylated to unmethylated DNA at the DMR within the promoter of PLAGL1 (ZAC) and HYMAI allows diagnosis of TNDM [Mackay et al 2005].
Family studies of inheritance of chromosome 6 markers from the mother and father are required to distinguish methylation mutations from UPD cases.
No other phenotypes are known to be associated with overexpression of PLAGL1 (ZAC) and HYMAI.
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 1930g at 39 weeks' gestation [Temple et al 2000]. 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 the children are treated with rehydration alone.
Macroglossia (big tongue) and umbilical hernia are sometimes observed. No other dysmorphic features are consistently associated with this condition.
In infancy: Diabetes 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.
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. Permanent diabetes mellitus can recur 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 individuals in whom recurrence has occurred. Permanent diabetes mellitus seems to be type 2 diabetes mellitus with some residual endogenous insulin production; however, insulin therapy is often needed in treatment. The earliest age of recurrence recorded is four years.
In adolescence: The average age for 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.
In adulthood: Women are also at risk of relapse during pregnancy and present as gestational diabetics.
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 14 to 28 years of age. He did not develop ketoacidosis but did develop evidence of microangiopathy [Valerio et al 2004].
No difference in the severity, duration, or relapse rate has been detected between the three mechanisms described [Temple et al 2000].
The only exception is cytogenetically visible duplication of 6q that can be associated with learning difficulties related to other genes within the duplicated region. In contrast, individuals with a submicroscopic duplication are of normal intelligence.
The majority of UPD6 is isodisomic, i.e., two copies of chromosome 6 are identical and therefore the affected individual is at increased risk of rare autosomal recessive disorders that may be unmasked by this unusual inheritance pattern [Abramowicz et al 1994]. 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.
Non-penetrance is rare but has been noted when siblings of affected individuals were found to have an identical duplication of 6q24 but no history of neonatal diabetes mellitus.
Anticipation has not been noted.
Prevalence of TNDM in the UK has been estimated as one in 400,000 [Shield et al 1997], but it is possible that TNDM is more common [Temple et al 2000].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
6q24-related TNDM accounts for only 50-60% of cases of diabetes mellitus presenting in the neonatal period [Cave et al 2000, Metz et al 2002].
Other genetic causes of neonatal diabetes:
KCNJ11-related neonatal diabetes. Mutations in KCNJ11 are an important cause of neonatal diabetes. This gene on chromosome 11 codes for the Kir 6.2 subunit of the ATP-sensitive potassium channel, present in pancreatic βcells. Affected infants also present with low birth weight and hyperglycemia. Presentation is usually slightly later than that seen in TNDM and birth weight is greater. Ketoacidosis is often present at diagnosis. Some of the children have epilepsy, hypotonia, and developmental delay in addition to diabetes mellitus. A genotype-phenotype correlation is emerging depending on the effect of the mutation on ATP binding [Gloyn et al 2004]. Although diabetes is usually permanent (PNDM) [Polak & Shield 2004], moderately activating mutations in KCNJ11 may cause transient relapsing diabetes akin to the 6q24 phenotype [Gloyn et al 2005].
IPF-1-related neonatal diabetes. Stoffers et al (1997) described the first specific gene mutation giving rise to PNDM in a child with pancreatic agenesis who was homozygous for a single nucleotide deletion in the IPF-1 gene 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].
Glucokinase gene-related neonatal diabetes. Homozygous missense mutations within the glucokinase gene have been reported as a rare cause of PNDM and should be considered, particularly in consanguineous families [Njolstad et al 2001, Njolstad et al 2003].
Wolcott-Rallison syndrome. Wolcott-Rallison syndrome is an autosomal recessive disorder characterized by infancy-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]. This gene is highly expressed in pancreatic islet cells, acting as a regulator of protein synthesis.
X-linked immunodysregulation, polyendocrinopathy, and enteropathy (IPEX). 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 individuals 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. IPEX syndrome is inherited in an X-linked manner.
Neonatal diabetes mellitus and cerebellar agenesis. This 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.
Suggested genetic testing strategy for infants with neonatal diabetes mellitus. The two most common causes of neonatal diabetes are 6q24-related TNDM and mutations in KCNJ11. Metz et al (2002) failed to demonstrate clear clinical indicators to differentiate 6q24-related 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, it is reasonable to test for 6q24-related aberrations first, followed by testing for KCNJ11 mutations.
For infants presenting from the third week onwards, it may be more appropriate to test for KCNJ11 mutations first, followed by testing for 6q24-related aberrations.
For infants with associated features or consanguineous parents, other genetic analysis may be appropriate.
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 utilized successfully in a number of cases in the UK and France [J P Shield, personal communication].
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.
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.
Once diabetes is in remission, parents need to be alerted to the possibility of recurrence of the diabetes, particularly during periods of illness. Symptoms such as excessive thirst, polyuria, and repeated bacterial infections should prompt measurement of blood glucose concentration.
Periodic glucose tolerance tests can be used to assess insulin secretion. Most children with transient neonatal diabetes 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].
If diabetes 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.
When the proband is identified as having TNDM caused by a 6q24 duplication inherited from his/her father, the sibs and offspring of the proband are at increased risk of inheriting the duplication. Screening for diabetes mellitus is appropriate for those family members who have inherited the 6q24 duplication from their father.
Although all individuals reported to have TNDM as the result of a methylation defect have been simplex cases, it is not clear if all cases are de novo.
Screening the mother and sibs of these individuals for diabetes mellitus may be appropriate.
Offspring of female probands with TNDM caused by a methylation defect may be at risk of having TNDM or of developing diabetes mellitus later in life and should be offered testing.
New therapeutic agents (glucagon-like synthetic analogs) may prove useful in the future [Valerio et al 2004].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
The macroglossia is not severe enough to require treatment.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Transient neonatal diabetes mellitus results from overexpression of an imprinted locus on chromosome 6q24 containing PLAGL1 (ZAC) and HYMAI by one of three mechanisms:
Paternal uniparental disomy of chromosome 6, typically a de novo event
Duplication of 6q24 (pat) can be a de novo occurrence or inherited. Occasionally the duplication can arise as part of a complex chromosomal rearrangement in a parent.
A methylation defect, usually a single occurrence in a family
Parents, sibs, and offspring of a proband
The risk to parents, sibs and offspring of a proband with TNDM is unlikely to be higher than the risk to the general population, as paternal uniparental disomy of chromosome 6 (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.
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 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 of a proband is likely not increased over that of the general population. (Although not described in TNDM, it is theoretically possible that a father could be mosaic for a 6q24 duplication in his germ cells that is not identified on analysis of his blood. In this instance the risk to sibs would be higher.)
If the father has the 6q24 duplication, the risk to each sib of inheriting the duplication is 50%. Because of non-penetrance, sibs who inherit the paternal 6q24 duplication may not develop TNDM, but are at increased risk of developing diabetes 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 TNDM caused by duplication of 6q24 has a 50% chance of inheriting the duplication and is at risk of developing TNDM and/or diabetes later in life.
Offspring of a female proband. Each child of a female with TNDM caused by duplication of 6q24 has a 50% chance of inheriting the duplication but is not at increased risk of developing TNDM or diabetes later in life.
Parents of a proband
All reported instances of individuals with a methylation defect have been simplex cases (i.e., a single occurrence) in the family.
Parents of a proband with TNDM caused by a methylation defect have not been reported as having a similar methylation defect or as having diabetes mellitus or of developing it later in life.
Sibs of a proband
Sibs of a proband with TNDM caused by a methylation defect do not appear to have an increased risk of having TNDM or of developing diabetes.
Because the cause of the methylation defect is not understood and it is possible that it is not de novo in all families, testing sibs of a proband for diabetes is appropriate.
Offspring of a proband. The risk to the offspring of individuals with TNDM caused by a methylation defect of developing TNDM or diabetes mellitus later in life is unknown but may be higher in offspring of a female proband.
Other family members. 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.
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. 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. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only. See DNA Banking for a list of laboratories offering this service.
Prenatal diagnosis for pregnancies at increased risk for a chromosome abnormality is possible by cytogenetic analysis of fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
No laboratories offering molecular genetic testing for prenatal diagnosis for TNDM caused by a methylation defect are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| PLAGL1 | 6q24 | Zinc finger protein PLAGL1 |
| HYMAI | 6q24 | Unknown |
| 601410 | DIABETES MELLITUS, TRANSIENT NEONATAL, 1 |
| 603044 | PLEOMORPHIC ADENOMA GENE-LIKE 1; PLAGL1 |
| 606546 | HYDATIDIFORM MOLE-ASSOCIATED AND IMPRINTED TRANSCRIPT; HYMAI |
The molecular pathogenesis of transient neonatal diabetes mellitus is not understood. All mechanisms described in relation to TNDM result in overexpression of PLAGL1. In humans, PLAGL1 is normally expressed only on the paternal allele and this is thought to be related to a lack of methylation within the differentially methylated region (DMR) in the promoter of the gene [Varrault et al 2001]. No enhancers or insulators of the region have been identified. It is not known why PLAGL1 overexpression causes early diabetes mellitus from which an individual recovers. PLAGL1 codes for a zinc finger protein and overexpression is known to lead to cell cycle arrest and apoptosis in cell lines, overexpression in vivo possibly causing reduction of beta cell mass in the pancreas and resulting in diabetes mellitus during times of excessive physiological stress. However, it is not clear whether extreme physiological stress occurs in the first three months of life and whether some natural switch in the mechanism of insulin release in infancy accounts for the return to normal.
In keeping with this hypothesis, Valerio et al (2004) have demonstrated in TNDM a specific defect of insulin secretion after glucose stimulation in which insulin secretion is possible through the stimulatory G protein pathway. Downstream targets of PLAGL1 are not yet known and research is continuing toward understanding the cellular pathway into which PLAGL1 fits.
At the molecular level, the picture is complicated by the discovery of HYMAI, which overlaps PLAGL1 (ZAC) and the TNDM DMR and which is also paternally expressed. HYMAI lacks an open reading frame and is not translated. It may regulate PLAGL1 expression; its relationship to PLAGL1 and TNDM is not yet known.
A mouse model for TNDM [Ma et al 2004] demonstrated impaired glucose homeostasis in mice over-expressing hZAC.
In fibroblasts from an individual with transient neonatal diabetes mellitus, the monoallelic expression of both PLAGL1 (ZAC) 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 (ZAC) promoter is localized to the CpG island harboring the methylation imprint associated with TNDM, and methylation of this promoter silenced its activity [Varrault et al 2001].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
10 October 2005 (me) Review posted to live Web site
10 February 2005 (ikt) Original submission
