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6q24-related transient neonatal diabetes mellitus

Reviewed February 2011

What is 6q24-related transient neonatal diabetes mellitus?

6q24-related transient neonatal diabetes mellitus is a type of diabetes that occurs in infants. This form of diabetes is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin. Insulin controls how much glucose (a type of sugar) is passed from the blood into cells for conversion to energy.

People with 6q24-related transient neonatal diabetes mellitus experience very slow growth before birth (severe intrauterine growth retardation). Affected infants have hyperglycemia and an excessive loss of fluids (dehydration), usually beginning in the first week of life. Signs and symptoms of this form of diabetes are transient, which means that they gradually lessen over time and generally disappear between the ages of 3 months and 18 months. Diabetes may recur, however, especially during childhood illnesses or pregnancy. Up to half of individuals with 6q24-related transient neonatal diabetes mellitus develop permanent diabetes mellitus later in life.

Other features of 6q24-related transient neonatal diabetes mellitus that occur in some affected individuals include an unusually large tongue (macroglossia); a soft out-pouching around the belly-button (an umbilical hernia); malformations of the brain, heart, or kidneys; weak muscle tone (hypotonia); deafness; and developmental delay.

How common is 6q24-related transient neonatal diabetes mellitus?

Between 1 in 215,000 and 1 in 400,000 babies are born with diabetes mellitus. In about half of these babies, the diabetes is transient. Researchers estimate that approximately 70 percent of transient diabetes in newborns is caused by 6q24-related transient neonatal diabetes mellitus.

What are the genetic changes related to 6q24-related transient neonatal diabetes mellitus?

6q24-related transient neonatal diabetes mellitus is caused by the overactivity (overexpression) of certain genes in a region of the long (q) arm of chromosome 6 called 6q24. People inherit two copies of their genes, one from their mother and one from their father. Usually both copies of each gene are active, or "turned on," in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person's father; others are active only when inherited from a person's mother. This phenomenon is known as genomic imprinting.

The 6q24 region includes paternally expressed imprinted genes, which means that normally only the copy of each gene that comes from the father is active. The copy of each gene that comes from the mother is inactivated (silenced) by a mechanism called methylation.

Overactivity of one of the paternally expressed imprinted genes in this region, PLAGL1, is believed to cause 6q24-related transient neonatal diabetes mellitus. Other paternally expressed imprinted genes in the region, some of which have not been identified, may also be involved in this disorder.

There are three ways that overexpression of imprinted genes in the 6q24 region can occur. About 40 percent of cases of 6q24-related transient neonatal diabetes mellitus are caused by a genetic change known as paternal uniparental disomy (UPD) of chromosome 6. In paternal UPD, people inherit both copies of the affected chromosome from their father instead of one copy from each parent. Paternal UPD causes people to have two active copies of paternally expressed imprinted genes, rather than one active copy from the father and one inactive copy from the mother.

Another 40 percent of cases of 6q24-related transient neonatal diabetes mellitus occur when the copy of chromosome 6 that comes from the father has a duplication of genetic material including the paternally expressed imprinted genes in the 6q24 region.

The third mechanism by which overexpression of genes in the 6q24 region can occur is by impaired silencing of the maternal copy of the genes (maternal hypomethylation). Approximately 20 percent of cases of 6q24-related transient neonatal diabetes mellitus are caused by maternal hypomethylation. Some people with this disorder have a genetic change in the maternal copy of the 6q24 region that prevents genes in that region from being silenced. Other affected individuals have a more generalized impairment of gene silencing involving many imprinted regions, called hypomethylation of imprinted loci (HIL).

About half the time, HIL is caused by mutations in the ZFP57 gene. Studies indicate that the protein produced from this gene is important in establishing and maintaining gene silencing. The other causes of HIL are unknown. Because HIL can cause overexpression of many genes, this mechanism may account for the additional health problems that occur in some people with 6q24-related transient neonatal diabetes mellitus.

It is not well understood how overexpression of PLAGL1 and other genes in the 6q24 region causes 6q24-related transient neonatal diabetes mellitus and why the condition improves after infancy. The protein produced from the PLAGL1 gene helps control another protein called the pituitary adenylate cyclase-activating polypeptide receptor (PACAP1), and one of the functions of this protein is to stimulate insulin secretion by beta cells in the pancreas. In addition, overexpression of the PLAGL1 protein has been shown to stop the cycle of cell division and lead to the self-destruction of cells (apoptosis). Researchers suggest that PLAGL1 gene overexpression may reduce the number of insulin-secreting beta cells or impair their function in affected individuals.

Lack of sufficient insulin results in the signs and symptoms of diabetes mellitus. In individuals with 6q24-related transient neonatal diabetes mellitus, these signs and symptoms are most likely to occur during times of physiologic stress, including the rapid growth of infancy, childhood illnesses, and pregnancy. Because insulin acts as a growth promoter during early development, a shortage of this hormone may account for the intrauterine growth retardation seen in 6q24-related transient neonatal diabetes mellitus.

Related Chromosome(s)

Changes involving this chromosome are associated with 6q24-related transient neonatal diabetes mellitus.

  • chromosome 6

Related Gene(s)

Changes in these genes are associated with 6q24-related transient neonatal diabetes mellitus.

  • HYMAI
  • PLAGL1
  • ZFP57

Can 6q24-related transient neonatal diabetes mellitus be inherited?

Most cases of 6q24-related transient neonatal diabetes mellitus are not inherited, particularly those caused by paternal uniparental disomy. In these cases, genetic changes occur as random events during the formation of reproductive cells (eggs and sperm) or in early embryonic development. Affected people typically have no history of the disorder in their family.

Sometimes, the genetic change responsible for 6q24-related transient neonatal diabetes mellitus is inherited. For example, a duplication of genetic material on the paternal chromosome 6 can be passed from one generation to the next.

When 6q24-related transient neonatal diabetes mellitus is caused by ZFP57 gene mutations, it is inherited in an autosomal recessive pattern. Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of 6q24-related transient neonatal diabetes mellitus?

These resources address the diagnosis or management of 6q24-related transient neonatal diabetes mellitus and may include treatment providers.

  • Gene Review: Diabetes Mellitus, 6q24-Related Transient Neonatal (http://www.ncbi.nlm.nih.gov/books/NBK1534)
  • Genetic Testing Registry: Transient neonatal diabetes mellitus 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1832386)
  • The Merck Manual for Healthcare Professionals (http://www.merckmanuals.com/professional/pediatrics/metabolic_electrolyte_and_toxic_disorders_in_neonates/neonatal_hyperglycemia.html)
  • University of Chicago Kovler Diabetes Center (http://monogenicdiabetes.uchicago.edu/)

You might also find information on the diagnosis or management of 6q24-related transient neonatal diabetes mellitus in Educational resources (http://ghr.nlm.nih.gov/condition/6q24-related-transient-neonatal-diabetes-mellitus/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/6q24-related-transient-neonatal-diabetes-mellitus/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about 6q24-related transient neonatal diabetes mellitus?

You may find the following resources about 6q24-related transient neonatal diabetes mellitus helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for 6q24-related transient neonatal diabetes mellitus?

  • 6q24-TNDM
  • TNDM type 1
  • transient neonatal diabetes mellitus 1

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about 6q24-related transient neonatal diabetes mellitus?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/gard).

What glossary definitions help with understanding 6q24-related transient neonatal diabetes mellitus?

apoptosis ; autosomal ; autosomal recessive ; cell ; cell division ; chromosome ; dehydration ; developmental delay ; diabetes ; diabetes mellitus ; duplication ; embryonic ; expressed ; gene ; gene silencing ; glucose ; hernia ; high blood sugar ; hormone ; hyperglycemia ; hypotonia ; imprinting ; inherit ; inheritance ; inherited ; insulin ; intrauterine growth retardation ; macroglossia ; maternal ; methylation ; muscle tone ; neonatal ; pancreas ; promoter ; protein ; receptor ; recessive ; reproductive cells ; secretion ; sperm ; stress ; transient ; uniparental disomy

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Barbetti F. Diagnosis of neonatal and infancy-onset diabetes. Endocr Dev. 2007;11:83-93. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17986829?dopt=Abstract)
  • Diatloff-Zito C, Nicole A, Marcelin G, Labit H, Marquis E, Bellanné-Chantelot C, Robert JJ. Genetic and epigenetic defects at the 6q24 imprinted locus in a cohort of 13 patients with transient neonatal diabetes: new hypothesis raised by the finding of a unique case with hemizygotic deletion in the critical region. J Med Genet. 2007 Jan;44(1):31-7. Epub 2006 Sep 13. (http://www.ncbi.nlm.nih.gov/pubmed/16971482?dopt=Abstract)
  • Docherty LE, Poole RL, Mattocks CJ, Lehmann A, Temple IK, Mackay DJ. Further refinement of the critical minimal genetic region for the imprinting disorder 6q24 transient neonatal diabetes. Diabetologia. 2010 Nov;53(11):2347-51. doi: 10.1007/s00125-010-1853-2. Epub 2010 Jul 30. (http://www.ncbi.nlm.nih.gov/pubmed/20668833?dopt=Abstract)
  • Gene Review: Diabetes Mellitus, 6q24-Related Transient Neonatal (http://www.ncbi.nlm.nih.gov/books/NBK1534)
  • Greeley SA, Tucker SE, Worrell HI, Skowron KB, Bell GI, Philipson LH. Update in neonatal diabetes. Curr Opin Endocrinol Diabetes Obes. 2010 Feb;17(1):13-9. doi: 10.1097/MED.0b013e328334f158. Review. (http://www.ncbi.nlm.nih.gov/pubmed/19952737?dopt=Abstract)
  • Mackay DJ, Boonen SE, Clayton-Smith J, Goodship J, Hahnemann JM, Kant SG, Njølstad PR, Robin NH, Robinson DO, Siebert R, Shield JP, White HE, Temple IK. A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus. Hum Genet. 2006 Sep;120(2):262-9. Epub 2006 Jul 1. (http://www.ncbi.nlm.nih.gov/pubmed/16816970?dopt=Abstract)
  • Mackay DJ, Callaway JL, Marks SM, White HE, Acerini CL, Boonen SE, Dayanikli P, Firth HV, Goodship JA, Haemers AP, Hahnemann JM, Kordonouri O, Masoud AF, Oestergaard E, Storr J, Ellard S, Hattersley AT, Robinson DO, Temple IK. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat Genet. 2008 Aug;40(8):949-51. doi: 10.1038/ng.187. Epub 2008 Jul 11. (http://www.ncbi.nlm.nih.gov/pubmed/18622393?dopt=Abstract)
  • Mackay DJ, Temple IK. Transient neonatal diabetes mellitus type 1. Am J Med Genet C Semin Med Genet. 2010 Aug 15;154C(3):335-42. doi: 10.1002/ajmg.c.30272. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20803656?dopt=Abstract)
  • Temple IK, Shield JP. 6q24 transient neonatal diabetes. Rev Endocr Metab Disord. 2010 Sep;11(3):199-204. doi: 10.1007/s11154-010-9150-4. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20922569?dopt=Abstract)
  • Temple IK, Shield JP. Transient neonatal diabetes, a disorder of imprinting. J Med Genet. 2002 Dec;39(12):872-5. Review. (http://www.ncbi.nlm.nih.gov/pubmed/12471198?dopt=Abstract)
  • Temple IK. Imprinting in human disease with special reference to transient neonatal diabetes and Beckwith-Wiedemann syndrome. Endocr Dev. 2007;12:113-23. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17923774?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: February 2011
Published: January 27, 2015