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Transient neonatal diabetes mellitus

Orpha number ORPHA99886
Synonym(s) TNDM
Prevalence -
Inheritance -
Age of onset -
ICD-10
  • P70.2
ICD-O -
OMIM
UMLS -
MeSH -
MedDRA -

Summary

Transient neonatal diabetes mellitus (TNDM) is a genetically heterogeneous form of neonatal diabetes (NDM, see this term) characterized by hyperglycemia presenting in the neonatal period that remits during infancy but recurs in later life in most patients.

The prevalence of neonatal diabetes is estimated to be between 1/95,000 to 1/400,000 live births. About 50% of NDM cases are transient (TNDM) and 50% permanent (PNDM, see this term). The condition has been reported in all ethnic groups and affects male and female infants equally.

Cardinal clinical manifestations include severe intrauterine growth retardation, hyperglycemia within the first week of life beginning in the neonatal period and resolving usually by 18 months of age, and dehydration. The most commonly reported congenital abnormalities are macroglossia and umbilical hernia. A wide range of different associated clinical signs including rarely neurological (as a rule no epilepsy), facial dysmorphism, deafness, cardiac, metabolic, kidney or urinary tract anomalies are reported. Developmental delay, and learning difficulties may also be observed. Affected infants usually require insulin initially, but the need for insulin gradually declines with time. Women who had TNDM as infants are at risk for relapse during pregnancy. Ketoacidosis is generally absent (except in patients with KCNJ11 and ABCC8 mutations).

TNDM is caused by 6q24 alterations consisting of paternal uniparental disomy, partial duplication of paternal origin, or relaxation of maternal imprinting in 6q24. All these alterations induce overexpression of imprinted genes at the 6q24 locus, most likely PLAGL1 (6q24-q25) and HYMAI (6q24.2). Heterozygous mutations in the KCNJ11 (11p15.1) and ABCC8 (11p15.1) genes account for 26% of cases. Homozygous or compound heterozygous ZFP57 (6p22.1) mutations have also been reported to cause TNDM.

Diagnosis is based on the cardinal clinical signs of TNDM and is confirmed by laboratory findings showing abnormal plasma insulin concentrations and by molecular genetic testing.

Differential diagnoses include permanent NDM, DEND syndrome (epilepsy, hypotonia, and developmental delay in addition to diabetes mellitus), intermediate DEND, and Wolcott-Rallison syndrome (see these terms) as well as all other syndromic forms of neonatal diabetes mellitus.

Prenatal diagnosis requires identification of a specific genetic defect in the family and is available clinically on a limited basis.

The family tree may be indicative of an imprinting disorder. Sporadic cases with de novo mutations have been reported, as well as autosomal recessive and autosomal dominant patterns of inheritance, complicating genetic counseling. In the case of (partial) uniparental disomy, the recurrence risk is probably close to zero. In partial duplication, there is a risk of recurrence.

Early diagnosis and appropriate treatment are crucial. Initial treatment mainly involves rehydration and intravenous insulin. Some infants however do not require insulin therapy. Insulin can rapidly be switched to the subcutaneous route or to continuous insulin pump therapy and discontinued once blood glucose levels have stabilized. During relapse of DM, which is poorly characterized, some patients can be treated with diet alone but others require oral sulfonylurea or insulin.

Rapid catch-up growth is normally achieved through insulin treatment and normal height and weight often reached by two years of age. Diabetes may recur in childhood, during puberty, or later in adulthood in about 85% of patients. Prognosis is generally good but depends on timely rehydration and adequate control of potential complications.

Expert reviewer(s)

  • Pr Michel POLAK

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Detailed information

Guidance for genetic testing
  • EN (2014,pdf)
Clinical genetics review
  • EN (2010)
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