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.
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 is available on a clinical basis to 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. Molecular genetic testing of ZFP57 is available on a limited clinical basis.
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. TIDM-HIL 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.