Diabetes Mellitus, 6q24-Related Transient Neonatal

Clinical 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 restriction, 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 may be present. 6q24-TNDM associated with a multilocus imprinting disturbance (MLID) can be associated with marked hypotonia, congenital heart disease, deafness, neurologic features including epilepsy, and renal malformations. Diabetes mellitus usually starts within the first week of life and lasts on average three months but can last longer than 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: The diagnosis of 6q24-TNDM is established in a proband with transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the 6q24 differentially methylated region (DMR). 6q24-TNDM is caused by overexpression of the imprinted genes at 6q24 (PLAGL1 and HYMAI). The DMR (i.e., PLAGL1 TSS alt-DMR) is present within the shared promoter of these genes. Normally, expression of the maternal alleles of PLAGL1 and HYMAI is silenced by DMR methylation and only the paternal alleles of PLAGL1 and HYMAI are expressed. Additional molecular genetic testing can establish the underlying genetic mechanism, which is required for genetic counseling. Three different genetic mechanisms resulting in twice the normal dosage of PLAGL1 and HYMAI (and thus causing 6q24-TNDM) are (1) paternal uniparental disomy of chromosome 6, (2) duplication of 6q24 on the paternal allele, and (3) hypomethylation of the maternal PLAGL1 TSS alt-DMR, resulting in inappropriate expression of the maternal PLAGL1 and HYMAI alleles. Maternal PLAGL1 TSS alt-DMR hypomethylation may result from an isolated imprinting variant or as part of MLID. Biallelic ZFP57 pathogenic variants account for almost half of TNDM-MLID.

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 modifications 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); monitoring of growth and development.

Agents/circumstances to avoid: Factors that predispose to late-onset diabetes or risk factors for cardiovascular disease.

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 pathogenic variants.

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 duplication of 6q24 can occur de novo, be inherited in an autosomal dominant manner, or be inherited as part of a complex chromosome rearrangement; TNDM caused by inherited duplication of 6q24 may recur in sibs and offspring of a proband if the duplication is inherited from the father. Prenatal diagnosis of paternal duplication of 6q24 is possible in pregnancies at risk for a structural chromosome abnormality. TNDM caused by hypomethylation of the PLAGL1 TSS alt-DMR is a de novo non-recurrent event in the majority of individuals, particularly if hypomethylation is restricted to this DMR and does not affect other imprinted loci. However, TNDM as part of a multilocus imprinting disturbance (TNDM-MLID) has a significant genetic component. TNDM-MLID is inherited in an autosomal recessive manner when caused by pathogenic variants in ZFP57; however, the phenotype of homozygous or compound heterozygous sibs is variable and cannot be predicted by molecular genetic testing. Pathogenic variants in additional genes are suspected of causing TNDM-MLID but are currently unknown. Therefore, caution should be exercised when counseling the heritability of TNDM associated with imprinting disturbance at the PLAGL1 TSS alt-DMR.