Clinical Characteristics and Remission Monitoring of 6q24-Related Transient Neonatal Diabetes

Introduction: Transient neonatal diabetes mellitus (TNDM) is a heterogeneous subtype of neonatal diabetes that usually presents within the first days or weeks of life, spontaneously remits in infancy, but can recur in childhood or adolescence as a permanent form of diabetes. Approximately 70% of TNDM cases are due to overexpression of genes at chromosome 6q24 (6q24-TNDM) caused by one of three potential mechanisms: paternal uniparental disomy (pUPD6), paternal duplication, or hypomethylation of the maternal allele. Our aim was to further elucidate the clinical characteristics of a relatively large group of individuals with this rare condition. Methods: Participants with a genetically confirmed diagnosis of 6q24-TNDM were identified through the University of Chicago Monogenic Diabetes Registry. Some participants had testing done on a clinical basis, with the remainder having received research-based genetic testing. Clinical information was extracted from survey responses and medical records. Results: There were 33 participants with 6q24-TNDM (58% were male). Eight (24%) had hypomethylation of the maternal allele, seven (21%) had paternal duplication, 17 (52%) had pUPD6, and one individual had 6q24 hypomethylation of unknown etiology. The median age of initial diabetes presentation was 2 days (n = 33). Remission occurred at a median age of 3 months (n = 28). The median age of relapse was 14 years (range 12-31 years, n = 9). The majority (71%) of participants were born small for gestational age and 32% of participants were born before 37 weeks gestation. The most common extra-pancreatic features were umbilical hernia (22%, n = 6/27), macroglossia (56%, n = 15/27), and speech pathologies (36%, n = 10/28). No significant differences in clinical characteristics were identified across the three genetic etiologies (pUPD6, paternal duplication, maternal hypomethylation). Conclusions: Clinical characteristics were not different across underlying genetic mechanism groups, suggesting that genetic testing is required to definitively determine the mechanism and diagnosis of 6q24-TNDM. Clarification of the specific underlying mechanism is strongly encouraged to clarify recurrence risk, but whether these subcategories may have other clinically relevant differences remains to be elucidated. Early assessment for speech therapy should be considered for this patient population. We recommend that patients in remission be equipped to check blood glucose levels as needed, such as during illness, and should continue seeing a diabetes provider at least occasionally, especially around the time of puberty and thereafter.