Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype–phenotype correlation in an international cohort of patients

Abstract

Aims/hypothesis 6q24 transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes presenting in the neonatal period that remits during infancy but, in a proportion of cases, recurs in later life. We aim to describe the clinical presentation of 6q24 TNDM in the largest worldwide cohort of patients with defined molecular aetiology, in particular seeking differences in presentation or clinical history between aetiological groups. Methods One-hundred and sixty-three patients with positively diagnosed 6q24 TNDM were ascertained from Europe, the Americas, Asia and Australia. Clinical data from referrals were recorded and stratified by the molecular aetiology of patients. Results 6q24 TNDM patients presented at a modal age of one day, with growth retardation and hyperglycaemia, irrespective of molecular aetiology. There was a positive correlation between age of presentation and gestational age, and a negative correlation between adjusted birthweight SD and age of remission. Congenital anomalies were significantly more frequent in patients with paternal uniparental disomy of chromosome 6 or hypomethylation of multiple imprinted loci defects than in those with 6q24 duplication or isolated hypomethylation defects. Patients with hypomethylation had an excess representation of assisted conception at 15%. Conclusions/interpretation This, the largest case series of 6q24 TNDM published, refines and extends the clinical phenotype of the disorder and confirms its clinical divergence from other monogenic TNDM in addition to identifying previously unreported clinical differences between 6q24 subgroups.

Congenital imprinting disorders: Application of multilocus and high throughput methods to decipher new pathomechanisms and improve their management

“…The power to detect low-level mosaicism by array analysis was additionally confirmed by Prickett et al [33] in a cohort of SRS patients: by hybridization of patients DNA onto DNA methylation microarrays the group provided proof of principle that this technique has a higher sensitivity than classical conventional singlelocus tests. Additionally, the use of methylation arrays contributes to the idenfication of novel candidate imprinted genes, and the epigenomic profiling expands the understanding of normal methylome and its disruption [34].…”

Glycemic control indicators in patients with neonatal diabetes mellitus

“…Although patients with TNDM require insulin therapy at the time of onset because of marked hyperglycemia, they can be weaned from insulin therapy at an average of 3 mo after the start of treatment [13][14][15][16] . This is called the remission period.…”

The Frequency of Methylation Abnormalities Among Estonian Patients Selected by Clinical Diagnostic Scoring Systems for Silver–Russell Syndrome and Beckwith–Wiedemann Syndrome

“…For our surprise, we detected one patient in the BWS group who had hypomethylation of PLAGL1 (6q24) and IGF2R (6q25) genes without 11p15 imprinting disorder. Hypomethylation of PLAGL1 gene should theoretically result in 6q24-related transient neonatal diabetes mellitus (TNDM) (Docherty et al, 2013;Temple et al, 2015). This is a rare imprinting disorder characterized by intrauterine growth retardation, transient neonatal diabetes, and in some cases, macroglossia, abdominal wall defects, hypotonia, congenital visceral anomalies, and developmental delay.…”