Clinical Guidance

Diabetes mellitus. No difference in the severity, duration, or relapse rate of diabetes has been detected between the 6q24-TNDM etiologic subgroups . Non-diabetes manifestations vary by causative genetic mechanism. Congenital anomalies were significantly more frequent in individuals with paternal uniparental disomy of chromosome 6 (UPD6) or MLID than in those with 6q24 duplication or isolated hypomethylation defects .

Source: GeneReviews — "Diabetes Mellitus, 6q24-Related Transient Neonatal"

Penetrance

Reduced penetrance of the 6q24-TNDM has rarely been described, but has been noted in sibs of affected individuals. The sibs reported did not have a history of neonatal diabetes mellitus but were found to have either a paternal duplication of 6q24 or biallelic ZFP57 pathogenic variants .

Source: GeneReviews — "Diabetes Mellitus, 6q24-Related Transient Neonatal"

Diagnostic Criteria

Suggestive Findings

Diagnosis of 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) should be suspected in individuals with the following clinical features:

• Severe intrauterine growth restriction

• Diabetes mellitus that commences in the first six weeks of life in a term infant and resolves by age 18 months. Presentation includes the following:

• Hyperglycemia

• Dehydration

• Plasma insulin concentrations that are low in the presence of high serum glucose concentrations

• Absence of ketoacidosis. Ketones are usually not present in the urine.

• Absence of islet cell antibodies

• Presence of a pancreas

Establishing the Diagnosis

The diagnosis of 6q24-TNDM is established in a proband with one of the following:

Source: GeneReviews — "Diabetes Mellitus, 6q24-Related Transient Neonatal"

Differential Diagnosis

Transient neonatal diabetes mellitus (TNDM) accounts for approximately 50% of diabetes mellitus presenting in the neonatal period . showed that 70% of TNDM was caused by 6q24 aberrations. Other genetic causes of transient neonatal diabetes mellitus include pathogenic variants in KCNJ11 and ABCC8, which usually cause permanent neonatal diabetes (see Permanent Neonatal Diabetes Mellitus). failed to demonstrate clear clinical indicators to differentiate 6q24-TNDM from other causes in a large cohort of 50 individuals presenting with neonatal diabetes. Other genetic causes of neonatal diabetes mellitus (isolated and syndromic, transient and permanent):

Source: GeneReviews — "Diabetes Mellitus, 6q24-Related Transient Neonatal"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with 6q24-related transient neonatal diabetes mellitus (6q24-TNDM), the following evaluations are recommended if they have not already been completed:

• Birth weight, length, and head circumference and any subsequent growth parameters

• General dysmorphology examination, preferably by a clinical geneticist, including evaluation of tongue size and umbilicus

• Neurologic examination and developmental assessment

• Investigation of the anatomy of the pancreas by ultrasound examination or MRI

• Echocardiogram and ultrasound examination of the liver and kidneys to help identify those infants likely to have 6q24-TNDM caused by ZFP57 pathogenic variants

• Brain MRI examination if evidence of developmental delay or hypotonia

• Serum glucose concentration

• C peptide measurement

• Pancreatic beta cell autoantibody measurements

• Liver function and thyroid function tests

• Consultation with a pediatric endocrinologist for follow up of diabetes

• Consultation with a clinical geneticist and/or genetic counselor

Individuals with multilocus imprinting disturbance (MLID) should be evaluated for hypotonia and other neurologic features including epilepsy, congenital heart disease, deafness, renal malformations, and pseudohypoparathyroidism with measurement of serum concentrations of calcium and phosphate and parathyroid hormone testing.

Treatment of Manifestations

Rehydration and IV insulin on a sliding scale ar...

Source: GeneReviews — "Diabetes Mellitus, 6q24-Related Transient Neonatal"

Clinical Guidance

General factors that predispose to late-onset diabetes (e.g., excessive weight gain) or risk factors for cardiovascular disorders should be avoided.

Source: GeneReviews — "Diabetes Mellitus, 6q24-Related Transient Neonatal"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Diabetes Mellitus, 6q24-Related Transient Neonatal"

Surveillance Guidelines

Periodic glucose tolerance tests can be used to assess insulin secretion. Most children with transient neonatal diabetes mellitus in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state. Insulin response to intravenous glucose loading is often normal but suggests future recurrence if abnormal . Measure growth (height, weight, head circumference) at regular intervals (i.e., at least every 6 months). Developmental assessment to identify any special educational needs is appropriate. Children with MLID need to be monitored for developmental delay and special educational needs.

Source: GeneReviews — "Diabetes Mellitus, 6q24-Related Transient Neonatal"