Fifty Shades of Pediatric Diabetes

Background: When presenting with overt symptoms and diabetic ketoacidosis, the diagnosis of type 1 diabetes in relatively simple. However, in some pediatric patients, presentation can be diverse and other types of diabetes should be considered, including monogenic diabetes.

Case history: A 3 year old child was referred for endocrine evaluation after a routine blood test revealed fasting glucose level of 120mg%. The child was usually healthy but had a global developmental delay. In his initial endocrine evaluation, post-prandial glucose level reached 195mg% and his HbA1c level was 6.8%. On examination, growth parameters were normal and no dysmorphism was noted. An autoimmune panel was negative. During a short follow-up period, glucose levels were stable, and the child was asymptomatic.

In view of a suspected diagnosis of MODY, a gene panel was carried out but revealed no pathology. At the age of 4 years, because of the developmental delay, Chromosomal Microarray Analysis (CMA) was performed, revealing a 2.5MB de novo deletion in the short arm of chromosome 7. The deletion includes the CCM2 gene known to be essential for neuronal plasticity, but also the GCK gene, known to cause MODY type 2. Exon and gene deletions are a very rare cause of MODY type 2.

Discussion:

- The differential diagnosis of pediatric diabetes- the most common pediatric diabetes is type 1 diabetes, however differential diagnosis includes monogenic diabetes (especially when antibodies are negative), which is divided into 3 main groups: neonatal diabetes (usually diagnosed before the age of 6 months), syndromic diabetes (e.g Wolfram syndrome, RCAD etc.) and MODY (14 types known to date of Maturity Onset Diabetes of the Young).

- The clinical value of the diagnosis- different types of diabetes can require different treatments and different long-term follow-up. For example, several types of monogenic diabetes which can be misdiagnosed as type 1 diabetes, can be treated by oral medications and do not require insulin. Other types might be progressive, can be missed at childhood and lead in adulthood to unnecessary complications.

- The holistic approach that is essential in the pediatric population- developmental delay, heart and kidney anomalies, visual impairment and other systemic signs and symptoms, might be connected to diabetes, and are important clues for the correct diagnosis and treatment.

- Why didn’t the panel diagnose the problem in this case? Some genetic panels include only sequencing of the relevant genes, and will miss deletions and duplications. Chromosal Microarray Analysis covers micro-chromosomal deletions and duplications, but will miss point mutations.

- It is important to understand the different tests available for the diagnosis of diabetes (e.g antibodies testing, genetic testing)- their meaning, the yield of each test, advantages and disadvantages.