ESPE Abstracts

Background: In contrast to monogenic diseases, contiguous gene syndrome (CGS) describes a clinical phenotype caused by a deletion or duplication of several neighbouring genes. Angelman or Williams-Beuren syndrome are examples demonstrating that deletion of several adjacent genes causes a complex clinical syndrome. However, CGS are very rare events in pediatric endocrinology, and require knowledge of clinical associations pointing towards specific potentially affected genes in local chromosomal proximity.

Objective and hypotheses: A male preterm geminus born at 30 weeks of gestation was admitted to NICU for further treatment. Selective metabolic screening was performed in the second week of life because of persistent hyponatremia and muscular hypotonia. Massive glyceroluria was detected, indicating glycerol kinase deficiency which mostly is clinically subtile and did not explain the clinical presentation. However, other genes in close proximity to the GK gene are DAX1 and DMD, which may cause congenital adrenal insufficiency and Duchenne muscular dystrophy. Indeed, during further course, increased ACTH, decreased cortisol, and elevated creatine kinase were found pointing to a CGS involving at least these three putative genes.

Method: Array-CGH was initiated to confirm contiguous gene deletion.

Results: Array-CGH showed deletion of DAX1, GK and DMD on Xp21.3. Additionally, IL1RAPL1 was deleted causing a variable spectrum of mental retardation, and further genes without known clinical association. Fortunately, the neighbouring gene for ornithine carbamoyltransferase (OTC), causing an urea cycle disorder, was not affected. Adrenal hypoplasia was confirmed by non-existent adrenal gland in ultrasound. Hydrocortisone and fludrocortisone replacement treatment was initiated with so far uncomplicated clinical course until the present age of now 9 months.

Conclusion: Contiguous deletion of x-chromosomal genes leads to a complex disease pattern involving multiple systems. The association of adrenal insufficiency, elevated creatine kinase, glyceroluria, and hyperammonemia in variable combinations strongly indicates a CGS with deletion of Xp21.3.