ESPE Abstracts

Aggrecan (ACAN) is the major proteoglycan in the articular cartilage, critical for the structure and function of growth plate cartilage.

Case Report: 11-year-old (y) boy admitted at 1.8 y of chronological age (CA), due to poor growth rate Height (H): 76 cm (−2.75 SDS). Initial physical examination: mild dysmorphic features and prepubertal external genitalia (two scrotal testes, 1 cc volume each). Neurologic maturation was normal. Initial bone age (BA) was estimated at 3.3 y. Routine and hormonal laboratory evaluations were normal. He was initially considered as a rare case of idiopathic short stature with advanced BA. No spontaneous catch up growth was observed during the first 4 years of follow up Given the clinical evidence an ACAN gene mutation was considered and studied by whole exome sequencing but no deleterious variants were found. Nevertheless, we identified a potential candidate gene: ADAMTS6 (Gene ID: 11174) with 2 heterozygous variants in the same allele, c.[2424T>G;2425C>T], p.[Asn808Lys; Leu809Phe]. These variants were predicted to be damaging by all in silico prediction tools, and were not found in any database. Segregation was confirmed by Sanger sequencing, revealing that his mother and sister were also heterozygous for these variants. At 7.5y of CA with a BA slightly advanced (8.5y), H: 107.9 cm (−3.03 SDS) even though a normal serum GH levels response to pharmacological arginine/clonidine stimulatory test was found, rhGH treatment (0.33 mg/Kg per day) was started. Moreover, at 10.5 y of CA, clinical evaluation showed increase of testicular volume (TV) (4/4 cc) and Tanner Stage (TS): G1, PH 1. Four months later, early and accelerated pubertal progression was observed (H: 127.4 cm (−1.77 SDS, rhGH treatment maximal ΔHSDS:+1.26, TV: 8/8 cc, TS: G3, PH: 3). Hormonal studies confirmed onset of puberty. According to present knowledge, there is no explanation to justify why the patient presented early onset of puberty and accelerated pubertal development. We speculate that ADAMTS6 mutation might be involved in the regulation of the early onset of puberty and accelerated pubertal tempo. Since aggrecan protein is involved in the regulation of developmental neural plasticity, we propose that the interaction between ADAMTS6 and aggrecan protein might be involved in the mechanism of early onset of puberty and accelerated pubertal tempo. Finally we propose ADAMTS6 as a candidate gene for idiopathic short stature and recommend further investigation to confirm this hypothesis.