Endocrine Abstracts

JOINT419

Introduction: The proteoglycan aggrecan, transcripted by ACAN gene, is the most abundant non-collagenous protein in the extracellular matrix in cartilaginous tissue. Variants in ACAN result in a broad phenotypic spectrum of skeletal dysplasias and various undefined short stature syndromes associated with accelerated bone maturation. We present the case of two brothers with short stature, treated with different growth-promoting therapies and later being diagnosed with ACAN variant.

Case report: Patient 1 was referred to our Endocrinology Unit for short stature and GH deficiency, confirmed with two stimulation tests. No significant medical history. He was born appropriate for gestational age; familiarity for short stature in mother and into the maternal line. He was treated with GH therapy from 5 years of age, with height improvement from < -2 SDS up to 10° centile. An anticipated puberty with rapid progression negatively affected patient final height, <-3 SDS. Extensive blood examinations, ACTH test, new CNS MRI and SHOX-gene analysis were normal. Patient 2, brother of patient 1, was referred at 5 years of age for short stature. GH deficiency was ruled out with GH-stimulation tests. Radiological evaluation showed advanced bone aged of 1.5 years. Adrenal axis evaluation was normal. At 9 years old he was diagnosed Central Precocious Puberty and was treated with GnRH agonist, Decapeptyl 3.75 mg/28 days. The therapy was suspended at the age of 12, with a skeletal age of 13. After 6 months, bone age advanced 1 more year, therefore, taking also into account the family history, he started aromatase-inhibitor therapy, anastrozole 1 mg/day, in order to slow down growth plate fusion. After pubertal spurt he was -2.5 SDS for height and genetic analysis were performed. Exome sequencing showed the heterozygous variant c.6620C>A (p.(Ser2207*)) in ACAN gene, inherited by his mother and presents also in his brother. This variant is not descripted in literature and in the Human Gene Mutation Database yet and it was classified as probably pathogenetic (ACMG).

Discussion: Genetic evaluation, with the widespread use of next-generation sequencing technology, has been demonstrated as an important tool to elucidate the causes of growth disorders. Patient 1 partially responded to GH treatment, as already reported in the literature. Treatment with GnRH analogue and aromatase inhibitor, carried out in patient 2, did not lead to better results and not effectively improve the final height. Bone age pathological progression due to aggrecan variant is still an open challenge.