ESPE Abstracts

Introduction: Aggrecan is a major proteoglycan component of the articular and growth plate extracellular matrix, encoded by the ACAN gene (MIM: 155760). Although short stature and various dysmorphic findings are observed in individuals with ACAN mutations, the relationship between genotype and phenotype is not clear.

Case: A 6.75-year-old pre-pubertal girl presented with disproportionate short stature. She was full term from unrelated parents with birthweight 3800g (1.21SD) and length of 52cm (1.22SD). At admission, her height was 110.7cm (-2.09SD) with a large trunk and sitting height/height ratio >2SDS. Paternal and maternal heights were 172cm (−0.68SD) and 159.1cm (-0.70SD), respectively, with mild dysmorphism of hands and feet. There was a strong paternal family history of short stature but none of osteoarthritis. She was dysmorphic (midfacial hypoplasia and high-arched palate), short neck, barrel chest, broad thumbs, shortmetacarpal (fourth, fifth) and metatarsal (third, fourth, fifth) bones, and pes planus. Growth hormone (GH) stimulation test peak was 7.9 ng/mL. There was no sign of skeletal dysplasia, besides cone-shaped epiphysis of the thumb distal phalanx on X-ray. Her bone age (BA) was consistent with chronological age (CA). Patient records from previous visitis showed BA was never advanced; she grew along the third percentile. Karyotype was 46,XX and SHOX gene analysis was normal. At the last visit, she was 12 years old with a height of 115.7cm (-2.07SD) and a growth velocity of 5.8 cm/year; and BA was consistent with CA with normal IGF-1 levels; she was still prepubertal. Her younger brother also had milder dysmorphic features. At admission, he was 3 years old, prepubertal and proportionate with a height of 91cm (-1.89SD). His laboratory and endocrine assessments were normal and BA also corresponded with CA. Whole exome sequencing was performed and a heterozygous variant of uncertain significance (c.3465G>T p.Ala116Ser) in the ACAN gene was found in the index patient, her father, and her brother. The evaluation of the affected children is continuing, although no treatment has started yet.

Discussion and Conclusion: It is reported that clinical course and phenotype of patients with short stature and pathogenic ACAN gene mutations are variable, even within families. For treatment, especially in patients with advanced BA, pubertal pause has been induced with GnRH treatment, and GH replacement therapy (GHRT) was attempted, but outcome data have been variable. Given the heterogeneity of growth in patients with ACAN variants, treatments should be tailored to affected individuals.