Endocrine Abstracts

JOINT3776

Introduction: Short stature is a common reason for seeking medical attention in childhood. Clinical variability and genetic heterogeneity make it difficult to identify the underlying cause in a significant portion of patients. One of the genes associated with a wide phenotypic spectrum of non-syndromic short stature is ACAN. The aggrecan protein, encoded by the ACAN gene, is a major proteoglycan component of the extracellular matrix of cartilage. Aggrecan plays a critical role in maintaining the structure necessary for the function of joints. We present a clinical case of autosomal-dominant spondyloepiphyseal dysplasia type Kimberley, caused by a novel variant in the ACAN gene.

Materials and Methods: A 3-year-8-month-old boy was referred to us because of his short stature. Birth weight 3000 g, length 48 cm. Early development was without any issues. There is no family history of short stature. The mother’s height is 164 cm, the father’s height is 184 cm, and the target height is 181.5 cm (SDS of target height: +0.65 SD). Upon examination, the patient’s condition was satisfactory. His height was 89.5 cm (SDS: -2.67), weight 12.5 kg (SDS BMI: -0.12), with a high forehead and relative macrocephaly. No instrumental data indicated a disruption in bone age.

Results: Molecular genetic testing was performed using a targeted panel for "Connective Tissue Diseases" via next-generation sequencing (NGS). A previously undescribed heterozygous variant was identified in the ACAN gene (NM 001369268.1): c.1793G>A, p.(Cys598Tyr), which was further validated by Sanger sequencing. Segregation analysis confirmed the variant as de novo in the family. Based on the ACMG pathogenicity criteria, the variant was classified as likely pathogenic and causal for spondyloepiphyseal dysplasia, Kimberley type with an autosomal-dominant inheritance pattern.

Conclusion: The polyetiological nature of short stature in pediatric practice requires expanded molecular genetic testing methods, such as targeted panels, whole-exome sequencing, and whole-genome sequencing. Identifying the causal variant allows for diagnosis verification, determination of further observation and treatment strategies for the patient and provides a health prognosis for the family.