Endocrine Abstracts

JOINT3695

Introduction: Severe short stature defined as height below -4 SD is extremely rare and typically indicates a genetic pathology. Despite its clinical significance, data on its genetic aetiology are limited. One of its subtypes, primordial dwarfism is a defect in overall body size determination rather than isolated bone growth. While milder forms of short stature is regulated by the GH–IGF-1 axis and growth plate, severe cases may involve fundamental cellular processes, such as cell division, DNA replication, and genome stability, leading to reduced cell proliferation. This study aims to map the genetic spectrum of severe short stature using next-generation sequencing (NGS) in a unique cohort of children from consanguineous families.

Patients and Methods: Thirty-three probands (16 females) with height ≤ 4SD from 1st cousin consanguinity (with/without syndromic features), examined in three centres for paediatric endocrinology in Iraq, Iran and Oman between January 2022 and February 2023, were included in the study. DNA of the proband, both parents, and health/affected siblings (when available) was obtained with informed consent. Probands’ DNA was analyzed by Whole Exome Sequencing. Data was processed by a bioinformatic pipeline and SNP and CNV variants were filtered using variant analysis software. Prioritized potentially pathogenic variants were evaluated by the ACMG standards and confirmed using Sanger sequencing.

Results: A monogenic cause of severe short stature was elucidated in 21/33 (64%) probands. Median height was -5. 4 SD (IQR -7. 3 to -4. 6 SD) and median age 8. 1 years (IQR 5. 2 to 11. 2). Pathogenic or likely pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR[2], GH1[2]), growth plate and extracellular matrix (ACAN, COL1A2, DYM[2], FN1), signal transduction and gene regulation (NF1, ZSWIM6), DNA repair and chromosomal stability (NIPBL, LIG4), cytoskeletal structure and cell division (CUL7, PCNT, POC1A), transmembrane transport and metabolism (SLC4A1, SLC7A7, SLC34A3, GNPNAT1), and apoptosis regulation (PDCD6IP). Homozygous pathogenic variants were prevalent, however there were 3 heterozygous variants, one de novo variant and one compound heterozygous variant. Majority of genes (12/18) were genes involved in fundamental cellular processes.

Conclusion: NGS is a valuable tool for uncovering the genetic basis of severe short stature, particularly in consanguineous populations where recessive inheritance patterns are common. Our findings highlight the genetic heterogeneity of severe short stature, and the presence of majority of variants outside the traditional GH-IGF-1 and growth plate pathways underscores the role of fundamental cellular mechanisms in extreme growth disorders.