Impact of Growth Hormone Treatment in Children From an Extended Family With ACAN-Related Short Stature - Clinical Genetics Short Report - Open Access

Sep 30, 2026

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Heterozygous ACAN gene variants are established causes of short stature. This retrospective study evaluated growth hormone (GH) treatment response in five related children from an extended family carrying a specific ACAN variant. GH was started at a mean age of 3.2 ± 2.1 years and administered for 6.4 ± 5.0 years. Height SDS improved from −3.3 ± 1.0 to −2.0 ± 1.1 (p = 0.001). Growth velocity SDS rose most during year one, with no observed adverse effects and no significant bone age advancement. Puberty began between 10 and 11.6 years in three children receiving adjunctive therapy.

LanguageEnglish

CategoryHealthcare

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Pages6

Reading Time15 min

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Introduction

Patients and Methods

Data Analysis

Results

Growth

Clinical Genetics SHORT REPORT OPEN ACCESS Impact of Growth Hormone Treatment in Children From an Extended Family With ACAN-Related Short Stature Einat Shalev-Goldman1,2 | Ayman Asaly1,2 | Hadas Ityel1,3 | Ben Pode-Shakked1,3 | Dalit Modan-Moses1,2 | Yael Levy-Shraga1,2 1Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel | 2Pediatric Endocrinology and Diabetes Unit, the Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel | 3The Institute for Rare Diseases, the Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel-Hashomer, Israel Correspondence: Yael Levy-Shraga ([yael.levy.shraga@gmail.com](yael.levy.shraga@gmail.com)) Received: 18 July 2025 | Revised: 6 August 2025 | Accepted: 12 August 2025 Funding: The authors received no specific funding for this work. Keywords: ACAN | growth hormone | idiopathic short stature | treatment ABSTRACT Heterozygous variants in the ACAN gene are a recognized cause of short stature. We aimed to evaluate the response to growth hormone (GH) treatment in members of an extended family carrying anACAN variant. Clinical and laboratory data of five related children were retrospectively collected. GH therapy was initiated at a mean age of 3.2 ± 2.1years and treated for 6.4 ± 5.0years. The height standard deviation scores (SDS) increased from −3.3 ± 1.0 to −2.0 ± 1.1 (p = 0.001), with a mean gain of 1.3 ± 0.3 SDS. The most notable increase in growth velocity SDS occurred during the first year of treatment (−0.5 ± 0.6 to 2.1 ± 1.2; p = 0.04) . No adverse effects were observed, and bone age did not advance significantly. Three children entered puberty between the ages of 10 and 11.6 years and received adjunctive gonadotropin releasing hormone analog therapy. Genetic testing identified a heterozygous nonsense variant in theACAN(c.2023C>T; p.Arg675*). Our findings suggest that GH therapy can improve growth velocity in children with ACAN-related short stature, though the degree of response varies even within the same family. The long-term impact on final adult height remains to be elucidated. 1 | Introduction Over the past two decades, several single-gene mutations have been identified as causes of short stature in patients initially classified as idiopathic short stature (ISS) [1] . One such cause is heterozygous variants in the ACAN gene [2] . Aggrecan, encoded by the ACAN gene, is a key proteoglycan component of the extracellular matrix in both the growth plate and articular cartilage. Deficiency in aggrecan disrupts the organization and maturation of chondrocytes, leading to premature hypertrophic differentiation and early cessation of growth [3] . Classically, individuals with heterozygous ACAN variants have been described as having disproportionate short stature and advanced bone age (BA) [2, 4, 5] . More recently, reported clinical findings include macrocephaly, brachydactyly, midface hypoplasia, a flat nasal bridge, hyperlordosis, and scoliosis. Aggrecan deficiency may also impair articular cartilage function, resulting in earlyonset osteoarthritis or osteochondritis dissecans [6] . However, advanced BA is not a consistent feature in all patients. In approximately 20% of cases, short stature may be the only notable finding [5, 7] . The impact of recombinant human growth hormone (rhGH) in children with heterozygous ACAN variants has been studied in recent years, but results remain inconclusive [5, 7–14] . A recent prospective study of 10 short-statured children over This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2025 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd. 374 Clinical Genetics, 2026; 109:374–379 [https://doi.org/10.1111/cge.70

FAQs

What genetic cause and study focus are examined in this report?

The report focuses on heterozygous variants in the ACAN gene as a cause of short stature, evaluating how children from an extended family respond to growth hormone therapy.

How was growth hormone therapy administered and for how long?

Growth hormone therapy was initiated at a mean age of 3.2 ± 2.1 years and continued for 6.4 ± 5.0 years, based on retrospective clinical records.

Did the children show improvement in height and growth velocity after treatment?

Height SDS increased from −3.3 ± 1.0 to −2.0 ± 1.1 (p = 0.001), and the largest rise in growth velocity SDS occurred during the first year of treatment.

Were there safety concerns or bone-age changes during treatment?

No adverse effects were observed, and bone age did not advance significantly during the treatment period.

Sep 30, 2026

Uploaded by dawugda