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[Clinical phenotype and genetic analysis of a child featuring short stature and multiple skeletal dysplasia]
Yongxue Lyu1, Fengfeng Qi, Zhenghua Fei
1Department of Pediatric Health Care, Huzhou Maternity and Child Health Care Hospital, Huzhou, Zhejiang 313000, China. guchunj@163.com.
Insights
Familial short stature in a child was linked to a likely pathogenic ACAN gene variant. Genetic analysis identified the c.2858dupA mutation, leading to improved height with growth hormone therapy.
Area of Science:
- Genetics
- Pediatrics
- Endocrinology
Background:
- Familial short stature presents a diagnostic challenge, often requiring detailed genetic analysis.
- Understanding the genetic underpinnings of growth disorders is crucial for effective management.
Observation:
- A pediatric patient presented with short stature (Z-score -2.03), midfacial dysplasia, and skeletal abnormalities.
- The patient's family history revealed short stature across multiple generations.
- Whole exome sequencing (WES) identified a heterozygous frameshifting variant (c.2858dupA) in the ACAN gene.
Findings:
- The identified ACAN variant (p.Asp953GlufsTer476) was classified as likely pathogenic according to ACMG guidelines.
- The variant was maternally inherited, confirming a hereditary component.
- Treatment with human recombinant growth hormone resulted in significant height improvement over 11 months.
Implications:
- This case highlights the ACAN gene variant as a probable cause of short stature in this family.
- Early genetic diagnosis and targeted growth hormone therapy can effectively manage ACAN-related skeletal dysplasias.
- Further research into ACAN gene function can elucidate mechanisms of skeletal development and growth.
Objective:
To analyze the clinical phenotype and genetic basis for a child featuring familial short stature.
Methods:
A child who was admitted to Huzhou Maternal and Child Health Care Hospital on October 7, 2021 for growth retardation and pectus carinatum was selected as the study subject. Physical exam and medical imaging was performed. The child was subjected to whole exome sequencing, and candidate variants were verified by Sanger sequencing and bioinformatic analysis.
Results:
The child, a 1-year-old male, had manifested with slightly short stature (Z = -2.03), midfacial dysplasia, and multiple skeletal dysplasia such as pectus carinatum, irregular vertebral morphology, and defect of lumbar anterior bones. His mother, maternal grandmother and great-maternal grandfather also had short stature. WES revealed that the child has harbored a heterozygous c.2858dupA (p.Asp953GlufsTer476) frameshifting variant of the ACAN gene, which was inherited from his mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2858dup (p.Sp953Glufster476) variant was classified as likely pathogenic (PVS1+PM2_Supporting). The patient has shown marked improved height after receiving 11 months of treatment with human recombinant growth hormone (supplemental dose) starting from 20 months of age.
Conclusion:
The ACAN: c.2858dup (p.Asp953GlufsTer476) variant probably underlay the pathogenesis of short stature in this child.
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