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ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment
Manouk van der Steen1,2, Rolph Pfundt3, Stephan J W H Maas3
1Dutch Growth Research Foundation, 3001 KB Rotterdam, The Netherlands.
Insights
ACAN gene mutations are found in some children born small for gestational age (SGA) with advanced bone age (BA). These mutations may benefit from growth hormone (GH) and GnRH analog (GnRHa) treatment, improving adult height.
Area of Science:
- Pediatric endocrinology
- Genetics
- Skeletal development
Background:
- Children born small for gestational age (SGA) can exhibit advanced bone age (BA) maturation during growth hormone (GH) therapy.
- ACAN gene mutations are associated with short stature and advanced BA in pediatric populations.
Purpose of the Study:
- To investigate the prevalence of ACAN gene mutations in short SGA children presenting with advanced BA.
- To evaluate the efficacy of GH treatment in these children.
Main Methods:
- Bone age (BA) assessment was performed on 290 GH-treated SGA children.
- ACAN gene sequencing was conducted on 29 SGA children with advanced BA (≥0.5 years greater than chronological age).
Main Results:
- ACAN gene mutations were identified in 13.8% (4/29) of SGA children with advanced BA.
- Mutations correlated with midface hypoplasia, joint problems, and broad great toes, forming a potential clinical scoring system.
- GH treatment combined with 2 years of gonadotropin-releasing hormone analog (GnRHa) therapy showed positive effects on adult height in affected children.
Conclusions:
- ACAN gene sequencing is recommended for SGA children with persistent short stature, advanced BA, and specific physical characteristics.
- The findings support the use of GH and GnRHa treatment in SGA children with ACAN gene mutations to optimize growth outcomes.
Background:
Some children born small for gestational age (SGA) show advanced bone age (BA) maturation during growth hormone (GH) treatment. ACAN gene mutations have been described in children with short stature and advanced BA.
Objective:
To determine the presence of ACAN gene mutations in short SGA children with advanced BA and assess the response to GH treatment.
Methods:
BA assessment in 290 GH-treated SGA children. ACAN sequencing in 29 children with advanced BA ≥0.5 years compared with calendar age.
Results:
Four of 29 SGA children with advanced BA had an ACAN gene mutation (13.8%). Mutations were related to additional characteristics: midface hypoplasia (P = 0.003), joint problems (P = 0.010), and broad great toes (P = 0.003). Children with one or fewer additional characteristic had no mutation. Of children with two additional characteristics, 50% had a mutation. Of children with three additional characteristics, 100% had a mutation. All GH-treated children with a mutation received gonadotropin-releasing hormone analog (GnRHa) treatment for 2 years from onset of puberty. At adult height, one girl was 5 cm taller than her mother and one boy was 8 cm taller than his father with the same ACAN gene mutation.
Conclusion:
This study expands the differential diagnosis of genetic variants in children born SGA and proposes a clinical scoring system for identifying subjects most likely to have an ACAN gene mutation. ACAN sequencing should be considered in children born SGA with persistent short stature, advanced BA, and midface hypoplasia, joint problems, or broad great toes. Our findings suggest that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRHa.
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