Diagnosis and treatment in a case of Acrodysostosis1 caused by PRKAR1A gene pathogenic variant

Objective: This study aims to investigate the clinical phenotypic characteristics of acrodysostosis1 (ACRDYS1) caused by PRKAR1A gene mutations, and discuss the correlation between genotype and phenotype by reviewing literatures. Methods: The clinical data of a 13-year-old male child with skeletal dysplasia and multiple hormone resistance was analyzed. The child's clinical exons were examined using second-generation target region capture high- throughput sequencing technology, and suspected mutated loci were verified in the parents through Sanger sequencing. Additionally, a literature review was conducted to analyze the relationship between clinical phenotypes and genotypes in other affected children. The treatment involved growth hormone (GH) for dwarfism and Chorionic Gonadotropin (HCG) for delayed sexual development. Results: The child presented with short stature (<= 3SD), low body mass (-1 similar to -2SD), facial bone abnormalities (wide face, wide eye spacing, maxillary hypoplasia, flattened nasal ridge, small and upturned nostrils), limb hypoplasia (stubby fingers and toes), and delayed puberty (13 years old with 1.5 ml testes and Tanner stage 1). Laboratory tests revealed resistance to parathyroid hormone and thyrotropin, complete growth hormone deficiency, and low testosterone. X-rays indicated skeletal hypoplasia of the extremities. Whole-exome sequencing identified a heterozygous missense mutation (c.524 A > G, p.A346T) in the PRKAR1A gene, which was classified as a pathogenic variant per ACMG. The child's clinical features confirmed ACRDYS1. A literature review showed a link between the PRKAR1A gene and the child's phenotype. The child initially presented with high Thyroid Stimulating Hormone (TSH) and was treated with levothyroxine, adjusted for normal thyroid hormone levels. Despite advanced bone age, severe short stature was addressed with GH therapy (0.16 IU/kg.d), increasing height by 9.6 cm in one year. The child also had small genitalia, treated with HCG, leading to significant enlargement. Conclusion: Clinicians should be attentive to whether children presenting with short stature, short fingers, and facial bone dysplasia also had comorbid hormonal resistance. Genetic testing can confirm the diagnosis of ACRDYS1. Remarkable results have been achieved in terms of height improvement through GH injections and sexual development enhancement through HCG injections. These findings suggested a new direction for studying the pathogenic mechanism of hormone resistance in ACRDYS1 children.