ESPE Abstracts

Keywords: Achondroplasia, Hypochondroplasia, Dwarfism, Fibroblast growth factor receptor-3.

Introduction: Achondroplasia (ACH) and hypochondroplasia (HCH) are the two most common forms of short-limb dwarfism. They are autosomal dominant diseases characterized by a rhizomelic shortening of the limbs, genu varum, trident hands, large head with frontal bossing and hypoplasia of the mid-face. Both ACH and HCH are caused by missense mutation in the FGFR3 gene located on chromosome 4p16.

Objective: To emphasize the importance of genetic tests in establishing the correct diagnosis of clinically suspected ACH and HCH.

Methods: The clinical data and genetic test results of 17 suspected children with ACH or HCH were analyzed between 2019 to 2021. DNA was isolated from the peripheral blood of the patient using the CentoXome® Trio including CNV analysis (Double stranded DNA capture baits against approximately 36.5 Mb of the human coding exome are used to enrich target regions from fragmented genomic DNA with the Twist Human Core Exome Plus kit), performed by CENTOGENE AG, Rostock, Germany. The genetic results are interpreted in the context of the provided clinical findings, family history, and other laboratory data. Anthropometric data were elaborated by Anthro and Anthro-plus software [z-scores are based on WHO standards (birth to 60 months) and WHO reference 2007 (61 months to 19 years] and statistical processing was done by SPSS.

Results: 17 patients (male /female ratio: 9/8) were clinically evaluated. 11 out 17 (64.7%) were clinically diagnosed with ACH and 6 out 17 (35,3%) with HCH. The first presented age was 3.96±3.60 years old (min. 0.09 yrs.; max. 12.99 yrs.). Heigh for age z-score (HAZ) of all patients at the time of clinical diagnosis was -3.51±1.44 z-score (min. -6,0 z-score; max. -0,75 z-score). The mean age of the patients at the time of genetic test was 6.27±4.21 yrs. (min. 0.32 yrs.; max. 14.77 yrs.) and HAZ was -4.56±1.76 z-score (min. -9.45 z-score; max. -0,75 z-score). After genetic test, the frequencies of diagnoses were as follow: FGFR3- mutation related Achondroplasia 13 (76.4%) patients; FGFR3- mutation related Hypochondroplasia 1 (5.9%) patient; ALPL mutation related AD hypophosphatasia 1 (5.9%) patient; IHH gene mutation related AD bradydactily type A1, 1 (5.9%) patient; COL2A1 gene mutation related to spondyloepiphyseal dysplasia congenital (SEDC),1 (5.9%) patient.

Conclusions: Genetic tests estimated +11.7% the frequency of ACH, -29.4% the frequency of HCH and identified a diagnosis discrepancy of 17.6% by detecting different pathologies than those suspected.