Principles of the differential diagnosis of achondroplasia and pseudoachondroplasia

Abstract

BACKGROUND: Achondroplasia and pseudoachondroplasia are hereditary systemic skeletal dysplasias characterized by a certain similarity of clinical manifestations; however, they have different etiopathogenetic mechanisms and confirmation methods for molecular genetic diagnosis. Their common phenotypic features often make differential diagnosis difficult during the clinical examination of patients, planning DNA diagnostics, and appropriate time detection of neurosurgical and orthopedic complications. AIM: This study aimed to identify differential diagnostic criteria for achondroplasia and pseudoachondroplasia and optimize the strategy for their molecular genetic diagnosis. MATERIALS AND METHODS: A comprehensive examination of 76 children from 74 unrelated families aged 1 month to 18 years with phenotypic signs of achondroplasia and pseudoachondroplasia was conducted. To clarify the diagnosis through genealogical and amnestic analysis, clinical and neurological examination data according to the standard method and radiographic data were used. Molecular genetic confirmation of diseases was conducted by searching for hotspot mutations in the FGFR3 gene, assessing the number of GAC repeats located in exon 13 of the COMP gene, and new-generation sequencing of the target panel consisting of 166 genes responsible for hereditary skeletal pathology. RESULTS: Based on a comparative analysis of the specific phenotypic characteristics, the criteria for the differential diagnosis of achondroplasia and pseudoachondroplasia were identified. The leading signs of achondroplasia are disproportionate nanism from birth, macrocrania, and facial dysmorphism, which are not specific to pseudoachondroplasia. Certain radiological features are essential in the differential diagnosis of pseudoachondroplasia, which should be considered when referring to patients for molecular genetic analysis. A deletion of the GAC repeat c.1417_1419del in the COMP gene was identified in 27% of patients with pseudoachondroplasia. Thus, the analyses of these two mutations in FGFR3 and COMP were conducted first. In the absence of target mutations, further diagnostic search should be continued with a target panel consisting of 166 genes responsible for hereditary skeletal pathology or whole-exome sequencing. CONCLUSIONS: The analysis of the clinical, radiological, and molecular genetic characteristics of patients with achondroplasia and pseudoachondroplasia, together with the literature data analysis, made it possible to clarify the differential diagnostic criteria for these diseases and optimize the algorithm for their molecular genetic diagnosis.