Journal Article

Dual diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly

Baker, Eleanor, Canham, Natalie, Kershaw, Christopher, McCarthy, Emma, Parks, Chris, Lyulcheva-Bennett, Ekaterina, Bennett, Daimark, Higgs, Jenny, Hennigan, Dawn, Gillies, Stuart

2024

Overview

Background Achondroplasia and mandibulofacial dysostosis with microcephaly (MFDM) are rare monogenic, dominant disorders, caused by gain-of-function fibroblast growth factor receptor 3 ( FGFR3 ) gene variants and loss-of-function elongation factor Tu GTP binding domain-containing 2 ( EFTUD2 ) gene variants, respectively. The coexistence of two distinct Mendelian disorders in a single individual is uncommon and challenges the traditional paradigm of a single genetic disorder explaining a patient’s symptoms, opening new avenues for diagnosis and management. Case Presentation We present a case of a female patient initially diagnosed with achondroplasia due to a maternally inherited pathogenic FGFR3 variant. She was referred to our genetic department due to her unusually small head circumference and short stature, which were both significantly below the expected range for achondroplasia. Additional features included distinctive facial characteristics, significant speech delay, conductive hearing loss, and epilepsy. Given the complexity of her phenotype, she was recruited to the DDD (Deciphering Developmental Disorders) study and the 100,000 Genomes project for further investigation. Subsequent identification of a complex EFTUD2 intragenic rearrangement confirmed an additional diagnosis of mandibulofacial dysostosis with microcephaly (MFDM). Conclusion This report presents the first case of a dual molecular diagnosis of achondroplasia and mandibulofacial dysostosis with microcephaly in the same patient. This case underscores the complexity of genetic diagnoses and the potential for coexistence of multiple genetic syndromes in a single patient. This case expands our understanding of the molecular basis of dual Mendelian disorders and highlights the importance of considering the possibility of dual molecular diagnoses in patients with phenotypic features that are not fully accounted for by their primary diagnosis.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Achondroplasia / Achondroplasia - complications / Achondroplasia - genetics / Biomedical and Life Sciences / Biomedicine / Birth defects / Blended phenotype / Case Report / Case studies / Coexistence / Comorbidity / Convulsions & seizures / Craniofacial dysostosis / Deep phenotyping / Developmental disabilities / Diagnosis / DNA sequencing / Dual molecular diagnosis / Dysostosis / Ears & hearing / Elongation factor EF-Tu / Epilepsy / Female / Fibroblast growth factor receptor 3 / Fibroblast growth factor receptors / Fibroblast growth factors / Gene Expression / Genes / Genetic disorders / Genetic testing / Genomes / Genomics / Genotype & phenotype / Health aspects / Hearing loss / Human Genetics / Humans / Intellectual disabilities / Learning disabilities / Mandibulofacial Dysostosis - genetics / Mandibulofacial dysostosis with microcephaly / Medical genetics / Medical research / Medicine, Experimental / Microarrays / Microcephaly / Microcephaly - complications / Microcephaly - diagnosis / Microcephaly - genetics / Microencephaly / Nucleotide sequencing / Peptide Elongation Factors - genetics / Phenotype / Phenotypes / Physiological aspects / Receptor, Fibroblast Growth Factor, Type 3 - genetics / Ribonucleoprotein, U5 Small Nuclear - genetics / Whole genome sequencing