Liverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, L8 7SS, UK.
Faculty of Health and Life Sciences, University of Liverpool, Liverpool, L69 7ZB, UK.
BMC Med Genomics. 2024 Sep 6;17(1):226. doi: 10.1186/s12920-024-01999-0.
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.
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).
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.
软骨发育不全症和伴有小颅畸形的下颌面骨发育不全（MFDM）是罕见的单基因显性遗传病，分别由成纤维细胞生长因子受体 3（FGFR3）基因功能获得性变异和伸长因子 Tu GTP 结合结构域包含蛋白 2（EFTUD2）基因功能丧失性变异引起。单一患者中同时存在两种截然不同的孟德尔疾病并不常见，这对单一遗传疾病解释患者症状的传统范式提出了挑战，为诊断和管理开辟了新的途径。
我们报告了一例女性患者，最初因母系遗传致病性 FGFR3 变异而被诊断为软骨发育不全症。由于她的头围和身高明显低于预期的软骨发育不全症范围，她被转介到我们的遗传科。其他特征包括独特的面部特征、明显的语言延迟、传导性听力损失和癫痫。鉴于其表型的复杂性，她被招募到 DDD（发育障碍解析）研究和 10 万基因组计划进行进一步研究。随后确定了一个复杂的 EFTUD2 基因内重排，证实了伴有小颅畸形的下颌面骨发育不全（MFDM）的额外诊断。
本报告首次报道了同一患者软骨发育不全症和伴有小颅畸形的下颌面骨发育不全症的双重分子诊断。该病例强调了遗传诊断的复杂性和单一患者中多种遗传综合征共存的可能性。该病例扩展了我们对双重孟德尔疾病分子基础的理解，并强调了在具有不完全由主要诊断解释的表型特征的患者中考虑双重分子诊断的可能性的重要性。
