Department of Paediatric Endocrinology and Diabetes, Bristol Royal Hospital for Children, University Hospitals Bristol and Weston NHS Foundation Trust, Maudlin Street, Bristol, BS2 8BJ, UK.
Department of Clinical Genetics, St Michael's Hospital, University Hospitals Bristol and Weston NHS Foundation Trust, Southwell Street, Bristol, BS2 8EG, UK.
BMC Med Genomics. 2024 Jun 15;17(1):160. doi: 10.1186/s12920-024-01931-6.
Fibrodysplasia Ossificans Progressiva (FOP; OMIM #135100) is an ultrarare genetic disorder characterised by congenital bilateral hallux valgus (CBHV), intermittent soft tissue swellings and progressive heterotopic ossification. We report a three-month-old girl with great toe abnormalities similar to FOP, in whom comprehensive clinical workup and genetic investigations illustrates an alternative diagnosis.
A three-month-old girl presented with CBHV. The antenatal period was unremarkable, she was born by spontaneous vaginal delivery with an uneventful subsequent course, except for maternal concern of her bent toes which received reassurance from several health professionals. Her mother's persisting concerns were explored via the internet and social media leading her to request referral to an expert bone centre for consideration of FOP. On examination, she was thriving, there was no dysmorphism, subcutaneous lumps, skeletal or extra-skeletal deformity except for shortened great toes with lateral deviation of the proximal and distal phalanges. FOP was a feasible diagnosis, for which CBHV is highlighted as an early sign. A cautionary potential diagnosis of FOP was counselled, including advice to defer intramuscular immunisations until genetic results available. Genetic investigation was undertaken through rapid whole genomic sequencing (WGS), with analysis of data from a skeletal dysplasia gene panel, which demonstrated no ACVR1variants. The only finding was a heterozygous variant of unknown significance in BMPR1B (c1460T>A, p.(Val487Asp)), which encodes a bone morphogenic receptor involved in brachydactyly syndromes A1, A2 and D and acromesomelic dysplasia 3 (only the latter being an autosomal recessive condition).
This report highlights that CBHV serves as a vital diagnostic indicator of FOP and affected infants should be considered and investigated for FOP, including precautionary management whilst awaiting genetic studies. The second educational aspect is that CBHV may not represent a generalised skeletal disorder, or one much less significant than FOP. Receptor-ligand BMP and Activins mediated interactions are instrumental in the intricate embryology of the great toe. Recognition of non-FOP conditions caused by alterations in different genes are likely to increase with new genomic technology and large gene panels, enhancing understanding of bone signaling pathways.
纤维性骨发育不良进展性（FOP；OMIM #135100）是一种罕见的遗传性疾病，其特征为先天性双侧大脚趾外翻（CBHV）、间歇性软组织肿胀和进行性异位骨化。我们报告了一名三个月大的女孩，其大脚趾异常与 FOP 相似，全面的临床检查和基因研究提供了另一种诊断。
一名三个月大的女孩表现出 CBHV。产前无异常，经阴道自然分娩，随后过程顺利，仅因母亲担心其脚趾弯曲，经多位健康专家检查后得到安抚。母亲持续关注该问题，通过互联网和社交媒体，导致她请求转介至专业骨中心，考虑 FOP 的可能。体格检查时，患儿发育良好，无畸形，无皮下肿块、骨骼或骨骼外畸形，仅大脚趾短缩，近节和远节趾骨侧向偏斜。FOP 是一种可行的诊断，其中 CBHV 是早期表现。对 FOP 进行了谨慎的潜在诊断，建议在获得基因结果之前，推迟肌内免疫接种。通过快速全基因组测序（WGS）进行基因检测，并分析骨骼发育不良基因面板的数据，未发现 ACVR1 变异。唯一的发现是 BMPR1B 中的杂合性未知意义变异（c1460T>A，p.（Val487Asp）），该基因编码一种参与短指畸形综合征 A1、A2 和 D 以及肢端骨发育不良 3 型（仅后者为常染色体隐性疾病）的骨形态发生受体。
本报告强调 CBHV 是 FOP 的重要诊断指标，应考虑患有 CBHV 的婴儿是否患有 FOP，包括在等待基因研究期间进行预防性管理。第二个教育方面是，CBHV 可能不是一种全身性骨骼疾病，或者比 FOP 轻得多。受体-配体 BMP 和激活素介导的相互作用在大脚趾的复杂胚胎发生中起着重要作用。随着新的基因组技术和大型基因面板的应用，识别不同基因改变引起的非 FOP 疾病的可能性增加，从而增强对骨信号通路的理解。
