Clinical trials in skeletal dysplasia: a paradigm for treating rare diseases.

BACKGROUND: Genetic skeletal dysplasia conditions (GSDs) account for 5% of all birth defects. Until recently, targeted treatments were only available for select few conditions; 1 however, opportunities arising from developments in molecular diagnostic technologies are now leading to unparalleled therapeutic advances. This review explores current GSD clinical trials, their challenges and the hopes for the future. SOURCES OF DATA: A systematic literature search of relevant original articles, reviews and meta-analyses restricted to English was conducted using PubMed up to February 2020 regarding emerging GSD therapies. AREAS OF AGREEMENT: We discuss current clinical trials for in achondroplasia, osteopetrosis, osteogenesis imperfecta, hypophosphataemic rickets, hypophosphatasia and fibrous ossificans progressiva. AREAS OF CONTROVERSY: We explore challenges in GSD drug development from clinician input, cost-effectiveness and evidenced-based practice. GROWING POINTS: We explore opportunities brought by earlier diagnosis, its treatment impact and the challenges of gene editing. AREAS TIMELY FOR DEVELOPING RESEARCH: We horizon scan for future clinical trials.

Cowden syndrome: new clinical features in a large family; joint hyperextensibility, dental abnormalities and gingival enlargement.

A 4-year-old boy presented with his mother to genetics in the 1980s, with a family history (FH) of macrocephaly and intellectual disability (ID). He remained undiagnosed until his mother developed multiple cancers and was diagnosed with Cowden syndrome (CS) in 2017, a rare, multisystem cancer predisposition syndrome. CS was then confirmed in multiple family members. Clinical examination revealed potentially novel features; gingival enlargement, dental abnormalities and joint hyperextensibility. These features could contribute to revised PTEN hamartoma tumour syndrome, National Comprehensive Cancer Network, minor diagnostic criteria. The paediatric CS phenotype is still emerging and features expressed in this family during childhood could potentially aid paediatric diagnosis. This case reminds clinicians to seek genetic input for PTEN testing when macrocephaly is identified alongside, a personal or FH of ID, early-onset tumours (especially breast, bowel or thyroid) or multiple tumours. Thus detailed FH is pivotal to earlier CS diagnosis and improved patient outcomes.