A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD)

• Published in: Human mutation Vol. 32; no. 8; pp. 877 - 886
• Main Authors: Potti, Tommy A., Petty, Elizabeth M., Lesperance, Marci M.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-08-2011; Hindawi Limited
• Subjects: Ankylosis; Brachydactyly; Brachydactyly - diagnosis; Brachydactyly - genetics; Brachydactyly - metabolism; Carpal Bones - abnormalities; Carpal Bones - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cartilage; Databases, Genetic; Dysostosis; Foot Deformities, Congenital - diagnosis; Foot Deformities, Congenital - genetics; Foot Deformities, Congenital - metabolism; Hand; Hand Deformities, Congenital - diagnosis; Hand Deformities, Congenital - genetics; Hand Deformities, Congenital - metabolism; Hearing loss; Hearing Loss - diagnosis; Hearing Loss - genetics; Hearing Loss - metabolism; Humans; Joints; Mutation; Mutation - genetics; NOG; NOG gene; noggin; Noggin protein; Nose; Phenotype; Polymorphism, Genetic; proximal symphalangism; Reviews; Signal transduction; Stapes - abnormalities; stapes ankylosis; Symphalangia; Syndrome; Synostosis - diagnosis; Synostosis - genetics; Synostosis - metabolism; Tarsal Bones - abnormalities; Tarsal Bones - metabolism
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.21515

The NOG gene encodes noggin, a secreted polypeptide that is important for regulating multiple signaling pathways during human development, particularly in cartilage and bone. The hallmark of NOG‐related syndromes is proximal symphalangism, defined by abnormal fusion of the proximal interphalangeal joints of the hands and feet. Many additional features secondary to NOG mutations are commonly but inconsistently observed, including a characteristic facies with a hemicylindrical nose, congenital conductive hearing loss due to stapes fixation, and hyperopia. The variable clinical presentations led to the designation of five different autosomal dominant syndromes, all subsequently found to have resulted from NOG mutations. These include (1) proximal symphalangism; (2) multiple synostoses syndrome 1; (3) stapes ankylosis with broad thumbs and toes; (4) tarsal‐carpal coalition syndrome; and (5) brachydactyly type B2. Herein, we review the phenotypic features associated with mutations in the NOG gene, demonstrating the overlapping characteristics of these syndromes. Due to the variable phenotypic spectrum within families and among families with the same mutation, we propose a unifying term, NOG‐related symphalangism spectrum disorder (NOG‐SSD), to aid in the clinical recognition and evaluation of all affected individuals with these phenotypes. These NOG gene variants are available in a new locus‐specific database (https://NOG.lovd.nl).Hum Mutat 32:1–10, 2011. © 2011 Wiley‐Liss, Inc.