Skeletal abnormalities are common features in Aymé‐Gripp syndrome

• Published in: Clinical genetics Vol. 97; no. 2; pp. 362 - 369
• Main Authors: Niceta, Marcello, Barbuti, Domenico, Gupta, Neerja, Ruggiero, Carlos, Tizzano, Eduardo F., Graul‐Neumann, Luitgard, Barresi, Sabina, Nishimura, Gen, Valenzuela, Irene, López‐Grondona, Fermina, Fernandez‐Alvarez, Paula, Leoni, Chiara, Zweier, Christiane, Tzschach, Andreas, Stellacci, Emilia, Del Fattore, Andrea, Dallapiccola, Bruno, Zampino, Giuseppe, Tartaglia, Marco
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.02.2020
• Subjects: Adolescent; Adult; Aymé‐Gripp syndrome; bone defects; Bone dysplasia; Cataract - genetics; Cataract - pathology; Cataracts; Child; Child, Preschool; Facies; Female; Genetic Predisposition to Disease; Growth Disorders - genetics; Growth Disorders - pathology; Hearing loss; Hearing Loss, Sensorineural - genetics; Hearing Loss, Sensorineural - pathology; Hip; Humans; Infant; Intellectual disabilities; Intellectual Disability - genetics; Intellectual Disability - pathology; Long bone; MAF; Male; Missense mutation; Musculoskeletal Abnormalities - genetics; Musculoskeletal Abnormalities - pathology; Mutation, Missense - genetics; Phenotypes; Proto-Oncogene Proteins c-maf - genetics; skeletal dysplasia; Young Adult; bone defects; MAF; Aymé-Gripp syndrome; skeletal dysplasia
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.13651

Aymé‐Gripp syndrome (AYGRPS) is a recognizable condition caused by a restricted spectrum of dominantly acting missense mutations affecting the transcription factor MAF. Major clinical features of AYGRPS include congenital cataracts, sensorineural hearing loss, intellectual disability, and a distinctive flat facial appearance. Skeletal abnormalities have also been observed in affected individuals, even though these features have not been assessed systematically. Expanding the series with four additional patients, here we provide a more accurate delineation of the molecular aspects and clinical phenotype, particularly focusing on the skeletal features characterizing this disorder. Apart from previously reported malar flattening and joint limitations, we document that carpal/tarsal and long bone defects, and hip dysplasia occur in affected subjects more frequently than formerly appreciated. Left panel, A, clustered Aymé‐Gripp syndrome (AYGRPS)‐causing MAF changes within the transactivation domain (TAD): C‐terminal DNA‐binding domain, “extended homology” (EHR), “basic motif” (BR), and leucine‐zipper (LZ) regions are shown. Left panel, B, amino acid alignments of the GSK3 motif among MAF orthologues. The priming Ser70 and four tandemly arranged phosphorylatable serine/threonine residues (Ser66, Thr62, Thr58, and Ser54) within GSK3 recognition region are displayed in black, while affected residues identified in this study are shown in red. Right panel, C, electropherograms of identified MAF variants found in the four affected subjects of this study. Right panel (below): delineation of skeletal findings characterizing AYGRPS (1c‐4f); dental abnormalities (3d), nail dystrophy (3e), and shortening of the fourth metatarsal (4c) are also shown.