Al-Awadi-Raas-Rothschild (limb/pelvis/uterus-hypoplasia/aplasia) syndrome and WNT7A mutations: Genetic homogeneity and nosological delineation

• Published in: American journal of medical genetics. Part A 2011-02, Vol.155A (2), p.332-336
• Main Authors: Garavelli, Livia, Wischmeijer, Anita, Rosato, Simonetta, Gelmini, Chiara, Reverberi, Sandro, Sassi, Silvia, Ferrari, Adriano, Mari, Francesca, Zabel, Bernhard, Lausch, Ekkehart, Unger, Sheila, Superti-Furga, Andrea
• Format: Article
• Language: English
• Subjects: Abnormalities, Multiple - classification; Abnormalities, Multiple - diagnosis; Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Amino Acid Sequence; Aplasia; autosomal recessive; Base Sequence; Biological and medical sciences; Clinical aspects; Diagnosis, Differential; Female; Foot Deformities, Congenital - diagnosis; Foot Deformities, Congenital - genetics; Foot Deformities, Congenital - pathology; Hand Deformities, Congenital - diagnosis; Hand Deformities, Congenital - genetics; Hand Deformities, Congenital - pathology; Humans; Hypoplasia; Infant; limb deficiency; Limb Deformities, Congenital - pathology; Limb malformations; Limbs; Male; Medical genetics; Medical sciences; Molecular Sequence Data; Mutation; Mutation, Missense; Pelvis; Pelvis - abnormalities; Phenotype; Phocomelia; Sequence Analysis, DNA; Syndrome; Uterus - abnormalities; Wnt Proteins - genetics; WNT7A
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.33793

The Al‐Awadi–Raas‐Rothschild syndrome (AARRS; OMIM 276820) and the Fuhrmann syndrome (FS; OMIM 228930) are distinct limb malformation disorders comprising different degrees of limb aplasia or hypoplasia. In 2006, Woods et al. found different recessive WNT7A mutations in one family segregating the AARRS phenotype and in a second family with FS. To explain the common genetic basis for the two clinically distinct disorders, functional studies were done showing that partial loss of WNT7A function resulted in FS, while complete loss of WNT7A function resulted in the more severe phenotype of AARRS. In spite of the elucidation of the molecular basis of AARRS, there remains to this day considerable diagnostic confusion that has culminated in the lumping of Schinzel phocomelia syndrome with AARRS; however, this phocomelic limb defect is quite different in its clinical aspect and pathogenesis from the limb findings of AARRS. Here, we report on a child with the AARRS phenotype and homozygosity for a non‐conservative E72K mutation in WNT7A, underline the homogeneity of the WNT7A‐associated AARRS phenotype, and propose differential diagnostic criteria for the AARRS reflecting the roles of WNT7A in limb development. © 2010 Wiley‐Liss, Inc.