Cenani–Lenz syndrome and other related syndactyly disorders due to variants in LRP4, GREM1/FMN1, and APC: Insight into the pathogenesis and the relationship to polyposis through the WNT and BMP antagonistic pathways

• Published in: American journal of medical genetics. Part A Vol. 179; no. 2; pp. 266 - 279
• Main Authors: Al‐Qattan, Mohammad M., Alkuraya, Fowzan S.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.02.2019; Wiley Subscription Services, Inc
• Subjects: Adenomatous polyposis coli; Adenomatous Polyposis Coli Protein - genetics; APC; BMP pathway; Bone morphogenetic proteins; Bone Morphogenetic Proteins - genetics; Cenani–Lenz; Dysostosis; Familial adenomatous polyposis; FMN1; GREM1; Humans; Intercellular Signaling Peptides and Proteins - genetics; LDL-Receptor Related Proteins - genetics; LRP4; Metacarpal; Mutation; Pedigree; Phenotypes; polyposis; Polyposis coli; Splicing; Syndactyly; Syndactyly - genetics; Syndactyly - physiopathology; WNT pathway; Wnt protein; Wnt Signaling Pathway - genetics; GREM1; WNT pathway; APC; Cenani-Lenz; BMP pathway; LRP4; FMN1; polyposis
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.60694

Cenani–Lenz (C–L) syndrome is characterized by oligosyndactyly, metacarpal synostosis, phalangeal disorganization, and other variable facial and systemic features. Most cases are caused by homozygous and compound heterozygous missense and splice mutations of the LRP4 gene. Currently, the syndrome carries one OMIM number (212780). However, C–L syndrome‐like phenotypes as well as other syndactyly disorders with or without metacarpal synostosis/phalangeal disorganization are also known to be associated with specific LRP4 mutations, adenomatous polyposis coli (APC) truncating mutations, genomic rearrangements of the GREM1‐FMN1 locus, as well as FMN1 mutations. Surprisingly, patients with C–L syndrome‐like phenotype caused by APC truncating mutations have no polyposis despite the increased levels of β catenin. The LRP4 and APC proteins act on the WNT (wingless‐type integration site family) canonical pathway, whereas the GREM‐1 and FMN1 proteins act on the bone morphogenetic protein (BMP) pathway. In this review, we discuss the different mutations associated with C–L syndrome, classify its clinical features, review familial adenomatous polyposis caused by truncating APC mutations and compare these mutations to the splicing APC mutation associated with syndactyly, and finally, explore the pathophysiology through a review of the cross talks between the WNT canonical and the BMP antagonistic pathways.