The molecular basis of human congenital limb malformations Aimée Zuniga * , Rolf Zeller, Simone Probst published online: 26 APR 2012 DOI: 10.1002/wdev.59 Article/wisId-WDEV59.html
Term Brief definition Human syndrome (Example) Gene affected (Examples) Amelia Absence of at least one limb Tetra-amelia: all four limbs missing (OMIM 273395); very rare WNT3 Micromelia or brachymelia Global term for abnormally small and imperfectly developed limbs. See specific terms below Proximal and Long Bone Defects Shoulder girdle/pelvis defects Scapula and clavicle; or pelvic and pubic bones are malformed. Cleidocranial dysplasia (OMIM 119600) RUNX2 Frequency 1:10 6 Ectromelia Long bones are missing or shortened See specific terms below Phocomelia Long bones are shortened or absent in one or several of the extremities. Hands and/or feet are present, but often malformed. The teratogen thalidomide can cause limb phocomelia (Box 1) Hemimelia Shortening or absence of one of the distal long bones (ulna, radius, tibia or fibula). Holt-Oram syndrome (OMIM 142900) TBX5 Frequency 1:10 5 Synostosis Fusion of adjacent bones. Craniosynostosis type 1 (OMIM 123100) TWIST1 Sirenomelia (Symmelia) Legs are fused. Sacra defect with anterior meningocele (OMIM 600145) Unknown Mostly fatal due to kidney malformations Hand and Foot Anomalies Adactyly All digits are absent Unknown Acheiria Missing hands or feet Acheiropody (OMIM 200500); very rare. SHH enhancer (Box 2) Syndactyly Fusion of digits. In ‘osseous syndactylies’ bones are fused. In ‘cutaneous syndactylies’ the soft tissue is affected Cenani-Lenz syndrome (OMIM 212780); rare LRP4 gene or GREM1-FMN1 landscape
Hypodactyly or Oligodactyly Fewer than five digits. Cenani-Lenz syndrome patients can be affected by oligodactyly See above Brachydactyly Digit length shorter than usual. Autosomal-dominant Brachydactyly (BDA), several types IHH (BDA1) BMPR1 , GDF5 (BDA2), ROR2 (BDB1) NOG (BDB2) GDF5 (BDC) HOXD13 (BDD, BDE1) OMIM 112500, 112600, 113000, 611317, 113100, 113200, 113300, 613382 Ectrodactyly/Split -hand and split- foot malformations Deficiency or absence of middle digits resulting in a split autopod. Split-hand and split-foot malformation (SHFM1-6, OMIM 183600, 313350, 246560, 605289, 606708, 225300) DLX5/6 (SHFM1) TP63 (SHFM4) HOXD cluster (SHFM5) WNT10B (SHFM6) Polydactyly: pre- axial, post-axial, central Formation of additional digits. Greig's Cephalopolysyndactyly (OMIM 175700) GLI3 The number of supernumerary digits can vary from one to several. ‘Pre-axial’ refers to extra digits on the side of the thumb and ‘post-axial’ refers to extra digits on the side of the little finger. ‘Central’ polydactylies result in duplications of middle digits. Mutations altering SHH directly or indirectly !
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