Talk:Musculoskeletal System - Limb Abnormalities

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Cite this page: Hill, M.A. (2021, May 14) Embryology Musculoskeletal System - Limb Abnormalities. Retrieved from


A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis

Biomed Res Int. 2019 Sep 15;2019:9652649. doi: 10.1155/2019/9652649. eCollection 2019.

Al-Qattan MM1,2.

1 Professor of Hand Surgery, King Saud University, Riyadh, Saudi Arabia. 2 King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Abstract Embryology of normal web space creation and the genetics of syndactyly in humans and experimental animals are well described in the literature. In this review, the author offers a 3-step pathway of pathogenesis for syndactyly. The first step is initiated either by the overactivation of the WNT canonical pathway or the suppression of the Bone Morphogenetic Protein (BMP) canonical pathway. This leads to an overexpression of Fibroblast Growth Factor 8 (FGF8). The final step is the suppression of retinoic acid in the interdigital mesenchyme leading to suppression of both apoptosis and extracellular matrix (ECM) degradation, resulting in syndactyly. Copyright © 2019 Mohammad M. Al-Qattan.

PMID: 31637260 PMCID: PMC6766129 DOI: 10.1155/2019/9652649

Epidemiology of limb reduction defects as registered in the Medical Birth Registry of Norway, 1970-2016: Population based study

PLoS One. 2019 Jul 17;14(7):e0219930. doi: 10.1371/journal.pone.0219930. eCollection 2019.

Klungsøyr K1,2, Nordtveit TI3, Kaastad TS4,5, Solberg S6, Sletten IN4, Vik AK4,7.

BACKGROUND: Following the Thalidomide disaster, the Medical Birth Registry of Norway (MBRN) was established in 1967, with epidemiological surveillance of congenital anomalies as one main aim. Limb reduction defects (LRD) constitute a rare and heterogeneous anomaly group, where correct registration and classification is important for surveillance and research. We aimed at reviewing and recoding LRD cases in the MBRN using the same classification system for all years, and evaluate time trends, characteristics and risk factors, 1970-2016. METHODS: After reviewing and recoding LRD cases using International Classification of Diseases (ICD), 10th version, for all years, time trends, association with major anomalies, risk factors and infant outcomes were calculated. Generalized linear models for the binomial family with log link gave relative risks (RR) with 95% confidence intervals (CI). Classification of LRD as suggested by European surveillance of congenital anomalies (EUROCAT) was attempted. RESULTS: Overall LRD prevalence, 1970-2016, was 4.4 per 10 000, slightly increasing during 1970-1981, followed by relatively stable rates. There were more defects in upper than lower limbs. Defects in hands/fingers were most common, but unspecific descriptions prevented classification of LRD according to EUROCAT. A majority of cases had associated anomalies, the most common being other limb defects, followed by cardiac defects and anomalies in the nervous and digestive systems. From 1999, 26% of LRD cases were terminated, more than 90% of these had associated major anomalies. Stillbirth, neonatal and infant mortality were higher among infants with LRD, also related to associated anomalies. Pre-gestational diabetes was associated with a more than three times increased risk of offspring total LRD, while no association with maternal epilepsy was found. Taking folate/multivitamin supplements before and/or during pregnancy was associated with lower risk of offspring LRD (adjusted RR 0.7; 95% CI 0.6-0.9), while daily smoking did not significantly increase the risk. CONCLUSION: The MBRN now has information on LRD coded by ICD-10 from 1970, but information is not specific enough to use other recommended classification systems. Collecting radiographic descriptions and/or more details from hospital records would improve the quality of the registry data. Taking folate supplements before/during pregnancy may reduce the risk of offspring LRD. PMID: 31314783 DOI: 10.1371/journal.pone.0219930


A multidisciplinary review of triphalangeal thumb

J Hand Surg Eur Vol. 2018 Oct 14:1753193418803521. doi: 10.1177/1753193418803521. [Epub ahead of print]

Potuijt JWP1, Galjaard RH2, van der Spek PJ3,4, van Nieuwenhoven CA1, Ahituv N5,6, Oberg KC7, Hovius SER1.


Despite being a rare congenital limb anomaly, triphalangeal thumb is a subject of research in various scientific fields, providing new insights in clinical research and evolutionary biology. The findings of triphalangeal thumb can be predictive for other congenital anomalies as part of an underlying syndrome. Furthermore, triphalangeal thumb is still being used as a model in molecular genetics to study gene regulation by long-range regulatory elements. We present a review that summarizes a number of scientifically relevant topics that involve the triphalangeal thumb phenotype. Future initiatives involving multidisciplinary teams collaborating in the field of triphalangeal thumb research can lead to a better understanding of the pathogenesis and molecular mechanisms of this condition as well as other congenital upper limb anomalies. KEYWORDS: Triphalangeal thumb; congenital limb deformities; genetic enhancer elements; hedgehog protein; polydactyly PMID: 30318985 DOI: 10.1177/1753193418803521


Prenatal exposure to environmental factors and congenital limb defects

Birth Defects Res C Embryo Today. 2016 Sep;108(3):243-273. doi: 10.1002/bdrc.21140. Epub 2016 Oct 21.

Alexander PG1, Clark KL1, Tuan RS2.


Limb congenital defects afflict approximately 0.6:1000 live births. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants, represents a major contributing factor to limb defects. Examples of well-recognized limb teratogenic agents include thalidomide, warfarin, valproic acid, misoprostol, and phenytoin. While the mechanism by which these agents cause dymorphogenesis is increasingly clear, prediction of the limb teratogenicity of many thousands of as yet uncharacterized environmental factors (pollutants) remains inexact. This is limited by the insufficiencies of currently available models. Specifically, in vivo approaches using guideline animal models have inherently deficient predictive power due to genomic and anatomic differences that complicate mechanistic comparisons. On the other hand, in vitro two-dimensional (2D) cell cultures, while accessible for cellular and molecular experimentation, do not reflect the three-dimensional (3D) morphogenetic events in vivo nor systemic influences. More robust and accessible models based on human cells that accurately replicate specific processes of embryonic limb development are needed to enhance limb teratogenesis prediction and to permit mechanistic analysis of the adverse outcome pathways. Recent advances in elucidating mechanisms of normal development will aid in the development of process-specific 3D cell cultures within specialized bioreactors to support multicellular microtissues or organoid constructs that will lead to increased understanding of cell functions, cell-to-cell signaling, pathway networks, and mechanisms of toxicity. The promise is prompting researchers to look to such 3D microphysiological systems to help sort out complex and often subtle interactions relevant to developmental malformations that would not be evident by standard 2D cell culture testing. Birth Defects Research (Part C) 108:243-273, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

KEYWORDS: anticonvulsant; cadmium; congenital limb defects; diabetes; environmental factors; ethanol; in vitro toxicity testing; limb development; microphysiological systems; misoprostol; organotypic culture models; phenytoin; prenatal exposure; teratogens; thalidomide; valproic acid; warfarin PMID 27768243 DOI: 10.1002/bdrc.21140


Role of Genetic Factors in the Pathogenesis of Radial Deficiencies in Humans

Curr Genomics. 2015 Aug;16(4):264-78. doi: 10.2174/1389202916666150528000412.

Elmakky A1, Stanghellini I1, Landi A2, Percesepe A1.


Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the congenital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia-absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans. KEYWORDS: Congenital upper limb anomalies; Radial deficiency; Thumb hypoplasia PMID 26962299


Sirenomelia phenotype in bmp7;shh compound mutants: a novel experimental model for studies of caudal body malformations

PLoS One. 2012;7(9):e44962. doi: 10.1371/journal.pone.0044962. Epub 2012 Sep 17.

Garrido-Allepuz C, González-Lamuño D, Ros MA. Source Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-SODERCAN-Universidad de Cantabria, Santander, Spain.


Sirenomelia is a severe congenital malformation of the lower body characterized by the fusion of the legs into a single lower limb. This striking external phenotype consistently associates severe visceral abnormalities, most commonly of the kidneys, intestine, and genitalia that generally make the condition lethal. Although the causes of sirenomelia remain unknown, clinical studies have yielded two major hypotheses: i) a primary defect in the generation of caudal mesoderm, ii) a primary vascular defect that leaves the caudal part of the embryo hypoperfused. Interestingly, Sirenomelia has been shown to have a genetic basis in mice, and although it has been considered a sporadic condition in humans, recently some possible familial cases have been reported. Here, we report that the removal of one or both functional alleles of Shh from the Bmp7-null background leads to a sirenomelia phenotype that faithfully replicates the constellation of external and internal malformations, typical of the human condition. These mutants represent an invaluable model in which we have analyzed the pathogenesis of sirenomelia. We show that the signaling defect predominantly impacts the morphogenesis of the hindgut and the development of the caudal end of the dorsal aortas. The deficient formation of ventral midline structures, including the interlimb mesoderm caudal to the umbilicus, leads to the approximation and merging of the hindlimb fields. Our study provides new insights for the understanding of the mechanisms resulting in caudal body malformations, including sirenomelia.

PMID 23028704

Thumb duplication: concepts and techniques

Clin Orthop Surg. 2012 Mar;4(1):1-17. Epub 2012 Feb 20.

Tonkin MA. Source Department of Hand Surgery and Peripheral Nerve Surgery, University of Sydney, Royal North Shore Hospital, St. Leonards, Australia.


Within the Oberg, Manske, Tonkin (OMT) classification, thumb duplications are a failure of formation and/or differentiation affecting the radial-ulnar axis of the hand plate. The Wassel description of seven types of thumb duplication provides a good structure from which an approach to management is based. The aim of surgical reconstruction is to obtain a stable, mobile thumb of adequate size and appropriate shape. The most common form of reconstruction is removal of the lesser digit and reconstruction of the dominant digit. Surgical techniques address the problems of deviation, instability and lack of size. The disadvantages of the Bilhaut-Cloquet procedure, these being joint stiffness and a nail ridge, may be lesser concerns when reconstruction of one digit will not create a satisfactory thumb of adequate mobility, stability, alignment and size. Complicated problems of triphalangism, triplication, ulnar dimelia and the rare circumstance in which neither of the duplicated thumbs may be adequately reconstructed present specific challenges which demand alternative techniques.

PMID 22379552


A clinical and experimental overview of sirenomelia: insight into the mechanisms of congenital limb malformations

Dis Model Mech. 2011 May;4(3):289-99. Epub 2011 Apr 18.

Garrido-Allepuz C, Haro E, González-Lamuño D, Martínez-Frías ML, Bertocchini F, Ros MA. Source Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-CSIC-SODERCAN, C. Herrera Oria s/n, 39011 Santander, Spain.


Sirenomelia, also known as sirenomelia sequence, is a severe malformation of the lower body characterized by fusion of the legs and a variable combination of visceral abnormalities. The causes of this malformation remain unknown, although the discovery that it can have a genetic basis in mice represents an important step towards the understanding of its pathogenesis. Sirenomelia occurs in mice lacking Cyp26a1, an enzyme that degrades retinoic acid (RA), and in mice that develop with reduced bone morphogenetic protein (Bmp) signaling in the caudal embryonic region. The phenotypes of these mutant mice suggest that sirenomelia in humans is associated with an excess of RA signaling and a deficit in Bmp signaling in the caudal body. Clinical studies of sirenomelia have given rise to two main pathogenic hypotheses. The first hypothesis, based on the aberrant abdominal and umbilical vascular pattern of affected individuals, postulates a primary vascular defect that leaves the caudal part of the embryo hypoperfused. The second hypothesis, based on the overall malformation of the caudal body, postulates a primary defect in the generation of the mesoderm. This review gathers experimental and clinical information on sirenomelia together with the necessary background to understand how deviations from normal development of the caudal part of the embryo might lead to this multisystemic malformation.

PMID 21504909

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (, which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.


Developmental dysplasia of the hip

Lancet. 2007 May 5;369(9572):1541-52.

Dezateux C, Rosendahl K. Source Centre of Epidemiology for Child Health, Institute of Child Health, London, UK.


In its severest form, developmental dysplasia of the hip is one of the most common congenital malformations. The pathophysiology and natural history of the range of morphological and clinical disorders that constitute developmental dysplasia of the hip are poorly understood. Neonatal screening programmes, based on clinical screening examinations, have been established for more than 40 years but their effectiveness remains controversial. Whereas systematic sonographic imaging of newborn and young infants has afforded insights into normal and abnormal hip development in early life, we do not clearly understand the longer-term outcomes of developmental hip dysplasia, its contribution to premature degenerative hip disorders in adult life, and the benefits and harms of newborn screening. High quality studies of the adult outcomes of developmental hip dysplasia and the childhood origins of early degenerative hip disease are needed, as are randomised trials to assess the effectiveness and safety of neonatal screening and early treatment.

PMID 17482986


There are several types of Brachydactyly:

Type OMIM Gene Locus (genetics) Also known as/Description
Type A1, BDA1 112500 IHH BDA1B 5p13.3-p13.2, 2q33-q35 Brachydactyly type A1 or Farabee-type brachydactyly. BDA1 is an autosomal dominant inherited disease. Features include: Brachydactyly, Short or absent phalanges, Extra carpal bones, Hypoplastic or absent ulna and Short metacarpal bones.
Type A2, BDA2 112600 BMPR1B GDF5 20q11.2, 4q23-q24 Brachydactyly type A2, Brachymesophalangy II or Brachydactyly Mohr-Wriedt type. Type A2 is a very rare form of brachydactyly. The phalanges of the index fingers and second toes are shortened.
Type A3, BDA3 112700 Brachydactyly type A3, Brachymesophalangy V or Brachydactyly-Clinodactyly.
Type A4, BDA4 112800 Brachydactyly type A4, Brachymesophalangy II and V or Brachydactyly Temtamy type
Type A5, BDA5 112900 Brachydactyly type A5 nail dysplasia.
Type A6, BDA6 112910 Brachydactyly type A6 or Osebold-Remondini syndrome.
Type A7, BDA7 Brachydactyly type A7 or Brachydactyly Smorgasbord type.[1]
Type B, BDB (or BDB1) 113000 ROR2 9q22 Brachydactyly type B.
Type C, BDC 113100 GDF5 20q11.2 Brachydactyly type C or Brachydactyly Haws type.
Type D, BDD 113200 HOXD13 2q31-q32 Brachydactyly type D.
Type E, BDE 113300 HOXD13 2q31-q32 Brachydactyly type E.
Type B and E 112440 ROR2 HOXD13 9q22, 2q31-q32 Brachydactyly types B and E combined, Ballard syndrome or Pitt-Williams brachydactyly.
Type A1B, BDA1B 607004 5p13.3-p13.2 Brachydactyly type A1, B.

Morphogenesis and dysmorphogenesis of the appendicular skeleton

Shum L, Coleman CM, Hatakeyama Y, Tuan RS. Birth Defects Res C Embryo Today. 2003 May;69(2):102-22. Review.

Cartilage patterning and differentiation are prerequisites for skeletal development through endochondral ossification (EO). Multipotential mesenchymal cells undergo a complex process of cell fate determination to become chondroprogenitors and eventually differentiate into chondrocytes. These developmental processes require the orchestration of cell-cell and cell-matrix interactions. In this review, we present limb bud development as a model for cartilage patterning and differentiation. We summarize the molecular and cellular events and signaling pathways for axis patterning, cell condensation, cell fate determination, digit formation, interdigital apoptosis, EO, and joint formation. The interconnected nature of these pathways underscores the effects of genetic and teratogenic perturbations that result in skeletal birth defects. The topics reviewed also include limb dysmorphogenesis as a result of genetic disorders and environmental factors, including FGFR, GLI3, GDF5/CDMP1, Sox9, and Cbfa1 mutations, as well as thalidomide- and alcohol-induced malformations. Understanding the complex interactions involved in cartilage development and EO provides insight into mechanisms underlying the biology of normal cartilage, congenital disorders, and pathologic adult cartilage.

PMID: 12955856