What is Tarsal Carpal Coalition Syndrome (TCC)?
TCC is a rare (1/1 000 000), autosomal dominant genetic condition characterized by progressive fusion of the bones in the wrists (carpal) and ankles (tarsal). Fusion may also occur in the bones that make up the fingers and toes, as well as the elbow. [1] The condition is caused by a mutation in NOG, the gene that encodes for the protein known as noggin. Noggin is involved in various processes responsible for the formation of nerve tissue, muscles, and bones. [2] TCC is a member of a family of diseases known as NOG-related symphalangism spectrum disorder (NOG-SSD) [3]. As a result, it is sometimes also referred to by this broader diagnostic term. |
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TCC Symptoms
In some cases, the symptoms of TCC can be apparent at or before birth. Deformities of the hands and feet may be visible in the womb, and newborns with TCC may exhibit reduced range of motion in the fingers, toes, elbows, and ankles. Shortening of the fingers and toes may also occur. [1]
In adults, symptoms are often more severe than those observed in infants as the disease will have had more time to progress. Early signs of TCC include worsening stiffness, pain, and immobility in affected joints. Patients may have an abnormal gait and/or pain when walking. As the disease progresses and fusion continues, deformities of the hands and feet may manifest. Such deformities include flat feet, inward or outward twisting of the feet, shortening of the fingers or toes, abnormal curvature of the fingers, or partial to complete fusion of the fingers and/or toes. Adults with TCC may have a history of delayed fine and gross motor skill development. [1]
In adults, symptoms are often more severe than those observed in infants as the disease will have had more time to progress. Early signs of TCC include worsening stiffness, pain, and immobility in affected joints. Patients may have an abnormal gait and/or pain when walking. As the disease progresses and fusion continues, deformities of the hands and feet may manifest. Such deformities include flat feet, inward or outward twisting of the feet, shortening of the fingers or toes, abnormal curvature of the fingers, or partial to complete fusion of the fingers and/or toes. Adults with TCC may have a history of delayed fine and gross motor skill development. [1]
Images courtesy of Lau GTY [4]
Diagnosis and Treatment
Diagnosis is a two-step process. First, some kind of imaging scan will show the characteristic bone fusion, joint deformity, and shortening of the fingers and toes. Notably, in children under 8, the bones may not have formed enough for bone fusion to show up in x-rays. Instead, cartilage fusion will cause any symptoms they complain of. Finally, genetic testing will show if a pathogenic variant of NOG is present. [1]
There is no cure for TCC. The main goals of most treatment plans are to 1) control pain and 2) preserve joint function. These goals can be accomplished in a variety of ways, including physical therapy, occupational therapy, and regular surgery aimed at reshaping the bone or tissue to improve function. [1]
There is no cure for TCC. The main goals of most treatment plans are to 1) control pain and 2) preserve joint function. These goals can be accomplished in a variety of ways, including physical therapy, occupational therapy, and regular surgery aimed at reshaping the bone or tissue to improve function. [1]
What is NOG-SSD?
NOG-SSD is a broad diagnostic term for a category of diseases all caused by mutations in NOG. These disorders include proximal symphalangism (SYM1), multiple synostoses syndrome 1 (SYNS1), stapes ankylosis with broad thumbs and toes (SABTT), brachydactyly type B2 (BDB2), and TCC. These disorders are all broadly characterized by joint fusion, however there are some differences in other symptoms a patient presents with. For example, SYM1, SYNS1, and SABTT are characterized by hearing loss, but TCC does not typically include this symptom. [3] Some disorders can even be caused by the same mutation in NOG. [7] Due to the similarities in mutations and symptoms, this family of disorders has been reclassified as one broad diagnostic term, NOG-related-symphalangism spectrum disorder (NOG-SSD).
Noggin Function
It is unknown exactly how mutations in NOG cause NOG-SSD. Under normal conditions, NOG is secreted as a homodimer and is maintained at the cell surface. [8] This complex can bind to and inhibit bone morphogenetic proteins (BMPs), specifically to BMP-4 and BMP-7. BMPs are involved in the development of bone and other tissues. [2] Mutations in NOG impair its ability to dimerize, which has been shown to cause NOG-SSD. [9] However, the mechanism by which NOG causes NOG-SSD is unknown. Certain mutations in NOG can cause a wide array of NOG-SSD symptoms. Differences in symptoms could be caused by epistatic modifiers. [4][7] |
References:
[1] Tarsal Carpal Coalition Syndrome - Symptoms, Causes, Treatment | NORD. rarediseases.org. https://rarediseases.org/rare-diseases/254208/
[2] NOG gene: MedlinePlus Genetics. medlineplus.gov. https://medlineplus.gov/genetics/gene/nog/
[3] Potti TA, Petty EM, Lesperance MM. A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD). Hum Mutat. 2011 Aug;32(8):877-86. doi: 10.1002/humu.21515. Epub 2011 Jun 21. PMID: 21538686.
[4] Lau GTY, Athalye-Jape G, Amery N. Tarsal-carpal coalition syndrome: importance of early diagnosis. BMJ Case Rep. 2019 Jun 6;12(6):e229391. doi: 10.1136/bcr-2019-229391. PMID: 31175114; PMCID: PMC6557331.
[5] https://radiopaedia.org/cases/normal-hand-radiograph?lang=us
[6] Berg, Ari R. MD, MBA; Pletcher, Beth A. MD; Edobor-Osula, O. Folorunsho MD, MPH. Natural Progression and Symptomatic Management of Tarsal-Carpal Coalition Syndrome: A Case Report. JBJS Case Connector 11(4):e20.00964, October-December 2021. | DOI: 10.2106/JBJS.CC.20.00964
[7] Mary E. Dixon, Peter Armstrong, David B. Stevens, Mike Bamshad, Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism, Genetics in Medicine, Volume 3, Issue 5, 2001, Pages 349-353, ISSN 1098-3600, https://doi.org/10.1097/00125817-200109000-00004.
[8] Groppe, J., Greenwald, J., Wiater, E. et al. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420, 636–642 (2002). https://doi.org/10.1038/nature01245
[9] Pang X, Wang Z, Chai Y, Chen H, Li L, Sun L, Jia H, Wu H, Yang T. A Novel Missense Mutation of NOG Interferes With the Dimerization of NOG and Causes Proximal Symphalangism Syndrome in a Chinese Family. Ann Otol Rhinol Laryngol. 2015 Sep;124(9):745-51. doi: 10.1177/0003489415582257. Epub 2015 Apr 17. PMID: 25888563.
[10] Ahmed, S., Metpally, R., Sangadala, S., & Reddy, B.V. (2009). Computational Design of Inhibitory Agents of BMP-Noggin Interaction to Promote Osteogenesis. World Academy of Science, Engineering and Technology, International Journal of Medical, Health, Biomedical, Bioengineering and Pharmaceutical Engineering, 3, 329-333.
[2] NOG gene: MedlinePlus Genetics. medlineplus.gov. https://medlineplus.gov/genetics/gene/nog/
[3] Potti TA, Petty EM, Lesperance MM. A comprehensive review of reported heritable noggin-associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term: NOG-related-symphalangism spectrum disorder (NOG-SSD). Hum Mutat. 2011 Aug;32(8):877-86. doi: 10.1002/humu.21515. Epub 2011 Jun 21. PMID: 21538686.
[4] Lau GTY, Athalye-Jape G, Amery N. Tarsal-carpal coalition syndrome: importance of early diagnosis. BMJ Case Rep. 2019 Jun 6;12(6):e229391. doi: 10.1136/bcr-2019-229391. PMID: 31175114; PMCID: PMC6557331.
[5] https://radiopaedia.org/cases/normal-hand-radiograph?lang=us
[6] Berg, Ari R. MD, MBA; Pletcher, Beth A. MD; Edobor-Osula, O. Folorunsho MD, MPH. Natural Progression and Symptomatic Management of Tarsal-Carpal Coalition Syndrome: A Case Report. JBJS Case Connector 11(4):e20.00964, October-December 2021. | DOI: 10.2106/JBJS.CC.20.00964
[7] Mary E. Dixon, Peter Armstrong, David B. Stevens, Mike Bamshad, Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism, Genetics in Medicine, Volume 3, Issue 5, 2001, Pages 349-353, ISSN 1098-3600, https://doi.org/10.1097/00125817-200109000-00004.
[8] Groppe, J., Greenwald, J., Wiater, E. et al. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420, 636–642 (2002). https://doi.org/10.1038/nature01245
[9] Pang X, Wang Z, Chai Y, Chen H, Li L, Sun L, Jia H, Wu H, Yang T. A Novel Missense Mutation of NOG Interferes With the Dimerization of NOG and Causes Proximal Symphalangism Syndrome in a Chinese Family. Ann Otol Rhinol Laryngol. 2015 Sep;124(9):745-51. doi: 10.1177/0003489415582257. Epub 2015 Apr 17. PMID: 25888563.
[10] Ahmed, S., Metpally, R., Sangadala, S., & Reddy, B.V. (2009). Computational Design of Inhibitory Agents of BMP-Noggin Interaction to Promote Osteogenesis. World Academy of Science, Engineering and Technology, International Journal of Medical, Health, Biomedical, Bioengineering and Pharmaceutical Engineering, 3, 329-333.