View source for Acheiropodia

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{{Infobox medical condition (new)
| name          = Acheiropodia
| image         = Autorecessive.svg
| caption       = Acheiropodia has an autosomal recessive pattern of [[inheritance]]
| symptoms      = 
| synonyms      = '''Horn-Kolb syndrome''', '''acheiropody''' and '''''aleijadinhos'' (Brazilian type)'''
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| image_size    = 200px
}}

'''Acheiropodia''', also known as Horn Kolb syndrome,<ref name="auto1">{{Cite journal |last1=Temur |first1=Ismail |last2=Ulker |first2=Kahraman |last3=Volkan |first3=Islim |last4=Karaca |first4=Mehmet |last5=Ersoz |first5=Mustafa |last6=Gul |first6=Abdulaziz |last7=Adiguzel |first7=Esat |date=2012 |title=The first case of Horn Kolb Syndrome in Turkey, diagnosed prenatally at the 23rd week of a pregnancy: A very rare and unusual case far from the original geography |url=http://dx.doi.org/10.12659/ajcr.883025 |journal=American Journal of Case Reports |volume=13 |pages=106–108 |doi=10.12659/ajcr.883025 |issn=1941-5923 |pmc=3615972 |pmid=23569502}}</ref> is a genetic condition that affects [[Limb (anatomy)|limb]] development, resulting in shortened arms and legs and absent hands and feet on both sides of the body at birth.<ref name="auto2">{{Cite journal |last1=Freire-Maia |first1=A. |last2=Freire-Maia |first2=N. |last3=Morton |first3=N. E. |last4=Azevêdo |first4=E. S. |last5=Quelce-Salgado |first5=A. |date=1975 |title=Genetics of acheiropodia (the handless and footless families of Brazil). VI. Formal genetic analysis |journal=American Journal of Human Genetics |volume=27 |issue=4 |pages=521–527 |issn=0002-9297 |pmc=1762812 |pmid=1155460}}</ref> Specifically, individuals are born missing the [[epiphysis]] typically found at the end of the [[humerus]] bone of the upper arm, the [[diaphysis]] which makes up the long section of the [[tibia]] bone of the shin, the [[Radius (bone)|radius]] and [[ulna]] bones which make up the lower arm, the [[fibula]] bone of the shin, and all hand and foot bones.<ref name="auto2" /> It was first discovered and is prevalent almost exclusively in [[Brazil]].<ref>{{Cite journal |last1=Freire-Maia |first1=Ademar |last2=Opitz |first2=John M. |date=1981 |title=Historical note: The extraordinary handless and footless families of Brazil – 50 years of acheiropodia |url=https://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320090108 |journal=American Journal of Medical Genetics |language=en |volume=9 |issue=1 |pages=31–41 |doi=10.1002/ajmg.1320090108 |issn=0148-7299 |pmid=7018242|url-access=subscription }}</ref>

== Discovery and prevalence ==

Acheiropodia was first described in [[Brazil]] in 1929 <ref>{{cite journal |last1=Peacock |first1=W. |title=Hereditary absence of hands and feet |journal=Eugenical News |date=1929 |volume=14 |issue=15 |pages=46–47}}</ref> and the variations in expression (the range in severity and type of signs and symptoms experienced by patients), namely the presence or absence of digits on upper limbs or the Bohomeletz bone (a small, elongated bone located at the upper limb tips, parallel to the humerus and suggested to be what would have developed into the [[ulna]]), were further documented in 1930.<ref name="Cook, 1930">{{cite journal |last1=Cook |first1=H. |title=The handless and footless family of Brazil again |journal=Eugenical News |date=1930 |volume=15 |issue=15 |pages=86–87}}</ref> It was noted that the presence of one or more digits on upper limbs was consistently associated with the absence of the Bohomeletz bone, and when the Bohomeletz bone was attached, digits were absent from the residual limbs.<ref name="Cook, 1930"/> Acheiropodia cases have been described in [[Turkey]], [[Argentina]], [[Ireland]], and the United States.<ref>{{cite journal |last1=Temur |first1=I |last2=Ulker |first2=K |last3=Volkan |first3=I |last4=Karaca |first4=M |last5=Ersoz |first5=M |last6=Gul |first6=A |last7=Adiguzel |first7=E |title=The ﬁrst case of Horn Kolb Syndrome in Turkey, diagnosed prenatally at the 23 rd week of a pregnancy: A very rare and unusual case far from the original geography |journal=Am J Case Rep |date=2012 |volume=13 |pages=106–108|doi=10.12659/AJCR.883025 |pmid=23569502 |pmc=3615972 }}</ref><ref name="Ulker et al., 2015">{{cite journal |last1=Ülker |first1=K |last2=Karasu |first2=Y |last3=Bozkurt |first3=M |last4=Gençdal |first4=S |last5=Bozkurt |first5=D. K. |last6=Şahin |first6=L |title=The second case of Horn Kolb Syndrome in the same woman in Turkey, diagnosed prenatally at 16 weeks of pregnancy |journal=Proceedings in Obstetrics and Gynecology |date=2015 |volume=5 |issue=1 |pages=1–6 |doi=10.17077/2154-4751.1282 |doi-access=free }}</ref><ref>{{cite journal |last1=Fraser |first1=G. R. |title=The handless and footless families of Brazil |journal=Lancet |date=1970 |volume=295 |issue=7657 |page=1171|doi=10.1016/S0140-6736(70)91237-7 |pmid=4192115 }}</ref><ref name="Ormazabal et al., 2015">{{cite journal |last1=Ormazabal |first1=M |last2=Vaccari |first2=N |last3=Szulepa |first3=R |last4=Bidondo |first4=M. P. |last5=Barbero |first5=P |last6=Groisman |first6=B |title=Aqueiropodia: primer reporte de caso en Argentina [Acheiropodia: first case report in Argentina] |journal=Archivos Argentinos de Pediatria |date=2015 |volume=113 |issue=5 |pages=e299–e303 |doi=10.5546/aap.2015.e299 |pmid=26294167 |doi-access=free }}</ref><ref name="Acheiropody: a report of two cases">{{cite journal |last1=Kruger |first1=LM |last2=Kumar |first2=A |title=Acheiropody: a report of two cases |journal=J Bone Joint Surg |date=1994 |volume=76A |issue=10 |pages=1557–1560|doi=10.2106/00004623-199410000-00017 |pmid=7929505 }}</ref> It was estimated that there were 3 cases of acheiropodia for every 10 million people.<ref name="auto2"/>

==Genetics==

Acheiropodia results from a change in the [[DNA]] sequence of the ''C7rof2'' gene.<ref name="Ianakiev-2001" /> [[Genes]] code for [[proteins]]. When this altered [[gene]] is [[Transcription (biology)|copied]] for its protein instructions, the resulting [[RNA|instructions]] are [[RNA splicing|processed]] differently from the unaltered [[RNA|instructions]]. This effectively cuts out one of the protein-coding segments called [[exon]] 4, which is needed for the final protein. The absence of this segment causes the [[Translation (biology)|reading of protein instructions]] to [[Nonsense mutation|stop prematurely]].<ref name="Ianakiev-2001" /> This leads to a shorter, non-functional [[protein]].

The ''C7rof2'' gene is the [[homolog|human equivalent]] of the mouse gene ''[[LMBR1]]'', which encodes an essential protein for limb development.<ref name="Ianakiev-2001">{{Cite journal |last1=Ianakiev |first1=P. |last2=van Baren MJ |first2=null |last3=Daly |first3=M. J. |last4=Toledo |first4=S. P. |last5=Cavalcanti |first5=M. G. |last6=Neto |first6=J. C. |last7=Silveira |first7=E. L. |last8=Freire-Maia |first8=A. |last9=Heutink |first9=P. |last10=Kilpatrick |first10=M. W. |last11=Tsipouras |first11=P. |date=2001 |title=Acheiropodia is caused by a genomic deletion in C7orf2, the human orthologue of the Lmbr1 gene |journal=American Journal of Human Genetics |volume=68 |issue=1 |pages=38–45 |doi=10.1086/316955 |issn=0002-9297 |pmc=1234933 |pmid=11090342}}</ref> When there is no functional protein present, limb development does not occur correctly, and individuals are born with acheiropodia.<ref name="Ianakiev-2001" /> However, all individuals have two sets of chromosomes and thus two copies of the ''C7orf2'' gene. The non-functional protein resulting from one altered gene does not interfere with the functional copy of the protein, so acheiropodia only occurs in those who have this rare change in both copies of ''C7orf2''.<ref name="Freire-Maia-1975" /> This makes it an [[Autosomal recessive|autosomal-recessive]] condition, meaning that individuals will only be affected by acheiropodia if both parents carry one copy of the altered gene without experiencing symptoms, resulting in the inheritance of one acheiropodia gene copy from each parent.<ref name="Freire-Maia-1975">{{Cite journal |last1=Freire-Maia |first1=A. |last2=Li |first2=W. H. |last3=Maruyama |first3=T. |date=1975 |title=Genetics of acheiropodia (the handless and footless families of Brazil). VII. Population dynamics |journal=American Journal of Human Genetics |volume=27 |issue=5 |pages=665–675 |issn=0002-9297 |pmc=1762833 |pmid=1163539}}</ref>
[[File:Acheiropodia Mutation.svg|thumb|467x467px|The rare variant in C7rof2 results in the processed RNA transcript missing exon 4. As a result, the [[translation (biology)|conversion]] from RNA to protein is halted early, resulting in a short, nonfunctional protein. Two mutated copies of the gene, leading to two nonfunctional proteins, are required for acheiropodia to develop.|center]]

The ''C7rof2'' DNA sequence is very stable and changes occur rarely, partly explaining the rarity of this condition.<ref name="Freire-Maia-1975" /> Since the rare gene copy is unlikely to be found in parents from two unrelated families, acheiropodia is often caused by [[Consanguine marriage|consanguineous marriages]] in which genetically related individuals have children together.<ref name="Ianakiev-2001" />

==Molecular mechanism==

[[File:Acheiropodia Chromatin Architecture (TAD).jpg|thumb|Model of the LMBR1-Sonic Hedgehog (SHH) topologically associating domain (TAD) impacted in Acheiropodia. The cohesin complex is a protein ring that assists in TAD formation. Removal of three CTCF sites changes the TAD organization, preventing the interaction of the ZRS enhancer with the SHH promoter. This results in decreased expression of SHH in Acheiropodia.<ref name="nature.com">{{cite journal |last1=Ushiki |first1=A |last2=Zhang |first2=Y |last3=Xiong |first3=C |last4=Zhao` |first4=J |last5=Georgakopoulo |first5=I |title=Deletion of CTCF sites in the SHH locus alters enhancer–promoter interactions and leads to acheiropodia |journal=Nature Communications |date=2021 |volume=12 |issue=1 |page=2282 |doi=10.1038/s41467-021-22470-z |pmid=33863876 |bibcode=2021NatCo..12.2282U |pmc=8052326 }}</ref>|500x500px]]In Acheiropodia, 12,000 letters of DNA are removed, eliminating three CCCTC-binding factor (CTCF) sites.<ref name="nature.com"/> [[CTCF]] [[binding site|sites are where CTCF proteins bind.]] CTCF proteins help organize the [[genome]] by forming a [[topologically associating domain]] (TAD).<ref name="nature.com"/> TADs are regions of the [[genome]] where specific [[genes]] and [[regulatory elements]], like [[enhancers]], are grouped together in close physical proximity. The [[genome]] is dynamic and spatial organization influences which proteins are produced in the cell. To produce a protein, genes need the help of other genomic regions to become active. These regulatory regions need to be near genes to enable physical interactions and control of [[gene expression|protein production]]. TADs enable frequent interactions of DNA elements within each group, thus assisting with regulating [[gene expression]], an essential developmental process. When the three [[CTCF]] sites are present, they help an [[Enhancer (genetics)|enhancer]] called ZRS (zone of polarizing activity regulatory sequence), which is found in intron 5 of the ''[[LMBR1]]'' gene, interact with the [[Sonic Hedgehog]] (SHH) [[Promoter (genetics)|promoter]].<ref name="nature.com"/> SHH is an important protein in limb development.<ref name="doi.org">{{cite journal |last1=Tickle |first1=C |last2=Barker |first2=H |title=The Sonic hedgehog gradient in the developing limb |journal=WIREs Developmental Biology |date=2013 |volume=12 |issue=1 |pages=275–290 |doi=10.1002/wdev.70 |pmid=24009037 |url=https://doi.org/10.1002/wdev.70.|url-access=subscription }}</ref> When the ZRS [[Enhancer (genetics)|enhancer]] can interact with the SHH [[Promoter (genetics)|promoter]], there is increased expression of the [[SHH protein]]. However, in the case of acheiropodia, the 3 [[CTCF]] sites are missing, which prevents ZRS from interacting with the SHH promoter.<ref name="nature.com"/> This results in decreased SHH protein production for [[limb development]].<ref name="doi.org"/>

==Diagnosis==
The rarity and subsequent lack of information on acheiropodia makes prenatal diagnosis difficult. Diagnosis depends on prenatal ultrasound screening, with a failure to visualize bones at the ends of fetal limbs.<ref name="auto1" /> Due to [[Expressivity (genetics)|variable expressivity]] (range in severity and types of signs and symptoms experienced by patients) of the C7rof2 gene, acheiropodia presents differently among affected individuals, adding to the difficulty of diagnosis.<ref name="auto4">{{Cite journal |last1=Grimaldi |first1=Angela |last2=Masiero |first2=D. |last3=Richieri-Costa |first3=A. |last4=Freire-Maia |first4=A. |last5=Opitz |first5=J. M. |date=1983 |title=Variable expressivity of the acheiropodia gene |url=https://onlinelibrary.wiley.com/doi/10.1002/ajmg.1320160420 |journal=American Journal of Medical Genetics |language=en |volume=16 |issue=4 |pages=631–634 |doi=10.1002/ajmg.1320160420 |issn=0148-7299 |pmid=6660253|url-access=subscription |hdl=11449/33884 |hdl-access=free }}</ref> Fingers are sometimes present, and a small bone at the tip of the shortened limb (the Bohomoletz bone) may or may not be present.<ref name="auto4" />

Acheiropodia has been diagnosed at as early as 16 weeks post-conception,<ref>{{Cite journal |last1=Ülker |first1=Kahraman |last2=Karasu |first2=Yetkin |last3=Bozkurt |first3=Murat |last4=Gençdal |first4=Servet |last5=Bozkurt |first5=Duygu Kara |last6=Şahin |first6=Levent |date=2015 |title=The second case of Horn Kolb Syndrome in the same woman in Turkey, diagnosed prenatally at 16 weeks of pregnancy |url=https://pubs.lib.uiowa.edu/pog/article/id/3567/ |journal=Proceedings in Obstetrics and Gynecology |language=en |volume=5 |issue=1 |pages=1–6 |doi=10.17077/2154-4751.1282 |issn=2154-4751 |doi-access=free}}</ref> although research on similar conditions suggests it may be diagnosed even earlier.<ref>{{Cite journal |last1=Sharony |first1=Reuven |last2=Browne |first2=Charlie |last3=Lachman |first3=Ralph S. |last4=Rimoin |first4=David L. |date=1993-09-01 |title=Prenatal diagnosis of the skeletal dysplasias |url=https://dx.doi.org/10.1016/0002-9378%2893%2990641-U |journal=American Journal of Obstetrics and Gynecology |volume=169 |issue=3 |pages=668–675 |doi=10.1016/0002-9378(93)90641-U |issn=0002-9378 |pmid=8372878|url-access=subscription }}</ref> If ultrasound screening indicates possible acheiropodia, further (more invasive) testing may be performed,<ref name="auto3">{{Cite journal |last1=Rajala |first1=Katri |last2=Kasanen |first2=Ellamaija |last3=Toiviainen-Salo |first3=Sanna |last4=Valta |first4=Helena |last5=Mäkitie |first5=Outi |last6=Stefanovic |first6=Vedran |last7=Tanner |first7=Laura |date=2022 |title=Genetic spectrum of prenatally diagnosed skeletal dysplasias in a Finnish patient cohort |journal=Prenatal Diagnosis |language=en |volume=42 |issue=12 |pages=1525–1537 |doi=10.1002/pd.6186 |issn=0197-3851 |pmc=9796183 |pmid=35611473}}</ref> including genetic analysis of either an [[Amniocentesis|amniotic fluid sample]] or placenta ([[Chorionic villus sampling|chorionic villus]]) sample to confirm diagnosis.<ref name="auto3" /><ref>{{Cite journal |last1=Brambati |first1=Bruno |last2=Tului |first2=Lucia |date=2005 |title=Chorionic villus sampling and amniocentesis |url=https://journals.lww.com/co-obgyn/abstract/2005/04000/chorionic_villus_sampling_and_amniocentesis.16.aspx |journal=Current Opinion in Obstetrics and Gynecology |language=en-US |volume=17 |issue=2 |pages=197–201 |doi=10.1097/01.gco.0000162191.22091.e9 |issn=1040-872X |pmid=15758614 |s2cid=25539327|url-access=subscription }}</ref> In the case of fetal death or termination, autopsy findings may conclude in a diagnosis.<ref name="auto3" />

== Treatment ==
Even with early prenatal diagnosis, due to its genetic basis acheiropodia cannot currently be prevented or cured. However, once a child is born with acheiropodia, [[Prosthesis|prosthetics]] could improve their quality of life.<ref name="auto">{{Cite journal |last1=Mano |first1=Hiroshi |last2=Fujiwara |first2=Sayaka |last3=Takamura |first3=Kazuyuki |last4=Kitoh |first4=Hiroshi |last5=Takayama |first5=Shinichiro |last6=Ogata |first6=Tsutomu |last7=Haga |first7=Nobuhiko |date=2021-07-01 |title=Treatment approaches for congenital transverse limb deficiency: Data analysis from an epidemiological national survey in Japan |url=https://www.sciencedirect.com/science/article/pii/S0949265820301470 |journal=Journal of Orthopaedic Science |volume=26 |issue=4 |pages=650–654 |doi=10.1016/j.jos.2020.05.008 |issn=0949-2658 |pmid=32600906 |s2cid=220268893|url-access=subscription }}</ref> Surgery may be considered on a case-by-case basis to optimize prosthetic fitting.<ref name="auto" /> Prosthetic fitting should occur before 2 years of age to minimize the risk of rejection.<ref name="auto" /> Ideally, fitting should begin around the 6-9 month mark, when healthy infants typically begin using their hands and feet to stand and handle objects.<ref name="auto" /> Even without prosthetics, many children with limb loss learn to functionally use their residual limbs and may prefer not to use [[prostheses]] so that they can maintain [[proprioception]] (i.e. sense of the body's position and motion) and [[sensory feedback]] that would otherwise be reduced.<ref>{{Cite journal |last1=Yigiter |first1=K. |last2=Ulger |first2=O. |last3=Sener |first3=G. |last4=Akdogan |first4=S. |last5=Erbahçeci |first5=F. |last6=Bayar |first6=K. |date=2005 |title=Demography and function of children with limb loss |journal=Prosthetics and Orthotics International |volume=29 |issue=2 |pages=131–138 |doi=10.1080/03093640500199703 |issn=0309-3646 |pmid=16281722 |hdl=11655/20901 |s2cid=42037061|hdl-access=free }}</ref> Some children may adapt with compensatory skills that are more effective than [[prostheses]].<ref name="Acheiropody: a report of two cases"/> A multidisciplinary approach may best treat the medical, psychological, and developmental challenges that may occur in infants missing all four limbs.<ref>{{Cite journal |last1=Lowe |first1=Kevin G. |last2=Boyce |first2=Joanne M. |date=2004 |title=Rehabilitation of a child with meningococcal septicemia and quadrilateral limb loss: a case report |journal=Archives of Physical Medicine and Rehabilitation |volume=85 |issue=8 |pages=1354–1357 |doi=10.1016/j.apmr.2003.09.030 |issn=0003-9993 |pmid=15295765}}</ref>

==Challenges with studying==

Acheiropodia has proven to be challenging for researchers to study. Mice often serve as a model system to study human disease due to their similar physiology and genetics. However, it was previously observed that when the 12,000 letters of DNA in the mouse equivalent of the ''C7rof2'' human gene were removed, limbs developed normally.<ref name="nature.com"/> The discrepancy in whether acheiropodia was present is likely due to differences in chromosomal interaction regulation, influenced by the location and orientation of the [[CTCF]] sites, among other factors, which may or may not be conserved between mice and humans.

Additionally, given the rarity of the condition there is a limited pool of affected patients who could participate in future [[research]]. The [[ethical]] implications with studying a gene expressed early in embryonic development, like the SHH gene, means that it can be difficult to obtain tissues for analysis.

==References==
{{reflist}}

== External links ==
* [http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=931 Overview] at [[Orphanet]]
* [http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1378047&blobtype=pdf PDF of Am. J. of Human Genetics article]{{dead link|date=July 2025|bot=medic}}{{cbignore|bot=medic}}
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|  OMIM           = 200500
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{{Congenital malformations and deformations of musculoskeletal system}}

[[Category:Congenital disorders of musculoskeletal system]]
[[Category:Autosomal recessive disorders]]
[[Category:Rare diseases]]
[[Category:Congenital amputations]]