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| Acheiropodia | |
|---|---|
| Other names | Horn-Kolb syndrome,acheiropody andaleijadinhos (Brazilian type) |
 | |
| Acheiropodia has an autosomal recessive pattern ofinheritance | |
| Specialty | Medical genetics  |
Acheiropodia, also known as Horn Kolb syndrome,[1] is a genetic condition that affectslimb development, resulting in shortened arms and legs and absent hands and feet on both sides of the body at birth.[2] Specifically, individuals are born missing theepiphysis typically found at the end of thehumerus bone of the upper arm, thediaphysis which makes up the long section of thetibia bone of the shin, theradius andulna bones which make up the lower arm, thefibula bone of the shin, and all hand and foot bones.[2] It was first discovered and is prevalent almost exclusively inBrazil.[3]
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Acheiropodia was first described inBrazil in 1929[4] 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 theulna), were further documented in 1930.[5] 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.[5] Acheiropodia cases have been described inTurkey,Argentina,Ireland, and the United States.[6][7][8][9][10] It was estimated that there were 3 cases of acheiropodia for every 10 million people.[2]
Acheiropodia results from a change in theDNA sequence of theC7rof2 gene.[11]Genes code forproteins. When this alteredgene iscopied for its protein instructions, the resultinginstructions areprocessed differently from the unalteredinstructions. This effectively cuts out one of the protein-coding segments calledexon 4, which is needed for the final protein. The absence of this segment causes thereading of protein instructions tostop prematurely.[11] This leads to a shorter, non-functionalprotein.
TheC7rof2 gene is thehuman equivalent of the mouse geneLMBR1, which encodes an essential protein for limb development.[11] When there is no functional protein present, limb development does not occur correctly, and individuals are born with acheiropodia.[11] However, all individuals have two sets of chromosomes and thus two copies of theC7orf2 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 ofC7orf2.[12] This makes it anautosomal-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.[12]
TheC7rof2 DNA sequence is very stable and changes occur rarely, partly explaining the rarity of this condition.[12] Since the rare gene copy is unlikely to be found in parents from two unrelated families, acheiropodia is often caused byconsanguineous marriages in which genetically related individuals have children together.[11]
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In Acheiropodia, 12,000 letters of DNA are removed, eliminating three CCCTC-binding factor (CTCF) sites.[13]CTCFsites are where CTCF proteins bind. CTCF proteins help organize thegenome by forming atopologically associating domain (TAD).[13] TADs are regions of thegenome where specificgenes andregulatory elements, likeenhancers, are grouped together in close physical proximity. Thegenome 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 ofprotein production. TADs enable frequent interactions of DNA elements within each group, thus assisting with regulatinggene expression, an essential developmental process. When the threeCTCF sites are present, they help anenhancer called ZRS (zone of polarizing activity regulatory sequence), which is found in intron 5 of theLMBR1 gene, interact with theSonic Hedgehog (SHH)promoter.[13] SHH is an important protein in limb development.[14] When the ZRSenhancer can interact with the SHHpromoter, there is increased expression of theSHH protein. However, in the case of acheiropodia, the 3CTCF sites are missing, which prevents ZRS from interacting with the SHH promoter.[13] This results in decreased SHH protein production forlimb development.[14]
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.[1] Due tovariable 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.[15] Fingers are sometimes present, and a small bone at the tip of the shortened limb (the Bohomoletz bone) may or may not be present.[15]
Acheiropodia has been diagnosed at as early as 16 weeks post-conception,[16] although research on similar conditions suggests it may be diagnosed even earlier.[17] If ultrasound screening indicates possible acheiropodia, further (more invasive) testing may be performed,[18] including genetic analysis of either anamniotic fluid sample or placenta (chorionic villus) sample to confirm diagnosis.[18][19] In the case of fetal death or termination, autopsy findings may conclude in a diagnosis.[18]
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,prosthetics could improve their quality of life.[20] Surgery may be considered on a case-by-case basis to optimize prosthetic fitting.[20] Prosthetic fitting should occur before 2 years of age to minimize the risk of rejection.[20] 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.[20] Even without prosthetics, many children with limb loss learn to functionally use their residual limbs and may prefer not to useprostheses so that they can maintainproprioception (i.e. sense of the body's position and motion) andsensory feedback that would otherwise be reduced.[21] Some children may adapt with compensatory skills that are more effective thanprostheses.[10] A multidisciplinary approach may best treat the medical, psychological, and developmental challenges that may occur in infants missing all four limbs.[22]
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 theC7rof2 human gene were removed, limbs developed normally.[13] The discrepancy in whether acheiropodia was present is likely due to differences in chromosomal interaction regulation, influenced by the location and orientation of theCTCF 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 futureresearch. Theethical 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.