Acheiropodia, also known as Horn Kolb Syndrome,[1] is a genetic condition that affects limb 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 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 and ulna bones which make up the lower arm, the fibula bone of the shin, and all hand and foot bones.[3] It was first discovered and is prevalent almost exclusively in Brazil.[4]
The C7rof2 gene is the human equivalent of the mouse gene LMBR1, which encodes an essential protein for limb development.[7] When there is no functional protein present, limb development does not occur correctly, and individuals are born with Acheiropodia.[7] 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.[8] This makes it an 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 rare gene copy from each parent.[8]
The mutation in C7rof2 results in the processed RNA transcript missing exon 4. As a result, the 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.
The C7rof2 DNA sequence is very stable and changes occur rarely, partly explaining the rarity of this condition.[9] Since the rare gene copy is unlikely to be found in parents from two unrelated families, Acheiropodia is often caused by consanguineous marriages in which genetically related individuals have children together.[10]
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.[11] Due to variable expressivity of the C7rof2 gene, Acheiropodia presents differently among affected individuals, adding to the difficulty of diagnosis.[12] Fingers are sometimes present, and a small bone at the tip of the shortened limb (the Bohomoletz bone) may or may not be present.[13]
Acheiropodia has been diagnosed at as early as 16 weeks post-conception,[14] although research on similar conditions suggests it may be diagnosed even earlier.[15] If ultrasound screening indicates possible Acheiropodia, further (more invasive) testing may be performed,[16] including genetic analysis of either an amniotic fluid sample or placenta (chorionic villus) sample to confirm diagnosis.[17][18] In the case of fetal death or termination, autopsy findings may conclude in a diagnosis.[19]
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, prosthetics could improve their quality of life.[20] Surgery may be considered on a case-by-case basis to optimize prosthetic fitting.[21] Prosthetic fitting should occur before 2 years of age to minimize the risk of rejection.[22] 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.[23] Even without prosthetics, many children with limb loss learn to functionally use their residual limbs.[24] A multidisciplinary approach may best treat the medical, psychological, and developmental challenges that may occur in infants missing all four limbs.[25]
