Congenital Femoral Deficiency Reconstruction and Lengthening 22 Surgery Dror Paley , David Y. Chong , and Daniel E. Prince Embryogenesis of the extremities occurs between 4 and Introduction 8 weeks after fertilization, and the majority of congenital anomalies occur during this period of time. Limb bud devel- Demographics opment begins with the lateral migration of two layers of mesoderm and outgrowth into the overlying ectoderm. Cells The often-cited incidence of congenital femoral defi ciency from the underlying somitic mesoderm ultimately form the (CFD) is 1 in 52,029 based on a review of the Edinburgh muscle tissue of the limb, while cells from the lateral plate Register of the Newborn by Rogala et al. published in 1974 mesoderm form cartilage and bones. Distinct but coordi- [ 1 ]. In retrospect, this may not be accurate, as the incidence nated molecular pathways primarily control each axis. In is based on the only case identifi ed during the 4.5-year col- the process of limb patterning, mesenchymal cells in the lection period from 1964 to 1968, notably, after thalidomide limb bud integrate positional information from the three use was discontinued. This survey is also representative of a axes, indicating a complex interplay of the responsible relatively homogenous population, of which no information factors [ 4 , 5 ]. is given regarding race, age, environmental exposure, medi- Development of the proximal-distal axis is at least par- cation usage, or socioeconomic status of the population. tially controlled by fi broblast growth factors (FGF) secreted by the apical ectodermal ridge (AER) [ 4 ]. The AER is a thick- ened layer of the ectoderm that forms over the distal edge of Embryology the limb bud. FGF secreted by the AER stimulates proximal- distal growth of the limb via differentiation of the underlying Fetal growth and development of the lower extremities are mesoderm. As part of a complex positive feedback loop, the controlled by a complex cascade of a multitude of growth signal to produce FGF is supplied by the underlying meso- factors that are expressed in a particular sequence and at derm. The AER signaling center is responsible for the differ- various concentrations during development. In the process of entiation of the underlying mesoderm and the development of limb patterning, mesenchymal cells in the limb bud integrate the limb in the proximal-to-distal direction. Removal of the positional information from the three axes [ 2 , 3 ]. AER results in arrest of limb outgrowth. Furthermore, ecto- pic implantation of the AER results in formation of an extra limb. The AER also contributes to interdigital necrosis, allowing separation of the initially webbed hand [ 6 ]. Defects D. Paley , MD, FRCSC (*) in the AER lead to anomalies such as limb truncation, trans- St. Mary’s Medical Center , Paley Advanced Limb Lengthening Institute , 901 45th Street, Kimmel Building , verse defi ciencies, and syndactyly [7 ]. The genetics of the West Palm Beach , FL 33407 , USA apical ectodermal ridge have been further elucidated as a e-mail: [email protected] complex interplay of related genes. Five paralogous gene D. Y. Chong , MD families, named Hox 9 through Hox 13, from Hox A and Department of Orthopedic Surgery , University of Oklahoma Hox D gene groups, come together co-linearly (HoxA-9 to Health Sciences Center , Oklahoma City , OK 73104 , USA HoxA-13 and HoxD-9 to HoxD-13) and play important roles e-mail: [email protected] in the AER. D. E. Prince , MD, MPH Development in the anteroposterior axis is patterned by Memorial Sloan Kettering Cancer Center , 1275 York Avenue , New York , NY 10065 , USA secretion of sonic hedgehog (SHH) from the zone of polar- e-mail: [email protected] izing activity (ZPA), a collection of cells along the posterior S. Sabharwal (ed.), Pediatric Lower Limb Deformities, 361 DOI 10.1007/978-3-319-17097-8_22, © Springer International Publishing Switzerland 2016 362 D. Paley et al. aspect of the limb bud. Transplantation of the ZPA from the the fourth or fi fth ray, unusual facies, Pierre-Robin sequence, posterior aspect to the anterior aspect of the limb bud causes and syndactyly of the toes. Considering the other congenital creation of a mirrored duplication of the ulnar aspect of the conditions that present in select individuals with CFD, the hand. In addition to its primary role in development of the underlying pathophysiology and, therefore, genetic causes anterior-posterior axis, the ZPA also contributes to mainte- are likely to be distinct in this group of patients. In other nance of proximal-to-distal limb development and partici- words, one must be careful to assume that all patients diag- pates in the feedback loop of the AER [4 ]. Mutations in nosed by today’s criteria with “CFD” will have the same Indian hedgehog, SHH, and PITX1 in humans have been underlying causality. implicated in lower extremity polydactyly, while mice stud- An inheritable genetic defect or susceptibility to other ies have shown an interaction between the expression of each risk factors or exposures at a particular stage in lower factor [ 2 , 8 ]. extremity development of the fetus would commonly pres- Development in the dorsal-ventral axis is regulated by the ent with bilateral involvement; however, bilateral involve- Wingless-type (Wnt) signaling pathway within the dorsal ment is rare, and associated with other known genetic ectoderm [ 3 ]. The Wnt pathway induces the underlying meso- defects, such as Pierre-Robin sequence. The Pierre-Robin derm to develop dorsal characteristics and is blocked in the sequence is primarily an anatomical defect of mandibular ventral ectoderm, allowing the development of ventral charac- outgrowth that impacts on oropharyngeal volume and teristics. In mice, inactivation of the Wnt signaling pathway patency of the palate. No single genetic abnormality has results in the development of biventral limbs. The Wnt path- been identifi ed in Pierre- Robin, though recent evidence way also contributes to regulation of SHH, refl ecting the com- shows that Sox9 may be a crucial step in the pathway [ 12 ]. plex interaction and coordination among the 3-dimensional Similarly, it is likely that a variety of inheritable genetic pathways responsible for limb development [ 4 , 6 ]. defects are responsible for a common resultant phenotype It is unlikely that CFD is caused solely by a defect in the with similar but varied congenital abnormalities. Conversely, overall function of the AER, as the distal portion of an a recent report of a child with Pierre-Robin and bilateral extremity affected by CFD is often normal. It is more likely CFD found that array comparative genomic hybridization that the defect is in the underlying mesodermal layer, within analysis showed no abnormalities at 1,543 loci while whole- the complex interplay of developmental proteins at a point exon analysis identifi ed no mutations suspected to be caus- more downstream in the differentiation of the limb. ative for the patient’s condition [ 13 ]. A subset of bone morphogenetic proteins (BMPs), known as growth/differentiation factors (GDFs), affect several skel- Pathophysiology and Genetics etal processes, including endochondral ossifi cation, synovial joint formation, and tendon and ligament repair. Studies in A single underlying genetic cause for CFD has not been elu- mice have suggested that GDF-5 defi ciency affects the com- cidated. In the senior author’s personal experience (over position and material properties of cortical bone tissue in the 1,000 patients with unilateral CFD) there was only one uni- femur, but the detailed mechanisms by which this occurs lateral case that had a parent with unilateral CFD. In con- remain to be determined [ 4 ]. Paley et al. reported radio- trast, in a smaller group of multi-limb congenital defi ciencies graphic mineralization of the pseudoarthrotic region of the including CFD on at least one limb, it was not uncommon to femur in patients with CFD with the application of exoge- fi nd a history of a fi rst- or second-degree relative with a con- nous BMP-2 directly to the area [ 14 ]. genital limb anomaly. Several authors have postulated a Other investigators have supported a teratogenic cause for genetic cause given that the presence of the condition at CFD as the phenotype is similar to the effects of thalidomide birth, its association with other abnormalities that have exposure in utero [15 ]. These effects imply that at a particular known genetic conditions, occasional bilateral involvement, stage in fetal growth an exposure in utero occurs causing a and reports of familial cases are supporting evidence for an downstream effect on the remaining growth of the affected underlying inheritable genetic defect with incomplete pene- lower extremity. The exact stage in development at which the tration or an autosomal recessive pattern of inheritance [ 9 – abnormality occurs could determine the severity of involve- 11 ]. It should be noted that phenotype has been used to ment. While a teratogenic exposure is possible as the underly- diagnose and classify patients with CFD, despite quite varied ing cause, given the embryology of the limb, the explanation clinical and radiographic presentations. As genetic and would have to involve a teratogen with transient effect only at molecular understanding of the disease progresses, it is the time of exposure. Thus, fetuses exposed to the teratogenic likely that grouping all patients into a single diagnosis of agent at one time point might have only mild CFD, exposed CFD will not be suffi cient. Some of the reported abnormali- only at the time of limb bud formation of the proximal femur, ties associated with CFD are fi bular hemimelia, femoral- while those fetuses with more severe involvement have per- fi bular- ulnar complex, patella aplasia/hypoplasia, absence of sistent exposure to the teratogenic agent. 22 Congenital Femoral Defi ciency Reconstruction and Lengthening Surgery 363 Endogenous retinoids, including vitamin A and retinoid Ligamentous Structures acid (the active form of vitamin A), have long have been Anterior-posterior instability of the knee is common in CFD, implicated in limb development and abnormalities [5 – 7 ].