BACKGROUND: Proximal Femoral Focal Deficiency (PFFD) is the most proximal manifestation of a syndrome involving Congenitally Shortened lower Limbs (CSL), which also affects the fibula and midline metatarsals. This pattern of congenital human long bone deficiencies corresponds, in a time dependent manner, to the failed ingrowth pathways of new blood vessels of the growing embryonic limb. The distal femoral condyles are, in contrast, served by an alternative vascular supply from around the knee joint, and so remain resistant to the CSL deficiency. AIM: We hypothesize that embryonic vascular dysgenesis causes PFFD, as well as the cardinal features of the Femoral, Fibular and midline Metatarsal deficiencies (FFM) syndrome. RESULTS: Arteriography of CSL with PFFD reveals diminution or failed formation of the Femoral Artery (FA), which corresponds to downstream skeletal reductions. It may also reveal preservation of the primitive Axial Artery (AA) of the embryonic limb. The combination of missing and retained primitive vessels inform the time, place, and nature of the etiologic vascular events. This suggests that PFFD is the visible expression of a normally prefigured cartilaginous scaffold of the femur, which develops in conformity with the available pattern of blood vessels present. The teratogen thalidomide, known to affect the forming embryonic vasculature, also produces PFFD indistinguishable from the naturally occurring entity. CONCLUSION: The entire spectrum of PFFD, including phocomelia, fibular, and metatarsal dystrophisms, should thus be regarded as downstream skeletal results of embryonic arterial dysgeneses.

Department of Neuroscience and Physiology Department of Radiation Oncology Department of Cell and Developmental Biology SUNY Upstate Medical University Syracuse New York USA

Department of Orthopaedics Institute for Postgraduate Medical Education and 1st Faculty of Medicine Charles University and Teaching Hospital Na Bulovce Prague Czech Republic

Department of Orthopedic Surgery Department of Cell and Developmental Biology Department of Pediatrics SUNY Upstate Medical University Syracuse New York USA

School of Medicine Medical Sciences and Nutrition Institute of Medical Sciences University of Aberdeen Aberdeen UK

See more in PubMed

Aitken, G. T. 1959. “Amputation as a Treatment for Certain Lower‐Extremity Congenital Abnormalities.” Journal of Bone and Joint Surgery. American Volume 41: 1267–1285. https://doi.org/10.2106/00004623‐195941070‐0000.

Aitken, G. T. 1969. “Proximal Femoral Focal Deficiency‐Definition, Classification and Management.” In Proximal Femoral Focal Deficiency‐a Congenital Anomaly: A Symposium, –22. National Academy of Sciences, 1.

Aitken, G. T. 1974. “Congenital Short Femur With Fibular Hemimelia.” Journal of Bone and Joint Surgery 56: 1306.

Ambler, C. A., J. L. Nowicki, A. C. Burke, and V. L. Bautch. 2001. “Assembly of Trunk and Limb Blood Vessels Involves Extensive Migration and Vasculogenesis of Somite‐Derived Angioblasts.” Developmental Biology 234: 352–364. https://doi.org/10.1006/dbio.2001.0267.

Amstutz, H. C., and P. D. Wilson Jr. 1962. “Dysgenesis of the Proximal Femur (Coxa Vara) and Its Surgical Management.” Journal of Bone and Joint Surgery. American Volume 44: 1–24. https://doi.org/10.2106/00004623‐196244010‐00001.

Arnold, W. D. 1959. “Congenital Absence of the Fibula.” Clinical Orthopaedics and Related Research 14: 20–29. https://journals.lww.com/clinorthop/toc/1959/01420.

Bedoya, M. A., N. A. Chauvin, D. Jaramillo, R. Davidson, B. D. Horn, and V. Ho‐Fung. 2015. “Common Patterns of Congenital Lower Extremity Shortening: Diagnosis, Classification, and Follow‐Up.” Radiographics 35: 1191–1207. https://doi.org/10.1148/rg.2015140196.

Bermejo‐Sanchez, E., L. Cuevas, E. Amar, et al. 2011. “Phocomelia: A Worldwide Descriptive Epidemiologic Study in a Large Series of Cases From the International Clearinghouse for Birth Defects Surveillance and Research, and Overview of the Literature.” American Journal of Medical Genetics: Part C Seminars in Medical Genetics 157, no. 4: 305–320. https://doi.org/10.1002/ajmg.c.30320.

Biko, D. M., R. Davidson, A. Pena, and D. Jaramillo. 2012. “Proximal Focal Femoral Deficiency: Evaluation by MR Imaging.” Pediatric Radiology 42: 50–56. https://doi.org/10.1007/s00247‐011‐2203‐3.

Boakes, J. L., P. M. Stevens, and R. F. Moseley. 1991. “Treatment of Genu Valgus Deformity in Congenital Absence of the Fibula.” Journal of Pediatric Orthopedics 11: 721–724. https://doi.org/10.1097/01241398‐199111000‐00004.

Boden, S. D., M. D. Fallon, R. Davidson, M. T. Mennuti, and F. S. Kaplan. 1989. “Proximal Femoral Focal Deficiency. Evidence for a Defect in Proliferation and Maturation of Chondrocytes.” Journal of Bone and Joint Surgery. American Volume 71: 1119–1129. https://doi.org/10.2106/00004623‐198971080‐00001.

Brent, R. L., and L. B. Holmes. 1988. “Clinical and Basic Science Lessons From the Thalidomide Tragedy: What Have We Learned About the Causes of Limb Defects?” Teratology 38: 241–251. https://doi.org/10.1002/tera.1420380308.

Brown, T. S., R. L. Wimberly, and J. G. Birch. 2017. “Avascular Necrosis in the Contralateral Hip in Patients With Congenital Femoral Deficiency: A Report of 3 Cases.” Journal of Pediatric Orthopedics 37: e28‐e31. https://doi.org/10.1097/BPO.0000000000000686.

Burkus, J. K., and J. A. Ogden. 1982. “Bipartite Primary Ossification in the Developing Human Femur.” Journal of Pediatric Orthopedics 2: 63–65. https://doi.org/10.1097/01241398‐198202010‐00009.

Caplan, A. I. 1985. “The Vasculature and Limb Development.” Cell Differentiation 16: 1–11. https://doi.org/10.1016/0045‐6039(85)90602‐5.

Chernoff, N., and J. M. Rogers. 2010. “Hypoxia and the Edema Syndrome: Elucidation of a Mechanism of Teratogenesis.” Birth Defects Research Part B Developmental and Reproductive Toxicology 89: 300–303. https://doi.org/10.1002/bdrb.20258.

Choi, I. H., G. E. Lipton, W. Mackenzie, J. R. Bowen, and S. J. Kumar. 2000. “Wedge‐Shaped Distal Tibial Epiphysis in the Pathogenesis of Equinovalgus Deformity of the Foot and Ankle in Tibial Lengthening for Fibular Hemimelia.” Journal of Pediatric Orthopedics 20: 428–436. https://doi.org/10.1097/01241398‐200007000‐00003.

Chomiak, J., M. Horak, M. Masek, M. Frydrychova, and P. Dungl. 2009. “Computed Tomographic Angiography in Proximal Femoral Focal Deficiency.” Journal of Bone and Joint Surgery. American Volume 91: 1954–1964. https://doi.org/10.2106/JBJS.H.00902.

Chung, S. M. 1976. “The Arterial Supply of the Developing Proximal End of the Human Femur.” Journal of Bone and Joint Surgery. American Volume 58: 961–970. https://doi.org/10.2106/00004623‐197658070‐00011.

Chung, S. M., and W. H. Riser. 1978. “The Histological Characteristics of Congenital Coxa Vara: A Case Report of a Five Year Old Boy.” Clinical Orthopaedics and Related Research 132: 71–81. https://doi.org/10.1097/00003086‐197805000‐00016.

Crock, H. V., and M. C. Crock. 1967. “The Lower End of the Femur.” In The Blood Supply of the Lower Limb Bones in Man (Descriptive and Applied), edited by H. V. Crock, 29–46. E&S Livingstone.

Danielsson, B., N. Vargesson, and C. Danielsson. 2023. “Teratogenicity and Reactive Oxygen Species After Transient Embryonic Hypoxia: Experimental and Clinical Evidence With Focus on Drugs Causing Failed Abortion in Humans.” Reproductive Toxicology 122: 108488. https://doi.org/10.1016/j.reprotox.2023.108488.

Dieulafe, R., and M. Cahuzac. 1935. “Un cas d'absence partielle congenitale due perone avec dissection.” Bordeaux Chirurgical 6: 196–210.

Digby, K. H. 1916. “The Measurement of Diaphysial Growth in Proximal and Distal Directions.” Journal of Anatomy and Physiology 50, no. Pt 2: 187–188.

Dirckx, N., M. Van Hul, and C. Maes. 2013. “Osteoblast Recruitment to Sites of Bone Formation in Skeletal Development, Homeostasis, and Regeneration.” Birth Defects Research. Part C, Embryo Today 99: 170–191. https://doi.org/10.1002/bdrc.21047.

Dora, C., M. Buhler, M. D. Stover, M. N. Mahomed, and R. Ganz. 2004. “Morphologic Characteristics of Acetabular Dysplasia in Proximal Femoral Focal Deficiency.” Journal of Pediatric Orthopedics. Part B 13: 81–87. https://doi.org/10.1097/00009957‐200403000‐00004.

Epps, C. H., Jr. 1983. “Proximal femoral focal deficiency.” Journal of Bone and Joint Surgery. American Volume 65: 867–870. https://doi.org/10.2106/00004623‐198365060‐00027.

Filipowska, J., K. A. Tomaszewski, L. Niedzwiedzki, J. A. Walocha, and T. Niedzwiedzki. 2017. “The Role of Vasculature in Bone Development, Regeneration and Proper Systemic Functioning.” Angiogenesis 20: 291–302. https://doi.org/10.1007/s10456‐017‐9541‐1.

Freund, E. 1936. “Congenital Defects of Femur, Fibula, Tibia.” Archives of Surgery 33: 349–391. https://doi.org/10.1001/archsurg.1936.01190030002001.

Galloway, J. L., I. Delgado, M. A. Ros, and C. J. Tabin. 2009. “A Reevaluation of X‐Irradiation‐Induced Phocomelia and Proximodistal Limb Patterning.” Nature 460, no. 7253: 400–404. https://doi.org/10.1038/nature08117.

Gardner, E., and D. J. Gray. 1950. “Prenatal Development of the Human Hip Joint.” American Journal of Anatomy 87: 163–211. https://doi.org/10.1002/aja.1000870202.

Gautier, E., K. Ganz, N. Krugel, T. Gill, and R. Ganz. 2000. “Anatomy of the Medial Femoral Circumflex Artery and Its Surgical Implications.” Journal of Bone and Joint Surgery. British Volume 82: 679–683. https://doi.org/10.1302/0301‐620x.82b5.10426.

Gillespie, R., and I. P. Torode. 1983. “Classification and Management of Congenital Abnormalities of the Femur.” Journal of Bone and Joint Surgery. British Volume 65: 557–568. https://doi.org/10.1302/0301‐620X.65B5.6643558.

Gold, N. B., M. N. Westgate, and L. B. Holmes. 2011. “Anatomic and Etiological Classification of Congenital Limb Deficiencies.” American Journal of Medical Genetics, Part A 155A, no. 6: 1225–1235. https://doi.org/10.1002/ajmg.a.33999.

Goldman, A. B., R. Schneider, and P. D. Wilson Jr. 1978. “Proximal focal femoral deficiency.” Journal of the Canadian Association of Radiologists 29: 101–107.

Greebe, J. 1977. “Congenital Anomalies of the Iliofemoral Artery.” Journal of Cardiovascular Surgery (Torino) 18: 317–323.

Grogan, D. P., S. M. Love, and J. A. Ogden. 1987. “Congenital Malformations of the Lower Extremities.” Orthopedic Clinics of North America 18: 537–554. https://doi.org/10.1016/s0030‐5898(20)30351‐5.

Grose, A. W., M. J. Gardner, P. S. Sussmann, D. L. Helfet, and D. G. Lorich. 2008. “The Surgical Anatomy of the Blood Supply to the Femoral Head: Description of the Anastomosis Between the Medial Femoral Circumflex and Inferior Gluteal Arteries at the Hip.” Journal of Bone and Joint Surgery. British Volume 90: 1298–1303. https://doi.org/10.1302/0301620X.90B10.20983.

Hamanishi, C. 1980. “Congenital Short Femur. Clinical, Genetic and Epidemiological Comparison of the Naturally Occurring Condition With That Caused by Thalidomide.” Journal of Bone and Joint Surgery. British Volume 62: 307–320. https://doi.org/10.1302/0301‐620x.62b3.7410462.

Harrison, T. J. 1961. “The Influence of the Femoral Head on Pelvic Growth and Acetabular Form in the Rat.” Journal of Anatomy 95, no. Pt 1: 12–24.

Harvey, W. 1651. Exercitatio anatomica de motu cordis et sanguinis in animalibus: cui accedunt Exercitationes duae anatomicae de circulatione sanguinis ad Joannem Riolanum filium (Editio novissima, indice ornata. ed.). Apud Johannem van Kerckhem.

Holmes, L. B., M. N. Westgate, H. Nasri, and M. H. Toufaily. 2018. “Malformations Attributed to the Process of Vascular Disruption.” Birth Defects Research 110, no. 2: 98–107. https://doi.org/10.1002/bdr2.1160.

Hootnick, D. 2014. “Brief Report. Embryonic Arterial and Skeletal Dysgenesis: Syracuse Colloquium on Congenital Arterial and Skeletal Birth Defects September 28 and 29, 2013.” Birth Defects Research Part A Clinical and Molecular Teratology 100: 789–791. https://doi.org/10.1002/bdra.23253.

Hootnick, D., N. A. Boyd, J. A. Fixsen, and G. C. Lloyd‐Roberts. 1977. “The Natural History and Management of Congenital Short Tibia With Dysplasia or Absence of the Fibula.” Journal of Bone and Joint Surgery. British Volume 59: 267–271. https://doi.org/10.1302/0301‐620X.59B3.893503.

Hootnick, D. R. 2020a. “Congenital Fibular Dystrophisms Conform to Embryonic Arterial Dysgenesis.” Anatomical Record 303, no. 11: 2792–2800. https://doi.org/10.1002/ar.24348.

Hootnick, D. R. 2020b. “Missing Midline Metatarsals Conform to Plantar Arterial Arch Dysgenesis.” Journal of the American Podiatric Medical Association 110. https://doi.org/10.7547/18‐031.

Hootnick, D. R. 2023. “Behold the Appearance of the Seemingly “Absent” Fibula: Reconsidering the Taxonomy of Congenital Limb Anomalies.” American Journal of Medical Genetics. Part A 191: 1656–1657. https://doi.org/10.1002/ajmg.a.63160.

Hootnick, D. R., and E. M. Levinsohn. 2022. “Embryology of the Lower Limb Demonstrates That Congenital Absent Fibula Is a Radiologic Misnomer.” Anatomical Record 305: 8–17. https://doi.org/10.1002/ar.24628.

Hootnick, D. R., E. M. Levinsohn, and D. S. Packard Jr. 1980a. “Midline Metatarsal Dysplasia Associated With Absent Fibula.” Clinical Orthopaedics and Related Research 150: 203–206. https://doi.org/10.1097/00003086‐198007000‐00034.

Hootnick, D. R., E. M. Levinsohn, P. A. Randall, and D. S. Packard Jr. 1980b. “Vascular Dysgenesis Associated With Skeletal Dysplasia of the Lower Limb.” Journal of Bone and Joint Surgery. American Volume 62: 1123–1129. https://doi.org/10.2106/00004623‐198062070‐00009.

Hootnick, D. R., D. S. Packard Jr., E. M. Levinsohn, and D. A. Factor. 1991. “The Anatomy of a Human Foot With Missing Toes and Reduplication of the Hallux.” Journal of Anatomy 174: 1–17.

Hootnick, D. R., D. S. Packard Jr., E. M. Levinsohn, M. R. Lebowitz, and J. P. Lubicky. 1984. “The Anatomy of a Congenitally Short Limb With Clubfoot and Ectrodactyly.” Teratology 29: 155–164. https://doi.org/10.1002/tera.1420290202.

Hootnick, D. R., and N. Vargesson. 2018. “The Syndrome of Proximal Femur, Fibula, and Midline Metatarsal Long Bone Deficiencies.” Birth Defects Research 110: 1188–1193. https://doi.org/10.1002/bdr2.1349.

Hootnick, D. R., N. Vargesson, and J. Birch. 2017. “Regarding a Limb With PFFD, Fibular Dimelia and Mirror Foot Deformity.” Journal of Pediatric Orthopedics. Part B 26: 589. https://doi.org/10.1097/BPB.0000000000000490.

Horton, J. A., and D. R. Hootnick. 2021. “The Vascular Origins of Antero‐Medial Tibial Bowing in Congenital Fibular Deficiency.” Anatomical Record 304, no. 9: 1889–1900. https://doi.org/10.1002/ar.24580.

Horton, J. A., M. F. Krisch, E. M. Levinsohn, and D. R. Hootnick. 2022. “Lateral Epiphyseal Narrowings With Absent Fibula Conform to a Vascular Pattern Deficiency.” Journal of the Pediatric Orthopaedic Society of North America 4, no. 3: 515. https://doi.org/10.55275/JPOSNA‐2022‐0083.

Jedral, T., P. Anyzewski, B. Ciszek, and G. Benke. 1996. “Vascularization of the Hip Joint in the Human Fetuses.” Journal of Folia Morphologica (Warsz) 55: 293–294.

Keret, D., and G. D. MacEwen. 1991. “Growth Disturbance of the Proximal Part of the Femur After Treatment for Congenital Dislocation of the Hip.” Journal of Bone and Joint Surgery. American Volume 73: 410–423. https://doi.org/10.2106/00004623‐199173030‐00012.

Kim, H. K., J. Burgess, A. Thoveson, P. Gudmundsson, M. Dempsey, and C. H. Jo. 2016. “Assessment of Femoral Head Revascularization in Legg‐Calve‐Perthes Disease Using Serial Perfusion MRI.” Journal of Bone and Joint Surgery. American Volume 98, no. 22: 1897–1904. https://doi.org/10.2106/JBJS.15.01477.

King, R. 1969. “Some concepts of proximal femoral focal deficiency.” In Proximal Femoral Focal Deficiency‐a Congenital Anomaly: A Symposium, 23–50. National Academy of Sciences.

Koman, L. A., L. C. Meyer, and F. H. Warren. 1982. “Proximal Femoral Focal Deficiency: Natural History and Treatment.” Clinical Orthopaedics and Related Research 162: 135–143. https://doi.org/10.1097/00003086‐198201000‐00023.

Kronenberg, H. M. 2003. “Developmental Regulation of the Growth Plate.” Nature 423, no. 6937: 332–336. https://doi.org/10.1038/nature01657.

Kruger, L. M., and R. D. Talbott. 1961. “Amputation and Prosthesis as Definitive Treatment in Congenital Absence of the Fibula.” Journal of Bone and Joint Surgery. American Volume 43: 625–642. https://doi.org/10.2106/00004623‐196143050‐00001.

Laurenson, R. D. 1964. “Bilateral Anomalous Development of the Hip Joint. Post Mortem Study of a Human Fetus, Twenty‐Six Weeks Old.” Journal of Bone and Joint Surgery. American Volume 46: 283–292. https://doi.org/10.2106/00004623‐196446020‐00005.

van der Lem, D., and H. Wetz. 1995. Classification of the so called proximal femoral focal deficiency (PFFD) as a spectrum of a longitudinal deficiency. European Paediatric Orthopaedic Society 14th Annual Meeting, Brussels.

Levinsohn, E. M., D. R. Hootnick, and D. S. Packard Jr. 1991. “Consistent Arterial Abnormalities Associated With a Variety of Congenital Malformations of the Human Lower Limb.” Investigative Radiology 26: 364–373. https://doi.org/10.1097/00004424‐199104000‐00015.

Lloyd‐Roberts, G. C., and A. H. C. Ratliff. 1978. Hip Disorders in Children. Butterworths.

Maes, C. 2013. “Role and Regulation of Vascularization Processes in Endochondral Bones.” Calcified Tissue International 92: 307–323. https://doi.org/10.1007/s00223‐012‐9689‐z.

McQueen, C., and M. Towers. 2020. “Establishing the Pattern of the Vertebrate Limb.” Development 147: dev177956. https://doi.org/10.1242/dev.177956.

Merker, H. J. 1977. “Considerations on the Problem of Critical Period During the Development of Limb Skeleton.” Birth Defects Original Article Series 13: 179–202.

Morgan, J. D., and E. W. Somerville. 1960. “Normal and Abnormal Growth at the Upper End of the Femur.” Journal of Bone and Joint Surgery. British Volume 42‐B, no. 2: 264–272. https://doi.org/10.1302/0301‐620X.42B2.264.

Needham, J., and A. Hughes. 2015. A History of Embryology. Cambridge University Press.

Newman, C. G. 1985. “Teratogen Update: Clinical Aspects of Thalidomide Embryopathy‐a Continuing Preoccupation.” Teratology 32: 133–144. https://doi.org/10.1002/tera.1420320118.

Nossov, S. B., I. L. Hollin, J. Phillips, and C. C. Franklin. 2022. “Proximal Femoral Focal Deficiency/Congenital Femoral Deficiency: Evaluation and Management.” Journal of the American Academy of Orthopaedic Surgeons 30: e899‐e910. https://doi.org/10.5435/JAAOS‐D‐21‐01186.

O'Rahilly, R. 1951. “Morphological Patterns in Limb Deficiencies and Duplications.” American Journal of Anatomy 89: 135–193. https://doi.org/10.1002/aja.1000890202.

Okumura, M., A. Ishikawa, T. Aoyama, et al. 2017. “Cartilage Formation in the Pelvic Skeleton During the Embryonic and Early‐Fetal Period.” Public Library of Science One 12: e0173852. https://doi.org/10.1371/journal.pone.0173852.

Owen‐Woods, C., and A. Kusumbe. 2022. “Fundamentals of Bone Vasculature: Specialization, Interactions and Functions.” Seminars in Cell & Developmental Biology 123: 36–47. https://doi.org/10.1016/j.semcdb.2021.06.025.

Packard, D. S., Jr., E. M. Levinsohn, and D. R. Hootnick. 1991. “Teratological Implications of Soft Tissue Abnormalities Found in Human Lower Limbs With Bony Defects.” Issues in Biomedicine 14: 157–169.

Packard, D. S., Jr., E. M. Levinsohn, and D. R. Hootnick. 1993a. “Extent of Duplication in Lower‐Limb Malformations Suggests the Time of the Teratogenic Insult.” Pediatrics 91: 411–413. https://doi.org/10.1542/peds.91.2.411.

Packard, D. S., Jr., E. M. Levinsohn, and D. R. Hootnick. 1993b. “Most Human Lower Limb Malformations Appear to Result From Postspecification Insults.” Progress in Clinical and Biological Research 383A: 417–426.

Pappas, A. M. 1983. “Congenital Abnormalities of the Femur and Related Lower Extremity Malformations: Classification and Treatment.” Journal of Pediatric Orthopedics 3, no. 1: 45–60. https://doi.org/10.1097/01241398‐198302000‐00009.

Patten, B. M. 1953. Human Embryology. McGraw‐Hill.

Persaud, T. V. N., A. E. Chudley, and R. G. Skalko. 1985. Basic Concepts in Teratology. A.R. Liss, Inc.

Pick, J. W., B. J. Anson, and F. L. Ashley. 1942. “The Origin of the Obturator Artery. A Study of 640 Body‐Halves.” American Journal of Anatomy 70: 317–343. https://doi.org/10.1002/aja.1000700206.

Poswillo, D. 1973. “The Pathogenesis of the First and Second Branchial Arch Syndrome.” Oral Surgery, Oral Medicine, and Oral Pathology 35: 302–328. https://doi.org/10.1016/0030‐4220(73)90070‐4.

Poswillo, D. 1975. “Hemorrhage in Development of the Face.” Birth Defects Original Article Series 11: 61–81.

Reiner, M. 1901. “Ueber den kongenitalen Femurdefekt.” Zeit. F. Orthop. Chir 9: 544.

Reyes, B. A., J. G. Birch, D. R. Hootnick, A. M. Cherkashin, and M. L. Samchukov. 2017. “The Nature of Foot Ray Deficiency in Congenital Fibular Deficiency.” Journal of Pediatric Orthopedics 37: 332–337. https://doi.org/10.1097/BPO.0000000000000646.

Ring, P. A. 1959. “Congenital Short Femur; Simple Femoral Hypoplasia.” Journal of Bone and Joint Surgery. British Volume 41‐B: 73–79. https://doi.org/10.1302/0301‐620X.41B1.73.

Ring, P. A. 1961. “Congenital Abnormalities of the Femur.” Archives of Disease in Childhood 36: 410–417. https://doi.org/10.1136/adc.36.188.410.

Risau, W. 1997. “Mechanisms of Angiogenesis.” Nature 386: 671–674. 0.1038/386671a0.

Rivera, R. E., D. R. Hootnick, A. R. Gingold, E. M. Levinsohn, L. M. Kruger, and D. S. Packard Jr. 1999. “Anatomy of a Duplicated Human Foot From a Limb With Fibular Dimelia.” Teratology 60: 272–282. https://doi.org/10.1002/(SICI)1096‐9926(199911)60:5<272::AID‐TERA8>3.0.CO;2‐E.

Rodriguez‐Ramirez, A., M. M. Thacker, L. C. Becerra, E. C. Riddle, and W. G. Mackenzie. 2010. “Limb Length Discrepancy and Congenital Limb Anomalies in Fibular Hemimelia.” Journal of Pediatric Orthopedics. Part B 19: 436–440. https://doi.org/10.1097/BPB.0b013e32832d5d7d.

Sadler, T. W. 2019. Langman's Medical Embryology. Wolters‐Kluwer.

Sanpera, I., Jr., and L. T. Sparks. 1994. “Proximal Femoral Focal Deficiency: Does a Radiologic Classification Exist?” Journal of Pediatric Orthopedics 14: 34–38. https://doi.org/10.1097/01241398‐199401000‐00008.

Schipani, E., C. Maes, G. Carmeliet, and G. L. Semenza. 2009. “Regulation of Osteogenesis‐Angiogenesis Coupling by HIFs and VEGF.” Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research 24: 1347–1353. https://doi.org/10.1359/jbmr.090602.

Schwarz, E. 1913. “Ueber die coxa vara congenita.” Beiträge zur Klinischen Chirurgie 87: 685–708.

Seeley, M. A., A. G. Georgiadis, and W. N. Sankar. 2016. “Hip Vascularity: A Review of the Anatomy and Clinical Implications.” Journal of the American Academy of Orthopaedic Surgeons 24: 515–526. https://doi.org/10.5435/JAAOS‐D‐15‐00237.

Senior, H. D. 1919a. “The Development of the Arteries of the Human Lower Extremity.” American Journal of Anatomy 25: 54–95. https://doi.org/10.1002/aja.1000250105.

Senior, H. D. 1919b. “An Interpretation of the Recorded Arterial Anomalies of the Human Leg and Foot.” Journal of Anatomy 53: 130–171.

Senior, H. D. 1925. “An Interpretation of the Recorded Arterial Anomalies of the Human Pelvis and Thigh.” American Journal of Anatomy 36: 1–46. https://doi.org/10.1002/aja.1000360102.

Senior, H. D. 1929. “Abnormal Branching of the Human Popliteal Artery.” American Journal of Anatomy 44: 111–120. https://doi.org/10.1002/aja.1000440105.

Senior, H. D. 1985. “Development of the Arteries.” In Gray's anatomy, edited by C. Clemente. Williams and Wilkins.

da Silva Dal Pizzol, T., F. P. Knop, and S. S. Mengue. 2006. “Prenatal Exposure to Misoprostol and Congenital Anomalies: Systematic Review and Meta‐Analysis.” Reproductive Toxicology 22, no. 4: 666–671. https://doi.org/10.1016/j.reprotox.2006.03.015.

Smithells, R. W., and C. G. Newman. 1992. “Recognition of Thalidomide Defects.” Journal of Medical Genetics 29: 716–723. https://doi.org/10.1136/jmg.29.10.716.

Song, M. H., C. H. Shin, I. H. Choi, and T. J. Cho. 2024. “Characteristics of Terminal Hemimelia: What Is the Difference Between Terminal Hemimelia and Classic Fibular Hemimelia?” Journal of Children's Orthopaedics 18: 179–186. https://doi.org/10.1177/18632521241227830.

Stockard, C. R. 1921. “Developmental Rate and Structural Expression: An Experimental Study of Twins, ‘Double Monsters' and Single Deformities, and the Interaction Among Embryonic Organs During Their Origin and Development.” American Journal of Anatomy 28: 115–277. https://doi.org/10.1002/aja.1000280202.

Strayer, L. M., Jr. 1971. “Embryology of the Human Hip Joint.” Clinical Orthopaedics and Related Research 74: 221–240. https://doi.org/10.1097/00003086‐197101000‐00029.

Strayer, L. M. 1943. “The Embryology of the Human Hip Joint.” Yale Journal of Biology and Medicine 16: 13–26. 6.

Taylor, G. I., and J. H. Palmer. 1987. “The Vascular Territories (Angiosomes) of the Body: Experimental Study and Clinical Applications.” British Journal of Plastic Surgery 40: 113–141. https://doi.org/10.1016/0007‐1226(87)90185‐8.

Therapontos, C., L. Erskine, E. R. Gardner, W. D. Figg, and N. Vargesson. 2009. “Thalidomide Induces Limb Defects by Preventing Angiogenic Outgrowth During Early Limb Formation.” Proceedings of the National Academy of Sciences of the United States of America 106: 8573–8578. https://doi.org/10.1073/pnas.0901505106.

Tickle, C. 2015. “How the Embryo Makes a Limb: Determination, Polarity and Identity.” Journal of Anatomy 227: 418–430. https://doi.org/10.1111/joa.12361.

Trueta, J. 1963. “The Role of the Vessels in Osteogenesis.” Journal of Bone and Joint Surgery. British Volume 45‐B: 402–418. https://doi.org/10.1302/0301‐620X.45B2.402.

Trueta, J. 1968. Studies of the Development and Decay of the Human Frame. WB Saunders Co.

Trueta, J., and J. D. Morgan. 1960. “The Vascular Contribution to Osteogenesis. I. Studies by the Injection Method.” Journal of Bone and Joint Surgery. British Volume 42‐B: 97–109. https://doi.org/10.1302/0301‐620X.42B1.97.

UK Government Report. 1964. “Deformities Caused by Thalidomide.” In Reports on Public Health and Medical Subjects. Ministry of Health.

Vargesson, N. 2015. “Thalidomide‐Induced Teratogenesis: History and Mechanisms.” Birth Defects Research. Part C, Embryo Today 105: 140–156. https://doi.org/10.1002/bdrc.21096.

Vargesson, N. 2019. “The Teratogenic Effects of Thalidomide on Limbs.” Journal of Hand Surgery, European Volume 44: 88–95. https://doi.org/10.1177/1753193418805249.

Vargesson, N., G. Hooper, G. Giddins, A. Hunter, P. Stirling, and W. Lam. 2023. “Thalidomide Upper Limb Embryopathy‐Pathogenesis, Past and Present Management and Future Considerations.” Journal of Hand Surgery, European Volume 48: 699–709. https://doi.org/10.1177/17531934231177425.

Vargesson, N., and D. R. Hootnick. 2017. “Arterial Dysgenesis and Limb Defects: Clinical and Experimental Examples.” Reproductive Toxicology 70: 21–29. https://doi.org/10.1016/j.reprotox.2016.10.005.

Vargesson, N., and T. Stephens. 2021. “Thalidomide: History, Withdrawal, Renaissance, and Safety Concerns.” Expert Opinion on Drug Safety 20: 1455–1457. https://doi.org/10.1080/14740338.2021.1991307.

Weathersby, H. T. 1959. “The Origin of the Artery of the Ligamentum Teres Femoris.” Journal of Bone and Joint Surgery. American Volume 41: 261–263. https://doi.org/10.2106/00004623‐195941020‐00007.

Westin, G. W., and F. O. Gunderson. 1969. “Proximal femoral focal in deficiency‐a review of treatment experiences.” In Proximal Femoral Focal Deficiency‐a Congenital Anomaly: A Symposium, 100–111. National Academy of Sciences.

Westin, G. W., D. N. Sakai, and W. L. Wood. 1976. “Congenital Longitudinal Deficiency of the Fibula: Follow‐Up of Treatment by Syme Amputation.” Journal of Bone and Joint Surgery. American Volume 58: 492–496. https://doi.org/10.2106/00004623‐197658040‐00011.

Williams, G. D., R. J. Sindelar, J. C. Peart, N. A. Martin, L. R. McIntire, and C. H. Martin. 1930. “Origin of the Deep and Circumflex Femoral Group of Arteries.” Anatomical Record 46: 273–279. https://doi.org/10.1002/ar.1090460307.

Zhao, Y., Q. Chen, L. Chen, S. G. F. Shen, and J. Dai. 2020. “Thalidomide Leads to Mandible Hypoplasia Through Inhibiting Angiogenesis and Secondary Hemorrhage in the Fetal Craniofacial Region in Rabbits.” Toxicology Letters 319: 250–255. https://doi.org/10.1016/j.toxlet.2019.11.023.

Zuniga, A. 2015. “Next Generation Limb Development and Evolution: Old Questions, New Perspectives.” Development 142: 3810–3820. https://doi.org/10.1242/dev.125757.

Zuniga, A., R. Zeller, and S. Probst. 2012. “The Molecular Basis of Human Congenital Limb Malformations.” Wiley Interdisciplinary Reviews: Developmental Biology 1: 803–822. https://doi.org/10.1002/wdev.59.