Embryology of the lower limb demonstrates that congenital absent fibula is a radiologic misnomer.

The congenitally shortened limb (CSL) with fibular deficiency or absence has historically been graded by plain radiography, while associated cartilaginous and arterial soft tissue anomalies have been comparatively neglected. Consistent pathological evidence of remnant cartilaginous bodies in place of the fibula presupposes earlier existence of a preformed cartilaginous template of the fibula. In complete fibular radiographic absences, often associated with midline metatarsal deficiencies, the two usual nutrient arteries to the fibula fail to form, as they normally would have, around the (16-18 mm stage) sixth embryonic week. The histopathology of fallow persisting fibular anlagen, in association with missing arteries and retained primitive arteries, suggests the anlage is a dystrophic, but otherwise normally prefigured, cartilaginous scaffold of the fibula. Thus, the widely employed term absent fibula, which has been grounded in plain radiography, is a misnomer. Additionally, since the metatarsals missing in congenitally shortened limb are midline, the related term, fibular hemimelia, is similarly inaccurate. A new taxonomy, based on embryological principles rather than radiographic appearance alone, will promote limb dystrophism as a more accurate term combining arrested embryonic vascular development and congenitally shortened limb of the lower extremity.

The vascular origins of antero-medial tibial bowing in congenital fibular deficiency.

Anteromedial bowing and shortening of the tibia are intrinsic features of limbs with congenital fibular deficiency (CFD). Tibial bowing occurs more frequently when the fibula is radiographically absent rather than deficient. The bowing has been attributed to rapid longitudinal growth of the tibial anlage coupled with anteromedial tibial bending moments of the posterior crural and lateral peroneal musculature unopposed in the absence of a fibular strut. Eccentric mechanical loading results in asymmetric mineral deposition and thickening of the diaphyseal cortex. Skeletogenesis depends upon an intimate interplay between the normally prefigured tibial cartilage anlage and beginning muscular contractile actions during initial vascularization of the anlage, while the embryonic limb vasculature is undergoing a series of transitions. A diaphyseal periosteal collar normally forms at the site of nutrient artery invasion and stabilizes the growing anlage. In CFD however, arteriography consistently reveals anomalous tibial nutrient arterial branches, which originate from a primitive axial artery rather than from the usual posterior tibial artery. These anomalous nutrient arteries enter the tibial shaft at the posterior aspect of the proximal metaphysis, establishing an eccentric bone collar. The developing vasculature of the embryonic limb is responsive to the then most metabolically active tissues. Disruption of the reciprocal relationship between the transitioning vasculature and the developing long bones is pivotal in producing the diverse skeletal malformations of the congenital short limb (CSL). Embryonic vascular dysgenesis contributes not only to the well-recognized congenital tibial and fibular shortenings but also predisposes to congenital anteromedial bowing of the tibia.

Missing Midline Metatarsals Conform to Plantar Arterial Arch Dysgenesis.

Midline metatarsal ray deficiencies, which occur in approximately half of congenital short limbs with fibular deficiency, provide the most distal and compelling manifestation of a fluid spectrum of human lower-extremity congenital long bone reductions; this spectrum syndromically affects the long bone triad of the proximal femur, fibula, and midline metatarsals. The bony deficiencies correspond to sites of rapid embryonic arterial transitioning. Long bones first begin to ossify because of vascular invasions of their respective mesenchymal/cartilage anlagen, proceeding in a proximal-to-distal sequence along the forming embryonic limb. A single-axis artery forms initially in the embryonic lower limb by means of vasculogenesis. Additional arteries evolve in overlapping transitional waves, in proximity to the various anlagen, during the sixth and seventh weeks after fertilization. An adult pattern of vessels presents by the eighth week. Arterial alterations, in the form of retained primitive embryonic vessels and/or reduced absent adult vessels, have been observed clinically at the aforementioned locations where skeletal reductions occur. Persistence of primitive vessels in association with the triad of long bone reductions allows a heuristic estimation of the time, place, and nature of such coupled vascular and bony dysgeneses. Arterial dysgenesis is postulated to have occurred when the developing arterial and skeletal structures were concurrently vulnerable to teratogenic insults because of embryonic arterial instability, a risk factor during arterial transition. It is herein hypothesized that flawed arterial transitions subject the prefigured long bone cartilage models of the rapidly growing limb to the risk of teratogenesis at one or more of the then most rapidly growing sites. Midline metatarsal deficiency forms the keystone of this developmental concept of an error of limb development, which occurs as a consequence of failed completion of the medial portion of the plantar arch. Therefore, the historical nomenclature of congenital long bone deficiencies will benefit from modification from a current reliance on empirical physical taxonomies to a developmental foundation.

Congenital fibular dystrophisms conform to embryonic arterial dysgenesis.

The congenital short limb (CSL) with fibular deficiency has traditionally been graded by plain radiography. The most popular orthopedic classification sorts the fibular dysmorphologies into three radiographic groupings: IA (thinned), IB (proximally truncated), or II (absent). In contrast, the soft tissues have been relatively neglected. Since bone formation of the fibula progresses from the anlage, a scaffolding cartilage mold intermediate, cartilage transformation to bone is dependent upon timely embryonic arterial invasion. Absences of the requisite arteries predicate specific skeletal dysmorphologies. The usual arterial supply of the fibula is comprised primarily of the anterior tibialis artery (ATA), which uniquely supplies the proximal portion of the fibula, and also joins the peroneal artery (PA) in supplying the mid to distal fibular shaft. Combinations of the two nutrient arteries allow four potential variations of fibular vascular supply, among which the ATA and PA conjoin to supply the normal fibula and variably supply the three dysmorphic fibular models. The IA and IB deformities conform, respectively, to the absences of the PA and the ATA. Combined ATA and PA absences present in the radiographically "absent" fibula. Thus, each of the four fibular (dys)morphologies conforms to a specific embryonic pattern of arterial development. The term "dystrophism" most accurately characterizes such malformed long bones.

The syndrome of proximal femur, fibula, and midline metatarsal long bone deficiencies.

Human lower limb congenital long bone deficiencies cluster primarily at three distinct skeletal locations. Proximal femoral and fibular reductions are known phenomena. In contrast, midline metatarsal deficiencies have been misrepresented as lateral. The popular term, "fibular hemimelia," is inaccurate and its use is discouraged. All three locations correspond to discrete sites of evolving angiogenesis during transition from a single embryonic axial limb artery to the familiar and complex adult arterial pattern. Initiation of bone formation of cartilaginous primordia of the long bones at all three sites occurs in proximity to, and depends upon, successful invasion by mature nutrient vessels, formed during the 6th and 7th weeks of embryonic development. The adult arterial pattern is fully established by 8th embryonic week. Arterial transitions occur later in development, around the time of cessation of the molecular processes of patterning/specification of the embryonic limb. Evidence of flawed embryonic arterial transitions, involving missing, reduced and/or retained primitive vessels in association with congenital skeletal reductions have been demonstrated at all three sites. Current molecular models of limb development do not explain the distribution of this triad of congenital skeletal reductions. These dysmorphologies are most accurately described as post-specification errors of limb development. Recognition of this distinctive model of limb maldevelopment demands further investigation to create a more exact taxonomy, one consistent with both clinical and molecular criteria. The established terminologies originated by Frantz and O'Rahilly should be reconsidered or abandoned. Designation of this clinical triad as a syndrome of proximal femur, fibula, and midline metatarsal dystrophisms initiates that endeavor.

The Nature of Foot Ray Deficiency in Congenital Fibular Deficiency.

BACKGROUND: Absent lateral osseous structures in congenital fibular deficiency, including the distal femur and fibula, have led some authors to refer to the nature of foot ray deficiency as "lateral" as well. Others have suggested that the ray deficiency is in the central portion of the midfoot and forefoot.We sought to determine whether cuboid preservation and/or cuneiform deficiency in the feet of patients with congenital fibular deficiency implied that the ray deficiency is central rather than lateral in patients with congenital fibular deficiency. METHODS: We identified all patients with a clinical morphologic diagnosis of congenital fibular deficiency at our institution over a 15-year period. We reviewed the records and radiographs of patients who had radiographs of the feet to allow determination of the number of metatarsals, the presence or absence of a cuboid or calcaneocuboid fusion, the number of cuneiforms present (if possible), and any other osseous abnormalities of the foot. We excluded patients with 5-rayed feet, those who had not had radiographs of the feet, or whose radiographs were not adequate to allow accurate assessment of these radiographic features. We defined the characteristic "lateral (fifth) ray present" if there was a well-developed cuboid or calcaneocuboid coalition with which the lateral-most preserved metatarsal articulated. RESULTS: Twenty-six patients with 28 affected feet met radiographic criteria for inclusion in the study. All affected feet had a well-developed cuboid or calcaneocuboid coalition. The lateral-most ray of 25 patients with 26 affected feet articulated with the cuboid or calcaneocuboid coalition. One patient with bilateral fibular deficiency had bilateral partially deficient cuboids, and the lateral-most metatarsal articulated with the medial remnant of the deformed cuboids. Twenty-one of 28 feet with visible cuneiforms had 2 or 1 cuneiform. CONCLUSIONS: Although the embryology and pathogenesis of congenital fibular deficiency remain unknown, based on the radiographic features of the feet in this study, congenital fibular deficiency should not be viewed as a global "lateral lower-limb deficiency" nor the foot ray deficiency as "lateral." LEVEL OF EVIDENCE: Level IV-prognostic study.

Arterial dysgenesis and limb defects: Clinical and experimental examples.

Limb malformations are amongst the most common and visible birth effects. Causes have been purported to include genetic aberrations as well as teratogens, such as thalidomide. Here we review the evidence for vascular disruption in the genesis of limb malformations through abnormal arterial transitioning and from events such as amniocentesis, uterine constriction, and through teratogen exposure. We use several clinical and experimental examples and highlight the need to understand more about the role the vascular system plays in the molecular mechanisms underpinning normal limb development.

Magnetic resonance angiography in clubfoot and vertical talus: a feasibility study.

UNLABELLED: Congenital vascular alterations of the normal adult arterial pattern have been associated with multiple congenital limb deformities including clubfoot and vertical talus. Investigators have observed absence of the anterior tibial artery and dorsalis pedis artery in most patients with clubfoot, and absence of the posterior tibial artery in all patients with vertical talus. We used magnetic resonance angiography to define the lower extremity vascular anatomy of two patients with left-sided vertical talus and right-sided clubfoot and one patient with bilateral vertical talus and cartilage-derived morphogenetic protein-1 (CDMP-1) gene mutation. Of the three patients, one had bilateral posterior tibial artery deficiencies while the other had bilateral anterior tibial artery deficiencies. The third patient with bilateral vertical talus and CDMP-1 mutation had normal arterial structure bilaterally. Though clubfoot and vertical talus have distinctly different clinical phenotypes, the association of each with arterial abnormalities suggests a common etiology during development. The presence of normal arterial structure in our patient with vertical talus and CDMP-1 mutation suggests that other nonvascular etiologies may be responsible for some cases of foot deformities. LEVEL OF EVIDENCE: Level IV, prognostic case series. See the Guidelines for Authors for a complete description of levels of evidence.

Ischemic necrosis following clubfoot surgery: the purple hallux sign.

Ischemic necrosis, which develops rarely after clubfoot surgery, may have a vascular etiology, since many idiopathic and neurogenic clubfeet have congenital deficiency of the anterior tibial and dorsalis pedis arteries. Dorsalis pedis deficiency is demonstrated more frequently in those clubfeet showing greater deformity. Substantial hypoplasia of the profunda femoris and posterior and anterior tibial arteries was evident in the affected limb of a patient in this series who underwent postoperative arteriography. Herein, we report massive necrosis in seven limbs of six patients after clubfoot surgery and have combined this series with seven previously published cases. Additional cases support our hypothesis that arterial deficiencies put some postoperative clubfeet at risk of perioperative ischemic necrosis. Necrosis occurs in those regions supplied by the congenitally diminished anterior tibial and dorsalis pedis arteries. Knowing that children with congenital vascular deficiency are at risk for ischemic necrosis, surgeons should be alert to the subtle, early signs of ischemia and be prepared to prevent or ameliorate the consequences of this condition. Since hypoperfusion in these postoperative feet is a surgical emergency, we propose clinical guidelines for treatment for this phenomenon, which we have named the purple hallux sign.

Congenital vertical talus in four generations of the same family.

OBJECTIVE: This paper presents four generations of a family with radiographically demonstrated congenital vertical talus (CVT) in whom a HOXD10 gene mutation was identified. Some members of the family with this mutation exhibited cavo-varus foot deformity consistent with a Charcot-Marie-Tooth (CMT)-like disorder. DESIGN AND PATIENTS: Physical examination was performed on nearly all of the affected and unaffected family members. DNA was extracted from blood obtained from 14 subjects who showed radiographic and clinical features of CVT (two of whom also had CMT), from two subjects with features of CMT but not CVT, and from 20 related family members who were clinically normal. RESULTS: Radiographs show the appearance of uncorrected CVT in infancy, in childhood, and in adulthood. DNA analysis revealed a mutation in a HOXD10 gene located on chromosome 2 in all of the affected but none of the unaffected family members. CONCLUSION: There is an autosomal-dominant-inherited mutation with complete penetrance which is found in all members of a pedigree with CVT, some of whom exhibit a CMT-like foot disorder. Radiologic findings vary depending on the severity of involvement, treatment provided and age of the patient.

A HOX gene mutation in a family with isolated congenital vertical talus and Charcot-Marie-Tooth disease.

Congenital vertical talus (CVT), also known as "rocker-bottom foot" deformity, is a dislocation of the talonavicular joint, with rigid dorsal dislocation of the navicular over the neck of the talus. This condition is usually associated with multiple other congenital deformities and only rarely is an isolated deformity. The reported familial cases are consistent with an autosomal dominant mode of inheritance with incomplete penetrance. In contrast, Charcot-Marie-Tooth disease (CMT) is thought to be a completely distinct heterogeneous group of disorders, with foot abnormalities that typically develop a high-arched "claw foot" appearance later in life. In the present study, DNA was isolated from 36 members of a single upstate (northern) New York white family of Italian descent in which both CVT and CMT were segregating. Whole-genome linkage analysis with Affymetrix GeneChip Mapping 10K Array defined a 7-Mb critical region on chromosome 2q31, which led to candidate-gene sequencing of six HOX genes and detection of a single missense mutation, M319K (956T-->A), in the HOXD10 gene. In the study family, this mutation was fully penetrant and exhibited significant evidence of linkage (LOD 6.33; theta =0), and it very likely accounts for both CVT and CMT in heterozygotes.