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

Abstract

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.