Billy A. Watson and Kerby C. Oberg
164
environmental factors. Careful examination, both prenatally and
postnatally, is key to early identification and management. Progress has
been made recently to improve the classification/diagnosis of CULA
using language that is inclusive of both basic and clinical sciences. In this
review, we incorporate a similar approach in providing a comprehensive
overview of CULA combining information regarding the molecular
landscape of limb development with the growing database of clinical
genetics. We will also highlight recent advances in risk-factor
association, diagnosis and management of congenital upper limb
anomalies.Keywords: limb development, limb dysmorphology, epidemiology,
classification, etiology, molecular diagnosis, treatment, review
EMBRYOLOGY
Limb development begins in the fourth week of gestation (Figure 1A) and
coincides with the development of other organs such as the heart, kidney, liver
and lungs. Consequently, Congenital Upper Limb Anomalies (CULA) can
occur in conjunction with other congenital anomalies. Vertebrate limb
development is under tight molecular regulation directing the number, location
and pattern of tetrapod limbs. Expression of Homeobox (Hox) genes along the
cranial-caudal or anterior-posterior axis of the developing embryo provides
segmental identity to the embryo and establishes presumptive limb fields
within the lateral plate mesoderm from which the limb buds will emerge
(Figure 1B) (Oliver et al., 1988; Burke et al., 1995; Wellik, 2009; Tanaka,
2016).
Limb Initiation
Limb bud initiation occurs as a complex interaction between wingless-
type MMTV (WNT), fibroblast growth factor (FGF) signals and T-box (TBX)
transcription factors in the mesenchyme of the presumptive limb field (Figure
1C). Murine Fgf10 knockouts develop tetra-amelia or failure of limb bud
initiation (Ng et al., 2002), whereas disruption of another member of the
pathway, WNT3A, has been shown to cause tetra-amelia in humans (Niemann
et al., 2004). TBX4 and TBX5 contribute to initiation and identity of the
hindlimb and forelimb, respectively (Gibson-Brown et al., 1996). Holt-Oram