Update on embryology of the upper limb.

Current concepts in the steps of upper limb development and the way the limb is patterned along its 3 spatial axes are reviewed. Finally, the embryogenesis of various congenital hand anomalies is delineated with an emphasis on the pathogenetic basis for each anomaly.

Sonographic identification of lower limb venous hypoplasia in the prenatal diagnosis of Klippel-Trénaunay syndrome.

We report the prenatal identification of lower-limb venous hypoplasia to support a provisional prenatal diagnosis of Klippel-Trénaunay syndrome (KTS). Ultrasound assessment of a fetus with marked lower-limb edema, cystic areas in the abdomen/pelvis/lower limbs and abnormal development of the feet demonstrated bilateral hypoplasia of the femoral and popliteal veins. The external iliac veins and the great saphenous veins were seen to be normal. The lower limb arterial system was present. These findings supported KTS as the most likely provisional diagnosis, and postnatal clinical evaluation confirmed that the infant is best classified in the spectrum of KTS. Venous hypoplasia was confirmed with a postnatal ultrasound examination of the lower limbs. This case suggests that careful examination of the lower-limb venous system may be helpful in making the prenatal diagnosis of KTS.

Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects.

The congenital malformation Split Hand-Foot Malformation (SHFM, or ectrodactyly) is characterized by a medial cleft of hands and feet, and missing central fingers. Five genetically distinct forms are known in humans; the most common (type-I) is linked to deletions of DSS1 and the distalless-related homeogenes DLX5 and DLX6. As Dlx5;Dlx6 double-knockout mice show a SHFM-like phenotype, the human orthologs are believed to be the disease genes. SHFM-IV and Ectrodactyly-Ectodermal dysplasia-Cleft lip (EEC) are caused by mutations in p63, an ectoderm-specific p53-related transcription factor. The similarity in the limb phenotype of different forms of SHFM may underlie the existence of a regulatory cascade involving the disease genes. Here, we show that p63 and Dlx proteins colocalize in the nuclei of the apical ectodermal ridge (AER). In homozygous p63- (null) and p63EEC (R279H) mutant limbs, the AER fails to stratify and the expression of four Dlx genes is strongly reduced; interestingly, the p63+/EEC and p63+/- hindlimbs, which develop normally and have a normally stratified AER, show reduced Dlx gene expression. The p63+/EEC mutation combined with an incomplete loss of Dlx5 and Dlx6 alleles leads to severe limb phenotypes, which are not observed in mice with either mutation alone. In vitro, DeltaNp63alpha induces transcription from the Dlx5 and Dlx6 promoters, an activity abolished by EEC and SHFM-IV mutations, but not by Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) mutations. ChIP analysis shows that p63 is directly associated with the Dlx5 and Dlx6 promoters. Thus, our data strongly implicate p63 and the Dlx5-Dlx6 locus in a pathway relevant in the aetio-pathogenesis of SHFM.

Full monosomy 21, prenatally diagnosed by fluorescent in situ hybridization.

We describe a case of full monosomy 21 which was prenatally diagnosed in chorionic villi by fluorescent in situ hybridization (FISH). Because of intrauterine fetal death, a curettage was performed and cytogenetic analysis of skin fibroblasts confirmed the presence of monosomy 21 in fetal cells. DNA investigations showed a paternal origin of the single chromosome 21. Inspection and autopsy of the fetus revealed several congenital malformations. Some of them have been reported in earlier studies of monosomy 21; others concern new observations. Regarding the eye, the following abnormalities were microscopically observed: absence of the anterior and posterior eye chambers, aniridy, a hypoplastic ciliary body, Peter's anomaly, and a double retina with secondary dysplasia. In addition, malformations of the extremities were seen: partial, proximal syndactyly of digits 3 and 4 of the right hand; pes varus position of the right foot; and transverse reduction defect at the tarsals of the left foot. To our knowledge, this is the first case in which full monosomy 21 has been proven.

Cystic hygroma as an early first-trimester ultrasound marker for recurrent Fryns' syndrome.

We present a case of a fetus who at a 12-week ultrasound examination was shown to have a large cystic hygroma. Fryns' syndrome was suspected because the mother's previous pregnancy had been affected by the condition. Pathological examination confirmed the diagnosis at this early stage of gestation. In families with increased risk for Fryns' syndrome, first-trimester ultrasound screening should be offered to exclude cystic hygroma as an ultrasound marker for this most often lethal malformation.

Mirror image duplication of the hands and feet: report of a sporadic case with multiple congenital anomalies.

Mirror image duplication of the hands and feet is a rare entity. Based on 3 previous reports, findings include nasal abnormalities, dimelia of ulna and fibula, tibial hypoplasia and mirror image duplication of hands and feet. We report on a sporadic case in which mirror image duplication was associated with multiple congenital anomalies. Although these cases may represent variable expression of the same dominantly transmitted complex polysyndactyly syndrome, it is possible that mirror image duplication of the hands and feet is a manifestation common to a number of distinct clinical entities. During limb bud development, duplication and aberrant positioning of the zone of polarizing activity in relation to the apical ectodermal ridge may account for the anatomic abnormalities of the hands and feet in these patients.

Anatomical basis for congenital deformities of the lower extremities. Part I. The hip and thigh.

Congenital deformities frequently produce problems not always discernible at birth. Often, a period of time is required for the development of signs and symptoms. The present discussion presents the intrauterine anatomy of a midterm fetus relative to conditions of the hip and thigh. Cryomicrotomy is used in this study to present the best anatomical evidence of the morphology involved.

Mirror polydactyly: pathogenesis based on a morphogen gradient theory.

We report on an infant with 7 toes of the left foot in a mirror configuration in association with ipsilateral duplication of the calcaneus and fibula, tibial aplasia, femoral hypoplasia, and a teratomatous sacrococcygeal tumour. The possible pathogenetic mechanisms leading to this limb abnormality are discussed with special emphasis on a field morphogen gradient hypothesis.