Ectrodactyly, Ectodermal Dysplasia, And Cleft Lip/palate Syndrome 1

This form of ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, designated EEC1, has been linked to chromosome 7q11.2-q21.3. Another form of the disorder, designated EEC3 (604292), is caused by mutation in the TP63 gene (603273).

Rudiger et al. (1970) suggested the designation EEC for the syndrome observed in a female child. The features were ectrodactyly of both hands and one foot, ectodermal dysplasia with severe keratitis, and cleft lip/palate. This disorder is probably the same as that reported in one of the patients of Rosselli and Gulienetti (1961) and probably different from the combination of ectrodactyly, anodontia and partial noncanalization of the lacrimal duct described in mother and son by Temtamy and McKusick (1969). Pashayan et al. (1974) reported affected sisters (their cases 2 and 3). Brill et al. (1972) described affected black mother and 3 of her 4 children. The 3 pedigrees reported by Walker and Clodius (1963) suggested irregular autosomal dominant inheritance of the combination of split hand and/or foot and cleft lip/palate. Atresia of the lacrimal puncta or other deformity of the lacrimal duct was present in some. Kuster et al. (1985) reported 2 families that illustrated variable expression and specifically indicated that ectrodactyly is not an obligate feature. Knudtzon and Aarskog (1987) described 2 unrelated children with the EEC syndrome who also had growth hormone deficiency and isolated absent septum pellucidum. They suggested that there is an association with isolated growth hormone deficiency, the latter being secondary to developmental hypothalamic defects. Among 13 patients with EEC, Rollnick and Hoo (1988) found that 7 had anomalies of the urinary tract and 3 had genital anomalies. They found frequent similar reports in the literature. Christodoulou et al. (1989) described choanal atresia as a feature. Tucker and Lipson (1990) also observed choanal atresia and described vesicoureteric reflux. Nardi et al. (1992) evaluated 25 EEC syndrome patients (14 isolated and 11 familial cases) for genitourinary tract anomalies, using intravenous pyelogram (IVP), voiding urethrocystography, and sonographic examination. Involvement of the urinary tract was found in 7 isolated and 6 familial cases.

Fryns et al. (1990) reported variable manifestations of EEC in 2 families, confirming that no symptom is obligatory for the diagnosis. In the absence of cleft lip/palate, EEC patients have a characteristic facial morphology with maxillary hypoplasia, short philtrum, and broad nasal tip. Tse et al. (1990) described sisters with the full-blown disorder; their mother had only minimal changes: preaxial polydactyly of the right hand and duplication of the terminal phalanx of the second toe of the left foot with 3/4 syndactyly. Anneren et al. (1991) suggested that low birth weight and polysyndactyly (without ectrodactyly) may be features of the EEC syndrome. Was she a germinal (somatic) mosaic for the dominant mutation? In 2 members of an affected family, EEC was diagnosed prenatally after 16 weeks of gestation by detection of cleft lip and palate on ultrasound examination. Rodini and Richieri-Costa (1990) reported on 20 Brazilian patients (11 sporadic and 9 familial) and gave a review of 13 disorders to be considered in the differential diagnosis: Rapp-Hodgkin syndrome (129400), the Hay-Wells or AEC syndrome (106260), the Rosselli-Gulienetti syndrome (225000), and others. Although patients with the EEC syndrome often suffer from repeated infections of the eyes, upper respiratory tract, and urogenital system, Obel et al. (1993) could demonstrate no immunologic abnormality in 4 patients. They concluded that the recurrent infections are related solely to the anatomic anomalies. Lacombe et al. (1993) described mother and daughter with features suggesting an overlap between the EEC syndrome and the LADD syndrome (149730). The mother had typical split foot deformity of both feet and severe malformations of the upper limbs with 2 ulnar digits on each hand. However, she did not have skin or hair abnormalities, oral clefting, or lacrimal difficulties. Her daughter had bilaterally low set, posteriorly rotated, small ears. By clinical examination and history, she had recurrent dacryocystitis and a chronic, mild, purulent eye discharge, mainly after sleep. The child had poor lacrimation, and the lacrimal puncta were hypoplastic. Scalp hair was sparse and brittle. There was no oral clefting.

Using transvaginal ultrasonography, Bronshtein and Gershoni-Baruch (1993) diagnosed bilateral cleft lip and lobster-claw deformities of the hands and feet, consistent with the diagnosis of the EEC syndrome, in a 14-week-old fetus. The fetus was aborted and the diagnosis was confirmed. The parents were unaffected.

Buss et al. (1995) identified 24 cases of EEC syndrome as part of a nationwide study in the UK. Ectodermal dysplasia, by study definition, was present in all cases and hair and teeth were universally affected. Nail dysplasia was present in 19 subjects (79%) and the skin was affected in 21 (87%). Hypohidrosis was not a prominent feature in the syndrome. Distal limb defects from simple syndactyly to tetramelic cleft hand and foot were identified, including preaxial anomalies. Oral facial clefting was identified in 14 cases (58%) and lacrimal duct anomaly in 21 (87%).

Roelfsema and Cobben (1996) analyzed 230 published cases (116 familial and 114 sporadic) of EEC syndrome. Ectrodactyly was found in 193 patients (84%), ectodermal dysplasia in 178 (77%), clefting in 156 (68%), and anomalies of lacrimal ducts in 135 (59%). Urogenital defects were reported in 52 patients, and conductive hearing loss in 33. Isolated cases were more severely affected than familial cases. Interfamilial variability was significantly greater than intrafamilial variability, pointing to genetic (allelic?) heterogeneity. The penetrance of the EEC mutation is between 93 and 98%. No signs of anticipation were apparent. Moerman and Fryns (1996) also emphasized the significance of urogenital anomalies in the EEC syndrome. They suggested that the Rapp-Hodgkin type of ectodermal dysplasia with clefting (129400) may be fundamentally the same condition as EEC.

London et al. (1985) pointed to the combination of urinary tract pathology with EEC. Hecht (1985) suggested that the combination be termed EECUT syndrome. Frick et al. (1997) described EECUT syndrome in a male infant born prematurely at 35 weeks of gestation and exhibiting features of EEC with urinary tract abnormalities: on the left, a large ureterocele; on the right, an atretic ureter. Both conditions led to intrauterine hydronephrosis, renal dysplasia, oligohydramnios, pulmonary hypoplasia, and perinatal death of the infant. Autopsy showed only small rudiments of thymic tissue containing single epithelial cells, completely devoid of Hassall corpuscles. The ureteral malformations were thought to be of epithelial origin as was also the defect in the thymus.

De Smet and Fryns (1995) reported the concurrence of a large omphalocele and anal atresia in a female newborn with the EEC syndrome. They found the association in 4 other unpublished patients, indicating that anal atresia may constitute a true manifestation of this autosomal dominant syndrome with variable expression.

Qumsiyeh (1992) reviewed 8 reports of the EEC syndrome associated with chromosome 7 anomalies and suggested that the responsible gene is in the region 7q11.2-q21.3. Hasegawa et al. (1991) had reported cases of the EEC syndrome in a grandfather, father and daughter, in association with a reciprocal translocation between chromosomes 7 and 9. High-resolution at chromosome banding studies showed that the breakpoints of this translocation were 7q11.21 and 9p12, or 7p11.2 and 9q12. By conventional chromosome banding methods, they could not distinguish between the 2 possibilities. Fukushima et al. (1993) performed fluorescence in situ hybridization on chromosome preparations from this family, using a chromosome 7-specific alpha-satellite probe and a chromosome 9-specific beta-satellite probe. These studies demonstrated that the breakpoints of the translocation were confined to 7q11.21 and 9p12. Scherer et al. (1994) constructed a physical map consisting of overlapping YAC clones for the region 7q21.3-q22.1 where one form of the split-hand/split-foot malformation (183600) had been mapped. By somatic cell hybrid and fluorescence in situ hybridization analyses, they defined split hand/split foot-associated chromosomal rearrangements in 12 patients. An SHFM1 critical interval of 1.5 Mb was established by analysis of 5 patients with deletions. Translocation or inversion breakpoints found in 6 patients were mapped within 700 kb of each other in the critical region. Scherer et al. (1994) were impressed by the fact that 8 of the patients analyzed were classified as having syndromic ectrodactyly, of which the EEC syndrome is a cardinal example.