Ectrodactyly, Ectodermal Dysplasia, And Cleft Lip/palate Syndrome 3

A number sign (#) is used with this entry because EEC syndrome-3 (EEC3) is caused by heterozygous mutation in the gene encoding p63 (TP63; 603273) on chromosome 3q28.

Description

Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome-3 (ECC3) is an autosomal dominant disorder comprising absence of the central parts of the hands and feet, resulting in split-hand/foot malformation, ectodermal dysplasia, and cleft lip with or without cleft palate (summary by Maas et al., 1996).

Also see EEC1 (129900), which has been mapped to chromosome 7q11.

Clinical Features

The features of EEC syndrome are ectrodactyly of hands and feet, ectodermal dysplasia, and cleft lip/palate. Maas et al. (1996) found great variability in the clinical manifestations of EEC in affected members of a large Dutch kindred. Specific genitourinary anomalies were found. A presenting problem in the proband at the age of 4 months involved micturition which required an effort and seemed painful. Cystoscopy showed a distal stricture of the urethra requiring internal urethrotomy and repeated dilatation of the urethra. Abnormally thin bladder epithelium was thought to be an explanation for the continuing complaints. A trial with a synthetic sulfonated glycosaminoglycan resulted in remarkable improvement with almost complete disappearance of complaints. The elder sister had similar complaints of burning sensation in the bladder without urinary tract infection. Biopsies of the bladder demonstrated very thin atrophic bladder epithelium. Similar remarkable improvement was achieved with the use of the synthetic sulfonated glycosaminoglycan.

Sripathomsawat et al. (2011) provided follow-up of the Dutch family with remote consanguinity reported by Maas et al. (1996). Twelve newly affected individuals were identified, with marked phenotypic variability. Limb defects were present in 12 of the 26 affected members, including 6 with split hand/foot and 1 with mesoaxial polydactyly. Two had cleft lip/palate, and 3 had mild manifestations of this feature, such as indentation of the upper vermilion border. One individual had features of the AEC syndrome (106260). Features of ectodermal dysplasia were also variable. Most had blonde, sparse hair with slow growth, thin nails, periorbital hyperpigmentation, and dental caries. Four had hypodontia, and 8 were edentulous on examination. Most notable, 12 of those affected had micturition difficulties, which tended to improve with age, and 1 had defecation difficulties. Sripathomsawat et al. (2011) emphasized that patients with EEC3 should have systematic dental examinations.

Kosaki et al. (2008) reported a Japanese infant with split hand-foot malformation and cleft lip and palate. He had underdevelopment of the central digital rays of both hands and feet, sparse hair, and thin and dry skin. Genetic analysis identified a heterozygous mutation in the p63 gene (R204W; 603273.0001). His father, who was found to be somatic mosaic for the mutation, had split hand-foot malformation, no cleft lip or palate, and whorl-like streaky pigmentary patterns of the skin following Blaschko lines. He had gray hair on the right half of his scalp and brown thin hair on the left side. He also had enamel hypoplasia and partial adontia. Extensive genetic analysis demonstrated that the father was mosaic for the mutation in peripheral blood and hair, although most of his sperm carried the mutation. Kosaki et al. (2008) concluded that the mutation was postzygotic in the father and resulted in gonosomal mosaicism.

Sripathomsawat et al. (2011) reported a Thai father and daughter with EEC3 confirmed by genetic analysis (R227P; 603273.0028). The 4-year-old daughter had dry and sparse dark hair, left cleft lip and palate, depressed nasal bridge, slightly dry skin, and thin nails. She had split hands and split right foot, as well as syndactyly of the right fourth and fifth toes. Her father had normal dark hair, dry skin, split right hand, bifid right thumb, and flexion contracture of the distal phalanx of the left index finger. His second toes were small and slender, and he had underdeveloped toenails. The father had significant dental involvement, with enamel hypoplasia, extensive dental caries, hypodontia of the mandibular canines, generalized microdontia, prominent marginal ridges of permanent maxillary incisors, round-shaped permanent molars, and barrel-shaped permanent maxillary central incisors. Both patients had normal nipples and no micturition problems.

Hyder et al. (2017) reported 2 unrelated males with molecularly confirmed EEC3 in whom genitourinary defects were prominent. The first patient was evaluated at 4 years of age for dysuria and straining on micturition and was found to have a small urethral meatal orifice, dilated urethra, and flaccid megacystis. He later developed a bladder diverticulum and required self-catheterization as treatment for his bladder dysfunction. The second patient had hydronephrosis prenatally, a bladder diverticulum, and urethral stenosis. By age 2 years, he had developed ureteral dilation that progressively worsened, eventually requiring tapering and reimplantation of his ureters. He had increased residual bladder volumes after surgery, but had not required self-catheterization. Both patients had typical features of EEC3 such as cleft palate, lacrimal duct abnormalities, microdontia, and sparse, blonde hair. Neither patient had severe limb defects; the first patient was missing only the distal phalange of the third digit on one hand, and the second patient had only cutaneous syndactyly of the second and third toes.

Mapping

To investigate the possibility that ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome is allelic to limb-mammary syndrome (LMS; 603543), Celli et al. (1999) used polymorphic markers from the 3q27 region for a linkage analysis in 5 families with EEC syndrome. Positive lod scores were obtained with markers from within the LMS interval for each of these families. The added Zmax across these families was 8.03 at marker D3S3530 at a recombination fraction theta = 0. Recombination events were observed between markers that define the LMS interval, D3S1580 and D3S1314, and the disease locus, indicating that these 5 EEC syndrome families map to the same 3-cM region of 3q27 that had been found for the LMS family reported by van Bokhoven et al. (1999). This colocalization and the overlapping clinical features of these disorders strongly suggested that the same gene is involved in this form of EEC syndrome (EEC3) and LMS. The critical region for EEC3/LMS was reduced to a 2.3-cM interval by a recombination event between marker D3S3530 and the genetic defect in EEC3 family Bri-1 (64:1 odds).

Molecular Genetics

By analysis of the TP63 gene, which is located in the critical LMS/EEC3 interval, Celli et al. (1999) identified heterozygous mutations in 9 unrelated EEC3 families. Eight mutations resulted in amino acid substitutions that were predicted to abolish the DNA binding capacity of p63 (see, e.g., 603273.0001-603273.0003); the ninth was a frameshift mutation (603273.0004). Transactivation studies with these mutant p63 isotypes provided a molecular explanation for the dominant character of p63 mutations in EEC3.

In a study of 4 European families with EEC3, Ianakiev et al. (2000) identified heterozygosity for 2 missense mutations in the TP63 gene (R279H, 603273.0007; and R304Q, 603273.0008, respectively). The R279H mutation was also identified in a 25-year-old female with features consistent with Rapp-Hodgkin syndrome (see 129400 and Bougeard et al., 2003).

In a Japanese girl who had EEC3 and developed diffuse large B-cell type non-Hodgkin lymphoma, Akahoshi et al. (2003) identified heterozygosity for a missense mutation in the TP63 gene (D312G; 603273.0015). They speculated that p63 may exert a biologic function as a tumor suppressor and suggested that malignant lymphoma should be considered an important complication of EEC3, inasmuch as 2 previous reports had also documented an association of EEC syndrome with malignant lymphoma (Gershoni-Baruch et al., 1997; Ogutcen-Toller et al., 2000).

In affected members of 3 unrelated families, 2 previously studied by O'Quinn et al. (1998), van Bokhoven et al. (2001) identified a missense mutation in the TP63 gene (R227Q; 603273.0024). Reisler et al. (2006) identified the R227Q mutation in a mother and daughter with ADULT syndrome (103285) and suggested that there may be considerable overlap between the EEC and ADULT syndromes.

Genotype/Phenotype Correlations

In affected members of 2 unrelated families with EEC syndrome, features of LMS, and severe micturition difficulties, Maclean et al. (2007) identified the R227Q mutation in the TP63 gene (603273.0024). Noting that 4 of the 6 cases/families reported with this mutation have manifested similar urinary symptoms (see van Bokhoven et al., 2001), Maclean et al. (2007) suggested that this represents a genotype/phenotype correlation.

History

In the Dutch family reported by Maas et al. (1996), O'Quinn et al. (1997, 1998) found linkage to chromosome 19, which was here designated EEC2. However, van Bokhoven et al. (2001) identified the R227Q mutation in affected members of this family, and the original linkage to chromosome 19 appears to have been a fortuitous finding (van Bokhoven, 2007).