DISEASE CARD

Definition

EEC (ectrodactyly, ectodermaly dysplasia, cleft lip/palate) syndrome is a rare autosomal dominant disorder characterized by ectrodactyly (congenital abnormality involving the absence or malformation of some fingers or toes), ectodermal dysplasia and cleft lip or palate. An association with TP63 gene mutations was first described by Celli et al in 1999.^{1, 2}
Mutations in this transcription factor have also been identified in other ectodermal dysplasia syndromes including AEC (ankyloblepharon-ectodermal dysplasia-clefting; Hay Wells; OMIM 106260) syndrome, limb–mammary syndrome (OMIM 603543), split-hand/foot malformation syndrome (OMIM 605289), ADULT (acro-dermato-ungual-lacrimal-tooth) syndrome (OMIM 103285) and, most recently, Rapp–Hodgkin syndrome (OMIM 129400).

Clinical Description

Infants are born with ectrodactyly (in > 90%), variable ectodermal dysplasia features and cleft lip or palate (in > 75%). Individuals may have widespread dry, atrophic and eczematous skin, hypotrichosis or total alopecia, nail dystrophy (or complete absence of nails) and hypodontia. Teeth may be small or abnormally shaped. Scalp hair is usually fine, sparse, coarse and may be wiry in texture and difficult to comb. Eyebrows, eyelashes, axillary, pubic and body hair may also be affected. Sweat glands are frequently reduced in numbers, causing impaired sweating and poor thermoregulation. A majority of individuals show atresia or hypoplasia of the lacrimal duct that may cause excessive tearing, conjunctivitis and blepharitis.

EEC syndrome is a non-progressive condition. However, there remains a great variability of other ectodermal dysplasia features that may become manifest in adulthood, like abnormalities in the genitourinary tract and of external genitalia (especially in those with Arg227Gln TP63 mutation), endocrine anomalies, choanal atresia, hearing loss, cholesteatoma and intellectual disability.^2-10

Pathogenesis

Many affected individuals display mutations in the TP63 gene, encoding the tumor protein p63. Currently known mutations are clustered within the DNA binding domain of the gene. The TP63 gene is a TP53 homolog, and is an important transcription factor in the development of normal skin and ectodermal structures. The expression of TP63 is more restrained in comparison to the ubiquitous nature of TP53 expression and is restricted to the embryonic ectoderm and the basal layers of epithelia (skin, cervix, oesophagus, mammary glands, prostate and urothelium). 
There is increasing evidence for genotype-phenotype correlation for TP63 – associated ectodermal dysplasia syndromes, as clustering of mutations in some of the phenotypes to specific sites of the p63 protein has been observed.^{11, 12} 

Diagnosis

Diagnosis is usually made by assessment of the clinical features either at, or soon after birth. Electron microscopic studies of hair shafts reveal longitudinal grooves, distorted bulbs and cuticular defects.¹³ Screening for TP63 gene mutation may allow confirmation of the diagnosis and genetic counselling. 

Differentialdiagnosis

Odontotrichomelic syndrome, Martinez syndrome, Zlotogora–Ogur syndrome and Rosselli–Gulienetti syndrome
 

Treatment

The management of the EEC syndrome requires expertise from various medical and surgical specialties. Surgical repair of the cleft lip or palate defects, lacrimal duct and limb defects as well as genitourinary abnormalities may become necessary. Topical emollients are helpful against dry, eczematous areas of skin. Individuals frequently require dentures, dental implants and bridges. 

Table 1.Tp63 related disorders

<sup>AD = autosomal dominant; ADULT = acro-dermato-ungual-lacrimal-tooth; AEC =  Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome; CL/P = cleft lip/cleft palate; EEC = ectrodactyly (split-hand/foot malformation), ectodermal dysplasia, clefting; SHFM4 = split-hand/foot malformation type type4; RHS=Rapp-Hodgkin syndrome
* strands of tissue that completely or partially fuse the upper and lower eyelids
** starch iodide sweat testing of the palms is rarely helpful in documenting sweating ability</sup>

References

^{1.    Rüdiger RA, Haase W, Passarge E. Association of ectrodactyly, ectodermal dysplasia, and cleft lip-palate. Am J Dis Child. 1970;120(2):160-163.
2.    Celli J, Duijf P, Hamel BC, et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell. 1999;99(2):143-153.
3.    Trüeb RM, Bruckner-Tuderman L, Wyss M, Widmer M, Wüthrich B, Burg G. Scalp dermatitis, distinctive hair abnormalities and atopic disease in the ectrodactyly-ectodermal dysplasia-clefting syndrome. Br J Dermatol. 1995;132(4):621-625.
4.    Sutton VR, van Bokhoven H. TP63-Related Disorders (last revision 04/2021). In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle; 1993.
5.    Rodini ES, Richieri-Costa A. EEC syndrome: report on 20 new patients, clinical and genetic considerations. Am J Med Genet. 1990;37(1):42-53.
6.    Christodoulou J, McDougall PN, Sheffield LJ. Choanal atresia as a feature of ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome. J Med Genet. 1989;26(9):586-589.
7.    Rollnick BR, Hoo JJ. Genitourinary anomalies are a component manifestation in the ectodermal dysplasia, ectrodactyly, cleft lip/palate (EEC) syndrome. Am J Med Genet. 1988;29(1):131-136.
8.    Küster W, Majewski F, Meinecke P. EEC syndrome without ectrodactyly? Report of 8 cases. Clin Genet. 1985;28(2):130-135.
9.    Rosenmann A, Shapira T, Cohen MM. Ectrodactyly, ectodermal dysplasia and cleft palate (EEC syndrome). Report of a family and review of the literature. Clin Genet. 1976;9(3):347-353.
10.    Maclean K, Holme SA, Gilmour E, et al. EEC syndrome, Arg227Gln TP63 mutation and micturition difficulties: Is there a genotype-phenotype correlation? Am J Med Genet A. 2007;143a(10):1114-1119.
11.    Zheng J, Liu H, Zhan Y, et al. Tooth defects of EEC and AEC syndrome caused by heterozygous TP63 mutations in three Chinese families and genotype-phenotype correlation analyses of TP63-related disorders. 2019;7(6):e704.
12.    Clements SE, Techanukul T, Coman D, Mellerio JE, McGrath JA. Molecular basis of EEC (ectrodactyly, ectodermal dysplasia, clefting) syndrome: five new mutations in the DNA-binding domain of the TP63 gene and genotype-phenotype correlation. Br J Dermatol. 2010;162(1):201-207.
13.    Tekin M, Ohle C, Johnson DE, Christmas JT, Bodurtha J. Counseling dilemmas in EEC syndrome. Genet Couns. 2000;11(1):19-24.}