Ectrodactyly-ectodermal dysplasia-cleft syndrome (EEC Syndrome)

Etiology (Ophthalmology 2012; 119:74)

• Autosomal dominant syndrome mapped to chromosome 3q27 (Cell 1999; 99:143).
• Highly variable expression
• Marked interfamilial and intrafamilial variability
• Origin is a p63 mutation (J Med Genet 2002; 39:559)
• p63 is a transcription factor, related to p53 and p73
• p63 contains two exons and encodes two different classes of proteins.
• Approximately 40 different pathogenic mutations (Br J Dermatol 2010; 162:201)
• Mostly missense nucleotide substitution mutations.
• Mutations in DNA-binding domain from exon 4-8.

Epidemiology

• Rare syndrome.
• Genders affected equally.
• Compared with other ectodermal dysplasia syndromes, EEC is more commonly associated with ocular abnormalities.

History (J Med Genet 1995; 32:716)

• Lacrimal drainage anomalies are a key feature of this syndrome
• Tearing
• Dacryocystitis
• Progressive keratopathy related to limbal stem cell deficiency
• Foreign body sensation
• Conjunctival injection
• Severe photophobia (Ophthalmology 1985; 92:1427).

Clinical features including less common presentation patterns

• Unusual patterns of lacrimal sac development – 21/23 EEC patients had lacrimal dysgenesis (Ophthalmology 2012; 119:74).
• Stenosis
• Absence
• “Hour glass” deformity
• Recurrent corneal epithelial defects
• Dry eye
• Tearing may be absent despite dacryostenosis (Br J Ophthalmol 1989; 73:261).
• Trichiasis
• Absent meibomian glands (Am J Ophthalmol 1984; 97:496)
• Meibomian gland defect was present in 23/23 EEC patients recently studied (Ophthalmology 2012; 119:74).
• Normal Schirmer test and abnormal tear breakup time (Graef Arch Clin Exp Ophthalmol 1997; 235:512).
• Mucin deficiency with reduced conjunctival goblet cells
• Corneal ulceration
• Corneal pannus and neovascularization
• Corneal thinning and scarring
• Spontaneous corneal perforation (Br J Ophthalmol 1989; 73:261).

Testing and evaluation for establishing the diagnosis

• Clinical diagnosis requires ≥2 of the 3 main features of the syndrome:
• Ectodermal dysplasia affecting the skin, hair, nails, teeth, sweat glands, lacrimal ducts, or mammary glands
• Hand or foot abnormalities consistent with the split hand–split foot spectrum (“lobster claw”)
• Cleft lip with or without cleft palate.
• Absence of meibomian glands may be diagnostic (Eye 1996; 10:355)

Testing and evaluation to determine staging or level of fundamental impairment

• Genetic testing of p63 gene (J Mol Diagnost 2012; 14:38)
• DNA extracted from peripheral blood

• Mostly sporadic mutation
• Many families identified and described

• Mutations in the p63 gene can cause 5 other syndromes, with some overlapping features:
• AEC syndrome (ankyloblepharon- ectodermal defects- cleft lip/palate syndrome, aka Hay–Wells syndrome)
• Characterized by congenital adhesion of the eyelids
• Ankyloblepharon filiforme adnatum
• Rapp–Hodgkin syndrome – ectodermal dysplasia and clefting
• Likely a variant of AEC syndrome
• Limb mammary syndrome
• Athelia is absence of nipple-areola complex
• Includes ectrodactyly and cleft palate
• Acro-dermato-ungual-lacrimal-tooth syndrome (“ADULT syndrome”) (Int J Dermatol 2012; 51:693).
• Much less common that EEC or AEC syndromes
• Also characterized by ectrodactyly (lobster claw deformity) and lacrimal dysgenesis
• Lacks clefting (typical of EEC) or ankylblepharon (typical of AEC)
• Split-hand and foot malformation type 4.

Natural history including common variants in disease evolution

• Main concern is visual loss from progressive keratopathy
• Lacrimal dysgenesis is managed in context of keratopathy
• Limbs are unusually functional despite severe deformity
• Ectodermal dysplasia is mostly cosmetic defect of skin, hair, nails

Medical therapy options

• Requires long term care of anterior segment eye abnormalities
• Lid hygiene for blepharitis
• Dry eye management
• Treatment of keratopathy with topical steroids and bandage contact lens may not be successful (Ophthalmology 1985; 92:1427).

Radiation therapy options

• None

Surgery options

• Lacrimal duct probing is not recommended for congenital nasolacrimal duct obstruction in this clefting syndrome (J Ped Ophthalmol 1970; 7:79).
• DCR surgery for discharge from the lacrimal sac, to limit corneal scarring and infection (Graef Arch Clin Exp Ophthalmol 1997; 235:512).
• Grafting for limbal stem cell deficiency.

Other management considerations

• With identification of molecular defect new treatment approaches may be possible

Common patterns of response to treatment and discuss strategies of follow-up and secondary treatment

• Loss of vision from limbal stem cell deficiency may not be preventable or treatable (Ophthalmology 2012; 119:74).

• Corneal transplant in ectodermal dysplasia is high risk
• DCR surgery mostly successful, compromised by ectodermal dysplasia

• Corneal perforation
• Corneal scarring
• Poor dentition
• Alopecia

• The syndrome was described in two publications in 1970 (Am J Dis Child 1970; 120:160; Am J Hum Gen 1970; 22:371).
• Edward Alfred Cockayne (English physician 1880-1956) observed similar, probably incomplete expression, in 1936 (Biometrika 1936; 28:60).
• Not related to Cockayne syndrome, autosomal recessive pigmentary retinopathy associated with xeroderma pigmentosum.

• Iorio ED, Kaye SB, Ponzin D, et al: Limbal stem cell deficiency and ocular phenotype in ectrodactyly-ectodermal dysplasia-clefting syndrome caused by p63 mutations. Ophthalmology 2012; 119:74.
• Celli J, Duijf P, Hamel BC, et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 1999; 99:143.  
• Buss PW, Hughes HE, Clarke A. Twenty-four cases of the EEC syndrome: clinical presentation and management. J Med Genet 1995; 32:716.
• Mondino BJ, Bath PE, Foos RY, et al. Absent meibomian glands in the ectrodactyly, ectodermal dysplasia, cleft lip-palate syndrome. Am J Ophthalmol 1984; 97:496
• Clements SE, Techanukul T, Coman D, et al. 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; 162:201.
• Rudiger RA, Haase W, Passarge E. Association of ectrodactyly, ectodermal dysplasia and cleft lip-palate. Am J Dis Child 1970; 120:160.
• Freire-Maia N: A newly recognized genetic syndrome of tetramelic deficiencies, ectodermal dysplasia, deformed ears, and other abnormalities. Am J Hum Gen 1970; 22:371.
• Kasmann B, Ruprecht KW: Ocular manifestations in a father and son with EEC syndrome. Graef Arch Clin Exp Ophthalmol 1997; 235:512.
• Baum JL, Bull MJ. Ocular manifestations of the ectrodactyly, ectodermal dysplasia, cleft lip-palate syndrome. Am J Ophthalmol 1974;78:211.
• Mawhorter LG, Ruttum MS, Koenig SB: Keratopathy in a family with the ectrodactyly-ectodermal dysplasia-clefting syndrome. Ophthalmology 1985; 92:1427.
• Bonnar E, Logan P, Eustace P: Absent meibomian glands: a marker for EeC syndrome. Eye 1996; 10:355.
• Kaiser-Kupfer M: Ectrodactyly, ectodermal dysplasia and clefting syndrome. Am J Ophthalmol 1973; 76:992.
• McNab AA, Potts MJ, Welham RAN: The EEC syndrome and its ocular manifestations. Br J Ophthalmol 1989; 73:261.
• Wiegmann OA, Walker FA: The syndrome of lobster claw deformity and nasolacrimal obstruction. J Ped Ophthalmol 1970; 7:79.
• Links to pertinent educational material for physicians and patients
• http://www.ectodermaldysplasia.org
• http://www.sindrome-eec.it