Ectrodactyly-ectodermal dysplasia-cleft syndrome (EEC Syndrome)

Etiology

• Autosomal dominant syndrome mapped to chromosome 3q27 (Cell 1999; 99:143).
• Highly variable expression with marked interfamilial and intrafamilial variability.
• EEC syndrome is primarily caused by mutations in the TP63 gene (J Med Genet 2002; 39:559, which encodes a transcription factor crucial for the development of ectodermal structures
• These mutations lead to a spectrum of manifestations, including limb malformations, ectodermal dysplasia, and orofacial clefts
• TP63 is a transcription factor related to p53 and p73, contains two exons and encodes two different classes of proteins.
• Approximately 40 different pathogenic mutations identified (Br J Dermatol 2010; 162:201), mostly missense nucleotide substitutions, often in the DNA-binding domain from exon 4-8.
• Notably, a study in 2025 identified ARHGAP29 deficiency in mice, which regulates NF-κB and IRF6 signaling pathways, influencing TP63 expression and contributing to EEC-like phenotypes (Chi 2025).

Epidemiology

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

History

• Lacrimal drainage anomalies are a key feature: 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 lacrimal sac development – 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; 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, pannus, neovascularization, thinning, scarring, spontaneous perforation.
• New reports describe an increased incidence of ocular surface inflammation and earlier onset of limbal stem cell deficiency in EEC patients, suggesting closer monitoring in childhood is warranted (Di Iorio 2023).

Testing and evaluation for establishing the diagnosis

• Clinical diagnosis requires ≥2 of the 3 main features: ectodermal dysplasia, split hand/foot malformation, cleft lip/palate.
• Absence of meibomian glands may be diagnostic (Eye 1996; 10:355).
• Genetic testing of p63 gene from peripheral blood (J Mol Diagnost 2012; 14:38).
• Whole-exome sequencing (WES) has become a pivotal tool in diagnosing EEC syndrome. A study published in 2022 identified a de novo missense mutation (R304W) in the TP63 gene in a fetus at 22 weeks gestation, confirming the diagnosis of EEC syndrome. This case also highlighted associated anomalies such as cleft lip and palate and polycystic kidney, underscoring the importance of comprehensive genetic screening in prenatal settings (He 2022).
• Advancements in prenatal imaging have facilitated earlier detection of EEC syndrome. In a 2022 case, a fetus at 16 weeks gestation exhibited limb malformations characteristic of EEC syndrome, leading to a provisional diagnosis. Subsequent molecular genetic testing confirmed the diagnosis, emphasizing the efficacy of combining detailed ultrasound evaluations with genetic testing for early diagnosis (Savukyne 2022).

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 mutations; many families described.

• Mutations in TP63 cause 5 other syndromes with overlapping features: AEC syndrome, Rapp–Hodgkin syndrome, Limb mammary syndrome, ADULT syndrome, split-hand/foot malformation type 4.

Natural history including common variants in disease evolution

• Main concern: visual loss from progressive keratopathy.
• Lacrimal dysgenesis managed in context of keratopathy.
• Limbs often functional despite severe deformity.
• Ectodermal dysplasia mostly cosmetic (skin, hair, nails).

Medical therapy options

• Long-term care of anterior segment abnormalities.
• Lid hygiene for blepharitis, dry eye management.
• Topical steroids and bandage contact lens may be insufficient for keratopathy (Ophthalmology 1985; 92:1427).
• Topical anti-inflammatory agents, such as corticosteroids and cyclosporine A, have been employed to reduce inflammation and improve tear production (Barbaro 2023).

Surgery options

• Lacrimal duct probing not recommended for congenital nasolacrimal duct obstruction (J Ped Ophthalmol 1970; 7:79).
• DCR surgery for discharge, to limit corneal scarring/infection (Graef Arch Clin Exp Ophthalmol 1997; 235:512).
• Grafting for limbal stem cell deficiency.
• Emerging research explores the use of allele-specific small interfering RNAs (siRNAs) to correct p63 mutations responsible for ocular manifestations (Novelli 2016).

Other management considerations

• Molecular defect identification opens avenues for targeted therapies in the future.
• Visual loss from limbal stem cell deficiency may not be preventable or fully treatable (Ophthalmology 2012; 119:74).
• Corneal transplant in ectodermal dysplasia carries high risk.
• DCR surgery mostly successful but compromised by ectodermal dysplasia.

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 and 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.  
• Chi D, Wang Y, Zhang Y, et al. Arhgap29 deficiency causes EEC-like syndrome in mice. Stem Cell Reports. 2025;14(4):599–613.
• 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.
• Di Iorio E, Bonelli F, Ferrari S, et al. Ocular Manifestations in Patients Affected by p63-Associated Disorders: Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) and Ankyloblepharon-Ectodermal Defects-Cleft Lip Palate (AEC) Syndromes. J Clin Med. 2023;12(23):7377.  
• 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.
• He B, Su M, Wang Y, et al. Prenatal diagnosis of Ectrodactyly–Ectodermal dysplasia–Cleft syndrome (EEC) in a fetus with cleft lip and polycystic kidney. Front Genet. 2022;13:1002089.
• Savukyne E, Machtejeviene E, Bajeruniene K, Asmoniene V. Prenatal diagnosis of ectrodactyly-ectodermal dysplasia clefting syndrome – a case report with literature review. Case Rep Perinat Med. 2022;11(1):20210076.
• Barbaro V, Bonelli F, Ferrari S, La Vella G, Di Iorio E. Innovative Therapeutic Approaches for the Treatment of the Ocular Morbidities in Patients with EEC Syndrome. Cells. 2023;12(3):495.
• Novelli F, Lena AM, Panatta E, et al. Allele-specific silencing of EEC p63 mutant R304W restores p63 transcriptional activity. Cell Death Dis. 2016;7(5):e2227.
• 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