Ectrodactyly–ectodermal dysplasia–cleft syndrome (EEC) is a member of the large group of inherited conditions referred to as the ectodermal dysplasia syndromes (EDS). These conditions share in common primary defects in the development of two or more ectodermally derived tissues. Most commonly affected are the nails, hair, teeth, skin, and sweat glands. The ocular surface can also be involved as it too derives from the embryonic ectoderm layer. In the spectrum of eye care, practitioners commonly encounter systemic associated conditions with ocular manifestations. This is a case report of a patient with a known disorder of the ectoderm, who originally presented with an anterior segment disorder, and was also found to have a retinal defect. It is of interest that while ocular surface disorders are expected in patients with ectoderm abnormalities, that a retinal defect was detected.
As a brief review of embryonic development, the ectoderm, one of the three primary germ layers, assists in the formation of the embryonic plate during the third week of development. By day 22, the neural tube has formed, with neural ectoderm lining the inside of the tube and surface ectoderm surrounding the tube. Both the neural and surface ectoderm layers are involved in the development of the ocular structures. The surface ectoderm gives rise to the crystalline lens, corneal epithelium, epithelium of the eyelid, meibomian glands, and the glands of Zeis and Moll. The neural ectoderm is responsible for development of the retinal pigment epithelium, neural retina, optic nerve fibers, epithelium of the ciliary body, and the iris (Table 1).1 Neural crest cells, which migrate from the neural tube into separate clusters along both sides of the neural tube, form, among other things, the fibroblasts in the cornea, sclera, and iris stroma. Neural crest cells also form the endothelial lining of the anterior chamber and myoblasts of the ciliary muscle.2
EDS is not a single disease entity, but rather a group of disorders which have in common an abnormality of ectodermal derived structures. An EDS-like condition was described by Thurnam in 1848.3 Since that time, more than 170 confirmed clinical conditions are understood to be part of this rare but large and complex group of conditions.4,5 As a group, the incidence of EDS is 7 in every 10,000 births.6 The conditions with the highest incidence are hypohidrotic ectodermal dysplasia, EEC, ankyloblepharon–ectodermal dysplasia–clefting syndrome and hidrotic ectodermal dysplasia.6 Each of these disorders displays primary defects in the development of two or more ectodermally derived tissues. The most common characteristics of these conditions are abnormalities in the hair, teeth, nails, and sweat glands, but many patients also display abnormal fingers, toes, ears, and defective salivary, lacrimal, and meibomian glands (Table 2).7–10
EDS of the skin with comorbid ocular involvement is known as Curtius syndrome.11 In some variants of EDS, corneal opacification and abnormalities of the tear film, meibomian glands, eyebrows, eyelashes, and lacrimal system have been described.7–10 Clinical evidence of alterations of the meibomian glands includes partial loss, attenuation of, or complete absence of the meibomian glands.10,12 Corneal disease is most likely an indirect consequence of the meibomian gland alteration and subsequent deficient lipid layer of the tear film.9,13 The ocular findings are usually bilateral, symmetrical, and result in chronic epiphora, recurrent infections, and secondary visual loss from corneal scarring.8 One study reported that a large percentage of patients (94.4%) complained of burning, foreign body sensation, tearing, and photophobia.10 However, the debilitating ocular surface repercussions of EDS are progressive and predominantly affect adults.10,12 It is worth noting that our patient had defects of both the ectoderm and neuroectoderm. Is there a possibility of an overlap of these embryonic layers in the varied presentations of these syndromes?
A 22-year-old white male college student presented to the urgent care eye clinic at Indiana University Health Center with an initial complaint of clear discharge and matting of the lashes in both eyes each morning for the past 3 days. He denied mucous discharge, purulent or mucopurulent discharge, photophobia, and itching. The patient also denied ocular pain, but stated that his eyes were more irritated at night. The patient also reported a concurrent nonproductive cough of 2-week duration for which he was self-treating with cough drops and over-the-counter “cold” medications. Patient history revealed chronically red and severely dry eyes for several years. He stated that he had previously seen eye care providers for redness of his eyes in the past and reported that vision had been poor in his left eye since he was a child. He was a nonsmoker, denied recreational drug use, and was a minimal alcohol user. The patient denied allergies or use of prescription medications. The patient was alert, oriented to person, place, and time with appropriate mood and affect. The patient was a reluctant historian, and previous medical records were not available. He had not seen an eye doctor in many years and brought with him a tube of ocular lubricant that was 4 years past its expiration date. The patient was only intermittently using the ocular lubricant. Use of this medication did not seem to help or exacerbate the condition. External observations of the patient revealed abnormal and sparse teeth; patchy baldness with coarse, thin hair (Fig. 1); abnormal mouth mucosa; deformity of the fingers and toes (Fig. 2); and dry, thin abnormal skin. Review of surgical history revealed correction of fused fingers and toes in infancy. Further review of systems revealed a familial hereditary condition of ectrodactyly ectodermal dysplasia, confirmed with discussions from the patient’s mother.
Best-corrected visual acuities at our initial examination were 20/30 OD and 20/200 OS. There was no improvement with pinhole. Refractive error was not assessed as this was an urgent care clinic. Extraocular motility testing was normal, with no nystagmus noted. There was no gross observation of ocular misalignment. Pupils were equal and reactive with no relative afferent pupillary defect. Slit-lamp examination revealed the following bilateral ocular findings: loss of eyelashes (Fig. 3), 3+ diffuse conjunctival injection, symblepharon formation (Fig. 4), palpebral inflammation, corneal scarring, pannus and neovascularization (OS > OD) (Fig. 5), and absence of meibomian gland orifices (Fig. 6). Minimal follicles, papillae, and chemosis of the conjunctiva were observed. The corneal findings were significant enough to account for the reduced best-corrected visual acuities. There was minimal corneal staining at this visit. There were no obvious lens abnormalities. Intraocular pressure was measured at 12 mm Hg OD and 13 mm Hg OS. Dilated fundus examination was deferred at this visit.
The patient was diagnosed with an acute presentation of bilateral nonspecific conjunctivitis, most likely secondary to the concurrent upper respiratory infection symptoms. Common differentials include, but are not limited to, toxic, allergic, atopic, viral, or bacterial conjunctivitis, blepharitis, ocular cicatricial pemphigoid, and Stevens-Johnson syndrome. The patient was treated with TobraDex (Alcon) ophthalmic suspension, one drop four times a day in both eyes, for 7 days. In addition, the patient was diagnosed with dry eye based on history and associated systemic condition. Initial management of the patient’s dry eye was to supplement with artificial tears. He was given Theratears to use at least four times a day and Genteal Gel to use at bedtime in both eyes. At subsequent follow-up evaluations, the patient displayed decreased signs and symptoms of conjunctivitis; specifically, he had decreased redness, discharge, and matting of the lashes. Within 2 weeks, the patient’s conjunctivitis resolved. At the follow-up examination, the patient agreed to a dilated fundus examination to complete an ocular health assessment. The fundus examination revealed a horseshoe tear in the temporal retina of the right eye with surrounding localized etinal detachment. The patient was asymptomatic for flashes, floaters, or visual field defects. There was a rim of subretinal fluid around the tear and a cystic tuft at the tip of the flap. A retinal specialist performed laser photocoagulation to seal the tear in the right eye the next day. There were no complications.
The patient did have a corneal specialist consultation. Management options, including the need for possible corneal transplantation at some point in the future, were extensively discussed. The patient was managed for the next two and a half years with Restasis (Allergan) twice a day in both eyes. The patient continued to use artificial tears and gel as a supplement when needed. Doxycycline, utilized for its anti-inflammatory properties, was also prescribed after verbal consultation with the corneal specialist. Although the patient did not have discernible meibomian glands, the thought was that the anti-inflammatory properties of the doxycycline may be of benefit to the patient’s ocular surface. The patient was prescribed doxycycline 100 mg BID for 3 months with a maintenance dose of 100 mg daily. The patient did feel a marked improvement in his overall dry eye symptoms on this regiment. The patient eventually moved out of the area and was lost to follow-up.
EEC syndrome was first described in 1804 by Eckhold and Martens 14,15 and named as a unique syndrome by Rüdiger and colleagues.16 The three definitive features of EEC are contained within the syndrome’s name: ectrodactyly (splitting of the hand and foot) ectodermal dysplasia (ectodermal defects such as defective nails, hypodontia, and hypotrichosis), and clefting of the lips or palate, or both.16 In an analysis of 230 published cases of EEC, Roefsema and Cobben17 found that ectrodactyly occurred in 84%, ectodermal dysplasia in 77%, and clefting in 68%. Additional common sequelae included lacrimal tract abnormalities (59%), urogenital abnormalities (23%), and conductive hearing loss (14%).17 In the 1970 report by Rüdiger and colleagues, a 2.5-year-old patient had ocular involvement of EEC with severe dystrophic keratitis and an absence of tears during crying.16
In the previous decade and a half, significant progress has been made toward understanding the genetic basis of EEC. The initial breakthrough occurred in 1998 when several laboratories identified and mapped gene p63 onto chromosome 3q27–29.18–21 At around the same time, van Bokhoven and colleagues22 mapped limb mammary syndrome, which is similar to EEC, onto chromosome 3q27. Yang and colleagues then reported that p63 knockout mice have significant defects in their limb, craniofacial, and epithelial development.23 Independently, Mills and colleagues reported that p63 knockout mice had a failure of the apical ectodermal ridge to differentiate, resulting in truncated or absent limbs.24 They further concluded that structures dependent upon epidermal-mesenchymal interactions during embryonic development fail to develop, e.g., hair follicles, teeth, mammary glands, salivary glands, and lacrimal glands. Finally, Celli and colleagues mapped EEC onto chromosome 3q27.25 Their analysis of gene p63 revealed heterozygous mutations in nine unrelated patients with EEC syndrome. Thus, p63 mutations act in a dominant fashion in humans, giving rise to a phenotype resembling the p63 knockout mice.
Following the initial series of papers relating EEC to gene p63 mutations, several different laboratories confirmed and expanded upon this finding. Ianakiev and colleagues26 reported that two unrelated families with split-hand and split-foot malformation [SHFM (MIM 183600)] (which has phenotype overlap with EEC17) and four unrelated families with EEC all had mutations of gene p63. They concluded that mutations in the p63 gene cause EEC. These conclusions were further solidified by Van Bokhoven and colleagues in an analysis of 43 individuals and families affected with EEC syndrome. They found that p63 gene mutations were detected in almost all (40/43) of the patients with EEC syndrome. Finally, Barrow and colleagues27 studied four patients with EEC, five with closely related syndromes, 30 with other syndromic orofacial clefts or limb anomalies, or both, and 62 with nonsyndromic orofacial clefts. They concluded that there was a common role for p63 in classical EEC syndrome, both familial and sporadic, but no role in any other related or nonsyndromic forms of orofacial clefts.
In summary, EEC syndrome is a well-characterized, autosomal dominant disorder that is clearly linked to chromosome 3q27 and heterozygous p63 mutations. Expressions of p63 are prominent in adult humans and mice in the proliferating epithelial basal cells layers of the epidermis.19 Embryonic expression in mice is prominent in the apical ectodermal ridge of the limbs and in the maxillary and mandibular branchial ectoderm, which are essential for the development of the underlying mesenchyme.23,24 Homozygous p63 knockout mice exhibit craniofacial abnormalities, limb truncations, and an absence of epidermal appendages such as hair follicles, tooth primordia, sebaceous glands, lacrimal glands, and salivary glands.23,24 In summary, p63 is a transcription factor gene that is essential to embryonic development.28 There are currently 10 identified protein isoforms created by p63 and all are involved in early embryonic development of ectodermal germ-layer structures.
The case reported here most likely represents a variant of EEC syndrome. This multisystem, variable condition is congenital and has been referred to as nonprogressive; however, the ocular manifestations may be the exception. Although EEC syndrome is an autosomal dominantly inherited condition, there is significant variation in its clinical presentation. Not only are there family to family differences but interfamilial variation is not uncommon. In rare cases, examination of family members can verify a suspected diagnosis in a patient who is missing one of the cardinal signs of ectrodactyly ectodermal dysplasia.29
In childhood, there are physical limitations and deformities that must be overcome. With adulthood, ocular manifestations add to the debilitating aspect of this syndrome. Aplasia and atresia of the meibomian glands are often the cause of severe and possibly blinding corneal neovascularization and scarring. Two factors lead to the formation of vascularized corneal scars: (a) obstruction of the tear ducts leads to recurrent secondary infections of the lid margin and conjunctiva; and (b) lack of, or incomplete development of, the meibomian glands leads to an insufficient lipid layer with subsequent deficient tear film.8–10,12 The ocular complications are usually bilateral, relatively symmetrical, and first present with complaints of burning, tearing, and photophobia.8,10
Although the ocular structures derived from surface ectoderm are known to be affected by EED, this patient also had retinal findings in the absence of confounding factors such as high myopia or trauma. Specifically, this patient had an asymptomatic retinal tear and localized detachment. Previous instances have been reported in which retinal imperfections were found in conjunction with EEC-related ocular surface disease.30 In one, a patient with EEC had a large retinal tear, while in the other a patient was born with bilateral total tractional detachments.30 More investigation is needed to determine whether EEC patients are at a higher risk for retinal tears and detachments.
The existing genetic literature does not address the question of neural ectoderm involvement in EEC, but other known aspects of EEC are also missing from these studies. While mental retardation occurs in approximately 10% of patients with EEC,31 the genetic p63 knockout studies of Mills and colleagues found no brain abnormalities.24 In fact, in the genetic studies published to date, not even abnormalities in ocular structures were reported.23,24 Thus, the genetic literature alone does not shed light on whether this patient’s retinal tear and detachment could have arisen from EEC.
Management of the chronic ocular manifestations of EEC is an involved process. Patients with EEC syndrome may present because of chronic ocular irritation and dry eye or because of symptoms of secondary acute keratoconjunctivitis, such as described in this case. Although managing the acute problem is the first priority, the doctor must not overlook the underlying and chronic corneal issues. Given that the underlying issue is chronic in nature, Restasis and doxycycline may be a beneficial therapy for the long-term management of these patients.
It is imperative for any eye care practitioner working with a patient with EEC to realize the corneal implications of this chronic ocular surface disease. Patients may present with bilateral severe dry eye with secondary corneal scarring and reduced visual acuity. Recurrent conjunctivitis as a result of ocular surface disease may require management with antibiotics and possibly also anti-inflammatory ophthalmic drops. Patients with EEC and ocular surface involvement require long-term monitoring and care because the secondary complications of the syndrome can lead to vision loss and even blindness. The possibility that EEC might also involve the neural ectoderm is intriguing. Although no conclusions can be reached based on such limited case reports, the variability of this disease is one of its hallmarks. By adding to the existing literature on EEC cases with retinal involvement, we hope to increase awareness of the possibility of neural ectoderm involvement in some variant of EEC so that population-based enquiries might result.
Accession number and URLs for data in this article are as follows:
GenBank, http://www.ncbi.nlm.nih.gov/Genbank/index.html [for the p63 gene (accession number BAA32593)]
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ [for SHFM (MIM 183600) and EEC (MIM 129900)]
Received: August 13, 2013; accepted November 5, 2013.
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