ABSENT MEIBOMIAN GLANDS: A MARKER FOR EECSYNDROME

ELIZABETH BONNAR, PATRICIA LOGAN and PETER EUSTACE Dublin, Ireland

SUMMARY watering eye for the previous week. He gave a

A patient with a 20 year history of severe keratocon­ history of continuous attendance at eye clinics in junctivitis of unknown origin was found, on assessment various hospitals since the age of 3 years and was at a blepharitis clinic, to have complete absence of currently attending our own clinic, where he had last meibomian glands. Further examination revealed the been seen 1 month previously. Maintenance medica­ features of EEC syndrome. To our knowledge, this is tion was antiviral ointment and artificial tears. Old the only case to have been diagnosed in this way. The notes were unavailable on admission but there had ocular complications of EEC syndrome and other been a previous spontaneous perforation of the left ectodermal dysplasias are reviewed. cornea at the age of 15 years, and an operation for a blocked tear duct on the right side at the age of 8 The combination of ectrodactyly (lobster claw years. deformity of the hands and feet), ectodermal Vision was 6/18 on the right and hand movements dysplasia (abnormalities of hair, teeth, nails and on the left. There was marked photophobia and sweat glands) and cleft lip and palate, known as EEC tearing on both sides. The left cornea was opacified syndrome, is a rare multiple congenital abnormal­ and vascularised 360°, with central thinning and a ity.1,2 Fewer than 180 cases have been reported in the small perforation just inferonasal to the pupil (Fig. literature?-S 1). The right cornea was opacified and vascularised Inheritance is autosomal dominant (AD), with superiorly. Conservative management of the perfora­ incomplete penetrance and variable expressivity, so tion was instituted. Because of 'severe blepharitis' that not all features are present in every case.6 thought to be contributory to the corneal condition, Sporadic cases also arise. the patient was referred to a blepharitis clinic where Ocular manifestations are frequent, the most he was seen the following morning. Screening common being disorders of the lacrimal drainage procedures for blepharitis were carried out, and system7,8 and sight-threatening keratopathy.9,lo Rarely, complete or partial absence of the meibo­ while the lids were thickened and red-rimmed, no mian glands has been recorded.9,1l,12 evidence of recognisable blepharitis, or any asso­ In this paper we describe how a patient with a 20 ciated skin condition such as atopy, eczema, rosacea year history of severe keratoconjunctivitis of or seborrhoea, could be found.13 Meibomian gland unknown origin was found, on assessment at a assessment, part of the screening procedure,14 blepharitis clinic, to have complete absence of revealed that there were no detectable duct orifices meibomian glands. Further examination revealed in any of the four eyelids (Fig. 2). No meibomian the features of EEC syndrome. To our knowledge, gland tissue could be demonstrated at the slit lamp, this is the only case to have been diagnosed in this either by everting the lids or by transillumination.1s way. There was no evidence of hypoplastic glands, or of glands or ducts distorted by inflammationor destruc­ tive lid disease. CASE REPORT Complete absence of meibomian glands was A 23-year-old man presented with a spontaneous suggestive of a congenital rather than an acquired perforation of the left cornea, and a painful, red, cause. Congenital absence of meibomian glands is exceedingly rare,1l,14 but has been reported in EEC Correspondence to: Dr Elizabeth Bonnar, MRCOphth, Uni­ syndrome .II and ill anhidrotic ectodermal versity Department of Ophthalmology, Mater Misericordiae 9 ,12 Hospital, Eccles Street, Dublin, Ireland. dysplasia.16,17

Eye (1996) 10,355-361 © 1996 Royal College of Ophthalmologists 356 E. BONNAR ET AL.

Fig. 1. Left cornea showing opacification, vascularisation Fig. 2. Right lower lid showing absence of meibomian and perforation. glands and duct openings.

Fig. 3. Sparse scalp hair with wire-wool consistency. Fig. 4. Plantar view of the feet showing ectrodactyly of the right foot with syndactyly of toes three and four on the left.

The patient's hands showed no deformity and was generally sparse and of a wire-wool consistency there was no cleft lip or palate. Although a history of (Fig. 3). Eyebrows and eyelashes were also sparse. sweating abnormality was absent, a search was made The teeth were grossly abnormal (Fig. 5). The for the other features of ectodermal dysplasia. The fingernails were ridged, split and deformed (Fig. 6). hair, in addition to showing male pattern baldness, Examination of the feet confirmed similar abnorm- ABSENT MEIBOMIAN GLANDS IN EEe SYNDROME 357

Fig. 5. Abnormal dentition: hypodontia and enamel Fig. 6. Fingernails showing ridging and splitting. dysplasia.

Fig. 7. View of soft palate showing bifid uvula. alities in the toenails but also revealed ectrodactyly keratoconjunctivitis remained obscure. The opacifi­ of the right foot, together with syndactyly of toes cation and vascularisation of the left cornea gradu­ three and four of the left foot (Fig. 4). On the basis of ally extended to 360°, central thinning developed and these findings - ectrodactyly of the foot and a spontaneous corneal perforation occurred when abnormalities of the hair, teeth and nails - a the patient was 15 years old. This healed with diagnosis of EEC syndrome with incomplete expres­ conservative management. Treatment thereafter sion was made. consisted of antiviral ointment and artificial tears, The full history became available with the old with occasional topical antibiotics for intercurrent notes. Since the age of 3 years the patient had acute conjunctivitis. Persistent symptoms were attended ophthalmology clinics in various hospitals, photophobia, blepharospasm and mild epiphora. initially with bilateral nasolacrimal obstruction and Systematic re-examination following the diagnosis infection, present since birth. Repeated probings showed the palpebral fissures were narrow and the were carried out and at 8 years a successful right lid margins thickened. The mucocutaneous junction dacryocystorhinostomy (DCR) was performed. was sharply demarcated but very irregular (Fig. 2). Examination at that time showed all four puncta to Conjunctival fibrosis was present in both lower be closed by fibrosis. A lacrimal fistula was also fornices with symblepharon on the left. Of the present below the right lower punctum. Other lacrimal puncta, only the right upper one could be features were extensive conjunctival fibrosis, and located. Schirmer's test with anaesthesia gave 8 mm changes in the upper cornea on both sides, consisting of wetting after 5 minutes on the right but only 3 mm of nebular opacification and ingrowth of pannus. on the left. With the addition of fluoresceinthere was Staff opinions were obtained in the different complete absence of the lipid patterns normally seen, hospitals he attended. Trachoma, herpes simplex so that the tear film break-up time was not infection, Stevens Johnson syndrome and cicatricial applicable. In a similar case 11 the tear film break­ pemphigoid were considered, but the aetiology of the up time was classified as instantaneous. Examination 358 E. BONNAR ET AL. of the lens and fundus was normal on both sides. attendance.9.11 The most recent review of the ocular Axial length measurement performed at a later date manifestations of EEC syndrome published in 198910 showed the eyes to be microphthalmic (R 20.63 mm, fails to mention either previous reports of absent L 20.80 mm). meibomian glands or the state of the meibomian A dental consultation identified the anomalies as glands in the five new patients presented, two of hypodontia (partial absence of the permanent teeth) whom had spontaneous corneal perforation. A and enamel hypoplasia. The clefting component of report in 1990 of penetrating keratoplasty following the EEC syndrome was also found, minimally spontaneous corneal perforation in two patients with expressed as a bifid short uvula (Fig. 7). EEC syndrome makes no mention of meibomian glands.19 It would seem that the meibomian glands PROGRESS AND MANAGEMENT suffer from the 'Cinderella' syndrome in relation to The perforation of the left cornea healed with ophthalmic assessment, and that the number of cases conservative management. Conjunctival swabs grew of reduced or absent glands reported so far is Staphylococcus aureus sensitive to fucidin, which was artificially low. prescribed for topical use. Occasional episodes of Ectrodactyly or lobster claw deformity of the acute conjunctivitis on both sides have usually hands or feet can range from partial or complete responded to Oc chloramphenicol. Nasal swabs at absence of a digit to the full cleft hand or foot one point gave a heavy growth of S. aureus and the deformity (absence of the third digit with clefting nasal carrier state was eliminated with the use of into the proximal portion of the hand or foot and mupirocin nasal ointment. Maintenance therapy syndactyly of the remaining digits on each side of the consists of artificial tears. The corneal signs remain cleft). It usually occurs bilaterally and foot involve­ stable, the corrected vision being 6/9 in the right eye ment is common.20 It is inherited as an AD trait and and 2/60 in the left. occurs most frequently as an isolated defect. An In view of the absence of meibomian glands, the incidence of 1 in 90 000 has been quoted in reduced tear production, the presence of symble­ Denmark.21 The earliest reference to ectrodactyly pharon and probable inherent ectodermal defect of in the literature appears to have been in 1770.21 Its the cornea and conjunctiva, we feel penetrating firstassociation with cleft lip and palate was recorded keratoplasty would have a poor outcome in this in 1804, with other reports by Cockayne22 in 1936 patient. The goblet cells, which provide the third and Walker and Clodius21 in 1963, both of which element of the tear film, may also be deficient due to stressed the common accompaniment of lacrimal inherent defects in the conjunctiva and secondary to tract abnormalities. The rare combination of ectro­ conjunctival fibrosis. We do not feel either conjunc­ dactyly, ectodermal dysplasia and cleft lip and palate tival biopsy or impression cytology is justified at was not described until 1970.1 To date fewer than 180 present. Recurrent infection poses the greatest threat cases have been reported in the literature. Asso­ to the integrity of the cornea. The condition has ciated findings in EEC syndrome include genitour­ stabilised since the eradication of the nasal carrier inary anomalies, deafness, melanocytic naevi, scalp state for S. aureus and we consider this an important dermatitis, psychomotor retardation and micro­ factor in the management. cephaly.4,5,7.11,23 The ectodermal dysplasias form a complex group DISCUSSION of rare disorders involving one or more of the classic There are estimated to be about 30-40 meibomian structures of ectodermal origin: hair, teeth, nails and glands in the upper lid and 20-40 in the lower.14 The sweat glands.2 They have been classifiedaccording to glands or ducts may be affected by destructive or which structures are affected and over 121 syn­ inflammatory lid disease. Congenital deficiency of dromes have been described? The anhidrotic or the glands has been reported/I>but complete absence hypohidrotic form is the best known, because of its of the glands, the key to the diagnosis in our patient, distinctive trait of absent or reduced sweating, is very rare. It has been reported in five previous hypotrichosis and cone-shaped teeth? Besides EEe cases of the EEC syndrome,1l·12 with reduced or syndrome two other ectodermal dysplasias are 'almost completely absent' glands being noted in commonly associated with clefting of the palate: three other cases.9.12 Absent meibomian glands have Rapp-Hodgkin sydrome, with ectodermal dysplasia, also been documented in two cases of anhidrotic/ cleft lip/palate and mid-facial hypoplasia,2,4 and hypohidrotic ectodermal dysplasia. 1 6.17 Despite Hay-Wells or AEC syndrome with ankyloblepharon, repeated examination over 20 years by a succession ectodermal defects and cleft lip/palate.2,4,24 of ophthalmologists the absence of meibomian The ocular complications of EEC syndrome can be glands in this patient came to light only in the setting both disabling and sight-threatening. Anomalies of of a specialist blepharitis clinic. In two similar cases the lacrimal drainage system are common, being the defect was noted only after several years' present in 84% of patients in one series? They range ABSENT MEIBOMIAN GLANDS IN EEC SYNDROME 359 from absence or atresia of the puncta to incomplete reported in the ophthalmic and general literature development or absence of the canalicula, lacrimal include photophobia, telecanthus, blepharitis, con­ sac or nasolacrimal ducts.8 Lacrimal drainage pro­ junctivitis,9 micro/anophthalmia,29,3o trichiasis, scanty blems have also been reported with ectrodactyly or absent eyebrows and cilia1.9,12,31 and reduced tear alone?5,26 and with ectrodactyly and clefting.21,22 production.!·12 In addition, Wald32 in 1993 described Similar abnormalities are found in patients with a baby, the 2.5 kg product of a full-term uncompli­ hypohidrotic ectodermal dysplasia,27 Rapp-Hodgkin cated pregnancy, with EEC syndrome and bilateral syndrome, AEC syndrome, and other ectodermal total tractional retinal detachment resembling stage 5 dysplasias.4,7 Dacryocystorhinostomy when neces­ retinopathy of prematurity. Hayakawa et at.33 in 1989 sary generally gives good results.1O One patient documented a case of ectrodactyly, ectodermal besides our own had a lacrimal fistula.1O dysplasia and macular dystrophy - 'EEM syndrome' Keratopathy is also common, with typical early - and quoted reports of six similar cases, all onset, and relentless progression from stromal autosomal recessive in inheritance and all born of infiltration and ingrowth of pannus to neovascular­ consanguineous parents. isation, opacification and thinning.8-12,19 Recurrent Table I summarises the ocular manifestations of erosions! and ulceration8,!1 have also been docu­ EEC syndrome and other ectodermal dysplasias. mented. In two patients besides our own the pannus Full-blown EEC syndrome is easily recognised and nebular opacification commenced in the upper early in life and prenatal diagnosis by ultrasound is third of the cornea.9,10 Spontaneous corneal perfora­ also possible?4 The variability of expression and lack tion has occurred in four previous cases.1O•19 Of of penetrance can make diagnosis difficult in the these, two healed with conservative managementlO individual patient,6 and children with the full-blown and two responded well to penetrating keratoplasty, syndrome may be born to a parent in whom the one requiring a repeat procedure.19 Penetrating condition is minimally expressed?5 Since the syn­ keratoplasty has also been performed on an intact drome was first described in 1970, the year this but opacified and vascularised cornea.9 Here the patient was born, it is not surprising that an early outcome was poor, with delay in re-epithelialisation diagnosis was not made. Delay in diagnosis was and recurrence of opacification. This patient had compounded by the absence of lobster claw defor­ absent meibomian glands, although the volume of mity of the hands, which is unusual, and minimal aqueous tear production was thought to be within clefting of the soft palate. normal limits. A keratopathy similar to that found in Inheritance of the condition is AD, with occasional EEC syndrome has also been noted in cases with sporadic mutations. Several reports emphasise the ectrodactyly alone26 and in anhidrotic ectodermal great phenotypic variability in EEC syndrome, the dysplasia,27.28 Aplasia or hypoplasia of the lacrimal need for a careful search for microsymptoms in glands leading to deficient tear production may be a potential gene carriers, and the difficultiesin genetic feature of hypohidrotic ectodermal dysplasia. counselling.6,7,34 Family history in our patient, as yet Other ocular manifestations of EEC syndrome incomplete, has so far been non-contributory.

Table I. The main features and ocular manifestations of EEC syndrome and other ectodermal dysplasias

Hypohidrotic EEC ectodermal AEC Rapp-Hodgkin EEM Syndrome syndrome dysplasia syndrome syndrome syndrome

Systemic manifestations Ectrodactyly, Hypohidrosis. Ankyloblepharon, Mid-facial Ectrodactyly, ectodermal hypotrichosis, ectodermal hypoplasia, ectodermal dysplasia, cleft cone-shaped dysplasia, cleft ectodermal dysplasia, lip/palate teeth lip/palate dysplasia, cleft macular dystrophy lip/palate Mode of inheritance AD AR/X-Iinked AD AD AR recessive Sparse cilia/brows + + + + Blepharitis/conjunctivitis + + + Photophobia/blepharospasm + + + Lacrimal drainage anomalies + + + + Decreased lacrimation + + Reduced/absent meibomian glands + + Keratopathy + + SpontGfneous corneal perforation + Macular dystrophy + Other Micro/ Glaucoma, Microphthalmia, anophthalmia, lenticular cataract retinal opacities detachment

AD, autosomal dominant; AR, autosomal recessive. 360 E. BONNAR ET AL.

The pathological basis for the sight-threatening systematic ophthalmological examination, including keratopathy in patients with EEC syndrome is eyelid and meibomian gland assessment, is manda­ probably multifactorial. By definition, tissues of tory. Careful enquiry into the dermatological, devel­ both ectodermal and mesodermal origin may be opmental and family history may also prove fruitful. affected. Baum and Bu1l9 felt that the corneal Key words: EEe syndrome, Ectodermal dysplasia, Meibomian abnormality was due to the primary ectodermal glands, Blepharitis, Keratitis, Penetrating keratoplasty. defects, since the keratopathy began in the upper part of the cornea, protected by the lid, while the aZY exposed cornea was normal. Mondino et REFERENCES suggested that absent meibomian glands and reduced 1. Rudiger RA, Haase W, Passarge E. 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