British Journal of Dermatology (1976) 94? 277.
The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: an autosomal dominant condition R.J.HAY AND R.S.WELLS The Department of Dermatology, Guy's Hospital, London, and The Department of Genetics, St John's Hospital for Diseases of the Skin, Lisle Street, London, WC2H 7BJ Accepted for publication 13 June 1975
SUMMARY
Seven patients from four families are reported who had an inherited condition of which the main features were ankyloblcpharon, ectodermal defects and cleft lip and palate. The ectodermal defects were partial or complete hair loss, absent or dystrophic nails, pointed widely spaced teeth and partial anhidrosis. Associated anomalies included lacrimal duct atresia, supernumerary nipples, syndactyly and auricular deformities. The inheritance of this abnormality was consistent with that of an autosomal dominant trait. The relationship between this and similar syndromes is discussed.
Ankyloblepharon, or fusion of the eyelids, is rarely complete. The lids are usually joined at birth by a solid band at the lateral or medial margins or by numerous epithelial strands. In the latter instance the condition is named ankyloblepharon filiforme adnatum, and the strands may contain elements of vascular and connective tissue. Where genetic evidence is available, the inheritance of ankyloblepharon has been described as that of an autosomal dominant condition (Sorsby, 1970). A genetic aetiology for ankyloblepharon filiforme adnatum is less certain, but it has been described in conjunction with cleft palate and lip (Long & Blandford, 1962). Genetically determined defects of ectodermal tissues have long attracted medical attention because of the bizarre appearances produced. Cockayne (1933) divided these disorders into two genetically distinct groups, the anhidrotic and the hidrotic ectodermal dysplasias, whose distinguishing features were the presence or absence of sweating, nail or dental defects. The anhidrotic form was X-linked and hidrotic ectodermal dysplasia was inherited as an autosomal dominant condition. There is no doubt that there are defects of other ectodermally derived tissues which may occur in isolation. These include both alopecia and anonychia. Again, there is genetic heterogeneity and amongst them there are some autosomal dominant varieties. The anomaly of cleft lip and palate is relatively common and may be due to many different causes. Correspondence address: Dr R.J.Hay, Department of Dermatology, Guy's Hospitalj London, SEi 9RT. E
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For example, it is known that teratogens may produce the condition, but it can also be inherited. An isolated cleft palate is under multifactorial (polygenic) influence. However, when cleft lip and palate are inherited in association with another abnormality, for example with congenital sinuses of the lower lip (Michaelides, Hay & Wells, 1975), ^he inheritance is often that of an autosomal dominant type. This is probably the case with the individuals described below. We are reporting seven individuals from four families who showed a combination of these three abnormalities which does not appear to h3ve been described before and which was probably inherited as an autosomal dominant condition. Ascertainment
The four probands were referred to the Genetic Clinic at St John's Hospital for Diseases of the Skin or to the Hospital for Sick Children, Great Ormond Street. One patient (case i) has been presented at a meeting of the Dermatology Section of the Royal Society of Medicine (Hay & Wells, 1975). Three of the individuals had been under the care of other dermatologists, before they were referred to us, and we are grateful to them for their permission to study these patients. Method of investigation
Pedigree details (Fig. i) were recorded at the first visit of each patient and a complete clinical examination was carried out. Where possible their families were visited in their homes and all were examined. Pedigree S
ur DOMole/temale unaffeded; • • Mcle/femaleatfectedi /pratwnd, •deceased,
FIGURE I. Pedigrees A, B and C.
FIGURE 2. Silflo impression irom an allccted patient. The number ot sweat pores seen is reduced compared with normal controls.
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Three patients (cases i, 3 and 7) were admitted to Guy's Hospital so that further studies could be performed. Sweating was evaluated by an impression technique using a silicone material, Silflo. Counts of active sweat glands from six areas (Table i) were recorded first, at rest; second, after iontophoresis of an aqueous solution of os",, pilocarpine; and third, after a hot bath. Casts were taken by spreading a fine layer of the Silflo resin over the skin in the areas tested and the resulting impression was then projected onto a screen through a i cm square grid. The area over each gland producing sweat showed up as a point of light (Fig. 2). These points could be counted and an approximate estimate of their size made. Finally a direct pore count was made of the impression under a dissecting microscope equipped with a micrometer scale. The use of similar methods in hidrotic ectodcrmal dysplasia and other conditions has been previously described (Harris, Polk & Willis, 1972). CLINICAL FEATURES Pedigree A
Case I. H.2 G.H. Female, aged i-jyears. This patient was born at full term after a normal delivery. The birth weight was not known. At birth her eyelids were fused by epitheUal strands at the lateral lid margins and were divided surgically. A median cleft palate and cleft lip on the right were also repaired shortly after birth. Her hair had always been sparse and was shed progressively through childhood. Hair fall was often exacerbated by periods of scalp infection. Her nails had been dystrophic since birth. Her teeth were poorly formed and pointed and had been removed by the age of 12 years. There was no specific difficulty with sweating. In addition, she had experienced recurrent episodes of photophobia and lacrimation. Family history. There was no family history of a similar disorder or of its components and there was no history of consanguinity. Her daughter is case 2. On examination. The patient was an adult female of normal bodily proportions. However, she had a striking facies, with broadened nasal bridge and hypoplastic maxilla. There was an incompletely repaired median cleft palate. Her chin was prominent. The scalp hair was almost totally absent. Some of her nails were dystrophic, and the abnormality varied in extent from total absence to a terminal dystrophy. Her skin was dry and relatively hairless, particularly in the axillae and pubic areas. There was a supernumerary nipple on each anterior axillary fold and partial syndactyly of the second and third toes. Her eyes were injected and the lashes were short and incurved. No lacrimal puncta could be discerned on either upper or lower eyelid on either side. There was palmar and plantar hyperkeratosis with obliteration of dermatoglyphic patterns. Her cardiovascular, nervous, respiratory and genital systems were all normal on clinical examination. Case 2. IH.3 M.H. Female, aged 2 years. This patient is the daughter of case i. Her birth weight was 32 kg. Like her mother, her eyelids were fused at the lateral margins by short bands. She was born with a cleft palate but no hare lip. From early childhood, her scalp hair was sparse, fair and wiry with some patches of alopecia where her scalp had been damaged by recurrent bacterial infections. She had dystrophic finger nails, but normal toe nails. There was no history of heat intolerance or recurrent colds. On examination. Her facial structure was difficult to evaluate because of her age. However, there was a posterior median cleft of the palate. Few teeth had erupted and those present were irregular and
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pointed. Her skin was dry. Her eyes were injected and there was a marginal blepharitis. Also the lacrimal puncta were small and atrophic. There was no palmar or plantar hyperkeratosis. Pedigree B
Case 3. II.2 K.C. Male, aged 38 years. This patient was born 3 weeks prematurely. His birth weight was 2 9 kg. It was not known if his eyelids were fused at birth. However he had a cleft palate without cleft lip. His hair, including eyebrows and eyelashes, had always been sparse. Finger nails had never formed and only the big toe nails on his feet. He never developed a full second dentition and his teeth were irregular in shape and carious from an early age. There was no heat intolerance. Recently he had had attacks of photophobia and lacrimation. Also, he was partially deaf in the left ear, with an onset during the last 10 years. Family history. There was no relevant history of skin problems but his mother was deaf in the left ear. No further details of this deafness were available. His only son is case 4. Medical history. He reported that he was treated for hypothyroidism in early childhood, but no record of this was available. He had also been investigated for right bundle branch block, discovered on a routine E.C.G. examination, but no cause was found. A benign granuloma was removed from his vocal cords in 1972.
FIGURE 3. Frontal view demonstrating the facies, alopecia and ear deformity.
On examination. His facies (Fig. 3) was strikingly similar to case i, with a broadened nasal bridge and sunken maxilla (Fig. 4). Again an incompletely repaired median cleft palate was noted. His teeth, which were widely spaced, had been extensively filled and capped. Finger (Fig. 5) and toe nails, apart from the big toe nails, were absent. His skin was dry with reticulate hyperpigmentation prominent on the forearms and in the axillae. His conjunctivae were injected and he was severely photophobic, but he reported that this tended to fluctuate. There was bilateral arcus senilis. There was a partial neural hearing loss in the left ear and
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FIGURE 4. Lateral view. Loss of prominence of maxilla is shown.
FIGURE 5. Close up view of middle three fingers ofthe right hand showing the loss of nail substance.
the external ear on this side was deformed and cup-shaped. His voice was hoarse. The palms and sole were hyperkeratotic and cracked. The cardiovascular, nervous, respiratory and genital systems were normal on examination. Case 4. III.3 M.C. Male, aged i month. This patient is the only son of case 3. His birth weight was 39 kg. He was born with fusion ofthe lateral lid margins and with a median cleft palate. Finger and toe nails were absent. Family history. His mother had idiopathic epilepsy, diagnosed in childhood, and was being treated with phenytoin, including during the time she was pregnant. On examination. There was a large mid-line cleft of the palate and moderate micrognathus was noted. One canine tooth had erupted. However, his hair was sparse and fair. There was a resolving
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ccphalhaematoma and cradle cap eczetna associated with a folliculitis. In addition, his eyelashes were sparse and there were no finger or toe nails. The skin on the legs and head was dry. There was partial ankyloblepharon filiforme adnatum more extensive on the left eye than the right. No other abnormalities were detected apart from a mild and asymptomatic phimosis. Pedigree C
Case 5, 11,7 R.W. Female, aged 32 years. This patient weighed 2 0 kg at hirth and delivery was normal: she was born with a cleft palate. Her hair was dark at birth but was shed rapidly. Subsequently there was some patchy regrowth with coarse fair hair, but this too was lost at puberty. She never had pubic or axillary hair and eyelashes were always sparse. Finger and toe nails were severely dystrophic. Both primary and secondary dentition were incomplete and irregular. The latter consisted of pointed teeth and many did not erupt. All teeth were shed by the age of 15 years. She had had attacks of photophobia in the past, but had never had treatment. Family history. A maternal cousin had a cleft lip and palate, but without any other defeas. No other relatives were affected, apart from her daughter (case 6). Past medical history. She reported that small nodules were removed from her eyelid margins when she was a child, but no detailed records were available. On examination. She hid the characteristic facies ofthe other adult members of this group, with a broad flat face. The repair of a median cleft ofthe palate was noted and her teeth were absent. Scalp hair was almost totally absent and her nails were all dystrophic and brittle. Her skin was dry. She had a chronic blepharitis, but all lacrimal duct puncta were visible. In addition there was palmo-plantar hyperkeratosis with partial obliteration ofthe dermatoglyphic patterns. Case 6. 111.3 •^'-W^- Female, aged I year. This patient is the daughter of case 5. Her birth weight was 31 kg, and the confinement was normal. She was born with a cleft palate. Ankyloblepharon from the lateral border up to the mid-line was divided surgically shortly after birth. However, her nails at birth were rudimentary. Subsequently she had developed two teeth, which were discoloured and irregularly pointed. Sweating was normal and there was no heat intolerance. On examination. There was a large mid-line cleft ofthe palate. The hair, nails and teeth were all dystrophic. There were no visible lacrimal puncta on either side and the lid margins were inflamed. In addition, there was an epicanthal fold on the right side. There were a number of filamentous bands joining the lateral walls of the posterior aspect of the vagina. There was also a posterior anal fissure. There was no abnormality of the cardiovascular, nervous or respiratory systems. Case 7, L.M. Female, aged loyears. (Pedigree not illustrated.) This patient's birth weight was 2-4 kg and she was 4 weeks premature. Her eyelids were fused at birth but spontaneous separation took place. There was a cleft palate but no cleft lip. Her hair was sparse and brittle. There were no nails at birth and subsequent growth was poor and dystrophic. Primary dentition had been retained. She had no photophobia. Family history. There was no family history of any relevant disorder. Consanguinity was excluded
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Past medical histoiy. Her choanal atresia was corrected surgically in 1964. The cleft palate and mandibular prognathism were repaired in 1966. On examination. This patient had the same characteristic fades with a hypoplastic maxilla and oval face. There was a central palatal defect with a surrounding rim of oral candidiasis, secondary to a palatal prosthetic plate. Her teeth were discoloured, carious and pointed, but all were present. Her hair was coarse and sparse, particularly in the occipital area, and there were some white hairs scattered anteriorly. Her nails were severely dystrophic. The skin was smooth, dry and relatively hairless. There was partial syndactyly of both second and third toes and of the third and fourth toes on the left (Fig. 7). There was also partial syndactyly ofthe third and fourth fingers bilaterally. Her left ear was deformed, with a cup-shaped auricle. The intercanthal distance was 32 mm and this is within the definition of telecanthus. There was
FIGURE 6. Lateral view of the face. Note the retention of partial ankyloblepharon of the left eye.
FIGURE 7, A view of the toes to illustrate thc degree of syndactyly.
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partial ankyloblepharon on the lateral lid margin ofthe left eye (Fig, 6). Upper lacrimal duct puncta were present, although the orifice on the left was reduplicated. Orifices on both lower lids were small and atrophic. No other abnormality was seen. RESULTS
Sweating tests were carried out as described above on cases i, 3 and 7. The results are summarized in Table I, In Case i there was a patchy loss of glands over most ofthe areas tested. The best response was on the hands to a thermal stimulus and large amounts of sweat were produced from fewer glands than normal. Sweat was produced for at least 20 min after cessation ofthe stimulus, whereas in the normal controls it stopped promptly. In cases 3 and 7 a similar patchy loss of sweating was seen, ahhough the response on the hands was not as dramatic. The results can be interpreted as a net loss of sweat glands, although the distribution of this loss was dissimilar in the patients tested. Hair shaft microscopy. Samples of hair from three ofthe patients were examined both in longitudinal profile and in cross-section under the light microscope. The hairs were of a relatively wide diameter and showed actual rotation at various points along the hair shaft. In the cross-section the hair cuticles were either thinned or absent, even though the sections were performed at a proximal point on the hair shaft. The shape of most ofthe hairs was markedly abnormal. There were multiple concavities on the perimeter ofthe hair which presented a scalloped appearance, as opposed to the smooth round or oval shape of normal hairs. Scanning electron microscopy confirmed the presence of a frequently defective cuticle and also showed longitudinal fluting of the hair shaft. The appearances presented by these hairs were identical to those seen in hereditary hypotrichosis (Marie-Unna Type) (Hutchinson & Weils, 1975)Other investigations
Cases I, 3 and 7 were admitted for investigation to Guy's Hospital, This included estimations of haemoglobin, white cell count, E,S.R., R.P,C,F,T. and V,D,R,L,, plasma proteins, liver function tests and blood sugar. All were normal. In case 3, serum lipids and thyroid function tests were studied because of the arcus senilis and the past history of hypothyroidism. Both these were normal. In addition, skull and chest X-rays were performed on these patients. These were also normal, although the skull films demonstrated the palatal defect. An E.CG, was performed on case 3 and this showed a right bundle branch block without any other evidence of cardiac pathology. An E.E.G, performed on case 7 at another hospital 4 years previously was reported as showing an area of dysfunction in the anterior part ofthe left hemisphere, A skin biopsy was taken from the axilla of case 3 and showed almost total absence of epidermal appendages. There were no other abnormal histologica! features apart from increased melanin deposition in the basal layer in part of the section. Slit lamp examination of the eyes of cases i, 3 and 7 was carried out after instillation of oculent fluorescein. Only case 3 showed evidence of keratitis. However, in case i there was no excretion ofthe dye into the nasal or oral cavities. This supported the clinical impression of atresia of the lacrimal ducts. The intelligence of all the patients studied was normal on gross testing. Genetic findings
The first three pedigrees are illustrated (pedigrees A, B and C, Fig. i). The inheritance of this
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disorder was compatible with that of an autosomal dominant trait, because both sexes were affected equally severely. Parents and children were afFected rather than siblings alone. The father to son transmission in pedigree C excluded X-linkage. The four probands were presumably the first recipients of a new abnormal mutation. There was no consanguinity. In the third family (cases 5 and 6) there was a maternal cousin who had a cleft lip and palate. He now lives abroad and could not be examined. The significance of this observation was hard to evaluate. There was no evidence in the other families of independent segregation of characters and it was possible that this one case was either a non-genetic variant or the unconnected expression of this relatively common genetic condition on its own. DISCUSSION
Differential diagnosis. The features common to all the patients were ankyloblepharon, ectodermal defects and cleft lip and palate. Ankyloblepharon was present in all patients apart from two (cases 3 and 4) in the form of ankyloblepharon filiforme adnatum. In case 4 it is possible that the tumours on thc eyelids removed in childhood were the remnants of this defect, Ectodermal defects, such as alopecia, hypodontia and nail dystrophy, were present in all cases. Cleft palate alone occurred in all families apart from the second group (pedigree B) where a cleft lip was present, in addition, in thc proband, Bowen & Armstrong (1973) described a genetically distinct but similar syndrome in which these defects occurred in two siblings in association with mental retardation. The inheritance was of an autosomal recessive type. However, ectodermal defects of comparable severity and inheritance have been described in association with cleft lip and palate alone (Rapp & Hodgkin, 1968). Two other similar conditions have been recorded. One, the E.E.C. syndrome (or ectrodactyly, ectodermal defects and clefting syndrome) has been described by a number of authors (Rudiger, Haase & Passarge, 1970; Brill, Hsu & Hirschhorn, 1972). The features of this syndrome are contrasted with those of our cases, and anhidrotic and hidrotic ectodermal dysplasia in Table 2, The other syndrome, the L,A,D.D, syndrome, the main features of which are lacrimal duct atresia, auricular deformities, dental and digital anomalies, covers a similar range of defects (Hollister et al, 1973)- All these conditions may be inherited as autosomal dominant traits, although, when the E,E,C, syndrome was associated with mental retardation, the inheritance was autosomal recessive (Freire-Maia, 197°)Ectodermal defects. The ectodermal defects in this syndrome share important features in common with the classical anhidrotic and hidrotic ectodermal dysplasias (Table 2), The presence of sweating, in reduced amounts, has already been noted in patients with features typical of anhidrotic ectodermal dysplasia (Everett et al, 1952), although this belies the description 'anhidrotic'. Until more satisfactory methods are available for evaluating the structure, distribution and response of sweat glands, this difficulty in defining the type of sweating abnormality will persist. It is likely that the distinction between the anhidrotic and hidrotic conditions, as separate phenotypes, is not as precise as was originally thought. However, the genetic differences remain and are extremely valuable as a guide to prognosis and inheritance, Cockayne (1933) reported a rare dominant form of anhidrotic ectodermal dysplasia and Kerr, Wells & Cooper (1966) discussed patients with this diagnosis, but the existence of this type has still not been substantiated. The associated abnormalities (Table 2) in our patients, such as syndactyly and supernumerary nipples, have all been described before in association with the ectodermal dysplasias. This is a further example of the similarities to be found in this group of disorders.
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It was difficult to find an adequate explanation for the characteristic facies of our patients. However, similar features have been described in patients with cleft palates and in their unaffected relatives (Frazer & Pashayan, 1970)- For instance, our group and theirs shared underdeveloped maxillae and a trapezoid facial shape. Hence the existence of a cleft palate in our patients may explain their facies. Embryological aspects. Ankyloblepharon, ectodermal defects and cleft palate appear to be a causally unrelated triad, but it may be possible to connect these disorders. Ectoderm, for instance, lines the fusing palatal processes. Persistence of this tissue layer along thc fusion line results in the formation of small epithelial rests identifiable by microscopy (Stark, 1954). The lacrimal duct is formed from a similar 'rest' of ectoderm entrapped by the fusing nasal processes. This proliferates at about the 35 mm stage of embryonic development and the solid cord of cells canalizes by dissolution ofthe central core (Duke-Elder, 1964). The developing eyelids are covered with ectoderm and during the process of formation of thc adult structure, both fusion and then separation of the joined parts occurs. The development of limb structure is known to be in part dependent upon a complex interaction between ectoderm and mesoderm, which, for instance, allows the development ofthe grooves between digits. Both syndactyly and ectrodactyly could result from a defect in this process. The term ectodermal dysplasia is used to describe a gross inherited defect apparently confined to ectodermal tissue. However, there is evidence to suggest that other germ layers may be affected as well. For instance. Reed, Lopez & Landing (1970) described some cases in which endoderm was abnormal. We know that mesoderm and ectoderm interact in the production of limb buds, feathers, hair and other specialized structures (Wessells, 1967), A fault in mesodermal tissue's ability to organize ectoderm might produce the picture of ectodermal dysplasia. In our cases there was no evidence of involvement of another germ layer although the past history of thyroid disease in case 3 could be relevant. It is therefore not possible to incriminate one embryonic germ layer as the sole abnormality in this syndrome. But the most readily apparent features may be explained in terms of either an abnormality of ectoderm itself or a defective interaction of ectoderm and mesoderm. CONCLUSION
This is the first time, to our knowledge, that this syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate has been described. The ectodermal defects seen in the patients recorded here were very striking and generally consistent. The scalp hair was wiry and sparse or absent. The nails were abnormal or absent. The teeth were pointed and spaced, and soon worn down or lost. Hypohidrosis was demonstrated in all the affected individuals. There was a history of ankyloblepharon or ankyloblepharon filiforme adnatum in most ofthe affected patients and they all had a cleft palate or cleft lip/cleft palate. None of these features was individually diagnostic, but together they contributed to the unusual appearance seen in this syndrome, ACKNOWLEDGMENTS
Our thanks to Dr E,M.Donaldson, Dr P.J.Feeny and Dr H.T.H.Wilson for referring their patients to us to study, and to the Herbert E.Dunhill Trust for a generous grant to finance the investigations. Dr P.E, Hutchinson helped with the examination ofthe hair, and Miss Susan Ellom with the tests of sweating. REFERENCES BOWEN, P. & ARMSTRONG, H.B. (1973) Cleft Up and palaiej eaodermal dysplasia, hand and foot anomalies and
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oligophrenia. In: Birth Defects Atlas and Compendium (Ed. by Daniel Bergsma), p. 262. The National Foundation, New York. BRILL, C.B., Hsu, L.Y.F. & HIRSCHHORN, K, (1972) The syndrome of ectrodactyly, ectodermal dysplasia and cleft lip and palate: report of a family demonstrating dominant inheritance pattern. Clinical Genetics, 3, 295. CocKAYNh, E.A. (193J) Inherited Abnormaluies of the Skin and its Appendages, pp. 218-219- Oxford University Press, London. DUKE-ELDEK, S. (1964) In: System of Ophthalmology. Vol. Ill, Part I, Chpt. VIII, pp. 240-245. EVERETT, F.G., JUMP, E.B., SUTHERLAND, W.F., SAVARA, B . S . & SUHER, T . (1952) Anhidrotic ectodermal dys-
plasia with andontia—a study of 2 families. Journal of the American Dental Association, 44, 173. FRAZER, F.C. & PASHAYAN, H . (1970) The relation of face shape to susceptibility to congenital cleft Up. Journal of Medical Genetics, 7, ti2. FREIRE-MAIA, N . (1970) A newly recognized genetic syndrome of tetramelic deficiencies, ectodermal dysplasia, deformed ears and other abnormalities. American Journal of Human Genetics, 22, 370. HARRIS, D.R., POLK, B.F. & WILLIS, I. (1972) Evaluating sweat gland activity with imprint techniques. Journa/ of Investigative Dermatology, 58, 78. HAY R.J. & WELLS, R.S. (1975) Syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate. Proceeditigs of the Royal Society of Medicine, 68, 536. HOLLISTER, D.W., KLEIN, S.H., D E JAGER, H.J., LACHMAN, R.S. & RIMOIN, D.L. (1973) The lacrimo-auriculo-
dento-digital syndrome. Journal of Pediatrics, 83, 438. HUTCHINSON, P.E. & WELLS, R.S. (1975) Hereditary hypotrichosis (Marie-Unna type). Proceedings of the /Joya/ Society of Medicine, 68, 534. KERR, C.B., WELLS, R.S. & COOPER, K.E. (t966) Gene eflFect on carriers of anhidrotic ectodermal dysplasia. Journal of Medical Genetics, 3, 169, KUNO, Y. (1956) Human Perspiration, Chpt. 2, p. 73. Charles C. Thomas, Illinois. LONG, J.C. & BLANDFORD, S.E. (1962) Ankyloblepharon filiforme adnatum with cleft lip and palate. American Journal of Ophthalmology, 53, 126. MiCHAELiDES, A.C, HAV, R.J. & WELLS, R.S. (1975) Congenital sinuses of the lower lip. Transactions of the .St John's Hospital Dermatological Society, 61, 82. RAPP, R.S. & HODGKIN, W.E. (1968) Anhidrotic ectodermal dysplasia: autosomal dominant inheritance with palate and lip anomalies. J'oHma/ of Medical Genetics, 5, 269. RKED, W.B., LOPEZ, D.A. & LANDING, B. (1970) Clinical spectrum of anhidrotic ectodermal dysplasia. Archives of Dermatology, 102, 134. RUDIGER, R.A., HAASE, W . & PASSARGE, E. (1970) The association of ectrodactyly, ectodermal dysplasia and cleft lip and palate. (Thc E.E.C. syndrome). American Journal of Diseases of Children, 120, 160. SoRSBY, A. Ct970) ophthalmic Genetics, Chpt. 11, p. 1S5. Butterworth, England. STARK, R.B. (1954) The pathogenesis of hair lip and cleft palate. Plastic and Reconstructive Surgery and the Transplantation Bulletin, 13, 20. WHSSELLS, N . K . (1967) Differentiation of epidermis and epidermal derivatives. New England Journal of Medicine 217, 33-
The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: an autosomal dominant condition R.J.HAY AND R.S.WELLS The Department of Dermatology, Guy's Hospital, London, and The Department of Genetics, St John's Hospital for Diseases of the Skin, Lisle Street, London, WC2H 7BJ Accepted for publication 13 June 1975
SUMMARY
Seven patients from four families are reported who had an inherited condition of which the main features were ankyloblcpharon, ectodermal defects and cleft lip and palate. The ectodermal defects were partial or complete hair loss, absent or dystrophic nails, pointed widely spaced teeth and partial anhidrosis. Associated anomalies included lacrimal duct atresia, supernumerary nipples, syndactyly and auricular deformities. The inheritance of this abnormality was consistent with that of an autosomal dominant trait. The relationship between this and similar syndromes is discussed.
Ankyloblepharon, or fusion of the eyelids, is rarely complete. The lids are usually joined at birth by a solid band at the lateral or medial margins or by numerous epithelial strands. In the latter instance the condition is named ankyloblepharon filiforme adnatum, and the strands may contain elements of vascular and connective tissue. Where genetic evidence is available, the inheritance of ankyloblepharon has been described as that of an autosomal dominant condition (Sorsby, 1970). A genetic aetiology for ankyloblepharon filiforme adnatum is less certain, but it has been described in conjunction with cleft palate and lip (Long & Blandford, 1962). Genetically determined defects of ectodermal tissues have long attracted medical attention because of the bizarre appearances produced. Cockayne (1933) divided these disorders into two genetically distinct groups, the anhidrotic and the hidrotic ectodermal dysplasias, whose distinguishing features were the presence or absence of sweating, nail or dental defects. The anhidrotic form was X-linked and hidrotic ectodermal dysplasia was inherited as an autosomal dominant condition. There is no doubt that there are defects of other ectodermally derived tissues which may occur in isolation. These include both alopecia and anonychia. Again, there is genetic heterogeneity and amongst them there are some autosomal dominant varieties. The anomaly of cleft lip and palate is relatively common and may be due to many different causes. Correspondence address: Dr R.J.Hay, Department of Dermatology, Guy's Hospitalj London, SEi 9RT. E
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For example, it is known that teratogens may produce the condition, but it can also be inherited. An isolated cleft palate is under multifactorial (polygenic) influence. However, when cleft lip and palate are inherited in association with another abnormality, for example with congenital sinuses of the lower lip (Michaelides, Hay & Wells, 1975), ^he inheritance is often that of an autosomal dominant type. This is probably the case with the individuals described below. We are reporting seven individuals from four families who showed a combination of these three abnormalities which does not appear to h3ve been described before and which was probably inherited as an autosomal dominant condition. Ascertainment
The four probands were referred to the Genetic Clinic at St John's Hospital for Diseases of the Skin or to the Hospital for Sick Children, Great Ormond Street. One patient (case i) has been presented at a meeting of the Dermatology Section of the Royal Society of Medicine (Hay & Wells, 1975). Three of the individuals had been under the care of other dermatologists, before they were referred to us, and we are grateful to them for their permission to study these patients. Method of investigation
Pedigree details (Fig. i) were recorded at the first visit of each patient and a complete clinical examination was carried out. Where possible their families were visited in their homes and all were examined. Pedigree S
ur DOMole/temale unaffeded; • • Mcle/femaleatfectedi /pratwnd, •deceased,
FIGURE I. Pedigrees A, B and C.
FIGURE 2. Silflo impression irom an allccted patient. The number ot sweat pores seen is reduced compared with normal controls.
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Three patients (cases i, 3 and 7) were admitted to Guy's Hospital so that further studies could be performed. Sweating was evaluated by an impression technique using a silicone material, Silflo. Counts of active sweat glands from six areas (Table i) were recorded first, at rest; second, after iontophoresis of an aqueous solution of os",, pilocarpine; and third, after a hot bath. Casts were taken by spreading a fine layer of the Silflo resin over the skin in the areas tested and the resulting impression was then projected onto a screen through a i cm square grid. The area over each gland producing sweat showed up as a point of light (Fig. 2). These points could be counted and an approximate estimate of their size made. Finally a direct pore count was made of the impression under a dissecting microscope equipped with a micrometer scale. The use of similar methods in hidrotic ectodcrmal dysplasia and other conditions has been previously described (Harris, Polk & Willis, 1972). CLINICAL FEATURES Pedigree A
Case I. H.2 G.H. Female, aged i-jyears. This patient was born at full term after a normal delivery. The birth weight was not known. At birth her eyelids were fused by epitheUal strands at the lateral lid margins and were divided surgically. A median cleft palate and cleft lip on the right were also repaired shortly after birth. Her hair had always been sparse and was shed progressively through childhood. Hair fall was often exacerbated by periods of scalp infection. Her nails had been dystrophic since birth. Her teeth were poorly formed and pointed and had been removed by the age of 12 years. There was no specific difficulty with sweating. In addition, she had experienced recurrent episodes of photophobia and lacrimation. Family history. There was no family history of a similar disorder or of its components and there was no history of consanguinity. Her daughter is case 2. On examination. The patient was an adult female of normal bodily proportions. However, she had a striking facies, with broadened nasal bridge and hypoplastic maxilla. There was an incompletely repaired median cleft palate. Her chin was prominent. The scalp hair was almost totally absent. Some of her nails were dystrophic, and the abnormality varied in extent from total absence to a terminal dystrophy. Her skin was dry and relatively hairless, particularly in the axillae and pubic areas. There was a supernumerary nipple on each anterior axillary fold and partial syndactyly of the second and third toes. Her eyes were injected and the lashes were short and incurved. No lacrimal puncta could be discerned on either upper or lower eyelid on either side. There was palmar and plantar hyperkeratosis with obliteration of dermatoglyphic patterns. Her cardiovascular, nervous, respiratory and genital systems were all normal on clinical examination. Case 2. IH.3 M.H. Female, aged 2 years. This patient is the daughter of case i. Her birth weight was 32 kg. Like her mother, her eyelids were fused at the lateral margins by short bands. She was born with a cleft palate but no hare lip. From early childhood, her scalp hair was sparse, fair and wiry with some patches of alopecia where her scalp had been damaged by recurrent bacterial infections. She had dystrophic finger nails, but normal toe nails. There was no history of heat intolerance or recurrent colds. On examination. Her facial structure was difficult to evaluate because of her age. However, there was a posterior median cleft of the palate. Few teeth had erupted and those present were irregular and
The A.E.C. Syndrome
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pointed. Her skin was dry. Her eyes were injected and there was a marginal blepharitis. Also the lacrimal puncta were small and atrophic. There was no palmar or plantar hyperkeratosis. Pedigree B
Case 3. II.2 K.C. Male, aged 38 years. This patient was born 3 weeks prematurely. His birth weight was 2 9 kg. It was not known if his eyelids were fused at birth. However he had a cleft palate without cleft lip. His hair, including eyebrows and eyelashes, had always been sparse. Finger nails had never formed and only the big toe nails on his feet. He never developed a full second dentition and his teeth were irregular in shape and carious from an early age. There was no heat intolerance. Recently he had had attacks of photophobia and lacrimation. Also, he was partially deaf in the left ear, with an onset during the last 10 years. Family history. There was no relevant history of skin problems but his mother was deaf in the left ear. No further details of this deafness were available. His only son is case 4. Medical history. He reported that he was treated for hypothyroidism in early childhood, but no record of this was available. He had also been investigated for right bundle branch block, discovered on a routine E.C.G. examination, but no cause was found. A benign granuloma was removed from his vocal cords in 1972.
FIGURE 3. Frontal view demonstrating the facies, alopecia and ear deformity.
On examination. His facies (Fig. 3) was strikingly similar to case i, with a broadened nasal bridge and sunken maxilla (Fig. 4). Again an incompletely repaired median cleft palate was noted. His teeth, which were widely spaced, had been extensively filled and capped. Finger (Fig. 5) and toe nails, apart from the big toe nails, were absent. His skin was dry with reticulate hyperpigmentation prominent on the forearms and in the axillae. His conjunctivae were injected and he was severely photophobic, but he reported that this tended to fluctuate. There was bilateral arcus senilis. There was a partial neural hearing loss in the left ear and
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FIGURE 4. Lateral view. Loss of prominence of maxilla is shown.
FIGURE 5. Close up view of middle three fingers ofthe right hand showing the loss of nail substance.
the external ear on this side was deformed and cup-shaped. His voice was hoarse. The palms and sole were hyperkeratotic and cracked. The cardiovascular, nervous, respiratory and genital systems were normal on examination. Case 4. III.3 M.C. Male, aged i month. This patient is the only son of case 3. His birth weight was 39 kg. He was born with fusion ofthe lateral lid margins and with a median cleft palate. Finger and toe nails were absent. Family history. His mother had idiopathic epilepsy, diagnosed in childhood, and was being treated with phenytoin, including during the time she was pregnant. On examination. There was a large mid-line cleft of the palate and moderate micrognathus was noted. One canine tooth had erupted. However, his hair was sparse and fair. There was a resolving
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ccphalhaematoma and cradle cap eczetna associated with a folliculitis. In addition, his eyelashes were sparse and there were no finger or toe nails. The skin on the legs and head was dry. There was partial ankyloblepharon filiforme adnatum more extensive on the left eye than the right. No other abnormalities were detected apart from a mild and asymptomatic phimosis. Pedigree C
Case 5, 11,7 R.W. Female, aged 32 years. This patient weighed 2 0 kg at hirth and delivery was normal: she was born with a cleft palate. Her hair was dark at birth but was shed rapidly. Subsequently there was some patchy regrowth with coarse fair hair, but this too was lost at puberty. She never had pubic or axillary hair and eyelashes were always sparse. Finger and toe nails were severely dystrophic. Both primary and secondary dentition were incomplete and irregular. The latter consisted of pointed teeth and many did not erupt. All teeth were shed by the age of 15 years. She had had attacks of photophobia in the past, but had never had treatment. Family history. A maternal cousin had a cleft lip and palate, but without any other defeas. No other relatives were affected, apart from her daughter (case 6). Past medical history. She reported that small nodules were removed from her eyelid margins when she was a child, but no detailed records were available. On examination. She hid the characteristic facies ofthe other adult members of this group, with a broad flat face. The repair of a median cleft ofthe palate was noted and her teeth were absent. Scalp hair was almost totally absent and her nails were all dystrophic and brittle. Her skin was dry. She had a chronic blepharitis, but all lacrimal duct puncta were visible. In addition there was palmo-plantar hyperkeratosis with partial obliteration ofthe dermatoglyphic patterns. Case 6. 111.3 •^'-W^- Female, aged I year. This patient is the daughter of case 5. Her birth weight was 31 kg, and the confinement was normal. She was born with a cleft palate. Ankyloblepharon from the lateral border up to the mid-line was divided surgically shortly after birth. However, her nails at birth were rudimentary. Subsequently she had developed two teeth, which were discoloured and irregularly pointed. Sweating was normal and there was no heat intolerance. On examination. There was a large mid-line cleft ofthe palate. The hair, nails and teeth were all dystrophic. There were no visible lacrimal puncta on either side and the lid margins were inflamed. In addition, there was an epicanthal fold on the right side. There were a number of filamentous bands joining the lateral walls of the posterior aspect of the vagina. There was also a posterior anal fissure. There was no abnormality of the cardiovascular, nervous or respiratory systems. Case 7, L.M. Female, aged loyears. (Pedigree not illustrated.) This patient's birth weight was 2-4 kg and she was 4 weeks premature. Her eyelids were fused at birth but spontaneous separation took place. There was a cleft palate but no cleft lip. Her hair was sparse and brittle. There were no nails at birth and subsequent growth was poor and dystrophic. Primary dentition had been retained. She had no photophobia. Family history. There was no family history of any relevant disorder. Consanguinity was excluded
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Past medical histoiy. Her choanal atresia was corrected surgically in 1964. The cleft palate and mandibular prognathism were repaired in 1966. On examination. This patient had the same characteristic fades with a hypoplastic maxilla and oval face. There was a central palatal defect with a surrounding rim of oral candidiasis, secondary to a palatal prosthetic plate. Her teeth were discoloured, carious and pointed, but all were present. Her hair was coarse and sparse, particularly in the occipital area, and there were some white hairs scattered anteriorly. Her nails were severely dystrophic. The skin was smooth, dry and relatively hairless. There was partial syndactyly of both second and third toes and of the third and fourth toes on the left (Fig. 7). There was also partial syndactyly ofthe third and fourth fingers bilaterally. Her left ear was deformed, with a cup-shaped auricle. The intercanthal distance was 32 mm and this is within the definition of telecanthus. There was
FIGURE 6. Lateral view of the face. Note the retention of partial ankyloblepharon of the left eye.
FIGURE 7, A view of the toes to illustrate thc degree of syndactyly.
The A.E.C. Syndrome
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partial ankyloblepharon on the lateral lid margin ofthe left eye (Fig, 6). Upper lacrimal duct puncta were present, although the orifice on the left was reduplicated. Orifices on both lower lids were small and atrophic. No other abnormality was seen. RESULTS
Sweating tests were carried out as described above on cases i, 3 and 7. The results are summarized in Table I, In Case i there was a patchy loss of glands over most ofthe areas tested. The best response was on the hands to a thermal stimulus and large amounts of sweat were produced from fewer glands than normal. Sweat was produced for at least 20 min after cessation ofthe stimulus, whereas in the normal controls it stopped promptly. In cases 3 and 7 a similar patchy loss of sweating was seen, ahhough the response on the hands was not as dramatic. The results can be interpreted as a net loss of sweat glands, although the distribution of this loss was dissimilar in the patients tested. Hair shaft microscopy. Samples of hair from three ofthe patients were examined both in longitudinal profile and in cross-section under the light microscope. The hairs were of a relatively wide diameter and showed actual rotation at various points along the hair shaft. In the cross-section the hair cuticles were either thinned or absent, even though the sections were performed at a proximal point on the hair shaft. The shape of most ofthe hairs was markedly abnormal. There were multiple concavities on the perimeter ofthe hair which presented a scalloped appearance, as opposed to the smooth round or oval shape of normal hairs. Scanning electron microscopy confirmed the presence of a frequently defective cuticle and also showed longitudinal fluting of the hair shaft. The appearances presented by these hairs were identical to those seen in hereditary hypotrichosis (Marie-Unna Type) (Hutchinson & Weils, 1975)Other investigations
Cases I, 3 and 7 were admitted for investigation to Guy's Hospital, This included estimations of haemoglobin, white cell count, E,S.R., R.P,C,F,T. and V,D,R,L,, plasma proteins, liver function tests and blood sugar. All were normal. In case 3, serum lipids and thyroid function tests were studied because of the arcus senilis and the past history of hypothyroidism. Both these were normal. In addition, skull and chest X-rays were performed on these patients. These were also normal, although the skull films demonstrated the palatal defect. An E.CG, was performed on case 3 and this showed a right bundle branch block without any other evidence of cardiac pathology. An E.E.G, performed on case 7 at another hospital 4 years previously was reported as showing an area of dysfunction in the anterior part ofthe left hemisphere, A skin biopsy was taken from the axilla of case 3 and showed almost total absence of epidermal appendages. There were no other abnormal histologica! features apart from increased melanin deposition in the basal layer in part of the section. Slit lamp examination of the eyes of cases i, 3 and 7 was carried out after instillation of oculent fluorescein. Only case 3 showed evidence of keratitis. However, in case i there was no excretion ofthe dye into the nasal or oral cavities. This supported the clinical impression of atresia of the lacrimal ducts. The intelligence of all the patients studied was normal on gross testing. Genetic findings
The first three pedigrees are illustrated (pedigrees A, B and C, Fig. i). The inheritance of this
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disorder was compatible with that of an autosomal dominant trait, because both sexes were affected equally severely. Parents and children were afFected rather than siblings alone. The father to son transmission in pedigree C excluded X-linkage. The four probands were presumably the first recipients of a new abnormal mutation. There was no consanguinity. In the third family (cases 5 and 6) there was a maternal cousin who had a cleft lip and palate. He now lives abroad and could not be examined. The significance of this observation was hard to evaluate. There was no evidence in the other families of independent segregation of characters and it was possible that this one case was either a non-genetic variant or the unconnected expression of this relatively common genetic condition on its own. DISCUSSION
Differential diagnosis. The features common to all the patients were ankyloblepharon, ectodermal defects and cleft lip and palate. Ankyloblepharon was present in all patients apart from two (cases 3 and 4) in the form of ankyloblepharon filiforme adnatum. In case 4 it is possible that the tumours on thc eyelids removed in childhood were the remnants of this defect, Ectodermal defects, such as alopecia, hypodontia and nail dystrophy, were present in all cases. Cleft palate alone occurred in all families apart from the second group (pedigree B) where a cleft lip was present, in addition, in thc proband, Bowen & Armstrong (1973) described a genetically distinct but similar syndrome in which these defects occurred in two siblings in association with mental retardation. The inheritance was of an autosomal recessive type. However, ectodermal defects of comparable severity and inheritance have been described in association with cleft lip and palate alone (Rapp & Hodgkin, 1968). Two other similar conditions have been recorded. One, the E.E.C. syndrome (or ectrodactyly, ectodermal defects and clefting syndrome) has been described by a number of authors (Rudiger, Haase & Passarge, 1970; Brill, Hsu & Hirschhorn, 1972). The features of this syndrome are contrasted with those of our cases, and anhidrotic and hidrotic ectodermal dysplasia in Table 2, The other syndrome, the L,A,D.D, syndrome, the main features of which are lacrimal duct atresia, auricular deformities, dental and digital anomalies, covers a similar range of defects (Hollister et al, 1973)- All these conditions may be inherited as autosomal dominant traits, although, when the E,E,C, syndrome was associated with mental retardation, the inheritance was autosomal recessive (Freire-Maia, 197°)Ectodermal defects. The ectodermal defects in this syndrome share important features in common with the classical anhidrotic and hidrotic ectodermal dysplasias (Table 2), The presence of sweating, in reduced amounts, has already been noted in patients with features typical of anhidrotic ectodermal dysplasia (Everett et al, 1952), although this belies the description 'anhidrotic'. Until more satisfactory methods are available for evaluating the structure, distribution and response of sweat glands, this difficulty in defining the type of sweating abnormality will persist. It is likely that the distinction between the anhidrotic and hidrotic conditions, as separate phenotypes, is not as precise as was originally thought. However, the genetic differences remain and are extremely valuable as a guide to prognosis and inheritance, Cockayne (1933) reported a rare dominant form of anhidrotic ectodermal dysplasia and Kerr, Wells & Cooper (1966) discussed patients with this diagnosis, but the existence of this type has still not been substantiated. The associated abnormalities (Table 2) in our patients, such as syndactyly and supernumerary nipples, have all been described before in association with the ectodermal dysplasias. This is a further example of the similarities to be found in this group of disorders.
288
R-J.Hay and R.S.Wells
It was difficult to find an adequate explanation for the characteristic facies of our patients. However, similar features have been described in patients with cleft palates and in their unaffected relatives (Frazer & Pashayan, 1970)- For instance, our group and theirs shared underdeveloped maxillae and a trapezoid facial shape. Hence the existence of a cleft palate in our patients may explain their facies. Embryological aspects. Ankyloblepharon, ectodermal defects and cleft palate appear to be a causally unrelated triad, but it may be possible to connect these disorders. Ectoderm, for instance, lines the fusing palatal processes. Persistence of this tissue layer along thc fusion line results in the formation of small epithelial rests identifiable by microscopy (Stark, 1954). The lacrimal duct is formed from a similar 'rest' of ectoderm entrapped by the fusing nasal processes. This proliferates at about the 35 mm stage of embryonic development and the solid cord of cells canalizes by dissolution ofthe central core (Duke-Elder, 1964). The developing eyelids are covered with ectoderm and during the process of formation of thc adult structure, both fusion and then separation of the joined parts occurs. The development of limb structure is known to be in part dependent upon a complex interaction between ectoderm and mesoderm, which, for instance, allows the development ofthe grooves between digits. Both syndactyly and ectrodactyly could result from a defect in this process. The term ectodermal dysplasia is used to describe a gross inherited defect apparently confined to ectodermal tissue. However, there is evidence to suggest that other germ layers may be affected as well. For instance. Reed, Lopez & Landing (1970) described some cases in which endoderm was abnormal. We know that mesoderm and ectoderm interact in the production of limb buds, feathers, hair and other specialized structures (Wessells, 1967), A fault in mesodermal tissue's ability to organize ectoderm might produce the picture of ectodermal dysplasia. In our cases there was no evidence of involvement of another germ layer although the past history of thyroid disease in case 3 could be relevant. It is therefore not possible to incriminate one embryonic germ layer as the sole abnormality in this syndrome. But the most readily apparent features may be explained in terms of either an abnormality of ectoderm itself or a defective interaction of ectoderm and mesoderm. CONCLUSION
This is the first time, to our knowledge, that this syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate has been described. The ectodermal defects seen in the patients recorded here were very striking and generally consistent. The scalp hair was wiry and sparse or absent. The nails were abnormal or absent. The teeth were pointed and spaced, and soon worn down or lost. Hypohidrosis was demonstrated in all the affected individuals. There was a history of ankyloblepharon or ankyloblepharon filiforme adnatum in most ofthe affected patients and they all had a cleft palate or cleft lip/cleft palate. None of these features was individually diagnostic, but together they contributed to the unusual appearance seen in this syndrome, ACKNOWLEDGMENTS
Our thanks to Dr E,M.Donaldson, Dr P.J.Feeny and Dr H.T.H.Wilson for referring their patients to us to study, and to the Herbert E.Dunhill Trust for a generous grant to finance the investigations. Dr P.E, Hutchinson helped with the examination ofthe hair, and Miss Susan Ellom with the tests of sweating. REFERENCES BOWEN, P. & ARMSTRONG, H.B. (1973) Cleft Up and palaiej eaodermal dysplasia, hand and foot anomalies and
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oligophrenia. In: Birth Defects Atlas and Compendium (Ed. by Daniel Bergsma), p. 262. The National Foundation, New York. BRILL, C.B., Hsu, L.Y.F. & HIRSCHHORN, K, (1972) The syndrome of ectrodactyly, ectodermal dysplasia and cleft lip and palate: report of a family demonstrating dominant inheritance pattern. Clinical Genetics, 3, 295. CocKAYNh, E.A. (193J) Inherited Abnormaluies of the Skin and its Appendages, pp. 218-219- Oxford University Press, London. DUKE-ELDEK, S. (1964) In: System of Ophthalmology. Vol. Ill, Part I, Chpt. VIII, pp. 240-245. EVERETT, F.G., JUMP, E.B., SUTHERLAND, W.F., SAVARA, B . S . & SUHER, T . (1952) Anhidrotic ectodermal dys-
plasia with andontia—a study of 2 families. Journal of the American Dental Association, 44, 173. FRAZER, F.C. & PASHAYAN, H . (1970) The relation of face shape to susceptibility to congenital cleft Up. Journal of Medical Genetics, 7, ti2. FREIRE-MAIA, N . (1970) A newly recognized genetic syndrome of tetramelic deficiencies, ectodermal dysplasia, deformed ears and other abnormalities. American Journal of Human Genetics, 22, 370. HARRIS, D.R., POLK, B.F. & WILLIS, I. (1972) Evaluating sweat gland activity with imprint techniques. Journa/ of Investigative Dermatology, 58, 78. HAY R.J. & WELLS, R.S. (1975) Syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate. Proceeditigs of the Royal Society of Medicine, 68, 536. HOLLISTER, D.W., KLEIN, S.H., D E JAGER, H.J., LACHMAN, R.S. & RIMOIN, D.L. (1973) The lacrimo-auriculo-
dento-digital syndrome. Journal of Pediatrics, 83, 438. HUTCHINSON, P.E. & WELLS, R.S. (1975) Hereditary hypotrichosis (Marie-Unna type). Proceedings of the /Joya/ Society of Medicine, 68, 534. KERR, C.B., WELLS, R.S. & COOPER, K.E. (t966) Gene eflFect on carriers of anhidrotic ectodermal dysplasia. Journal of Medical Genetics, 3, 169, KUNO, Y. (1956) Human Perspiration, Chpt. 2, p. 73. Charles C. Thomas, Illinois. LONG, J.C. & BLANDFORD, S.E. (1962) Ankyloblepharon filiforme adnatum with cleft lip and palate. American Journal of Ophthalmology, 53, 126. MiCHAELiDES, A.C, HAV, R.J. & WELLS, R.S. (1975) Congenital sinuses of the lower lip. Transactions of the .St John's Hospital Dermatological Society, 61, 82. RAPP, R.S. & HODGKIN, W.E. (1968) Anhidrotic ectodermal dysplasia: autosomal dominant inheritance with palate and lip anomalies. J'oHma/ of Medical Genetics, 5, 269. RKED, W.B., LOPEZ, D.A. & LANDING, B. (1970) Clinical spectrum of anhidrotic ectodermal dysplasia. Archives of Dermatology, 102, 134. RUDIGER, R.A., HAASE, W . & PASSARGE, E. (1970) The association of ectrodactyly, ectodermal dysplasia and cleft lip and palate. (Thc E.E.C. syndrome). American Journal of Diseases of Children, 120, 160. SoRSBY, A. Ct970) ophthalmic Genetics, Chpt. 11, p. 1S5. Butterworth, England. STARK, R.B. (1954) The pathogenesis of hair lip and cleft palate. Plastic and Reconstructive Surgery and the Transplantation Bulletin, 13, 20. WHSSELLS, N . K . (1967) Differentiation of epidermis and epidermal derivatives. New England Journal of Medicine 217, 33-
