J Med Genet: first published as 10.1136/jmg.25.1.47 on 1 January 1988. Downloaded from

Syndrome of the month

Journal of Medical Genetics 1988. 25. 47-51

Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES syndrome) CHRISTINE OLEY AND MICHAEL BARAITSER From the Clinical Genetics Unit, The Hospitals for Sick Children, Great Ormond Street, London WC]N3JH

Although von Ammon' first used the term blephar- Clinical features (figs 1 to 6) phimosis in 1841, it was Vignes2 in 1889 who first associated blepharophimosis with ptosis and epican- B LEPHARO PHIM OS IS thus inversus. In 1921, Dimitry3 reported a family in The palpebral fissure is reduced in horizontal which there were 21 affected subjects in five dimension. The normal horizontal fissure length in generations. He described them as having ptosis adults is 25 to 30 mm whereas in this syndrome it is alone and did not specify any other features, usually 20 to 22 mm."' although photographs in the report show that they probably had the full syndrome. Dimitry's pedigree PTOSIS

was updated by Owens et a/ in 1960. The syndrome Blepharoptosis literally means a falling of the lids. copyright. appeared in both sexes and was transmitted as a The palpebral fissure is abnormally small in the Mendelian dominant. In 1935, Usher5 reviewed the reported cases. By then, 26 pedigrees had been published with a total of 175 affected persons with transmission mainly through affected males. There was no consanguinity

in any pedigree. In three pedigrees, parents who http://jmg.bmj.com/ obviously carried the gene were unaffected. Well over 150 families have now been reported and there is no doubt about the autosomal dominant pattern of inheritance. However, like Usher,5 several authors have noted that transmission is mainly through affected males and less commonly through affected females.4 6 Reports by Moraine et al7 and Townes and Muechler8 have described on September 30, 2021 by guest. Protected families where all affected females were either infertile with primary or secondary amenorrhoea or had menstrual irregularity. Zlotogora et a/9 described one family and analysed 38 families reported previously. They proposed the existence of two types: type I, the more common type, in which the syndrome is transmitted by males only and affected females are infertile, and type II, which is transmitted by both affected females and males. There is male to male transmission in both types and both are inherited as an autosomal dominant trait. They found complete penetrance in type I and slightly reduced penetrance in type II.

Received for publication I June 1987. FIG 1 Typical posture assumed because ofptosis. Note Accepted for publication 6 June 1987. narrowing ofpalpebralfissures and cup shaped right ear. 47 J Med Genet: first published as 10.1136/jmg.25.1.47 on 1 January 1988. Downloaded from

48 Christine Oley and Michael Baraitser

FIG 2 Same patient as infig 1. Note telecanthus, smooth skin over eyelids, andflat nasal bridge.

vertical dimension. It is caused by the absence or persons assume a characteristic posture with the impairment of the function of the levator palpebrae head tilted backwards, the brow furrowed, and the superioris muscle and is usually bilateral and sym- chin arched upward (figs 1 and 3). metrical. To compensate for the ptosis, affected copyright. EPICANTHUS INVERSUS Unlike other types of epicanthus, epicanthus inver- sus improves only slightly with age. It is character- ised by a small skin fold which arises from the lower lid and runs inwards and upwards (fig 2). Associated with this is an increased length of the medial canthal ligament and a lack of the normal depression seen athttp://jmg.bmj.com/ the internal canthus. The effect of blepharophimosis, ptosis, and epi- canthus inversus is to reduce the size of the palpebral fissure by reducing it in both height and width.

ASSOCIATED OCULAR FEATURES /6 Telecanthus is seen in the majority of patients. This on September 30, 2021 by guest. Protected refers to a lateral displacement of the inner canthi leading to a widening of the intercanthal distance. The interpupillary distance remains unchanged. The eyelids are often covered by smooth skin without eyelid folds and deficient amounts of skin in both eyelids may be found at surgery" (fig 2). The eyebrows are increased in their vertical height and they are drawn up into a pronounced convex arch. This is attributed to the stretching of hair bearing skin as a consequence of the constant contraction of the frontalis muscle (fig 3). Abnor- malities of the eyelid margin are frequently seen. The margin of the upper lid has a slight S shaped FIG 3 Affected child, just sitting at 12 months. Note arched curve and the lower lid usually has an abnormal eyebrows. concavity downwards, particularly laterally where J Med Genet: first published as 10.1136/jmg.25.1.47 on 1 January 1988. Downloaded from

Syndrome ofthe month 49

FIG 4 Same patient as in fig 3 with unaffected sibs, who now attends normal school.

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an ectropion might occur. Frequently, there is mos, anophthalmos, microcornea, hypermetropia, lateral displacement of the upper and lower lacrimal divergent strabismus, nystagmus, amblyopia, and puncta, even more than would be expected from the trichiasis. Several authors have commented on the brown eyes in lateral displacement of the inner canthi. apparent increased frequency of copyright. Occasional ocular findings include microphthal- affected persons.'2 http://jmg.bmj.com/ on September 30, 2021 by guest. Protected

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FI ain gd w n afyar eoesrey '** riM FIG 6 Same patient as in fig 5, after three operations, the last one at 18 years. She has secondary amenorrhoea. J Med Genet: first published as 10.1136/jmg.25.1.47 on 1 January 1988. Downloaded from so Christine Oley and Michael Baraitser

NON-OCULAR FEATURES feature. Therefore, congenital simple ptosis,21 A flat, broad nasal bridge occurs frequently (fig 2). ptosis with external ophthalmoplegia,22 Noonan There is one report of a bony deficiency with absent syndrome,23 Marden-Walker syndrome,24 Schwartz- supraorbital ridges and an absent nasoglabellar Jampel syndrome,25 Dubowitz syndrome,26 and angle.1 Higih arched palate has been reported in a Smith-Lemli-Opitz syndrome27 must all be con- few cases.4 3 Protruding, simple, or cup shaped ears sidered. have been reported occasionally'4 (fig 1). Smith'5 has suggested some may have generalised hypoto- Inheritance nia. Cardiac defects have been reported.'6 Intellec- tual development is usually normal although mild Autosomal dominant transmission is well estab- mental retardation has occasionally been reported. 17 lished. Differentiation of the syndrome into two Delay in sitting alone often occurs during the first types by Zlotogora et at) shows that penetrance is year of life, mostly because the infant tilts its head in 100% in type I where there is transmission by males order to see and then falls backwards. Psychological only and affected females are infertile. In type II, problems secondary to the altered facial appearance penetrance is 96*5% and transmission occurs do occur. 18 Many Caucasian children are teased through both sexes. Zlotogora et at) also found there because they look Oriental and some are diagnosed was a deviation from the expected sex ratio among initially as having Down's syndrome. children of affected fathers in both types. In type I, most of the children were males and most male INFERTILITY offspring were affected, whereas in type II, most of There is a high incidence of menstrual irregularity the children were females and most of the female and infertility in females. Although primary hypogo- offspring were affected. nadism has been suggested as a cause of the female Although distinction between the two types is infertility,9 it appears to be responsible in only a few important for counselling females about the likeli- hood of being fertile, if the rate of new mutations is cases, with the cause in most remaining unknown. copyright. Townes and Muechler' reported a family where all as high as 50%, as suggested by Jones and Collin,19 affected females had primary ovarian failure. They then counselling of isolated cases is extremely had a normal female karyotype and normal breast difficult. development, and pubic and axillary hair was scant but in the normal female distribution. Laparoscopy Pathogenesis revealed a small uterus and small atrophic ovaries. There was raised serum testosterone, serum luteinis- In 1930 Waardenburg,28 after studying the embry- ing hormone, and follicle stimulating hormone and ology of human fetuses, proposed that the ocularhttp://jmg.bmj.com/ after administration of cyclical oestrogen and prog- defect in this syndrome occurred during the third esterone therapy regular withdrawal bleeding occur- month of intrauterine life. This would coincide with red. However, Jones and Collin'9 reviewed 37 the critical period in the development of the ovary known cases, and of the six females of child bearing and the initial formation of the uterus through age two had normal menstrual periods, three had Mullerian duct fusion. scanty irregular periods with no definite cycle, and one had primary amenorrhoea. One of the women Management/treatment on September 30, 2021 by guest. Protected with normal periods had had a child and one woman with irregular periods had had three miscarriages. Many children require early surgery because of the Primary hypogonadism with raised gonadotrophins visual difficulties associated with the ptosis and and low oestrogen and progesterone was evident in blepharophimosis. As distinct from other conditions only one but four others had abnormal hormone associated with ptosis, there is very little improve- function which was difficult to interpret. ment in the appearance and function with age. It has also been suggested that the infertility is an Surgery is far more difficult than for isolated autosomal dominant sex limited trait transmitted by ptosis because of the associated epicanthus inversus, males and affecting females only, similar to the type the variable degree of blepharophimosis, and the of inheritance described in the Stein-Leventhal frequent finding of deficient eyelid skin. Early syndrome. 2) surgery is recommended to minimise being teased at school, although the final results of surgical Differential diagnosis correction may be better in older children and in adults.29 Surgery is started between the ages The differential diagnosis includes those conditions of three and five years, although severe ptosis may in which ptosis or blepharophimosis is a major require earlier correction. J Med Genet: first published as 10.1136/jmg.25.1.47 on 1 January 1988. Downloaded from

Syndrome of the month 51 Many surgical techniques have been described but genital anomaly syndrome with blepharophimosis. J Pediawr 1979;95:1010-2. most seem to involve initial canthal surgery to '4 Kohn R. Romano PE. Blepharoptosis, blepharophimosis. epi- improve the blepharophimosis before ptosis correc- canthus inversus and telecanthus-a syndrome with no name. tion is possible. However, combined surgery has Am J Ophthalmol 1971;72:625-32. been used in children with less severe 15 Smith DW. Recognisable patterns of hunanti ;nalfor,namtions. 3rd ed. Philadelphia: Saunders. 1982:170-1. manifestations.3t 16 Beauchamp GR. Blepharophimosis and cardiopathy. J Paediatr Ophthalmol Strabismus 1980;17:227-8. We are grateful to Mrs Melanie Barham for secreta- 7 Sacrez R, Francfort J, Juif JG, de Grouchy J. Le blepharophi- rial assistance and to Mr Roland Brooks for photo- mosis complique familial. Etude des membres de la famille Ble. Ann Pediatr (Paris) 1963;10:493-501. graphic work. We would also like to thank Mr D N 18 O'Connor G, McGregor M. Associated congenital abnormali- Matthews, Consultant Plastic Surgeon for fig 5. ties of the eyelids and appendages. Plast Reconistr Surg 1953 ;1 1:348-52. References 19 Jones CA, Collin JRO. Blepharophimosis and its association with female infertility. Br J Ophthalmol 1984;68:533-4. von Ammon FA. Klinische darstellung der krankheiten und 21) Givens JR, Wiser WL, Coleman SA, Wilroy RS, Anderson RN. auges, bildungsfehler des menschlichen der augenglides und der Fish SA. Familial ovarian hyperthecosis: a study of two families. thranewerkzeuge. Berlin: G Reimers, 1841. Am J Obst Gvnecol 1971;110:959-72. 2 Vignes A. Epicanthus hereditaire. Rev Gen Ophtalmol (Paris) 21 Spaeth EB. A classification for congenital ptosis. Atn J 1889;8:438-9. 3 Ophthalmol 1943;26:1326-7. Dimitry TJ. Hereditary ptosis. Am J Ophthalmol 1921;4:655-8. 22 Rank BK. The genetic approach to hereditary congenital ptosis. 4 Owens N, Hadley R, Kloepfer HW. Hereditary blepharophimo- Aust NZ J Surg 1959:;28:274-9. sis, ptosis and epicanthus inversus. J Int Coll Surg 1960;33: 23 Allanson JE. Noonan syndrome. J Med Geniet 1987:24:9-13. 558-74. 24 King CR, Magenis E. The Marden-Walker syndrome. J Med 5 Usher CH. Bowman's lecture on a few hereditary eye affections. Genet 1978;15:366-9. Trans Ophthalmol Soc UK 1935;LV: 194-206. 25 Schwartz 0, Jampel RS. Congenital blepharophimosis associ- Genet Statis Med 6 Edmund J. Blepharophimosis congenita. Acta ated with a unique gencralised myopathy. Arch Ophthaltnol 1957;7:279-84. 1962;68:52-7. 7 Lenoel Moraine C, Titeca C, Delplace MP, Grenier B, Y, 26 Dubowitz V. Familial low birth weight dwarfism with an unusual et copyright. Ribadeau-Dumas JL. Blepharophimosis familial sterilitc facies and a skin eruption. J Med Genet 1965;2:12-17. feminine. J Genet Hum 1976;24(suppl):125-32. 27 Smith DW, Lemli L, Opitz JM. A newly recognised syndrome of 8 Townes PL, Muechler EK. Blepharophimosis, ptosis, epican- multiple congenital anomalies. J Pediatr 1964;64:21(t-7. thus inversus and primary amenorrhoea. Arch Ophthalmol 2X Waardenburg PJ. Die Zuruchfuhrung ciner reike erhlichange- 1979;97:1664-6. borener familiarer augenmissbildungen auf cine fixation 9 Zlotogora J, Sagi M, Cohen T. The blepharophimosis, ptosis normaler fetaler verhaltnisse. Arch Ophthalmnol 1930);124:221-9. and epicanthus inversus syndrome: delineation of two types. Am 29 Johnson CC. Operations for epicanthus and blepharophimosis. J Hum Genet 1983;35:1020-7. Am J Ophthalmol 1956;41:71-9. Johnson CC. Surgical repair of the syndrome of epicanthus 31' Elliot D, Wallace AF. Ptosis with blepharophimosis and http://jmg.bmj.com/ inversus, blepharophimosis and ptosis. Arch Ophthalmol epicanthus inversus. Br J Plast Surg 1986;39:244-8. 1964;71:510-6. Lewis S, Arons M, Lynch J, Blocker T. The congenital eyelid syndrome. Plast Reconstr Surg 1967;39:271-7. Correspondence and requests for reprints to Dr 12 Mcllroy JH. Hereditary ptosis with epicanthus: a case with Michael Baraitser, Department of Clinical Genetics, pedigree extending over 4 generations. Proc R Soc Med 1930:23:285-8. Institute of Child Health, 30 Guilford Street, 3 Pueschel SM, Barsel-Bowers G. A dominantly inherited con- London WC1N 1EH. on September 30, 2021 by guest. Protected