Syndrome of the month

Journal of Medical Genetics 1988. 25. 47-51

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

Although von Ammon' first used the term blephar-phimosis in 1841, it was Vignes2 in 1889 who firstassociated blepharophimosis with ptosis and epican-thus inversus. In 1921, Dimitry3 reported a family inwhich there were 21 affected subjects in fivegenerations. He described them as having ptosisalone and did not specify any other features,although photographs in the report show that theyprobably had the full syndrome. Dimitry's pedigreewas updated by Owens et a/ in 1960. The syndromeappeared in both sexes and was transmitted as aMendelian dominant.

In 1935, Usher5 reviewed the reported cases. Bythen, 26 pedigrees had been published with a total of175 affected persons with transmission mainlythrough affected males. There was no consanguinityin any pedigree. In three pedigrees, parents whoobviously carried the gene were unaffected.Well over 150 families have now been reported

and there is no doubt about the autosomal dominantpattern of inheritance. However, like Usher,5several authors have noted that transmission ismainly through affected males and less commonlythrough affected females.4 6 Reports by Moraine etal7 and Townes and Muechler8 have describedfamilies where all affected females were eitherinfertile with primary or secondary amenorrhoea orhad menstrual irregularity. Zlotogora et a/9described one family and analysed 38 familiesreported previously. They proposed the existence oftwo types: type I, the more common type, in whichthe syndrome is transmitted by males only andaffected females are infertile, and type II, which istransmitted by both affected females and males.There is male to male transmission in both types andboth are inherited as an autosomal dominant trait.They found complete penetrance in type I andslightly reduced penetrance in type II.

Received for publication I June 1987.Accepted for publication 6 June 1987.

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Clinical features (figs 1 to 6)

B LEPHARO PHIM OS ISThe palpebral fissure is reduced in horizontaldimension. The normal horizontal fissure length inadults is 25 to 30 mm whereas in this syndrome it isusually 20 to 22 mm."'

PTOSISBlepharoptosis literally means a falling of the lids.The palpebral fissure is abnormally small in the

FIG 1 Typical posture assumed because ofptosis. Notenarrowing ofpalpebralfissures and cup shaped right ear.

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48 Christine Oley and Michael Baraitser

FIG 2 Same patient as in fig 1.Note telecanthus, smooth skin over

eyelids, and flat nasal bridge.

vertical dimension. It is caused by the absence orimpairment of the function of the levator palpebraesuperioris muscle and is usually bilateral and sym-metrical. To compensate for the ptosis, affected

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FIG 3 Affected child, just sitting at 12 months. Note archedeyebrows.

persons assume a characteristic posture with thehead tilted backwards, the brow furrowed, and thechin arched upward (figs 1 and 3).EPICANTHUS INVERSUSUnlike 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 lowerlid and runs inwards and upwards (fig 2). Associatedwith this is an increased length of the medial canthalligament and a lack of the normal depression seen atthe internal canthus.The effect of blepharophimosis, ptosis, and epi-

canthus inversus is to reduce the size of thepalpebral fissure by reducing it in both height andwidth.

ASSOCIATED OCULAR FEATURESTelecanthus is seen in the majority of patients. Thisrefers to a lateral displacement of the inner canthileading to a widening of the intercanthal distance.The interpupillary distance remains unchanged. Theeyelids are often covered by smooth skin withouteyelid folds and deficient amounts of skin in botheyelids may be found at surgery" (fig 2).The eyebrows are increased in their vertical

height and they are drawn up into a pronouncedconvex arch. This is attributed to the stretching ofhair bearing skin as a consequence of the constantcontraction 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 shapedcurve and the lower lid usually has an abnormalconcavity downwards, particularly laterally where

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Syndrome of the month

FIG 4 Same patient as in fig 3 withunaffected sibs, who now attendsnormal school.

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an ectropion might occur. Frequently, there islateral displacement of the upper and lower lacrimalpuncta, even more than would be expected from thelateral displacement of the inner canthi.

Occasional ocular findings include microphthal-

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FI ain gd w n afyar eoesrey

mos, anophthalmos, microcornea, hypermetropia,divergent strabismus, nystagmus, amblyopia, andtrichiasis. Several authors have commented on theapparent increased frequency of brown eyes inaffected persons.'2

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FIG 6 Same patient as in fig 5, after three operations, thelast one at 18 years. She has secondary amenorrhoea.

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Christine Oley and Michael Baraitser

NON-OCULAR FEATURESA flat, broad nasal bridge occurs frequently (fig 2).There is one report of a bony deficiency with absentsupraorbital ridges and an absent nasoglabellarangle.1 Higih arched palate has been reported in afew cases.4 3 Protruding, simple, or cup shaped earshave been reported occasionally'4 (fig 1). Smith'5has suggested some may have generalised hypoto-nia. Cardiac defects have been reported.'6 Intellec-tual development is usually normal although mildmental retardation has occasionally been reported. 17Delay in sitting alone often occurs during the firstyear of life, mostly because the infant tilts its head inorder to see and then falls backwards. Psychologicalproblems secondary to the altered facial appearancedo occur. 18 Many Caucasian children are teasedbecause they look Oriental and some are diagnosedinitially as having Down's syndrome.

INFERTILITYThere is a high incidence of menstrual irregularityand infertility in females. Although primary hypogo-nadism has been suggested as a cause of the femaleinfertility,9 it appears to be responsible in only a fewcases, with the cause in most remaining unknown.Townes and Muechler' reported a family where allaffected females had primary ovarian failure. Theyhad a normal female karyotype and normal breastdevelopment, and pubic and axillary hair was scantbut in the normal female distribution. Laparoscopyrevealed a small uterus and small atrophic ovaries.There was raised serum testosterone, serum luteinis-ing hormone, and follicle stimulating hormone andafter administration of cyclical oestrogen and prog-esterone therapy regular withdrawal bleeding occur-red. However, Jones and Collin'9 reviewed 37known cases, and of the six females of child bearingage two had normal menstrual periods, three hadscanty irregular periods with no definite cycle, andone had primary amenorrhoea. One of the womenwith normal periods had had a child and one womanwith irregular periods had had three miscarriages.Primary hypogonadism with raised gonadotrophinsand low oestrogen and progesterone was evident inonly one but four others had abnormal hormonefunction which was difficult to interpret.

It has also been suggested that the infertility is anautosomal dominant sex limited trait transmitted bymales and affecting females only, similar to the typeof inheritance described in the Stein-Leventhalsyndrome. 2)

Differential diagnosis

The differential diagnosis includes those conditionsin which ptosis or blepharophimosis is a major

feature. Therefore, congenital simple ptosis,21ptosis with external ophthalmoplegia,22 Noonansyndrome,23 Marden-Walker syndrome ,24 Schwartz-Jampel syndrome,25 Dubowitz syndrome,26 andSmith-Lemli-Opitz syndrome27 must all be con-sidered.

Inheritance

Autosomal dominant transmission is well estab-lished. Differentiation of the syndrome into twotypes by Zlotogora et at) shows that penetrance is100% in type I where there is transmission by malesonly and affected females are infertile. In type II,penetrance is 96*5% and transmission occursthrough both sexes. Zlotogora et at) also found therewas a deviation from the expected sex ratio amongchildren of affected fathers in both types. In type I,most of the children were males and most maleoffspring were affected, whereas in type II, most ofthe children were females and most of the femaleoffspring were affected.Although distinction between the two types is

important for counselling females about the likeli-hood of being fertile, if the rate of new mutations isas high as 50%, as suggested by Jones and Collin,19then counselling of isolated cases is extremelydifficult.

Pathogenesis

In 1930 Waardenburg,28 after studying the embry-ology of human fetuses, proposed that the oculardefect in this syndrome occurred during the thirdmonth of intrauterine life. This would coincide withthe critical period in the development of the ovaryand the initial formation of the uterus throughMullerian duct fusion.

Management/treatment

Many children require early surgery because of thevisual difficulties associated with the ptosis andblepharophimosis. As distinct from other conditionsassociated with ptosis, there is very little improve-ment in the appearance and function with age.

Surgery is far more difficult than for isolatedptosis because of the associated epicanthus inversus,the variable degree of blepharophimosis, and thefrequent finding of deficient eyelid skin. Earlysurgery is recommended to minimise being teasedat school, although the final results of surgicalcorrection may be better in older childrenand in adults.29 Surgery is started between the agesof three and five years, although severe ptosis mayrequire earlier correction.

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Syndrome of the month

Many surgical techniques have been described butmost seem to involve initial canthal surgery toimprove the blepharophimosis before ptosis correc-tion is possible. However, combined surgery hasbeen used in children with less severemanifestations.3t

We are grateful to Mrs Melanie Barham for secreta-rial assistance and to Mr Roland Brooks for photo-graphic work. We would also like to thank Mr D NMatthews, Consultant Plastic Surgeon for fig 5.

References

von Ammon FA. Klinische darstellung der krankheiten undbildungsfehler des menschlichen auges, der augenglides und derthranewerkzeuge. Berlin: G Reimers, 1841.

2 Vignes A. Epicanthus hereditaire. Rev Gen Ophtalmol (Paris)1889;8:438-9.

3 Dimitry TJ. Hereditary ptosis. Am J Ophthalmol 1921;4:655-8.4 Owens N, Hadley R, Kloepfer HW. Hereditary blepharophimo-

sis, ptosis and epicanthus inversus. J Int Coll Surg 1960;33:558-74.

5 Usher CH. Bowman's lecture on a few hereditary eye affections.Trans Ophthalmol Soc UK 1935;LV: 194-206.

6 Edmund J. Blepharophimosis congenita. Acta Genet Statis Med1957;7:279-84.

7 Moraine C, Titeca C, Delplace MP, Grenier B, Lenoel Y,Ribadeau-Dumas JL. Blepharophimosis familial et sterilitcfeminine. J Genet Hum 1976;24(suppl):125-32.

8 Townes PL, Muechler EK. Blepharophimosis, ptosis, epican-thus inversus and primary amenorrhoea. Arch Ophthalmol1979;97:1664-6.

9 Zlotogora J, Sagi M, Cohen T. The blepharophimosis, ptosisand epicanthus inversus syndrome: delineation of two types. AmJ Hum Genet 1983;35:1020-7.Johnson CC. Surgical repair of the syndrome of epicanthusinversus, blepharophimosis and ptosis. Arch Ophthalmol1964;71:510-6.Lewis S, Arons M, Lynch J, Blocker T. The congenital eyelidsyndrome. Plast Reconstr Surg 1967;39:271-7.

12 Mcllroy JH. Hereditary ptosis with epicanthus: a case withpedigree extending over 4 generations. Proc R Soc Med1930:23:285-8.

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genital anomaly syndrome with blepharophimosis. J Pediawr1979;95:1010-2.

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canthus inversus and telecanthus-a syndrome with no name.

Am J Ophthalmol 1971;72:625-32.15 Smith DW. Recognisable patterns of hunanti ;nalfor,namtions. 3rd

ed. Philadelphia: Saunders. 1982:170-1.16 Beauchamp GR. Blepharophimosis and cardiopathy. J Paediatr

Ophthalmol Strabismus 1980;17:227-8.7 Sacrez R, Francfort J, Juif JG, de Grouchy J. Le blepharophi-mosis complique familial. Etude des membres de la famille Ble.Ann Pediatr (Paris) 1963;10:493-501.

18 O'Connor G, McGregor M. Associated congenital abnormali-ties of the eyelids and appendages. Plast Reconistr Surg1953 ;1 1:348-52.

19 Jones CA, Collin JRO. Blepharophimosis and its associationwith female infertility. Br J Ophthalmol 1984;68:533-4.

21) Givens JR, Wiser WL, Coleman SA, Wilroy RS, Anderson RN.Fish SA. Familial ovarian hyperthecosis: a study of two families.Am J Obst Gvnecol 1971;110:959-72.

21 Spaeth EB. A classification for congenital ptosis. Atn JOphthalmol 1943;26:1326-7.

22 Rank BK. The genetic approach to hereditary congenital ptosis.Aust NZ J Surg 1959:;28:274-9.

23 Allanson JE. Noonan syndrome. J Med Geniet 1987:24:9-13.24 King CR, Magenis E. The Marden-Walker syndrome. J Med

Genet 1978;15:366-9.25 Schwartz 0, Jampel RS. Congenital blepharophimosis associ-

ated with a unique gencralised myopathy. Arch Ophthaltnol1962;68:52-7.

26 Dubowitz V. Familial low birth weight dwarfism with an unusualfacies and a skin eruption. J Med Genet 1965;2:12-17.

27 Smith DW, Lemli L, Opitz JM. A newly recognised syndrome ofmultiple congenital anomalies. J Pediatr 1964;64:21(t-7.

2X Waardenburg PJ. Die Zuruchfuhrung ciner reike erhlichange-borener familiarer augenmissbildungen auf cine fixationnormaler fetaler verhaltnisse. Arch Ophthalmnol 1930);124:221-9.

29 Johnson CC. Operations for epicanthus and blepharophimosis.Am J Ophthalmol 1956;41:71-9.

31' Elliot D, Wallace AF. Ptosis with blepharophimosis andepicanthus inversus. Br J Plast Surg 1986;39:244-8.

Correspondence and requests for reprints to DrMichael Baraitser, Department of Clinical Genetics,Institute of Child Health, 30 Guilford Street,London WC1N 1EH.

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