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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.
47
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
overeyelids, 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
/6
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.
,#1-
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-
A.
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
riM'**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 diagnosisThe 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/treatmentMany 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.
so
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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.
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Owens N, Hadley R, Kloepfer HW. Hereditary blepharophimo-
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23 Allanson JE. Noonan syndrome. J Med Geniet 1987:24:9-13.24
King CR, Magenis E. The Marden-Walker syndrome. J Med
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Correspondence and requests for reprints to DrMichael Baraitser,
Department of Clinical Genetics,Institute of Child Health, 30
Guilford Street,London WC1N 1EH.
51
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(BPES syndrome)epicanthus inversus syndrome Blepharophimosis,
ptosis,
C Oley and M Baraitser
doi: 10.1136/jmg.25.1.471988 25: 47-51 J Med Genet
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