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European Journal of Medical Genetics 57 (2014) 576e578

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European Journal of Medical Genetics

journal homepage: http : / /www.elsevier .com/locate/ejmg

Clinical report

Co-occurrence of congenital hydronephrosis and FOXL2-associatedblepharophimosis, ptosis, epicanthus inversus syndrome (BPES)

Reena Gulati a,*, Hannah Verdin b, Dhanapathi Halanaik c, B. Vishnu Bhat a,Elfride De Baere b

aDepartment of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, IndiabCenter for Medical Genetics, Ghent University, Ghent University Hospital, Ghent, BelgiumcDepartment of Nuclear Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India

a r t i c l e i n f o

Article history:Received 16 February 2014Accepted 1 August 2014Available online 2 September 2014

Keywords:BlepharophimosisPtosisEpicanthus inversusCongenital hydronephrosisFOXL2 mutation

* Corresponding author. Department of PediatricsPondicherry 605006, India. Tel.: þ91 9443437740; fax2272067.

E-mail address: g97rina@gmail.com (R. Gulati).

http://dx.doi.org/10.1016/j.ejmg.2014.08.0041769-7212/� 2014 Elsevier Masson SAS. All rights res

a b s t r a c t

Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is an autosomal dominantly inheritedcongenital malformation of the eyelids. Diagnostic criteria include blepharophimosis, ptosis, epicanthusinversus and telecanthus. Type _ BPES has additional features of premature ovarian failure and femaleinfertility, while type __ occurs isolated. We report a two-year old male child with typical features of BPESand bilateral congenital hydronephrosis. The child, first-born to non-consanguineous parents, presentedto us with hypertension. Congenital hydronephrosis and reduced renal function were confirmed by renaldynamic scan. Pyeloplasty and stent placement were performed with subsequent resolution of hyper-tension. On follow up, growth and development are appropriate for age. His father has similar but lesssevere features of BPES. Sequencing of the FOXL2 gene revealed a heterozygous FOXL2 mutationc.672_701dup, which is a recurrent 30-bp duplication leading to expansion of the polyalanine tract(p.Ala225_Ala234dup), in both father and son. Additional atypical clinical features have been reportedpreviously in BPES patients with this mutation. However, this is the first report of a renal congenitalanomaly in a BPES patient with this or other mutations. Although a pleiotropic effect of the FOXL2mutation cannot be excluded, the co-occurrence of congenital hydronephrosis and BPES may representtwo different entities.

� 2014 Elsevier Masson SAS. All rights reserved.

1. Introduction

Blepharophimosis syndrome or BPES, a rare genetic dys-morphism of the eyelids, is defined by narrow palpebral fissures,drooping eyelids, epicanthal folds and telecanthus, the fouressential features of this syndrome (OMIM 110100). Type _ and __are differentiated by presence or absence of premature ovarianfailure (POF) and female infertility. Molecular analysis in patients ofdifferent ethnicities has revealed mutations in a single gene, theforkhead box L2 gene (FOXL2) which encodes a forkhead tran-scription factor [De Baere et al., 2001]. FOXL2 contains a highlyconserved forkhead domain and a polyalanine tract. Itsexpression in developing eyelids and fetal and adult ovaries iswell established [Cocquet et al., 2003].

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erved.

The syndrome is inherited in an autosomal dominant mannerthough more than half the cases are attributable to de novo muta-tions. Intragenic mutations are the most prevalent cause of BPES(81%). An important fraction of BPES cases is caused by heterozy-gous deletions however. These deletions can encompass the FOXL2gene (12%) or can be located outside the FOXL2 transcription unit,removing regulatory elements necessary for the correct transcrip-tion of FOXL2 (5%) [Beysen et al., 2009; D’Haene et al., 2009, 2010].Among the more than 135 FOXL2 mutations described, theintragenic ones are typically found in patients with normalintellectual ability [Beysen et al., 2004]. Polyalanine expansionsare common and often related to BPES type __ [Beysen et al.,2009; De Baere et al., 2003]. However, occasional atypical clinicalfeatures have been reported in BPES patients with FOXL2mutations [Beysen et al., 2009].

2. Clinical report

We report a two-year old male child with typical features ofBPES who presented to us at one year of age with complaints of

Fig. 2. Lateral displacement of the inner canthal lacrimal punctum in the proband, ahallmark of BPES.

R. Gulati et al. / European Journal of Medical Genetics 57 (2014) 576e578 577

difficulty in micturition. He is the first born of non-consanguineousparents aged 25 and 29 years, of South Indian Tamil origin. Thepatient was born at term by normal delivery and weighed 2.7 kg atbirth. Unusual appearance of the eyes was noticed at birth.

He has severe blepharophimosis and ptosis andmaintains a chinup posture (Fig.1). There is no apparent strabismus or abnormal eyemovements. Examination of lower eyelids revealed temporallydisplaced lacrimal puncta (Fig. 2) which is a signature sign ofBPES. His nasal bridge is broad and flat with an upturned andbroad nasal tip and a short philtrum. He has a round face,protruding ears and a bow shaped upper lip.

At 5 months of age, he was found to be hypertensive. Anultrasonogram of abdomen showed bilateral hydronephrotic kid-neys with thinned out parenchyma. His renal function tests (bloodurea 27 mg/dl and serum creatinine 0.6 md/dl) were within normallimits. Renal dynamic scan performed with Technetium 99 showedbilateral hydronephrosis (Fig. 3). The right kidney was normallyfunctioning and non-obstructed. A grossly enlarged left kidneyhad impaired function and an obstructive clearance pattern sug-gestive of pelvi-ureteric junction obstruction.

Echocardiogram was normal and growth hormone level waswithin normal limits. Pyeloplasty with stent placement was carriedout on left side and anti-hypertensive treatment was initiated. Onfollow up at one and two year age his growth and developmentalmilestones were appropriate for age. At the age of 2 years, hyper-tension has resolved and his renal function test reports continue tobe normal.

Karyotype was reported as male normal 46,XY. Molecularanalysis was conducted on genomic DNA isolated from a peripheralvenous blood sample. Sequencing of FOXL2 identified a heterozy-gous mutation c.672_701dup which is a recurrent 30-bp duplica-tion leading to a polyalanine expansion (p.Ala225_Ala 234dup).

The father of the proband has a similar but much milderanomaly of the eyelids that were never considered abnormal by thefamily (Fig. 4). Upon sequence analysis, father was found to carrythe familial mutation in a heterozygous state. Abdominalultrasound of either of the parents did not reveal any renalabnormality. No other family member is reported to be clinicallyaffected and there is no history of infertility in any female relative.

3. Discussion

Both subtypes of BPES are caused by mutations in the single-exon gene FOXL2. Although majority of BPES cases manifest onlythe eyelid phenotype, there are occasional reports of additionaltypical or atypical manifestations in patients with different muta-tions [Beysen et al., 2009].

Here, our patient presented with previously recognized featuresincluding laterally displaced lacrimal puncta in the lower eyelids,considered to be an important landmark in the diagnosis of BPES.This finding has implications for surgical management of the con-dition [Decock et al., 2011; Haghighi et al., 2012]. In addition he hasa broad nasal bridge, short philtrum, a round face, an upturnedsmall nose, bow shaped upper lip and prominent protruding lowset ears. Abnormal lop ears have previously been described inone member of a three generation Iranian family affected by

Fig. 1. Facial picture of proband at the age of 2 years with blepharophimosis, ptosis,epicanthus inversus and floppy ears.

severe BPES, caused by a missense mutation outside the forkheaddomain [Haghighi et al., 2012].

We report for the first time the presence of congenital bilateralhydronephrosis in a male child with BPES and a heterozygouspolyalanine expansion of þ10 residues. These mutations make upnearly 30% of all intragenic mutations and tend to be associatedwith type __ BPES [De Baere et al., 2003]. Atypical findings reportedin relation to this and other intragenic mutations include amongstothers a cleft lip and palate, Duane syndrome, ventricular septaldefect, complex heart defect, growth hormone deficiency, growthretardation, Burkitt’s lymphoma and developmental delay[Beysen et al., 2009]. In these cases, it cannot be excludedwhether or not some of these features can be attributed to awider pleiotropic effect of the gene. Here, congenitalhydronephrosis may have occurred secondary to pelvi-uretericjunction obstruction. This is part of a spectrum of congenitalanomalies of kidney and urinary tract (CAKUT) which may be iso-lated or part of a syndrome. CAKUTshare a number of known and asyet unknown underlying mutations in multiple genes involved in

Fig. 3. Renal scan of the proband before pyeloplasty showing reduced function of theleft kidney.

Fig. 4. Facial picture of the father of the proband with milder features of BPES.

R. Gulati et al. / European Journal of Medical Genetics 57 (2014) 576e578578

embryogenesis, with minor contribution of each to their causation[Renkema et al., 2011]. Although FOXL2 mRNA was reported to beexpressed in the goat mesonephros [Pailhoux et al., 2001], noFOXL2 protein expression could be demonstrated in human andgoat fetal kidneys [Cocquet et al., 2003].

Familial cases of BPES are inherited in an autosomal dominantfashion, the only exception reported is that of a South Indian familywhere autosomal recessively inherited type _ BPES was associatedwith a homozygous short polyalanine expansion of þ5 residues inFOXL2 [Nallathambi et al., 2007a,b]. There is a spectrum ofmutations reported in patients with BPES from India includingthe one found in our patient and several others [Chawla et al.,2013; Kaur et al., 2011; Kumar et al., 2004; Nallathambi et al.,2007a,b].

The father of our patient displayed milder features of BPES andno other familymembers were known to be affected. The differencein severity of blepharophimosis may be explained by phenotypicvariability in an autosomal dominant condition leading to minimalexpression in an affected individual. As no female family membersare affected, the type of BPES cannot be confirmed. This hasimportant implications in the context of genetic counseling of thefamily.

In summary, our study contributes to the mutation andphenotypic spectrum of patients with BPES. This is the first reportof congenital hydronephrosis or any other renal congenital anom-aly in a patient with BPES.

Acknowledgments

The authors thank the parents of the patient for their supportand permission for publication. This work was supported by grantfrom the Research Foundation Flanders (FWO) (FWO 3G079711, to

E.D.B.). H.V. is a postdoctoral fellow of the FWO, and E.D.B. is seniorclinical investigator of the FWO.

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