Gene 512 (2013) 532–535

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Short Communication

Pediatric diagnosis not made until adulthood: A case of Wolf–Hirschhorn syndrome

Antonietta Coppola a,b, Krishna Chinthapalli a,b, Peter Hammond c,Josemir W. Sander a,b,d, Sanjay M. Sisodiya a,b,⁎a Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London, UKb Epilepsy Society, Chesham Lane, Chalfont St Peter, Bucks, UKc Molecular Medicine Unit, UCL Institute of Child Health, London, UKd SEIN-Stichting Epilepsie Instellingen Nederland, Achterweg 5, 2103 SW Heemstede, The Netherlands

Abbreviations: ACTH, adrenocorticotropic hormoneArray-CGH, array comparative genomic hybridization;reductase; EEG, electroencephalography; F, female; FRacid type, rare, fra(X)(q27.3); FISH, fluorescence in-situized tonic–clonic seizures; HG, human genome; IQ, intelmagnetic resonance imaging; NIPBL, Nipped-B homolsyndrome; SCN1A, sodium channel, voltage-gated, typedeviations;WHS,Wolf–Hirschhorn Syndrome; ZFHX1B, zi⁎ Corresponding author at: Department of Clinical an

Institute of Neurology, Queen Square, London, WC1N8612; fax: +44 20 3448 8615.

E-mail address: s.sisodiya@ucl.ac.uk (S.M. Sisodiya).

0378-1119/$ – see front matter © 2012 Elsevier B.V. Alhttp://dx.doi.org/10.1016/j.gene.2012.09.108

a b s t r a c t

a r t i c l e i n f o

Article history:Accepted 29 September 2012Available online 11 October 2012

Keywords:Wolf–HirschhornEpilepsyArray-CGHStereophotogrammetry

Wolf–Hirschhorn syndrome is a well-known clinical entity caused by a terminal deletion of the short arm ofchromosome 4 (4p-). The diagnosis is usually made in childhood because of the pathognomonic facialdysmorphism, multi-organ involvement and seizures. Epilepsy is a major medical complication during thefirst years of life, with seizures typically being frequent, although they tend to improve or cease with age.We report on a woman diagnosed with WHS in her thirties by array-CGH. She presents with milder dysmor-phic features, recognized by stereophotogrammetry and seizures persistent in adulthood.

© 2012 Elsevier B.V. All rights reserved.

1. Introduction

Wolf–Hirschhorn Syndrome (WHS) was first described by Cooperand Hirschhorn (1961) and then by Wolf et al. (1965). It is usuallydue to a partial deletion of the short arm of the chromosome 4, occur-ring de novo, but can also result from an unbalanced translocation. Thetypical clinical features usually drive a genetic diagnosis in early life.People with WHS show pathognomonic dysmorphic facial features(including prominent glabella and nose, hypertelorism, high-archedeyebrows, micrognathia and downturned mouth corners) (Battaglia etal., 1999), associated with multiple organ defects (bilateral cleft lip orpalate, congenital heart defects, urogenital, skin and skeletal anomalies)(Battaglia et al., 1999), and varying degrees of neurological impairment(Battaglia and Carey, 2005; Battaglia et al., 1999). Almost all peoplewithWHS have seizures, with seizure onset usually being in the first year oflife (Battaglia and Carey, 2005; Battaglia et al., 2003; Kagitani-Shimonoet al., 2005; Zankl et al., 2001). Seizures are often triggered by fever and

; AEDs, anti-epileptic drugs;DHCR7, 7-dehydrocholesterolAXA/FRARE, fragile site, folichybridization; GTCSs, general-ligent quotient; M, male; MRI,og; PRDS, Pitt–Rogers–DanksI, alpha subunit; Stdv, standardncfinger binding homeobox 1b.d Experimental Epilepsy, UCL3BG, UK. Tel.: +44 20 3448

l rights reserved.

tend to be refractory: status epilepticus may be frequent. They can in-clude infantile spasms, generalized tonic–clonic seizures (GTCSs), com-plex partial seizures, atypical absences, myoclonic seizures and tonicseizures. Seizures usually improve or cease with age (Worthington etal., 2008). Two distinct EEG patterns have been described after 1 year ofage: 1) frequent, diffuse, atypical slow waves or spike and wave com-plexes, often occurring in long bursts and activated by slow wave sleep;2) high amplitude fast spike-polyspike and wave complexes over theoccipital region often triggered by eye closure (Battaglia and Carey,2005 ; Battaglia et al., 2003).

WHS occurs in about 1/50,000 newborns, with a female preponder-ance (2:1 F:M) (Lurie et al., 1980). This rate is probably an underesti-mate, as cases may be missed due to lack of recognition or inadequatecytogenetic analysis (Battaglia et al., 2001). Approximately half of allcases can be recognized on regular G-banding (Battaglia et al., 2001).Targeted fluorescence in-situ hybridization (FISH) may be employed ifthe clinical diagnosis is suspected. Recently, array comparative genomichybridization (array-CGH) has allowed the identification of a greaternumber of chromosomal rearrangements undetectable with conven-tional cytogenetic analysis (G-band karyotype and FISH) (Mulley andMefford, 2011). Specifically, South et al. used aCGH to study 33 patientswith a clinical diagnosis of WHS and unremarkable previous karyotype,combined with WHS-specific FISH, and found a much higher thanexpected frequency of unbalanced translocations (15/33, 45%) (Southet al., 2008).

We report on an adult withmild dysmorphism, refractory epilepsyand moderate learning disability for whom a diagnosis of WHS wasnot made until her fourth decade.

533A. Coppola et al. / Gene 512 (2013) 532–535

2. Materials and methods

2.1. Case description

This 34-year-old woman is the only child of healthy unrelated par-ents. Pregnancy was complicated by pre-eclampsia. She was bornslightly after term and was small for gestational age. Soon afterbirth she presented with feeding problems and disturbed sleep.

Seizure onset was at 16 weeks: during a febrile episode, she hadeyelid flickering culminating in a GTCS. At 7 months, further GTCSsled to treatment with phenobarbital. She was noted to be floppyand inactive, unable to roll or crawl. At 10 months, infantile spasmswere noted and an 18-day course of adrenocorticotropic hormone(ACTH) was given. EEG showed excessive slow components andmultifocal discharges over the posterior third of the head in the wak-ing state. Spasms disappeared and nitrazepam was started to controlGTCSs. Subsequent psychomotor development was delayed: she startedwalking after 2 years and never spoke in sentences. At 3 years of age, shehad her first episode of convulsive status epilepticus. At 4 years, she wasweaned off nitrazepam andwas off treatment and seizure free until aged13 yearswhen atonic seizures appeared. At that time the EEGwasmark-edly disturbed with right-sided slow and sharp wave discharges oftenprovoked by eye closure. In the following years seizures worsened,with frequent episodes of status epilepticus. Several AEDswere used, sin-gly or in association (valproate, carbamazepine, gabapentin, acetazol-amide, lamotrigine, topiramate, levetiracetam, oxcarbazepine).

She was referred at 23 years. Examination showed milddysmorphism (microcephaly, prominent nose, small hands and feet),with no other organ involvement. Neurological examination wasunremarkable except for brisk tendon reflexes and a divergent strabis-mus. She had moderate intellectual disability: IQ assessed throughStanford–Binet Scale (C-M) was below 60. No syndromic diagnosishad been made despite three clinical genetic reviews. She was ontopiramate and valproate.

She currently has 1–3 seizures per month, which are complex par-tial or convulsive seizures exacerbated by fever. Her last EEG showedparoxysmal activity consisting of irregular slow waves or peakedwaveforms over the frontal regions, mainly left-sided. A brain MRIscan at age 34 showed a marked thinning of the corpus callosumand minor prominence of the ventricles suggestive of loss in whitematter bulk. She also underwent quantitative facial analysis usingsurface modeling techniques (Novy et al., 2012) which classified hersubtle facial dysmorphism as WHS-like (Fig. 1). Serial pictures ofthe patients showing the evolution of her dysmorphism over theyears are shown in the supplementary data (Supplementary DataFig. 1).

2.2. Genetic history and diagnosis

Several genetic tests had been previously performed: standardG-banded karyotype, DHCR7 gene screening for Smith–Lemli–OpitzSyndrome, SCN1A analysis for Dravet syndrome, FRAXA/FRARE muta-tions for Fragile X syndrome, DNA methylation analysis for AngelmanSyndrome, ZFHX1B gene mutations for Mowat–Wilson syndrome, andNIPBL gene mutations for Cornelia De Lange syndrome. None of thesewere informative.

Array-CGH (Nimblegen 135k) showed a 4p16.3 deletion (frombp116640 to bp1976542; HG19) of approximately 1.8 Mb, which issmaller than typically found in WHS. Fig. 2 shows a screenshot ofthe rearrangement and the genes included which are also listed inthe supplementary data.

3. Discussion

WHS is a well-recognized malformation syndrome resulting frompartial 4p terminal deletion. The clinical picture is often characterized

by pathognomonic facial dysmorphism, somatic defects, cognitiveimpairment and seizures (Battaglia et al., 1999, 2001), commonlyresulting in diagnosis in early life. In this case, no diagnosis hadbeen made despite three clinical genetic evaluations.

Our patient showed only mild dysmorphism with no somatic de-fects, and a moderate learning disability, features that together werenot immediately suggestive of WHS. Subtle dysmorphic features,such as microcephaly and a prominent nose are, however, compatiblewith WHS and a dense surface model analysis classified her facialshape as WHS-like (Hammond et al., 2012).

She suffered from severe epilepsy in her early childhoodwith differ-ent type of seizures exacerbated by fever and often leading to statusepilepticus, typical of WHS. Her EEG features were also consistentwith abnormalities often described in association withWHS (excessiveslow components, multifocal discharges over the posterior third of thehead during wakefulness and discharges often associated with eye clo-sure). Unlike the usual reported natural history, her epilepsy did not im-provewith age and she still has up to three seizures amonth on therapy.

Before the diagnosis wasmade, she underwent several genetic tests,based upon various components of the phenotype: intellectual disabil-ity and dysmorphism; specific dysmorphic aspects (Smith–Lemli–Opitzand Cornelia De Lange syndromes), or type of seizures and EEG(Dravet, Angelman and Mowat–Wilson syndromes). An array-CGHwas performed at 33 years of age, detecting a small 4p deletion notvisible on standard karyotyping.

A milder WHS, also known as Pitt–Rogers–Danks syndrome(PRDS) has been reported in people with mild but typical WHS-likedysmorphism,mild-to-moderate intellectual disability, limited organ in-volvement and a better outcome (Pitt et al., 1984; Zankl et al., 2001). Inthese patients, the dysmorphic features can be easily recognized in child-hood and they become more subtle in adulthood as seen in our case.Many suggest that WHS and PRDS are same phenotype (Wright et al.,1998), while others suggest that the difference in phenotype reflects ge-netic variability (Partington and Turner, 1999; Partington et al., 1997).Our case differs from typicalWHS cases as therewere no somatic defectsand epilepsy is refractory compared to that in people with PRDS.

This case highlights several issues: milder dysmorphic featurescan be missed by clinical examination even when performed by ge-neticists, especially in adulthood. Dysmorphic features may becomemore or less marked with aging and a review of photographs frominfancy onwards may be helpful. Array-CGH is an important clinicaldiagnostic tool in adults with refractory epilepsy and additional fea-tures, even when a clinical diagnosis has not been made (Galizia etal., 2012). Quantitative facial analysis is a tool in development thatmay supplement genetic tests, and may in some cases suggest a diag-nosis by highlighting similarities with other people affected with thesame syndrome (Hammond et al., 2012; Novy et al., 2012), evenwhen visually apparent features are less obvious to the human eye.Lastly, the phenotypic spectrum of even well-known syndromesmay be broader than typically appreciated. In adults especially,aCGH testing may allow a diagnosis to be made that would currentlybe made in childhood, but these adults represent the ‘lost genera-tion’ for whom relevant testing was not available in their childhood(Galizia et al., 2012).

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.gene.2012.09.108.

Acknowledgments

Wewould like to thank the patient's family for giving us permis-sion to report their daughter's case. This work was undertaken atUCLH/UCL, which received a proportion of funding from the Depart-ment of Health's NIHR Biomedical Research Centres fundingscheme. The work was also supported by the Freemasons' GrandCharity.

Fig. 1. (a) A face signature graph showing facial shape variation in a group of 401 control subjects (unfilled circles), 110 subjects with WHS (gray circles), and the current patient(black circle). The face signature refers to the normalized displacement of 25,000 points on a target face surface relative to a sex-matched group of 50 controls (for each patient),whose mean age matches that of the target. The face signature graph comprises nodes representing face signatures of individuals and lines linking each face signature to its nearestneighbor using the generalized Euclidean metric: square root of squared differences of displacements of corresponding surface points on both faces. The patient's face signature ismapped to a cluster of individuals with WHS. (b) A face surface heat map created using 3D stereophotogrammetry and dense surface modeling. The heat map compares thepatient's face with the mean age-matched face of 50 female control subjects. A red-blue spectrum shows inward-outward displacement in a direction perpendicular to the surface,expressed in terms of standard deviations (Stdv) from the mean face surface. There is reduced facial height shown by the presence of red over the forehead and lower mandible. Thelower face does not have an atypical shape (green), except for a prominent lower lip. Flattening of the nasal bridge and both maxillae are indicated by red patches. Conversely, themedial supraorbital ridges are prominent (blue), although the glabella and nasal root are spared.

534 A. Coppola et al. / Gene 512 (2013) 532–535

Fig. 2. The figure shows a screenshot of the deletion (http://genome.ucsc.edu). The red box on the top left indicates the position of the locus on chromosome 4. The black bar in-dicates our patient's deletion; red bars indicate patients with this deletion reported in Decipher; blue bars indicates patients with duplication reported in Decipher (http://decipher.sanger.ac.uk/). Coordinates relate to HG19.

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