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CLINICAL REPORT

Hemiconvulsion–Hemiplegia–Epilepsy SyndromeWith 1q44 Microdeletion: Causal orChance Association

Rekha Gupta,1 Meenal Agarwal,1 Vijay R. Boqqula,2 Rajendra V. Phadke,3 and Shubha R. Phadke1*1Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India2Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India3Department of Radiodiagnosis, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Manuscript Received: 2 July 2013; Manuscript Accepted: 8 August 2013

How to Cite this Article:Gupta R, Agarwal M, Boqqula VR, Phadke

RV, Phadke SR. 2013. Hemiconvulsion–

hemiplegia–epilepsy syndrome with 1q44

microdeletion: Causal or chance

association.

Am J Med Genet Part A 9999:1–4.

Hemiconvulsion–hemiplegia–epilepsy (HHE) syndrome is a rare

syndrome characterized by childhood onset partial motor con-

vulsions, hemiplegia, and epilepsy in sequence. Exact pathogen-

esis is not clear. Here we are describing a 3-year-old girl with

HHE syndrome with cytogenetic microarray (CMA) showing

deletion of 1.8Mb in 1q44 region. Along with HHE syndrome,

the patient also had global developmental delay, subtle facial

dysmorphism, and preaxial polydactyly. Clinical phenotype of

1q44 microdeletion syndrome is quite variable. Main clinical

features are microcephaly, seizures, and abnormality of corpus

callosum. We compared the patient’s phenotype with other

patients in 10 previously publishedpapers of 1q44microdeletion

syndrome. HNRNPU and FAM36A are two important genes in

the deleted region. HNRNPU genemediate long range control of

SHH gene which is likely explanation of preaxial polydactyly in

the present patient. HHE may be a chance co-occurrence.

� 2013 Wiley Periodicals, Inc.

Key words: hemiconvulsion–hemiplegia–epilepsy (HHE);

cytogenetic microarray (CMA); 1q44 microdeletion; preaxial

polydactyly

Grant sponsor: Indian Council of Medical Research.�Correspondence to:

Shubha R. Phadke, D.M., Department of Medical Genetics, Sanjay

Gandhi Post Graduate Institute of Medical Sciences, Raebarely Road,

Lucknow, Uttar Pradesh 226014, India.

E-mail: shubharaophadke@gmail.com

Article first published online in Wiley Online Library

(wileyonlinelibrary.com): 00 Month 2013

DOI 10.1002/ajmg.a.36198

INTRODUCTION

Hemiconvulsion–hemiplegia–epilepsy (HHE) syndrome is a dis-

order, which is usually characterized by childhood onset partial

motor convulsions, hemiplegia, and epilepsy in sequence. Initial

event may be triggered by fever, trauma or underlying inherited

hypercoagulable states that is, factorVLeidenmutationandprotein

S deficiency [Mondal et al., 2006]. However exact pathogenesis is

still unclear. Here we describe a 3-year-old girl who presented to us

with HHE syndrome and cytogenetic microarray (CMA) showed

1.8Mb deletion in 1q44 region.

CLINICAL REPORT

A 3-year-old girl presented with global developmental delay, hemi-

paresis of right side, and seizures. She was born to a non-consan-

guineous couple. Antenatal and perinatal periods were uneventful

2013 Wiley Periodicals, Inc.

and birth weight was 3.5 kg (50th centile as per Indian standard).

Her parents had noticed developmental delay in the early infantile

period. She achievedneck control and sitting at 6–7 and8–9months

of age, respectively. At 1 year of age she had two episodes of

convulsions involving right side of body. Following the first episode

she was unconscious for an hour. After 2 months she again had

prolonged seizures and had to be put on ventilatory support. After

recovery she developed right sided hemiparesis. After second epi-

sode she was given antiepileptic medications. She had repeated

convulsions even on medication.

On examination she had mild facial dysmorphism including

apparent hypertelorism and short upturned nose. There was no

facial asymmetry. Her thumbs were broad and right hallux was

duplicated (Fig. 1A,B). Her head circumference was 46.5 cm (10th

centile as per Indian standard) and height was 76 cm (<3rd centile

as per Indian standard). Neurological examination showed mildly

increased tone in right upper and lower limb with normally

elicitable deep tendon reflexes. Her planter reflexes were flexor

1

FIG. 1. A: Facial phenotype of patient showing hypertelorism and short upturned nose. B: Preaxial polydactyly in right foot (U), Broad hallux in

left foot (L). Coronal (C) and (D) axial T2 weighted MRI images at the age of 1.5 year showing affected left cerebral hemisphere cortex with

swelling and effaced sulci and lateral ventricle. The gray matter and white matter distinction is poor with an overall increase in signal

intensity. Thalamus is also affected. Follow-up imaging 18 months later shows atrophy of the left cerebral hemisphere. T1 weighted axial

image (E) and T2 weighted axial image (F).

2 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

on both sides. At present she could stand with support. She was

unable to speak meaningful words and was not toilet trained.

Her brain magnetic resonance imaging (MRI) images are pre-

sented in Figure 1C–F. MRI brain done at the time of episode of

convulsions at one and half year of age showed swelling of left

cerebral hemisphere cortex with effaced sulci, dilated lateral ven-

tricles, thin corpus callosum, poor distinction of grey and white

matter with overall increase in signal intensity including bilateral

thalami. MRI done at the age of 3 years showed atrophy of the left

cerebral hemisphere.On thebasis of characteristic history andbrain

MRI findings, diagnosis of HHE syndrome was made.

Her karyotype at 550-band level was normal. Due to presence of

global developmental delay and preaxial polydactyly we performed

CMA (Affymetrix 2.7M array) on DNA extracted from leukocytes.

CMA report showed presence of 1.8Mb deletion on chromosome

1q44 (CMA report-arr1q44(244744522–246608189)X1) (Fig. 2).

Apart from this deletion, one copy number gain of 531 Kb size was

also found in 19q13.2–13.31 that was interpreted as variant of

unknown significance probably of pathogenic significance.

(arr19q13.2q13.31(43281095–43812893)X3. This region was over-

lapping with OMIM loci of specific language impairment, episodic

ataxia, benign infantile familial seizures, and autosomal recessive

mental retardation 11.

DISCUSSION

We present a girl with global developmental delay with preaxial

polydactyly with history and brain MRI consistent with the diag-

nosis of HHE syndrome. CMA analysis showed microdeletion on

1q44 region. Microdeletion of 1q44 region has already been de-

scribed in association with intellectual disability in the literature

[Thierry et al., 2012]. We reviewed 10 published papers with 1q44

microdeletion syndrome and a comparative analysis of clinical

features along with the deleted regions is shown in Table SI. Out of

35 patients exact breakpoints were available in 19 patients and

deleted areas are diagrammatically represented in Figure 3. Eigh-

teen patients and the present patient showed a common region of

deletion spanning 244744552–245100000. The genes located in the

common shared region are PPPDE1, FAM36A,NCRNA00201, and

HNRNPU. Phenotypes of 1q44 microdeletion syndrome are quite

variable and all the features are not present in every case. Seizures,

thin corpus callosum, andmicrocephaly are reported in 80%, 85%,

and 90% cases, respectively [Ballif et al., 2012]. Along with the size

ofmicrodeletion, reducedpenetrance, variable expressivity, andco-

inheritance of various other copy number variants may be respon-

sible for the observed clinical variability. Consistent with the

previous reports our patient had thinning of corpus callosum

FIG. 2. Cytogenetic microarray showing 1.8 Mb deletion on chromosome region 1q44.

GUPTA ET AL. 3

but did not have microcephaly. Hill et al. [2007] described a

candidate region for microcephaly by finding microcephaly in 6

out of 7 patients of 1q44 deletion. This candidate region is not

deleted in the present patient. AKT3 gene which is considered as a

candidate gene formicrocephaly andaplasia of corpus callosumwas

FIG. 3. Deleted segments in various patients with deletion 1q44: patient

245100000. It contains genes PPPDE1, FAM36A, NCRNA00201, and HNRN

patient 4: Zaki et al. [2012]; patients 5–8: Caliebe et al. [2010]; patien

not deleted in present case [Boland et al., 2007]. The patient

described by Lall et al. had translocation between chromosomes

1 and 11 and duplication of 11q ter as well. The breakpoints of 1q44

were outside the common shared deleted region. Hence, this case

had additional features like cat like cry, laryngomalacia, ectopic

1–19 shared a common region from break points 244744522–

PU (patient 1: present patient; patients 2 and 3: Aktas et al. [2010];

ts 9–19: Thierry et al. [2012]; patient 20: Lall et al. [2011]).

4 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

placement of anus, cardiac defect, etc. HHE syndrome and abnor-

malities of digits including polydactyly have not been described in

any of these published reports. The involved region in present

patient harbors few genes including C1orf101, PPPDE1, FAM36A,

NCRNA00201, HNRNPU, EFCAB2, KIF26B, and SMYD3. Out of

these genes HNRNPU gene has been implicated in growth and

development inmice. Also Zhao et al. [2009] studiedmousemodel

of polydactyly and concluded that HNRNPU mediates long range

regulationofShhgene.Thismay explain thepresenceof polydactyly

in present patient. None of the genes in the deleted regions in this

patient code for proteins involves in immune function, inflamma-

tion or thrombotic abnormalities, which are hypothesized in the

pathogenesis of HHE. This is the first case of HHE syndrome in

whichCMAfindings have been described. Cause ofHHE syndrome

remains unexplained in present case and HHEmay be a chance co-

occurrence. CMA analysis in more cases with HHE syndrome may

help us in identifying pathogenic mechanism behind this rare

condition.

This case report extends the spectrum of 1q44 microdeletion

syndrome with HHE syndrome and polydactyly which has never

been reported in literature. The function of many genes in this

region is still not well established and their association with clinical

phenotype cannot be explained.

ACKNOWLEDGMENTS

Wewish to acknowledge the funding of Indian Council of Medical

Research, New Delhi for cytogenetic microarray evaluation and

thank the family for the support.

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SUPPORTING INFORMATION

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version of this article at the publisher’s web-site.

TABLE SI. Comparative Analysis of Clinical Features and Sizes of

1q44 Microdeletion in Previous Published Reports