Iype et al. BMC Medical Genetics (2015) 16:104
DOI 10.1186/s12881-015-0251-5

RESEARCH ARTICLE

Open AccessA large Indian family with rearrangementof chromosome 4p16 and 3p26.3 anddivergent clinical presentations
Thomas Iype1†, Vafa Alakbarzade2,3*†, Mary Iype1†, Royana Singh4†, Ajith Sreekantan-Nair2, Barry A. Chioza2,
Tribhuvan M. Mohapatra4, Emma L. Baple2,7,8, Michael A. Patton2,6, Thomas T. Warner3, Christos Proukakis5,Abhi Kulkarni6 and Andrew H. Crosby2*

Abstract
Background: The deletion of the chromosome 4p16.3 Wolf-Hirschhorn syndrome critical region (WHSCR-2) typicallyresults in a characteristic facial appearance, varying intellectual disability, stereotypies and prenatal onset of growth
retardation, while gains of the same chromosomal region result in a more variable degree of intellectual deficit anddysmorphism. Similarly the phenotype of individuals with terminal deletions of distal chromosome 3p (3p deletion
syndrome) varies from mild to severe intellectual deficit, micro- and trigonocephaly, and a distinct facial appearance.
Methods and results: We investigated a large Indian five-generation pedigree with ten affected family members inwhich chromosomal microarray and fluorescence in situ hybridization analyses disclosed a complex rearrangement
involving chromosomal subregions 4p16.1 and 3p26.3 resulting in a 4p16.1 deletion and 3p26.3 microduplication inthree individuals, and a 4p16.1 duplication and 3p26.3 microdeletion in seven individuals. A typical clinical presentationof WHS was observed in all three cases with 4p16.1 deletion and 3p26.3 microduplication. Individuals with a 4p16.1
duplication and 3p26.3 microdeletion demonstrated a range of clinical features including typical 3p microdeletion or
4p partial trisomy syndrome to more severe neurodevelopmental delay with distinct dysmorphic features.
Conclusion: We present the largest pedigree with complex t(4p;3p) chromosomal rearrangements and diverse clinicaloutcomes including Wolf Hirschorn-, 3p deletion-, and 4p duplication syndrome amongst affected individuals.
Keywords: Wolf–Hirschhorn syndrome, WHS, Complex rearrangement of chromosome 4p16, 3p deletion syndrome,
4p partial trisomy syndrome, Mental Retardation, Developmental delay

Background
Microscopically visible rearrangements of chromosome
4p16 may result in two separate syndromes: Wolf–
Hirschhorn syndrome (WHS) and partial trisomy 4p
syndrome. WHS is a well-recognized contiguous genedeletion syndrome associated with prenatal and postnatal growth delay, a typical ‘Greek warrior helmet’ appearance of the nose, microcephaly, and neurologicalfeatures including seizures, hypotonia and varying degrees
of intellectual impairment [1]. In contrast, 4p16 duplication results in partial trisomy 4p syndrome, which gives* Correspondence: v.alakbarzade@exeter.ac.uk; a.h.crosby@exeter.ac.uk†
Equal contributors
2
Molecular Genetics, RILD Institute, University of Exeter, Royal Devon andExeter NHS Hospital, Wonford, Exeter, UK
Full list of author information is available at the end of the article

rise to variable clinical manifestations including intellectual disability, developmental delay and distinctive facial
features [2–4].
About 40–45 % of the WHS cases involve an unbalanced translocation and a deletion of 4p as well as partial
trisomy of a different chromosome arm [5]. These unbalanced translocations may be de novo, or inherited from aparent with a balanced chromosomal rearrangement. Different rearrangements of chromosome 4p causing WHS
and partial trisomy 4p syndrome in the same family havebeen reported [2–4, 6], as have a few reports of isolated
unbalanced translocation involving chromosomes 4 and 3[7–10]. The size of the chromosomal rearrangement andclinical presentations vary in these cases. Terminal andinterstitial deletions of the short arm of chromosome 3© 2015 Iype et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Iype et al. BMC Medical Genetics (2015) 16:104

comprises another contiguous gene deletion syndrome(3p deletion syndrome), which may also present with avariable clinical phenotype and associated with a numberof different causal deletions. The core features of the
syndrome typically include cognitive handicap, growth
retardation, microcephaly, and facial dimorphism (ptosis,
downslanting palpebral fissures and micrognathia), whilevariable features include congenital heart defects, postaxial
polydactyly, cleft palate, renal and intestinal anomalies[11, 12]. In this report, we document a large Indianpedigree in which individuals have inherited varying
combinations of an unusual chromosomal translocation involving chromosome 4p16 and a small sectionof chromosome 3p26.3, resulting in a range of clinicalphenotypes including Wolf–Hirschhorn syndrome, 4p
partial trisomy- and 3p deletion syndrome.

Methods and results
Study approval

The present studies were reviewed and approved by
the senior investigators from Banaras Hindu University,
Varanasi, UP and Medical College, Trivandrum, Kerala
and Royal Devon & Exeter NHS Foundation Trust. All
tissue samples were taken with informed consent in accordance with all ethical standards and protocols. The

Page 2 of 7

ethical clearance number is EC/847 and EC registration
No. ECR/526/INSt/UP2014. All subjects or their guardians
provided informed consent prior to their participation in
the study and for publishing this research article. Written
parental consent also was obtained to publish any imagesof minors. Written informed consent was obtained to publish the photographs of affected individuals.
Clinical report

The family, from Kerala (South India), comprises a total of
36 members over five generations (Fig. 1). All 10 affectedsubjects were evaluated by a neurologist and a clinicalgeneticist. Pregnancy and delivery of 9/10 affected individuals was uncomplicated, with delivery at gestational age
38 weeks while IV:11 was born pre-term. Patient clinicaldata and findings are summarized in Tables 1 and 2.
V:1 (born in 2000) and V:2 (born in 2004) are the only
affected siblings in generation V of the pedigree. Birthweight was 1.5 kg in both cases, length and head circumference at birth were not reported. V:1 was floppy atbirth, and developed severe physical and psychomotor
developmental delay (sitting at 4 years, currently can only
stand with support, delayed or poor eye contact and no
speech). A past history of febrile seizures and status epilepticus is reported. Stereotypies of recent onset included

Fig. 1 Left panel: family pedigree including an illustration of the chromosome 3 and 4 al rearrangement detected. Right panel: normal
chromosome 3 telomere, demarcated with green circle (a) and normal chromosome 4 telomere, with red circle (b). A balanced translocation
outcome is shown in c, while unbalanced translocation outcomes are shown in d (3p duplication and 4p deletion) and e (3p deletion,
4p duplication)

Iype et al. BMC Medical Genetics (2015) 16:104

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Table 1 Clinical presentation of the three patients with thechromosomes 4p16 deletion and 3p26.3 duplication
V:1

V:2

IV:13

Age

12.5

8.8

12

GenderF

F

M

109 /-5.9

110 /-5.3

128 /-0.3

43 /-8.8

42 /-8.0

48 /-4.2

+

+

+

+

+

+

Growth Parameters
Height (cm/SDSa)a

Head circumference (cm/SDS )Severe mental retardation
Facial features of WHS::• High arched eyebrows• Broad flat nasal bridge

+

+

+

• Prominent nasal tip

+

+

+

• Prominent eyes

+

+

+

• Ocular hypertelorism

+

+

+

• Short philtrum

+

+

+

• Downturned mouth

+

+

+

• Micrognathia

+

+

+

Seizures-++

Prenatal growth delay

+

+

+

Hypotonia

+

+

+

a

SDS standard deviation score (http://www.who.int/childgrowth/standards/en/);above (−2 SDS) normal averagerocking and repeated hand washing. Dysmorphic facial
features were noted (Table 1; Additional file 1: Figure S1)
as well as hand malformations including tapering-longfingers, bilateral inability to abduct the thumb, single transverse palmar crease, hypermobile metacarpophalangeal
joints of thumb, overlapping fingers and pes planus.
Neurological examination at 12 years of age revealed:
increased tone and reflexes in lower limbs. At the ageof 12 she developed stereotypic body movements suchas bending from side to side, body rocking and handwashing. The younger sibling (V:2) required ventilation
for a month post-delivery. Developmental milestones were
delayed, walked with support at age 2. Speech is limited
to a few words and she is unable to read and write.
Generalised tonic-clonic seizures developed at 17 months.
Unilateral agenesis of the kidney was seen on ultrasound.
Additional clinical features included sacral dimple,
overlapping and tapered fingers, flexion contracture ofproximal interphalangeal joints, inability to abduct the
thumb, simian hand line, hypermobile metocarpophalangeal joint of thumb, rocker bottom feet, prominent
talus, medial malleolus, ear deformities (left preauricularsinus, small ears with small lobule, ‘cauliflower’ shaped left
ear and pointed pinna). Neurological examination conducted at age 8 revealed left lower motor neuron facial
palsy, reduced tone (upper limbs), and increased tonein the lower extremities with exaggerated reflexes. MRI

imaging of the brain showed hypo-dense lesions infrontal lobes.
IV:13 is a maternal cousin of siblings V:1 and V:2. His
birth weight was 1.8 kg. Developmental concerns werenoted early on and progress was similar to V:1. At theage of 2 he had not developed speech and walking, could
sit with support and independently roll from back tofront. He developed epilepsy with generalized tonic-clonicseizures at 12 months, which is currently under control onphenytoin. He also has swallowing difficulties, droolingand urinary incontinence. He responds to noise, and recognizes his parents. Behavioral problems include selfharm and stereotypies including body rocking movements.
Facial features are as described in Table 1 and ear and limb
deformities resembling those of V:2. Additional findings
included: strabismus, a high arched palate, cleft lip, fixed
flexion deformity of the elbows, flat occiput and widely
spaced nipples. Neurological examination revealed generalized hypotonia, brisk reflexes and out-turned feet. Ultrasonography revealed kidney malformation, and brain MRI
revealed dysgenesis of the corpus callosum.
Individual IV:11 was born pre-term (birth weight 1.2 kg)
to consanguineous parents. He had severe developmental
delay with no speech and walked with support at age 3.
He responds to sounds but hearing function has not beentested. He has a history of surgically treated cleft lip andcomplex partial seizures. On neurological examination
he had gaze evoked nystagmus, limb ataxia, gait ataxia;
exaggerated knee and ankle jerks and up-going plantar
reflexes. The dysmorphic features are described in Table 2
and Additional file 1: Figure S1. Additional findings on
examination were sacral dimple, strabismus and hypospadius. Behavioral abnormalities included stereotypies including rocking, hand wringing, repeated hand washing,head banging and self-harm.
III:4 was the eldest affected child of the third generation.
She had no speech or walk until age 2 and has medicallyresistant secondarily generalized tonic-clonic seizures. At
the time of assessment she could not walk unaided, herspeech was dysarthric with limited vocabulary and she wasunable to read or write. Neurological examination revealed
kyphosis, reduced upper limb deep tendon reflexes, absent
knee and ankle jerk, hypotonia, scanning speech, gaze
evoked nystagmus, and an ataxic gait. Facial features wereas described in Table 2. Her daughter, IV:2, started to walkat age 3 and speak at age 4. She displayed aggressive behavior and had mild intellectual impairment. Neurologicalexamination revealed absent knee and ankle jerks anddysarthria. No history of seizures was reported, and distinctive dysmorphic features were noted (Table 2).
IV:17 was born to consanguineous parents. Apart frommild learning difficulties and limited vocabulary, no neurological or other physical abnormalities were detected
on examination.

Case

III:4

IV:8

IV:9

IV:2

IV:11

IV:1

IV:17

Age

40

20.5

16.7

16.1

14.1

11.7

7.9

Sex

F

M

M

F

M

M

F

Developmental delay +

+

+

-

+

+

+

Intellectual disability

Severe

Mild

Mild

Mild

SevereMild

Mild

Height (cm/SDS)

157/-1.1

179/0.2

172/-0.4

151/-2.0

130/-3.8

143/-0.3

122/-0.4

Head circumference(cm/SDS)

52/-2.5

55/-1.3/Mild53.5/-1.9/

53/-1.7

49/-4.1/

51/-2.4/

51/-1.5

Shape

NAD

Brachycephaly

Brachycephaly

NAD

Trigonocephaly

Brachycephaly

NAD

Facial features

Prominent supraorbital
ridges & glabella; prominent
midface; prognathism

Mild prominence
Prominent supraorbital
Mild prominence of supraorbital Hypertelorism, Prominentsupraorbital ridges & ridges & glabella; prominent ridges & glabella; prominent
midface; Flat broad nasal
midface; mild prognathism midface; prognathismtip, low hanging columella
glabella

NAD

NAD

Flat nasal
bridge

NAD

NAD

NAD

Iype et al. BMC Medical Genetics (2015) 16:104

Table 2 Clinical presentation of the seven patients with chromosomes 4p16.1 duplication and 3p26.3 microdeletion

Highly arched eyebrows
Low frontal and nuchal
hair line
Nose

Prominent nasal tip

Prominent nasal tip

Prominent nasal tip

Prominent nasal tip

Broad high nasal bridge

Mouth

Thin vermillion of theupper lip; High archedpalate; cleft lip; gum
hypertrophy

NADa

High arched palate

NAD

Ears

Strabismus

Low set ears

Prominent ears, malformed
helix

Prominent, low set ears

Low set ears; malformed
helix

Low set ears

NAD

Hand deformity

Campodactyly

Campodactyly

Long digits

NAD

Campodactyly

Clindactily

NAD

Feet deformity

Pes cavus; inversion deformityof feetSeizures

+

-b

-

-

+

-

-

Prominent nasal tipa

Short philtrum
Cleft lipbNAD- no abnormality detected; - no seizures

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Iype et al. BMC Medical Genetics (2015) 16:104

IV:8, IV:9 and IV:1 had delayed walking and speech at
2.5 – 3 years, and similar levels of mild learning difficulties. The birth weight of only IV:8 was documented(2.5 kg). Individual IV:8 could never run due to poor
balance, and although he went to a school up to tenth
grade, his intellectual abilities are limited. On neurological examination had mild upper and lower motor
neuron signs, ataxia and could not stand on his heels.
Brain MRI revealed mild cerebral atrophy. Case IV:9 had
a previous history of lumbar discectomy. All the observed phenotypic abnormalities are described in Table 2
and Additional file 1: Figure S1.
Microarray analysis and flourescent in situ hybridization(FISH)

DNA samples from family members were genotyped
using the Illumina HumanCytoSNP-12 v2.1 microarrays todetect copy-number variations (CNVs). The Illumina Infinium HD assay protocol was followed and the array processed on a BeadStation 500G. Image data was processed in
the Illumina GenomeStudio software to generate genotype
calls, B allele frequency and logR ratio values. These were
further analysed for CNVs using Illumina’s KaryoStudiosoftware. This revealed a 3p26.3 (0–2144867)x3duplicationand 4p16.3-16.1 (0–10308871)x1 deletion in three affectedindividuals (IV:13; V:1; V:2), and a reciprocal 3p26.3 (0–2118422)x1deletion and 4p16.3-16.1 (0–10290552)x3duplication in seven affected individuals (III:4; IV:8; IV:9; IV:2;
IV:11; IV:1; IV:17), including two (III:4 and IV:11) withmore severe phenotype than others (Additional file 1: Table
S1, Figure S1 and Figure S2). For FISH, Kreatech probes
D4S33060 and D3S4558 were used to define either balanced or unbalanced t(3p;4p) translocations in three individuals, case V:2, IV:9 and III:3 on whom samples wereavailable for study (Additional file 1: Figure S3).

Discussion and conclusions
We describe a complex reciprocal translocation involving
chromosomes 3 and 4 in ten affected family members of afive-generation pedigree, resulting in clinical manifestationsof 3 rare chromosomal syndromes. This is, to our knowledge, the first reported case study of a chromosomal
imbalance that combines chromosome 4p deletion (WHS),
4p partial trisomy and 3p deletion syndromes in the samefamily. Nine of the 10 affected family members (II:2; III:7;
III:10; III:12; III:14; III:17 and IV:4) were born from ahealthy parent with a balanced translocation of chromosomes 3 and 4, while a single affected individual (IV:2)
inherited her imbalanced chromosomal complement fromher affected mother (III:4) who herself displayed the same
4p16.1 duplication and 3p.26.3 microdeletion.
Deletion of the chromosome 4p region has previously
been shown to result in a widely recognized phenotype

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compared with gains of the same region, which result in
more variable clinical manifestations. The family describedhere includes three family members with chromosome 4p
deletion resulting in WHS, all of whom displayed the typical clinical features of this condition. The characteristic
phenotype of WHS includes a typical facial appearance, significant intellectual disability and poor growth [13]. The
high arched eyebrows and prominent nasal tip that wereseen in all three WHS cases described here may relate to
the progression of these facial features with age, as has beenpreviously suggested [1]. Similarly, the ear hand and feetanomalies, and dysgenesis of corpus callosum, have previously been documented in WHS cases [1, 14].
At a molecular level, within the terminal 1.9 Mb region
on 4p16.3, Wolf-Hirschhorn syndrome candidate region 2(WHSCR-2) was described as the likely critical region for
WHS [15]. Candidate genes in that region have been suggested to cause particular clinical aspects of WHS [16, 17].
Haploinsufficiency of the WHSC1 gene [OMIM 602952],
which is disrupted by the proximal breakpoint of WHSCR2, has been associated with both facial characteristics andgrowth delay [18, 19]. The LETM1 gene, residing entirely
within WHSCR-2, is considered to play an importantrole in the pathogenesis of seizures [20–24]. However,genotype–phenotype correlation analyses suggested that
haploinsufficiency of LETM1 alone may not be sufficientin causing seizures and that loss of the terminal 1.5 Mb
region with breakpoint at ~300 kb from the LETM1
locus, preserving LETM1, is critical for the developmentof a seizure disorder [25]. Large deletions of chromosome
4p16 incorporating both critical regions are typically associated with profound intellectual disability, seizures andpsychosis in addition to the typical facial appearance[15, 18, 19]. Our microarray analysis of the three WHS
cases described here with 4p16.3-16.1 deletion and3p26.3 duplication identified a ~5 Mb deletion encompassing WHSCR-2 which resulted in severe developmental delay with absent (2/3) or impaired speech (1/3),
absent (2/3) or significantly delayed onset of walking(1/3), as well as generalized tonic-clonic seizures (3/3)
and behavioral abnormalities (2/3), consistent withthose previously described in WHS.
Compared to the classical presentation seen in thethree WHS patients, the seven chromosome 4p partial
trisomy patients displayed a much more variable clinicalpicture. The degree of intellectual deficit present acrossthe seven cases varied from severe (2/7) to mild (4/7).
The majority of the seven patients displayed clinical features previously described for trisomy of 4p syndrome,
including prominent supraorbital ridges (5/7), prominent nasal tip (5/7), prognathism (3/7), camptodactyly (2/7) and malformed and low-set ears (5/7). Although headcircumference was reduced in all seven cases, height was
variable ranging from normal (5/7) to short stature (2/7)

Iype et al. BMC Medical Genetics (2015) 16:104(Table 2). Overexpression or inactivating mutations of
two genes mapping to the chromosomal region involved,
fibroblast growth factor receptor 3 (FGFR3) and WHSC1,
have been reported to be associated with overgrowth features such as macrocephaly, campodactyly and tall stature[26, 27]. FGFR3 is a physiological negative regulator ofbone growth, and has been associated with syndromic presentations affecting bone growth including the overgrowth
syndrome-CATSHL (campodactyly, tall stature, and hearing loss) [26]. Similarly, overexpression of WHSC1 has
been suggested as a contributor to the overgrowth seen
as part of this condition. In mice, haploinsufficency of
WHSC1 resulted in growth retardation [27]. Two of the
7 chromosome 4p duplication cases (III:4 and IV:11)
demonstrated discordant clinical manifestations including
severe intellectual disability, short stature, microcephaly,
generalized tonic-clonic seizures, gum hypertrophy andcerebellar signs, compared with relatively mild learning
difficulties in the remaining five cases (IV:8; IV:9; IV:2;
IV:1 and IV:17). The cerebellar signs and gum hypertrophy
seen in the 2 severely affected cases may relate to longterm phenytoin treatment.
The craniofacial features observed in 1 of the 2 partial
4p trisomy cases (IV:11), including high arched eye brows,
hypertelorism, trigonocephaly as well as marked reduction
in growth milestones and behavioral changes, are not previously recognized in partial 4p trisomy syndrome (Table 2;& Additional file 1: Figure S1). While this may reflect as-yet
unrecognized clinical variability in this disorder, it is more
likely to be due to the complexity of the chromosome
imbalance in these cases.
The chromosome 3pter rearrangement defined here
is somewhat smaller compared with rearrangements
previously reported as part of chromosome 3p duplication
syndrome. The 2.7 Mb chromosome 3 microdeletion detected in this family includes the CNTN4 and CHL1 genes,
which have previously been shown to have a pleotropic
effect and contribute to learning difficulties in affectedindividuals [28–33]. Further, CNTN4 deletion has been
associated with microcephaly, trigonocephaly, hypertelorism, growth retardation and ear abnormalities. Howeverthese clinical features were present in only two of theseven chromosome 3p26.3 microdeletion cases (III:4 &IV:11) presented here. This may mean that other factors
including age of examination, other genes in the 3pter region, epigenetic phenomena, expression or regulatory variation and the unmasking of recessive variants residing on
the other unperturbed allele, may also be required for thedevelopment of these features.

Availability of supporting data
All the supporting data are included as Additional file 1
and available in the online version of the paper.

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Additional file
Additional file 1: Supplemental information includes a table that
illustrates DNA copy alterations identified using micro-array copy
number analysis, the photos of affected individuals, the illustrationof beadarray analysis of SNP data, used to identify the chromosomal
subregion duplication and deletion events present in family members,
and FISH karyotype analyses. (DOCX 1037 kb)
Abbreviations
WHS: Wolf–Hirschhorn syndrome; CNVs: Copy-number variations;
WHSCR: Wolf–Hirschhorn syndrome critical regions; CATSHL: Campodactyly,
tall stature, and hearing loss; FGFR3: Fibroblast growth factor receptor 3;
LETM1: Leucine zipper/EF-hand-containing transmembrane protein 1.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
AHC and TI conceived, designed and supervised the project. VA, AS-H, AK
and BAC performed experiments. TI and MI aided in family recruitment. TI,
VA, CP, ELB, RS, MAP, TMM and TTW aided in assessment of clinical data. VA
and AHC wrote the manuscript. All authors read and approved the final
version of the manuscript.
Acknowledgement
The work was supported by UK Medical Research Council grants G1002279
and G1001931 and by the Newlife Foundation for disabled children.
Author details
1
Department of Neurology, Government Medical College,
Thiruvananthapuram, Kerala, India. 2Molecular Genetics, RILD Institute,
University of Exeter, Royal Devon and Exeter NHS Hospital, Wonford, Exeter,
UK. 3Reta Lila Weston Institute of Neurological Studies, UCL Institute of
Neurology, London, UK. 4Department of Anatomy and Microbiology, Instituteof Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
5
Clinical Neuroscience, Royal Free Campus, UCL Institute of Neurology,
London, UK. 6Southwest Thames Regional Genetics Centre, St George’s
Healthcare NHS Trust, London SW17 0RE, UK. 7Human Genetics and Genomic
Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
8
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
Received: 10 July 2015 Accepted: 4 November 2015

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