American Journal of Medical Genetics 134A:12–23 (2005)

An Interstitial Deletion of Chromosome 7 at Band q21:A Case Report and ReviewWinnie Courtens,1* Stefan Vermeulen,2 Wim Wuyts,1 Ludwine Messiaen,2 Jan Wauters,1 Lieve Nuytinck,2

Nils Peeters,1 Katrien Storm,1 Frank Speleman,2 and Markus M. Nothen1

1Department of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium2Department of Medical Genetics, University Hospital Ghent, Ghent, Belgium

We report on a girl with moderate developmentaldelay and mild dysmorphic features. Cytogeneticinvestigations revealed a de novo interstitialdeletion at the proximal dark band on the longarm of chromosome 7 (7q21.1-q21.3) in all analyzedG-banded metaphases of lymphocytes and fibro-blasts. Fluorescence in situ hybridization (FISH)and molecular studies defined the breakpoints at7q21.11 and 7q21.3 on the paternal chromosome 7,with the proximal deletion breakpoint betweenthe elastin gene (localized at 7q11.23) andD7S2517, and the distal breakpoint betweenD7S652 and the COL1A2 gene (localized at7q21.3-q22.1). Deletions of interstitial segmentsat the proximal long arm of chromosome 7 at q21are relatively rare. The karyotype–phenotypecorrelation of these patients is reviewed anddiscussed. The clinical findings of patients with adeletion at 7q21 significantly overlap with thoseof patients with maternal uniparental disomy ofchromosome 7 (matUPD(7)) and Silver–Russellsyndrome (SRS, OMIM 180860). Therefore, 7q21might be considered a candidate chromosomalregion for matUPD(7) and SRS.� 2005 Wiley-Liss, Inc.

KEY WORDS: chromosome 7q; interstitial dele-tion; Silver–Russell syndrome;maternal uniparental disomy 7;ectrodactyly/split-hand/foot mal-formation 1

INTRODUCTION

Interstitial deletions of the proximal light band on thelong arm of chromosome 7 at 7q11.23, causing the Williams–Beuren syndrome, are frequently described and well-known.Interstitial deletions of the long arm of chromosome 7 of thedark band just distal to this region or of band 7q21, are,however, rare.

Here, we report a de novo interstitial deletion of the long armof chromosome 7 at band q21, diagnosed in a 2-year-old girlwith moderate psychomotor retardation and mild dysmorphicfeatures. The clinical findings of the proband are comparedwith other published cases with interstitial 7q21 deletion in anattempt to identify common phenotypic aspects. The observa-tion that clinical findings of patients with a deletion at 7q21overlap with those of patients with maternal unidisomy 7(matUPD(7)) and Silver–Russell syndrome (SRS, OMIM180860) suggests 7q21 as a candidate chromosomal region forthese disorders.

MATERIALS AND METHODS

Cytogenetic and FluorescenceIn Situ Hybridization (FISH) Analyses

GTG-banding analysis including high resolution karyotyp-ing was performed on metaphases obtained from PHA-stimulated lymphocytes from the patient and her parents,according to standard procedures. A GTG-banded karyotype(according to standard procedures) was also performed onfibroblasts of the patient.

FISH was performed with 7q locus specific RP11-BAC probes(Fig. 2b) obtained through screening of the November 2002freeze of the human genome project (http://genome.ucsc.edu).

Molecular Analyses

DNA was extracted from peripheral blood samples from theproband and the parents according to standard procedures.The following markers were studied: D7S2415, D7S2479,D7S489, D7S2490, D7S2517, D7S669, D7S644, D7S492,D7S657, D7S652, D7S2430, D7S2431, D7S479. In addition, atetranucleotide repeat residing in intron 1 of the elastin geneand a VNTR in intron 12 of theCOL1A2 gene [Pepe, 1993] wereanalyzed. Primers and amplification conditions for amplifica-tion of all markers were obtained from the Genome Database(and all forward primers were modified with a M13 sequencepreceding the locus specific sequence). Physical and geneticpositions were obtained from the NCBI genome database(http://www.ncbi.nlm.nih.gov/mapview/map_search.cgi). PCRwas performed according to standard procedures with bothlocus specific primers and FAM-fluorescent labeled M13primers. PCR products were analyzed on an ABI3100 geneticanalyzer.

CLINICAL REPORT

The patient was the first child of a healthy 33-year-old G1P1mother and a 26-year-old unrelated father. There was nofamily history of miscarriages, malformations, or develop-mental delay. Ultrasounds at 31 weeks of gestation revealedthe onset of intra-uterine growth retardation. Deliveryoccurred spontaneously at term but was complicated by fetaldistress and meconial inhalation. Birthweight, length, andoccipitofrontal head circumference (OFC) were 2,400 g (<3rd

Grant sponsor: Research Grant of the Fund for ScientificResearch, Flanders Belgium; Grant numbers: 1.5.183.02,G.0200.03.

*Correspondence to: Winnie Courtens, M.D., Department ofMedical Genetics, University Hospital Antwerp, Universiteits-plein 1, B-2610 Antwerp, Belgium.E-mail: winnie.courtens@ua.ac.be

Received 18 September 2003; Accepted 12 December 2003

DOI 10.1002/ajmg.a.30106

� 2005 Wiley-Liss, Inc.

centile), 48 cm (3rd–10th centile), and 32 cm (<3rd centile),respectively. The neonatal period was complicated by ‘‘seizure-like episodes’’ and a gastric ulcer. When crying, the girldisplayed a mild asymmetry of the mouth. Cerebral ultra-sounds, electroencephalogram, metabolic screen, and ultra-sounds of liver and pancreas were normal. During infancy, thechild had frequent respiratory infections and a gastro-esophageal reflux. The ‘‘seizure-like episodes’’ disappearedafter the age of 10 months. Her psychomotor development wasretarded, i.e., she smiled at the age of 9 months, sat un-supported at the age of 13 months, and began to walk at the ageof 28 months. From the age of 13 months on, she receivedspecial training to improve her motor skills and her language.

Her developmental quotient at the age of 11 and 20 months wasevaluated at 60 and 47, respectively.

At the age of 2 years and 4 months, her weight, length, andOFC were 11,200 kg (3rd–10th centile), 85 cm (3rd–10thcentile), and 46 cm (3rd centile), respectively. She had a sacraldimple, a slight hyperlaxity of the fingers and was hypotonic.There was mild facial dysmorphism consisting of a highforehead, small palpebral fissures, hypertelorism, telecanthus,flat broad nasal bridge, short nose, midfacial hypoplasia, thinupper lip, everted lower lip, crowded teeth, low-set ears,microretrognathia, slight palpebral ptosis of the right eye, andasymmetry of the mouth when crying (Fig. 1). She also hadsmall hands and wide-spaced nipples.

Fig. 1. The proband at the age of 28 months, 6 years (frontal views), and 7 years 5 months (frontal and lateral view). [Color figure can be viewed in theonline issue, which is available at www.interscience.wiley.com.]

Interstitial Deletion Chromosome 7q 13

On follow-up at 7 years and 5 months of age, her weight(21,600 kg), length (117 cm), and OFC (50 cm) were stillsituated between the 3rd and 10th centile. She still under-went special training to improve motor skills and language.Psychomotor testing at the age of 4 years and 63

4 years reveal-ed a global developmental age of 2 years and 31

2 years,respectively. She was able to talk (but still with some dif-ficulties), had a good social contact and was a very activegirl. She had a similar facial dysmorphism as described

above but developed a relatively large mouth with down-turned corners (Fig. 1). Ophthalmological evaluation re-vealed bilateral hypermetropia. Skeletal X-rays showed amild lumbar scoliosis, bilateral coxa valga with subluxa-tion of the right hip, and a normal bone age. Further com-plementary investigations were negative, including a brainnuclear magnetic resonance (performed at the age of9 months), cardiac and renal ultrasounds, ECG and auditorytesting.

Fig. 2. a: Partial karyotype and ideogram of both chromosomes 7 of the patient—the deleted chromosome is on the right; (b) the breakpoints of the deletedregion in the proband according to the molecular (analysis of microsatellite markers from chromosome 7q in the patient and her parents) and FISH analyses.The deletion occurred on the paternal chromosome between 75.82 and 92.59 Mb. [Color figure can be viewed in the online issue, which is available atwww.interscience.wiley.com.]

14 Courtens et al.

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RESULTS

Cytogenetic Analyses

GTG-banded chromosomes obtained from the lymphocytesand the fibroblasts of the proband showed an interstitialdeletion at the proximal dark band on the long arm of chro-mosome 7 in all 50 analyzed metaphases: only a small faintband instead of a heavy dark one was present at band 7q21(Fig. 2a). Parental karyotypes were normal, indicating a denovo origin of the deletion.

FISH Studies

FISH analyses showed a deletion of the following 7q21probes RP11-261L16, RP11-175K20, RP11-91M13, RP11-638A9, RP11-1099C19, and RP11-455I9. The probes proximalof the breakpoint, RP11-44F22 (7q11.23) and RP11-441N19(7q11.23), and distal from the breakpoint, RP11-101N13(7q21), RP11-89A20 (7q21), and RP11-95A10 (7q21), were notdeleted (Fig. 2b).

Molecular Analyses

PCR analysis of polymorphic markers from this region wasperformed to determine the boundaries of the deletion. Adeletion on the paternally derived chromosome 7 was observedfor markers D7S2517, D7S669, D7S644, D7S657, and D7S652.Two copies were present for the markers D7S2415, D7S489,D7S479, and both the elastin and COL1A2 genes (Fig. 2b). Theremaining markers were non-informative. Hence, the break-points flanking the deletion resided in the cytogenetic bands7q21.11 and 7q21.3. We estimated the size of the deletion toapproximately 16.77 Mb, based upon the physical location ofthe deleted BACs and the molecular markers in the humanDNA sequence (Fig. 2b). Based upon these data the proband’skaryotype is 46,XX,del(7)(q21.1q21.3).

LITERATURE DATA

Including the case we describe here and other reports in theliterature, a total of 22 patients with an interstitial deletionat 7q21 have been reported. A major difficulty in comparingpatients with apparently similar breakpoints, is that thedescription of the breakpoints, especially in older publications,is debatable and that the further delineation of the breakpointsby FISH or molecular techniques was lacking in most cases.We, therefore, reviewed the photographs of the karyotypes ofthe published, non-mosaic deletion cases at 7q21, and selectedthose with a similarly looking karyotype as in our patient. Theyare represented in Table I. The cases described by Seabrightand Lewis [1978] (case 1), Klep-de Pater et al. [1979], andGibson et al. [1982] were included in this table because thephotographs of the chromosomes of these cases clearly showthat the G-band negative segment q11 is unaffected by thedeletion and that loss has occurred at the dark band q21.

Table II represents the cases with a somewhat largerdeletion than in our case (deletion of the entire band 7q21).The cases with a breakpoint more proximal as well as thosewith a breakpoint more distal (in or distal to 7q22) or both wereexcluded. Most deletions occurred de novo (6/8). The followingclinical signs were frequently observed (see Table II for numberof observations): pre- and post-natal growth deficiency, earlyinfancy feeding problems, developmental delay/mental retar-dation, hypotonia, genital anomalies, microcephaly, asym-metry, split-hand/foot, hernia, and mild facial dysmorphismconsisting of ear anomalies, micro-/retrognathia, flat/broadnasal bridge, and high forehead. Gastro-oesophageal reflux,impaired hearing, high arched/cleft palate, ophthalmologicanomalies, abnormal EEG, and/or seizures, the presence of a

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16 Courtens et al.

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(<P

5)

2.3

00

Bir

thle

ngth

(cm

)?

41.9

?43.8

37.5

50

Bel

owth

em

ean

?40

(<P

10)

?O

FC

(cm

)?

30.5

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mall

)B

elow

the

mea

n?

29.5

(<P

10)

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esta

tion

al

age

34

wee

ks

At

term

37

wee

ks

39

wee

ks

34

wee

ks

At

term

32

wee

ks

At

term

33

–34

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ks

At

term

IUG

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þ�

þþ

þþ

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0

Wei

gh

t(k

g)

6.3

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5)

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15

(P10)

3.5

(P25)

Len

gth

(cm

)66

(<P

5)

?103

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51

(P10)

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C(c

m)

39.7

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3)

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43

46.5

(�3S

D)

34.5

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D)

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2)

At

age

10

mon

ths

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onth

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ths

10

mon

ths

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t-n

ata

lG

Rþ

��

�1/4

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ure

toth

rive/

pos

t-n

ata

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wth

reta

rdati

on

?þ þ

�þ

(S)

þþ þ

?þ

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0

Earl

yin

fan

cyfe

edin

gp

roble

ms

??

(<P

5)

þþ

þ(p

erm

an

ent

fed

by

sto-

mach

gavage

at

2yea

rs)

�þ

?þ

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0

Gast

ro-e

sop

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flu

xfr

equ

ent

small

vom

its

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þþ

(S)

þ?

??

3/1

0

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elop

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tal

del

ay/

men

tal

reta

rdati

onþ

(at

7m

onth

s!

2m

onth

sle

vel

)þ

(10

mon

ths:

som

ed

elay;

sign

ifica

nt

ap

ath

y)

þ(S

)(a

t9

mon

ths:

QD

3m

onth

s;ch

air

-bou

nd

at

31 2

yea

rs)

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)(u

nable

tost

an

dw

ith

out

sup

por

t(2

yea

rs),

poo

rre

act

ion

toen

vir

onm

ent)

þ(a

t4

yea

rs,

4m

onth

s!

2–

21 2

yea

rsle

vel

)

þ(a

t18

mon

ths:

QD

6m

onth

s)þ

(S)

þ(S

)(a

t10

mon

ths:

skil

lsat

the

1–

2m

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sle

vel

)

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)9/9

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oton

iaþ

?þ

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�(h

yp

erto

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0A

bn

orm

al

EE

Gan

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rse

izu

res

þ þþ

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mon

ths)

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þ?

þþ

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0

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lit

han

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sep

alm

ar

crea

seon

1h

an

d

Bil

at

sin

gle

palm

ar

crea

ses

�þ

(fee

t)þ

(bot

hfe

etþ

righ

th

an

d;

left

han

dN

exce

pt

for

clin

odact

V)

�� C

lin

odact

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dan

d5th

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ger

s

þ(r

igh

th

an

dþ

bot

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et;

left

han

dN

)

� (sh

ort

fin

ger

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ad

thu

mb

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atþ

hyp

opl

nail

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eet

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th

an

d)

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0

Mic

ro/r

etro

gn

ath

ia?

?þ

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roþ

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og)

?þ

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rog)

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icro

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ro)

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0F

lat/

bro

ad

nasa

lbri

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?þ

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sm?

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þ�

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0

(Con

tinued

)

TA

BL

EII

.(C

ontinued

)

Vale

nti

ne

an

dS

ergov

ich

[1977]b

,cJoh

nso

net

al.

[1978]c

Cra

wfu

rdet

al.

[1979],

case

2D

elP

orto

etal.

[1983]b

Pfe

iffe

r[1

984]

You

ng

etal.

[1984],

case

4C

hit

ayat

etal.

[1988]

Taja

raet

al.

[1989]

Zack

owsk

iet

al.

[1990]b

McE

lvee

net

al.

[1995]

Tot

al

Pala

tecl

eft

hig

hþ

þcl

eft

(clo

sed

at

9m

onth

s)þ

þþ

Narr

ow1/1

04/1

0E

ar

an

omali

esþ

(low

-set

)þ

(malf

orm

ed)

�þ

(low

-set

;p

oste

rior

lyro

tate

dþ

malf

orm

ed)

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ow-s

et;

poo

rly

dif

fere

nti

ate

dsm

all

ears

)

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ver

fold

edau

ricl

es;

ver

ysm

all

ears

)

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rom

inen

tan

dsm

all

)þ

(malf

orm

ed)

þ(p

oste

rior

lyan

gu

late

dþ

pea

ked

)

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mall

,d

ysp

last

ic,

pos

teri

orly

rota

ted

)

9/1

0

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ebra

lfi

ssu

res

?S

ligh

tly

dow

n-s

lan

tin

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all

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ond

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ap

edA

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gol

oid

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0

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mm

etry

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part

ial

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al

pals

y)

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EG

)þ

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dan

omali

es)

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ku

ll)

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ric

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ital

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is)

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m)

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ph

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usþ

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tral

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eatu

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stic

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ects

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ulm

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osis

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inal

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pair

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feet

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icro

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at

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ican

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ofth

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dof

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oid

al

syst

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all

asy

mm

cran

ium

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all

opti

cn

erves

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min

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ican

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al;

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ver

e

TA

BL

EII

I.M

an

ifes

tati

ons

inP

ati

ents

Wit

ha

Del

etio

nat

Ban

d7q21

bu

tS

mall

erT

han

inou

rP

ati

ent

Fagan

etal.

[1989],

case

2R

ober

tset

al.

,[1

991]

Mari

non

iet

al.

[1995]

Sla

vot

inek

etal.

[1997]

Tot

al

Des

crib

edd

elet

edre

gio

nof

7q

q21.2!

q21.3

q21.3

q21.2!

q22.1

(pate

rnal

del

)q21.3

Ass

ocia

ted

an

omali

es/fi

nd

ings

�D

er(7

)(i

nse

rtio

n7q

in7p

at

p15.1

)�

�

De

nov

oþ

þþ

dir

ins

(22;7

)mat

3/4

Sex

FM

MF

2M

/2F

Age

7m

onth

s5

yea

rs28

mon

ths

18

mon

ths

7m

onth

s–

5yea

rsB

irth

wei

gh

t(g

)3.1

60

2.2

00

2.2

00

(<P

3)

2.0

80

(<P

3)

Bir

thle

ngth

(cm

)49

?45.5

(<P

3)

?O

FC

(cm

)32.5

?29

(<P

3)

?G

esta

tion

al

age

41

wee

ks

(poo

rw

eigh

tgain

du

rin

gth

e3rd

trim

este

r)35

wee

ks

39

wee

ks

(slo

win

gof

feta

lgro

wth

by

6–

7m

onth

s)38

wee

ks

(IU

GR

from

31

wee

ks

ofges

tati

on)

IUG

Rþ

þþ

þ4/4

Wei

gh

t(k

g)

P10

–50

P3

10.2

(<P

3)

5.5

80

(�P

3)

Len

gth

(cm

)P

10

–50

<P

381.2

(<P

3)

66.5

(<P

3)

OF

C(c

m)

P3

P50

30

(<P

3)

39.5

(�P

3)

At

age

7m

onth

s5

yea

rs28

mon

ths

10

mon

ths

Fail

ure

toth

rive

pos

t-n

ata

lgro

wth

reta

rdati

onþ

þþ þ

3/4

Earl

yin

fan

cyfe

edin

gp

roble

ms

þ(g

ast

rost

omy

un

til

age

1yea

r)þ

2/4

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ro-e

sop

hagea

lre

flu

x/

freq

uen

tsm

all

vom

its

0/4

Dev

elop

men

tal

del

ay/m

enta

lre

tard

ati

onþ

(at

7m

onth

s!

5–

6m

onth

sle

vel

)þ

(IQ

84

at

6yea

rs;

ver

bal

72;

per

f100)

þ(p

ull

sh

imse

lfto

sitt

ing

pos

itio

n;

no

dis

cern

ible

wor

ds)

þ(m

oder

ate

)4/4

Hyp

oton

iaþ

1/4

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lit-

han

d/f

oot

Oth

eran

omali

es�

þ(f

our

lim

bs)

þ(f

eet)

small

han

ds;

<P

3þ

(lef

th

an

d)

3/4

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ro/r

etro

gn

ath

iaþ

þ�

?þ

3/4

Fla

t/bro

ad

nasa

lbri

dge

þ?

þþ

3/4

Hyp

erte

lori

sm?

þþ

þ3/4

Mou

th:

dow

n-t

urn

edco

rner

s�

??

þ(t

hin

up

per

lip

)þ

(th

inu

pp

erli

p)

2/4

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an

omali

esþ

(alo

bu

larþ

exce

ssiv

eh

elic

al

curv

ing)

þ(p

ost

rota

tion

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xed

flex

ion

ofth

eh

eli-

cesþ

low

-set

)

þ(p

rom

inen

tan

ti-t

ragu

s;ov

erfo

lded

hel

ices

;att

ach

edea

rlob

es)

þ(l

ow-s

etþ

over

fold

edh

elic

es)

4/4

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ebra

lfi

ssu

res

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ort

Sh

ort

Sh

ort:

2/4

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al

asy

mm

etry

þ1/4

(Im

pre

ssio

nof

slig

ht

asy

mm

etry

onp

hot

ogra

ph

)H

igh

fore

hea

dþ

þ�

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fnes

sþ

1/4

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iap

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ern

iaP

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pla

gio

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haly

sacral dimple, delayed bone age and cardiac defects were alsorecorded.

In Table III patients with a somewhat smaller deletion thanin our case (a deletion of a subband of band 7q21) were sum-marized. The brief report by Milunsky et al. [1989], describinga fetus with a de novo deletion of 7q21.2!q22 with facialdysmorphism (ocular hypertelorism; low-set ears) and ventri-cular septal defect, was not included because the report lackeda detailed clinical description. All four cases presented intra-uterine growth retardation, recorded in 3/4 cases during the3rd trimester of pregnancy, developmental delay/mental re-tardation, and dysmorphism, consisting of ear anomalies,micro/retrognathia, hypertelorism, flat/broad nasal bridge,and high forehead. Frequently observed signs were (seeTable III for number of observations) early infancy feedingproblems, failure to thrive/post-natal growth retardation, andshort palpebral fissures. Deafness and diaphragmatic herniawere present in one case. Cleft/high palate, teeth anomalies;abnormal EEG, and/or seizures; genital, renal, and intestinalanomalies; cardiac defects, inguinal/umbilical hernia, andsacral dimple were not recorded in these patients with a smalldeletion at 7q21 (Table III).

DISCUSSION

This girl with moderate psychomotor retardation and milddysmorphic findings, presented a de novo interstitial deletionat the proximal dark band on the long arm of the paternallyderived chromosome 7 (7q21.1-q21.3) in all analyzed meta-phases of blood and skin. The determination of the breakpointsof the deletion was studied using FISH and molecular analyses(Fig. 2b) and confirmed that the elastin gene, localized at7q11.23 (near to the proximal breakpoint), and the COL1A2gene, localized at 7q21.3-q22.1 (near to the distal breakpoint),were not deleted in our patient.

A deletion similar to our patient’s has, to our knowledge, onlybeen described in seven cases (Table I). All these deletionsoccurred de novo. All patients presented mild to moderatedevelopmental delay and prenatal growth retardation withthe following common clinical signs (see Table I for numberof observations): feeding problems in infancy, post-natalgrowth retardation, genital anomalies, hypotonia, hearingloss (conductive and/or sensorineural) and mild dysmorphismconsisting of micro/retrognathia, flat broad nasal bridge,hypertelorism, ear anomalies, high forehead, and mild asym-metry, small palpebral fissures, teeth anomalies, and higharched/cleft palate. The OFC was mostly in the lower normalrange (5/7), with one case with relative macrocephaly. Occa-sional anomalies were gastro-oesophageal reflux, abnormalEEG, and/or seizures, the presence of a sacral dimple, andhernia. Cardiac anomalies were not observed. A number ofclinical signs were observed in single cases and are given inTable I.

Split-hand/foot malformation or ectrodactyly was presentin 41% (9/22) of all patients with a deletion at band 7q21(Tables I–III). More than half of described cases with deletionof chromosome 7 involving q21 are, however, reported withoutectrodactyly (Table IV). This is in accordance with the findingthat the gene for SHFM1 (OMIM 183600) has been located on7q21.2-q21.3 (OMIM). A critical interval was proposed at7q21.3 between D7S527 (94.1 Mb) and D7S1798 (95.0 Mb)[Crackower et al., 1996]. Based upon the mapping of ourpatient, this region is situated about 1.5 Mb more distal thanthe deleted region in our patient.

Cases with split-hand/foot malformation have also beenreported in association with congenital hearing loss (OMIM220600), including two families with linkage to the SHFM1locus in 7q21 (OMIM 605617) [Tackels-Horne et al., 2001]. Inpatients with deletion of 7q21, deafness occurred in 23% (5/22)

TA

BL

EIV

.P

ati

ents

Wit

hIn

ters

titi

al

Del

etio

nat

7q21-q

22

an

dth

eP

rese

nce

/Abse

nce

ofE

ctro

dact

yly

orS

pli

t-H

an

d/F

oot

Rep

orte

dp

ati

ents

pre

sen

tin

gw

ith

spli

t-h

an

d/f

oot

Rep

orte

dp

ati

ents

wit

hou

tsp

lit-

han

d/f

oot

Mor

eyan

dH

iggin

s[1

990]

del

7q21.3!

31.3

Ayra

ud

etal.

[1976]

del

7q21!

q31

Riv

era

etal.

[1991]

del

7q22

Hig

gin

son

etal.

[1976]

del

7q21!

q32

Mon

tgom

ery

etal.

[2000]

del

7q21.2!

q31.2

You

ng

etal.

[1984]

(case

3)

Mil

un

sky

etal.

[1989]

del

7q11.2

1!

q21.1

1d

el7q21.2!

q22

Fro

mT

able

I(d

elet

ion

7q21.1!

21.3

):F

rom

Table

I(d

elet

ion

7q21.1!

21.3

):N

un

eset

al.

[1994]

(Or

dis

talbre

ak

poi

nt

at

q22.1

?)S

eabri

gh

tan

dL

ewis

[1978]

(case

1)

Haber

lan

dt

etal.

[2001]

Kle

p-d

eP

ate

ret

al.

[1979]

(case

2)

Fro

mT

able

II(d

elet

ion

7q11!

21/2

2):

Gib

son

etal.

[1982]

Del

Por

toet

al.

[1983]

Ost

rer

etal.

[1984]

Pfe

iffe

r[1

984]

Fry

ns

etal.

[1987]

Taja

raet

al.

[1989]

Pre

sen

tp

ati

ent

McE

lvee

net

al.

[1995]

Fro

mT

able

II(d

elet

ion

7q11!

21/2

2):

Fro

mT

able

III

(asm

all

del

etio

nin

asu

bban

dof

ban

d7q21):

Vale

nti

ne

an

dS

ergov

ich

[1977]

Rob

erts

etal.

[1991]

del

7q21.3

Joh

nso

net

al.

[1978]

Mari

non

iet

al.

[1995]

del

7q21.2!

22.1

Cra

wfu

rdet

al.

[1979]

Sla

vot

inek

etal.

[1997]

del

7q21.3

You

ng

etal.

[1984]

(case

4)

Ch

itayat

etal.

[1988]

Zack

owsk

iet

al.

[1990]

Fro

mT

able

III(a

small

del

etio

nin

asu

bban

dof

ban

d7q21):

Fagan

etal.

[1989]

20 Courtens et al.

of all cases (Tables I–III), more than half of which (3/5) also hadsplit-hand/foot malformation. The gene responsible for deaf-ness in 7q21 deletion patients might thus be situated close tothe gene responsible for split-hand/foot malformation. Inter-estingly, the patient reported by Haberlandt et al. [2001] had asimilar cytogenetic deletion (del 7q21.1-q21.3 pat) as ourpatient, but was discordant from our patient by the presenceof deafness and split-hand/foot. Molecular studies with 7qmicrosatellite markers showed that the deletion in the patientdescribed by Haberlandt et al. [2001] partly overlapped withthe deletion in our patient but extended 3–4 Mb further tothe distal end of chromosome 7, suggesting that the locusresponsible for the combination of split-hand/foot malforma-tion and deafness is situated between D7S652 (94 Mb) andD7S248 (98 Mb).

Because of the known association of cleft lip/palate in EEC1(OMIM 129900), an autosomal dominant syndromic ectrodac-tyly with variable manifestations, located at 7q11.2-21.3, wealso reviewed the presence of the clinical findings in thissyndrome (cleft palate, cleft lip, ectodermal dysplasia, andgenital anomalies) in patients with 7q21 deletion. Cleft palatewas present in 4/22 patients (18%) and three of them (3/4) alsohad split-hand/foot malformation (Tables I–III). Genitalanomalies occurred in 36% (8/22) of the cases. Cleft lip andectodermal dysplasia were, however, not described in patientswith a 7q21 deletion (Tables I–III).

Molecular analysis showed that the deletion in our patientoccurred de novo on the paternal chromosome 7, with theproximal deletion breakpoint between the elastin gene andD7S2517 and the distal breakpoint between D7S652 and theCOL1A2gene (Fig. 2b). Thus, our patient presented a maternalmonosomy for a 16.77 Mb region (between 75.82 and 92.59 Mb)at 7q21.1-q21.3. Parental imprinting is a well-known find-ing for chromosome 7. Maternal uniparental disomy 7(matUPD(7)) is known to cause pre- and post-natal growthretardation, OFC in the lower normal range, retarded bonematuration and a specific facial dysmorphism including atriangular face, a high broad forehead and a pointed chin. Lessfrequent signs are broad mouth with down-turned corners,

prominent ears, hemi-hypotrophy, clinodactyly, and delayedpsychomotor development [Kotzot et al., 2000]. These clinicalfindings strikingly resemble the phenotype of the SRS.Recently, different authors demonstrated that up to 10% ofpatients with the phenotype of SRS have maternal UPD(7)[Hitchins et al., 2001b], suggesting at least one imprinted geneon chromosome 7 that is involved in the pathogenesis of SRS. Ithas been suggested that no apparent clinical differences existbetween SRS cases with and without matUPD(7) [Bernardet al., 1999; Kotzot et al., 2000] although a milder SRSphenotype with only slight craniofacial dysmorphism has beendescribed in matUPD(7) patients [Hannula et al., 2001]. So far,no single genetic cause for this syndrome has been found, andit seems probable that more than one gene is associated withthis syndrome with such a non-specific phenotype. One of thecandidate regions on chromosome 7 for SRS has been proposedat 7p11.2 after the discovery of a segmental duplication of7p11.2-p13 in one SRS patient, encompassing the GRB10,IGFBP1, and IGFBP3 genes [Monk et al., 2000]. However, fourseries of 36, 11, 84, and 84 families, respectively, did not findevidence for duplication of genes in that region [Monk et al.,2000; Martinez et al., 2001; Mergenthaler et al., 2001; Riegelet al., 2003]. Segmental UPD for the same region could also beexcluded in 95 patients [Riegel et al., 2003]. The IGFBP1,IGFBP3, and GRB10 genes, were furthermore considered asunlikely to be involved in SRS. [Wakeling et al., 2000; Hitchinset al., 2001a; McCann et al., 2001].

When comparing clinical signs of patients with 7q21 deletion(see Tables I–III for more detailed information) with those ofSRS and matUPD(7) (Table V), a significant clinical overlap isobserved. This may suggest an involvement of a paternallyexpressed imprinted gene on chromosome 7q21 in the devel-opment of clinical features associated with matUPD(7). In thereviewed 7q21 deletion cases (Tables I–III), the parent-of-origin of the deleted chromosome 7 is not described except forthe cases reported by Marinoni et al. [1995], Haberlandt et al.[2001] and in the present patient, where the deletion occurredon the paternal chromosome 7. In the case reported byZackowski et al. [1990], the deletion was also of paternal origin

TABLE V. Clinical Features in SRS Patients, matUPD(7) Cases and Patients With 7q21 Deletion

Clinical features In SRSa In matUPD(7)a In 7q21 deletionb In deletion 7q21patc

MajorIUGR þþþþ þþþþ þþþþ (20/22¼91%) þþþþ (4/4)Post-natal growth retardation þþþþ þþþþ þþþ (13/21¼ 62%) þþþþ (4/4)Triangular face/facial dysmorph-ism

þþþ þþ þþþþ (22/22¼100%) þþþþ (4/4)

MinorClinodactyly Vth finger þþþ þþ þ (3/22¼14%) � (0/4)Relative macrocephaly þþþ þþþ þ (2/21¼9.5%) � (0/4)Ear anomalies/low-set ears þþþ þþ þþþþ (20/22¼91%) þþþþ (4/4)Asymmetry/hemihypertrophy þþ þþ þþ (10/22¼45%) þþ/þþþ (2/4)Mouth with down-turned corners þþ þ þþ (8/22¼36%) þþ/þþþ (2/4)Muscular hypotrophy/tonia þþ þ þþ (8/22¼ 36%) þþþ (3/4)Motor/neuropsychological delay þþ þþ þþþþ (22/22¼ 100%) þþþþ (4/4)Irregular spacing of teeth/teethanomalies

þþ þ þþ (7/22¼ 32%) þþ/þþþ (2/4)

Syndactyly þ � � (0/22) � (0/4)Genital abnormalities þþ 1/2 þþ (8/22¼ 36%) þþþ (3/4)Speech delay þþ þþ þþþþ (22/22¼ 100%) þþþþ (4/4)Feeding difficulties þþþ þþ þþþ (13/21¼ 62%) þþþ (3/4)Micrognathia þþ � þþþ (13/22¼ 59%) þþþ (3/4)Cleft/high arched palate þ þ þþ (9/22¼ 41%) þþ/þþþ (2/4)Frontal bossing/high forehead þþþ þþ þþþ (13/22¼ 59%) þþþ (3/4)

þþþþ: in> 80% of the cases; þþþ: between 50 and 80% of the cases; þþ: between 20 and 50% of the cases; þ: <20% of the cases; �: feature not described.aAs reviewed by Hitchins et al. [2001b] and Hannula et al. [2001].bcfr Tables Iþ IIþ III.cZackowski et al. [1990]; Marinoni et al. [1995]; Haberlandt et al. [2001]; present patient.

Interstitial Deletion Chromosome 7q 21

because the anomaly resulted from a direct insertion (9;7)inherited from the father. The clinical signs of these patientsoverlap with most clinical signs of SRS and matUPD(7)(Table V). Other findings observed in 7q21 deletion patients(Tables I–III), such as hearing loss, teeth anomalies, frequentgastro-intestinal complications (such as gastro-oesophagealreflux) and hipdysplasia (a clinical finding presented by ourpatient), were also recorded in SRS patients [Bernard et al.,1999; Anderson et al., 2002]. The onset of intrauterine growthdelay during the early third trimester, and the presence of mildfacial asymmetry [Valentine and Sergovich, 1977; Fryns et al.,1987; Nunes et al., 1994; present patient] observed in 7q21patients can also be observed on the clinical photographs ofpatients with mat UPD(7) [Kotzot et al., 2000; Hannula et al.,2001]. Interestingly, it was suggested that a novel imprintedregion may exist at 7q21 [Hitchins et al., 2001a]. PEG10 orpaternally expressed 10 was indeed recently proposed as anovel imprinting gene located on human chromosome 7q21[Ono et al., 2001].

We can conclude that, as a result of the review of the clinicalphenotype of patients with interstitial deletion 7q21, thisregion should be taken into consideration as being responsiblefor the clinical phenotype of patients with matUPD(7), andpossibly for the SRS phenotype.

ACKNOWLEDGMENTS

We thank the parents for their collaboration; as well asN. Vandenbroek, C.Vantieghem, and M.Yoruk for their experttechnical assistance; and The Wellcome Trust Sanger Institute(Hinxton, Cambridge, UK) for providing us with the probes forchromosome 7q.

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