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The West London Medical Journal Vol 1 No 2 pp 25-29
REVERSED DUPLICATION OF THE
DISTAL LONG SEGMENT OF
CHROMOSOME 1 IN A FEMALE INFANT
Tom Marrs, 1 Louise Wilson 2 , Shahid Husain13
ABSTRACT
We report here the first published case of inverted duplication of the
distal long segment of chromosome 1 (46,XX,inv dup(1)(q44q32.3)) carried
on 1q in a female infant. Antenatally the infant was diagnosed with moderate
pulmonary stenosis. Postnatal phenotypic features included large fontanelles,
wide sagital suture, broad forehead, triangular face with pointed chin, long
philtrum, thin upper lip, short palpebral fissures, posteriorly rotated ears,
bilateral single palmar creases, short halluces and deep-set toe nails.
Subsequently, she developed hypotonia, marked developmental delay and
ocular abnormalities. The features of this case and those reported previously
provide further support for the distal 1q trisomy phenotype.
INTRODUCTION
Partial duplication of the long arm of chromosome 1 is an uncommon
finding that can arise in many ways. The most common mechanism involves
unbalanced translocation, which results in both partial 1q trisomy and a
corresponding loss of genetic material. In these cases it is difficult to
separate the phenotypic features that have been caused by genetic material
that has been either duplicated or deleted. In order to characterise the
phenotype associated with excess chromosomal material, study of cases with
isolated duplications is required.
Seven cases of isolated distal 1q trisomy have been reported in the
literature (Steffensen et al., 1977; Flatz and Fonatsch, 1979; Lungarotti et al.,
1
Neonatal Unit, Homerton University Hospital
Department of Clinical Genetics, Great Ormond Street Hospital
3
Corresponding author; Paediatric Centre, Institute of Cell and Molecular Science,
Barts and the London School of Medicine and Dentistry, Homerton University
Hospital, London, E9 6SRUK. Email;[email protected] Tel; 020 8510 7952;
Fax: 020 8510 7850
2
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1979; Clark et al., 1994; Duba et al., 1997; Ramesh et al., 2000; Nowaczyk
et al., 2003). These probands had duplications starting at the breakage “hot
spot” from 1q31 – 1q32 and thus carried similar replicated material. Five
reports described simple tandem duplication segments carried on the long
arm of chromosome 1 (Steffensen et al., 1977; Flatz and Fonatsch, 1979;
Lungarotti et al., 1979, Ramesh et al 2000 and Nowaczyk et al., 2003) and
two reports identified the insertion of the reversed duplication onto the tip of
the short arm of chromosome 1 (Clark et al., 1994; Duba et al., 1997). The
case we now report is unusual as here the duplication is an inverted sequence
carried on the long arm of chromosome 1 in a female infant.
CLINICAL REPORT
A 43 year old Caucasian mother in her third pregnancy booked for
routine antenatal care at 19 weeks gestation. Her previous two offspring
were normal. She had conceived naturally and was not in a consanguineous
relationship. Routine antenatal scanning at 19 weeks gestation showed
dilatation of the fetal pulmonary trunk. Fetal echocardiography at 22 weeks
showed right ventricular hypertrophy with stenotic pulmonary valve and
reduced leaflet excursion; the fetus was diagnosed with moderate pulmonary
stenosis. The parents declined an offer of chorionic villous sampling.
The pregnancy progressed normally until scans at 37 weeks gestation
showed fetal blood flow re-distribution and decreased fetal growth rate. The
mother accepted an offer of induction of labour.
A female infant was born in good condition at 37+4 weeks weighing 2390
grams (9th – 25th centile) and admitted to the Neonatal Unit for observation.
On examination she was found to have a harsh systolic murmur radiating to
her back, but there was no cardiovascular compromise. Echocardiography
confirmed moderate pulmonary stenosis and also demonstrated a large
fenestrated ASD. Her neonatal course was unremarkable.
When reviewed at 6 weeks of age, she weighed 2500 grams (2nd centile)
and her head circumference was 35.9cm (75th – 91st centile). Anterior and
posterior fontanelles were large and her sagital suture was wide. She had a
broad forehead, pointed chin, triangular face, long philtrum, thin upper lip
and short palpebral fissures. Her ears were posteriorly rotated and had
pointed helicies. Bilateral single palmar creases, unusual placement of the
thumbs and short halluces with deep-set toe nails were present.
A balloon valvotomy of her pulmonary valve was performed at 5 months
of age and her ASD was repaired at 11 months. Percutaneous gastrostomy
was performed at 8 months of age because of repeated aspiration secondary
to oesophageal disco-ordination. After an initial period of normal
neurological development, she developed hypotonia and marked
developmental delay. She also developed exotropia, a small optic disc in the
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left eye, tortuous retinal vessels bilaterally, right eye lagophthalmos and
corneal erosions.
CYTOGENETIC ANALYSIS
Initial karyotype screening showed irregular material added to the long
arm of chromosome 1. The irregular material was identified by M-banding
as an inverted duplication of segment from 1q32.3 to 1q44.
Both parents have normal karyotypes, making our case a de novo
genotype.
DISCUSSION
This is the first example of a female with inverted distal 1q trisomy
carried on 1q. The karyotypes of the case presented here and those reported
previously are shown in Table 1.
Our case shows considerable similarities with the previously described
cohort of 7 pure distal 1q trisomy children, which allows further
characterisation of the distal 1q trisomy syndrome. The key features of distal
1q trisomy syndrome consist of macrocephaly and distinctive triangular
facies combined with cardiac, urogenital and gastro-intestinal abnormalities.
These children have large fontanelles and wide sutures. Despite a wide
forehead, the face is small and triangular, with pointed chin, short palpebral
fissures and rotated abnormal ears. There is failure to thrive, which might be
compounded by co-existing cardiac structural defects or gastro-intestinal
dysfunction. Other hallmarks include urogenital abnormality and
overcrowded or shortened halluces. The frequency of key phenotypic
features in this and previous case reports is shown in Table 2.
Table 1 Karyotype of cases with partial duplication of the long arm of
chromosome 1
Reference
1
2
3
4
5
6
7
This case
Karyotype
46,XX,dup(1)(q32qter), onto tip of p
46,XY,inv dup(1)(qterq32), onto tip of p
46,XX,dup(1)(q32q44), tandem
46,XY,dup(1)(q31q43), tandem
46,XY,dup(1)(q32q44)
46,XX,dup(1)(q32q42)
46,XY,dup(1)(q32q44), tandem
46,XX,inv dup(1)(q44q32.3)
In addition to the features described above, the case reported by Duba
and colleagues (2) showed additional abnormalities consisting of tracheal
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stenosis, sensorineural deafness and bilateral cleft lip and palate. As can be
seen from Table 1, this case was the only one previously reported with
inversion of the duplicated chromosomal material, which led to the
suggestion of a link between the inversion and additional abnormalities (5).
Although our case also exhibited inversion of the duplicated segment,
clinical features remain consistent with the non-inverted distal 1q trisomy
children. The absence of such extensive abnormalities in our case suggests
that inversion of the duplicated segment has not markedly altered the
phenotype of our case.
REFERENCES
1. Clark BJ, Lowther GW, Lee WR. Congenital ocular defects
associated with an abnormality of the human chromosome 1: trisomy
1q32-qter. J Pediatr Ophtal Strab 1994;31:41-45.
2. Duba H-C, Erdel M, Löffler J, Bereuther L, Fischer H, Utermann B,
Uttermann G. Detection of a de novo duplication of 1q32-qter by
FISH in a boy with multiple malformations: further delineation of
the trisomy 1q syndrome. J Med Genet 1997;34:309-313.
3. Flatz S, Fonatsch C. Partial trisomy 1q due to tandem duplication. J
Clin Genet 1979; 15:541-542.
4. Lungarotti MS, Falorni A, Calabro A, Passalacqua F, Dallapiccola
B. De Novo duplication 1q32-q42: variability of phenotypic features
in partial 1q trisomics. J Med Genet 1979;17:398-402.
5. Nowaczyk MJM, Bayani J, Freeman V, Watts J, Squire J, Xu J. De
Novo 1q32q44 duplication and distal 1q trisomy syndrome.
American Journal of Medical Genetics 2003;120A:229-233.
6. Ramesh KH, Wei D, Cheng L, Soni S, Green N, Levy P, et al.,
(2000) Duplication 1q32q42 syndrome in a child with alphathalassaemia trait [abstract]. Am J Hum Genet 2000;67 Suppl
2,125:A636.
7. Steffensen DM, Chu EHY, Speert DP, Wall PM, Mellinger K, Kelch
RP. Partial trisomy of the long arm of human chromosome 1 as
demonstrated by in situ hybridisation with 5S ribosomal RNA. Hum
Genet 1977;36:25-33.
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Wide sutures and fontanelle
Prominent wide forehead
Short palpebral fissures
Low-set rotated ears
Pointed chin
Failure to thrive
Toe abnormalities
Relative macrocephaly
Developmental delay
Nervous abnormalities
Abnormal function
Anatomical defect
Anatomical anomalies
Facies and head
Somatic phenotype
CNS
Gastro-intestinal
Cardiovascular
Urogenital
100%
71%
71%
100%
86%
86%
100%
100%
100%
100%
100%
100%
71%
Percentage
frequency*
Scarred left kidney
Pulmonary stenosis with
ASD
Severe reflux and
aspiration requiring PEG
placement
Y
Y
Squint with small L optic
disc
Y
Short halluces with deepset nails
Y
Y
Y
Y
Y
Current case
PDA with aberrant carotid (7), VSD (1), PS +
AS (2), PDA with aortic shelf (5)
Stenotic common bile duct (7), jejunal
obstruction (1), duodenal obstruction and
malrotation (2)
Similarly described (1-5,7)
Exception Clark (1) case died at 19hrs
Cataract and anterior chamber abnormalities
(1), ventriculomegaly (2,3,5)
Similarly described (1-5,7)
Crowded overlapping toes (2-5,7), short
halluces (1)
Similarly described (1-5,7)
Similarly described (1-5,7)
Similarly described (1-7)
Similarly described (1-5,7)
Similarly described (2,4,5,7)
Previously reported cases
Hypospadias (2-4,7), cryptorchidism (2,3,7),
ureteral stenosis (3), horseshoe kidney (1),
dysplastic kidneys (2)
* The frequency was calculated from this case and six reported previously; the case from reference 6 was excluded because of paucity of clinical features provided
Feature
Phenotypic frequency in cases of partial duplication of the long arm of chromosome 1
System
Table 2