1998 a 29 YEAR OLD MOTHER AND A SIXTY YEAR OLD FATHER HAVE a SON WITH de novo complex chromosomal rearrangement

He was hypotonic and he could neither stand
up nor walk. Speech was lacking. A mild facial dysmorphy
was noted, including a long face, a large nose with anteverted
nostrils, micrognathy, a pronounced philtrum, long teeth and
low set ears. There was neither visceral malformation nor
anomaly in standard laboratory investigations such as
electroencephalography, electromyography or skeletal X-ray
examination.



Human Reproduction vol.13 no.7 pp.1801–1803, 1998
CASE REPORT
Advanced paternal age and de-novo complex
chromosomal rearrangement in offspringB.Benzacken1,4, J.P.Siffroi2, B.Straub2,
C.Le Bourhis2, S.Sauvion3, J.Gaudelus3,
J.P. Dadoune2 and J.P.Wolf1
1Laboratoire d’Histologie, Embryologie, Cytoge´ne´tique et Biologie
de la Reproduction, Hoˆpital Jean Verdier, 93140, Bondy,
2Laboratoire d’Histologie, Biologie de la Reproduction et
Cytoge´ne´tique, Hoˆpital Tenon, Paris and 3Service de Pe´diatrie,
Hopital Jean Verdier, 93140, Bondy, France
4To whom correspondence should be addressed
We report one case of a de-novo complex chromosomal
rearrangement (CCR), t(1;5;13)ins(14;13), in an abnormal
19-month-old boy. Clinical features associated were a mild
facial dysmorphy and a psychomotor retardation. Parental
ages were, respectively, 29 years for the mother and
60 years for the father. We point out the usefulness of
fluorescence in-situ hybridization in elucidating CCRs, and
discuss the possible correlation between the existence of a
chromosomal aberration and advanced paternal age.
Key words: complex chromosomal rearrangement/fluorescence
in-situ hybridization/mental retardation/reproduction/paternal
age
Introduction
Complex chromosomal rearrangements (CCRs) are defined as
reciprocal exchanges between three or more chromosomes.
They are rare events in human pathology and only about 100
CCRs have been reported as constitutional findings (Batista
et al., 1994). The involvement of several chromosomes and
the high number of breakpoints can make cytogenetic diagnosis
very difficult when classical banding techniques or highresolution
methods only are used. Here we report the molecular
study by fluorescence in–situ hybridization (FISH) of an
apparently balanced 4-chromosome CCR in an abnormal child.
Advanced paternal age, as a possible causal factor, is discussed.
Case report
The proband was a boy, born from a 29-year-old healthy
mother and from a 60-year-old father. The parents were
unrelated, and they already had a normal child. Pregnancy,
labour and delivery were uneventful; birthweight was 3830 g,
length 53 cm and head circumference 37 cm.
At 19 months, the child was referred for a psychomotor
retardation evaluation. He was 80 cm high and weighed
© European Society for Human Reproduction and Embryology 1801
10.1 kg (–1SD). He was hypotonic and he could neither stand
up nor walk. Speech was lacking. A mild facial dysmorphy
was noted, including a long face, a large nose with anteverted
nostrils, micrognathy, a pronounced philtrum, long teeth and
low set ears. There was neither visceral malformation nor
anomaly in standard laboratory investigations such as
electroencephalography, electromyography or skeletal X-ray
examination.
Cytogenetic investigations were performed on blood cell
cultures using R-banding and bromodeoxyuridine (BrdU)
incorporation. The karyotype revealed a complex chromosomal
rearrangement involving chromosomes 1, 5, 13 and 14 with
at least five breakpoints (Figure 1). Molecular study by FISH,
using whole chromosome paint probes (Biosys®, France),
allowed the precise identification, first, of a complex translocation
implicating the long arms of chromosomes 1, 5 and 13
and, second, of an insertion of a part of the long arm of
chromosome 13 into the long arm of chromosome 14 (Figure 1).
Therefore, the proband’s karyotype was apparently balanced,
46,XY,t(1;5;13)(q32.2;q14;q12).ish t(1;5;13)(wcp131; wcp11;
wcp51)ins(14;13)(q12.2;q12q31).ish ins (14;13)(wcp131;
wcp131).
The parents’ and brother’s karyotypes were normal even
after high-resolution cytogenetic techniques. According to this
result, no analysis by FISH was necessary in the parents.
In order to determine parental origin of this CCR, polymorphisms
of the 13 and 14 acrocentric chromosomes’ short
arms and of the secondary constriction of chromosome 1 were
analysed in the proband and his parents. Only the latter was
informative: indeed, parental chromosomes 1 were distinguishable
by the size of their secondary constrictions, and the
comparison with the translocated chromosome 1 in the proband
allowed us to assume that CCR had arisen during paternal
spermatogenesis (Figure 2).
Discussion
............................................
Since continual divisions of spermatogonia throughout adult
life may result in structural rearrangements of chromosomes
which may persist in a clone, it seems reasonable to consider
that pregnancies from elderly fathers, especially those who are
more than 50 years old, present genetically increased risk and
that fetal karyotype analyses can be proposed in these cases.