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CASE REPORT
Objective: To report the inheritance of a pericentric inversion in chromosome 7 through the three progenies,
congenital hydronephrosis, and recurrent miscarriages in an extended family.
Design: Case report.
Setting: Medical Faculty of Cukurova University in Turkey.
Patient(s): Referred by obstetrics and gynecology clinic.
Intervention(s): Fetal urine and lymphocytic karyotype.
Main Outcome Measure(s): Chromosomal analysis from fetal urine and peripheral blood lymphocytes were
performed according to standard cytogenetic methods.
Result(s): We assessed an extended family in which a large pericentric inversion in chromosome 7 is segregating;
one of the three progenies with the karyotype 46,XY,inv(7)(p22;q22) was heterozygote for the inversion and pre-
sented with congenital hydronephrosis. His mother, mother’s brother, grandfather, grandfather’s brother, and his
daughter were similar for the inversion.
Conclusion(s): This case describes the further molecular characterization of these breakpoints on the short or long
arm of chromosome 7(p22-q22). The inv(7) is also associated with fetal wastage and may be playing a role in the
etiology of the family’s miscarriages. These findings can be used in clinical genetics and may be an effective tool
for reproductive guidance and genetic counseling. (Fertil Steril 2007;-:-–-. 2007 by American Society for
Reproductive Medicine.)
Key Words: Congenital hydronephrosis, recurrent miscarriages, fetal urine, cytogenetic diagnosis, pericentric
inversion 7
Inversions are among the least frequent chromosomal rear- been reported; some were ascertained because of abnormal
rangements in newborns, with an incidence of 0.012%. recombinant children and others exhibited generations of
This is the lowest incidence among the four types of chromo- only balanced and normal offspring (2). Empiric studies
somal abnormalities. Theoretically, there are three possible have suggested that a carrier of a pericentric inversion can
types of gametes: one with normal balanced inversion, one have a liveborn child with abnormal chromosomes. Overall,
with a duplication of the inverted long-arm material and a de- the risk of a carrier with a pericentric inversion producing
letion of the short-arm chromatin, and one with duplication of a child with an unbalanced karyotype is 1%–10% (3). Famil-
the short-arm material and a deletion of the long-arm chro- ial rearrangements involving chromosome 7 have been
matin (1). Gametes with the unbalanced inversion may cause reported infrequently. The majority of children with unbal-
spontaneous fetal death and malformed offspring. Many dif- anced karyotypes from such families have small deletions
ferent pericentric inversions (a chromosomal defect in which of the distal portion of 7q or duplications of distal 7p. Loss
a segment of the chromosome including the centromere of heterozygosity studies have implicated 7q22 in uterine
breaks off and reattaches in the reverse direction) have leiomyoma (4–6).
We observed a family with a pericentric inversion in chro-
Received September 1, 2006; revised and accepted February 9, 2007. mosome 7[inv(7)(p22;q22)] for three generations with only
kur, Emekli Sandıg
Supported by health societies (SSK, Bag ı). one liveborn infant with congenital hydronephrosis, which
Reprint requests: Osman Demirhan, Ph.D., Department of Medical Biol-
resulted from a maternal inversion; in addition, there were
ogy and Genetics, Faculty of Medicine, University of Cukurova, 01330
Adana, Balcali, Turkey (FAX: 90-322-338-65-72; E-mail: osdemir@cu. two previous consecutive early abortions and five healthy
edu.tr). individuals. Congenital hydronephrosis, one of the most
FIGURE 1
Pedigree of the family.
1.e2 Demirhan et al. Inheritance of pericentric inversion in chromosome 7 Vol. -, No. -, - 2007
ARTICLE IN PRESS
FIGURE 2 FIGURE 3
Gross appearance of the proband. Ultrasonography demonstrating a coronal view of
the proband back, showing marked hydronephrosis
of the left kidney.
inv(7)(p22;q22) were found in the karyotypes of the mother, cle. It has been reported that abortions mostly are caused by
mother’s brother, grandfather, grandfather’s brother, and his balanced translocations (9). Theoretically, this inversion in-
daughter (Fig. 4A and B). This showed that the pericentric in- volves <1% of the haploid autosomal length, and therefore
version of the fetus was derived from chromosome 7 of the a fetus with either a duplication or deletion is likely to be vi-
mother, which was also derived from her father. able unless essential genes in this segment are present that are
deleterious in an aneuploid conceptus. A phenotypically nor-
Chromosomal analyses also were performed for the grand-
mal mother and her child with hydronephrosis, mother’s
father’s sister (II-2) and brother (II-7), for his daughter (III-
brother, grandfather, grandfather’s brother, and his daughter
16), and for the husband (II-8). The grandfather’s sister,
were shown to have the inversion in chromosome 7 (Fig.
who had two spontaneous abortions, had a normal karyotype,
1). Here we presented balanced and unbalanced rearrange-
but the grandfather’s brother, whose wife had one spontane-
ments of chromosome 7 in conceptuses of a phenotypically
ous abortion, and his daughter (III-16) had the pericentric
normal mother, mother’s brother, grandfather, grandfather’s
inversion (Fig. 1).
brother, and his daughter.
As we have reported in this article, the proband, the third
DISCUSSION
pregnancy of the family, is phenotypically normal but has
Carriers of large pericentric inversions are at risk for meiotic a balanced inversion involving chromosome 7. This rear-
recombination within the inverted segment, resulting in du- rangement was performed in the heterozygous state and
plication or deletion of chromosomes in the gametes (2). In- was apparently harmonized with the mother’s. This type of
versions are among the least frequent chromosome inversion is not known to be associated with any clinical ef-
rearrangements in the newborn, with an incidence of fect because there is no genetic material lost. At the same
0.012% (1). Among the pericentric inversions, those of chro- time, the balanced carrier offspring are complementary mei-
mosome 7 are not frequent in males (4.3%–6.2% of all peri- otic products that usually lead to a normal phenotype (12).
centric inversion) (10, 11). The unbalanced inversion in Therefore, this situation can be accepted as a normal variant,
gametes may cause spontaneous fetal death and malformed harmless or asymptomatic. However, the prenatal and postna-
offspring. In our study, spontaneous abortions of individuals tal karyotypes of the newborn infant were the same as the
with inversion in chromosome 7 could be related to the unbal- mother’s [46,XY,inv(7)(p22;q22)], and he was not healthy
anced inversion in gametes. Liveborn individuals with rear- (noted hydronephrosis). If the chromosome behaves normally
ranged chromosomes have been reported in offspring of an during the meiotic divisions, half of the gametes receive a nor-
inv(7) carrier. Overall, the risk that a carrier of a pericentric mal chromosome, and the other half, a chromosome with the
inversion will produce a child with an unbalanced karyotype duplication (13). These showed that the offspring receive the
is 1%–10% (3). Here, we presented a segregation of a bal- gamete that has the inversion from the mother.
anced inversion in chromosome 7 [inv(7)(p22;q22)] of a phe-
notypically normal mother that led to one offspring with Antenatal diagnosis of a solitary kidney of the proband
a viable balance and two abortions with unbalanced outcome. was performed at 27 weeks’ gestation. This is the first re-
The inversion was present also in her brother, father, and un- ported case of the association of inversion 7 with congenital
1.e4 Demirhan et al. Inheritance of pericentric inversion in chromosome 7 Vol. -, No. -, - 2007
ARTICLE IN PRESS
hydronephrosis. Complete assessment of the malformation very early spontaneous abortions of unbalanced conceptuses.
showed a left hydronephrosis caused by a mega ureter. Con- The pericentric inversions are associated with fetal wastage
genital hydronephrosis is one of the most common problems and may play a role in the etiology of the other miscarriages
confronting pediatric urologists and frequently shown by of the family, because the absence of evidence of recombina-
prenatal diagnosis, often seen at the second trimester. The tion in inverted chromosomes could be related to the location,
newborn evaluation for hydronephrosis may be time con- within the duplicated/deleted regions, of dosage-sensitive
suming, invasive, and costly; however, it can often prevent loci that affect the viability of an embryo when they are pres-
sequela from congenital uropathy. Hydronephrosis may be ent in an unbalanced state. Sherman et al. (11) reviewed 216
defined as an abnormal dilation of the renal pelvis and/or pedigrees with pericentric inversions and found the recur-
calyces, accompanied afterward by changes in the renal pa- rence risk to be 6.9%. Daniel et al. (27) suggested a 10%–
renchyma. Renal function of the unique kidney with hydro- 15% risk for carriers with short segments of chromosomal
nephrosis can be diagnosed early and promptly treated. material distal to the ends of the inversion. In our study, a phe-
When hydronephrosis is diagnosed prenatally, it is called notypically normal mother and grandmother with a history of
fetal hydronephrosis. A strong correlation has been estab- multiple miscarriages could also be related to the pericentric
lished between prenatally detected hydronephrosis and post- inversion of chromosome 7, which may be the reason for the
natal genitourinary pathology, but this correlation is not previous consecutive early abortions. Perhaps the large size
perfect (14). Hydronephrosis also has an association with an- of the inversion in this family, with predisposition to very
euploidy and is a component of several well-described syn- short duplicated and/or deleted segments in the affected chil-
dromes. Clinically, interstitial fibrosis and renal atrophy are dren, led to a high survival rate for these individuals. Pro-
common outcomes of long-term urethral obstruction. band’s mother was counseled for the prenatal diagnosis in
Recently, growth factors such as transforming growth fac- the next pregnancy. Theoretically, for a carrier of a pericentric
tor-b and epidermal growth factor have been reported to inversion, the risk of producing a child with an unbalanced
play a role in the development and progression of fibrotic karyotype is 1%–10% (3). The detection of couples with
and sclerotic changes in the obstructed kidney (15). It has chromosomal anomalies can undoubtedly help to prevent
been suggested that the epithelial-to-mesenchymal transition the births of malformed infants.
is a major factor leading to renal fibrosis at congenital hydro-
In conclusion, our findings suggest heterogeneity for the
nephrosis in children. The kidney is a major site of production
breakpoint in bands 7p22 and 7q22. Furthermore, molecu-
of epidermal growth factor (16). Epidermal growth factor ap-
lar studies may help to find genes in the 7p–q critical re-
pears to have several important functions in the modulation of
gions that are involved in the pathogenesis and lead to
renal growth, glomerular hemodynamics, renal metabolism,
the identification of the disease. However, for couples
tubular transport, and eicosanoid synthesis (17). Furthermore,
with any known chromosomal rearrangements, prenatal di-
epidermal growth factor appears to govern renal cell prolifer-
agnosis is essential if a viable offspring with an abnormal
ation during fetal life (18). Documentation of unique kidney
clinical outcome is likely. It is also recommended that
renal function early in pregnancy can be helpful in defining
cases of clinically normal individuals with unbalanced kar-
prenatal management and therefore in improving prognosis.
yotypes be published, so that an informed decision can be
Live-born individuals with rearranged chromosomes have made by parents prenatally when a similar rearrangement is
been reported in five offspring of carriers of an inv(7) (19, identified. Studies with more cases may help to delineate
20). Two of these were duplicated for a short-arm segment the inv(7)(p22;q22) phenotype.
(21, 22). Cytogenetic analyses and molecular loss of hetero-
zygosity studies suggest that chromosome band 7q22 is a crit-
ical region that is associated with 7q malignant myeloid
disorders (23–25). In a reported case (26), the mother had REFERENCES
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1.e6 Demirhan et al. Inheritance of pericentric inversion in chromosome 7 Vol. -, No. -, - 2007