| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Case Report |
* Department of Dermatology;
Institute of Human Genetics and Anthropology,
University Medical Center Freiburg, Freiburg, Germany;
MVZ-Laboratory of Human Genetics, Munich,
Germany; and Andrologicum, Munich,
Germany.
| Correspondence to: Dr Markus Braun-Falco, Department of Dermatology, University of Freiburg, Hauptstraße 7, 79104 Freiburg, Germany (e-mail: markus.braun-falco{at}uniklinik-freiburg.de). |
| Received for publication November 10, 2006; accepted for publication March 22, 2007. |
Case Report
A 36-year-old man with azoospermia and a desire for children for 1.5 years
was referred to the andrological outpatient department. The andrological
history revealed surgery of the penis at age 3, and mumps infection without
complicating autoimmune orchitis. Detailed information about the surgery was
not available. Any infections or traumas in the genital area or undescended
testicles were denied. The patient was a nonsmoker and nonalcoholic and was
taking no regular medication. Physical examination of both testicles showed
elastic consistency and a volume of approximately 15 ml; the deferent ducts,
epididymides, and prostate were normal by palpation. There was a linear scar
on the skin of the penis that did not influence erections. Testicular
ultrasonography revealed a homogenous echo without signs of malignancy.
Bilateral Doppler ultrasonography of the plexus pampiniformis did not
demonstrate reflux during the Valsalva maneuver. A semen analysis after 5 days
of sexual abstinence, performed twice within 2 months according to the World
Health Organization guidelines
(1999), demonstrated
azoospermia with normal ejaculate volume (2.5 mL), pH 7.7, fructose level of
29.0 µmol/ejaculate, and liquefaction time of 20 minutes. Although the
levels of granulocyte elastase (1.038 ng/mL) and 
-glucosidase (22
mU/mL) in the seminal plasma were slightly abnormal, bacterial cultures
excluded genital infection with pathologic bacteria, gonococci or mycoplasma.
Seminal plasma IgA antibodies against Chlamydia trachomatis were not
elevated. The levels of follicle-stimulating hormone (FSH) were within normal
limits. A GTG-, CBG-banded cytogenetic analysis
(Figure 1) was performed and
demonstrated balanced (Y;1) translocation (ie, karyotype 46, X, t(Y;1)
(q12;q25), without deletions in the azoospermic-factor AZF a, b or c regions),
and 
F508 mutation of the CFTR gene (CFTR intron 8 poly-T: 7T/9T) at one
allele (heterozygous carrier of F508). The reported t(Y;1) (q12;q25)
was further characterized by fluorescent in situ hybridization (FISH) using
locus-specific probes DAZ (deleted in azoospermia), CDY (chromodomain Y), DYZ1
of Yq12, and the SYBL1 (X-Y) homologous region (pseudoautosomal region 2,
PAR2) at the long arms of the X and Y chromosomes, which clearly confirmed
that the breakpoint of the Y chromosome was located within the heterochromatin
area of Yq12 outside the AZF a, b or c regions
(Figure 2a and b). Bilateral
multiple testicular biopsies revealed almost identical alterations, namely
seminiferous tubules with slightly diminished diameters, thickened fibrous
membranes, and rarification of germinative epithelial tissues. Within the
tubules, one could observe spermatogonia, primary and secondary spermatocytes,
but no spermatids or spermatozoa, which led to a diagnosis of maturation
arrest of spermatogenesis at the level of secondary spermatocytes
(Figure 3).
|
|
|
Discussion
The patient presented herein with azoospermia and otherwise normal
phenotype displayed a de novo reciprocal translocation with breakpoints within
the heterochromatic region in Yq12 outside the AZF and at chromosome 1q25. To
our knowledge, a t(Y;1) (q12;q25) translocation has not been described to
date. We were able to find ten other cases with t(Y;1) translocations in the
literature (Table). Two of
these aberrations were unbalanced with a familial der(1) t(Y;1) (q12;p36)
translocation, which had been transmitted as a chromosomal variant through
males and females down several generations without affecting their phenotypes.
The male carriers had no reproductive problems, due to a normal Y chromosome,
while the women had repeated miscarriages, although they were de facto capable
of giving birth (Morel et al,
2002). Two other reports have described young children, primarily
with neurological symptoms, who had normal external genitalia
(Narahara et al, 1978;
Al-Awadi et al, 1985). The
remaining 6 cases and our case demonstrated spermatogenic arrest. The
translocation breakpoints in these cases were confined to the long arm of the
Y chromosome and were variable at chromosome 1. Two of the Y-breakpoints lay
within the euchromatic region at q11, whereas the others were localized to the
heterochromatin, and in one case to the telomere region. AZF regions a, b, and
c were investigated in 4 cases but no deletions were detected
(Maraschio et al, 1994;
Pabst et al, 2002;
Pinho et al, 2005). Concerning
the AZF regions, it has usually been assumed that male infertility results
from breakpoints within the AZF regions at Yq11, whereas males are fertile
when the breakpoints occur within the heterochromatin
(Vogt and Fernandes, 2003).
However, the azoospermia in the present case and the 3 cases mentioned above
was associated with breakpoints outside the AZF region
(Maraschio et al, 1994;
Pabst et al, 2002;
Pinho et al, 2005) and a
fertile male with breakpoint in the Yq11 euchromatic region
(Teyssier et al, 1993), which
demonstrates that this rule is not applicable to balanced reciprocal (Y,1)
translocations. In our clinical case, FISH analysis using a variety of probes
for DAZ, CDY, DYZ1, and PAR2 clearly revealed a breakpoint within the
heterochromatic region of Yq12. For Y;autosome translocations outside the AZF
region, a failure to form the sex vesicle due to unpairing of the Y and X
chromosomes has been suggested to inhibit homolog segregation and cause
spermatogenic arrest, and eventually spermatocyte degeneration
(Delobel et al, 1998;
Pabst et al, 2002;
Pinho et al, 2005). Since the
male-specific region of the Y chromosome has recently been characterized, the
detailed information about more than 150 transcription units inside and
outside the AZF region will help to identify distinct factors involved in
genetic spermatogenic arrest (Skaletsky,
2003).
|
In the (Y;1) translocation, Y breakpoints, as well as breakpoints in chromosome 1 obviously cause azoospermia. A male-specific infertility locus on chromosome 1 has been proposed recently (Bache et al, 2004). A large analysis comparing 464 infertile males to a cohort of 912 individuals with unique rearrangements covering almost all constitutional chromosomal abnormalities, conducted in Denmark over the last 40 years, has revealed a general excess of breakpoints on chromosome 1 associated with infertility. The regions that contributed most to the significant difference in distribution of breakpoints were 1q21, 1q32, 1q24, 1p22, and 1q12 in decreasing number and significance. This contrasts to the chromosome 1 breakpoints in our list of (Y;1) translocations, which were located at 1p11, 1p12, 1q11, 1q25, and twice at 1p34.3, respectively. This inconsistency does not necessarily exclude a pathological role of chromosome 1 in t(Y;1)-related azoospermia, although no concrete explanation currently exists for its influence (Bache et al, 2004).
In summary, the present case reveals a new de novo t(Y;1) translocation, with breakpoints in the heterochromatin of the Y chromosome outside the AZF region and in chromosome 1q25, which is associated with azoospermia.
References
Al-Awadi SA, Naguib KK, Farag T, Teebi AS, Cuschieri A, Al-Othman
SA, Sundareshan TS. Complex translocation involving chromosomes Y, 1, and 3
resulting in deletion of segment 3q23
q25. J Med
Genet. 1985;23: 91
-92.
Bache I, Assche EV, Cingoz S, Bugge M, Tumer Z, et al. An excess of chromosome 1 breakpoints in male infertility. Eur J Hum Genetics. 2004;12: 993 -1000.[CrossRef]
Delobel B, Djlelati R, Gabriel-Robez O, Croquette M-F, Rousseaux-Prevost R, Rousseaux J, Rigot J-M, Rumpler Y. Y-autosome translocation and infertility: usefulness of molecular, cytogenetic and meiotic studies. Hum Genet. 1998; 102: 98 -102.[CrossRef][Medline]
Gregori-Romero M, Lopez-Gines C, Gil R, Galan Sanchez F, Pellin-Perez A. Dos nuevos casos de translocacion Y-autosoma asociada con azoospermia. Rev Clin Esp. 1990; 187: 71 -73.[Medline]
Hsu LYF. Phenotype/karyotype correlations of Y chromosome aneuploidy with emphasis on structural aberrations in postnatally diagnosed cases. Am J Med Genet. 1994; 53: 108 -140.[CrossRef][Medline]
Maraschio P, Tupler R, Dainotti E, Cortinovis M, Tiepolo L. Molecular analysis of a human Y;1 translocation in an azoospermic male. Cytogenet Cell Genet. 1994; 65: 256 -260.[Medline]
Moreau N, Teyssier M, Rollet J. A new case of (Y;1) balanced
reciprocal translocation in an infertile man with Hodgkin's disease.
J Med Genet. 1987; 24: 379
-380.
Morel F, Douet-Guilbert N, Le Bris M-J, Amice V, Le Martelot MT, Roche S, Valéri A, Derrien V, Amice J, De Braekeleer M. Chromosomal abnormalities in couples undergoing intracytoplasmic sperm injection. A study of 370 couples and review of the literature. Int J Androl. 2004;27: 178 -182.[CrossRef][Medline]
Morel F, Duguépéroux I, McElreavey K, Le Bris M-J,
Herry A, Parent P, Le Martelot M-T, Fellous M, De Braekeleer M. Transmission
of an unbalanced (Y;1) translocation in Brittany, France. J Med
Genet. 2002;39: e52
.
Narahara K, Yabuuchi H, Kimura S, Kimoto H. A case of a reciprocal translocation between the Y and No 1 chromosome. Jpn J Hum Genet. 1978;23: 225 -231.[CrossRef]
Pabst B, Glaubitz R, Schalk T, Schneider U, Schulze W, Miller K. Reciprocal translocation between Y chromosome long arm euchromatin and the short arm of chromosome 1. Ann Gen. 2002; 45: 5 -8.
Pinho MJ, Neves R, Costa P, Ferras C, Sousa M, Alves C, Almeida C,
Fernandes S, Silva J, Ferras L, Barros A. Unique t(Y;1) (q12;q12) reciprocal
translocation with loss of the heterochromatic region of chromosome 1 in a
male with azoospermia due to meiotic arrest: a case report. Hum
Reprod. 2005;20: 689
-696.
Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature. 2003; 423: 825 -837.[CrossRef][Medline]
Teyssier M, Rafat A, Pugeat M. Case of (Y;1) familial translocation. Am J Med Genet. 1993; 46: 339 -340.[CrossRef][Medline]
Vogt PH, Fernandes S. Polymorphic DAZ gene family in polymorphic structure of AZF locus: artwork or functional for human spermatogenesis? APMIS. 2003;111: 115 -127.[CrossRef][Medline]
World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction. New York: Cambridge University Press; 1999.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
