Gonadal dysgenesis in a patient with an X;3 translocation: case report and review.

A patient with primary amenorrhoea and absence of secondary sex characteristics was found to have a balanced X;3 translocation. This phenotype is reported in approximately one-third of the balanced X;autosome translocation cases. The normal X chromosome is inactive in the present case which is in agreement with most of the similar cases. A review of the 66 balanced X;autosome translocations reported to date is presented.     

X-short arm deletion gonadal dysgenesis in two siblings due to unique translocation (Xp-;16p+)

A family demonstrating short arm deletion of the X chromosome as a consequence of X-16 balanced translocation in the mother is reported. The two Xp- sisters exhibit clinical signs of gonadal dysgenesis, while the balanced carriers are phenotypically normal. To our knowledge this represents the only example of both the balanced carrier state for an X translocation and its genetic consequence occurring in the offspring, as well as the involvement of X-16 interchange. Literature data of 37 additional cases of verified X translocations are discussed.     

X-inactivation pattern in three cases of X/autosome translocation

We describe an X/15 translocation which was balanced in a phenotypically normal mother [46,X,t(X;15)(p22;q15)] and unbalanced in her phenotypically abnormal daughter [46,X,der(X),t(X;15)(p22;q15)mat]. A third case involves a balanced X/21 translocation in a girl with a multiple congenital anomaly-retardation syndrome [46,X,t(X;21)(p11;p11?)]. 5-BrdU acridine orange banding on lymphocytes revealed late replication of the normal X chromosome in the mother and of the normal or abnormal X chromosome in the two other cases. Our findings are only partially consistent with previous observations. All X-inactivation patterns can be explained by random inactivation and subsequent selection against specific cell lines. Furthermore, the findings in our patient with X/21 translocation support the hypothesis of the existence of one inactivation center on Xq.     

X;14 translocation: An exception to the critical region hypothesis on the human X-chromosome

We report on a family in which an X;14 translocation has been identified. A phenotypically normal female, carrier of an apparently balanced X-autosome translocation t(X;14) (q22;q24.3) in all her cells and a small interstitial deletion of band 15q 112 in some of her cells had 2 offspring. She represents a fifth case of balanced X-autosome translocation with the break point inside the postulated critical region of Xq(q13 q26) associated with fertility. The break point in this case is located in Xq22, the same band as in four previously published exceptional cases. In most of her cells, the normal X was inactivated. Her daughter, the proposita, has an unbalanced karyotype 46,X,der(X), t(X;14)(q22;q24.3)mat, del(15)(q11.1q11.3)mat. She is mildly retarded and has some Prader-Willi syndrome manifestations. She has two normal 14 chromosomes, der(X), and deletion 15q11.2. Her clinical abnormalities probably could be attributed to the deletions 15q and Xq rather than 14q duplication. In most of cells, der(X) was inactivated. We assume that spreading of inactivation was extended to the 14q segment on the derivative X. Late replication and gene dose studies support this view. Another daughter, who inherited the balanced X;14 translocation and not deletion 15 chromosome, is phenotypically normal.     

X;14 translocation:an exception to the critical region hypothesis on the human X-chromosome

We report on a family in which an X;14 translocation has been identified. A phenotypically normal female, carrier of an apparently balanced X-autosome translocation t(X;14)(q22;q24.3) in all her cells and a small interstitial deletion of band 15q112 in some of her cells had 2 offspring. She represents a fifth case of balanced X-autosome translocation with the break point inside the postulated critical region of Xq(q13 q26) associated with fertility. The break point in this case is located in Xq22, the same band as in four previously published exceptional cases. In most of her cells, the normal X was inactivated. Her daughter, the proposita, has an unbalanced karyotype 46,X,der(X), t(X;14)(q22;q24.3)mat, del(15)(q11.1q11.3)mat. She is mildly retarded and has some Prader-Willi syndrome manifestations. She has two normal 14 chromosomes, der(X), and deletion 15q11.2. Her clinical abnormalities probably could be attributed to the deletions 15q and Xq rather than 14q duplication. In most of cells, der(X) was inactivated. We assume that spreading of inactivation was extended to the 14q segment on the derivative X. Late replication and gene dose studies support this view. Another daughter, who inherited the balanced X;14 translocation and not deletion 15 chromosome, is phenotypically normal.     

X chromosome replication patterns in a case of X;9 balanced translocation.

A case of X;9 balanced translocation in a female with amenorrhoea is reported. The X breakpoint was at Xq21, inside the 'critical region'. The normal X was consistently late replicating in blood lymphocytes and skin and ovary fibroblasts.     

H-Y antigen expression in patients with X-autosomal translocations and gonadal dysgenesis

Cells from three patients with early gonadal failure and a balanced reciprocal translocation involving the long arm of the X chromosome and an autosome were studied. Fibroblasts from a patient with a similar balanced reciprocal translocation but normal reproductive capabilities were also studied. Two of the four patients were found to have serologically detectable H-Y antigen on their cells. Since H-Y antigen has been found on the cells of other patients with X chromosome abnormalities but without a Y chromosome, it is thought that the X chromosome plays a role in the regulation of H-Y antigen expression. This study suggests that the long arm of the X chromosome may be involved but the location of a regulatory gene cannot be identified in these studies. These cases do not permit us to implicate H-Y antigen as a cause of gonadal dysgenesis and early gonadal failure in females who have structurally abnormal X chromosomes.     

A balanced de novo X/autosome translocation in a girl with manifestations of Lowe syndrome

The Oculo-cerebro-renal syndrome of Lowe is an X-linked recessive disorder characterised by mental and growth retardation, renal rickets with renal tubular acidosis, generalised aminoaciduria, hypotonia, cataracts, glaucoma and frontal bossing. Manifestations of this syndrome were seen in a girl with no family history of the disorder, but who was found to have a de novo balanced X/3 translocation, with a breakpoint at Xq25. She had also inherited a balanced 14/17 translocation from her father. It is postulated that the clinical picture may be the result of disruption of the X chromosome within the gene at the locus for Lowe syndrome, with non-random inactivation of the normal X, which may permit the expression of this X-linked recessive disorder in a girl.     

Translocation X;9(q24;q34) in a girl with ovary dysfunction

A balanced de novo translocation X;9(q24;q34) was discovered in a 21-year-old girl with oligomenorrhoea. The structurally normal X was late replicating in all cells. The results indicate that an X chromosome breakpoint at q24 provokes ovary dysfunction.     

Noninactivation of a portion of Xq28 in a balanced X-autosome translocation

We present a balanced translocation (X;9) (q28;q21) in which the normal X chromosome is preferentially active. The derivative X chromosome is inactive in 93% of fibroblasts, but the X portion translocated onto chromosome 9 is not inactivated, as apparent from DNA methylation and chromosome replication patterns. Consequently, the patient is functionally disomic for the part of Xq28 distal to the locus LICAM.     

A de novo X;13 translocation with abnormal phenotype.

We describe a female infant who presented with hypotonia and developmental delay. Her karyotype showed a de novo balanced translocation between the X chromosome and chromosome 13, with breakpoints at Xq13 and 13p11. The normal X was late replicating in all cells examined. The cause of this patient's abnormal phenotype is discussed.     

Severe, neonatal-onset OTC deficiency in twin sisters with a de novo balanced reciprocal translocation t(X;5)(p21.1;q11)

OTC deficiency, the most common urea cycle defect, is transmitted as a partially dominant X-linked trait. The most severe form of the disease, however, is usually restricted to males. We report on monozygotic female twins with severe neonatal-onset OTC deficiency and a de novo balanced reciprocal translocation t(X;5)(p21.1;q11). Disruption of the OTC gene on the derivative X-chromosome was confirmed by FISH analysis. Consistent inactivation of the normal X could be demonstrated by RGB staining. Manifestation of X-linked recessive disorders in females due to a balanced reciprocal X-autosome translocation has previously been described in Duchenne muscular dystrophy and several other disorders but not in OTC deficiency. This report emphasizes the importance of chromosome analysis in any female manifesting severe OTC deficiency.     

PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus–Merzbacher disease in a girl

Fonseca ACS, Bonaldi A, Costa SS, Freitas MR, Kok F, Vianna‐Morgante AM. PLP1 duplication at the breakpoint regions of an apparently balanced t(X;22) translocation causes Pelizaeus–Merzbacher disease in a girl. PLP1 (proteolipid protein1 gene) mutations cause Pelizaeus–Merzbacher disease (PMD), characterized by hypomyelination of the central nervous system, and affecting almost exclusively males. We report on a girl with classical PMD who carries an apparently balanced translocation t(X;22)(q22;q13). By applying array‐based comparative genomic hybridization (a‐CGH), we detected duplications at 22q13 and Xq22, encompassing 487–546 kb and 543–611 kb, respectively. The additional copies were mapped by fluorescent in situ hybridization to the breakpoint regions, on the derivative X chromosome (22q13 duplicated segment) and on the derivative 22 chromosome (Xq22 duplicated segment). One of the 14 duplicated X‐chromosome genes was PLP1.The normal X chromosome was the inactive one in the majority of peripheral blood leukocytes, a pattern of inactivation that makes cells functionally balanced for the translocated segments. However, a copy of the PLP1 gene on the derivative chromosome 22, in addition to those on the X and der(X) chromosomes, resulted in two active copies of the gene, irrespective of the X‐inactivation pattern, thus causing PMD. This t(X;22) is the first constitutional human apparently balanced translocation with duplications from both involved chromosomes detected at the breakpoint regions.     

Cytogenetic and molecular investigation of a balanced Xq13q translocation in a patient with retinoblastoma

We report on a 4-year-old girl with retinoblastoma and de novo balanced translocation [46,X,t (X;13) (q23;q13)]. Unilateral retinoblastoma was discovered at age 9 months along with developmental delay and several manifestations of Turner syndrome. Chromosome studies showed an X/13 translocation and an X inactivation pattern showing the translocated X chromosome active in all 50 cells examined. Standard Southern blot analysis and pulsed field gel electrophoresis using a 3.8 kb EcoR1 fragment of the cDNA probe to the 3′ end of the RB1 locus demonstrated a normal genomic pattern. The results of the cytogenetic and molecular analysis suggests that the RB1 locus has not been disrupted by the chromosome rearrangement. This case is the fifth report of an X/13 translocation associated with a retinoblastoma.     

Mosaicism for a small marker chromosome resulting from a familial Robertsonian translocation (21;22)

Here we describe a group of 14 patients carrying different X-autosome translocations and exhibiting phenotypes that demonstrate the range of alterations induced by such aberrations. All male carriers of an X-autosome translocation in our investigation group were infertile, whereas fertility in the female carriers was dependent on the position of the break-point in the X chromosome. Fertile women with translocation break-points outside of the critical region (Xq13-q26) in some cases passed on the translocation to their offspring. In balanced female carriers in our group, the normal X chromosome was usually inactivated, allowing full expression of genes on the translocated segments. In one case, disruption of the dystrophine gene in Xp21 led to the manifestation of Duchenne muscular dystrophy in a female carrier. Inactivation of the derivative X (Xt) in a balanced female carrier led to a partial monosomy of the autosome/disomy of the X chromosome and resulted in an aberrant phenotype. In unbalanced carriers, Xt is generally late-replicating/inactive, although failed spreading of inactivation to the autosomal segment often results in a partial trisomy, as evidenced by the case of an unbalanced translocation carrier in our group.     

Cytogenetic and molecular investigation of a balanced Xq13q translocation in a patient with retinoblastoma.

We report on a 4-year-old girl with retinoblastoma and de novo balanced translocation [46,X,t (X;13) (q23;q13)]. Unilateral retinoblastoma was discovered at age 9 months along with developmental delay and several manifestations of Turner syndrome. Chromosome studies showed an X/13 translocation and an X inactivation pattern showing the translocated X chromosome active in all 50 cells examined. Standard Southern blot analysis and pulsed field gel electrophoresis using a 3.8 kb EcoR1 fragment of the cDNA probe to the 3' end of the RB1 locus demonstrated a normal genomic pattern. The results of the cytogenetic and molecular analysis suggests that the RB1 locus has not been disrupted by the chromosome rearrangement. This case is the fifth report of an X/13 translocation associated with a retinoblastoma.     

Preaxial acrofacial dysostosis (Nager syndrome) associated with an inherited and apparently balanced X;9 translocation: Prenatal and postnatal late replication studies

We report on an infant with preaxial acrofacial dysostosis (Nager syndrome) who was diagnosed prenatally as having an apparently balanced X/autosome translocation [46,X,t(X;9)(p22.1;q32)mat] inherited from a previously diagnosed mosaic translocation carrier mother [46,XX/46,X,t(X;9)(p22.1;q32)]. Replication studies on amniocytes showed the normal X chromosome to be late replicating while the same studies repeated on the infant's lymphocytes showed the translocated X chromosome to be late replicating in most cells. Late replication studies of the mother's lymphocytes demonstrated that the normal X chromosome was late replicating in most cells. The presence of Nager syndrome in this infant may be the result of critical break-points and/or position effects on chromosome 9, inducing expression of a gene responsible for the syndrome. © 1993 Wiley-Liss, Inc.     

Balanced X;15 translocation 46,X,t(X;15)(q21;q23) associated with primary amenorrhea

Cytogenetic studies on a woman with primary amenorrhea showed an X;15 translocation, karyotype 46,X,t(X;15)(q21;q23). Fifteen percent of the buccal cells showed a normal-sized sex chromatin body. The normal X chromosome was uniformly inactivated. Many balanced X;15 translocations have been reported; however, breakpoints in our patient differ from those reported previously. This case also supports earlier evidence that ovarian development fails when the breakpoint of the X chromosome is in the region X q13-q25 or q13-q27.     

X/autosome translocation in three generations ascertained through an infant with trisomy 16p due to failure of spreading of X-inactivation

We report on a reciprocal translocation t(X;16)(q28;p12) detected in a newborn girl with clinical manifestations of partial trisomy 16p. A balanced translocation was found in the mother and in the maternal grandmother. Replication studies on lymphocytes and fibroblasts showed nonrandom X-inactivation in both the patient and her mother. In the mother, the derivative X (der(X)) was active, whereas the normal X was late replicating. In contrast, in the patient the der(X) was late replicating, and there was no spreading of X-inactivation onto the autosomal segment, thus giving an explanation for the full clinical picture of partial trisomy 16p. © 1996 Wiley-Liss, Inc.     

Further evidence localising the gene for Hunter''s syndrome to the distal region of the X chromosome long arm.

Cytogenetic re-evaluation of a fibroblast cell line from a female Hunter's syndrome case with a balanced X;autosome translocation, which had previously been reported to have a breakpoint in Xq26 to Xq27, showed the breakpoint to be either between Xq27 and Xq28 or within Xq28. The normal X chromosome was preferentially inactivated, supporting the view that the translocation had disrupted the Hunter gene. The new localisation is now in full agreement with our previous linkage work and other published data. Results of further linkage studies using probes defining the loci DXS86, DXS144, DXS100, DXS102, DXS105, F8C, and DXS134 are also consistent with our original conclusion that the Hunter locus lies within the distal region of the X chromosome long arm.