XY sex reversal and gonadal dysgenesis due to 9p24 monosomy

We describe a case of XY sex reversal, gonadal dysgenesis, and gonadoblastoma in a patient with a deletion of 9p24 due to a familial translocation. The rearranged chromosome 9 was inherited from the father; the patient's karyotype was 46,XY,der(9)t(8;9)(p21;p24)pat. A review shows that 6 additional patients with 46,XY sex reversal associated with monosomy of the distal short arm of chromosome 9 have been observed. The observation that all 7 patients with sex reversal share a deletion of the distal short arm of chromosme 9 is consistent with the hypothesis that the region 9p24 contains a gene or genes necessary for male sex determination. This present case narrows the chromosome interval containing a critical sex determination gene to the relatively small region 9p24. A molecular analysis of this region will provide a means to identify a gene invoved in male sex determination. Am. J. Med. Genet. 73:321–326, 1997. © 1997 Wiley-Liss, Inc.     

Maternal translocation (9;18) with two abnormal offspring each with different chromosome derivatives.

We report a phenotypically normal woman with an apparently balanced reciprocal translocation between chromosomes 9 and 18 [46,XX,t(9;18)(p22;p11.2)], giving rise to unbalanced chromosome complements in two of her children, each of whom received a different derivative chromosome. The proband's karyotype is 46,XY,-18,+der(18), t(9;18)(p22;p11.2)mat, which results in a duplication of the distal portion of the short arm of chromosome 9 with a concomitant deletion of much of the short arm of chromosome 18. The karyotype of the proband's brother is 46, XY,-9,+der(9),t(9;18)(p22;p11.2)mat, which results in a deletion of the distal short arm of chromosome 9 and a duplication of most of the short arm of chromosome 18. The phenotype of each child is significantly different from that of his sib and is not consistent with any previously reported chromosome abnormality.     

A pericentric inversion of chromosome 9 and a rearrangement involving chromosomes 9 and 10, observed in two generations. Clinical description of chromosome 9 (p12-p21) deletion syndrome

The clinical picture associated with a deletion of a central part of the short arm of chromosome no. 9 is described in two siblings. The clinical signs differ from those described in deletion of the terminal part of the short arm. Pericentric inversion of chromosome no. 9, combined with a rearrangement involving chromosomes 9 and 10, was found in the mother and the maternal grandmother of the propositus.     

Prenatal Diagnosis of an Inherited Translocation Between Chromosomes No. 9 and 18

A phenotypically normal woman has an apparently balanced reciprocal translocation between chromosomes No. 9 and No. 18 (translocation 9p-; 18p+), which was transmitted in an unbalanced state to an infant and a fetus. In the latter instance, chromosome analysis of cultured amniotic cells disclosed an abnormal karyotype, which was identical to that of the first affected child. The therapeutically aborted fetus was grossly abnormal and resembled the affected child. The physical features noted are those frequently associated with chromosome abnormalities, although not diagnostic for any specific syndrome. We presume that the chromosome abnormality in the affected offspring represents partial duplication of the short arm of chromosome No. 9 and partial deletion of the short arm of chromosome No. 18. No marked resemblance is noted between these cases and reported cases of trisomy 9 or of partial deletion of the short arm of 18.     

Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA

The distal region on the short arm of chromosome 9 is of special interest for scientists interested in sex development as well as in the clinical phenotype of patients with the 9p deletion syndrome, characterized by mental retardation, trigonocephaly and other dysmorphic features. Specific genes responsible for different aspects of the phenotype have not been identified. Distal 9p deletions have also been reported in patients with 46,XY sex reversal, with or without 9p deletion syndrome. Within this region the strongest candidates for the gonadal dysgenesis phenotype are the DMRT genes; however, the genetic mechanism is not clear yet. Multiple ligation-dependent probe amplification represents a useful technique to evaluate submicroscopic interstitial or distal deletions that would help the definition of the minimal sex reversal region on 9p and could lead to the identification of gene(s) responsible of the 46,XY gonadal disorders of sex development (DSD). We designed a synthetic probe set that targets genes within the 9p23-9p24.3 region and analyzed a group of XY patients with impaired gonadal development. We characterized a deletion distal to the DMRT genes in a patient with isolated 46,XY gonadal DSD and narrowed down the breakpoint in a patient with a 46,XY del(9)(p23) karyotype with gonadal DSD and mild symptoms of 9p deletion syndrome. The results are compared with other patients described in the literature, and new aspects of sex reversal and the 9p deletion syndrome candidate regions are discussed.     

Schizophrenia and mental retardation in an adult male with a de novo interstitial deletion 9(q32q34.1).

A 28 year old man with mental retardation and therapeutically controlled schizophrenia was found to have a de novo interstitial deletion in the long arm of a chromosome 9 (46,XY,del(9)(q32q34.1). Additional phenotypic abnormalities included short stature, a short webbed neck with a low posterior hairline, dysmorphic facies, a narrow palate with an inverted V soft palate, and tapered fingers with bilateral short fifth metacarpals. Interstitial deletion of chromosome 9 is a rare finding and we are aware of only one other case involving the q32q34.1 region.     

Complex de novo rearrangement of chromosome 9 with clinical features of monosomy 9p syndrome

A girl with a complex rearrangement of chromosome 9 is reported. She shows the characteristic clinical features of monosomy 9p syndrome. The rearrangement was apparently preceded by four breaks which resulted in a presumptive tiny deletion of the distal end of the short arm, inversion of the rest of this arm and a proven deletion of the secondary constriction region of the long arm. By means of C-banding, it was possible to demonstrate the paternal origin of the rearranged chromosome 9. Finally, it is shown that the region determining the phenotypic expression of monosomy 9p syndrome is seemingly located at band 9p24.     

Chromosome 9p deletion syndrome and sex reversal: Novel findings and redefinition of the critically deleted regions

Deletions of the short arm of chromosome 9 are associated with two distinct clinical entities. Small telomeric 9p24.3 deletions cause genital anomalies in male subjects, ranging from disorder of gonadal sex to genital differentiation anomalies, while large terminal or interstitial deletions result in 9p-malformation syndrome phenotype. The critical region for non-syndromic 46,XY sex reversal was assigned to a 1?Mb interval of chromosome 9p, extending from the telomere to the DMRT genes cluster. The 9p-syndrome was assigned to bands 9p22.3p24.1, but a phenotypic map has not been established for this condition, probably because of the lack of detailed molecular and/or phenotypic characterization, as well as frequent involvement of additional chromosome rearrangements. Here, we describe a unique patient with a small isolated 9p terminal deletion, characterized by array-CGH and FISH, who shows a complex phenotype with multiple physical anomalies, resembling the 9p-syndrome, disorder of sex development with gonadoblastoma, congenital heart defect and epilepsy. The observed deletion includes the 46,XY sex-reversal critical region, excluding the region so far associated with the 9p-syndrome. Genotype-phenotype correlations are tentatively established comparing our patient to seven other previously reported males with isolated terminal 9p deletions, finely defined at a molecular level. Our observations expand the 9p deletion clinical spectrum, and add significantly to the definition of a 9p-syndrome critical region. ? 2012 Wiley Periodicals, Inc.     

dic(9; 20): A new recurrent chromosome abnormality in adult acute lymphoblastic leukemia

Loss of chromosome 20 and rearrangement of the short arm of chromosome 9 were identified by banding analysis of three adult patients with acute lymphoblastic leukemia (ALL). The G-banding pattern suggested and identical deletion of 9p, but, also, an unbalanced translocation with chromosome 20 was taken into consideration. Dual-color chromosome painting with probes for chromosomes 9 and 20 revealed the presence of material from chromosome 20 at the short arm of the abnormal chromosome 9 in all three cases. Centromeric alpha-satellite DNA of both chromosome 9 and chromosome 20 was demonstrated by fluorescence in situ hybridization and indicated the presence of a dicentric chromosome. The hybridization of a YAC clone of the short arm of chromosome 20 proved that the dicentric chromosome contained the short arm of chromosome 20, which had been suspected from the G-banding pattern. Thus, the rearrangement was interpreted as dic(9; 20)(pl I;qi I . ? I). Because this was the sole chromosome abnormality in two patients, dic(9; 20) may be a primary chromosome aberration in ALL. In one case, a 9q⁺ chromosome derived from a Philadelphia (Ph) translocation was involved in the formation of the dicentric chromosome. Immunophenotyping revealed CD 1o⁺ B-cell precursor ALL in all three cases. Whereas the two patients in whom dic(9; 20) was the sole cytogenetically detectable change are in continuous complete remission for 10 and 45 months, respectively, the Ph⁺ patient relapsed with leukemia and died 8 months after diagnosis. © 1995 Wiley-Liss, Inc.     

A complex rearrangement associated with sex reversal and the Wolf-Hirschhorn syndrome: a cytogenetic and molecular study.

We report a male infant referred with multiple congenital abnormalities consistent with the Wolf-Hirschhorn syndrome. Cytogenetic analysis showed a chromosome complement of 46,XX with a deletion of 4p15.2----4pter and its replacement by material of unknown origin. The patient was positive for a number of Yp probes including SRY, the testis determining factor, and in situ hybridisation localised the Yp material to the tip of the short arm of one X chromosome. Using pDP230, a probe for the pseudoautosomal region, and M27 beta, which recognises a locus in proximal Xp, the material translocated on to 4p was identified as originating from the short arm of the paternal X chromosome. The most reasonable explanation for this complex rearrangement is two separate exchange events involving both chromatids of Xp during paternal meiosis. An aberrant X-Y interchange gave rise to the sex reversal and an X;4 translocation resulted in additional, apparently active Xp material and a deletion of 4p which produced the Wolf-Hirschhorn phenotype.     

Double chromosome anomaly: Interstitial deletion 5q and reciprocal translocation (1;11) (p22;q21)

We describe a girl with multiple congenital abnormalities and developmental delay; her karyotype showed an apparently balanced translocation between the short arm of chromosome 1 and the long arm of chromosome 11, and an interstitial deletion of the long arm of chromosome 5 (q15q31). The clinical findings are compared with those described in other cases of 5q deletion, and the origin of the chromosome rearrangements is briefly discussed.     

Disappearance of a highly unusual clone, 46,XY,del(7)(p12),t(9;22)(q34;q11) in chronic myeloid leukemia after treatment with recombinant interferon and cytosine arabinoside.

A patient with the typical features of the stable phase of chronic myeloid leukemia (CML) displayed two karyotypically related subclones. In addition to the t(9;22), cells from one clone contained a deletion of the short arm of chromosome 7, del(7)(p12), [46,XY,del(7)(p12),t(9;22)(q34;q11)]; the other contained only the standard translocation [46,XY,t(9;22)(q34;q11)]. Cells with a deletion of the short arm of chromosome 7 at band p12 as the only additional abnormality have not been observed previously in CML. Conventional chemotherapy with hydroxyurea and then with recombinant interferon-alpha (rIFN-alpha) did not reduce the population of either subclone. However, after treatment with a combination of rIFN-alpha and low-dose cytosine arabinoside (LoDac) continuously infused subcutaneously (s.c.), cells from the clone with the deleted chromosome 7 disappeared and normal metaphases were demonstrable.     

A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators.

Deletion of the distal short arm of chromosome 9 (9p) has been reported in a number of cases to be associated with gonadal dysgenesis and XY sex reversal, suggesting that this region contains one or more genes required in two copies for normal testis development. Recent studies have greatly narrowed the interval containing this putative autosomal testis-determining gene(s) to the distal portion of 9p24.3. We previously identified DMRT1, a human gene with sequence similarity to genes that regulate the sexual development of nematodes and insects. These genes contain a novel DNA-binding domain, which we named the DM domain. DMRT1 maps to 9p24. 3 and in adults is expressed specifically in the testis. We have investigated the possible role of DM domain genes in 9p sex reversal. We identified a second DM domain gene, DMRT2, which also maps to 9p24.3. We found that point mutations in the coding region of DMRT1 and the DM domain of DMRT2 are not frequent in XY females. We showed by fluorescence in situ hybridization analysis that both genes are deleted in the smallest reported sex-reversing 9p deletion, suggesting that gonadal dysgenesis in 9p-deleted individuals might be due to combined hemizygosity of DMRT1 and DMRT2.     

Partial monosomy 7 with interstitial deletions in two infants with differing congenital abnormalities.

Two cases of interstitial deletion of chromosome 7 are presented, one involving the short arm and the other the long arm. The cytogenetic, dermatoglyphic, and clinical findings are compared with previously reported cases of chromosome 7 deletion. The patient with a short arm deletion differs clinically from the previously reported cases but, in common with a least one previous case, has a low total finger ridge count. His interstitial deletion involving the 7p13 leads to 7p21 region also differs from 7p deletions reported in earlier cases. The patient with a long arm deletion has an interstitial loss of the region between 7q11 and 7q21, corresponding to one of three groups of 7q deletion that have been recognised. The phenotypic changes in this group are less well defined than in the other two and the patient presented here differs clinically from the previously reported cases, apart from one phenotypically normal mosaic case, in lacking morphological abnormalities. He shares with one previous case both epilepsy and a high intensity of dermal ridge patterns.     

Sex reversal in a child with a 46,X,Yp+ karyotype: support for the existence of a gene(s), located in distal Xp, involved in testis formation.

We report on a sex reversed Japanese child with a 46,X,Yp+ karyotype, minor dysmorphic features, and no testicular development. The Yp+ chromosome was derived by translocation of an Xp fragment (Xp21-Xp22.3) to Yp11.3. This has resulted in deletion of distal part of the Y chromosome pseudoautosomal region (DXYS15-telomere) and duplication of the X specific region (DXS84-PABX) and proximal part of the pseudoautosomal region (MIC2-DXYS17). No deletion of the Y specific region was detected nor was any mutation found in SRY. Cytogenetic analysis suggests that the proximal part of the Xp fragment is the most distal part of the short arm of the Yp+ chromosome (Xp21----Xp 22.3::Yp11.3----Yqter). No chromosomal mosaicism was detected. These results are similar to previous reports of sex reversal in four subjects with a 46,Y,Xp+ karyotype. We conclude that the sex reversal is a direct, or indirect, consequence of having two active copies of the distal part of Xp and may indicate the presence of a gene(s) which acts in the testis determination or differentiation pathway.     

Telomere-telomere (end to end) fusion of chromosomes 7 and 22 with an interstitial deletion of chromosome 7p11.2-->p15.1: phenotypic consequences and possible mechanisms

We report a rare case of a de novo end to end fusion of chromosomes 7 and 22 in conjunction with an interstitial deletion of chromosome 7p11.2p15.1 in a newborn with congenital anomalies. The proband presented for chromosome analysis with bilateral cataracts, dysmorphic facies and distal limb abnormalities. Chromosome analysis showed a 45,XY,der(22)psu dic(22;7)(p13;p22.3)del(7)(p11.2p15.1) karyotype. This short arm to short arm fusion of chromosomes 7 and 22 resulted in a pseudodicentric chromosome. The interstitial deletion in the short arm of chromosome 7 was likely a result of breakage and reunion related to instability of the dicentric chromosome. Loss of genetic material in this region of chromosome 7p has been implicated in the pathophysiology of craniosynostosis and cephalopolysyndactyly syndromes.     

Analysis of tumor suppressor gene on human chromosome 9 in mouse x human somatic cell hybrids

Deletions of the short arm of human chromosome 9 (9p) are common in human leukemia and solid tumors. The minimum region of overlap of these deletions, located between the interferon genes and the methylthioadenosine phosphorylase gene, is partially syntenic with a region of mouse chromosome 4 that has tumor suppressor activity. Somatic cell hybrids between tumorigenic, MTAP-deficient, mouse L cells, and MTAP-competent human cells containing either a normal copy of 9p or a 9p with a deletion involving band 9p21 were selected in culture conditions that require MTAP activity for continued growth. Somatic cell hybrids that contained a normal copy of 9p rarely formed tumors in nude mice. Cells from the rare tumors that grew had lost the normal 9p. Hybrid cells that contained a 9p with deletions formed tumors more frequently, and cells from these tumors retained the 9p deletion chromosome. These results provide evidence that a tumor suppressor gene (or genes) is located on human chromosome 9 within the region of deletion.     

The deletion 9p syndrome. A 61-year-old man with deletion of short arm 9

Deletion of short arm 9 was found in a 61-year-old, mentally retarded male with few of the previously described signs typical of deletion of short arm 9 in children. A survey is given of the nine previously described cases of deletion of short arm 9.     

De novo interstitial deletion del(1)(p21p32).

A girl aged 14 years 9 months, overweight, with severe psychomotor retardation, short stature, a sheep-like face, malformed ears, skeletal and dermatoglyphic abnormalities, and partial deletion of the short arm of chromosome 1 is presented. The karyotype was 46,XX,del(1)(qter to p22::p32 to pter).