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A Rare Case: Non-Syndromic 46,XX Testicular DSD with Derivative Autosome

A Rare Case: Non-Syndromic  46,XX Testicular DSD with  Derivative Autosome

*Banu SG,1 Habib S,2 Islam SS,3 Bhuiyan AZ4

Abstract

46,XX testicular disorder of sex development (DSD) is a known cause of male infertility. Derivative chromosomes formed by complex rearrangements and translocations between two or more autosomes are also found to play role in male and female infertility in different studies. Combinations of sex chromosomal DSD and derivative autosomes are rare and unique. We report a case of 46,XX testicular DSD with a derivative autosome formed by rearrangement between chromosomes 2 and 3. The person was phenotypically normal (non-syndromic) with only complaint of infertility.

[Journal of Histopathology and Cytopathology, 2018 Jul; 2 (2):162-167]

Key words: 46, XX testicular DSD, derivative chromosome, infertility

 

  1. *Dr. Sultana Gulshana Banu, Associate Professor, Department of Pathology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka. sgbanu.bsmmu@gmail.com
  2. Saequa Habib, Associate Professor, Department of Pathology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka.
  3. SM Shahedul Islam, Scientific Officer, Department of Pathology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka.
  4. ARM Zakaria Bhuiyan, Resident, MD Pathology, Department of pathology,Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka.

*For correspondence

Introduction

Disorder of sex development (DSD) is a congenital condition where there is a disagreement between chromosomal, gonadal and phenotypic  sex.1 The discrepancies  among  these three determinants are highly variable and depend on patients’ cytogenetic and molecular abnormalities.2 The Chicago Consensus Nomenclature (2005) divides DSD into three broad categories: sex chromosomal DSD, 46,XY DSD and 46,XX DSD. Each of these has subclassifications with defined characteristics. Non-syndromic 46XX testicular DSD is a subclass of 46,XX DSD in which the person is phenotypically male and possesses testes.3 These individuals, though are deficient of a Y chromosome, have SRY (sex-determining region on Y) gene in one of the X chromosomes. This SRY gene induces development of testes that are, however, often smaller in size with impairment of spermatogenesis of varying degrees. As a result the persons are infertile though otherwise normal.4 The mechanisms underlying SRY-positive 46,XX testicular DSD are understood by multiple studies.5,6

A derivative chromosome (der) is a structurally rearranged chromosome generated either by a rearrangement involving two or more chromosomes, or by multiple aberrations within a single chromosome. The term always refers to the chromosome that has an intact centromere.7 The structural  changes involving autosomes, in different studies, are also seen to be associated with male and female infertility.8-11

We report a case of male infertility  with a combination of 46,XX testicular DSD and a derivative autosome formed by rearrangement between chromosomes 2 and 3. To our knowledge, no report has been published so far with this unique combination.

Case Report

A 30 year old male person and his 26 year old wife attended the Gynaecology Outdoor, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka with the complaint of infertility. On query, they revealed that they had been married for four years and had not been using any contraceptive. Their past and present medical history, family history and drug history were non-contributory. The wife was examined physically in the Gynaecology Outdoor and no abnormality was detected. She was advised an ultrasonography of pelvic organs, thyroid function tests, and assay of sex hormones (oestrogen, progesterone) and their trophic hormones (follicle stimulating hormone and luteinizing hormone). The husband was advised semen analysis, ultrasonography of the testes, serum levels of testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH).

The reports of investigations of the wife were normal. Those of the husband revealed azoospermia, small-sized testes with heterogenous echotexture on ultrasonography, low serum level of testosterone and high LH. His thyroid function tests, however, were normal. The couple was next advised karyotyping to find out chromosomal abnormality if any. They were referred to the department of Pathology, BSMMU.

The wife’s karyotype was found normal with normal autosomes and sex chromosomes (46,XX). The husband was found having abnormalities in both autosomes and sex chromosomes. His karyotype showed two X chromosomes and a large derivative chromosome which appeared a long chromosome 2 with attached extra portion to its long arm. The extra portion was recognized as the long arm of chromosome 3. The karyogram also showed single normal second and single normal third chromosome. The other chromosome 3 was clearly deficient of its long arm and consisted only of the short arm. We reported the karyotype as 46, XX + der(2)t(2;3) (qter;q). The man was advised a FISH (fluorescence in situ hybridization) to study the breakpoints of the involved chromosomes; however, he did not come for a follow-up and we could not get further information.

Figure 1. Photomicrograph of a chromosome spread showing a derivative autosome formed of chromosomes 2 and 3 (black arrow), one normal chromosome 2 and one normal chromosome 3 (white arrows). The spread also shows two X chromosomes (in ellipses) and short arm of the other chromosome 3 (star).

Figure 2. Karyogram of the study case: 46, XX, der(2)t(2;3) (qter;q).

Discussion

Male infertily can result from a variety of genetic, chromosomal, developmental, hormonal and other causes like infections. There are a number of genetic and chromosomal aberrations related to male infertility. Disorders of sex development (DSD) are a group of sex chromosomal aberrations commonly associated with male and female infertility. Though the DSD categories usually show varying degrees of genital and other phenotypic  abnormalities, the 46,XX testicular DSD subgroup males are sometimes phenotypically normal with mere complaints of infertility.4,5 On examination, however, these persons often show small testes and different levels of cryptorchidism. Impairment of spermatogenesis ranges from oligo-, through astheno- and teratozoospermia to complete azoospermia.5 The testicular development in these Y-deficient individuals is instructed by the SRY (sex-determining region on Y) gene present in the paternally derived X chromosome. The SRY gene which is normally located in Y chromosome, is generally misplaced on to the X chromosome in the affected person’s father during  formation of sperm cells. This occurs in a random fashion by an abnormal exchange of genetic material between the chromosomes (translocation).4,6

 

Among the structural chromosomal abnormalities, complex rearrangements involving sex chromosomes and/or autosomes in various combinations are seen. Derivative chromosomes formed by reciprocal translocations between autosomes are found associated with both male and female infertility.7,8 These are, however, rare in humans. Relatively commoner are rearrangements within Y chromosome (deletions, inversions, insertions) in males and within chromosome 9 in both males and females.9

Other reported patterns are very rare and appear unique events. Lauricella SA, et al (2016) found an infertile mosaic woman with a karyotype  45,XX,der(18)t(18;21)(p11;q21)-21/46,XX,t(18;21)(p11;q21). 86% of her cell lines showed 45,XX-21 pattern and only 14% showed 46,XX pattern containing the derivative (18 & 21) chromosome. This is explained by the marked instability of the derivative chromosomes which can be reduced in size or disappear during karyotype evolution. The authors also explained the patient’s infertility despite having two X chromosomes by the possibility of formation of a high risk offspring affected by an unbalanced chromosomal disorder (deletion or duplication of chromosomes 18 and 21) that might had been eliminated every time of attempted conception.

The patient of the present report is already an XX male; however, the unbalanced derivative (2 & 3) chromosome he possesses can be explained similarly in having a role in his infertility. Song SH, et al (2011) found impaired spermatogenesis ranging from oligo-, astheno-, teratozoospermia to complete azoospermia in their male subjects with complex chromosomal rearrangements (CCRs) of various combinations. Among their 10 cases, there were inversions within chromosome 3, complex translocations between chromosomes 2, 7 and 4, and between chromosomes 2, 19 and 22, and also other patterns. All these cases, however, possessed normal male sex chromosomes, that is 46, XY.

Other similar studies on autosomal rearrangements producing derivative autosomes also showed association with male infertility.10,11

Conclusion

Cases of male and female infertility are best investigated through a multidisciplinary approach involving cytogenetic, molecular, hormonal, histopathological and imaging studies. With cytogenetic study, rare sex chromosomal and autosomal rearrangements forming derivative chromosomes should be kept in mind for proper evaluation.

References

  1. Chan AOK, But WM, Lee CY, Lam YY. Aetiological bases of 46, XY disorders of sex development in the Hong Kong Chinese population. Hong Kong Med J. 2015; (21): 499-510.
  2. Tian L, Chen M, Peng JH, Jhang JW, Li L. Clinical characteristics, cytogenetic and molecular findings in patients with disorders of sex development. J Huazhong Univ Sci Technol [Med Sci]. 2014; 34(1): 81-86.
  3. Hughes IA. Disorders of sex development : a new definition and classification. Best Pract Res Clin Endocrinol 2008; 22(1): 119-134.
  4. Délot EC, Vilain EJ. Nonsyndromic 46, XX testicular disorders of sex development. 2003 Oct 30 [Updated 2015 May 7]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews [Internet], Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/book/NBK1416/
  5. Barseghyan H, Délot EC, Vilain EJ. New genomic technologies: an aid for diagnosis of disorders of sex development. Horm Metab Res. 2015; 47: 312-320.
  6. Grinspon RP, Rey RA. Disorders of sex development with testicular differentiation in SRY-negative 46, XX individuals: Clinical and genetic aspects. Sex Dev. 2016; 10: 1-11.
  7. Simons A, Shaffer LG, Hastings RJ. Cytogenetic nomenclature: Changes in the ISCN 2013 compared to the 2009 edition. Cytogenet Genome Res. 2013; 141: 1-6.
  8. Lauricella SA, Buse M, Cavani S, Cuttaia HC, Malacarne M, Mazara MV, et al. A rare complex structural chromosomal anomaly in mosaic due to the instability of a derivative chromosome 18 in a female infertile patient. J Down Syndr Chr Abnorm. 2016; 2: 110. Doi: 10.4172/2472-1115.1000110.
  9. Kim JW, Chang EM, Song SH, Park SH, Yoon TK, Shim SH. Complex chromosomal rearrangements in infertile males: complexity of rearrangements affects spermatogenesis. Fertil Steril. 2011; 95(1): 349-352.e5.
  10. Ergul E, Liehr T, Mrasek K, Sazci A. A de novo complex chromosome rearrangement involving three chromosomes (2,13 and 18) in an oligospermic male. (e9-e12) Fertil Steril. 2009; 92: 391.
  11. Coco R, Rahn MI, Estanga PG, Antonioli G, Solari AJ. A constitutional complex chromosomal rearrangement involving meiotic arrest in an azoospermic male: case report. Hum Reprod. 2004; 19: 2784-2790.
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Paraneoplastic Pemphigus-Mixed Bullous Disease Type –Report of a Rare Blistering Condition with IgA Deposition

Paraneoplastic Pemphigus-Mixed Bullous Disease Type –Report of a Rare Blistering Condition with IgA Deposition

*Kabir AN,1 Kamal M,2  Das RK3

Abstract

A male patient of 55 years with generalized lymphadenopathy was diagnosed as Non-Hodgkin’s lymphoma. After treatment with four cycles of combined chemotherapy of Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisolon (CHOP) the patient developed blistering lesions all over the body. Histological examination of lesional skin showed both suprabasal and subepidermal bullae. Direct immunofluorescence (DIF) test of perilesional skin revealed linear deposition of IgA, C3 and fibrin along the basement membrane zone (BMZ); and deposition of IgG both in the epidermal intercellular substance and along BMZ. Indirect immunofluorescence (IIF) test using patient’s serum on normal human skin and Long-Evans rat urinary bladder showed linear deposition of circulating IgA along the BMZ. Protein electrophoresis on cellulose acetate membrane showed increased Gamma globulin fraction. This is a case of paraneoplastic pemphigus-mixed bullous disease type showing strong reactivity to IgA, which has not been described in literature.

[Journal of Histopathology and Cytopathology, 2018 Jul; 2 (2):157-161]

Keywords: Pemphigus, paraneoplastic, mixed bullous disease

Introduction

The term ‘pemphigus’ refers to mucocutaneous diseases that are characterized by intraepithelial blisters, caused by a loss of normal cell-cell adhesion  (acantholysis), and are associated with autoantibodies against cell-surface proteins of stratified squamous epithelium.1 Blisters in patient with high titres of autoantibody with underlying neoplasms, most frequently lymphoma, are referred as paranneoplastic pemphigus. A case with clinical features, histologic and immunofluorescence abnormalities of pemphigoid and pemphigus with IgM paraprotein having underlying cancer was described as paraneoplastic mixed bullous disease.2 A patient with paraneoplastic pemphigus-mixed bullous disease type showing strong reactivity to IgA is presented below.

  1. *Dr. AKM Nurul Kabir, Associate Professor, Department of Pathology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. kabir56@gmail.com
  2. Mohammed Kamal, Professor, Department of Pathology Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh.
  3. Ruhini Kumar Das, Professor and Head of Pathology, M Abdur Rahim Medical College, Dinajpur.

 

*For correspondence

Case History

A 55 years old man from Munshiganj district, Bangladesh was admitted at the Medicine ward of the Bangabandhu Sheikh Mujib Medical University (BSMMU) Hospital, Dhaka on the 23rd June 2001 with complaints of multiple neck and axillary swellings. Physical examination of the patient revealed mild anaemia with generalized lymphadenopathy. The lymph nodes were discrete and non-tender.

The laboratory investigations showed haemoglobin 9.5 g/dL, platelet count 300×109/L, blood urea 22 mg/dL and serum creatinine  0.7 mg/dL. X- Ray Chest (P/A view) showed left sided pleural effusion but sputum for AFB was negative and Tuberculin test also was insignificant. Ultrasonography of whole abdomen revealed lymphadenopathy. Fine needle aspiration cytology (FNAC) of cervical lymph node (June 26, 2001) showed features of non-Hodgkin’s lymphoma (NHL), small cell type, and subsequently by histopathological examination of left axillary node confirmed as NHL, low grade (July 08, 2001).

The patient was treated with four cycles of Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisolon (CHOP) and six month later he presented with vesiculo-bullous lesion all over the body and clinically was suspected as a case of paraneoplastic pemphigus (Figure 1).

Histopathological tests done from lesional and perilesional skin for routine examination and direct immunofluorescence (DIF) test, respectively. Routine Hematoxylin and Eosin (H & E) stained sections revealed suprabasal clefts with few acantholytic cells and a small subepidermal bulla containing fibrin, neutorphils and small number of eosinophils (Figure 2 & 3). On DIF test, cryostat sections incubated with rabbit antihuman sera conjugated with FITC made by Medic Italy, showed linear deposits of IgA (++), C3 (+), fibrin (+) and focal deposits of IgM at basement membrane zone (BMZ). Faint deposits of IgG at BMZ and in epidermal intercellular substance were also seen. In indirect immunofluorescence (IIF) test, incubation of normal human skin with serum of the patient showed strong linear deposition of IgA and faint deposit of IgM along the BMZ. IIF test on Long-Evans rat urinary bladder sections also showed linear deposition of IgA along the BMZ (Figure 4). Protein electrophoresis on cellulose acetate membrane at pH 8.8 revealed  raised gamma globulin level (27% , normal 12-18%).

 

 

Discussion

Pemphigus  is the disease, characterized by intraepithelial blisters, caused by a loss of normal cell-cell adhesion, and are associated with autoantibodies against cell-surface proteins of stratified squamous epithelia. Anhalt et al1 first described paraneoplastic pemphigus in 1990. The authors reported five patients with underlying neoplasms, who developed oral erosions and bullous skin eruptions and described as paraneoplastic pemphigus. They suggested five criteria to define paraneoplastic pemphigus 1)  Painful mucosal erosions, sometimes with a skin eruption that eventually results in blisters and erosions, in the setting of confirmed or occult malignancy 2) Histopathologic changes of acantholysis, keratinocyte necrosis, and interface dermatitis 3) DIF observation of immunoreactants, typically IgG and complement (C3) within the epidermal intercellular space as well as at the epidermal basement membrane 4) IIF observation of circulating antibodies specific for stratified squamous or transitional epithelia 5) Immunoprecipitation of a complex of proteins with molecular weights of 250, 230, 210 and 190-kd. The 250-kd and 230-kd antigens correspond with desmoplakin- I and bullous pemphigoid antigen respectively. Identities of 210-kd and 190-kd antigens were not known.  They used rodent urinary bladder epithelium for the screening of paraneoplastic pemphigus as antigens of pemphigus vulgaris and pemphigus foliaceus are not expressed in this tissue. Later in 1993 Camisa and colleague proposed major and minor criteria for the diagnosis of neoplasia induced pemphigus.3

 

These are:

Major criteria

Polymorphous muco-cutaneous eruption

Concurrent internal neoplasia.

Characteristic serum immunoprecipitation findings

Minor criteria

Positive cytoplasmic staining of rat bladder epithelium by IIF

Intercellular and basement zone immunoreactants on DIF of perilesional tissue.

Acantholysis in biopsy specimen from at least one anatomical site of involvement.

A patient should be considered to have the neoplasia induced pemphigus if all three major or two major and two or more minor criteria are met.

In paraneoplstic pemphigus the tumour antigens evoke an immune response that is primarily humoral. The neoplasm does not appear to produce the autoantibodies in paraneoplastic pemphigus. Non-neoplastic B lymphocytes are probably responsible,  as invivo-bound immunoglobulins are polyclonal.3

In the present case the lesions were polymorphous, crusted and vesicular eruptions all over the body and developed after treatment of Non-Hodgkin’s lymphoma. The lesions were both suprabasal with acantholytic cells and subepidermal representing mixed bullous lesion of pemphigus and   pemphigoid. Bystryn and colleagues described a case with mixed bullous disease exhibiting combined features of cicatrical pemphigoid and pemphigus and associated with a B-cell lymphoma producing IgM paraprotein.2 In DIF testing of present case faint deposition of IgG was seen in intercellular substance and along BMZ.  Deposition of IgA was strong but it was seen along BMZ. The combination of intercellular and subepidermal deposition of immunoreactants is a clue to the diagnosis of paraneoplastic pemphigus.4 Because circulating antibodies that bind to the cell surface of stratified squamous epithelia are common to all forms of pemphigus, other substrates, such as rodent bladder, is useful in distinguishing paraneoplastic pemphigus from pemphigus vulgaris or pemphigus foliaceus. Binding to rat bladder transitional epithelium is specific for circulating autoantibodies from patients with paraneoplastic pemphigus with a specificity of 83%. However, testing on rat bladder has a sensitivity of only 75%4. In present case the important antibody deposition was IgA and located along BMZ of rat urinary bladder, but no deposit is seen at intercellular space of bladder epithelium. These features are indicative of new entity not yet described previously. Bystryn and colleagues found that the IgM  paraprotein was deposited to intercellular antigen of human skin but did not react to mammalian bladder in their case. In the present case two major and almost three minor criteria, for the diagnosis of paraneoplastic pemphigus proposed above, are met. We believe that this condition represents a novel bullous disease, and diagnosed as paraneoplastic pemphigus (mixed bullous disease type).  Though the immunoprecipitation analysis is a standard diagnostic procedure for paraneoplastic pemphigus because it has higher specificity and sensitivity than IIF testing,4 unfortunately as it is not widely available, is not done in this case.

Conclusion

Paraneoplastic pemphigus may present with variable features. The present case of paraneoplastic pemphigus has distinct features with autoantibody – IgA to some components of BMZ. Strong reactivity of IgA to BMZ illustrates a distinct bullous disease associated with paraneoplastic syndromes and at least one possible mechanism for such eruption is the production of anti-skin antibodies in patient with malignant B cells. However, definite nature of antigens remains to be explored and the full spectum of bullous disease associated with underlying cancers remains to be determined. As possibility of underlying malignancy including lymphoma is present in a small proportion of patients of pemphigus, complete physical examination and laboratory investigations are mandatory in cases of blistering disease5 and IIF test with rat urinary bladder may be included in the suspected cases.

References

  1. Anhalt GJ, Stanley JR et al. Paraneoplastic pemphigus. An autoimmuno mucocutaneous disease associated with neoplasia. N. Eng. J. Med. 1990; 323:1729.
  2. Brystryn JC, Hodak E, Gao SQ et al. A paraneoplastic mixed bullous skin disease associated with anti-skin antibodies and a B-cell lymphoma. Arch Dermatol 1993;129:870.
  3. Camisa C, Helm TN. Paraneoplastic pemphigus is a disninct neoplasia-induced autoimmune disease. Arch Dermatol. 1993; 129:883.
  4. Goldberg L, Nisar N. Pemphigus paraneoplastic. Boston University eMedicine online [internet]. 2003 January (Cited 2004), Available from http// www. eMedicine.com/dem/pemphigus/paraneoplastic.
  5. Schofield OMV, Hunter JAA. Disease of skin in: Haslett C, Chilvers ER, Hunter JAA et al, Davidson’s Principles and Practice of Medicine (18th eds). Edinburgh, Churchill Living stone 1999; pp877-921.
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Balanced X-Autosome Translocation in Infertile Woman: Report of Two Cases

Balanced X-Autosome Translocation in Infertile Woman: Report of Two Cases

*Habib S,1 Islam SS2

Abstract
Individuals with apparently balanced translocations, often, show no clinical findings. X-chromosomal translocations involving different autosomes have been reported. The phenotypic manifestations of these translocations depend on several factors. X-autosome translocations can also affect fertility where chromosomal changes result in inactivation of genes governing reproduction. This report is described two cases of phenotypically normal Bangladeshi women with the complaint of primary infertility associated with secondary amenorrhea and streak ovaries. Chromosomal analysis revealed an apparently balanced reciprocal translocation involving the long arm of the X chromosome (q2) with the short arm of chromosome 1(p3) and the long arm of chromosome 19(q13) in all the cells with the karyotype 46,X,t(X:1)(q22:p32) and 46,X,t(X:19)(q22:q13.1). Studies examining X-chromosome deletions have predicted that Xq aberrations within the Xq13–Xq27 region can result in gonadal failure. Reciprocal translocations between autosomes and gonosomes contribute significantly to primary infertility.

[Journal of Histopathology and Cytopathology, 2018 Jul; 2 (2):151-156]

Keywords: Balanced X-autosome translocation, phenotype, Primary infertility

Introduction

X-autosome translocations are rare and associated with different phenotypes. There are balanced and unbalanced X-autosome translocation. Balanced type is usually associated with normal phenotype whereas the unbalanced one is with various congenital anomalies. Phenotypic effects of balanced X-autosome translocations in females: a retrospective survey of 104 cases reported from UK laboratories by Water JJ et al.1 Their cases were: multiple congenital abnormalities and/or developmental delay (MCA/DD): 26 (42%); gonadal dysfunction: 22 (35%); phenotypically normal with or without recurrent miscarriage (NRM): 9 (15%); recognized X-linked syndrome: 5 (8%). X chromosome translocations are frequently associated with primary or secondary amenorrhea. In this report, the clinical, biochemical and cytogenetic aspects of two healthy infertile women with balanced X-autosome translocation between chromosome X and two different autosomes: chromosome 1 and 19 were presented.

 

  1. *Dr. Saequa Habib MBBS MD (Pathology) Associate Professor, Department of Pathology, Bangabandhu Sheikh Mujib Medical University. saequa20@yahoo.com
  2. SM Shahedul Islam, B Sc, M Sc (Biochemistry & Molecular Biology) Scientific Officer, Department of Pathology, Bangabandhu Sheikh Mujib Medical University.

 

*For correspondence

 

Case Presentation

Case 1

A 27 year-old female with the complaint of primary infertility, was referred to the department of Pathology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh for cytogenetic evaluation. She was born to a nonconsanguineous parent and her mother had no menstrual problem. Her siblings were healthy. Her menarche was at 13 years of age but she had irregular menstruation with 4-8 months interval. She was married for 7 years. Her husband lived abroad. Her physical examination revealed normal height and weight and showed normal intelligence. On per vaginal examination small uterus was found with no abnormality of the external genitalia. Her luteinizing hormone and TSH level were normal but follicle stimulating hormone and anti-Mullerian hormone were at postmenopausal level. Ultrasound examination of the pelvis revealed normal uterus and streak ovaries.

Cytogenetic analysis of the peripheral blood lymphocytes was carried out according to the standard karyotyping technique. Peripheral blood lymphocytes were stimulated with phytohemagglutinin and harvested at 72 hours with colchicine. Hypotonic treatment was given to the cells and then they were fixed with Carnoy’s fixative. Standard GTG banding was done.2 Karyotype analysis of 100 metaphases revealed a pattern of 46, X, t(X;1)(q22; p32), suggestive of a balanced sex autosome translocation involving the long arm of chromosome X and short arm of chromosome 1 (Figure 1). ISCN guidelines for the chromosomal nomenclature (2016) were followed for the karyotype analysis and analysed by using Leica DM6000 B Motorized microscope and Leica Cytovision software.3 Parental and siblings karyotypes were not done.

Case 2

A 32 year-old female was referred with the complaint of primary infertility. She had two sisters and they had children. She had delayed puberty with menarche at the age of 15 years. After then menstruation occurred only after taking pills. She was married for 16 years. Her height was 5 feet 3 inch and weight was 60 kg. She was graduated and was a health worker. She had complaint of decrease libido. On per vaginal examination small uterus was found with no abnormality of the external genitalia. Her luteinizing hormone, thyroid stimulating hormone, prolactin and testosterone level were normal but follicle stimulating hormone was at postmenopausal level. Ultrasound examination of the pelvis revealed hypoplastic uterus and streak ovaries.

Cytogenetic analysis of the peripheral blood lymphocytes was carried out and standard GTG banding was done.2 Karyotype analysis of 100 metaphases revealed 46, X, t(X;19)(q22; p13.1), suggestive of a balanced sex autosome translocation involving the long arm of chromosome X and long arm of chromosome 19 (Figure 2).

Table  I: Previously reported cases of balanced X; 1 and X; 19 translocations

Symptoms Karyotypes Data by
Developmental delay 46, X, t (X; 1)(p22.1;p31) de novo Waters JJ et al1 (2001)
Recurrent miscarriages 46, X, t (X; 1)(p22.1;p32) de novo
Learning difficulties 46, X, t (X; 1)(p11.4;p36.3) de novo
Mother: abnormal scan 46, X, t (X; 1)(q26;p22) de novo
Multiple congenital anomalies/developmental delay 46, X, t (X; 1)(q26;p22) mat
Primary amenorrhea 46X: t (X; 1) (q21;p32) de novo Venkateshwari A et al9 (2015)

 
Primary amenorrhea 46,X,t(X; 1)( q22;p13) Razavi Z and   Momtaz HE10 (2017)
Primary amenorrhea 46,X,t(X;19)(q28;p13.1) Shetty DL et al11 (2014)

 

 

 

 

 

 

 

 

 

Figure 1. Photomicrograph of a karyotype showing translocation between chromosome X and chromosome 1 [46, X, t(X; 1) (q22; p32)] (Giemsa stain).

 

 

 

 

 

 

 

 

 

Figure 2. Photomicrograph of a karyotype showing translocation between chromosome X and chromosome 19 [46, X, t(X; 19) (q22; p13.1)] (Giemsa stain).

Discussion

Chromosomal conditions involving the sex chromosomes often affect sex determination (whether a person has the sexual characteristics of a male or a female), sexual development, and the ability to have children (fertility). The signs and symptoms of these conditions vary widely and range from mild to severe. They can be caused by missing or extra copies of the sex chromosomes or by structural changes in the chromosomes.

X-autosome translocations are rare, being estimated to occur in about 1/30,000 live births.4   In cases of balanced X-autosome translocation in female carriers, the normal X chromosome is usually inactivated, leaving the derivative X chromosome in the active state. The present cases revealed sex autosome translocation in phenotypically normal female with secondary amenorrhea. Cytogenetic analysis revealed 46, X, t (X; 1) (q22; p32) and 46, X, t(X; 19) (q22; p13.1) karyotype indicating its possible association with irregular menstruation and abnormal hormone level. Most carriers of an X-autosome translocation are phenotypically normal.5,6,1 In female carriers, gonadal dysgenesis may occur, and ∼9% may have multiple anomalies and/or mental retardation.7 Since the 2 copies of the X chromosome are necessary for ovarian development and integrity, the gonadal dysgenesis with infertility in our patient can be attributed to the partial loss of Xq, which contains various genes necessary for a normal ovarian reproductive function. MG Mattei et al concluded that  in X-autosome translocation 50% women will be sterile.8 There are reported cases of balanced X; 1 and X;19 translocations with different clinical manifestations including infertility showed in Table I.

Balanced X-autosome translocations show exchange between long arm segments of an X chromosome to an autosome with larger number of breakpoints. Infertility because of gonadal dysgenesis is common among those women in whom the breakpoint in the derivative X-chromosome involves the critical region Xq13–q26.1,5,6 X-autosome translocation causing gonadal dysgenesis with bilateral streak gonads as well as aberrant ovarian and sex development has been demonstrated by numerous studies.12, 13 Translocations involving the long arms of the X-chromosome and several autosomes (1–4, 6–9, 11, 12, 14, 15, 17, 19, 21, and 22), resulting in various degrees of gonad dysfunction, have also been reported.14

X-autosomal translocations are generally of maternal in origin or may arise in de novo.6 Fertility effects of a balanced X-autosome translocation vary depending on the sex of the carrier, the position of the translocation breakpoints and the pattern of X-inactivation.5,6,7 In the reported cases X autosome translocation may be de novo as their siblings had no menstrual abnormality. To conclude that balanced X-autosome translocation can be a cause secondary amenorrhea associated with infertility and should be investigated by cytogenetic analysis followed by genetic counseling.

References

  1. Waters JJ, Campbell PL, Crocker AJ, Campbell CM. Phenotypic effects of balanced X-autosome translocations in females: a retrospective survey of 104 cases reported from UK laboratories. Hum Genet 2001; 108 (4): 318– 27.
  2. Verma RS and Babu A. Human chromosome: manual of basic techniques.1st New York, USA. 1989: pp 4-44, 152-165.
  3. ISCN: an international system for human cytogenomic nomenclature .In Jean McGowan-Jordan, Annet Simons, Michael Schmid eds. Cytogenetic and Genome Research. New York, Karger. 2016: Vol. 149, No. 1-2.
  4. Sharp AJ, Spotswood HT, Robinson DO, Turner BM, Jacobs PA. Molecular and cytogenetic analysis of the spreading of X inactivation in X;autosome translocations. Hum Mol Genet. 2002; 11 (25): 3145– 56.
  5. Madan, K. Balanced structural changes involving the human X: effect on sexual phenotype.  Genet.1983; 63: 216–221.
  6. Kalz‐Füller B, Sleegers E, Schwanitz G, Schubert R. Characterisation, phenotypic manifestations and X‐inactivation pattern in 14 patients with X‐autosome translocations.  Genet.1999; 55: 362–366.
  7. Schmidt, M. and Du Sart, D.) Functional disomies of the X chromosome influence the cell selection and hence the X inactivation pattern in females with balanced X‐autosome translocations: a review of 122 cases. J. Med. Genet1992; 42:161–169.
  8. Mattei MG, Mattei JF, Ayme S Giraud F. X-Autosome translocation: cytogenetic characteristics and their consequences. Hum Genet 1982; 61:295-309.
  9. Venkateshwari A, Srilekha A, Veena K, Sujatha M, Jyothy A. A Rare De Novo Balanced 1X; 1 Translocation in an Indian Female with Primary Amenorrhea. J Reprod Infertil. 2015; 16: 171–3.
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