- Email: [email protected]
Balanced reciprocal X-1 translocation (46,X,t(X;1)(q22;p32) and primary amenorrhea
European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 338–346
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
LETTERS TO THE EDITOR—BRIEF COMMUNICATIONS Balanced reciprocal X-1 translocation (46,X,t(X;1)(q22;p32) and primary amenorrhea Dear Editors, Chromosomal aberrations constitute around 20% causes of primary amenorrhoea. Most of these are numerical aberrations. Of the rare structural chromosomal anomalies, balanced reciprocal translocations involving X chromosome and autosomes 3, 4, 6, 9, 12, 15, 18, 22 and 1 are known. Only seven cases of balanced
reciprocal translocation between X chromosome and autosome 1 with different breakpoint locations have been reported. We report the first case of a novel balanced reciprocal translocation between X chromosome and autosome 1 and a karyotype pattern of 46,X,t(X;1)(q22;p32). A 17 years old girl presented to our outpatient department with primary amenorrhoea. She was a product of non consanguineous marriage, had no systemic illness and had one elder normal female sibling. Examination revealed a height of 40 700 and breasts in Tanner
Fig. 1. Microphotograph (GTG Banding of chromosomes) demonstrating the reciprocal X to autosome 1 translocation. 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
Letters to the Editor—Brief Communications / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 338–346
stage 2 and sparse axillary and pubic hair. The external genitalia were pre pubertal in appearance. Other anthropometric measurements were normal. Hematological investigations revealed a normal blood count, serum prolactin levels of 10 ng/ml (normal range 3–25 ng/ml), high FSH (180 mIU/ml) and LH (94 mIU/ml). Ultrasonography of abdomen & pelvis demonstrated a hypoplastic uterus of size 32 mm 12 mm 8 mm with empty ovarian fossae. Bilateral kidneys and ureters were reported normal. Twenty metaphases obtained from peripheral blood leucocytes analysed by GTG Banding technique demonstrated a balanced reciprocal translocation between long arm of X chromosome and short arm of chromosome 1 with a pattern of 46,X,t(X;1)(q22;p32) (Fig. 1). The girl was started on combined oral pills after she failed to have withdrawal bleeding on progesterone challenge test. She menstruated after 3 months of therapy. X-autosome translocations occur in 1/10,000 to 3/10,000 live births [1]. The carriers of unbalanced translocations usually present with multiple congenital anomalies and mental retardation (MCA–MR) syndromes. Primary amenorrhoea is the presenting feature in 0.5–1.6% cases of X-autosome translocations [2]. Translocations resulting in deletion or breakage of a gene responsible for gonadal development could account for the gonadal dysfunction. Alternately, hemizygous status of a recessive gene consequent upon inactivation of the normal X chromosome could also result in inhibition of development of gonads. The latter theory is supported by the observation that the normal X chromosome is usually found to be late replicating in individuals with balanced X; autosome translocations [2]. Third, a position effect mutation may also contribute to the phenotypic features in a few. The X-autosome translocations are usually of maternal origin or arise denovo [3]. All the denovo balanced X-autosome translocations reported so far are of paternal origin and are more likely to be associated with abnormal outcome, suggesting that denovo status versus breakpoint location is the most important risk factor in defining the phenotype [4]. Therman et al. noted that 45 of the 118 translocation carriers in whom the breakpoint was in the critical region (Xq13–q22, Xq22–q26) had gonadal dysgenesis [5]. This critical region is the fifth brightest segment in the human genome and consist mainly of Q-bright material. It contains two ‘supergenes’ which are responsible for normal ovarian development. The effect exerted by this region is independent of the breakpoint within the region and of the chromosome bands to which the broken ends are attached [5]. This may account for the amenorrhoea and gonadal dysgenesis observed in cases where the translocation involved Xq13 to Xq28. Altered gene dosage caused by the X;1 translocation along with X chromosome inactivation in our patient could have contributed to her phenotypic abnormality. It is suggested that the novel abnormal karyotype probably did not interrupt any genes or highly conserved genes even though a position effect mutation was not tested in our patient. References [1] Binkert F, Spreiz A, Ho¨ckner M, et al. Parental origin and mechanism of formation of a 46,X,der(X)(pter ! q21.1:: p11.4 ! pter)/45,X karyotype in a woman with mild Turner syndrome. Fertil Steril 2010;94(1). 350.e12-5. [2] Therman E, Patau K. Abnormal X chromosomes in man: origin, behavior and effects. Humangenetik 1974;25(1):1–16. [3] Kalz-Fuller B, Sleegers E, Schwanitz G, Schubert R. Characterization: phenotypic manifestations and X-inactivation pattern in 14 patients with X-autosomal translocations. Clin Genet 1999;55(5):362–6. [4] Waters JJ, Campbell PL, Crocker AJM, 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. [5] Therman E, Laxova R, Susman B. The critical region on the human Xq. Hum Genet 1990;85(5):455–61.
339
Nirmala Duhan* Roopa Malik Manisha Upadhyaya Department of Obstetrics and Gynecology, Pt B D Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India *Corresponding author. Tel.:+91 9896016348; fax: +0091 1262 211301 E-mail addresses: [email protected], [email protected] (N. Duhan). Received 30 July 2014 Accepted 7 August 2014 http://dx.doi.org/10.1016/j.ejogrb.2014.08.018
Pfeiffer syndrome: the importance of prenatal diagnosis Dear Editors, We found that Pfeiffer Syndrome (PS) was first described in 1964 and has an incidence of 1/100.000 neonates. Conventionally, PS is classified into three types. All types demonstrate craniofacial anomalies (craniosynostosis, midface retrusion, hypertelorism, proptosis) and limb deformities (brachydactyly, syndactyly, broad thumbs/great toes). Type 1 is the mildest phenotype with normal intelligence and generally good outcome. Type 2 has a poor prognosis and is characterized by a cloverleaf skull. Type 3 is an intermediate form with a very short skull base, severe proptosis, but without the cloverleaf skull. PS is an autosomal dominant condition, genetically heterogeneous with mutations in the FGFR1 or FGFR2 gene [1–5]. In our clinic we saw a 31-year-old primi-gravida, known with PS caused by a FGFR1 mutation. She was referred to our level 3 unit at 25 6/7 weeks of gestation. She was known to have the classical limb deformities: broad abducted thumbs and great toes (Fig. 1D). Her medical history was otherwise uneventful. Prenatal diagnosis comprising first trimester screening revealed no increased risk for trisomy 13, 18 and 21. She did not opt for amniocentesis. At 20 weeks of gestation advanced ultrasound examination was performed and showed no structural anomalies, normal growth and amount of amniotic fluid. She was referred because of threatened preterm labor. Ultrasound examination at admittance showed polyhydramnios and broad, deviated big toes of the fetus (Fig. 1A). Shortly afterwards she delivered of a daughter [weight 1.030 kg (+1SD), head circumference 25 cm (+1SD)]. Apgar scores were 8 and 9 after, respectively, 1 and 5 min. Umbilical cord blood gas analysis was normal. Physical examination showed a clinically normal skull shape. Both thumbs and big toes were broad and deviated in varus position (Fig. 1B). There was no syndactyly. Postnatal DNA-analysis confirmed the P252R (FGFR1 ex5) mutation. Previously the family of the index patient was investigated at the department of Clinical Genetics. DNA-analysis showed the FGFR1 mutation in the index patient, a sister and her mother. The index patient was born at term. During this pregnancy her mother had 25 weeks of bed rest because of premature contractions. Her sister was born at 32 weeks of gestation. It is not known at what
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
LETTERS TO THE EDITOR—BRIEF COMMUNICATIONS Balanced reciprocal X-1 translocation (46,X,t(X;1)(q22;p32) and primary amenorrhea Dear Editors, Chromosomal aberrations constitute around 20% causes of primary amenorrhoea. Most of these are numerical aberrations. Of the rare structural chromosomal anomalies, balanced reciprocal translocations involving X chromosome and autosomes 3, 4, 6, 9, 12, 15, 18, 22 and 1 are known. Only seven cases of balanced
reciprocal translocation between X chromosome and autosome 1 with different breakpoint locations have been reported. We report the first case of a novel balanced reciprocal translocation between X chromosome and autosome 1 and a karyotype pattern of 46,X,t(X;1)(q22;p32). A 17 years old girl presented to our outpatient department with primary amenorrhoea. She was a product of non consanguineous marriage, had no systemic illness and had one elder normal female sibling. Examination revealed a height of 40 700 and breasts in Tanner
Fig. 1. Microphotograph (GTG Banding of chromosomes) demonstrating the reciprocal X to autosome 1 translocation. 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
Letters to the Editor—Brief Communications / European Journal of Obstetrics & Gynecology and Reproductive Biology 181 (2014) 338–346
stage 2 and sparse axillary and pubic hair. The external genitalia were pre pubertal in appearance. Other anthropometric measurements were normal. Hematological investigations revealed a normal blood count, serum prolactin levels of 10 ng/ml (normal range 3–25 ng/ml), high FSH (180 mIU/ml) and LH (94 mIU/ml). Ultrasonography of abdomen & pelvis demonstrated a hypoplastic uterus of size 32 mm 12 mm 8 mm with empty ovarian fossae. Bilateral kidneys and ureters were reported normal. Twenty metaphases obtained from peripheral blood leucocytes analysed by GTG Banding technique demonstrated a balanced reciprocal translocation between long arm of X chromosome and short arm of chromosome 1 with a pattern of 46,X,t(X;1)(q22;p32) (Fig. 1). The girl was started on combined oral pills after she failed to have withdrawal bleeding on progesterone challenge test. She menstruated after 3 months of therapy. X-autosome translocations occur in 1/10,000 to 3/10,000 live births [1]. The carriers of unbalanced translocations usually present with multiple congenital anomalies and mental retardation (MCA–MR) syndromes. Primary amenorrhoea is the presenting feature in 0.5–1.6% cases of X-autosome translocations [2]. Translocations resulting in deletion or breakage of a gene responsible for gonadal development could account for the gonadal dysfunction. Alternately, hemizygous status of a recessive gene consequent upon inactivation of the normal X chromosome could also result in inhibition of development of gonads. The latter theory is supported by the observation that the normal X chromosome is usually found to be late replicating in individuals with balanced X; autosome translocations [2]. Third, a position effect mutation may also contribute to the phenotypic features in a few. The X-autosome translocations are usually of maternal origin or arise denovo [3]. All the denovo balanced X-autosome translocations reported so far are of paternal origin and are more likely to be associated with abnormal outcome, suggesting that denovo status versus breakpoint location is the most important risk factor in defining the phenotype [4]. Therman et al. noted that 45 of the 118 translocation carriers in whom the breakpoint was in the critical region (Xq13–q22, Xq22–q26) had gonadal dysgenesis [5]. This critical region is the fifth brightest segment in the human genome and consist mainly of Q-bright material. It contains two ‘supergenes’ which are responsible for normal ovarian development. The effect exerted by this region is independent of the breakpoint within the region and of the chromosome bands to which the broken ends are attached [5]. This may account for the amenorrhoea and gonadal dysgenesis observed in cases where the translocation involved Xq13 to Xq28. Altered gene dosage caused by the X;1 translocation along with X chromosome inactivation in our patient could have contributed to her phenotypic abnormality. It is suggested that the novel abnormal karyotype probably did not interrupt any genes or highly conserved genes even though a position effect mutation was not tested in our patient. References [1] Binkert F, Spreiz A, Ho¨ckner M, et al. Parental origin and mechanism of formation of a 46,X,der(X)(pter ! q21.1:: p11.4 ! pter)/45,X karyotype in a woman with mild Turner syndrome. Fertil Steril 2010;94(1). 350.e12-5. [2] Therman E, Patau K. Abnormal X chromosomes in man: origin, behavior and effects. Humangenetik 1974;25(1):1–16. [3] Kalz-Fuller B, Sleegers E, Schwanitz G, Schubert R. Characterization: phenotypic manifestations and X-inactivation pattern in 14 patients with X-autosomal translocations. Clin Genet 1999;55(5):362–6. [4] Waters JJ, Campbell PL, Crocker AJM, 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. [5] Therman E, Laxova R, Susman B. The critical region on the human Xq. Hum Genet 1990;85(5):455–61.
339
Nirmala Duhan* Roopa Malik Manisha Upadhyaya Department of Obstetrics and Gynecology, Pt B D Sharma Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India *Corresponding author. Tel.:+91 9896016348; fax: +0091 1262 211301 E-mail addresses: [email protected], [email protected] (N. Duhan). Received 30 July 2014 Accepted 7 August 2014 http://dx.doi.org/10.1016/j.ejogrb.2014.08.018
Pfeiffer syndrome: the importance of prenatal diagnosis Dear Editors, We found that Pfeiffer Syndrome (PS) was first described in 1964 and has an incidence of 1/100.000 neonates. Conventionally, PS is classified into three types. All types demonstrate craniofacial anomalies (craniosynostosis, midface retrusion, hypertelorism, proptosis) and limb deformities (brachydactyly, syndactyly, broad thumbs/great toes). Type 1 is the mildest phenotype with normal intelligence and generally good outcome. Type 2 has a poor prognosis and is characterized by a cloverleaf skull. Type 3 is an intermediate form with a very short skull base, severe proptosis, but without the cloverleaf skull. PS is an autosomal dominant condition, genetically heterogeneous with mutations in the FGFR1 or FGFR2 gene [1–5]. In our clinic we saw a 31-year-old primi-gravida, known with PS caused by a FGFR1 mutation. She was referred to our level 3 unit at 25 6/7 weeks of gestation. She was known to have the classical limb deformities: broad abducted thumbs and great toes (Fig. 1D). Her medical history was otherwise uneventful. Prenatal diagnosis comprising first trimester screening revealed no increased risk for trisomy 13, 18 and 21. She did not opt for amniocentesis. At 20 weeks of gestation advanced ultrasound examination was performed and showed no structural anomalies, normal growth and amount of amniotic fluid. She was referred because of threatened preterm labor. Ultrasound examination at admittance showed polyhydramnios and broad, deviated big toes of the fetus (Fig. 1A). Shortly afterwards she delivered of a daughter [weight 1.030 kg (+1SD), head circumference 25 cm (+1SD)]. Apgar scores were 8 and 9 after, respectively, 1 and 5 min. Umbilical cord blood gas analysis was normal. Physical examination showed a clinically normal skull shape. Both thumbs and big toes were broad and deviated in varus position (Fig. 1B). There was no syndactyly. Postnatal DNA-analysis confirmed the P252R (FGFR1 ex5) mutation. Previously the family of the index patient was investigated at the department of Clinical Genetics. DNA-analysis showed the FGFR1 mutation in the index patient, a sister and her mother. The index patient was born at term. During this pregnancy her mother had 25 weeks of bed rest because of premature contractions. Her sister was born at 32 weeks of gestation. It is not known at what