J Med Genet: first published as 10.1136/jmg.17.3.216 on 1 June 1980. Downloaded from Journal ofMedical Genetics, 1980, 17, 216-221 Gonadal dysgenesis in a patient with an X;3 translocation: case report and review NANCY J CARPENTER, BURHAN SAY, AND DAVID BROWNING From the Children's Medical Center, University of Tulsa, and Tulsa Medical College, University of Oklahoma, Tulsa, Oklahoma, USA SUMMARY 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. Up to mid 1979, 102 cases of balanced and un- The patient has three sisters, all of whom have had balanced X;autosome translocations have been the normal sexual development. There is no family subjects of 53 reports. These cases have provided history of similar developmental disorders. There information on the patterns of inactivation of the was no consanguinity between the parents. The ages X chromosome and on the relative position of of the mother and father at the time of the patient's various loci on this chromosome. Associated with birth were 33 and 35 years, respectively. copyright. these chromosomal rearrangements are a variety of A buccal smear was 24 % positive for sex chroma- clinical findings including amenorrhoea, hypogona- tin. The Barr bodies appeared normal in size. dism, and multiple congenital anomalies and mental Karyotype analysis from peripheral blood revealed retardation (MCA-MR) in the majority of the a balanced X;3 translocation (fig 1). The G banded balanced carriers and MCA-MR syndromes in the karyotype was 46,X,t(X;3)(Xpter-*Xq22::3pl1l* unbalanced carriers. 3pter;3qter-*3pl I :Xq22-*Xqter). Fig 2 illustrates We present a patient with a balanced de novo the breakpoints in the long arm ofthe X chromosome http://jmg.bmj.com/ X;3 translocation. A review of the phenotypes and and the short arm of chromosome 3. Using the patterns of X inactivation in patients with balanced BUdR terminal pulse technique followed by staining X;autosome translocations reveals the complexities with acridine orange,' the normal X chromosome of X chromosome inactivation. was identified as late replicating in all of the 49 Case report on September 24, 2021 by guest. Protected A 17-year-old girl was referred for primary amenor- rhoea and lack of secondary sex characteristics. During a laparoscopy, bilateral streak gonads and a markedly hypoplastic uterus were noted. A normal vagina and cervix were present and no abnormalities 3 of the external genitalia were observed. The serum .I follicle stimulating hormone (FSH) level was greater than 100 mouse uterine units/24 h and the x luteinising hormone (LH) level was 36 mIU/ml 3 der 3 der X at the age of 14. Repeat gonadotrophin levels at the age of 15 gave values of greater than 100 mouse uterine units/24 h for FSH and 59 mIU/ml for LH. Her weight and height were 37 kg and 156 cm, respectively. FIG 1 G banditng of the normal and derivative 3 and X Received for publication 20 July 1979 chromosomes of the patient. 216 J Med Genet: first published as 10.1136/jmg.17.3.216 on 1 June 1980. Downloaded from Gonadal dysgenesis in a patient with an X;3 translocation: case report and review 217 3 der 3 der X x FIG 2 Diagram of the tranislocation breakpoints. metaphases analysed. The karyotypes of the parents the effective hemizygosity of a recessive gene were normal. inhibiting gonadal development as a result of Dermatoglyphic analysis of the proband showed inactivation of one X chromosome, and (2) the an essentially normal pattern with a total finger breakage or deletion of a gene for gonadal develop- ridge count of 138. Gene marker studies including ment as a result of translocation. Sarto et a/36 copyright. red cell antigens, Xga, and 20 selected enzymes on identified a 'critical region' for such loci from the proband and her parents were not informative. approximately Xq21 to Xq25. Summitt and associ- ates48 propose extending the boundaries of this Discussion region to Xql3 and Xq27. Patterns of X inactivation in these cases have been X;autosome translocations have been reported in- shown by terminal pulsing of chromosome cultures volving each of the autosomes except for chromo- with 3H thymidine or bromodeoxyuridine (BUdR) http://jmg.bmj.com/ somes 10 and 11, and a large number of breakpoints before autoradiography or differential staining on the X chromosome and the autosomes have been with acridine orange. Therman et at49 proposed that identified. Carriers of unbalanced translocations an X inactivation centre on the proximal part of Xq present with MCA-MR syndromes reflecting the is essential for inactivation of any X chromosome. partial aneuploidy of the autosomal segments in- In cases of balanced X;autosome translocations, volved and the X inactivation pattern. The balanced the normal X is usually found to be late replicating translocation carriers express different phenotypes (inactive) as in the present case.47 A few exceptions ranging from clinically normal females to those with have been reported in which the X portion of the on September 24, 2021 by guest. Protected MCA-MR syndromes. In the patients with MCA- translocated chromosome,7 131819 23 2631 32 or the MR syndromes, a position effect or spreading of entire translocated X,6 40 46 iS late replicating. It is inactivation over the autosomal loci involved may not known whether there is preferential inactivation be the underlying cause. A review of the 66 balanced of the normal X chromosome or random inactiva- translocation cases included in the 45 reports to tion followed by selective survival of cells in which date is given in the table. Seventeen of these patients, the translocated X remains active. Inactivation including the case reported here, had primary usually results in the least genetic imbalance and amenorrhoea. In two separate studies, a total of thus the expression of the mildest phenotypic 150 women with primary amenorrhoea were effects. However, the exceptional case reported by identified and two were found to have X;autosome Thelen et a!40 in which the patient expressed the translocations (1 .3 %).22 36 However, a report of characteristics of the 18q- syndrome through in- 429 women with primary amenorrhoea including activation of the translocated autosomal as well as these two cases gave an incidence of 05%.47 Two the X chromosomal segment points out the un- hypotheses have been proposed to explain the predictability of this phenomenon. gonadal dysfunction observed in such patients: (1) During genetic counselling of fertile balanced J Med Genet: first published as 10.1136/jmg.17.3.216 on 1 June 1980. 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Downloaded from Gonadal dysgenesis in a patient with an X;3 translocation: case report and review 219 7a~~~~~ (C4 (C r. 0 r.~~~~~'0 '0 o* 0.0to cU >C0CC 0 0 0 M ~ 4)~~~~~~~~~~.-0 4..0 o (C0 11(C :j*. .4) z 0 C .0 ((. 0 4) d 40 >0 C n 10 4)4'a04)40 (cO V '00 .. EE o 0o 0 00~ ~ 0 copyright. II II liii I~~~~~I 0 ~~~~~~~4 http://jmg.bmj.com/ 0 ~~~~X00 '-a0Xe on September 24, 2021 by guest. Protected 0~~~~~~~~0 0 C H-=Cd '5 C. Z c Cd C -0 *.e (4 0op2:&.*H > >CN4t-4 J Med Genet: first published as 10.1136/jmg.17.3.216 on 1 June 1980. Downloaded from 220 Nancy J Carpenter, Burhan Say, and David Browning X;autosome translocation carriers, the risk of having 14 Francke U, Busby N, Shaw D, Brown MG. Intra- chromosomal gene mapping in man: assignment of unbalanced offspring with multiple congenital nucleoside phosphorylase to region 14cen-14q21 by anomalies should be emphasised. The parents of interspecific hybridization of cells with a t(X;14) patients with reproductive failure and de novo (p22;q21) translocation.