- Email: [email protected]
Prenatal diagnosis of 47,XXX
American Journal of Obstetrics and Gynecology (2005) 192, 1469–71
www.ajog.org
Prenatal diagnosis of 47,XXX Fady Khoury-Collado, MD,* Ammar N. Wehbeh, MD, Allan J. Fisher, MD, Allan T. Bombard, MD, Zeev Weiner, MD Department of Obstetrics and Gynecology, Lutheran Medical Center, Brooklyn, NY Received for publication August 30, 2004; revised October 30, 2004; accepted December 7, 2004
KEY WORDS 47,XXX Down syndrome Triple screen Single umbilical artery Echogenic intracardiac focus
We report 2 cases of 47,XXX that were diagnosed prenatally and were screened positive for trisomy 21 by biochemical and ultrasound markers. These cases underline the importance of discussing the sex chromosome abnormalities during the genetic counseling after an abnormal triple screen test or ultrasound examination.
Ó 2005 Elsevier Inc. All rights reserved.
Screening for Down syndrome with maternal serum markers is a well-established component of prenatal care. Fetal ultrasound ‘‘markers’’ are also being used to screen for Down syndrome, commonly in combination with serum markers. Patients who are ‘‘screen positive’’ are offered a diagnostic procedure (ie, amniocentesis or chorionic villous sampling), which can detect, in addition to Down syndrome, other chromosome abnormalities. We report here 2 cases of 47,XXX that were diagnosed prenatally and were screened positive for trisomy 21 by biochemical markers and by ultrasound examination. We hope that our findings will contribute to the prenatal diagnosis of this sex chromosome aneuploidy.
Case 1 A 42-year-old woman was seen at 10 weeks of gestation for her first prenatal visit. At 16 weeks of gestation, * Reprint requests: Fady Khoury-Collado, MD, 97 Evergreen Ave, Staten Island, NY 10305. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.12.037
a triple-marker screening test was performed that demonstrated an increased risk for both trisomy 21 and trisomy 18 (maternal serum alfa fetoprotein, 0.68 MoM; b human chorionic gonadotropin, 1.45 MoM; unconjugated estriol, 0.43 MoM; risk for trisomy 21, O1/10; risk for trisomy 18, 1/71). The patient had genetic counseling followed by amniocentesis that revealed 47,XXX in all 20 cells that were analyzed. A detailed anatomic ultrasound examination was performed, and no abnormalities were noted. The patient was counseled about the prognosis of this condition, and she decided to continue with the pregnancy. She was delivered at 39 weeks of gestation by cesarean delivery for a nonreassuring fetal heart rate. Apgar scores were 4 and 9 at 1 and 5 minutes, respectively. The birth weight was 2515 g. The neonatal examination revealed no structural malformations or dysmorphic features. The genitalia were of normal female. The neonatal course was uneventful. Postnatal fetal blood karyotyping confirmed the diagnosis of 47,XXX. Examination up to 5 months of age by a pediatric geneticist revealed normal developmental milestones and no abnormal features.
1470
Case 2 A 34-year-old woman was seen for her first prenatal visit at 18 weeks of gestation. The patient was referred for a routine obstetric ultrasound examination, which revealed a twin pregnancy (dichorionic diamniotic) with twin A showing a single umbilical artery and an echogenic intracardiac focus. Considering the sonographic findings, along with the maternal age in a twin pregnancy, the patient was referred for genetic counseling; she decided to have an amniocentesis for twin A. The result was 47, XXX in all 20 cells that were analyzed. The patient decided to continue the pregnancy after being counseled about the prognosis. During the follow-up period, discordance was noted between the twins (twin A being smaller than twin B), with no difference in the amniotic fluid amount. Antenatal testing was started at 26 weeks of gestation with reassuring findings until 38 weeks of gestation when the patient had early labor and was delivered by cesarean delivery for breech presentation of twin A. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively, for both twins. The birth weight was 2370 g for twin A and 2890 g for twin B. The examination at birth confirmed a 2-vessel umbilical cord in twin A. The genitalia of twin A were normal female. No malformations or dysmorphic features were noted. The 47,XXX karyotype was confirmed from peripheral fetal blood. The neonatal course was uneventful. An examination at 2 months of age by a pediatric geneticist revealed normal developmental milestones and no abnormal features.
Comment Female infants with 47,XXX are relatively common, occurring in 0.1% of liveborn female infants.1 Most of these infants have a normal phenotype.2 Only a few cases with 47,XXX karyotype and congenital malformations are reported in the literature.3-6 One third of female infants with 47,XXX show some mental or behavioral problems, usually of minor significance.1 Females infants with 47,XXX have also been reported to experience delayed menarche and premature ovarian failure.1 There are limited reports on the prenatal diagnosis of 47,XXX. The indication for cytogenetic studies in the prenatally diagnosed cases of 47,XXX are, generally, either advanced maternal age or after the detection of abnormal findings on a prenatal fetal ultrasound examination (oligohydramnios, fetal hydrops, intraoral mass, dysplastic kidneys).3,4,6 The cases that were diagnosed postnatally occurred as the result of the detection of various congenital anomalies, mainly of the genitourinary tract (ambiguous genitalia, ovarian dysgenesis, exstrophy of the cloaca, renal atrophy/agenesis).3,5 It has been established that sex chromosome aneuploidy increases with increasing maternal age and is
Khoury-Collado et al detected after a triple-marker serum screening test, the results of which are positive for Down syndrome, at a higher rate than expected in the general population.7,8 However, in reviewing the data from the large Down syndrome screening trials and from isolated case reports of 47,XXX, we found only 2 cases of prenatal diagnosis of 47,XXX where the indication for invasive testing was a triple-marker serum screening that indicated a high risk of Down syndrome (with a cutoff value of 1:270 or higher).9,10 We found another report of prenatal diagnosis of 47,XXX after ‘‘abnormal’’ serum markers,11 although the latter report did not specify which serum markers were used and what the result indicated (ie, increased risk of trisomy 21 and/or trisomy 18 and/or neural tube defects). To the best of our knowledge, our case of a prenatal diagnosis of 47,XXX after a triple marker serum screening test that was positive for both trisomy 21 and trisomy18 is the first to be reported. Echogenic intracardiac focus was first described in 1987 by Schechter et al.12 It has since become one of the sonographic ‘‘soft’’ markers that are associated with an increased risk of Down syndrome.13 Chromosome abnormalities other than trisomy 21, including sex chromosome abnormalities, have been reported in association with an echogenic intracardiac focus.14,15 However, we found no reported case of an echogenic intracardiac focus that was associated with the 47,XXX karyotype. A single umbilical artery has been associated with malformations of all major organ systems and chromosomal defects.16 When detected on a prenatal ultrasound examination, a detailed search for other associated fetal anomalies is performed; if found, prenatal fetal karyotyping usually is offered. We found only one report of a single umbilical artery that was associated with the diagnosis of 47,XXX.3 At 22 weeks of gestation, the obstetric sonogram revealed severe oligohydramnios and bilateral cystic dysplastic kidneys. The fetus was aborted, and postmortem examination detected the single umbilical artery along with multiple other associated anomalies. The diagnosis of 47,XXX was made by postnatal fetal blood karyotyping. We found no report of prenatal diagnosis of 47,XXX after ultrasound detection of a single umbilical artery with no other congenital malformations. We conclude that our 2 cases of prenatal diagnosis of 47,XXX underline the importance of discussing the sex chromosome abnormalities during the genetic counseling after an abnormal triple screen test or ultrasound examination.
References 1. Simpson JL, Elias S. Sex chromosomal polysomies (47,XXY; 47,XYY; 47,XXX), sex reversed (46,XX) males, and disorders of the male reproductive ducts. In: Simpson JL, Elias S, editors. Genetics in obstetrics and gynecology. Philadelphia: Saunders; 2003. p. 323-41.
Khoury-Collado et al 2. Linden MG, Bender BG, Robinson A. Intrauterine diagnosis of sex chromosome aneuploidy. Obstet Gynecol 1996;87:468-75. 3. Hoang MP, Wilson KS, Schneider NR, Timmons CF. Case report of a 22-week fetus with 47,XXX karyotype and multiple lower mesodermal defects. Pediatr Dev Pathol 1999;2:58-61. 4. Kim ES, Gross TL. Prenatal ultrasound detection of a congenital epulis in a triple X female fetus: a case report. Prenat Diagn 1999;19:774-6. 5. Lin HJ, Ndiforchu F, Patell S. Exstrophy of the cloaca in a 47,XXX child: review of genitourinary malformations in tripleX patients. Am J Med Genet 1993;45:761-3. 6. Spear GS, Porto M. 47,XXX chromosome constitution, ovarian dysgenesis, and genito-urinary malformation. Am J Med Genet 1988;29:511-5. 7. Haddow JE, Palomaki GE, Knight GJ, Cunningham GC, Lustig LS, Boyd PA. Reducing the need for amniocentesis in women 35 years of age or older with serum markers for screening. N Engl J Med 1994;330:1114-8. 8. Kellner LH, Weiss RR, Weiner Z, Neuer M, Martin GM, Schulman H, et al. The advantages of using triple-marker screening for chromosomal abnormalities. Am J Obstet Gynecol 1995;172:831-6. 9. Haddow JE, Palomaki GE, Knight GJ, Williams J, Pulkkinen A, Canick JA, et al. Prenatal screening for Down’s syndrome with the use of maternal serum marker. N Engl J Med 1992;327:588-93.
1471 10. Benn PA, Horne D, Briganti S, Greenstein RM. Prenatal diagnosis of diverse chromosome abnormalities in a population of patients identified by triple-marker testing as screen positive for Down syndrome. Am J Obstet Gynecol 1995;173:496-501. 11. Perrotin F, Guichet A, Marret H, Potin J, Body G, Lansac J. Devenir prenatal des anomalies des chromosomes sexuels diagnostiquees pendant la grossesse: analyse retrospective de 47 cas. J Gynecol Obstet Biol Reprod 2000;29:668-76. 12. Schechter AG, Fakhry J, Shapiro LR, Gewitz MH. In utero thickening of the chordae tendinae: a cause of intracardiac echogenic foci. J Ultrasound Med 1987;6:691-5. 13. Sotiriadis A, Makrydimas G, Ioannidis JPA. Diagnostic performance of intracardiac echogenic foci for Down syndrome: a metaanalysis. Obstet Gynecol 2003;101:1009-16. 14. Huggon IC, Cook AC, Simpson JM, Smeeton NC, Sharland GK. Isolated echogenic foci in the fetal heart as marker of chromosomal abnormality. Ultrasound Obstet Gynecol 2001;17:11-6. 15. Winter TC, Anderson AM, Cheng EY, Komarniski CA, Souter VL, Uhrich SB, et al. Echogenic intracardiac focus in 2ndtrimester fetuses with trisomy 21: usefulness as a US marker. Radiology 2000;216:450-6. 16. Rembouskos G, Cicero S, Longo D, Sacchini C, Nicolaides KH. Single umbilical artery at 11-14 weeks’ gestation: relation to chromosomal defects. Ultrasound Obstet Gynecol 2003;22: 567-70.
www.ajog.org
Prenatal diagnosis of 47,XXX Fady Khoury-Collado, MD,* Ammar N. Wehbeh, MD, Allan J. Fisher, MD, Allan T. Bombard, MD, Zeev Weiner, MD Department of Obstetrics and Gynecology, Lutheran Medical Center, Brooklyn, NY Received for publication August 30, 2004; revised October 30, 2004; accepted December 7, 2004
KEY WORDS 47,XXX Down syndrome Triple screen Single umbilical artery Echogenic intracardiac focus
We report 2 cases of 47,XXX that were diagnosed prenatally and were screened positive for trisomy 21 by biochemical and ultrasound markers. These cases underline the importance of discussing the sex chromosome abnormalities during the genetic counseling after an abnormal triple screen test or ultrasound examination.
Ó 2005 Elsevier Inc. All rights reserved.
Screening for Down syndrome with maternal serum markers is a well-established component of prenatal care. Fetal ultrasound ‘‘markers’’ are also being used to screen for Down syndrome, commonly in combination with serum markers. Patients who are ‘‘screen positive’’ are offered a diagnostic procedure (ie, amniocentesis or chorionic villous sampling), which can detect, in addition to Down syndrome, other chromosome abnormalities. We report here 2 cases of 47,XXX that were diagnosed prenatally and were screened positive for trisomy 21 by biochemical markers and by ultrasound examination. We hope that our findings will contribute to the prenatal diagnosis of this sex chromosome aneuploidy.
Case 1 A 42-year-old woman was seen at 10 weeks of gestation for her first prenatal visit. At 16 weeks of gestation, * Reprint requests: Fady Khoury-Collado, MD, 97 Evergreen Ave, Staten Island, NY 10305. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.12.037
a triple-marker screening test was performed that demonstrated an increased risk for both trisomy 21 and trisomy 18 (maternal serum alfa fetoprotein, 0.68 MoM; b human chorionic gonadotropin, 1.45 MoM; unconjugated estriol, 0.43 MoM; risk for trisomy 21, O1/10; risk for trisomy 18, 1/71). The patient had genetic counseling followed by amniocentesis that revealed 47,XXX in all 20 cells that were analyzed. A detailed anatomic ultrasound examination was performed, and no abnormalities were noted. The patient was counseled about the prognosis of this condition, and she decided to continue with the pregnancy. She was delivered at 39 weeks of gestation by cesarean delivery for a nonreassuring fetal heart rate. Apgar scores were 4 and 9 at 1 and 5 minutes, respectively. The birth weight was 2515 g. The neonatal examination revealed no structural malformations or dysmorphic features. The genitalia were of normal female. The neonatal course was uneventful. Postnatal fetal blood karyotyping confirmed the diagnosis of 47,XXX. Examination up to 5 months of age by a pediatric geneticist revealed normal developmental milestones and no abnormal features.
1470
Case 2 A 34-year-old woman was seen for her first prenatal visit at 18 weeks of gestation. The patient was referred for a routine obstetric ultrasound examination, which revealed a twin pregnancy (dichorionic diamniotic) with twin A showing a single umbilical artery and an echogenic intracardiac focus. Considering the sonographic findings, along with the maternal age in a twin pregnancy, the patient was referred for genetic counseling; she decided to have an amniocentesis for twin A. The result was 47, XXX in all 20 cells that were analyzed. The patient decided to continue the pregnancy after being counseled about the prognosis. During the follow-up period, discordance was noted between the twins (twin A being smaller than twin B), with no difference in the amniotic fluid amount. Antenatal testing was started at 26 weeks of gestation with reassuring findings until 38 weeks of gestation when the patient had early labor and was delivered by cesarean delivery for breech presentation of twin A. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively, for both twins. The birth weight was 2370 g for twin A and 2890 g for twin B. The examination at birth confirmed a 2-vessel umbilical cord in twin A. The genitalia of twin A were normal female. No malformations or dysmorphic features were noted. The 47,XXX karyotype was confirmed from peripheral fetal blood. The neonatal course was uneventful. An examination at 2 months of age by a pediatric geneticist revealed normal developmental milestones and no abnormal features.
Comment Female infants with 47,XXX are relatively common, occurring in 0.1% of liveborn female infants.1 Most of these infants have a normal phenotype.2 Only a few cases with 47,XXX karyotype and congenital malformations are reported in the literature.3-6 One third of female infants with 47,XXX show some mental or behavioral problems, usually of minor significance.1 Females infants with 47,XXX have also been reported to experience delayed menarche and premature ovarian failure.1 There are limited reports on the prenatal diagnosis of 47,XXX. The indication for cytogenetic studies in the prenatally diagnosed cases of 47,XXX are, generally, either advanced maternal age or after the detection of abnormal findings on a prenatal fetal ultrasound examination (oligohydramnios, fetal hydrops, intraoral mass, dysplastic kidneys).3,4,6 The cases that were diagnosed postnatally occurred as the result of the detection of various congenital anomalies, mainly of the genitourinary tract (ambiguous genitalia, ovarian dysgenesis, exstrophy of the cloaca, renal atrophy/agenesis).3,5 It has been established that sex chromosome aneuploidy increases with increasing maternal age and is
Khoury-Collado et al detected after a triple-marker serum screening test, the results of which are positive for Down syndrome, at a higher rate than expected in the general population.7,8 However, in reviewing the data from the large Down syndrome screening trials and from isolated case reports of 47,XXX, we found only 2 cases of prenatal diagnosis of 47,XXX where the indication for invasive testing was a triple-marker serum screening that indicated a high risk of Down syndrome (with a cutoff value of 1:270 or higher).9,10 We found another report of prenatal diagnosis of 47,XXX after ‘‘abnormal’’ serum markers,11 although the latter report did not specify which serum markers were used and what the result indicated (ie, increased risk of trisomy 21 and/or trisomy 18 and/or neural tube defects). To the best of our knowledge, our case of a prenatal diagnosis of 47,XXX after a triple marker serum screening test that was positive for both trisomy 21 and trisomy18 is the first to be reported. Echogenic intracardiac focus was first described in 1987 by Schechter et al.12 It has since become one of the sonographic ‘‘soft’’ markers that are associated with an increased risk of Down syndrome.13 Chromosome abnormalities other than trisomy 21, including sex chromosome abnormalities, have been reported in association with an echogenic intracardiac focus.14,15 However, we found no reported case of an echogenic intracardiac focus that was associated with the 47,XXX karyotype. A single umbilical artery has been associated with malformations of all major organ systems and chromosomal defects.16 When detected on a prenatal ultrasound examination, a detailed search for other associated fetal anomalies is performed; if found, prenatal fetal karyotyping usually is offered. We found only one report of a single umbilical artery that was associated with the diagnosis of 47,XXX.3 At 22 weeks of gestation, the obstetric sonogram revealed severe oligohydramnios and bilateral cystic dysplastic kidneys. The fetus was aborted, and postmortem examination detected the single umbilical artery along with multiple other associated anomalies. The diagnosis of 47,XXX was made by postnatal fetal blood karyotyping. We found no report of prenatal diagnosis of 47,XXX after ultrasound detection of a single umbilical artery with no other congenital malformations. We conclude that our 2 cases of prenatal diagnosis of 47,XXX underline the importance of discussing the sex chromosome abnormalities during the genetic counseling after an abnormal triple screen test or ultrasound examination.
References 1. Simpson JL, Elias S. Sex chromosomal polysomies (47,XXY; 47,XYY; 47,XXX), sex reversed (46,XX) males, and disorders of the male reproductive ducts. In: Simpson JL, Elias S, editors. Genetics in obstetrics and gynecology. Philadelphia: Saunders; 2003. p. 323-41.
Khoury-Collado et al 2. Linden MG, Bender BG, Robinson A. Intrauterine diagnosis of sex chromosome aneuploidy. Obstet Gynecol 1996;87:468-75. 3. Hoang MP, Wilson KS, Schneider NR, Timmons CF. Case report of a 22-week fetus with 47,XXX karyotype and multiple lower mesodermal defects. Pediatr Dev Pathol 1999;2:58-61. 4. Kim ES, Gross TL. Prenatal ultrasound detection of a congenital epulis in a triple X female fetus: a case report. Prenat Diagn 1999;19:774-6. 5. Lin HJ, Ndiforchu F, Patell S. Exstrophy of the cloaca in a 47,XXX child: review of genitourinary malformations in tripleX patients. Am J Med Genet 1993;45:761-3. 6. Spear GS, Porto M. 47,XXX chromosome constitution, ovarian dysgenesis, and genito-urinary malformation. Am J Med Genet 1988;29:511-5. 7. Haddow JE, Palomaki GE, Knight GJ, Cunningham GC, Lustig LS, Boyd PA. Reducing the need for amniocentesis in women 35 years of age or older with serum markers for screening. N Engl J Med 1994;330:1114-8. 8. Kellner LH, Weiss RR, Weiner Z, Neuer M, Martin GM, Schulman H, et al. The advantages of using triple-marker screening for chromosomal abnormalities. Am J Obstet Gynecol 1995;172:831-6. 9. Haddow JE, Palomaki GE, Knight GJ, Williams J, Pulkkinen A, Canick JA, et al. Prenatal screening for Down’s syndrome with the use of maternal serum marker. N Engl J Med 1992;327:588-93.
1471 10. Benn PA, Horne D, Briganti S, Greenstein RM. Prenatal diagnosis of diverse chromosome abnormalities in a population of patients identified by triple-marker testing as screen positive for Down syndrome. Am J Obstet Gynecol 1995;173:496-501. 11. Perrotin F, Guichet A, Marret H, Potin J, Body G, Lansac J. Devenir prenatal des anomalies des chromosomes sexuels diagnostiquees pendant la grossesse: analyse retrospective de 47 cas. J Gynecol Obstet Biol Reprod 2000;29:668-76. 12. Schechter AG, Fakhry J, Shapiro LR, Gewitz MH. In utero thickening of the chordae tendinae: a cause of intracardiac echogenic foci. J Ultrasound Med 1987;6:691-5. 13. Sotiriadis A, Makrydimas G, Ioannidis JPA. Diagnostic performance of intracardiac echogenic foci for Down syndrome: a metaanalysis. Obstet Gynecol 2003;101:1009-16. 14. Huggon IC, Cook AC, Simpson JM, Smeeton NC, Sharland GK. Isolated echogenic foci in the fetal heart as marker of chromosomal abnormality. Ultrasound Obstet Gynecol 2001;17:11-6. 15. Winter TC, Anderson AM, Cheng EY, Komarniski CA, Souter VL, Uhrich SB, et al. Echogenic intracardiac focus in 2ndtrimester fetuses with trisomy 21: usefulness as a US marker. Radiology 2000;216:450-6. 16. Rembouskos G, Cicero S, Longo D, Sacchini C, Nicolaides KH. Single umbilical artery at 11-14 weeks’ gestation: relation to chromosomal defects. Ultrasound Obstet Gynecol 2003;22: 567-70.