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47,XXX Turner mosaicism: Implications for prenatal counseling and estrogen therapy at puberty
Phenotype, ovarian function, and growth in patients with 45,X/47,XXX Turner mosaicism: Implications for prenatal counseling and estrogen therapy at puberty Joanne Blair, MRCP, John Tolmie, FRCP, Anne S. Hollman,† FRCP, and Malcolm D. C. Donaldson, MD, FRCP Objective: Our objective was to determine whether girls with the rare Turner 45,X/47,XXX mosaic karyotype are less severely affected than girls with 2 commoner karyotypes. Study design: We evaluated growth status, phenotype, and ovarian function in 7 girls with 45,X/47,XXX mosaicism, age-matching each with 2 girls with 45,X and 1 with 45,X/46,Xi(X)(q10) karyotypes. Results: For the index, 45,X, and 45,X/46,Xi(X)(q10) groups, respectively, the median/mean height SD score at the start of growth hormone therapy/comparable age was –2.0 (–1.2), –2.3 (–2.4), and –2.6 (–2.6), cardiac anomalies were identified in 0 of 7, 4 of 14, and 1 of 7, renal abnormalities in 0 of 7, 4 of 14, and 3 of 7, middle ear problems in 2 of 7, 11 of 14, and 4 of 7, and special educational needs in 0 of 7, 3 of 14, and 1 of 7. Complete spontaneous puberty with menarche was seen in all but 1 girl older than 12 years in the index group compared with only 1 girl in the comparison groups. Ovarian tissue was identified in 6 of 7, 0 of 14, and 1 of 7 girls, and the mean folliclestimulating hormone was 6, 25, and 21 U/L, respectively. Conclusion: Girls with 45,X/47,XXX karyotype are mildly affected, with good preservation of ovarian function. This result has important implications for prenatal counseling and the need for estrogen therapy at puberty. (J Pediatr 2001;139:724–8)
Turner syndrome, defined as a loss or abnormality of the second X chromosome, is a common chromosomal abnormality affecting 1:2000 live female
births.1 The syndrome is characterized by growth retardation, ovarian dysgenesis, and phenotypic abnormalities, but there is considerable variation, with a
From the Department of Child Health, Duncan Guthrie Institute of Medical Genetics, and the Department of Radiology, Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland. †Deceased.
Submitted for publication Oct 27, 2000; revisions received May 10, 2001, July 3, 2001; accepted July 6, 2001. Reprint requests: M.D.C. Donaldson, MD, Department of Child Health, Royal Hospital for Sick Children, Yorkhill, Glasgow, G3 8SJ, Scotland. Copyright © 2001 by Mosby, Inc 0022-3476/2001/$35.00 + 0 9/21/118571 doi:10.1067/mpd.2001.118571
724
minority of girls showing minimal dysmorphic features, adequate growth, and spontaneous, progressive puberty or a combination of these. With the advent of improved antenatal ultrasound techniques, fetal chromosome abnormalities are more easily identified.2,3 Therapeutic abortion may be offered if Turner syndrome is diagnosed4; therefore more precise correlation between the Turner karyotype and the clinical manifestations of the syndrome would have important implications for counseling at the time of diagnosis. FSH SDS
Follicle-stimulating hormone Standard deviation score
The improved prognosis for growth and ovarian function for girls with 45,X/46,XX mosaicism is well recognized.5-10 Otherwise, attempts to correlate phenotype and karyotype have largely been unsuccessful, although weak associations have been reported, including more marked short stature and increased incidence of thyroiditis with the X-isochromosome9-12 and increased frequency of cardiac, renal, and craniofacial anomalies with 45,X monosomy.13-16 However, it may be that significant correlations exist for the rarer karyotypes but have not so far been recognized because of insufficient numbers in any given study. The purpose of this study was to test our hypothesis that the rare 45,X/47,XXX mosaic karyotype, which affects 1.7% of patients with Turner
BLAIR ET AL
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VOLUME 139, NUMBER 5 syndrome,17 is associated with a milder phenotype than usual.
METHODS Patients with Turner syndrome caused by 45,X/47,XXX mosaicism were identified through the Scottish Turner syndrome database, which was established in 1990 and has been regularly updated. Each case was agematched with two 45,X and one 45,X/46,Xi(X)(q10) girls by the identification of patients with the date of birth closest to the index case. All index cases agreed to participate in the study. Where a patient in the comparison group declined to participate in the study, the girl with the next closest date of birth was invited. Patients were invited to attend an appointment with the principal investigator (J.B.) and a clinical geneticist (J.T.), who was blinded to the karyotype. Ovarian function was assessed clinically on the basis of spontaneous onset of puberty, menarche, and a regular menstrual cycle, biochemically by basal follicle-stimulating hormone levels, and by pelvic ultrasonography by a single observer (A.S.H.) comparing ovarian volume with normative data as previously described.18 Growth status was assessed by recording height SD score at the time of the start of growth hormone therapy and at review with the 1990 United Kingdom standards of Freeman et al. 19 When girls in the index group did not receive growth hormone, height SDS was recorded at the age closest to the mean age of the start of growth hormone in the age-matched control group. Because the data were not normally distributed, betweengroup differences in median height SDS were analyzed with the MannWhitney test. In an attempt to document dysmorphism objectively, we agreed on specific features to be assessed by the clinical geneticist (J.T.), who was blinded to
the karyotype of each patient. The following features were selected, scoring between 0 (absent) and 5 (severe): epicanthic folds, oblique palpebral fissures, ptosis, low set ± rotated ears, micrognathia, squint, dental overcrowding ± need for dental extractions or other orth-odontic treatment, neck webbing or low hair line, hyperconvex nails and puffy nail folds, cubitus valgus, short fourth or fifth metacarpals or metatarsals, lymphedema of hands or feet, and nevi. The 13 features chosen thus yielded an arbitrary maximum score of 65. Cardiac abnormalities detected on clinical evaluation or by cardiac ultrasonography and renal tract abnormalities found on routine imaging (ultrasonography ± dimercapto– succinic acid scan) were noted. Middle ear problems including otitis media with effusion, the need for insertion of ventilation tubes, and hearing loss were also noted. Special educational needs were assessed by recording whether girls had attended mainstream education with no help in an age-appropriate class, had needed to repeat a year during primary or secondary education or had required extra help, or had received education in a special school. Approval for the study was obtained from the Yorkhill Ethics Committee, and written consent was obtained from all participants.
RESULTS Seven girls with Turner syndrome caused by 45,X/47,XXX mosaicism aged 6.1 to 20.4 years (mean 14.3 years) were identified; all agreed to be studied. Two of these patients had been given the diagnosis before birth. Fourteen girls with 45,X who were 6.4 to 20.3 years (mean 13.7 years) and 7 girls with 45,X/46,Xi(X)(q10) who were 6.1 to 19.5 years (mean 14.0 years) agreed to be in the comparison groups. Seven girls with these karyotypes declined to take part.
Growth Three of the 7 girls in the index group have not required growth hormone therapy in view of satisfactory height status. This result was in contrast to the girls in the comparison groups, all of whom received treatment. The median/mean (range) height SDS at the time of the start of growth hormone/equivalent age was –2.0/–1.2 (–2.6 to +0.5) for the index cases, –2.3/–2.4 (–3.8 to –1.5) for the 45,X group, and –2.6/–2.6 (–3.3 to –1.9) for the 45,X/46,Xi(X)(q10) group (Table). At review, the mean height SDS had increased in all groups. The median/ mean (range) height SDS values were –0.7/–0.7 (–2.6 to +1.1) for the index cases, –1.3/ –1.5(–3.3 to –0.4) for the 45,X group, and –2.2/–2.2 (–4.3 to –1.1) for the 45,X/46,Xi(X)(q10) group. The between-group differences were not significant, although the difference in median height SDS at review between the index and 45,X/46,Xi(X)(q10) groups almost reached significance (P = .053).
Ovarian Function 45,X/47,XXX GROUP. All 6 girls older than 10 years had a spontaneous puberty, with the exception of 1 girl who received estrogen as a matter of protocol at the age of 8 years. All 5 girls older than 12 years had a spontaneous menarche with regular menstrual cycles without medication, again with the exception of the girl who received estrogen. Pelvic ultrasonography identified ovarian tissue in 6 of the 7 cases. The girl whose ovaries were not seen had a spontaneous, progressive puberty. The mean basal FSH in this group was 6 U/L (range 3.2 to 11.8 U/L). 45,X GROUP. Pelvic ultrasonography failed to identify ovarian tissue in any of these girls. Although 2 of the 14 girls had a spontaneous puberty, none achieved menarche without the use of estrogen. The mean basal FSH in this 725
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Table. Comparative growth and ovarian function in 7 index cases versus age-matched control group
Karyotype 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq
Current age (y)
Ht SDS at start Growth hormone /equivalent age
Current height SDS
6.1 6.4 7.3 6.1 10.6 10.6 10.1 9.9 12.6 13.4 12.7 12.5 12 11.3 11.5 13.4 20.1 17.3 16.9 19.5 20.4 18.6 20.3 18.7 18.3 18.2 16.5 18
0.5 –3.3 –1.6 –2.6 –0.3 –1.9 –1.5 –2.4 – 2.6 –1.7 –1.6 –1.9 0.5 –1.8 –2.2 –2.5 –2.0 –2.9 –2.3 –2.8 –2.2 –2.8 –3.8 Data not available –2.1 –3.8 –3 –3.3
–0.3 –2.7 –0.8 –2.8 1.1 –1.1 –1.6 –1.3 –0.7 –2.3 –1.3 –1.3 0.3 –1.8 –0.4 –2.2 –1.3 –0.9 –2.1 –1.1 –1.3 –0.7 –1.3 –4.3 –2.6 –3.3 –0.9 –2.3
group was 25 U/L (range 1.3 to 71 U/L). 45,X/46,XI(X)(Q10). Only 1 of these girls had visible ovarian tissue on ultrasonography, and this was the only patient to have a spontaneous puberty and menarche. The basal FSH in this group was 21 U/L (4.7 to 53.1 U/L).
Phenotype As anticipated, there was marked variability in the severity of dysmorphic features within each group of patients (Figure). The girls in the index group scored consistently lower than those in the comparison groups (mean 726
Ovarian volume R/L (mL)
Spontaneous puberty
Spontaneous menarche
Visualized N/A N/A Not visualized N/A N/A Not visualized N/A N/A Not visualized N/A N/A 2.3/2.4 Yes N/A Not visualized No N/A Not visualized No N/A Not visualized No N/A Not visualized Yes Yes Not visualized No No Not visualized Yes No 2.5 / 0.8 Yes Yes 6.3 / 2.4 Yes Yes Not visualized No No Not visualized No No Not visualized No No 2.6 / Not visualized Yes Yes Not visualized No No Not visualized No No Not visualized No No 3 / 4.6 Yes Yes Not visualized No No Not visualized Yes No Not visualized No No 4.8 / 4.2 E2 from 8 years E2 from 8 years Not visualized No No Not visualized No No Not visualized No No
score 6, range 0 to 10), and 1 of the girls who had been given the diagnosis before birth showed no dysmorphic features. Girls with the 45,X karyotype were the most severely affected (mean score 21, range 15 to 37), although there was considerable overlap with the 45,X/46,Xi(X)(q10) group (mean score 14, range 12 to 28). CARDIAC AND RENAL ABNORMALITIES. No renal or cardiac abnormalities were identified in the girls in the index group. The girls in the 45,X group were found to have the following anomalies: horseshoe kidneys (2), cross-fused ectopia (1), malrotated kidneys (1), non-
Basal FSH (U/L) 5.8 52.8 60.3 4.7 11.8 7.7 71 31.3 5.6 14.2 40.6 7.1 4.7 25.1 1.7 12.6 3.2 13.4 1.3 16.7 7.5 4.8 19.5 53.1 3.6 2.2 35.7 21.2
functioning kidney (1), coarctation of aorta (2), bicuspid aortic valve (1), and aortic stenosis (1). In the 7 girls in the 45,X/46,Xi(X)(q10) group, the following anomalies were identified: horseshoe kidney (1), malrotated kidney (2) with duplex ureters in one of these, and bicuspid aortic valve (1). MIDDLE EAR PROBLEMS. One of the index cases had required ventilation tube insertion for otitis media with effusion, and 1 other girl had documented hearing loss. Of the 7 patients in the 45,X/46,Xi(X)(q10) group, 4 had a history of otitis media with effusion, for which 2 required ventilation tubes.
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VOLUME 139, NUMBER 5 The frequency of middle ear pathologic conditions was greatest in the 45,X group. Of the 14 girls in the 45,X group, 1 had sensory hearing loss and wore hearing aids. Ten of the remaining 13 had had otitis media with effusion, 8 of whom had been treated with ventilation tubes. SPECIAL EDUCATIONAL NEEDS. Four of the 28 girls had special educational needs, of whom 3 had a 45,X karyotype and 1 had 45,X/46,Xi(X)(q10) mosaicism.
Figure. Phenotype score derived from 13 dysmorphic features (graded 0 - 5) in 28 girls with Turner syndrome according to karyotype. Girls with 45,X/47,XXX mosaicism have distinctly lower phenotype scores.
DISCUSSION This study confirms our impression that women and girls with Turner syndrome caused by 45,X/47,XXX mosaicism are more mildly affected clinically, especially with regard to phenotype and ovarian function. Although the median height SDS before and after treatment was not significantly different in the index group compared with that in the comparison groups, the fact that 3 of the index cases were not deemed to need growth hormone treatment and that height SDS at review was within the normal range for 6 of the 7 girls does indicate that individuals with the 45,X/47,XXX karyotype are less likely to manifest growth impairment than those with the commoner karyotypes. By blinding our geneticist to the karyotype of the subjects and scoring their degree of dysmorphism, we demonstrated that there is a milder expression of dysmorphic features in the patients with 45,X/47,XXX. Also, although the absolute number of patients with cardiac, renal, and middle ear abnormalities was small, it is noteworthy that none of the patients in the index group had any cardiac or renal abnormalities demonstrated, and only 2 had middle ear disease. By contrast, 9 of the 14 girls in the 45,X group and 4 of the 7 girls in the 45,X/46,Xi(X)(q10) group had malformations of the heart or renal
tract or both. The strong association between Turner syndrome and middle ear pathology20 is amply demonstrated, with all but 6 of the 21 girls in the comparison group having had problems. Although up to 20% of girls with Turner syndrome enter puberty spontaneously, few will achieve menarche without the use of estrogens.7,8,21 By contrast, with the exception of 1 girl who received estrogen as a matter of protocol at age 8 years, all our girls with 45,X/47,XXX who were 10 years or older had a spontaneous puberty, and those older than 12 years had a spontaneous menarche. We suggest that whereas the families of girls with typical Turner’s syndrome should be counseled that estrogen therapy at puberty is very likely to be required, girls with the 45,X/47,XXX variety can expect to go through puberty normally without treatment. The prognosis for childbearing in our 7 girls with 45,X/47,XXX mosaicism is guarded but optimistic. Tarani et al22 reviewed the outcome of spontaneous pregnancy in 74 women with Turner syndrome, including 12 patients with the 45,X/47,XXX karyotype. Although only 62 (38%) of 160 pregnancies in the whole group resulted in healthy liveborn children, the outcome was normal in 16 (unknown in 2) of 20 pregnancies in the 45,X/47,XXX group.
The educational difficulties of girls with 45,X have been well documented.23-26 Studies of girls with 47,XXX have reported highly variable but generally poor cognitive development with a high incidence of maladaptive behavior and psychiatric illness.26,27 It is a little surprising, therefore, that girls who are mosaic for these two chromosomal abnormalities appear to have no cognitive or behavioral abnormality. It would seem that the clinical effects of haploinsufficiency of the genes in the 45,X cells are ameliorated by the 47,XXX cell line. We thank Dr. John Schulga from Stirling, Dr. Stephen Greene from Dundee, Dr. Christopher Kelnar from Edinburgh, and Dr. Peter Smail from Aberdeen for allowing us to study their patients.
REFERENCES 1. Nielson J, Wohlet TM. Chromosome abnormalities found among 34910 newborn children: results from a 13 year incidence study in Arhus, Denmark. Hum Genet 1991;87:81-3. 2. Nicolaides K, Snijders RJ, Gosden CM, Berry C, Campbell S. Ultrasonographically detectable markers of foetal chromosomal abnormality. Lancet 1992;340:704-7. 3. Wenstrom KD, Boots LR, Cosper PC. Multiple screening test: identification of foetal cystic hygroma, hydrops and sex 727
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chromosome aneuploidy. J Matern Fetal Med 1996;5:31-5. Liden M, Bender BG, Robinson A. Intrauterine diagnosis of sex chromosome aneuploidy. Obstet Gynecol 1996;87:468-75. Koerberl DD, McGillivray B, Sybert VP. Prenatal diagnosis of 45,X/46,XX mosaicism and 45,X: implications for postnatal outcome. Am J Hum Genet 1996;47:661-6. Mazzanti L, Cacciari E, Bergamaschi R, Tassinari D, Magnani C, Perri A, et al. Pelvic ultrasound in patients with Turner’s syndrome: age-related findings in different karyotypes. J Pediatr 1997;131:135-40. Pasquino AM, Passeri F, Pucarelli I, Segni M, Municchi G. Spontaneous pubertal development in Turner’s Syndrome. J Clin Endocrinol Metab 1997; 82:1810-3. Massa G, Vanderschueren-Lodeweyckx M, Malvaux P. Linear growth in patients with Turner’s syndrome: influence of spontaneous puberty and parental height. Eur J Pediatr 1990; 149:246-50. Low LC, Sham C, Kwan E, Karlberg J, Cheung PT, Pang H, et al. Spontaneous growth in Chinese patients with Turner’s syndrome and influence of karyotype. Acta Paediatr 1997; 86:18-21. Cohen A, Kauli R, Lavagetto, A, Roitmano Y, Pertzelan A, Romano C, et al. Final height of girls with Turner’s syndrome: correlation with karyotype and parental height. Acta Paediatr 1995;84:550-4. de-Kerdanet M, Lucas J, Lemee F, Lecornu M. Turner’s syndrome of Xisochromosome and Hashimoto’s thy-
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roiditis. Clin Endocrinol (Oxf) 1994;41:673-6. Ivarsson SA, Ericsson UB, Nilsson KO, Gustafsson J, Hagenas L, Hager A, et al. Thyroid autoantibodies, Turner’s syndrome and growth hormone therapy. Acta Paediatr 1995;84:63-5. Mazzanti L, Caccciari E. Congenital heart disease in patients with Turner’s syndrome. Italian Study Group for Turner’s syndrome. J Pediatr 1998; 133:688-92. Gotzsche CO, Krag-Olsen B, Nielson J, Soernsen KE, Kristensen BO. Prevalence of cardiovascular malformations and association with karyotype in Turner’s syndrome. Arch Dis Child 1994;71:433-6. Flynn M T, Ekstrom L, De Arce M, Costigan C. Prevalence of renal malformation in Turner’s syndrome. Paediatr Nephrol 1996;10:498-500. Mibtbo M, Witsh PJ, Halse A. Craniofacial morphology in young patients with Turner’s syndrome. Eur J Orthod 1996;18:215-25. Kleczkowska A, Dmoch E, Kubein E, Fryns JP, Van den Berghe H. Cyogenetic findings in a consecutive series of 478 patients with Turner’s syndrome. The Lueven experience. Genet Couns 1990;1:227-33. Griffin IJ, Cole TJ, Duncan K, Hollman AS, Donaldson MDC. Pelvic ultrasound measurements in normal girls. Acta Paediatr 1995; 84:536-43. Freeman JV, Cole TJ, Chinn S, Jones PR, White EM, Preece MA. Cross sectional stature and weight reference curves for the UK. Arch Dis Child 1995;73:17-24.
20. Stenberg AE, Nylen O, Windh M, Hultcrantz M. Otological problems in children with Turner’s syndrome. Heart Res 1998;124:85-90. 21. Matarazzo P, Lala R, Artesani L, Franceshchini P, De Sanctis C. Sonographic appearance of ovaries and gonadotrophin levels as prognostic tools of spontaneous puberty in girls with Turner’s syndrome. J Pediatr Endocrinol Metab 1995;8:267-74. 22. Tarani L, Lampariello S, Raguso G, Colloridi F, Pucarelli I, Pasquino AM, et al. Pregnancy in patients with Turner’s syndrome: six new cases and review of literature. Gynecol Endocrinol 1998;12:83-7. 23. Bender BG, Puck M, Salbenblatt J, Robinson A. Cognitive development of unselected girls with complete and partial X monosomy. Pediatrics 1984; 73:175-81. 24. Mazzocco MM. A process approach to describing mathematics difficulties in girls with Turner syndrome. Pediatrics 1998;102:492-6. 25. Siegal PT, Clopper R, Stabler B. The psychological consequences of Turner’s syndrome and review of National Co-operative Growth Study Psychological Substudy. Pediatrics 1998; 102:488-91. 26. Bender BG, Harmon RJ, Linden MG, Robinson A. Psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. Pediatrics 1995;96:302-8. 27. Linden MG, Bender BG, Harmon RJ, Mrazek DA, Robinson A. 47,XXX: What is the prognosis? Pediatrics 1998;82:619-26.
Turner syndrome, defined as a loss or abnormality of the second X chromosome, is a common chromosomal abnormality affecting 1:2000 live female
births.1 The syndrome is characterized by growth retardation, ovarian dysgenesis, and phenotypic abnormalities, but there is considerable variation, with a
From the Department of Child Health, Duncan Guthrie Institute of Medical Genetics, and the Department of Radiology, Royal Hospital for Sick Children, Yorkhill, Glasgow, Scotland. †Deceased.
Submitted for publication Oct 27, 2000; revisions received May 10, 2001, July 3, 2001; accepted July 6, 2001. Reprint requests: M.D.C. Donaldson, MD, Department of Child Health, Royal Hospital for Sick Children, Yorkhill, Glasgow, G3 8SJ, Scotland. Copyright © 2001 by Mosby, Inc 0022-3476/2001/$35.00 + 0 9/21/118571 doi:10.1067/mpd.2001.118571
724
minority of girls showing minimal dysmorphic features, adequate growth, and spontaneous, progressive puberty or a combination of these. With the advent of improved antenatal ultrasound techniques, fetal chromosome abnormalities are more easily identified.2,3 Therapeutic abortion may be offered if Turner syndrome is diagnosed4; therefore more precise correlation between the Turner karyotype and the clinical manifestations of the syndrome would have important implications for counseling at the time of diagnosis. FSH SDS
Follicle-stimulating hormone Standard deviation score
The improved prognosis for growth and ovarian function for girls with 45,X/46,XX mosaicism is well recognized.5-10 Otherwise, attempts to correlate phenotype and karyotype have largely been unsuccessful, although weak associations have been reported, including more marked short stature and increased incidence of thyroiditis with the X-isochromosome9-12 and increased frequency of cardiac, renal, and craniofacial anomalies with 45,X monosomy.13-16 However, it may be that significant correlations exist for the rarer karyotypes but have not so far been recognized because of insufficient numbers in any given study. The purpose of this study was to test our hypothesis that the rare 45,X/47,XXX mosaic karyotype, which affects 1.7% of patients with Turner
BLAIR ET AL
THE JOURNAL OF PEDIATRICS
VOLUME 139, NUMBER 5 syndrome,17 is associated with a milder phenotype than usual.
METHODS Patients with Turner syndrome caused by 45,X/47,XXX mosaicism were identified through the Scottish Turner syndrome database, which was established in 1990 and has been regularly updated. Each case was agematched with two 45,X and one 45,X/46,Xi(X)(q10) girls by the identification of patients with the date of birth closest to the index case. All index cases agreed to participate in the study. Where a patient in the comparison group declined to participate in the study, the girl with the next closest date of birth was invited. Patients were invited to attend an appointment with the principal investigator (J.B.) and a clinical geneticist (J.T.), who was blinded to the karyotype. Ovarian function was assessed clinically on the basis of spontaneous onset of puberty, menarche, and a regular menstrual cycle, biochemically by basal follicle-stimulating hormone levels, and by pelvic ultrasonography by a single observer (A.S.H.) comparing ovarian volume with normative data as previously described.18 Growth status was assessed by recording height SD score at the time of the start of growth hormone therapy and at review with the 1990 United Kingdom standards of Freeman et al. 19 When girls in the index group did not receive growth hormone, height SDS was recorded at the age closest to the mean age of the start of growth hormone in the age-matched control group. Because the data were not normally distributed, betweengroup differences in median height SDS were analyzed with the MannWhitney test. In an attempt to document dysmorphism objectively, we agreed on specific features to be assessed by the clinical geneticist (J.T.), who was blinded to
the karyotype of each patient. The following features were selected, scoring between 0 (absent) and 5 (severe): epicanthic folds, oblique palpebral fissures, ptosis, low set ± rotated ears, micrognathia, squint, dental overcrowding ± need for dental extractions or other orth-odontic treatment, neck webbing or low hair line, hyperconvex nails and puffy nail folds, cubitus valgus, short fourth or fifth metacarpals or metatarsals, lymphedema of hands or feet, and nevi. The 13 features chosen thus yielded an arbitrary maximum score of 65. Cardiac abnormalities detected on clinical evaluation or by cardiac ultrasonography and renal tract abnormalities found on routine imaging (ultrasonography ± dimercapto– succinic acid scan) were noted. Middle ear problems including otitis media with effusion, the need for insertion of ventilation tubes, and hearing loss were also noted. Special educational needs were assessed by recording whether girls had attended mainstream education with no help in an age-appropriate class, had needed to repeat a year during primary or secondary education or had required extra help, or had received education in a special school. Approval for the study was obtained from the Yorkhill Ethics Committee, and written consent was obtained from all participants.
RESULTS Seven girls with Turner syndrome caused by 45,X/47,XXX mosaicism aged 6.1 to 20.4 years (mean 14.3 years) were identified; all agreed to be studied. Two of these patients had been given the diagnosis before birth. Fourteen girls with 45,X who were 6.4 to 20.3 years (mean 13.7 years) and 7 girls with 45,X/46,Xi(X)(q10) who were 6.1 to 19.5 years (mean 14.0 years) agreed to be in the comparison groups. Seven girls with these karyotypes declined to take part.
Growth Three of the 7 girls in the index group have not required growth hormone therapy in view of satisfactory height status. This result was in contrast to the girls in the comparison groups, all of whom received treatment. The median/mean (range) height SDS at the time of the start of growth hormone/equivalent age was –2.0/–1.2 (–2.6 to +0.5) for the index cases, –2.3/–2.4 (–3.8 to –1.5) for the 45,X group, and –2.6/–2.6 (–3.3 to –1.9) for the 45,X/46,Xi(X)(q10) group (Table). At review, the mean height SDS had increased in all groups. The median/ mean (range) height SDS values were –0.7/–0.7 (–2.6 to +1.1) for the index cases, –1.3/ –1.5(–3.3 to –0.4) for the 45,X group, and –2.2/–2.2 (–4.3 to –1.1) for the 45,X/46,Xi(X)(q10) group. The between-group differences were not significant, although the difference in median height SDS at review between the index and 45,X/46,Xi(X)(q10) groups almost reached significance (P = .053).
Ovarian Function 45,X/47,XXX GROUP. All 6 girls older than 10 years had a spontaneous puberty, with the exception of 1 girl who received estrogen as a matter of protocol at the age of 8 years. All 5 girls older than 12 years had a spontaneous menarche with regular menstrual cycles without medication, again with the exception of the girl who received estrogen. Pelvic ultrasonography identified ovarian tissue in 6 of the 7 cases. The girl whose ovaries were not seen had a spontaneous, progressive puberty. The mean basal FSH in this group was 6 U/L (range 3.2 to 11.8 U/L). 45,X GROUP. Pelvic ultrasonography failed to identify ovarian tissue in any of these girls. Although 2 of the 14 girls had a spontaneous puberty, none achieved menarche without the use of estrogen. The mean basal FSH in this 725
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Table. Comparative growth and ovarian function in 7 index cases versus age-matched control group
Karyotype 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq 45,X/47,XXX 45,X 45,X 45,X/46,XiXq
Current age (y)
Ht SDS at start Growth hormone /equivalent age
Current height SDS
6.1 6.4 7.3 6.1 10.6 10.6 10.1 9.9 12.6 13.4 12.7 12.5 12 11.3 11.5 13.4 20.1 17.3 16.9 19.5 20.4 18.6 20.3 18.7 18.3 18.2 16.5 18
0.5 –3.3 –1.6 –2.6 –0.3 –1.9 –1.5 –2.4 – 2.6 –1.7 –1.6 –1.9 0.5 –1.8 –2.2 –2.5 –2.0 –2.9 –2.3 –2.8 –2.2 –2.8 –3.8 Data not available –2.1 –3.8 –3 –3.3
–0.3 –2.7 –0.8 –2.8 1.1 –1.1 –1.6 –1.3 –0.7 –2.3 –1.3 –1.3 0.3 –1.8 –0.4 –2.2 –1.3 –0.9 –2.1 –1.1 –1.3 –0.7 –1.3 –4.3 –2.6 –3.3 –0.9 –2.3
group was 25 U/L (range 1.3 to 71 U/L). 45,X/46,XI(X)(Q10). Only 1 of these girls had visible ovarian tissue on ultrasonography, and this was the only patient to have a spontaneous puberty and menarche. The basal FSH in this group was 21 U/L (4.7 to 53.1 U/L).
Phenotype As anticipated, there was marked variability in the severity of dysmorphic features within each group of patients (Figure). The girls in the index group scored consistently lower than those in the comparison groups (mean 726
Ovarian volume R/L (mL)
Spontaneous puberty
Spontaneous menarche
Visualized N/A N/A Not visualized N/A N/A Not visualized N/A N/A Not visualized N/A N/A 2.3/2.4 Yes N/A Not visualized No N/A Not visualized No N/A Not visualized No N/A Not visualized Yes Yes Not visualized No No Not visualized Yes No 2.5 / 0.8 Yes Yes 6.3 / 2.4 Yes Yes Not visualized No No Not visualized No No Not visualized No No 2.6 / Not visualized Yes Yes Not visualized No No Not visualized No No Not visualized No No 3 / 4.6 Yes Yes Not visualized No No Not visualized Yes No Not visualized No No 4.8 / 4.2 E2 from 8 years E2 from 8 years Not visualized No No Not visualized No No Not visualized No No
score 6, range 0 to 10), and 1 of the girls who had been given the diagnosis before birth showed no dysmorphic features. Girls with the 45,X karyotype were the most severely affected (mean score 21, range 15 to 37), although there was considerable overlap with the 45,X/46,Xi(X)(q10) group (mean score 14, range 12 to 28). CARDIAC AND RENAL ABNORMALITIES. No renal or cardiac abnormalities were identified in the girls in the index group. The girls in the 45,X group were found to have the following anomalies: horseshoe kidneys (2), cross-fused ectopia (1), malrotated kidneys (1), non-
Basal FSH (U/L) 5.8 52.8 60.3 4.7 11.8 7.7 71 31.3 5.6 14.2 40.6 7.1 4.7 25.1 1.7 12.6 3.2 13.4 1.3 16.7 7.5 4.8 19.5 53.1 3.6 2.2 35.7 21.2
functioning kidney (1), coarctation of aorta (2), bicuspid aortic valve (1), and aortic stenosis (1). In the 7 girls in the 45,X/46,Xi(X)(q10) group, the following anomalies were identified: horseshoe kidney (1), malrotated kidney (2) with duplex ureters in one of these, and bicuspid aortic valve (1). MIDDLE EAR PROBLEMS. One of the index cases had required ventilation tube insertion for otitis media with effusion, and 1 other girl had documented hearing loss. Of the 7 patients in the 45,X/46,Xi(X)(q10) group, 4 had a history of otitis media with effusion, for which 2 required ventilation tubes.
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VOLUME 139, NUMBER 5 The frequency of middle ear pathologic conditions was greatest in the 45,X group. Of the 14 girls in the 45,X group, 1 had sensory hearing loss and wore hearing aids. Ten of the remaining 13 had had otitis media with effusion, 8 of whom had been treated with ventilation tubes. SPECIAL EDUCATIONAL NEEDS. Four of the 28 girls had special educational needs, of whom 3 had a 45,X karyotype and 1 had 45,X/46,Xi(X)(q10) mosaicism.
Figure. Phenotype score derived from 13 dysmorphic features (graded 0 - 5) in 28 girls with Turner syndrome according to karyotype. Girls with 45,X/47,XXX mosaicism have distinctly lower phenotype scores.
DISCUSSION This study confirms our impression that women and girls with Turner syndrome caused by 45,X/47,XXX mosaicism are more mildly affected clinically, especially with regard to phenotype and ovarian function. Although the median height SDS before and after treatment was not significantly different in the index group compared with that in the comparison groups, the fact that 3 of the index cases were not deemed to need growth hormone treatment and that height SDS at review was within the normal range for 6 of the 7 girls does indicate that individuals with the 45,X/47,XXX karyotype are less likely to manifest growth impairment than those with the commoner karyotypes. By blinding our geneticist to the karyotype of the subjects and scoring their degree of dysmorphism, we demonstrated that there is a milder expression of dysmorphic features in the patients with 45,X/47,XXX. Also, although the absolute number of patients with cardiac, renal, and middle ear abnormalities was small, it is noteworthy that none of the patients in the index group had any cardiac or renal abnormalities demonstrated, and only 2 had middle ear disease. By contrast, 9 of the 14 girls in the 45,X group and 4 of the 7 girls in the 45,X/46,Xi(X)(q10) group had malformations of the heart or renal
tract or both. The strong association between Turner syndrome and middle ear pathology20 is amply demonstrated, with all but 6 of the 21 girls in the comparison group having had problems. Although up to 20% of girls with Turner syndrome enter puberty spontaneously, few will achieve menarche without the use of estrogens.7,8,21 By contrast, with the exception of 1 girl who received estrogen as a matter of protocol at age 8 years, all our girls with 45,X/47,XXX who were 10 years or older had a spontaneous puberty, and those older than 12 years had a spontaneous menarche. We suggest that whereas the families of girls with typical Turner’s syndrome should be counseled that estrogen therapy at puberty is very likely to be required, girls with the 45,X/47,XXX variety can expect to go through puberty normally without treatment. The prognosis for childbearing in our 7 girls with 45,X/47,XXX mosaicism is guarded but optimistic. Tarani et al22 reviewed the outcome of spontaneous pregnancy in 74 women with Turner syndrome, including 12 patients with the 45,X/47,XXX karyotype. Although only 62 (38%) of 160 pregnancies in the whole group resulted in healthy liveborn children, the outcome was normal in 16 (unknown in 2) of 20 pregnancies in the 45,X/47,XXX group.
The educational difficulties of girls with 45,X have been well documented.23-26 Studies of girls with 47,XXX have reported highly variable but generally poor cognitive development with a high incidence of maladaptive behavior and psychiatric illness.26,27 It is a little surprising, therefore, that girls who are mosaic for these two chromosomal abnormalities appear to have no cognitive or behavioral abnormality. It would seem that the clinical effects of haploinsufficiency of the genes in the 45,X cells are ameliorated by the 47,XXX cell line. We thank Dr. John Schulga from Stirling, Dr. Stephen Greene from Dundee, Dr. Christopher Kelnar from Edinburgh, and Dr. Peter Smail from Aberdeen for allowing us to study their patients.
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