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Descriptive analyses of Turner syndrome: 49 cases in Tunisia
Annales d’Endocrinologie 71 (2010) 111–116
Original article
Descriptive analyses of Turner syndrome: 49 cases in Tunisia Le syndrome de Turner : étude descriptive de 49 cas en Tunisie M. Elleuch a,∗ , M. Mnif Feki a , M. Kammoun a , N. Charfi a , N. Rekik a , A. Bouraoui b , T. Kammoun b , N. Belguith c , H. Kammoun c , M.T. Sfar d , M. Hachicha b , M. Abid a a
Endocrinology department, Hedi Chaker hospital, 3029 Sfax, Tunisia b Pediatric department, Hedi Chaker hospital, 3029 Sfax, Tunisia c Genetic department, Medecine university, 3029 Sfax, Tunisia d Pediatric department, Fatouma Bourguiba Hospital, Monastir, Tunisia Available online 12 February 2010
Résumé Le syndrome de Turner est lié à l’absence ou à l’anomalie de l’un des deux chromosomes X entraînant une haplo-insuffisance des gènes impliqués dans le développement et la maintenance du capital ovarien chez un sujet de phénotype féminin. Nous rapportons les résultats d’une étude rétrospective sur 21 ans, réalisée chez 49 patientes porteuses d’un syndrome de Turner. L’âge moyen de nos patientes était de 14 ans (un jour–42 ans). Vingt-quatre pour cent d’entre elles étaient diagnostiquées à l’âge adulte (supérieur ou égal à 20 ans). Le syndrome de Turner était diagnostiqué plus tardivement en cas de mosaïque (p = 0,001). Le but de cette étude est d’établir les caractéristiques cliniques, hormonales, cytogénétiques et évolutives d’une population de turnériennes tunisiennes et de rechercher des corrélations génotype–phénotype. Le retard statural était présent dans 85 % des cas ; il était plus fréquent chez les jeunes et dans les monosomies. Le syndrome dysmorphique était objectivé dans 85 % des cas ; il était significativement plus fréquent en cas de monosomie (p = 0,003). Le retard pubertaire était présent dans 62,4 % des cas ; il était quasi-constant en cas de monosomie (p = 0,05). L’atteinte ovarienne était plus sévère en cas de monosomie (p = 0,04). Nos résultats font état de la fréquence élevée des pathologies auto-immunes (18 cas sur 46) notamment de dysthyroidies (huit cas). L’atteinte hépatobiliaire était plus fréquente dans les cas de mosaïque par rapport aux monosomes. La taille moyenne finale était plus élevée en cas de mosaïque : 150,5 cm versus 141 cm chez les monosomes et 138,8 cm dans les mosaïques avec anomalies de structures. © 2010 Elsevier Masson SAS. Tous droits réservés. Mots clés : Syndrome de Turner ; Retard statural ; Syndrome dysmorphique ; Retard pubertaire
Abstract Turner syndrome is linked to the absence or abnormality of one of the X chromosome leading to haplo-insufficiency of genes involved in the development and maintenance of the ovarian stock in women. We report the results of a 21-year retrospective study, conducted in 49 patients with Turner syndrome. The purpose of this study was to establish the clinical, hormonal, cytogenetic and evolutive pattern of a Tunisian population with Turner syndrome and to search for correlations between genotype and phenotype. The average age of our patients at diagnosis was 14 years (1 day–42 years). Twenty-four percent of them were diagnosed in adulthood (greater or equal to 20 years). Turner syndrome was diagnosed later in the case of mosaicism (P = 0.001). Short stature was present in 85% of cases; it was more frequent among the youngest and monosomics. The dysmorphic syndrome was observed in 85% of cases; it was significantly more frequent in monosomics (P = 0.003). Delayed puberty was present in 62.4% of cases, it was almost constant in monosomics (P = 0.05). The loss of ovarian function was more severe in case of monosomia compared to other forms (P = 0.04). Our results report a high frequency of autoimmune diseases (18/46 cases) including dysthyroidism (eight cases). Hepato biliary affections were more frequent in mosaicism compared to monosomy. The average final height was greater even in mosaicism estimated at 150.5 cm compared to 141 cm in monosomics and 138.8 cm in mosaics with abnormal structures. © 2010 Elsevier Masson SAS. All rights reserved. Keywords: Turner syndrome; Short stature; Dysmorphic syndrome; Delayed puberty
∗
Corresponding author. E-mail address: elleuch [email protected] (M. Elleuch).
0003-4266/$ – see front matter © 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ando.2009.12.013
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M. Elleuch et al. / Annales d’Endocrinologie 71 (2010) 111–116
1. Introduction Turner syndrome (TS) is a chronic disease related to the absence or abnormality of one of the two X chromosomes causing haplo-insufficiency of genes involved in the development and maintenance of ovaries capital in a patient with female phenotype [1]. TS occurs in about 1/2500 to 1/5000 female births [2]. The phenotype is the result of haplo-insufficiency of the gene on the X chromosome that prevents premature inactivation of the X chromosome during the embryogenesis process [3]. Furthermore, this syndrome may involve various visceral malformations especially in the heart and the kidneys with a variable frequency related mainly to the type of chromosomal deletion (monosomy or mosaicism). The purpose of this study is to determine the clinical, hormonal, cytogenetic and the evolving characteristics of Tunisian female patients with TS and to search for correlations between genotype and phenotype. 2. Patients and methods This retrospective multicenter study was conducted in 49 patients seen over a period of 21 years, from 1987 to 2008 in the Endocrinology and Pediatric wards in Sfax and the Pediatrics ward in Monastir (Tunisia). The cytogenetic study was based on cell culture using standard technique [2]. An analysis of at least 15 mitoses was made for all patients. We divided our population into three groups according to the chromosome formula. We found 29 cases of monosomy, 12 cases of mosaic without structural abnormalities and eight cases of anomalies with mosaic structures (Table 1). We also studied the various complications of this syndrome: • cardiovascular complications were detected by physical examination and confirmed by echocardiography. This exam was performed in 16 patients. Renal complications were detected by renal ultrasound performed in 37 patients; • hypothyroidism and other autoimmune diseases were screened by physical exam and biological assessment; • the impaired glucose tolerance was systematically analysed by fasting plasma glucose test;
Fig. 1. Age range of our patients. Répartition de nos patientes selon les tranches d’âge.
• hepatobiliary disorders and dyslipidemia were detected on the basis of blood tests performed in 28 and 27 patients respectively. SPSS 11.5 was used to search for correlations between phenotype and genotype. The cohort was also assessed in adulthood. 3. Results 3.1. Age The average age of our patients at the time of diagnosis was 14 years (1 day–42 years). In the majority; diagnosis was established between the ages of 10 and 20 years. Twenty-four percent of our patients were diagnosed in adulthood (greater or equal to 20 years) (Fig. 1). Turner syndrome was diagnosed at a late stage in case of mosaicism. Indeed the average age of monosomics was 18.4 years versus 24.5 years for mosaics without structural abnormalities and 21.3 years for anomalies with mosaic structures (P = 0.01) (Fig. 2). Familial Turner syndrome was reported in one family with three TS in sisters. These patients were aged respectively 31, 17 and 13 years. They were born to consanguineous parents. The cytogenetic study showed a homogeneous monosomy 45XO in
Table 1 Results of cytogenetic studies in our patients. Résultats cytogénétiques. Chromosome formula
Number of cases
Frequency (%)
Monosomy 45 XO Mosaicism without structural anomalies 45X/46XX 45X/46XX/47XXX 45X/46XX/49XXXXX 45X/46XY Mosaicism with structural anomalies 46 Xi (xq)/45 46 Xi (Xp)/46XX Mosaicism with Y chromosome
29 12 7 1 1 2 8 5 3 1
58.5 24 13 2.1 2.1 4.3 17.3 10.8 6.5 2.1
Fig. 2. Correlation between age and chromosome formula. Corrélation tranche d’age/caryotype.
M. Elleuch et al. / Annales d’Endocrinologie 71 (2010) 111–116
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3.4. Dysmorphic syndrome A dysmorphic syndrome was found in the majority of patients (85%). It was significantly more frequent in cases of monosomy than in mosaicism with or without structural abnormalities (P = 0.003) (Fig. 4) Dysmorphic syndrome was also more common in younger patients whatever the karyotype but not significantly. 3.5. Pubertal development
Fig. 3. Frequency of statural delay according to chromosome formula. Fréquence du retard statural en fonction de la formule chromosomique.
the two younger sisters and mosaicism 45XO/46XX in the older sister and a 46 XX mosaicism in the mother.
Delayed puberty was present in 62.4% of cases. The delayed puberty was an almost constant sign in monosomy (15/20 monosomy at the age of puberty) with a significant difference (P = 0.05). Spontaneous puberty was more common in patients with mosaicism with or without abnormal structures, but no significant difference between the three groups (P = 0.2) was noted (Table 2 and Fig. 5). The average serum FSH was 82.5 mU/ml (1–180), and 18.6 mU/ml (0.19–41) for LH. 3.6. Ultrasound data
3.2. Consanguinity Parental consanguinity was found in more than half of the cases (60%). 3.3. Short Stature Growth failure was present in 85% of cases. A positive correlation between the height of the patients and their parents was observed (P = 0.05). Short stature was more frequent among young patients but no correlation with the karyotype was noted. Short stature was particularly common in monosomic patients (23 cases compared with six cases in mosaicism without structural abnormalities and 10 cases among the mosaic patients with abnormal structures) (Fig. 3). Results of the cytogenetic study and the distribution by chromosome formula are given in Table 1.
Fig. 4. Frequency of dysmorphic syndrome according to chromosome formula. Fréquence du syndrome dysmorphique en fonction de la formule chromosomique.
The ovarian damage was more severe in monosomies than the other chromosomal forms (P = 0.04) (Fig. 6 and Table 3). Urinary anomalies and/or heart disease were more frequent in monosomies and mosaicism without abnormal structures while Table 2 Pubertal disorders. Anomalies pubertaires. Pubertal abnormalitis
Number
Frequency (%)
Imbuberism Delayed puberty Primary amenorrhea Secondary amenorrhea Spaniomenorrhea Spontaneous secondary sexual character Spontaneous menarche
19 10 25 2 2 5 4
55.8 29.4 81 7 7 14.7 13
Fig. 5. Repartition of pubertal anomalies according to chromosome formula. Répartition des anomalies pubertaires selon la formule chromosomique.
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M. Elleuch et al. / Annales d’Endocrinologie 71 (2010) 111–116 Table 4 Associated disorders. Pathologies associées.
Fig. 6. Ovarian anomalies according to chromosome formula. Anomalies ovariennes selon la formule chromosomiques. Table 3 Results of pelvic ultra sound analysis. Résultats de l’échographie pelvienne. Results
Number
Frequency (%)
Indetectable ovary Detectable ovary Streak ovary Uterus hypoplasia
31 8 7 10
83.7 23.5 22.5 27
Pathology
Frequency (%)
Thyroid disorders Hashimoto disease Basedow disease Goiter Auto immune disease Poly rheumatoid arthritis Coeliac disease Alopecia Type 1diabete Disorder of glucid tolerance Heart anomaly (stenosis of PA, AI, coartation of the aorta, aortic stenosis) Kideny disorders (3 renal ectopia, 1duplicity, 1 agenesis, 1 hydronephrosis) Adrenal ganglioneuroma Raukitansky syndrome ORL disorders Liver disorders Cytolysis Cholestasis
8 cases (15) 2/8 (25) 2/8 (25) 4/8 (50) 10 cases (22) 2/10 (20) 3/10 (30) 3/10 (30) 2/10 (20) 13 cases (28.2) 8/16 (5) 6/37 (16.2) 1 case (2.1) 1 case (2.1) 5 cases (11) 17 cases (37) 7/28 (25) 10/24 (41)
AI: aortic insufficiency PA: pulmonary artery.
3.10. Evaluation in adulthood they were nearly absent in cases of abnormal structures, but with no significant difference (P = 0.09). These malformations were more common in young people.
Our results indicated a high incidence of autoimmune diseases associated with Turner syndrome 39.1% (18/46) including thyroid dysfunction in eight cases (15%). These diseases were more frequent in monosomies (P = 0.1) and in young patients (Table 4).
The evolution of TS in adulthood was studied in 24 patients. The spontaneous final height, measured in patients not treated with GH, averaged 143.7 cm (127–165). The spontaneous final height was higher in cases of mosaicism without structural abnormalities (150.5 cm) versus (141 cm) in monosomy and (138.8 cm) in mosaicism with abnormal structures. Metabolic disorders were present only in monosomies and mosaicism without structural abnormalities. The average body mass index (BMI) of our adult patients was 20.9 kg/m2 (15–30). Three patients (12%) were overweight; one patient was obese with a BMI at 30 kg/m2 . Dyslipidemia was observed in six patients (25%) and four patients (16%) suffered from type 2 diabetes. Hypertension was noted in two patients (8%). Psycho-affective disturbances were noted in two patients (8%). There was also a higher incidence of impaired learning abilities among monosomies (6/29; 20.9%). Three patients had a normal life; three out of 24 patients had a normal sexual life. One patient died of acute heart failure at the age of 14.
3.9. Treatment of growth failure and delayed puberty
4. Discussion
Treatment with growth hormone (GH) was prescribed for seven patients (27%) of patients at the age to be treated. The dose was 0.9 to 1 IU/kg/week. This treatment was started at an average chronological age of 11 years (8.5 to 14 years), an average bone age of 9 years (7 to 10 years) with a mean duration of 2 years (0.5–5 years). The mean statural gain was 13.5 cm (1 to 25 cm) with an average final height of 135 cm (122 to 148). The statural gain was greater if the age at onset was younger. Hormone replacement therapy was prescribed for 13 patients with completion of puberty after 2 years of treatment.
Compared to the literature findings, our study reports a higher rate of homogeneous monosomies. Indeed various studies show a rate of monosomy ranging between 36.6 and 45% [4–7] and a rate of mosaicism without structural abnormalities varying between 33 and 41% [3–8]. Several studies show an earlier age on diagnosis in case of monosomy. Sybeert et al. [9] showed that 25% of mosaic patients were diagnosed in adulthood. Short stature is associated with haplo-insufficiency of the SHOX gene located in the pseudo autosomal region of the X (Xp11-22) [4–23] and Y (YP 11). It is often a diagnosing circumstance
3.7. Hepatobiliary disorders Hepatobiliary disorders were detected by biological tests. We noted a hepatic cytolysis in 7/28 cases (25%) and cholestatic liver in 10/24 cases. It was more common in cases of mosaicism than in monosomy. 3.8. Autoimmunity
M. Elleuch et al. / Annales d’Endocrinologie 71 (2010) 111–116
of TS with a rate of 54% in our study which seems higher than that of Virginia et al. who reported that 1/3 of patients with TS are diagnosed in childhood and are revealed by short stature (RS) [5]. Our results are consistent with those of Elsheik et al. who reported a higher frequency of short stature (RS) in monosomy and mosaicism with abnormal structures. These results are due to the loss of one allele of the gene SHOX [2–5,8]. Gonadal dysgenesis is due to the haplo-insufficiency of genes involved in ovarian maintenance located on the long arm of the X chromosome, Xq26 (POF1) and Xq 13-21 (POF2) [11]. In contrast, a deletion of the distal short arm is compatible with a normal ovarian function [12–15]. In literature, spontaneous puberty is seen in 2–5% [13], which fits the data of our series. Both the stature study conducted on 704 patients and the Italian multicenter study conducted on 522 patients show spontaneous puberty occurs in 9.8% and 16.1% respectively [14]. The presence of spontaneous puberty was more frequent in mosaicism with or without structural abnormalities compared to monosomies and this point was confirmed by several studies [15]. In fact only 14% of monosomies versus 32% of mosaic patients, with a second X chromosome, show signs of puberty [17]. Sybert et al. [16] showed in 10 cases of TS, that 8/10 girls have follicles in their ovaries, and that the follicular density of ovarian cortex is greater in mosaicism. The presence of chromosome Y that predicts a high risk of gonadoblastoma is reported in 6.4% in our study, which is concordant with the literature result (6.2%) [3]. Renal malformations are nine times more frequent among patients with TS than in the general population [17]. Different studies report a rate of renal malformations from 25 to 43% which exceeds the rate reported by our study, which is probably due to the lack of systematic renal ultrasound examination [18–29]. Congenital heart diseases are noted in 17 to 45% of patients [10], which agrees with our results (50%). Autoimmune thyroiditis is especially diagnosed at an early age with a peak at 4 years [21], which was confirmed in our study. Livadas et al. reported a thyroid dysfunction in 24% of 84 patients aged between 0 to 19 years [21]. Apart from treatment with GH, Elsheikh et al. reported a spontaneous final height at 143 to 147 cm in Caucasian patients [20], which joins our results. Obesity is a common problem in the TS [25]. The etiology of obesity is so far unexplained but several studies have addressed the role of estrogen deficiency [31]. It was also shown that hormone replacement therapy decreases fat mass and the ratio TT/TH in these patients but without changing BMI [26,27]. Type 2 diabetes is twice to four times as common among TS patients than in the general population [28,29]. Thus the frequency of carbohydrate disorders reported in the literature varies from 10 to 34% [30,31], which was also found in our study. In a recent study of 28 women the rate of dyslipidemia was 50% [20]. Several studies report a beneficial effect of GH therapy on lipid metabolism with lowering LDL-C and increasing HDL-c [32]. Murphy et al. [20–33] have shown that women with 45XO had a significantly lower performance score compared with patients who had a mosaic. Preservation of the activity of the ring chromosome is respon-
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sible for mental retardation; in consequence the inactivated X ring is associated with normal intelligence [24]. In the literature, the frequency of patients who reach a higher level of schooling varies from 19 to 33% [20]. Our findings corroborate with some data from the literature as 12% of the patients attended the university. A Danish study reported an average age at death at 65 years from cardiovascular diseases in 50% [34,35]. The only death in our data was a 14-year-old girl in a setting of acute cardiac failure. Schoemakher et al. report that mortality in Turner’s syndrome is three times higher than in the general population [6]. 5. Conclusion Turner syndrome is a genetic syndrome most frequently characterised by short stature, dysmorphic syndrome and gonadal failure. These are the main problems a multidisciplinary team monitors and manages during childhood. Endocrinologists should focus on the different aspects of this syndrome in order to ensure adequate care of these patients. 6. French version A french version of this article is available at doi: 10.1016/j.ando.2009.1.013. Conflict of Interest The authors have not declared any conflict of interest.
References [1] Fénichel P, Letur H. Procreation in turner’s syndrome: Which recommendation before, during and after pregnancy? Gynecol Obstet Fertil 2008;36:891–7. [2] Kammoun L, Chaabouni M, Trabelsi I, Ouertani L, Karoua I, Chelly R. Genetic analysis of Turner syndrome: 89 cases in Tunisia. Ann Endocrinol 2000;69:440–5. [3] Minousk Schoemaker, Anthony Swerdlow, Higgins CD, Wright AF, Jacobs PA. Cancer incidence in women with Turner syndrome in Great Britain: A national cohort study. Lancet Oncol 2008;9:239–46. [4] Cheng L, Maclennan GT, Pan CX, et al. Allelic loss of the active X chromosome during bladder carcinogenesis. Arch Pathol Lab Med 2004;128:187–90. [5] Virginia P, Sybert MD, Elizabeth Mc. Turner’s Syndrome. N Engl J Med 2004;351:1227–38. [6] Minousk S, Anthony S, Craig H, Wright AF, Jacobs PA. Mortality in women with Turner syndrome in great Britain: A national cohort study. JCEM 2008;23:1049–66. [7] Claus Hojbjerg Gravholt, Jens Fedder. Occurrence of gonadoblastoma in females with Turner syndrome and Y chromosome material: A population study. JCEM 2000;85:3199–202. [8] Carolyn A. Care of girls and women with Turner syndrome: A guideline of the Turner syndrome study group. JCEM 2007;92:10–25. [9] Sybert VP. Phenotypic effects of mosaicism for a 47 XXX cell line in Turner syndrome. J Med Genet 2002;39:217–21. [10] Sylvie Cabrol. Le syndrome de Turner. Ann Endocrinol (Paris) 2007;68:2–9. [11] Davison RM, Fox M, Conway GS. Mapping of the POF1 locus and identification of putative genes for premature ovarian failure. Mol Hum Reprod 2000;6:314–8.
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[12] Ogata T, Muroya K, Matsuo N, Shinohara O, Yorifuji T, Nishi Y, et al. Turner syndrome and Xp deletions: Clinical and molecular studies in 47 patients. JCEM 2001;86:5498–508. [13] Leandro Soriano-Guillen, Joel Coste, Emmanuel Ecosse, Juliane Léger, Sylvie Cabrol. Adult height and pubertal Growth in Turner syndrome after treatment with recombinant Growth hormone. JCEM 2005;90:5197–204. [14] Pienkowski C, Menendez M, Cartault A, Lorenzini F, Lesourd F. Syndrome de Turner et procréation. Gynecol Obstet Fertil 2008;36:1030–4. [15] Pasquino AM, Passeri F, Pucarelli, Segni M, Municchi G. Spontaneous pubertal development in Turner’s syndrom Italian Study Group for Turner’s Syndrome. J Clin Endocrinol Metab 1997;82:1810–3. [16] Sybert VP, Mc Cauley E. Turner’s syndrome. N Engl J Med 2004;351:1227–38. [17] Lippe B, Geffner ME, Dietrich RB, Boechat MN, Kangarloo H. Renal malformations in patients with Turner syndrome: Imaging in 141 patients. Pediatrics 1988;82:852–6. [18] Matthies F, Macdiarmid WD, Rallison ML, Tyler FH. Renal anomalies in Turner’s syndrome: Types and suggested embryo-genesis. Clin Pediatr 1971;10:561–5. [19] Flynn MT, Ekstrom L, De Arce M, Costigan C. Prevalence of renal malformation in Turner syndrome. Pediatr Nephrol 1996;10:498–500. [20] Elsheikh M, Dunger B, Conway S. Turner syndrome in adulthood. Endocr Rev 2002;23:120–40. [21] Livadas S, Xekouki P, Fouka F, Kanaka-Gantenbein C, et al. Prevalence of thyroid dysfunction in Turner’s syndrome: Along-term follow-up study and brief literature review. Thyroid 2005;15:1061–6. [22] El-Mansoury M, ryman I, Berntorp K, Hanson C. Hypothyroidism is common in Turner syndrome: Results of a five-year follow – up. J Clin Endocrinol Metab 2005;90:2131–5. [23] Radetti G, Mazzanti L, Paganini C, et al. Frequency, clinical and laboratory features of thyroiditis in girls with Turner’s syndrome The Italien study group for Turner’s syndrome. Acta Pediatr 1995;84:909–12.
[24] Ross JL. Lipid abnormalities in Turner syndrome. J Pediatr 1995;120:242–5. [25] Romans SM, Stefanatos G, Roeltgen DP, Kushner H, Ross JL. Transition to young adulthood in Ullrich-Turner Syndrom: Neurodevelopmental changes. Am J Med Genet 1998;79:140–7. [26] Andrade RJ, Alcantara R, Fraile JM, Lazo MD, et al. Chronic asymptomatic intrahepatic cholestasis associated with Turner’s syndrome. Gastroenterol Hepatol 1995;18:375–8. [27] Floreani A, Molaro M, aragiotta A, Naccarato R. Chronic cholestasis associated with Turner’s syndrome. Digestion 1999;60:587–9. [28] Okada Y. The quality of life of Turner women in comparison with grownup GH deficient women. Endocr J 1994;41:345–54. [29] Pavlidis K, Mc cauley E, Sybert VP. psychosocial and sexual functioning in women with Turner syndrome. Clin Genet 1995;47:85–9. [30] Toublanc JE, Thibaud F, Lecointre C. Psychosocial and sexuel outcome in women with Turner syndrome. Contracept Fertil Sex 1997;25:633–8. [31] Lanes R, Gunezler P, Palacios A, Villaroel O. Serum lipids, lipoprotein Ip(a), and plasminogen activator inhibitor-1 in patients with Turner syndrome befor and during growth hormone and estrogen therapy. Fertil Steril 1997;68:473–7. [32] Ross JL, Kushner H, Roeltgen DP. Developmental changes in motor function in girls with Turner syndrome. Pediatr Neurol 1996;15:317–32. [33] Murphy DG, Allen G, Haxby JV, Largay KA, Daly E, et al. The effects of sex steroids, and the X chromosome, on female brain function: A study of the neuropsychology of adult Turner syndrome. Neuropsychologia 1994;32:1309–23. [34] Price WH, Clayton JF, Collyer S, De Mey R, Wilson J. Mortality ratios, life expectancy, and causes of death in patients with Turner’s syndrome. J Epidemiol Community Health 1986;40:97–102. [35] Naeraa RW, Gravholt CH, Hansen J, Nielsen J, Juul S. Turner syndrome in a life span perspective: Research and clinical aspect. Amsterdam: Elsevier; 1995. pp. 323–323.
Original article
Descriptive analyses of Turner syndrome: 49 cases in Tunisia Le syndrome de Turner : étude descriptive de 49 cas en Tunisie M. Elleuch a,∗ , M. Mnif Feki a , M. Kammoun a , N. Charfi a , N. Rekik a , A. Bouraoui b , T. Kammoun b , N. Belguith c , H. Kammoun c , M.T. Sfar d , M. Hachicha b , M. Abid a a
Endocrinology department, Hedi Chaker hospital, 3029 Sfax, Tunisia b Pediatric department, Hedi Chaker hospital, 3029 Sfax, Tunisia c Genetic department, Medecine university, 3029 Sfax, Tunisia d Pediatric department, Fatouma Bourguiba Hospital, Monastir, Tunisia Available online 12 February 2010
Résumé Le syndrome de Turner est lié à l’absence ou à l’anomalie de l’un des deux chromosomes X entraînant une haplo-insuffisance des gènes impliqués dans le développement et la maintenance du capital ovarien chez un sujet de phénotype féminin. Nous rapportons les résultats d’une étude rétrospective sur 21 ans, réalisée chez 49 patientes porteuses d’un syndrome de Turner. L’âge moyen de nos patientes était de 14 ans (un jour–42 ans). Vingt-quatre pour cent d’entre elles étaient diagnostiquées à l’âge adulte (supérieur ou égal à 20 ans). Le syndrome de Turner était diagnostiqué plus tardivement en cas de mosaïque (p = 0,001). Le but de cette étude est d’établir les caractéristiques cliniques, hormonales, cytogénétiques et évolutives d’une population de turnériennes tunisiennes et de rechercher des corrélations génotype–phénotype. Le retard statural était présent dans 85 % des cas ; il était plus fréquent chez les jeunes et dans les monosomies. Le syndrome dysmorphique était objectivé dans 85 % des cas ; il était significativement plus fréquent en cas de monosomie (p = 0,003). Le retard pubertaire était présent dans 62,4 % des cas ; il était quasi-constant en cas de monosomie (p = 0,05). L’atteinte ovarienne était plus sévère en cas de monosomie (p = 0,04). Nos résultats font état de la fréquence élevée des pathologies auto-immunes (18 cas sur 46) notamment de dysthyroidies (huit cas). L’atteinte hépatobiliaire était plus fréquente dans les cas de mosaïque par rapport aux monosomes. La taille moyenne finale était plus élevée en cas de mosaïque : 150,5 cm versus 141 cm chez les monosomes et 138,8 cm dans les mosaïques avec anomalies de structures. © 2010 Elsevier Masson SAS. Tous droits réservés. Mots clés : Syndrome de Turner ; Retard statural ; Syndrome dysmorphique ; Retard pubertaire
Abstract Turner syndrome is linked to the absence or abnormality of one of the X chromosome leading to haplo-insufficiency of genes involved in the development and maintenance of the ovarian stock in women. We report the results of a 21-year retrospective study, conducted in 49 patients with Turner syndrome. The purpose of this study was to establish the clinical, hormonal, cytogenetic and evolutive pattern of a Tunisian population with Turner syndrome and to search for correlations between genotype and phenotype. The average age of our patients at diagnosis was 14 years (1 day–42 years). Twenty-four percent of them were diagnosed in adulthood (greater or equal to 20 years). Turner syndrome was diagnosed later in the case of mosaicism (P = 0.001). Short stature was present in 85% of cases; it was more frequent among the youngest and monosomics. The dysmorphic syndrome was observed in 85% of cases; it was significantly more frequent in monosomics (P = 0.003). Delayed puberty was present in 62.4% of cases, it was almost constant in monosomics (P = 0.05). The loss of ovarian function was more severe in case of monosomia compared to other forms (P = 0.04). Our results report a high frequency of autoimmune diseases (18/46 cases) including dysthyroidism (eight cases). Hepato biliary affections were more frequent in mosaicism compared to monosomy. The average final height was greater even in mosaicism estimated at 150.5 cm compared to 141 cm in monosomics and 138.8 cm in mosaics with abnormal structures. © 2010 Elsevier Masson SAS. All rights reserved. Keywords: Turner syndrome; Short stature; Dysmorphic syndrome; Delayed puberty
∗
Corresponding author. E-mail address: elleuch [email protected] (M. Elleuch).
0003-4266/$ – see front matter © 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.ando.2009.12.013
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1. Introduction Turner syndrome (TS) is a chronic disease related to the absence or abnormality of one of the two X chromosomes causing haplo-insufficiency of genes involved in the development and maintenance of ovaries capital in a patient with female phenotype [1]. TS occurs in about 1/2500 to 1/5000 female births [2]. The phenotype is the result of haplo-insufficiency of the gene on the X chromosome that prevents premature inactivation of the X chromosome during the embryogenesis process [3]. Furthermore, this syndrome may involve various visceral malformations especially in the heart and the kidneys with a variable frequency related mainly to the type of chromosomal deletion (monosomy or mosaicism). The purpose of this study is to determine the clinical, hormonal, cytogenetic and the evolving characteristics of Tunisian female patients with TS and to search for correlations between genotype and phenotype. 2. Patients and methods This retrospective multicenter study was conducted in 49 patients seen over a period of 21 years, from 1987 to 2008 in the Endocrinology and Pediatric wards in Sfax and the Pediatrics ward in Monastir (Tunisia). The cytogenetic study was based on cell culture using standard technique [2]. An analysis of at least 15 mitoses was made for all patients. We divided our population into three groups according to the chromosome formula. We found 29 cases of monosomy, 12 cases of mosaic without structural abnormalities and eight cases of anomalies with mosaic structures (Table 1). We also studied the various complications of this syndrome: • cardiovascular complications were detected by physical examination and confirmed by echocardiography. This exam was performed in 16 patients. Renal complications were detected by renal ultrasound performed in 37 patients; • hypothyroidism and other autoimmune diseases were screened by physical exam and biological assessment; • the impaired glucose tolerance was systematically analysed by fasting plasma glucose test;
Fig. 1. Age range of our patients. Répartition de nos patientes selon les tranches d’âge.
• hepatobiliary disorders and dyslipidemia were detected on the basis of blood tests performed in 28 and 27 patients respectively. SPSS 11.5 was used to search for correlations between phenotype and genotype. The cohort was also assessed in adulthood. 3. Results 3.1. Age The average age of our patients at the time of diagnosis was 14 years (1 day–42 years). In the majority; diagnosis was established between the ages of 10 and 20 years. Twenty-four percent of our patients were diagnosed in adulthood (greater or equal to 20 years) (Fig. 1). Turner syndrome was diagnosed at a late stage in case of mosaicism. Indeed the average age of monosomics was 18.4 years versus 24.5 years for mosaics without structural abnormalities and 21.3 years for anomalies with mosaic structures (P = 0.01) (Fig. 2). Familial Turner syndrome was reported in one family with three TS in sisters. These patients were aged respectively 31, 17 and 13 years. They were born to consanguineous parents. The cytogenetic study showed a homogeneous monosomy 45XO in
Table 1 Results of cytogenetic studies in our patients. Résultats cytogénétiques. Chromosome formula
Number of cases
Frequency (%)
Monosomy 45 XO Mosaicism without structural anomalies 45X/46XX 45X/46XX/47XXX 45X/46XX/49XXXXX 45X/46XY Mosaicism with structural anomalies 46 Xi (xq)/45 46 Xi (Xp)/46XX Mosaicism with Y chromosome
29 12 7 1 1 2 8 5 3 1
58.5 24 13 2.1 2.1 4.3 17.3 10.8 6.5 2.1
Fig. 2. Correlation between age and chromosome formula. Corrélation tranche d’age/caryotype.
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3.4. Dysmorphic syndrome A dysmorphic syndrome was found in the majority of patients (85%). It was significantly more frequent in cases of monosomy than in mosaicism with or without structural abnormalities (P = 0.003) (Fig. 4) Dysmorphic syndrome was also more common in younger patients whatever the karyotype but not significantly. 3.5. Pubertal development
Fig. 3. Frequency of statural delay according to chromosome formula. Fréquence du retard statural en fonction de la formule chromosomique.
the two younger sisters and mosaicism 45XO/46XX in the older sister and a 46 XX mosaicism in the mother.
Delayed puberty was present in 62.4% of cases. The delayed puberty was an almost constant sign in monosomy (15/20 monosomy at the age of puberty) with a significant difference (P = 0.05). Spontaneous puberty was more common in patients with mosaicism with or without abnormal structures, but no significant difference between the three groups (P = 0.2) was noted (Table 2 and Fig. 5). The average serum FSH was 82.5 mU/ml (1–180), and 18.6 mU/ml (0.19–41) for LH. 3.6. Ultrasound data
3.2. Consanguinity Parental consanguinity was found in more than half of the cases (60%). 3.3. Short Stature Growth failure was present in 85% of cases. A positive correlation between the height of the patients and their parents was observed (P = 0.05). Short stature was more frequent among young patients but no correlation with the karyotype was noted. Short stature was particularly common in monosomic patients (23 cases compared with six cases in mosaicism without structural abnormalities and 10 cases among the mosaic patients with abnormal structures) (Fig. 3). Results of the cytogenetic study and the distribution by chromosome formula are given in Table 1.
Fig. 4. Frequency of dysmorphic syndrome according to chromosome formula. Fréquence du syndrome dysmorphique en fonction de la formule chromosomique.
The ovarian damage was more severe in monosomies than the other chromosomal forms (P = 0.04) (Fig. 6 and Table 3). Urinary anomalies and/or heart disease were more frequent in monosomies and mosaicism without abnormal structures while Table 2 Pubertal disorders. Anomalies pubertaires. Pubertal abnormalitis
Number
Frequency (%)
Imbuberism Delayed puberty Primary amenorrhea Secondary amenorrhea Spaniomenorrhea Spontaneous secondary sexual character Spontaneous menarche
19 10 25 2 2 5 4
55.8 29.4 81 7 7 14.7 13
Fig. 5. Repartition of pubertal anomalies according to chromosome formula. Répartition des anomalies pubertaires selon la formule chromosomique.
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M. Elleuch et al. / Annales d’Endocrinologie 71 (2010) 111–116 Table 4 Associated disorders. Pathologies associées.
Fig. 6. Ovarian anomalies according to chromosome formula. Anomalies ovariennes selon la formule chromosomiques. Table 3 Results of pelvic ultra sound analysis. Résultats de l’échographie pelvienne. Results
Number
Frequency (%)
Indetectable ovary Detectable ovary Streak ovary Uterus hypoplasia
31 8 7 10
83.7 23.5 22.5 27
Pathology
Frequency (%)
Thyroid disorders Hashimoto disease Basedow disease Goiter Auto immune disease Poly rheumatoid arthritis Coeliac disease Alopecia Type 1diabete Disorder of glucid tolerance Heart anomaly (stenosis of PA, AI, coartation of the aorta, aortic stenosis) Kideny disorders (3 renal ectopia, 1duplicity, 1 agenesis, 1 hydronephrosis) Adrenal ganglioneuroma Raukitansky syndrome ORL disorders Liver disorders Cytolysis Cholestasis
8 cases (15) 2/8 (25) 2/8 (25) 4/8 (50) 10 cases (22) 2/10 (20) 3/10 (30) 3/10 (30) 2/10 (20) 13 cases (28.2) 8/16 (5) 6/37 (16.2) 1 case (2.1) 1 case (2.1) 5 cases (11) 17 cases (37) 7/28 (25) 10/24 (41)
AI: aortic insufficiency PA: pulmonary artery.
3.10. Evaluation in adulthood they were nearly absent in cases of abnormal structures, but with no significant difference (P = 0.09). These malformations were more common in young people.
Our results indicated a high incidence of autoimmune diseases associated with Turner syndrome 39.1% (18/46) including thyroid dysfunction in eight cases (15%). These diseases were more frequent in monosomies (P = 0.1) and in young patients (Table 4).
The evolution of TS in adulthood was studied in 24 patients. The spontaneous final height, measured in patients not treated with GH, averaged 143.7 cm (127–165). The spontaneous final height was higher in cases of mosaicism without structural abnormalities (150.5 cm) versus (141 cm) in monosomy and (138.8 cm) in mosaicism with abnormal structures. Metabolic disorders were present only in monosomies and mosaicism without structural abnormalities. The average body mass index (BMI) of our adult patients was 20.9 kg/m2 (15–30). Three patients (12%) were overweight; one patient was obese with a BMI at 30 kg/m2 . Dyslipidemia was observed in six patients (25%) and four patients (16%) suffered from type 2 diabetes. Hypertension was noted in two patients (8%). Psycho-affective disturbances were noted in two patients (8%). There was also a higher incidence of impaired learning abilities among monosomies (6/29; 20.9%). Three patients had a normal life; three out of 24 patients had a normal sexual life. One patient died of acute heart failure at the age of 14.
3.9. Treatment of growth failure and delayed puberty
4. Discussion
Treatment with growth hormone (GH) was prescribed for seven patients (27%) of patients at the age to be treated. The dose was 0.9 to 1 IU/kg/week. This treatment was started at an average chronological age of 11 years (8.5 to 14 years), an average bone age of 9 years (7 to 10 years) with a mean duration of 2 years (0.5–5 years). The mean statural gain was 13.5 cm (1 to 25 cm) with an average final height of 135 cm (122 to 148). The statural gain was greater if the age at onset was younger. Hormone replacement therapy was prescribed for 13 patients with completion of puberty after 2 years of treatment.
Compared to the literature findings, our study reports a higher rate of homogeneous monosomies. Indeed various studies show a rate of monosomy ranging between 36.6 and 45% [4–7] and a rate of mosaicism without structural abnormalities varying between 33 and 41% [3–8]. Several studies show an earlier age on diagnosis in case of monosomy. Sybeert et al. [9] showed that 25% of mosaic patients were diagnosed in adulthood. Short stature is associated with haplo-insufficiency of the SHOX gene located in the pseudo autosomal region of the X (Xp11-22) [4–23] and Y (YP 11). It is often a diagnosing circumstance
3.7. Hepatobiliary disorders Hepatobiliary disorders were detected by biological tests. We noted a hepatic cytolysis in 7/28 cases (25%) and cholestatic liver in 10/24 cases. It was more common in cases of mosaicism than in monosomy. 3.8. Autoimmunity
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of TS with a rate of 54% in our study which seems higher than that of Virginia et al. who reported that 1/3 of patients with TS are diagnosed in childhood and are revealed by short stature (RS) [5]. Our results are consistent with those of Elsheik et al. who reported a higher frequency of short stature (RS) in monosomy and mosaicism with abnormal structures. These results are due to the loss of one allele of the gene SHOX [2–5,8]. Gonadal dysgenesis is due to the haplo-insufficiency of genes involved in ovarian maintenance located on the long arm of the X chromosome, Xq26 (POF1) and Xq 13-21 (POF2) [11]. In contrast, a deletion of the distal short arm is compatible with a normal ovarian function [12–15]. In literature, spontaneous puberty is seen in 2–5% [13], which fits the data of our series. Both the stature study conducted on 704 patients and the Italian multicenter study conducted on 522 patients show spontaneous puberty occurs in 9.8% and 16.1% respectively [14]. The presence of spontaneous puberty was more frequent in mosaicism with or without structural abnormalities compared to monosomies and this point was confirmed by several studies [15]. In fact only 14% of monosomies versus 32% of mosaic patients, with a second X chromosome, show signs of puberty [17]. Sybert et al. [16] showed in 10 cases of TS, that 8/10 girls have follicles in their ovaries, and that the follicular density of ovarian cortex is greater in mosaicism. The presence of chromosome Y that predicts a high risk of gonadoblastoma is reported in 6.4% in our study, which is concordant with the literature result (6.2%) [3]. Renal malformations are nine times more frequent among patients with TS than in the general population [17]. Different studies report a rate of renal malformations from 25 to 43% which exceeds the rate reported by our study, which is probably due to the lack of systematic renal ultrasound examination [18–29]. Congenital heart diseases are noted in 17 to 45% of patients [10], which agrees with our results (50%). Autoimmune thyroiditis is especially diagnosed at an early age with a peak at 4 years [21], which was confirmed in our study. Livadas et al. reported a thyroid dysfunction in 24% of 84 patients aged between 0 to 19 years [21]. Apart from treatment with GH, Elsheikh et al. reported a spontaneous final height at 143 to 147 cm in Caucasian patients [20], which joins our results. Obesity is a common problem in the TS [25]. The etiology of obesity is so far unexplained but several studies have addressed the role of estrogen deficiency [31]. It was also shown that hormone replacement therapy decreases fat mass and the ratio TT/TH in these patients but without changing BMI [26,27]. Type 2 diabetes is twice to four times as common among TS patients than in the general population [28,29]. Thus the frequency of carbohydrate disorders reported in the literature varies from 10 to 34% [30,31], which was also found in our study. In a recent study of 28 women the rate of dyslipidemia was 50% [20]. Several studies report a beneficial effect of GH therapy on lipid metabolism with lowering LDL-C and increasing HDL-c [32]. Murphy et al. [20–33] have shown that women with 45XO had a significantly lower performance score compared with patients who had a mosaic. Preservation of the activity of the ring chromosome is respon-
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sible for mental retardation; in consequence the inactivated X ring is associated with normal intelligence [24]. In the literature, the frequency of patients who reach a higher level of schooling varies from 19 to 33% [20]. Our findings corroborate with some data from the literature as 12% of the patients attended the university. A Danish study reported an average age at death at 65 years from cardiovascular diseases in 50% [34,35]. The only death in our data was a 14-year-old girl in a setting of acute cardiac failure. Schoemakher et al. report that mortality in Turner’s syndrome is three times higher than in the general population [6]. 5. Conclusion Turner syndrome is a genetic syndrome most frequently characterised by short stature, dysmorphic syndrome and gonadal failure. These are the main problems a multidisciplinary team monitors and manages during childhood. Endocrinologists should focus on the different aspects of this syndrome in order to ensure adequate care of these patients. 6. French version A french version of this article is available at doi: 10.1016/j.ando.2009.1.013. Conflict of Interest The authors have not declared any conflict of interest.
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