J Pediatr Endocrinol Metab 2015; aop
Petrit Hoxha, Anila Babameto-Laku, Gentian Vyshka*, Klodiana Gjoka, Dorina Minxuri, Elira Myrtaj and Luljeta Çakërri
Turner syndrome in Albania and the efficacy of its treatment with growth hormone DOI 10.1515/jpem-2014-0350 Received August 20, 2014; accepted April 24, 2015
Abstract: The aim of this study was the evaluation of Turner syndrome inside the Albanian population, its clinical, cytological and genetic characteristics, the accompanying pathologies, and the efficacy of the treatment with the growth hormone. We performed a retrospective analysis of 59 patients suffering from this syndrome (aging from 5 to 23 years old). The diagnosis of female patients suffering from Turner syndrome is delayed, with a mean age at the moment of diagnosis of 13.74 years (5–23 years). The main reason for seeking medical advice was the growth retardation or a delayed puberty. Available data for 52 patients showed that the most frequent accompanying pathologies were the following: thyroid autoimmune disorders (59%), cardiovascular anomalies (43%), renal pathologies (41%), hearing impairment (4.3%) and hypertension (3.3%). Follow-up for the growth rate was possible for 52 patients out of the total of 59 patients. Twenty-five of the female patients suffering Turner syndrome and forming part of our study sample were treated with growth hormone for a period averaging 3 years and 4 months. A variety of reasons was identified as responsible for the missed treatment in 27 patients. We saw an enhanced growth (in terms of body height) within the treated subgroup, when compared with the untreated subgroup (27 patients), especially during the first 3 years of the follow-up. No side effects of this *Corresponding author: Gentian Vyshka, MD, Faculty of Medicine, Biomedical and Experimental Department, University of Medicine in Tirana, Albania, Phone: +355692828140, Fax: +35542362268, E-mail: [email protected]. http://orcid.org/0000-0001-5286-1265 Petrit Hoxha: Service of Pediatrics, University Hospital Center “Mother Theresa”, Tirana, Albania Anila Babameto-Laku: Faculty of Medicine, Department of Immunology and Genetics, University of Medicine in Tirana, Tirana, Albania Klodiana Gjoka, Dorina Minxuri and Elira Myrtaj: Service of Endocrinology, University Hospital Center “Mother Theresa”, Tirana, Albania Luljeta Çakërri: Faculty of Medicine, Biomedical and Experimental Department, University of Medicine in Tirana, Albania
treatment were reported. Both groups of patients initiated as well a sexual hormone therapy (estrogens and progesterone) for inducing puberty at the age of 12 years. Further work is needed for an early diagnosis of this syndrome, the prompt treatment with growth hormone and the monitoring of accompanying disorders. This will ensure a better quality of life and an improvement of the longevity of patients suffering from the Turner syndrome. Keywords: accompanying disorders; final height; growth hormone; karyotype; Turner syndrome.
Introduction Turner syndrome (TS) represents a common chromosomal anomaly affecting female patients, with a frequency approaching one case every 2000 births according to some authors; other sources suggest a figure of 1 out of every 5000 newborn girls (1, 2). This syndrome is related to the complete or the partial absence of a chromosome X, thus resulting in a karyotype 45X and a female phenotype. Some female patients suffering from this syndrome will present with a mosaic karyotype, with a wide range of phenotypes (3). Accompanying clinical characteristics of TS include a wide range of anomalies, such as ovarian insufficiency, infertility, short stature, other cardiac and renal malformations, hypertension, diabetes, hypothyroidism and hearing impairment (4–7). Most frequently, the affected patients present with a short stature and a premature ovarian insufficiency. Short stature, affecting as much as 95% of the females with TS, is partially due to the loss of a copy of the gene SHOX, located in the chromosome X (8). The loss of this genetic material might be responsible for some skeletal anomalies, including short metacarpal or metatarsal bones, and cubitus valgus. Due to this defect, linear growth will slow down right from the intrauterine period, and the stature will be shorter than average during childhood and adolescence, with a final height reaching 143–145 cm. On the other hand, the final height of females suffering from TS will increase with several centimeters,
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2 Hoxha et al.: Turner syndrome treatment with GH in the case of an early and prompt therapy with growth hormone (GH), if started during childhood (9–11). Infertility is another major concern of these patients. Most of female patients suffering from TS will have a decreased ovarian function right from early childhood, and consequently puberty will fail to start. Some adolescents might present breast development and menstruations, but no further pubertal changes will be seen. Only a slim part of female patients will have a normal ovarian function and regular periods till the age of twenties, with the appearance of a premature ovarian insufficiency thereafter. In view of the absence of a spontaneous pubertal development, an estrogen-based therapy is started. Lowdose estrogen therapy combined with GH will improve the final height outcomes, but a very early start of the therapy, or otherwise the use of high doses of hormonal drugs, will adversely affect the final height (12, 13). Estrogen-progesterone therapy in TS patients will continue till the age of 50s, with the aim of safeguarding secondary sexual characteristics and protecting from osteoporosis. TS might be accompanied by other medical conditions, leading to severe morbidity and mortality and affecting the quality of life of the patients. Most important among those are cardiovascular malformations, such as the hypoplasia of left ventricle, aortic coarctation, bicuspid aortic valve and aortic dissection in adult age (14). Close cardiologic monitoring after initial evaluation is therefore warranted (15). Among different methods of assessment of the aortic morphology, magnetic resonance imaging has been recently suggested as a highly reliable option (16). Patients suffering from TS are at risk of suffering from autoimmune disorders, most frequently from thyroid gland pathologies. Half of TS patients are positive for antithyroid antibodies, and 10%–30% of those will suffer from hypothyroidism (17). Other autoimmune disorders that are met include celiac disease, Crohn disease and ulcerous colitis (18). An increased insulin resistance and diabetes mellitus of type 2 is seen as well in TS patients, when compared to the general population. Diabetes is seen mostly in the adult age, accompanied with overweight. Structural malformations of the urinary tract are a common finding in TS patients, with duplication of pyelocaliceal system among others (7, 19). Although not directly influencing the renal function, such malformations might provoke an obstructive hydronephrosis. The majority of TS patients have a normal intelligence level, but a small part might show an important developmental retardation, requiring special assistance even during adulthood. Mental retardation is more frequently
met in patients with ring or marker chromosomes (7). Difficulties in learning, including impairment of non-verbal, mathematical, motor coordination and visuospatial executive functions are reported in the literature (7, 20–22). Magnetic resonance imaging of the brain and positronemission tomography studies have yielded no definitive results with regard to the changes found and the respective correlation with the neurocognitive status of the patients. Females suffering from TS will show increased immaturity, social isolation and higher anxiety levels, with facial and emotional recognition deficits (23–25). All this spectrum of neuropsychiatric problems will of course lead to interpersonal and behavioral problems (26, 27).
Materials and methods The Service of Pediatrics, University Hospital Centre of Tirana, is the only tertiary facility covering the entire Albanian territory, with all specific pediatric pathologies referred herein, including rare and orphan diseases. From the period 1993 to 2013 we registered 59 female patients suffering from TS and compiled a detailed national database with regard to this specific disease. The present study was undertaken with the aim to analyze the characteristics of TS in the Albanian population, as well as to evaluate the efficacy of its treatment with growth hormone, particularly vis-à-vis the final height and the growth rate of the patients. Similar studies have been performed elsewhere by other authors (28, 29). This is the first one dealing with patients from Albania. Inclusion criterion for the study was the confirmation of the diagnosis with the karyotype analysis. Exclusion criteria were the following: the presence of any acute illness or other endocrine or metabolic disorders; previous use of drugs influencing the presence of spontaneous puberty or otherwise interacting pharmacologically with the growth hormone. Patients with growth retardation due to other pathologies were excluded as well. All patients were retrospectively analyzed for the data available on the karyotype, phenotypic characteristics and accompanying pathologies such as renal disease, cardiac disease, ocular diseases, metabolic disorders, celiac disease, and autoimmune thyroid disease. Furthermore, we analyzed the effect of the growth hormone treatment on the growth velocity and final height. GH therapy was administered to patients with TS who did not meet the exclusion criteria and did not have closed epiphyses. The untreated subgroup of 27 patients was studied retrospectively with regard to the reasons of this missed GH treatment. The main reason for this non-treatment was the lack of reimbursement of the therapy from the national health system, but fear from hormonal therapy side effects and poor access to specialized centers were identified as possible reasons as well, with the distance of home from the University Hospital Center being a major challenge for the treatment. The biosynthetic human growth hormone, Norditropin® [Novo Nordisk] was applied subcutaneously once daily to each patient, in a dosage of 0.04 mg/kg weight. Dosage adjustment was performed monthly, according to the weight changes of the treated patient. The
Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 7/30/15 4:32 PM
Hoxha et al.: Turner syndrome treatment with GH 3 treatment with GH was stopped when the growth rate was
Petrit Hoxha, Anila Babameto-Laku, Gentian Vyshka*, Klodiana Gjoka, Dorina Minxuri, Elira Myrtaj and Luljeta Çakërri
Turner syndrome in Albania and the efficacy of its treatment with growth hormone DOI 10.1515/jpem-2014-0350 Received August 20, 2014; accepted April 24, 2015
Abstract: The aim of this study was the evaluation of Turner syndrome inside the Albanian population, its clinical, cytological and genetic characteristics, the accompanying pathologies, and the efficacy of the treatment with the growth hormone. We performed a retrospective analysis of 59 patients suffering from this syndrome (aging from 5 to 23 years old). The diagnosis of female patients suffering from Turner syndrome is delayed, with a mean age at the moment of diagnosis of 13.74 years (5–23 years). The main reason for seeking medical advice was the growth retardation or a delayed puberty. Available data for 52 patients showed that the most frequent accompanying pathologies were the following: thyroid autoimmune disorders (59%), cardiovascular anomalies (43%), renal pathologies (41%), hearing impairment (4.3%) and hypertension (3.3%). Follow-up for the growth rate was possible for 52 patients out of the total of 59 patients. Twenty-five of the female patients suffering Turner syndrome and forming part of our study sample were treated with growth hormone for a period averaging 3 years and 4 months. A variety of reasons was identified as responsible for the missed treatment in 27 patients. We saw an enhanced growth (in terms of body height) within the treated subgroup, when compared with the untreated subgroup (27 patients), especially during the first 3 years of the follow-up. No side effects of this *Corresponding author: Gentian Vyshka, MD, Faculty of Medicine, Biomedical and Experimental Department, University of Medicine in Tirana, Albania, Phone: +355692828140, Fax: +35542362268, E-mail: [email protected]. http://orcid.org/0000-0001-5286-1265 Petrit Hoxha: Service of Pediatrics, University Hospital Center “Mother Theresa”, Tirana, Albania Anila Babameto-Laku: Faculty of Medicine, Department of Immunology and Genetics, University of Medicine in Tirana, Tirana, Albania Klodiana Gjoka, Dorina Minxuri and Elira Myrtaj: Service of Endocrinology, University Hospital Center “Mother Theresa”, Tirana, Albania Luljeta Çakërri: Faculty of Medicine, Biomedical and Experimental Department, University of Medicine in Tirana, Albania
treatment were reported. Both groups of patients initiated as well a sexual hormone therapy (estrogens and progesterone) for inducing puberty at the age of 12 years. Further work is needed for an early diagnosis of this syndrome, the prompt treatment with growth hormone and the monitoring of accompanying disorders. This will ensure a better quality of life and an improvement of the longevity of patients suffering from the Turner syndrome. Keywords: accompanying disorders; final height; growth hormone; karyotype; Turner syndrome.
Introduction Turner syndrome (TS) represents a common chromosomal anomaly affecting female patients, with a frequency approaching one case every 2000 births according to some authors; other sources suggest a figure of 1 out of every 5000 newborn girls (1, 2). This syndrome is related to the complete or the partial absence of a chromosome X, thus resulting in a karyotype 45X and a female phenotype. Some female patients suffering from this syndrome will present with a mosaic karyotype, with a wide range of phenotypes (3). Accompanying clinical characteristics of TS include a wide range of anomalies, such as ovarian insufficiency, infertility, short stature, other cardiac and renal malformations, hypertension, diabetes, hypothyroidism and hearing impairment (4–7). Most frequently, the affected patients present with a short stature and a premature ovarian insufficiency. Short stature, affecting as much as 95% of the females with TS, is partially due to the loss of a copy of the gene SHOX, located in the chromosome X (8). The loss of this genetic material might be responsible for some skeletal anomalies, including short metacarpal or metatarsal bones, and cubitus valgus. Due to this defect, linear growth will slow down right from the intrauterine period, and the stature will be shorter than average during childhood and adolescence, with a final height reaching 143–145 cm. On the other hand, the final height of females suffering from TS will increase with several centimeters,
Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 7/30/15 4:32 PM
2 Hoxha et al.: Turner syndrome treatment with GH in the case of an early and prompt therapy with growth hormone (GH), if started during childhood (9–11). Infertility is another major concern of these patients. Most of female patients suffering from TS will have a decreased ovarian function right from early childhood, and consequently puberty will fail to start. Some adolescents might present breast development and menstruations, but no further pubertal changes will be seen. Only a slim part of female patients will have a normal ovarian function and regular periods till the age of twenties, with the appearance of a premature ovarian insufficiency thereafter. In view of the absence of a spontaneous pubertal development, an estrogen-based therapy is started. Lowdose estrogen therapy combined with GH will improve the final height outcomes, but a very early start of the therapy, or otherwise the use of high doses of hormonal drugs, will adversely affect the final height (12, 13). Estrogen-progesterone therapy in TS patients will continue till the age of 50s, with the aim of safeguarding secondary sexual characteristics and protecting from osteoporosis. TS might be accompanied by other medical conditions, leading to severe morbidity and mortality and affecting the quality of life of the patients. Most important among those are cardiovascular malformations, such as the hypoplasia of left ventricle, aortic coarctation, bicuspid aortic valve and aortic dissection in adult age (14). Close cardiologic monitoring after initial evaluation is therefore warranted (15). Among different methods of assessment of the aortic morphology, magnetic resonance imaging has been recently suggested as a highly reliable option (16). Patients suffering from TS are at risk of suffering from autoimmune disorders, most frequently from thyroid gland pathologies. Half of TS patients are positive for antithyroid antibodies, and 10%–30% of those will suffer from hypothyroidism (17). Other autoimmune disorders that are met include celiac disease, Crohn disease and ulcerous colitis (18). An increased insulin resistance and diabetes mellitus of type 2 is seen as well in TS patients, when compared to the general population. Diabetes is seen mostly in the adult age, accompanied with overweight. Structural malformations of the urinary tract are a common finding in TS patients, with duplication of pyelocaliceal system among others (7, 19). Although not directly influencing the renal function, such malformations might provoke an obstructive hydronephrosis. The majority of TS patients have a normal intelligence level, but a small part might show an important developmental retardation, requiring special assistance even during adulthood. Mental retardation is more frequently
met in patients with ring or marker chromosomes (7). Difficulties in learning, including impairment of non-verbal, mathematical, motor coordination and visuospatial executive functions are reported in the literature (7, 20–22). Magnetic resonance imaging of the brain and positronemission tomography studies have yielded no definitive results with regard to the changes found and the respective correlation with the neurocognitive status of the patients. Females suffering from TS will show increased immaturity, social isolation and higher anxiety levels, with facial and emotional recognition deficits (23–25). All this spectrum of neuropsychiatric problems will of course lead to interpersonal and behavioral problems (26, 27).
Materials and methods The Service of Pediatrics, University Hospital Centre of Tirana, is the only tertiary facility covering the entire Albanian territory, with all specific pediatric pathologies referred herein, including rare and orphan diseases. From the period 1993 to 2013 we registered 59 female patients suffering from TS and compiled a detailed national database with regard to this specific disease. The present study was undertaken with the aim to analyze the characteristics of TS in the Albanian population, as well as to evaluate the efficacy of its treatment with growth hormone, particularly vis-à-vis the final height and the growth rate of the patients. Similar studies have been performed elsewhere by other authors (28, 29). This is the first one dealing with patients from Albania. Inclusion criterion for the study was the confirmation of the diagnosis with the karyotype analysis. Exclusion criteria were the following: the presence of any acute illness or other endocrine or metabolic disorders; previous use of drugs influencing the presence of spontaneous puberty or otherwise interacting pharmacologically with the growth hormone. Patients with growth retardation due to other pathologies were excluded as well. All patients were retrospectively analyzed for the data available on the karyotype, phenotypic characteristics and accompanying pathologies such as renal disease, cardiac disease, ocular diseases, metabolic disorders, celiac disease, and autoimmune thyroid disease. Furthermore, we analyzed the effect of the growth hormone treatment on the growth velocity and final height. GH therapy was administered to patients with TS who did not meet the exclusion criteria and did not have closed epiphyses. The untreated subgroup of 27 patients was studied retrospectively with regard to the reasons of this missed GH treatment. The main reason for this non-treatment was the lack of reimbursement of the therapy from the national health system, but fear from hormonal therapy side effects and poor access to specialized centers were identified as possible reasons as well, with the distance of home from the University Hospital Center being a major challenge for the treatment. The biosynthetic human growth hormone, Norditropin® [Novo Nordisk] was applied subcutaneously once daily to each patient, in a dosage of 0.04 mg/kg weight. Dosage adjustment was performed monthly, according to the weight changes of the treated patient. The
Brought to you by | University of Queensland - UQ Library Authenticated Download Date | 7/30/15 4:32 PM
Hoxha et al.: Turner syndrome treatment with GH 3 treatment with GH was stopped when the growth rate was
