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Precocious Puberty in Turner Syndrome Variant
Case Report Precocious Puberty in Turner Syndrome Variant Jong Uk Baek MD 1, Hong Kyu Park MD 2, Eun Jung Shim MD 1, Il Tae Hwang MD, PhD 3,* 1 2 3
Department of Pediatrics, Hallym University Sacred Heart Hospital, Anyang, Korea Department of Pediatrics, Ajou University Hospital, Suwon, Korea Department of Pediatrics, Kangdong Sacred Heart Hospital, Seoul, Korea
a b s t r a c t Background: Turner syndrome is due to the absence of all or significant parts of one of the sex chromosomes in females. Turner syndrome is a common cause of ovarian failure, and hypergonadotropic hypogonadism occurs in virtually all affected individuals. One case of a variant Turner syndrome with precocious puberty is presented. Case: An eight-year-old girl was referred with complaints of short stature and breast budding. A physical examination revealed a Tanner stage III for breast development and her bone age was 11 years. Chromosome analysis showed a karyotype of 46,X,del(x)(p11.2). Summary and Conclusion: To preserve growth potential, careful examinations are recommended for pediatric patients with an unusual growth pattern. Key Words: Abnormal growth, Precocious puberty, Turner syndrome
Introduction
Turner syndrome (TS) is due to the absence of all or significant parts of one of the sex chromosomes in females and affects approximately 1 in 2,500 live births.1 In about 50% of cases, conventional karyotype analysis reveals complete loss of one X chromosome; the remaining affected individuals show variable structural defects of the X chromosome such as mosaicism, partial deletions, or translocations. TS is often accompanied by congenital structural abnormalities, such as bicuspid aortic valve, aortic coarctation, and horseshoe kidney. TS is a common cause of primary ovarian failure, and hypergonadotropic hypogonadism occurs in virtually all affected individuals due to premature loss of oocytes either during fetal development or the postnatal period, causing the ovaries to regress into fibrous streaks.2 However, the incidence of spontaneous puberty in these females is reported to be as high as 30% and is even higher in patients with mosaicism. Less than 4% of these females progress to menarche, and only about 1% can achieve spontaneous pregnancy.3,4 We report a rare case of precocious puberty in a girl with variant TS. Case
An 8-year-old girl was referred to our pediatric endocrinology outpatient clinic with complaints of short stature and breast budding. She was born at term with a birth weight of 2,800 g (9th percentile) and a length of 49 cm The authors indicate no conflicts of interest. * Address correspondence to: Il Tae Hwang, MD, PhD, Department of Pediatrics, Hallym University, Kangdong Sacred Heart Hospital, 445, Gil-dong, Gangdong-gu, Seoul, 134-701, Korea; Phone: þ82-2-2224-2251; Fax þ82-2-482-8334 E-mail address: [email protected] (I.T. Hwang).
(35th percentile). There was no family history of genetic or congenital disorders. Her height on referral was 120.1 cm, which placed her in the 4th percentile on a Korean standard growth chart and at the 75th percentile on a Korean TS growth chart; her weight was 30.8 kg (69th percentile). The mid-parental height was 158.0 cm (29th percentile). A physical examination revealed a Tanner stage III for breast development and Tanner stage I for pubic hair development, genu varum and cubitus valgus. Her bone age was 11 years. Chromosome analysis showed a karyotype of 46,X, del(x)(p11.2). The size and shape of the heart were normal on echocardiography and a kidney ultrasound revealed no abnormalities of the urinary tract. Pelvic ultrasound demonstrated normal-sized ovaries and uterus. Thyroid function tests revealed triiodothyronine (T3) 154.8 ng/dL (normal range: 80-200 ng/dL), free thyroxin (fT4) 1.10 ng/dL (normal range: 0.93-1.7 ng/dL), and thyroid stimulating hormone (TSH) 0.20 mIU/mL (normal range: 0.27-5.0 mIU/ mL). The patient was negative for antimicrosomal antibody (14 IU/mL, normal range: 0-34 IU/mL), and positive for antithyroglobulin antibody (457 IU/mL, normal range: 0-115 IU/ mL). A gonadotropin-releasing hormone (GnRH) agonist stimulation test demonstrated a basal LH level of 0.9 mIU/ mL with a peak level of 10.4 mIU/mL at 30 minutes and a basal FSH level of 9.1 mIU/mL with a peak level of 18.2 mIU/mL at 60 minutes. A slightly elevated serum estradiol level of 20.5 pg/mL was observed, and serum levels of IGF-1 and IGFBP-3 were within normal limits. These findings were consistent with precocious puberty. The patient was treated with a GnRH agonist and growth hormone. Regression of breast development was noted after three months of treatment, and serum estradiol concentrations decreased into the normal limits for prepubertal girls.
1083-3188/$ - see front matter Ó 2012 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpag.2012.05.017
e114
J.U. Baek et al. / J Pediatr Adolesc Gynecol 25 (2012) e113ee114
Summary and Conclusion
Precocious puberty in TS patients is very rare; four patients have been reported, and all of them showed mosaic TS.5e7 There is no literature reporting precocious puberty associated with complete monosomy or variant TS as was found in our reported patient. Individuals with TS manifest various physical characteristics, but short stature and ovarian failure are the most consistent clinical features. The correlations between genotype and phenotype are not yet well understood.8,9 Genes responsible for ovarian function are thought to be located on both the short and long arms of the X chromosome. The proximal region (near the centromere) of the short arm of the X chromosome is more likely to be associated with ovarian function. The ubiquitin specific protease 9, X-linked (USP9X) gene, located in the proximal region of the short arm of the X chromosome (Xp11.4), is a candidate for the gonadal dysgenesis associated with TS.10 Another important gene for normal ovarian function is bone morphogenetic protein 15 (BMP15), which also maps to a locus on the short arm near the centromere of the X chromosome (Xp11.2).11 However, TS patients who have very distal (near the telomere) deletions of the short arm of the X chromosome generally tend to retain normal ovarian function.8 Our patient showed a deletion in a proximal region of the short arm of the X chromosome, but her ovarian function was relatively intact, with spontaneous pubertal progression at the time of investigation. The positive antithyroglobulin antibody and slightly decreased serum TSH level do not seem to be related to the pubertal development in this patient because the thyroid function was normal. We did not perform an ovarian biopsy, but it is assumed that follicular atresia would not occur widely, and there might be sufficient functional oocytes. Precocious puberty without any other evidence of peripheral causes suggests there may be abnormalities in the hypothalamic feedback system that is responsible for gonadal maturation. It can be assumed that increased serum levels of gonadotropic hormones to compensate for blunted ovarian function continuously stimulate the positive feedback loop. Premature ovarian failure and its implications such as infertility or delayed puberty are confronting psychosocial issues in patients with TS because such traits are associated with self-esteem and social adjustment.12 For this reason, pubertal induction with estrogen in appropriately aged girls with TS is important. Early initiation of growth hormone
treatment allows a longer period of estrogen-free growth hormone exposure and results in a taller final height.13 Affected girls without typical features of TS often are not diagnosed until adolescence when they are examined to determine the reasons for short stature or delayed puberty. Some patients receive the diagnosis in adulthood because of recurrent pregnancy loss or infertility. Approximately onethird of patients with TS are detected in mid-childhood when assessed for short stature. One survey estimated that more than 20% of TS patients had been diagnosed after 12 years of age.14 By then, most had failed to enter puberty and had missed the opportunity to be treated with growth hormone, resulting in significant deficits in height. In girls with mosaic karyotypes, growth retardation may begin in mid-childhood after eight years of age. If premature puberty is combined with TS or if the parents are tall, the height of the patient would be within the normal range, and the diagnosis of TS may be further delayed. Careful examinations are recommended for patients with an unusual growth pattern in order to provide appropriately timed pubertal induction without compromising growth potential. References 1. Nielsen J, Wohlert M: Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet 1991; 87:81 2. Weiss L: Additional evidence of gradual loss of germ cells in the pathogenesis of streak ovaries in Turner's syndrome. J Med Genet 1971; 8:540 3. Pasquino AM, Passeri F, Pucarelli I, et al: Spontaneous pubertal development in Turner's syndrome. Italian Study Group for Turner's Syndrome. J Clin Endocrinol Metab 1997; 82:1810 4. Hovatta O: Pregnancies in women with Turner's syndrome. Ann Med 1999; 31:106 5. Huseman CA: Mosaic Turner syndrome with precocious puberty. J Pediatr 1983; 102:892 6. Evanchec KA, Rotenstein D: Treatment of precocious puberty in two patients with Turner mosaicism. J Pediatr Endocrinol Metab 2005; 18:819 7. Sabin MA, Zacharin MR: Precocious puberty in Turner syndrome. J Paediatr Child Health 2007; 43:776 8. Ogata T, Muroya K, Matsuo N, et al: Turner syndrome and Xp deletions: clinical and molecular studies in 47 patients. J Clin Endocrinol Metab 2001; 86:5498 9. Zinn AR, Ross JL: Molecular analysis of genes on Xp controlling Turner syndrome and premature ovarian failure (POF). Semin Reprod Med 2001; 19:141 10. Ranke MB, Saenger P: Turner's syndrome. Lancet 2001; 358:309 11. Di Pasquale E, Beck-Peccoz P, Persani L: Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet 2004; 75:106 12. Carel JC, Elie C, Ecosse E, et al: Self-esteem and social adjustment in young women with Turner syndrome-influence of pubertal management and sexuality: population-based cohort study. J Clin Endocrinol Metab 2006; 91:2972 13. Reiter EO, Blethen SL, Baptista J, et al: Early initiation of growth hormone treatment allows age-appropriate estrogen use in Turner's syndrome. J Clin Endocrinol Metab 2001; 86:1936 14. Massa G, Verlinde F, De Schepper J, et al: Trends in age at diagnosis of Turner syndrome. Arch Dis Child 2005; 90:267
Department of Pediatrics, Hallym University Sacred Heart Hospital, Anyang, Korea Department of Pediatrics, Ajou University Hospital, Suwon, Korea Department of Pediatrics, Kangdong Sacred Heart Hospital, Seoul, Korea
a b s t r a c t Background: Turner syndrome is due to the absence of all or significant parts of one of the sex chromosomes in females. Turner syndrome is a common cause of ovarian failure, and hypergonadotropic hypogonadism occurs in virtually all affected individuals. One case of a variant Turner syndrome with precocious puberty is presented. Case: An eight-year-old girl was referred with complaints of short stature and breast budding. A physical examination revealed a Tanner stage III for breast development and her bone age was 11 years. Chromosome analysis showed a karyotype of 46,X,del(x)(p11.2). Summary and Conclusion: To preserve growth potential, careful examinations are recommended for pediatric patients with an unusual growth pattern. Key Words: Abnormal growth, Precocious puberty, Turner syndrome
Introduction
Turner syndrome (TS) is due to the absence of all or significant parts of one of the sex chromosomes in females and affects approximately 1 in 2,500 live births.1 In about 50% of cases, conventional karyotype analysis reveals complete loss of one X chromosome; the remaining affected individuals show variable structural defects of the X chromosome such as mosaicism, partial deletions, or translocations. TS is often accompanied by congenital structural abnormalities, such as bicuspid aortic valve, aortic coarctation, and horseshoe kidney. TS is a common cause of primary ovarian failure, and hypergonadotropic hypogonadism occurs in virtually all affected individuals due to premature loss of oocytes either during fetal development or the postnatal period, causing the ovaries to regress into fibrous streaks.2 However, the incidence of spontaneous puberty in these females is reported to be as high as 30% and is even higher in patients with mosaicism. Less than 4% of these females progress to menarche, and only about 1% can achieve spontaneous pregnancy.3,4 We report a rare case of precocious puberty in a girl with variant TS. Case
An 8-year-old girl was referred to our pediatric endocrinology outpatient clinic with complaints of short stature and breast budding. She was born at term with a birth weight of 2,800 g (9th percentile) and a length of 49 cm The authors indicate no conflicts of interest. * Address correspondence to: Il Tae Hwang, MD, PhD, Department of Pediatrics, Hallym University, Kangdong Sacred Heart Hospital, 445, Gil-dong, Gangdong-gu, Seoul, 134-701, Korea; Phone: þ82-2-2224-2251; Fax þ82-2-482-8334 E-mail address: [email protected] (I.T. Hwang).
(35th percentile). There was no family history of genetic or congenital disorders. Her height on referral was 120.1 cm, which placed her in the 4th percentile on a Korean standard growth chart and at the 75th percentile on a Korean TS growth chart; her weight was 30.8 kg (69th percentile). The mid-parental height was 158.0 cm (29th percentile). A physical examination revealed a Tanner stage III for breast development and Tanner stage I for pubic hair development, genu varum and cubitus valgus. Her bone age was 11 years. Chromosome analysis showed a karyotype of 46,X, del(x)(p11.2). The size and shape of the heart were normal on echocardiography and a kidney ultrasound revealed no abnormalities of the urinary tract. Pelvic ultrasound demonstrated normal-sized ovaries and uterus. Thyroid function tests revealed triiodothyronine (T3) 154.8 ng/dL (normal range: 80-200 ng/dL), free thyroxin (fT4) 1.10 ng/dL (normal range: 0.93-1.7 ng/dL), and thyroid stimulating hormone (TSH) 0.20 mIU/mL (normal range: 0.27-5.0 mIU/ mL). The patient was negative for antimicrosomal antibody (14 IU/mL, normal range: 0-34 IU/mL), and positive for antithyroglobulin antibody (457 IU/mL, normal range: 0-115 IU/ mL). A gonadotropin-releasing hormone (GnRH) agonist stimulation test demonstrated a basal LH level of 0.9 mIU/ mL with a peak level of 10.4 mIU/mL at 30 minutes and a basal FSH level of 9.1 mIU/mL with a peak level of 18.2 mIU/mL at 60 minutes. A slightly elevated serum estradiol level of 20.5 pg/mL was observed, and serum levels of IGF-1 and IGFBP-3 were within normal limits. These findings were consistent with precocious puberty. The patient was treated with a GnRH agonist and growth hormone. Regression of breast development was noted after three months of treatment, and serum estradiol concentrations decreased into the normal limits for prepubertal girls.
1083-3188/$ - see front matter Ó 2012 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpag.2012.05.017
e114
J.U. Baek et al. / J Pediatr Adolesc Gynecol 25 (2012) e113ee114
Summary and Conclusion
Precocious puberty in TS patients is very rare; four patients have been reported, and all of them showed mosaic TS.5e7 There is no literature reporting precocious puberty associated with complete monosomy or variant TS as was found in our reported patient. Individuals with TS manifest various physical characteristics, but short stature and ovarian failure are the most consistent clinical features. The correlations between genotype and phenotype are not yet well understood.8,9 Genes responsible for ovarian function are thought to be located on both the short and long arms of the X chromosome. The proximal region (near the centromere) of the short arm of the X chromosome is more likely to be associated with ovarian function. The ubiquitin specific protease 9, X-linked (USP9X) gene, located in the proximal region of the short arm of the X chromosome (Xp11.4), is a candidate for the gonadal dysgenesis associated with TS.10 Another important gene for normal ovarian function is bone morphogenetic protein 15 (BMP15), which also maps to a locus on the short arm near the centromere of the X chromosome (Xp11.2).11 However, TS patients who have very distal (near the telomere) deletions of the short arm of the X chromosome generally tend to retain normal ovarian function.8 Our patient showed a deletion in a proximal region of the short arm of the X chromosome, but her ovarian function was relatively intact, with spontaneous pubertal progression at the time of investigation. The positive antithyroglobulin antibody and slightly decreased serum TSH level do not seem to be related to the pubertal development in this patient because the thyroid function was normal. We did not perform an ovarian biopsy, but it is assumed that follicular atresia would not occur widely, and there might be sufficient functional oocytes. Precocious puberty without any other evidence of peripheral causes suggests there may be abnormalities in the hypothalamic feedback system that is responsible for gonadal maturation. It can be assumed that increased serum levels of gonadotropic hormones to compensate for blunted ovarian function continuously stimulate the positive feedback loop. Premature ovarian failure and its implications such as infertility or delayed puberty are confronting psychosocial issues in patients with TS because such traits are associated with self-esteem and social adjustment.12 For this reason, pubertal induction with estrogen in appropriately aged girls with TS is important. Early initiation of growth hormone
treatment allows a longer period of estrogen-free growth hormone exposure and results in a taller final height.13 Affected girls without typical features of TS often are not diagnosed until adolescence when they are examined to determine the reasons for short stature or delayed puberty. Some patients receive the diagnosis in adulthood because of recurrent pregnancy loss or infertility. Approximately onethird of patients with TS are detected in mid-childhood when assessed for short stature. One survey estimated that more than 20% of TS patients had been diagnosed after 12 years of age.14 By then, most had failed to enter puberty and had missed the opportunity to be treated with growth hormone, resulting in significant deficits in height. In girls with mosaic karyotypes, growth retardation may begin in mid-childhood after eight years of age. If premature puberty is combined with TS or if the parents are tall, the height of the patient would be within the normal range, and the diagnosis of TS may be further delayed. Careful examinations are recommended for patients with an unusual growth pattern in order to provide appropriately timed pubertal induction without compromising growth potential. References 1. Nielsen J, Wohlert M: Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet 1991; 87:81 2. Weiss L: Additional evidence of gradual loss of germ cells in the pathogenesis of streak ovaries in Turner's syndrome. J Med Genet 1971; 8:540 3. Pasquino AM, Passeri F, Pucarelli I, et al: Spontaneous pubertal development in Turner's syndrome. Italian Study Group for Turner's Syndrome. J Clin Endocrinol Metab 1997; 82:1810 4. Hovatta O: Pregnancies in women with Turner's syndrome. Ann Med 1999; 31:106 5. Huseman CA: Mosaic Turner syndrome with precocious puberty. J Pediatr 1983; 102:892 6. Evanchec KA, Rotenstein D: Treatment of precocious puberty in two patients with Turner mosaicism. J Pediatr Endocrinol Metab 2005; 18:819 7. Sabin MA, Zacharin MR: Precocious puberty in Turner syndrome. J Paediatr Child Health 2007; 43:776 8. Ogata T, Muroya K, Matsuo N, et al: Turner syndrome and Xp deletions: clinical and molecular studies in 47 patients. J Clin Endocrinol Metab 2001; 86:5498 9. Zinn AR, Ross JL: Molecular analysis of genes on Xp controlling Turner syndrome and premature ovarian failure (POF). Semin Reprod Med 2001; 19:141 10. Ranke MB, Saenger P: Turner's syndrome. Lancet 2001; 358:309 11. Di Pasquale E, Beck-Peccoz P, Persani L: Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet 2004; 75:106 12. Carel JC, Elie C, Ecosse E, et al: Self-esteem and social adjustment in young women with Turner syndrome-influence of pubertal management and sexuality: population-based cohort study. J Clin Endocrinol Metab 2006; 91:2972 13. Reiter EO, Blethen SL, Baptista J, et al: Early initiation of growth hormone treatment allows age-appropriate estrogen use in Turner's syndrome. J Clin Endocrinol Metab 2001; 86:1936 14. Massa G, Verlinde F, De Schepper J, et al: Trends in age at diagnosis of Turner syndrome. Arch Dis Child 2005; 90:267