Clinical manifestations and diagnosis of Turner syndrome (gonadal dysgenesis)
- Paul Saenger, MD, MACE
Paul Saenger, MD, MACE
- Professor Emeritus of Pediatrics
- Albert Einstein College of Medicine
- Section Editors
- Peter J Snyder, MD
Peter J Snyder, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Pituitary Disease
- Section Editor — Male Reproductive Endocrinology
- Professor of Medicine
- University of Pennsylvania School of Medicine
- Helen V Firth, DM, FRCP, DCH
Helen V Firth, DM, FRCP, DCH
- Section Editor — Genetics
- Consultant Clinical Geneticist
- Addenbrooke's Hospital, Cambridge, UK
- Mitchell Geffner, MD
Mitchell Geffner, MD
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Keck School of Medicine, University of Southern California
Turner syndrome is an important cause of short stature in girls and primary amenorrhea in young women that is usually caused by loss of part or all of an X chromosome. The clinical manifestations and diagnosis of Turner syndrome will be reviewed here. Treatment of this disorder is discussed separately. (See "Management of Turner syndrome (gonadal dysgenesis)".)
Turner syndrome, first described in 1938 , is the most common sex chromosome abnormality in females and occurs in approximately 1/2,500 live births, based on data from Europe, Japan, and the United States . The true prevalence of Turner syndrome is difficult to ascertain, since those with mild phenotypic features may remain undiagnosed .
Molecular studies have shown that the maternal X is retained in two-thirds of patients with Turner syndrome and the paternal X in the remaining one-third . More than one-half of all patients with Turner syndrome have a mosaic chromosomal complement (eg, 45,X/46,XX) detectable in peripheral blood leukocytes [5,6]. Mosaicism with a normal cell line in the fetal membranes may be necessary in all affected cases for adequate placental function and fetal survival .
The identification of mosaicism depends directly upon the method of ascertainment. It varies from 34 percent with conventional cytogenetic techniques to 60 percent with fluorescence in situ hybridization (FISH) techniques to 74 percent in a study in which reverse transcriptase polymerase-chain-reaction (PCR) assays were used .
Some patients with Turner syndrome lack only part of one sex chromosome, and the Turner syndrome phenotype can be seen with a variety of structural abnormalities, such as isochromosomes, rings, or terminal deletions . A rare but very informative class of Turner syndrome includes patients who have deletions of the Y chromosome that remove the testes-determining gene, SRY; these individuals develop as females. Based upon this finding and the fact that males require only one X chromosome for normal development, Ferguson-Smith hypothesized that copies of Turner syndrome genes are also present on the Y chromosome.
- Turner HH. A syndrome of infantilism, congenital webbed neck, and cubitus valgus. Endocrinology 1938; 28:566.
- Bondy CA, Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab 2007; 92:10.
- Gunther DF, Eugster E, Zagar AJ, et al. Ascertainment bias in Turner syndrome: new insights from girls who were diagnosed incidentally in prenatal life. Pediatrics 2004; 114:640.
- Mathur A, Stekol L, Schatz D, et al. The parental origin of the single X chromosome in Turner syndrome: lack of correlation with parental age or clinical phenotype. Am J Hum Genet 1991; 48:682.
- FERGUSON-SMITH MA. KARYOTYPE-PHENOTYPE CORRELATIONS IN GONADAL DYSGENESIS AND THEIR BEARING ON THE PATHOGENESIS OF MALFORMATIONS. J Med Genet 1965; 2:142.
- Simpson JL. Gonadal dysgenesis and abnormalities of the human sex chromosomes: current status of phenotypic-karyotypic correlations. Birth Defects Orig Artic Ser 1975; 11:23.
- Held KR, Kerber S, Kaminsky E, et al. Mosaicism in 45,X Turner syndrome: does survival in early pregnancy depend on the presence of two sex chromosomes? Hum Genet 1992; 88:288.
- Binder G, Koch A, Wajs E, Ranke MB. Nested polymerase chain reaction study of 53 cases with Turner's syndrome: is cytogenetically undetected Y mosaicism common? J Clin Endocrinol Metab 1995; 80:3532.
- Wooten N, Bakalov VK, Hill S, Bondy CA. Reduced abdominal adiposity and improved glucose tolerance in growth hormone-treated girls with Turner syndrome. J Clin Endocrinol Metab 2008; 93:2109.
- Rao E, Weiss B, Fukami M, et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet 1997; 16:54.
- Ross JL, Scott C Jr, Marttila P, et al. Phenotypes Associated with SHOX Deficiency. J Clin Endocrinol Metab 2001; 86:5674.
- Ross JL, Kowal K, Quigley CA, et al. The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: contrasting children with Leri-Weill dyschondrosteosis and Turner syndrome. J Pediatr 2005; 147:499.
- Huber C, Rosilio M, Munnich A, et al. High incidence of SHOX anomalies in individuals with short stature. J Med Genet 2006; 43:735.
- Sybert VP, McCauley E. Turner's syndrome. N Engl J Med 2004; 351:1227.
- Loscalzo ML, Van PL, Ho VB, et al. Association between fetal lymphedema and congenital cardiovascular defects in Turner syndrome. Pediatrics 2005; 115:732.
- Clark EB. Neck web and congenital heart defects: a pathogenic association in 45 X-O Turner syndrome? Teratology 1984; 29:355.
- Mazzanti L, Cacciari E. Congenital heart disease in patients with Turner's syndrome. Italian Study Group for Turner Syndrome (ISGTS). J Pediatr 1998; 133:688.
- McCarthy K, Bondy CA. Turner syndrome in childhood and adolescence. Expert Rev Endocrinol Metab 2008; 3:771.
- Wyss D, DeLozier CD, Daniell J, Engel E. Structural anomalies of the X chromosome: personal observation and review of non-mosaic cases. Clin Genet 1982; 21:145.
- dos Santos AP, Andrade JG, Piveta CS, et al. Screening of Y chromosome microdeletions in 46,XY partial gonadal dysgenesis and in patients with a 45,X/46,XY karyotype or its variants. BMC Med Genet 2013; 14:115.
- Sävendahl L, Davenport ML. Delayed diagnoses of Turner's syndrome: proposed guidelines for change. J Pediatr 2000; 137:455.
- Ranke MB, Pflüger H, Rosendahl W, et al. Turner syndrome: spontaneous growth in 150 cases and review of the literature. Eur J Pediatr 1983; 141:81.
- Brook CG, Mürset G, Zachmann M, Prader A. Growth in children with 45,XO Turner's syndrome. Arch Dis Child 1974; 49:789.
- Sylvén L, Hagenfeldt K, Bröndum-Nielsen K, von Schoultz B. Middle-aged women with Turner's syndrome. Medical status, hormonal treatment and social life. Acta Endocrinol (Copenh) 1991; 125:359.
- Freriks K, Timmermans J, Beerendonk CC, et al. Standardized multidisciplinary evaluation yields significant previously undiagnosed morbidity in adult women with Turner syndrome. J Clin Endocrinol Metab 2011; 96:E1517.
- Elsheikh M, Hodgson HJ, Wass JA, Conway GS. Hormone replacement therapy may improve hepatic function in women with Turner's syndrome. Clin Endocrinol (Oxf) 2001; 55:227.
- El-Mansoury M, Berntorp K, Bryman I, et al. Elevated liver enzymes in Turner syndrome during a 5-year follow-up study. Clin Endocrinol (Oxf) 2008; 68:485.
- Bakalov VK, Gutin L, Cheng CM, et al. Autoimmune disorders in women with turner syndrome and women with karyotypically normal primary ovarian insufficiency. J Autoimmun 2012; 38:315.
- Chiovato L, Larizza D, Bendinelli G, et al. Autoimmune hypothyroidism and hyperthyroidism in patients with Turner's syndrome. Eur J Endocrinol 1996; 134:568.
- Ostberg JE, Conway GS. Adulthood in women with Turner syndrome. Horm Res 2003; 59:211.
- 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.
- Hadnott TN, Gould HN, Gharib AM, Bondy CA. Outcomes of spontaneous and assisted pregnancies in Turner syndrome: the U.S. National Institutes of Health experience. Fertil Steril 2011; 95:2251.
- Singh RP, Carr DH. The anatomy and histology of XO human embryos and fetuses. Anat Rec 1966; 155:369.
- Massarano AA, Adams JA, Preece MA, Brook CG. Ovarian ultrasound appearances in Turner syndrome. J Pediatr 1989; 114:568.
- King CR, Magenis E, Bennett S. Pregnancy and the Turner syndrome. Obstet Gynecol 1978; 52:617.
- Reyes FI, Koh KS, Faiman C. Fertility in women with gonadal dysgenesis. Am J Obstet Gynecol 1976; 126:668.
- Gravholt CH, Juul S, Naeraa RW, Hansen J. Morbidity in Turner syndrome. J Clin Epidemiol 1998; 51:147.
- Cramer JW, Bartz PJ, Simpson PM, Zangwill SD. The spectrum of congenital heart disease and outcomes after surgical repair among children with Turner syndrome: a single-center review. Pediatr Cardiol 2014; 35:253.
- Ho VB, Bakalov VK, Cooley M, et al. Major vascular anomalies in Turner syndrome: prevalence and magnetic resonance angiographic features. Circulation 2004; 110:1694.
- Gøtzsche CO, Krag-Olsen B, Nielsen J, et al. Prevalence of cardiovascular malformations and association with karyotypes in Turner's syndrome. Arch Dis Child 1994; 71:433.
- Elsheikh M, Casadei B, Conway GS, Wass JA. Hypertension is a major risk factor for aortic root dilatation in women with Turner's syndrome. Clin Endocrinol (Oxf) 2001; 54:69.
- Sachdev V, Matura LA, Sidenko S, et al. Aortic valve disease in Turner syndrome. J Am Coll Cardiol 2008; 51:1904.
- Ilyas M, Chu C, Ettles D, et al. Evaluation by magnetic resonance imaging of aortic dilatation and coarctation in adult Turner syndrome patients. Clin Endocrinol (Oxf) 2006; 65:154.
- Lin AE, Lippe B, Rosenfeld RG. Further delineation of aortic dilation, dissection, and rupture in patients with Turner syndrome. Pediatrics 1998; 102:e12.
- Matura LA, Ho VB, Rosing DR, Bondy CA. Aortic dilatation and dissection in Turner syndrome. Circulation 2007; 116:1663.
- Carlson M, Airhart N, Lopez L, Silberbach M. Moderate aortic enlargement and bicuspid aortic valve are associated with aortic dissection in Turner syndrome: report of the international turner syndrome aortic dissection registry. Circulation 2012; 126:2220.
- Karnis MF, Zimon AE, Lalwani SI, et al. Risk of death in pregnancy achieved through oocyte donation in patients with Turner syndrome: a national survey. Fertil Steril 2003; 80:498.
- Practice Committee of the American Society for Reproductive Medicine. Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. Fertil Steril 2006; 86:S127.
- Nathwani NC, Unwin R, Brook CG, Hindmarsh PC. The influence of renal and cardiovascular abnormalities on blood pressure in Turner syndrome. Clin Endocrinol (Oxf) 2000; 52:371.
- Landin-Wilhelmsen K, Bryman I, Wilhelmsen L. Cardiac malformations and hypertension, but not metabolic risk factors, are common in Turner syndrome. J Clin Endocrinol Metab 2001; 86:4166.
- Fudge EB, Constantacos C, Fudge JC, Davenport M. Improving detection of hypertension in girls with turner syndrome using ambulatory blood pressure monitoring. Horm Res Paediatr 2014; 81:25.
- Bondy CA, Van PL, Bakalov VK, et al. Prolongation of the cardiac QTc interval in Turner syndrome. Medicine (Baltimore) 2006; 85:75.
- Bondy CA, Bakalov VK. Investigation of cardiac status and bone mineral density in Turner syndrome. Growth Horm IGF Res 2006; 16 Suppl A:S103.
- Bondy CA, Ceniceros I, Van PL, et al. Prolonged rate-corrected QT interval and other electrocardiogram abnormalities in girls with Turner syndrome. Pediatrics 2006; 118:e1220.
- Dalla Pozza R, Bechtold S, Urschel S, et al. QTc interval prolongation in children with Turner syndrome: the results of exercise testing and 24-h ECG. Eur J Pediatr 2009; 168:59.
- Ostberg JE, Donald AE, Halcox JP, et al. Vasculopathy in Turner syndrome: arterial dilatation and intimal thickening without endothelial dysfunction. J Clin Endocrinol Metab 2005; 90:5161.
- Rubin K. Turner syndrome and osteoporosis: mechanisms and prognosis. Pediatrics 1998; 102:481.
- Gravholt CH, Vestergaard P, Hermann AP, et al. Increased fracture rates in Turner's syndrome: a nationwide questionnaire survey. Clin Endocrinol (Oxf) 2003; 59:89.
- Landin-Wilhelmsen K, Bryman I, Windh M, Wilhelmsen L. Osteoporosis and fractures in Turner syndrome-importance of growth promoting and oestrogen therapy. Clin Endocrinol (Oxf) 1999; 51:497.
- Bakalov VK, Chen ML, Baron J, et al. Bone mineral density and fractures in Turner syndrome. Am J Med 2003; 115:259.
- Bakalov VK, Axelrod L, Baron J, et al. Selective reduction in cortical bone mineral density in turner syndrome independent of ovarian hormone deficiency. J Clin Endocrinol Metab 2003; 88:5717.
- Gravholt CH, Fedder J, Naeraa RW, Müller J. Occurrence of gonadoblastoma in females with Turner syndrome and Y chromosome material: a population study. J Clin Endocrinol Metab 2000; 85:3199.
- Schoemaker MJ, Swerdlow AJ, Higgins CD, et al. Cancer incidence in women with Turner syndrome in Great Britain: a national cohort study. Lancet Oncol 2008; 9:239.
- Denniston A. Turner's syndrome. Lancet 2001; 358:2169.
- Chrousos GA, Ross JL, Chrousos G, et al. Ocular findings in Turner syndrome. A prospective study. Ophthalmology 1984; 91:926.
- Adhikary HP. Ocular manifestations of Turner's syndrome. Trans Ophthalmol Soc U K 1981; 101 (Pt 4):395.
- Mason JO 3rd, Tasman W. Turner's syndrome associated with bilateral retinal detachments. Am J Ophthalmol 1996; 122:742.
- Elsheikh M, Wass JA, Conway GS. Autoimmune thyroid syndrome in women with Turner's syndrome--the association with karyotype. Clin Endocrinol (Oxf) 2001; 55:223.
- El-Mansoury M, Bryman I, Berntorp K, et al. Hypothyroidism is common in turner syndrome: results of a five-year follow-up. J Clin Endocrinol Metab 2005; 90:2131.
- Bonamico M, Pasquino AM, Mariani P, et al. Prevalence and clinical picture of celiac disease in Turner syndrome. J Clin Endocrinol Metab 2002; 87:5495.
- Caprio S, Boulware S, Diamond M, et al. Insulin resistance: an early metabolic defect of Turner's syndrome. J Clin Endocrinol Metab 1991; 72:832.
- Handler MZ, Derrick KM, Lutz RE, et al. Prevalence of pilomatricoma in Turner syndrome: findings from a multicenter study. JAMA Dermatol 2013; 149:559.
- Wood S, Nguyen D, Hutton K, Dickson W. Pilomatricomas in Turner syndrome. Pediatr Dermatol 2008; 25:449.
- Bengtzen AR, Grossniklaus HE, Bernardino CR. Multiple pilomatrixoma in Turner syndrome. Ophthal Plast Reconstr Surg 2009; 25:229.
- Brazzelli V, Larizza D, Martinetti M, et al. Halo nevus, rather than vitiligo, is a typical dermatologic finding of turner's syndrome: clinical, genetic, and immunogenetic study in 72 patients. J Am Acad Dermatol 2004; 51:354.
- Lowenstein EJ, Kim KH, Glick SA. Turner's syndrome in dermatology. J Am Acad Dermatol 2004; 50:767.
- Azcona C, Bareille P, Stanhope R. Lesson of the week: Turner's syndrome mosaicism in patients with a normal blood lymphocyte karyotype. BMJ 1999; 318:856.
- Rivkees SA, Hager K, Hosono S, et al. A highly sensitive, high-throughput assay for the detection of Turner syndrome. J Clin Endocrinol Metab 2011; 96:699.
- Rivkees SA. Ending the late diagnosis of Turner syndrome through a novel high-throughput assay. Pediatr Endocrinol Rev 2012; 9 Suppl 2:698.
- Gemmill RM, Pearce-Birge L, Bixenman H, et al. Y chromosome--specific DNA sequences in Turner-syndrome mosaicism. Am J Hum Genet 1987; 41:157.
- Tsuchiya K, Reijo R, Page DC, Disteche CM. Gonadoblastoma: molecular definition of the susceptibility region on the Y chromosome. Am J Hum Genet 1995; 57:1400.
- Navot D, Laufer N, Kopolovic J, et al. Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. N Engl J Med 1986; 314:806.
- Saenger P, Wikland KA, Conway GS, et al. Recommendations for the diagnosis and management of Turner syndrome. J Clin Endocrinol Metab 2001; 86:3061.
- Ranke MB, Saenger P. Turner's syndrome. Lancet 2001; 358:309.
- Bender B, Puck M, Salbenblatt J, Robinson A. Cognitive development of unselected girls with complete and partial X monosomy. Pediatrics 1984; 73:175.
- Migeon BR, Luo S, Stasiowski BA, et al. Deficient transcription of XIST from tiny ring X chromosomes in females with severe phenotypes. Proc Natl Acad Sci U S A 1993; 90:12025.
- Collins AL, Cockwell AE, Jacobs PA, Dennis NR. A comparison of the clinical and cytogenetic findings in nine patients with a ring (X) cell line and 16 45,X patients. J Med Genet 1994; 31:528.
- McCauley E, Feuillan P, Kushner H, Ross JL. Psychosocial development in adolescents with Turner syndrome. J Dev Behav Pediatr 2001; 22:360.
- Skuse DH, James RS, Bishop DV, et al. Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function. Nature 1997; 387:705.
- CLINICAL MANIFESTATIONS
- Typical features
- Ovarian failure
- Short stature
- Renal anomalies
- Cardiovascular disease
- - Coarctation/aortic valve disease
- - Aortic dissection
- - Hypertension
- - Other
- Risk of malignancy
- Ocular abnormalities
- Autoimmune disorders
- Metabolic issues
- Y chromosome mosaicism
- Other tests
- Psychologic and educational issues
- FAMILY SUPPORT
- INFORMATION FOR PATIENTS