Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Evaluation of the infant with atypical genitalia (disorder of sex development)

Christopher P Houk, MD
Lynne L Levitsky, MD
Section Editors
Laurence S Baskin, MD, FAAP
Mitchell E Geffner, MD
Deputy Editor
Alison G Hoppin, MD


Infants with a congenital discrepancy between external genitalia, gonadal, and chromosomal sex are classified as having a disorder of sex development. A 2006 consensus conference suggested that the potentially pejorative terms "pseudohermaphrodite," "hermaphrodite," and "intersex" be replaced by the diagnostic category "disorders of sex development" (DSD) [1]. Although the term DSD has been accepted by the medical community, patients and support groups question its usefulness and appropriateness based on three criticisms: first, that DSD is an overly broad term that applies to conditions in which no sexual/gender disruption are expected (eg, Turner syndrome, Trisomy X, many females with congenital adrenal hyperplasia [CAH], and others); second, that the use of the word 'disorder' is seen as pejorative by some; and third, that an umbrella term like DSD lacks sufficient specificity to be helpful diagnostically, and is therefore unnecessary. Many of these groups do not accept the DSD designation and feel that it should be abandoned by the medical community. Until a consensus is reached on this issue, we will use the term DSD but will employ it only in relation to those patients in whom there is altered physical sexual differentiation (conditions previously captured by the term "intersex"). Many of these individuals present as newborns with an atypical genital appearance often termed "ambiguous genitalia." We will not use DSD to refer to conditions in which genital/gender discordance is not expected, such as Klinefelter syndrome, Turner syndrome, undescended testes, or most forms of hypospadias.

DSDs with genital abnormalities sufficient to prompt evaluation occur in approximately one in 1000 to 4500 live births [2-4]. Manifestations may include bilateral cryptorchidism (picture 1), scrotal or perineal hypospadias, clitoromegaly (picture 2A-B), posterior labial fusion (picture 3), phenotypic female appearance with a palpable gonad (with or without inguinal hernia) (picture 4), or hypospadias with a unilateral nonpalpable gonad (picture 5A-B). DSDs also include infants with discordant genitalia and sex chromosomes (picture 6). 46,XY infants with palpable gonads and simple hypospadias or microphallus, although undervirilized, do not have truly atypical genitalia and are discussed separately. (See "Clinical features and diagnosis of male hypogonadism" and "Hypospadias: Pathogenesis, diagnosis, and evaluation".)

The evaluation of the infant with a DSD is presented here. The management of such infants, which is critical and often controversial in the absence of well-defined outcome-based guidelines, is discussed separately. (See "Management of the infant with atypical genitalia (disorder of sex development)".)


A logical approach to the infant with a disorder of sex development (DSD) requires a basic understanding of normal human sexual differentiation. This process is reviewed here briefly and discussed in detail elsewhere. (See "Normal sexual development".)

In early fetal development, both XX and XY fetuses have similar reproductive structural anlage; this period is referred to as the sexually indifferent phase of sexual development. This ambisexual state continues until the formation of the bipotential gonad at seven weeks, when fetuses bearing a Y chromosome begin developing testes, thereby becoming sexually distinct from fetuses without a Y chromosome. Normal ovarian development also requires active genetic pathways. Thereafter, gonadal differentiation and function determines the genital phenotype. Multiple genes contribute to normal sexual differentiation; mutations in these genes can lead to various DSDs (table 1A-B).

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Apr 19, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Lee PA, Houk CP, Ahmed SF, et al. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics 2006; 118:e488.
  2. Hughes IA, Nihoul-Fékété C, Thomas B, Cohen-Kettenis PT. Consequences of the ESPE/LWPES guidelines for diagnosis and treatment of disorders of sex development. Best Pract Res Clin Endocrinol Metab 2007; 21:351.
  3. Blackless M, Charuvastra A, Derryck A, et al. How sexually dimorphic are we? Review and synthesis. Am J Hum Biol 2000; 12:151.
  4. Thyen U, Lanz K, Holterhus PM, Hiort O. Epidemiology and initial management of ambiguous genitalia at birth in Germany. Horm Res 2006; 66:195.
  5. Ahmed SF, Hughes IA. The genetics of male undermasculinization. Clin Endocrinol (Oxf) 2002; 56:1.
  6. Clarkson MJ, Harley VR. Sex with two SOX on: SRY and SOX9 in testis development. Trends Endocrinol Metab 2002; 13:106.
  7. Achermann JC, Meeks JJ, Jameson JL. Phenotypic spectrum of mutations in DAX-1 and SF-1. Mol Cell Endocrinol 2001; 185:17.
  8. Ozisik G, Achermann JC, Meeks JJ, Jameson JL. SF1 in the development of the adrenal gland and gonads. Horm Res 2003; 59 Suppl 1:94.
  9. Wada Y, Okada M, Hasegawa T, Ogata T. Association of severe micropenis with Gly146Ala polymorphism in the gene for steroidogenic factor-1. Endocr J 2005; 52:445.
  10. Wada Y, Okada M, Fukami M, et al. Association of cryptorchidism with Gly146Ala polymorphism in the gene for steroidogenic factor-1. Fertil Steril 2006; 85:787.
  11. Canto P, Söderlund D, Reyes E, Méndez JP. Mutations in the desert hedgehog (DHH) gene in patients with 46,XY complete pure gonadal dysgenesis. J Clin Endocrinol Metab 2004; 89:4480.
  12. Little M, Wells C. A clinical overview of WT1 gene mutations. Hum Mutat 1997; 9:209.
  13. Niaudet P, Gubler MC. WT1 and glomerular diseases. Pediatr Nephrol 2006; 21:1653.
  14. Klamt B, Koziell A, Poulat F, et al. Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms. Hum Mol Genet 1998; 7:709.
  15. Vainio S, Heikkilä M, Kispert A, et al. Female development in mammals is regulated by Wnt-4 signalling. Nature 1999; 397:405.
  16. Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ. A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman. N Engl J Med 2004; 351:792.
  17. Al-Qattan MM. Molecular basis of the clinical features of Al-Awadi-Raas-Rothschild (limb/pelvis/uterus-hypoplasia/aplasia) syndrome (AARRS) and Fuhrmann syndrome. Am J Med Genet A 2013; 161A:2274.
  18. Siggers P, Carré GA, Bogani D, et al. A novel mouse Fgfr2 mutant, hobbyhorse (hob), exhibits complete XY gonadal sex reversal. PLoS One 2014; 9:e100447.
  19. Chung CL, Lu CW, Cheng YS, et al. Association of aberrant expression of sex-determining gene fibroblast growth factor 9 with Sertoli cell-only syndrome. Fertil Steril 2013; 100:1547.
  20. Ross AJ, Capel B. Signaling at the crossroads of gonad development. Trends Endocrinol Metab 2005; 16:19.
  21. Bagheri-Fam S, Sim H, Bernard P, et al. Loss of Fgfr2 leads to partial XY sex reversal. Dev Biol 2008; 314:71.
  22. Gibbons RJ, Wada T, Fisher CA, et al. Mutations in the chromatin-associated protein ATRX. Hum Mutat 2008; 29:796.
  23. Smith CA, McClive PJ, Western PS, et al. Conservation of a sex-determining gene. Nature 1999; 402:601.
  24. Lee MM, Donahoe PK, Hasegawa T, et al. Mullerian inhibiting substance in humans: normal levels from infancy to adulthood. J Clin Endocrinol Metab 1996; 81:571.
  25. Baskin LS. Hypospadias and urethral development. J Urol 2000; 163:951.
  26. Li Y, Sinclair A, Cao M, et al. Canalization of the urethral plate precedes fusion of the urethral folds during male penile urethral development: the double zipper hypothesis. J Urol 2015; 193:1353.
  27. Feldman KW, Smith DW. Fetal phallic growth and penile standards for newborn male infants. J Pediatr 1975; 86:395.
  28. Davidoff F, Federman DD. Mixed gonadal dysgenesis. Pediatrics 1973; 52:725.
  29. Phillip M, De Boer C, Pilpel D, et al. Clitoral and penile sizes of full term newborns in two different ethnic groups. J Pediatr Endocrinol Metab 1996; 9:175.
  30. Oberfield SE, Mondok A, Shahrivar F, et al. Clitoral size in full-term infants. Am J Perinatol 1989; 6:453.
  31. Riley WJ, Rosenbloom AL. Clitoral size in infancy. J Pediatr 1980; 96:918.
  32. Sutphen R, Galán-Goméz E, Kousseff BG. Clitoromegaly in neurofibromatosis. Am J Med Genet 1995; 55:325.
  33. Sane K, Pescovitz OH. The clitoral index: a determination of clitoral size in normal girls and in girls with abnormal sexual development. J Pediatr 1992; 120:264.
  34. Verkauf BS, Von Thron J, O'Brien WF. Clitoral size in normal women. Obstet Gynecol 1992; 80:41.
  35. Quigley CA, De Bellis A, Marschke KB, et al. Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 1995; 16:271.
  36. Callegari C, Everett S, Ross M, Brasel JA. Anogenital ratio: measure of fetal virilization in premature and full-term newborn infants. J Pediatr 1987; 111:240.
  37. Yu H, Patel SB. Recent insights into the Smith-Lemli-Opitz syndrome. Clin Genet 2005; 68:383.
  38. Sarafoglou K, Banks K, Kyllo J, et al. Cases of congenital adrenal hyperplasia missed by newborn screening in Minnesota. JAMA 2012; 307:2371.
  39. Greaves RF, Pitkin J, Ho CS, et al. Hormone modeling in preterm neonates: establishment of pituitary and steroid hormone reference intervals. J Clin Endocrinol Metab 2015; 100:1097.
  40. Kuiri-Hänninen T, Sankilampi U, Dunkel L. Activation of the hypothalamic-pituitary-gonadal axis in infancy: minipuberty. Horm Res Paediatr 2014; 82:73.
  41. Johansen Taber KA, Dickinson BD, Wilson M. The promise and challenges of next-generation genome sequencing for clinical care. JAMA Intern Med 2014; 174:275.
  42. Tobias ES, McElreavey K. Next generation sequencing for disorders of sex development. Endocr Dev 2014; 27:53.
  43. Flück CE, Miller WL. P450 oxidoreductase deficiency: a new form of congenital adrenal hyperplasia. Curr Opin Pediatr 2006; 18:435.
  44. Grumbach MM, Auchus RJ. Estrogen: consequences and implications of human mutations in synthesis and action. J Clin Endocrinol Metab 1999; 84:4677.
  45. Gasca S, Canizares J, De Santa Barbara P, et al. A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination. Proc Natl Acad Sci U S A 2002; 99:11199.
  46. Huang B, Wang S, Ning Y, et al. Autosomal XX sex reversal caused by duplication of SOX9. Am J Med Genet 1999; 87:349.
  47. Cox JJ, Willatt L, Homfray T, Woods CG. A SOX9 duplication and familial 46,XX developmental testicular disorder. N Engl J Med 2011; 364:91.
  48. Lee MM, Donahoe PK, Silverman BL, et al. Measurements of serum müllerian inhibiting substance in the evaluation of children with nonpalpable gonads. N Engl J Med 1997; 336:1480.
  49. Rey RA, Belville C, Nihoul-Fékété C, et al. Evaluation of gonadal function in 107 intersex patients by means of serum antimüllerian hormone measurement. J Clin Endocrinol Metab 1999; 84:627.
  50. Krob G, Braun A, Kuhnle U. True hermaphroditism: geographical distribution, clinical findings, chromosomes and gonadal histology. Eur J Pediatr 1994; 153:2.
  51. Tomaselli S, Megiorni F, De Bernardo C, et al. Syndromic true hermaphroditism due to an R-spondin1 (RSPO1) homozygous mutation. Hum Mutat 2008; 29:220.
  52. Morel Y, Rey R, Teinturier C, et al. Aetiological diagnosis of male sex ambiguity: a collaborative study. Eur J Pediatr 2002; 161:49.
  53. Winter JS, Hughes IA, Reyes FI, Faiman C. Pituitary-gonadal relations in infancy: 2. Patterns of serum gonadal steroid concentrations in man from birth to two years of age. J Clin Endocrinol Metab 1976; 42:679.
  54. Forest MG, Sizonenko PC, Cathiard AM, Bertrand J. Hypophyso-gonadal function in humans during the first year of life. 1. Evidence for testicular activity in early infancy. J Clin Invest 1974; 53:819.
  55. Kim CJ, Lin L, Huang N, et al. Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc. J Clin Endocrinol Metab 2008; 93:696.
  56. Cara JF, Moshang T Jr, Bongiovanni AM, Marx BS. Elevated 17-hydroxyprogesterone and testosterone in a newborn with 3-beta-hydroxysteroid dehydrogenase deficiency. N Engl J Med 1985; 313:618.
  57. Lutfallah C, Wang W, Mason JI, et al. Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 2002; 87:2611.
  58. Misra M, MacLaughlin DT, Donahoe PK, Lee MM. Measurement of Mullerian inhibiting substance facilitates management of boys with microphallus and cryptorchidism. J Clin Endocrinol Metab 2002; 87:3598.
  59. Schnitzer JJ, Donahoe PK. Surgical treatment of congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001; 30:137.
  60. Mendez JP, Schiavon R, Diaz-Cueto L, et al. A reliable endocrine test with human menopausal gonadotropins for diagnosis of true hermaphroditism in early infancy. J Clin Endocrinol Metab 1998; 83:3523.
  61. French S, Rodriguez L, Schlesinger A, et al. FSH Injections and Ultrasonography Determine Presence of Ovarian Components in the Evaluation of Ovotesticular Disorders of Sex Development. Int J Pediatr Endocrinol 2009; 2009:507964.
  62. Knebelmann B, Boussin L, Guerrier D, et al. Anti-Müllerian hormone Bruxelles: a nonsense mutation associated with the persistent Müllerian duct syndrome. Proc Natl Acad Sci U S A 1991; 88:3767.
  63. Imbeaud S, Carré-Eusèbe D, Rey R, et al. Molecular genetics of the persistent müllerian duct syndrome: a study of 19 families. Hum Mol Genet 1994; 3:125.
  64. Imbeaud S, Belville C, Messika-Zeitoun L, et al. A 27 base-pair deletion of the anti-müllerian type II receptor gene is the most common cause of the persistent müllerian duct syndrome. Hum Mol Genet 1996; 5:1269.
  65. Swain A, Narvaez V, Burgoyne P, et al. Dax1 antagonizes Sry action in mammalian sex determination. Nature 1998; 391:761.
  66. Lalli E, Sassone-Corsi P. DAX-1, an unusual orphan receptor at the crossroads of steroidogenic function and sexual differentiation. Mol Endocrinol 2003; 17:1445.
  67. Forest MG. Pattern of the response of testosterone and its precursors to human chorionic gonadotropin stimulation in relation to age in infants and children. J Clin Endocrinol Metab 1979; 49:132.
  68. Faisal Ahmed S, Iqbal A, Hughes IA. The testosterone:androstenedione ratio in male undermasculinization. Clin Endocrinol (Oxf) 2000; 53:697.
  69. Latronico AC, Anasti J, Arnhold IJ, et al. Brief report: testicular and ovarian resistance to luteinizing hormone caused by inactivating mutations of the luteinizing hormone-receptor gene. N Engl J Med 1996; 334:507.
  70. Latronico AC. Naturally occurring mutations of the luteinizing hormone receptor gene affecting reproduction. Semin Reprod Med 2000; 18:17.
  71. Givens JR, Wiser WL, Summitt RL, et al. Familial male pseudohermaphroditism without gynecomastia due to deficient testicular 17-ketosteroid reductase activity. N Engl J Med 1974; 291:938.
  72. Mendonca BB, Inacio M, Arnhold IJ, et al. Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase 3 deficiency. Diagnosis, psychological evaluation, and management. Medicine (Baltimore) 2000; 79:299.
  73. Andersson S, Moghrabi N. Physiology and molecular genetics of 17 beta-hydroxysteroid dehydrogenases. Steroids 1997; 62:143.
  74. Walsh PC, Madden JD, Harrod MJ, et al. Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974; 291:944.
  75. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE. Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 1974; 186:1213.
  76. Imperato-McGinley J, Gautier T, Pichardo M, Shackleton C. The diagnosis of 5 alpha-reductase deficiency in infancy. J Clin Endocrinol Metab 1986; 63:1313.
  77. Luteinizing hormone/chorigonadotropin receptor. In: Online Mendelian Inheritance in Man. Johns Hopkins University, Baltimore, MD, 2003. Available at: www.ncbi.nlm.nih.gov:80/entrez/dispomim.cgi?id=152790 (Accessed on February 09, 2008).
  78. Rousseau-Merck MF, Misrahi M, Atger M, et al. Localization of the human luteinizing hormone/choriogonadotropin receptor gene (LHCGR) to chromosome 2p21. Cytogenet Cell Genet 1990; 54:77.
  79. Berthezène F, Forest MG, Grimaud JA, et al. Leydig-cell agenesis: a cause of male pseudohermaphroditism. N Engl J Med 1976; 295:969.
  80. Pérez-Palacios G, Scaglia HE, Kofman-Alfaro S, et al. Inherited male pseudohermaphroditism due to gonadotrophin unresponsiveness. Acta Endocrinol (Copenh) 1981; 98:148.
  81. Ahmed SF, Cheng A, Dovey L, et al. Phenotypic features, androgen receptor binding, and mutational analysis in 278 clinical cases reported as androgen insensitivity syndrome. J Clin Endocrinol Metab 2000; 85:658.
  82. Jamin SP, Arango NA, Mishina Y, Behringer RR. Genetic studies of MIS signalling in sexual development. Novartis Found Symp 2002; 244:157.
  83. Dessens AB, Cohen-Kettenis PT, Mellenbergh GJ, et al. Association of prenatal phenobarbital and phenytoin exposure with genital anomalies and menstrual disorders. Teratology 2001; 64:181.
  84. Yiee JH, Baskin LS. Environmental factors in genitourinary development. J Urol 2010; 184:34.
  85. Tordjman K, Jaffe A, Trostanetsky Y, et al. Low-dose (1 microgram) adrenocorticotrophin (ACTH) stimulation as a screening test for impaired hypothalamo-pituitary-adrenal axis function: sensitivity, specificity and accuracy in comparison with the high-dose (250 microgram) test. Clin Endocrinol (Oxf) 2000; 52:633.
  86. Ledig S, Hiort O, Wünsch L, Wieacker P. Partial deletion of DMRT1 causes 46,XY ovotesticular disorder of sexual development. Eur J Endocrinol 2012; 167:119.
Topic Outline