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Neonatology pp 1–24Cite as

Disorders of Sexual Development in Newborns

Abstract

The understanding, care and treatment of newborns born with disorders of sex development conditions have evolved considerably over the last few decades. Biological assessment of atypical genitalia is based on a structured sequence of endocrine and genetic investigations, starting from a suitable history and a complete examination of the external genital anatomy. Investigations are particularly relevant in 46,XY DSD where the diagnostic yield is less successful than in the 46,XX conditions. The era of next generation sequencing is increasingly being applied to investigate complex medical diseases of unknown cause, including DSD. The challenge for health professionals will lie in integrating vast amounts of genetic information with phenotypes and counselling families appropriately. Regarding those who require evaluation before gender assignment is made, each “generation” of approach reflects the contemporary biological, social and psychological understanding. The most recent generation needs to consider the significantly changed societal viewpoints regarding the acceptance and expansion beyond a binary perception of sexuality. This together with advances in genetic etiologies, surgical refinements and psychological support should result in better care and quality of life (QoL) outcomes for patients with these conditions.

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References

  • Abacı A, Çatlı G, Berberoğlu M (2015) Gonadal malignancy risk and prophylactic gonadectomy in disorders of sexual development. J Pediatr Endocrinol Metab 28(9–10):1019–1027. doi:10.1515/jpem-2014-0522

    PubMed  Google Scholar 

  • Achermann JC, Hughes IA (2007) Disorders of sex development. In: Kronenberg H, Melmed S, Polonsky K, Larsen PR (eds) Williams textbook of endocrinology, 11th edn. Saunders Elsevier, Philadelphia

    Google Scholar 

  • Ahmed SF, Bryce J, Hiort O (2014) International networks for supporting research and clinical care in the field of disorders of sex development. In Understanding differences and disorders of sex development (DSD). Endocrine development, vol 27. pp 284–292 https://www.karger.com/Article/Abstract/363676

    Google Scholar 

  • Ahmed SF, Achermann JC, Arlt W et al (2016) Society for endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (revised 2015). Clin Endocrinol 84:771–788

    Article  Google Scholar 

  • Ainsworth C (2015) Sex redefined. Nature 518(7539):288–291. http://www.ncbi.nlm.nih.gov/pubmed/25693544

    Google Scholar 

  • Austin J, Tamar-Mattis A, Mazur T et al (2011) DSD: when and how to tell the patient. Pediatr Endocrinol Rev 8:213–217

    PubMed  Google Scholar 

  • Balsamo A, Cacciari E, Piazzi S et al (1996) Congenital adrenal hyperplasia: neonatal mass screening compared to clinical diagnosis only in the Emilia-Romagna Region of Italy (1980–1995). Pediatrics 98:362–367

    CAS  PubMed  Google Scholar 

  • Balsamo A, Baldazzi L, Menabò S, Cicognani A (2010) Impact of molecular genetics on congenital adrenal hyperplasia management. Sex Dev 4:233–248

    Article  CAS  PubMed  Google Scholar 

  • Bertelloni S, Baroncelli GI, Ghirri P et al (2001) Hormonal treatment for unilateral inguinal testis: comparison of four different treatments. Horm Res 55:236–239

    CAS  PubMed  Google Scholar 

  • Bertelloni S, Scaramuzzo RT, Parrini D et al (2007) Early diagnosis of 5-alpha-reductase deficiency in newborns. Sex Dev 1:147–151

    Article  CAS  PubMed  Google Scholar 

  • Bertelloni S, Balsamo A, Giordani L et al (2009) 17beta-Hydroxysteroid dehydrogenase-3 deficiency: from pregnancy to adolescence. J Endocrinol Invest 32:666–670

    Article  CAS  PubMed  Google Scholar 

  • Bertelloni S, Baldinotti F, Russo G, Ghirri P, Dati E, Michelucci A, Moscuzza F, Meroni S, Colombo I, Sessa MR, Baroncelli GI (2016) 5α-reductase-2 deficiency: clinical findings, endocrine pitfalls, and genetic features in a large Italian cohort. Sex Dev 10:28–36

    Article  CAS  PubMed  Google Scholar 

  • Biason-Lauber A (2010) Control of sex development. Best Pract Res Clin Endocrinol Metab 24:163–186

    Article  PubMed  Google Scholar 

  • Biason-Lauber A, Chaboissier MC (2015) Ovarian development and disease: the known and the unespected. Semin Cell Dev Biol 45:59–67

    Article  CAS  PubMed  Google Scholar 

  • Biason-Lauber A, Miller WL, Pandey AV, Flück CE (2013) Of marsupials and men: backdoor dihydrotestosterone synthesis in male sexual differentiation. Mol Cell Endocrinol 371:124–132. http://www.ncbi.nlm.nih.gov/pubmed/23376007

    Google Scholar 

  • Brain CE, Creighton SM, Mushtaq I et al (2010) Holistic management of DSD. Best Pract Res Clin Endocrinol Metab 24:335–354

    Article  PubMed  PubMed Central  Google Scholar 

  • Burkhard FZ, Parween S, Udhane SS, Fluck CE, Pandey AV (2016) P450 oxidoreductase deficiency: analysis of mutations and polymorphisms. J Steroid Biochem Mol Biol. doi:10.1016/j.jsbmb.2016.04.003

    PubMed  Google Scholar 

  • Cools M, Drop SL, Wolffenbuttel KP et al (2006) Germ cell tumors in the intersex gonad: old paths, new directions, moving frontiers. Endocr Rev 27:468–484

    Article  CAS  PubMed  Google Scholar 

  • Cools M, Wolffenbuttel KP, Drop SLS, Oosterhuis JW, Looijenga LH (2011) Gonadal development and tumor formation at the crossroads of male and female sex determination. Sex Dev 5:167–180

    Article  CAS  PubMed  Google Scholar 

  • Cools M, Simmonds M, Elford S, Gorter J, Ahmed SF, D’Alberton F, Springer A, Hiort O; Management Committee of the European Cooperation in Science and Technology Action BM1303 (2016) Response to the council of Europe human rights commissioner’s issue paper on human rights and intersex people. Eur Urol. pii: S0302-2838(16)30179-8. doi:10.1016/j.eururo.2016.05.015. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/27210458

    Google Scholar 

  • D’Alberton F (2010) Disclosing DSD and opening the doors. Sex Dev 4:304–309

    Article  PubMed  Google Scholar 

  • D’Alberton F et al (2015) Quality of life and psychological adjustment of women living with 46, XY differences of sex development. J Sex Med 12(6):1440–1449

    Article  PubMed  Google Scholar 

  • di Clemente N, Belville C (2006) Anti-Müllerian hormone receptor defect. Best Pract Res Clin Endocrinol Metab 20:599–610

    Article  PubMed  Google Scholar 

  • Elsheikh M, Dunger DB, Conway GS, Wass JA (2002) Turner’s syndrome in adulthood. Endocr Rev 23:120–140

    CAS  PubMed  Google Scholar 

  • Ferraz-de Souza B, Lin L, Acherman JC (2011) Steroidogenic Factor 1 (SF1, NR5A1) and human diseases. Mol Cell Endocrinol 336:198–205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghirri P, Scaramuzzo MR, Greggio N, Salerno MC (2015) (Italian) Protocollo diagnostico e management in età neonatale. In http://www.gruppodistudio-it-dsd.org/diffsvilup/32_protoc_neonatale_dsd.pdf

  • Ghirri P, Ciulli C, Vuerich M et al (2002) Incidence at birth and natural history of cryptorchidism: a study of 10,730 consecutive male infants. J Endocrinol Invest 25:709–715

    Article  CAS  PubMed  Google Scholar 

  • Ghirri P, Scaramuzzo RT, Bertelloni S et al (2009) Prevalence of hypospadias in Italy according to severity, gestational age and birthweight: an epidemiological study. Riv Ital Pediatr 35:18

    Article  Google Scholar 

  • Gillam LH, Hewitt JK, Warne GL (2010) Ethical principles for the management of infants with DSD. Horm Res Paediatr 74:412–418

    Article  CAS  PubMed  Google Scholar 

  • Hewitt J, Zacharin M (2015) Hormone replacement in disorders of sex development: current thinking. Best Pract Res Clin Endocrinol Metab 29:437e447

    Article  Google Scholar 

  • Hsu LY, Benn PA (1999) Revised guidelines for the diagnosis of mosaicism in amniocytes. Prenat Diagn 19:1081–1082

    Article  CAS  PubMed  Google Scholar 

  • Hughes IA, Deeb A (2006) Androgen resistance. Best Pract Res Clin Endocrinol Metab 20:577–598

    Article  CAS  PubMed  Google Scholar 

  • Hughes IA, Lim HN, Martin H et al (2001) Developmental aspects of androgen action. Mol Cell Endocrinol 185:33–41

    Article  CAS  PubMed  Google Scholar 

  • Hughes IA, Nihoul-Fékété C, Thomas B, Cohen-Kettenis PT (2007) Consequences of the ESPE/LWPES guidelines for diagnosis and treatment of disorders of sex development. Best Pract Res Clin Endocrinol Metab 21:351–365

    Article  PubMed  Google Scholar 

  • Imperato-McGinley J, Zhu YS (2002) Androgens and male physiology the syndrome of 5-alpha-reductase-2 deficiency. Mol Cell Endocrinol 198:51–59

    Article  CAS  PubMed  Google Scholar 

  • Janjua NR, Frederiksen H, Skakkebaek NE et al (2008) Urinary excretion of phthalates and paraben after repeated whole-body topical application in humans. Int J Androl 31:118–130

    Article  CAS  PubMed  Google Scholar 

  • Joint LWPES/ESPE CAH Working Group (2002) Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins pediatric endocrine society and the European society for paediatric endocrinology. J Clin Endocrinol Metab 87:4048–4053

    Article  Google Scholar 

  • Jones ME, Boon WC, McInnes K et al (2007) Recognizing rare disorders: aromatase deficiency. Nat Clin Pract Endocrinol Metab 3:414–421

    Article  CAS  PubMed  Google Scholar 

  • Jurgensen M, Kleinemeier E, Lux A et al (2010) Psychosexual development in children with DSD: results from the German clinical evaluation study. J Pediatr Endocrinol Metab 23:565–578

    Article  CAS  PubMed  Google Scholar 

  • Kalfa N, Philibert P, Baskin LS, Sultan C (2011) Hypospadias: interactions between environment and genetics. Mol Cell Endocrinol 335:89–95

    Article  CAS  PubMed  Google Scholar 

  • Kleinemeier E, Jurgensen M, Lux A et al (2010) Psychological adjustment and sexual development of adolescents with DSD. J Adolesc Health 47:463–471

    Article  PubMed  Google Scholar 

  • Kolesinska Z, Ahmed SF, Niedziela M, Bryce J, Molinska-Glura M, Rodie M, Jiang J, Sinnott RO, Hughes IA, Darendeliler F, Hiort O, van der Zwan Y, Cools M, Guran T, Holterhus PM, Bertelloni S, Lisa L, Arlt W, Krone N, Ellaithi M, Balsamo A, Mazen I, Nordenstrom A, Lachlan K, Alkhawari M, Chatelain P, Weintrob N (2014) Changes over time in sex assignment for disorders of sex development. Pediatrics 134(3):e710–e715. doi:10.1542/peds.2014-1088. Epub 2014 Aug 4. http://www.ncbi.nlm.nih.gov/pubmed/25092939

    Google Scholar 

  • Lajic S, Nordenström A, Hirvikoski T (2008) Long-term outcome of prenatal treatment of congenital adrenal hyperplasia. Endocr Dev 13:82–98

    CAS  PubMed  Google Scholar 

  • Latronico AC, Arnhold IJ (2006) Inactivating mutations of LH and FSH receptors–from genotype to phenotype. Pediatr Endocrinol Rev 4:28–31

    PubMed  Google Scholar 

  • Lee YS, Cheng AW, Ahmed SF (2007) Genital anomalies in Klinefelter’s syndrome. Horm Res 68:150–155

    CAS  PubMed  Google Scholar 

  • Mac Laughlin DT, Danahoe PK (2004) Sex determination and differentiation. N Engl J Med 350:367–378

    Article  CAS  Google Scholar 

  • Manna PR, Stocco DM (2005) Regulation of the steroidogenic acute regulatory protein expression: functional and physiological consequences. Curr Drug Targets Immune Endocr Metabol Disord 5:93–108

    Article  CAS  PubMed  Google Scholar 

  • Massart F, Saggese G (2009) Sex steroidal targets & genetic susceptibility to idiopathic cryptorchidism. Pediatr Endocrinol Rev 6:481–490

    PubMed  Google Scholar 

  • McCarty MM (2008) Estradiol and the developing brain. Physiol Rev 88:91–124

    Article  Google Scholar 

  • Menabò S, Balsamo A, Nicoletti A et al (2008) Three novel AMH gene mutations in a patient with persistent müllerian duct syndrome and normal AMH serum dosage. Horm Res 70:124–128

    Article  PubMed  Google Scholar 

  • Menabò S, Polat S, Baldazzi L, Kulle AE, Holterhus PM, Grötzinger J, Fanelli F, Balsamo A, Riepe FG (2014) Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: functional consequences of four CYP11B1 mutations. Eur J Hum Genet 22(5):610–616. doi:10.1038/ejhg.2013.197. Epub 2013 Sep 11. PubMed PMID: 24022297; PubMed Central PMCID: PMC3992560. http://www.ncbi.nlm.nih.gov/pubmed/24022297

    Google Scholar 

  • Mendonca BB, Domenice S, Arnhold IJP, Costa EMF (2009) 46, XY disorders of sex development (DSD). Clin Endocrinol 70:173–187

    CAS  Google Scholar 

  • Meyer-Bahlburg HFL et al (2016) Gender assignment, reassignment and outcome in disorders of sex development: update of the 2005 consensus conference. Horm Res Paediatr 85(2):112–118

    Article  CAS  PubMed  Google Scholar 

  • Migeon CJ, Berkovitz DG, Brown TR (1994) Sexual differentiation and ambiguity. In: Kappy MS, Blizzard RM, Migeon CJ (eds) The diagnosis and treatment of endocrine disorders in childhood and adolescence, 4th edn. Thomas, Springfield

    Google Scholar 

  • Nabhan ZM, Lee PA (2007) Disorder of sex development. Curr Opin Obstet Gynecol 19:440–445

    Article  PubMed  Google Scholar 

  • Nielsen J, Wohlert M (1991) Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet 87:81–83

    Article  CAS  PubMed  Google Scholar 

  • Nihoul-Fekete C, Lortat-Jacob S, Cachin O, Josso N (1984) Preservation of gonadal function in true hermaphroditism. J Pediatr Surg 19:50–55

    Article  CAS  PubMed  Google Scholar 

  • Polizzi A, Balsamo A, Bal MO, Taruscio D (2014) Rare diseases research and practice. Endocr Dev 27:234–256. http://www.ncbi.nlm.nih.gov/pubmed/25247660

  • Saggese G, Ghirri P, Gabrielli S, Cosenza GC (1989) Hormonal therapy for cryptorchidism with a combination of human chorionic gonadotropin and follicle-stimulating hormone. Success and relapse rate. Am J Dis Child 143:980–982

    Article  CAS  PubMed  Google Scholar 

  • Samtani R, Bajpai M, Ghosh PK, Saraswathy KN (2010) SRD5A2 gene mutations – a population-based review. Pediatr Endocrinol Rev 8(1):34–40

    PubMed  Google Scholar 

  • Sax L (2002) How common is intersex? A response to Anne Fausto- Sterling. J Sex Res 39:174–178

    Article  PubMed  Google Scholar 

  • Schweizer K et al (2014) Gender experience and satisfaction with gender allocation in adults with diverse intersex conditions (divergences of sex development, DSD). Psychol Sex 5(1):56–82

    Google Scholar 

  • Seo JY, Park HD, Kim JW, Oh HJ, Yang JS, Chang YS, Park WS, Lee SY (2014) Steroid profiling for congenital adrenal hyperplasia by tandem mass spectrometry as a second-tier test reduces follow-up burdens in a tertiary care hospital: a retrospective and prospective evaluation. J Perinat Med 42(1):121–127. http://www.ncbi.nlm.nih.gov/pubmed/23989111

  • Shearer BM, Thorland EC, Gonzales PR, Ketterling RP (2007) Evaluation of a commercially available focused aCGH platform for the detection of constitutional chromosome anomalies. Am J Med Genet A 143:2357–2370

    Article  Google Scholar 

  • Simm D, Degenhardt K, Gerdemann C et al (2008) Chronological age of patients with Turner syndrome at diagnosis. Klin Padiatr 220:16–20

    Article  CAS  PubMed  Google Scholar 

  • Slowikowska-Hilczer J, Szarras-Czapnik M, Wolski JK, Oszukowska E, Hilczer M, Jakubowski L, Walczak-Jedrzejowska R, Marchlewska K, Filipiak E, Kaluzewski B, Baka-Ostrowska M, Niedzielski J, Kula K (2015) The risk of neoplasm associated with dysgenetic testes in prepubertal and pubertal/adult patients. Folia Histochem Cytobiol 53(3):218–226

    Article  PubMed  Google Scholar 

  • Speiser PW (2007) Prenatal and neonatal diagnosis and treatment of congenital adrenal hyperplasia. Horm Res 68(Suppl 5):90–92

    PubMed  Google Scholar 

  • Speiser PW, White PC (2003) Congenital adrenal hyperplasia. N Engl J Med 349:776–788

    Article  CAS  PubMed  Google Scholar 

  • Telvi L, Lebbar A, Del Pino O (1999) 45,X/46,XY mosaicism: report of 27 cases. Pediatrics 104(2 Part 1):304–308

    Article  CAS  PubMed  Google Scholar 

  • Toppari J (2008) Environmental endocrine disrupters. Sex Dev 2:260–267

    Article  CAS  PubMed  Google Scholar 

  • Turcu AF, Auchus RJ (2015) The next 150 years of congenital adrenal hyperplasia. J Steroid Biochem Mol Biol 153:63–71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warne GL (2008) Long-term outcome of disorders of sex development. Sex Dev 2:268–277

    Article  CAS  PubMed  Google Scholar 

  • Warne G, Raza J (2008) Disorders of sex development (DSDs), their presentation and management in different cultures. Rev Endocr Metab Disord 9:227–236

    Article  PubMed  Google Scholar 

  • Wittassek M, Angerer J (2008) Phthalates: metabolism and exposure. Int J Androl 31:131–138

    Article  CAS  PubMed  Google Scholar 

  • Wohlfahrt-Veje C, Main KM, Skakkebæk NE (2009) Testicular dysgenesis syndrome; fetal origin of adult reproductive problems. Clin Endocrinol (Oxf) 71:459–465

    Article  Google Scholar 

  • Yamada G, Satoh Y, Baskin LS, Cunha GR (2003) Cellular and molecular mechanisms of development of external genitalia. Differentiation 71:445–470

    Article  PubMed  Google Scholar 

  • Zimmermann B, Zhong XY, Holzgreve W et al (2007) Real-time quantitative polymerse chain reaction measurement of male fetal DNA in maternal plasma. Methods Mol Med 132:43–49

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medical and Surgical Sciences, Pediatric Unit, Center for Rare Endocrine Diseases (CARENDO BO), S.Orsola Malpighi University Hospital, Bologna, Italy

    Antonio Balsamo, Franco D’Alberton & Alessandro Cicognani

  2. Neonatology and Neonatal Intensive Care Unit, Santa Chiara University Hospital, Pisa, Italy

    Paolo Ghirri, Rosa T. Scaramuzzo & Antonio Boldrini

  3. Adolescent Medicine Unit, Division of Pediatrics, S. Chiara Hospital, University of Pisa, Pisa, Italy

    Silvano Bertelloni

Authors
  1. Antonio Balsamo
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  2. Paolo Ghirri
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  3. Silvano Bertelloni
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  4. Rosa T. Scaramuzzo
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  5. Franco D’Alberton
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  6. Alessandro Cicognani
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  7. Antonio Boldrini
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Corresponding authors

Correspondence to Antonio Balsamo , Paolo Ghirri , Silvano Bertelloni , Rosa T. Scaramuzzo , Franco D’Alberton , Alessandro Cicognani or Antonio Boldrini .

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Editors and Affiliations

  1. Siena, Italy

    Giuseppe Buonocore

  2. Medicina della Riproduzione, Università di Siena Dipto. Pediatria, Ostetricia e, Siena, Italy

    Rodolfo Bracci

  3. Liverpool Women's Hospital Neonatal Unit, Liverpool, United Kingdom

    Michael Weindling

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Balsamo, A. et al. (2016). Disorders of Sexual Development in Newborns. In: Buonocore, G., Bracci, R., Weindling, M. (eds) Neonatology. Springer, Cham. https://doi.org/10.1007/978-3-319-18159-2_260-1

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  • DOI: https://doi.org/10.1007/978-3-319-18159-2_260-1

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  1. Latest

    Disorders of Sexual Development in Newborns
    Published:
    21 December 2017

    DOI: https://doi.org/10.1007/978-3-319-18159-2_260-2

  2. Original

    Disorders of Sexual Development in Newborns
    Published:
    05 January 2017

    DOI: https://doi.org/10.1007/978-3-319-18159-2_260-1

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