Prenatal management of disorders of Sex development
Introduction
Disorders of sex development (DSD) are very challenging conditions requiring management by highly specialised medical teams to allow consideration of all aspects of diagnosis, treatment and ethical issues. Although rare, DSD is usually identified at the first physical examination after birth. However, in recent years, DSD has become more and more a prenatal medical issue. Probably the most common circumstance is a pregnancy presenting with a family history of an inherited form of DSD. Less common is the discovery of abnormal genitalia by prenatal ultrasonography or, and very rarely, discordance between the genetic sex determined by karyotyping, performed because of an increased risk of aneuploidy, and the phenotypic sex observed by ultrasonography. Ideally, these patients should be referred to a specialised multidisciplinary team including a pediatric endocrinologist, geneticist, paediatric radiologist and paediatric urological surgeon. This team should also have access to expertise in hormonal profiling and molecular genetics.
In this paper we shall briefly review some aspects regarding the prenatal presentation and management of DSD. We shall start by describing the sonographic appearance of normal genitalia and methods of determining genetic sex before discussing the prenatal management of pregnancies with the unexpected finding of genital ambiguity on prenatal ultrasound. Finally, we will review the prenatal management of pregnancies at high risk of DSD, keeping in mind that this is a rapidly developing field, dependent not only on the experience of the medical team but also patient access to advanced technical imaging and molecular genetic analyses. Local social, ethical and legal aspects may also influence management.
Section snippets
Normal appearances and evaluation of fetal genitalia
The appearance of normal fetal genitalia and the accuracy of sonographic fetal sex assignment across gestation are well documented [1], [2]. However, reliable identification of fetal genital dysmorphology requires an experienced operator. In early pregnancy the genital tubercule is identical in size in male and female fetuses. From 12 weeks' gestation the critical observation is variation in the angle or ‘sagittal sign’ of the tubercle (Fig. 1) which allows for highly accurate sonographic
Determination of genetic sex
Traditionally, determination of genetic sex has been performed by karyotype, fluorescent in-situ hybridisation (FISH) or quantitative fluorescent polymerase chain reaction (qfPCR) analysis of amniocytes or chorionic villi following invasive techniques such as amniocentesis or chorionic villus sampling (CVS), both of which carry a risk of miscarriage of around 0.5–1% in experienced hands [10]. The identification of cell free fetal DNA (cffDNA) circulating in maternal blood has offered the
The management of fetuses presenting with the unexpected finding of genital ambiguity
Genital abnormalities are a rare finding on prenatal ultrasound but can be seen when detailed examination is performed following detection of another structural abnormality or, and more commonly, when the genitalia are examined because of parental curiosity. The aetiology of these unexpected genital anomalies is broad and includes an isolated anomaly, an underlying genetic syndrome, intra-uterine fetal growth restriction (IUGFR), chromosomal abnormalities and, although very rare, anomalies of
Prenatal management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH)
Amongst the rare adrenal steroidogenesis biosynthesis disorders that lead to DSD, CAH due to 21-hydroxylase deficiency (CYP 21 CAH) is less rare than 11-β-hydroxysteroids dehydrogenase deficiency. Despite half a century of experience of CYP 21 CAH, the paediatric management of this condition remains challenging and the prenatal management even more so. Neonatal screening for CYP 21 CAH, based on 17-hydroxyprogesterone (17OHP) measurement from blood collected early after birth on filter paper,
Issues arising in CYP 21 CAH prenatal treatment
Prenatal treatment aimed at preventing masculinisation of affected female fetuses may be effective for fetuses at risk for classic CYP 21 CAH but is not appropriate for non-classic types (13–16). Although today's early diagnosis of fetal sex allows restriction of steroid treatment to mothers carrying female fetuses, as summarised in the consensus statement on CAH management, “the appropriateness, ethics, and outcomes of the prenatal treatment of CAH with dexamethasone remain controversial” [28]
Conclusions
Prenatal presentation of DSD is rare but demands sensitive and timely management by an experienced and expert team, which should include expertise in fetal medicine, genetics, paediatric endocrinology and paediatric urology. Rapid developments in molecular genetics and other technology will influence diagnosis and management, possibly rendering some of the conclusions of this paper outdated. Existing and any future prenatal treatment requires co-ordinated and long-term follow-up studies to
Acknowledgements
LSC is partially funded by the Great Ormond Street Children's Charity and the National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.
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