Management of Atypical Genitalia & Suspected DSD in the Neonate

Examine each testis to determine if they are palpable/impalpable and descended (within the scrotum) or undescended (outwith the scrotum).

If a patient has hypospadias that is not penoscrotal or perineal and no other features of concern are present, no immediate action is required. Advise the parents against circumcision until after surgical review and refer to the Urology Team at RHC. A good urinary stream should be observed prior to discharge.

A child with a suspected DSD may present with one or more of these features:

• a bifid scrotum
• bilateral undescended testes
• clitoromegaly (phallus >0.8mm in an apparent female infant)
• micropenis (phallus <2cm stretched penile length in an apparent male infant)
• proximal (penoscrotal or perineal) hypospadias
• distal or midshaft hypospadias in combination with any of the above features

If any of these features are detected at delivery and there is uncertainty about the sex of the baby, explain to the parents that it is not possible to tell whether their infant is a girl or a boy. Do not guess the sex, or even voice your suspicions as this can be unhelpful to the parents - it is extremely difficult to ‘change’ the sex of a baby in the light of results if the parents have started to adjust to the baby being a particular sex, and may have told friends or relatives this sex.

Advise the parents not to name the baby, and to think carefully about who they tell that the baby has been born, as this may be an issue that they wish to remain confidential until a sex has been assigned. A single room would allow more frequent private discussions.

Registration of the birth must be delayed until the sex has been assigned. The baby should be referred to as ‘your baby’ or ‘the baby’ but not ‘it’, ‘he’ or ‘she’ and a white cot card (not blue or pink)) can be used.

Clinical psychology support should be offered to the parents of every newborn where sex assignment is delayed. Please contact the Clinical Psychology Service at RHC, Glasgow on 0141 451 6574.  

In the event that the above features are picked up late, i.e at neonatal discharge check when sex may have already been assigned, the neonatal consultant on-call should be informed on the day so that the concerns regarding the genitalia can be conveyed to parents. Advise the parents that the sex of the baby is uncertain, and further assessment will need to be carried out over the next few days.

• The neonatal consultant on call should be informed about the baby.
• History and examination should be carried out by an experienced clinician (Appendix 2).
• The patient should be discussed during working hours with the Endocrine Registrar at the Royal Hospital for Children (RHC), Glasgow, who can be contacted on 0141 451 5799 (85799 while in hospital), and who will liaise with the Endocrinology Consultant on-call. They will be asked to document any discussions on Clinical Portal even if they do not attend to see the child.

Second Line Tests - These tests should be performed after discussion with RHC Endocrine Team and will depend on the clinical presentation

Further investigations to identify the cause of DSD are discussed in Appendix 3 but should not be ordered without discussion with the endocrine team. These may include:-  

• hCG stimulation test, this will normally be carried out at RHC
• DNA analysis
• Imaging by Laparoscopy/Genitogram/Genitoscopy

The process of bringing together some of the initial information usually takes about 5 working days. 

All abnormal sex chromosome results should be flagged to the on-call endocrine consultant once identified.

In some cases, however, where sex assignment is difficult and/or the chromosome result is complicated, laparoscopy may be required, and the process may take longer and often up to 2 weeks. It is important to try to avoid burdening the parents with too much information during the process, as this may give conflicting messages about the sex before final conclusions are reached. This is especially true where some investigations such as ultrasound may be difficult to interpret in a newborn. Although it is important to explain why tests are being done, it is probably best to try to bring things together for the parents once all the information is available. To this end it is helpful to have a surgical opinion early, as this gives a view of the long-term anatomical possibilities. Results will be explained to the family by a consultant member of the DSD team.

Depending on the case, ongoing management may require the help of several members of the DSD MDT. The extent and frequency of this will be decided by the DSD team prior to discharge in the more complex cases. As a default, all cases of suspected DSD should be reviewed at the second Monday of the month clinic held by Prof Ahmed at RHC which is also attended by Emily Fraser from Clinical Psychology and Dr Ruth McGowan from Clinical Genetics. 

Biology of DSD

Primordial germ cells migrate to the genital ridge from the yolk sac at approximately 6 weeks of gestation in the human embryo. Wilms Tumour 1 (WT1) and Steroidogenic Factor 1 (SF1) genes result in the development of bipotential gonads from these cells.

Usually, if a Y chromosome is present, the development of Mullerian structures is inhibited by the production of a glycoprotein called Anti-Mullerian Hormone (AMH). With the production of testosterone by the Leydig cells, the mesonephric (Wolffian) duct increases in size and differentiates into the epididymis, vas deferens and prostate. 5-dihydrotestosterone (DHT) is produced by the conversion of testosterone by the enzyme 5α-reductase, resulting in the development of male external genitalia and testicular descent. If there is no Y chromosome present, the Mullerian structures usually develop into female internal genitalia and ovaries develop. The absence of DHT also results in the development of female external genitalia. There are many factors involved in the differentiation of the sex organs into male or female and there is potential for a disruption of this process at multiple different stages. The clinical phenotype will therefore depend on the nature of disruption.

Classification of DSD

There are three broad groups: sex chromosome DSD, 46,XY DSD and 46,XX DSD.

Sex chromosome DSD

Sex chromosome DSD includes conditions such as 47,XXY (Klinefelter syndrome and variants), 45,X (Turner syndrome and variants), 45,X/46,XY (mixed gonadal dysgenesis) and 46,XX/46,XY (chimerism). These are often diagnosed antenatally with confirmation of the diagnosis after birth. Antenatal diagnosis allows for focussed evaluation of the other complications associated with these disorders, for example, cardiac anomalies in Turner syndrome. It also provides the opportunity to offer counselling to families prior to the birth.

46,XY DSD

46,XY DSD has three broad categories: disorders of gonadal (testicular) development, disorders in androgen synthesis or action and other causes, including hypogonadotrophic hypogonadism, cryptorchidism and isolated hypospadias. They are a heterogeneous group of disorders, where the phenotype is consistent with reduced male sex hormone action.

46, XX DSD

46, XX DSD encompasses disorders of gonadal (ovarian) development, such as gonadal dysgenesis and disorders secondary to androgen excess. Most commonly, the high levels of androgens responsible for virilisation in 46,XX DSD patients are secondary to production by the foetal adrenal glands and amongst them 21 hydroxylase deficiency CAH is the most common disorder. Androgen excess during pregnancy may be endogenous (secondary to an adrenal adenoma, dermoid cyst, Sertoli-Leydig tumour, sex cord stromal tumour or metastatic carcinoma) or exogenous (secondary to danazol, progestins or potassium sparing diuretics). Exogenous steroids taken during pregnancy can also cause posterior fusion of the labia, clitoral enlargement and increased degrees of androgenisation. Where clinically possible, mothers should be advised of the potential risks associated with taking medications which increase androgen production during pregnancy and an alternative sought.

A focussed clinical history should be taken from the parents, addressing the following issues:

• Parental consanguinity, history of salt-losing, unexplained infant deaths or DSD in relatives. These elements may indicate autosomal recessive genetic disorders associated with disturbed steroidogenesis.
• Maternal ingestion of drugs or exposure to specific environmental factors capable of inhibiting virilisation of the foetus during the pregnancy.
• Whether the pregnancy was planned - Some of the progestogen-containing drugs used for assisted-conception techniques are associated with a higher likelihood of male offspring with genital anomalies.
• In cases where parents have had some prenatal advice and discussion, it is useful to have access to these previous discussions and to seek parents’ recollection of these discussions.
• Results of prenatal tests if available.
• Social history with an enquiry about the family’s social network.

In particular the clinician should look out for:

• Any dysmorphic features, in particular midline defects (suggesting abnormalities of the hypothalamic-pituitary axis). 
• The state of hydration and blood pressure (daily measurement until formal diagnosis)
• Jaundice (associated with hypopituitarism)
• Urine dip for protein (associated with renal anomalies)
• Pre feed blood glucose – commence hypoglycaemia screening protocol (see neonatal guidelines)
• Examination of the external genitalia
  • Inspection - Is there more than expected pigmentation of the genitalia with a genital anomaly? If so the baby may have congenital adrenal hyperplasia (CAH)
  • Palpation for gonads or swellings in labioscrotal fold or inguinal region.
    If there are palpable gonads, the baby is probably a male (but don’t share this opinion with parents)
  • There are various scoring systems available to assess the external genitalia. We recommend the use of the External Masculinising Score initially, shown below. This is useful to tell the Endocrine team when referring the patient.

Websites

Scottish DSD network                  

DSD Families - An information and support resource for families with children, teens and young adults who have a DSD

Information Leaflets

The following information leaflets are available on the Scottish DSD network website at this URL: https://www.sdsd.scot.nhs.uk/families/

• What is a DSD?
• DSD Families – When your baby is born with genitals that look different… The first days.
• The Story of Sex Development
• Nursery and Your Son
• For parents of children with peno-scrotal/ proximal hypospadias and differences of sex development
• Congenital Adrenal Hyperplasia (CAH) Information Sheet
• Information about Genetic Testing Sheet
• Genetic Testing Information for Families
• Hypospadias for parents
• Mayer-Rokitansky-Küster-Hauser (MRKH) Information Sheet
• Undescended Testes Information Sheet
• Vaginal Dilation Information Sheet
• Glossary of Terms

Current Version Authors

• Angela Lucas-Herald, Clinical Lecturer, RHC, Glasgow
• Faisal Ahmed, Consultant Endocrinologist, RHC, Glasgow
• Emily Fraser, Psychologist, RHC, Glasgow
• Ruth McGowan, Consultant Geneticist, QEUH, Glasgow
• Jane McNeilly, Consultant Biochemist, QEUH, Glasgow
• Stuart O’Toole, Consultant Urologist, RHC, Glasgow
• Martina Rodie, Consultant Neonatologist RHC, Glasgow
• Guftar Shaikh, Consultant Endocrinologist, RHC, Glasgow

Original version authors

• Suet Ching Chen, Paediatric Endocrinology Registrar, RHC, Glasgow
• Angela Lucas-Herald, Clinical Lecturer, RHC, Glasgow
• Martina Rodie, Clinical Lecturer, RHC, Glasgow
• Faisal Ahmed, Consultant Endocrinologist, RHC, Glasgow
• Alan Jackson, Consultant Neonatologist, PRM, Glasgow
• Andrew Powls, Consultant Neonatologist, PRM, Glasgow

Original version other specialists consulted

• Helen McDevitt, Consultant Neonatologist, RHC, Glasgow
• Ruth McGowan, Clinical Geneticist, South Glasgow Hospitals
• Jane McNeilly, Consultant Biochemist, RHC, Glasgow
• Guftar Shaikh, Consultant Endocrinologist, RHC, Glasgow
• Avril Mason, Consultant Endocrinologist, RHC, Glasgow
• Jarod Wong, Consultant Endocrinologist, RHC, Glasgow
• Ruth Hind, Clinical Psychologist, RHC, Glasgow
• Stuart O’Toole, Consultant Urologist, RHC, Glasgow
• Nicola Brindley, Consultant Surgeon, RHC, Glasgow
• Ruth Allen, Consultant Radiologist, RHC, Glasgow