Introduction

Disorders of sexual development (DSD) include various congenital conditions in which there is an inconsistency between chromosomal, gonadal, and anatomical sex.
DSD in neonates is an endocrine and psychological emergency due to several reasons.

• The commonest cause of DSD is congenital adrenal hyperplasia, which is a medical emergency.
• Determination of the sex.
• Parental psychosocial stressors

Pathophysiology

Sexual determination results from molecular events that direct the undifferentiated bipotential gonad to the development of the testis or ovary. The bipotential gonad is developed from the urogenital crest, between weeks 6 to 7 of fetal life. During the bipotential stage, several genes are expressed in the gonadal crests. The function of protein products of these genes, gene dosage, and the resulting levels of gene expression determine gonadal differentiation. In response to the activation of the testis-specific or ovary-specific pathway with parallel repression of the opposite pathway, the bipotential gonad will differentiate into either the testis or the ovary.

Several genes upstream of SRY not sex-specific, are expressed early in the gonadal and are essential for sexual development. The absence of some of these genes leads to sex reversal. As the very same genes are affecting the development of the adrenal and renal systems, patients with DSD can have associated renal malformations and adrenal dysfunction.

Sex determination in a patient with DSD is a challenge to clinicians as it depends on multiple factors.

Clinical Presentation

In the newborn period

• Atypical genitalia
• Hemodynamic instability
• Hyperpigmentation
• Jaundice
• Poor weight gain and dehydration

Which neonate with atypical genitalia needs to be referred to the endocrine team

• Isolated perineal Hypospadias
• Familial hypospadias
• Isolated micropenis (less than 2 cm)
• Bilateral/ Unilateral undescended testicles
• Isolated clitoromegaly with or without posterior labial fusion
• Clitoral length is more than 8 mm.
• Female genitalia with inguinal or labial mass

In late childhood or the adolescent age group.  

• Delayed puberty in boys– In boys, absent testicular enlargement by the age of 14 years.
• Primary amenorrhea with or without breast development
• Clitoromegaly, acne and virilization in a girl

May have been associated following features

• Hypertension
• Syndromic features
• Sparse pubic and axillary hair
• Gynaecomastia

Management

In case of suspected DSD, please contact the nearby endocrine service at the earliest to arrange the basic management for the patient. It is important to discuss the above as the approach to management for each patient is different depending on the clinical presentation and psychosocial background.  Also, most of the endocrine tests are not available in the government sector thus should be carefully decided for each individual. Requesting tests without discussing with the endocrine team will cost the family more unnecessarily.

Newborn

1. Newborn observed with atypical genitalia in the newborn examination,

Monitor the vital parameters during the admission (heart rate, blood pressure, blood glucose level)

Serum electrolyte levels, renal functions, and urine for albumin levels after 96 hours of life.

Ultrasound scan of the pelvis and kidney, ureters, and bladder. We expect details of the kidney anomalies, presence of Mullerian structures, and morphology of male genital structures. As this investigation is operator-dependent, we recommend a scan by a Pediatric radiologist if available.

Cardiac system examination – some patients with DSD can have associated cardiac malformations. 

Karyotype.

We do not recommend arranging random 17 OHP levels as it depends on the assay method and is expensive. The endocrine team will organize a stimulated sample from a reliable lab along with other relevant investigations.

2. Newborn admitted to the emergency department with a collapse episode

Basic life support and resuscitation as required.

Examination of the genital region.

Differential diagnosis at this stage is

–        Sepsis

–        Cardiac disease

–        Metabolic disease

–        Congenital adrenal hyperplasia / hypoplasia.

Blood investigations- Blood glucose level, electrolytes, blood gas, serum cortisol level, septic screening.

IV hydrocortisone 25 mg stat followed by 6.25 mg 6 hourly (suggest after a random cortisol level if possible)

Urgent phone consultation with the endocrine team.

Adolescent

All girls with delayed puberty need a thorough clinical examination to exclude Turner syndrome. Thus, it is important to measure the height and blood pressure of all patients.

We recommend following investigations as a baseline.

• Thyroid function tests
• Bone age X-ray
• Ultrasound scan of the pelvis and abdomen (presence of uterus, ovarian sizes, presence of follicles, male genital structures, renal anomalies, and the size of the adrenal glands).
• Endocrinologists prefer to read the bone age by themselves, therefore please send the image or the films along with the patient upon consultation.
• Hormonal investigations will be decided by the endocrinologist as required, depending on the individual.

Important Consideration

The role of the general pediatrician/neonatologist in an encounter with a patient with DSD is a basic explanation, initial management of the unwell baby/child, arrangement of first line investigations, and early referral to the subspecialty teams.      

Communication with patients with DSD and their parents is a major element in management. Patients with DSD are managed by a group of specialists who have expertise in the field. The team leader is usually the Pediatric Endocrinologists who will be communicating with the family directly. Generally, team members will discuss the results of the tests and patient management before reaching the family.

Thus, we recommend not to assign sex for patients on encounter with such a patient nor register the birth until the team makes the decision.

We do not recommend explaining the results of the tests to parents or family at your level as this may confuse the family and the patients.

References

1. BSPED guidelines on Clinical Standards for the Management of an Infant or Adolescent presenting with a suspected disorder of sex development (DSD), 2017.

2. Clinical guidelines for the management of sexual disorders in childhood; Published by the intersex society of North America, First edition;2006.

3. RACPGP guidelines on A guide to differences/ disorders of sex development/intersex in children and adolescents by K A Vora and S Srinivasan;2020  

4.Lee PA, Nordenström A, Houk CP, et al. Global disorders of sex development update since 2006: Perceptions, approach and care. Horm Res Paediatr 2016;85(3):158–80. doi: 10.1159/000442975

Prepared by,

Dr. D S Gamage
Consultant in Paediatric Endocrinology, 
Teaching Hospital Kurunegala