Evaluation of a Difference or Disorder of Sex Development

Table 1. The clinical members of the MDT and their potential roles in providing care to the patient and the parents
	Role
Neonatologist or General Paediatrician	- Initial explanation - Management of the unwell child - Initiation of first-line investigations - Seek advice from paediatric subspecialist (endocrine or surgical) with an interest in DSD
Paediatric Endocrinologist	- Detailed explanation over multiple visits -Management of the unwell child - Interpreting first-line investigations and planning second-line investigations - Organize timely and appropriate involvement of other members of MDT - Act as the link between the parents and MDT - Initiate and monitor long-term medical therapy such as steroid or sex steroid therapy
Paediatric Radiologist	- Interpret and often perform ultrasound scans in the newborn - Judge the reliability of ultrasound scans in the newborn esp when the results may influence sex assignment
Paediatric Urologist	- Assessment of external anatomy - Explanation of the anatomy and results of imaging - Explanation of pros and cons of surgery - Develop a plan for complex imaging (other than pelvic ultrasound) and further assessment of the anatomy - Perform procedures such as laparoscopy, biopsy, reconstructive surgery and gonadectomy - Organize timely and appropriate involvement of other members of MDT
Paediatric Specialist Nurse	- Provide general support to the patient and parents in addition to that provided by other members of the MDT - Arrange specialist investigations - Liaise with the rest of the DSD team, including the clinical psychologist
Clinical Psychologist	- Provide specialist support to parents soon after birth - Provide support to the growing up child and the parents - Develop an individualized plan for each family - Guide the MDT on timing and tempo of explanation of the condition to the older child and adolescent
Clinical Endocrine Biochemist*	- Facilitate timely analysis of samples - Provide specialist support and interpretation of results - Guide subsequent biochemical tests - Facilitate storage of samples for analysis at a later stage
Clinical Geneticist	- Facilitate timely analysis of chromosome analysis - Closer involvement in the child with dysmorphic features - Oversee the process of genetic analysis - Facilitate storage of samples for analysis at a later stage - Genetic counselling
Gynaecologist	- Availability at an early stage to discuss future outcome and map long-term care pathway in the affected girl - Discuss issues related to sexual function, reproductive function and surgery - Assess the understanding & review the diagnosis - Assess the need for psychology support in the adolescent girl - Initiate and monitor long-term sex steroid therapy - Perform examination, investigative and therapeutic procedures in the adolescent girl - Oversee vaginal dilator training with specialist nurse
Adult Endocrinologist	- Investigate and manage the adolescent presenting for the first time after the age of 16 yrs - Liaise with other members of the MDT - Act as the link between the patient and MDT - Initiate and monitor long-term medical therapy such as steroid or sex steroid therapy - Act as the transition link for adolescents under paediatric care
Service Coordinator	- Oversees the coordination of a complex clinical service - Responsible for data management - Oversees activities related to audit and benchmarking of services - Oversees public and professional engagement of the service

Table 2. Characteristics of 46, XX DSD associated with androgen excess
	Inheritance & Gene	Genitalia	Wolffian duct derivatives	Mullerian duct derivatives	Gonads	Typical signs and symptoms	Hormone profile
21-hydroxylase def	Autosomal Recessive, CYP21A2	Wide range of atypical genitalia	Absent	Normal	Ovary	Severe adrenal insufficiency in infancy ± salt loss; moderate-to-severe androgenization at birth	Decreased cortisol and/or mineralocorticoids. Increased 17-hydroxyprogesterone, 21-deoxycortisol, androstenedione, testosterone, and/or plasma renin (activity)
11β-hydroxylase def	Autosomal Recessive, CYP11B1	Wide range of atypical genitalia	Absent	Normal	Ovary	Adrenal insufficiency in infancy; moderate-to-severe androgenization at birth; arterial hypertension often developing at different ages	Decreased cortisol, corticosterone, aldosterone, and or plasma renin (activity) Increased 11-deoxycortisol, 11-deoxycorticosterone, androstenedione, testosterone
3β-hydroxysteroid dehydrogenase II def	Autosomal Recessive, HSD3B2	Commonly clitoromegaly or mild virilization, can also be normal	Absent	Normal	Ovary	Severe adrenal insufficiency in infancy ± salt loss, androgenization during childhood and puberty, premature pubarche	Increased concentrations of Δ⁵ C_21- and C_19- steroids, 17 hydroxypregnenolone and DHEA suppressible by dexamethasone
P450 oxidoreductase def	Autosomal Recessive, POR	Wide range of atypical genitalia including normal female	Absent	Normal	Ovary	Variable androgenization at birth and puberty, glucocorticoid deficiency, features of skeletal malformations. Maternal androgenization during pregnancy onset second trimester possible	Combined P450c17 and P450c21 insuff, normal or low cortisol with poor response to ACTH stim, elevated 17-hydroxyprogesterone, testosterone, progesterone and corticosterone; low oestradiol
P450 aromatase def	Autosomal Recessive, CYP19A1	Wide range of atypical genitalia	Absent	Normal	Ovary	Delayed bone age, development of ovarian cysts during infancy, childhood and puberty. Maternal androgenization during pregnancy	High androgens in cord blood, androgens may stay elevated or normalize soon after birth
Glucocorticoid insensitivity	Autosomal Dominant, GRα	Normal female	Absent	Normal	Ovary	Typically presents in young women with signs of androgen excess and fatigue with or without mineralocorticoid excess, hypertension and bilateral adrenal hyperplasia.	High/normal ACTH and high serum and urinary cortisol and lack of suppression to dexamethasone

Table 3. Characteristics of 46, XY disorders of sex development associated with deficiency of androgens or androgen action
	Inheritance & Gene	Genitalia	Wolffian duct derivatives	Mullerian duct derivatives	Gonads	Typical features	Hormone profile
LH deficiency or bioinactivity	Multiple causes of congenital hypogonadotropic hypogonadism (CHH)	Micropenis, undescended testes, rarely more atypical. Often normal male	Normal	Absent	Testes	May be associated with other features of hypopituitarism or syndromes associated with CHH. May present in early infancy or adolescence with pubertal delay.	Poor response to LHRH stimulation test, low AMH, variable testosterone response to hCG stimulation test.
Leydig cell hypoplasia	Autosomal Recessive, LH/HCGR	Wide range of atypical genitalia including normal female	Hypoplastic	Absent	Testes	Underandrogenization with variable failure of sex hormone production at puberty	Low T and DHT, elevated LH and FSH, exaggerated LH response to LHRH, poor T and DHT response to hCG stimulation
7-Dehydrocholesterol reductase deficiency	Autosomal Recessive, DHCR7	Wide range of atypical genitalia	Normal	Absent	Testes	Usually part of Smith-Lemli-Opitz syndrome	Variable elevation of 7-dehydrocholesterol. Maybe associated with adrenal insufficiency including mineralocorticoid deficiency
Lipoid congenital adrenal hyperplasia	Autosomal Recessive, STAR	Female, rarely atypical or male	Hypoplastic or normal	Absent	Testes	Severe adrenal insufficiency in infancy with salt loss, failure of pubertal development, rare cases associated with isolated glucocorticoid deficiency	Usually deficient of glucocorticoids, mineralocorticoids and sex steroids
P450 side-chain cleavage deficiency	Autosomal Recessive, CYP11A1	Female, rarely atypical or hypospadias	Hypoplastic or normal	Absent	Testes	Severe adrenal insufficiency in infancy with salt loss ranging to milder adrenal insufficiency with onset in childhood	Usually deficient of glucocorticoids, mineralocorticoids and sex steroids
3β-hydroxysteroid dehydrogenase II deficiency	Autosomal Recessive, HSD3B2	Wide range of atypical genitalia including apparently normal female genitalia	Normal	Absent	Testes	Severe adrenal insufficiency in infancy ± salt loss, poor androgenization at puberty with gynaecomastia	Increased concentrations of Δ⁵ C_21- and C_19- steroids, 17 hydroxypregnenolone and DHEA suppressible by dexamethasone
Combined 17α-hydroxylase/17,20-lyase deficiency	Autosomal Recessive, CYP17A1	Wide range of atypical genitalia	Absent or hypoplastic	Absent	Testes	Absent or poor androgenization at puberty, gynaecomastia, hypertension	Decreased T, increased LH & FSH, low cortisol, increased plasma deoxycorticosterone, corticosterone and progesterone, decreased plasma renin activity, low renin hypertension with hypokalaemic alkalosis
Isolated 17,20-lyase deficiency	Autosomal Recessive, CYP17A1, usually affecting key redox domains, alternatively caused by cytochrome b5 variants (CYB5)	Wide range of atypical genitalia	Absent or hypoplastic	Absent	Testes	Absent or poor androgenization at puberty, gynaecomastia	Decreased T, DHEA, androstenedione and oestradiol, abnormal increase in plasma 17-hydroxyprogesterone and 17-hydroxypregnenolone, increased LH and FSH, increased ratio of C_21-deoxysteroids to C₁₉ steroids after hCG stim. Normal glucocorticoid and mineralocorticoid levels
P450 oxidoreductase deficiency	Autosomal Recessive, POR	Wide range of atypical genitalia	Absent or hypoplastic	Absent	Testes	Variable androgenization at birth and puberty, glucocorticoid deficiency, features of skeletal malformations (Antley-Bixler syndrome) Maternal androgenization during pregnancy onset second trimester possible	Combined P450c17 and P450c21 insuff, normal or low cortisol with poor response to ACTH stim, elevated 17-hydroxyprogesterone, T low
Cytochrome b5 deficiency	Autosomal Recessive	Wide range of atypical genitalia including normal female	Hypoplastic or normal	Absent	Testes	Associated with clinical and biochemical features of methemoglobinemia. Low methemoglobin reductase activity and low red cell cytochrome b5.	Low androgen metabolite excretion with increased excretion of pregnenetriol and normal mineralocorticoid and glucocorticoid metabolite excretion. Ratio of corticosterone over cortisol metabolites normal and elevated ratio of 17-alpha-hydroxyprogesterone over androgen metabolites
17β-hydroxysteroid dehydrogenase type 3 deficiency	Autosomal Recessive HSD17B3	Wide range of atypical genitalia including normal female	Present	Absent	Testes	Androgenization at puberty, gynaecomastia variable	Increased plasma oestrone, decreased ratio of testosterone/androstenedione and oestradiol after hCG stim, increased FSH and LH
5α-reductase-2 deficiency	Autosomal Recessive SRD5A2	Wide range of atypical genitalia including normal female	Normal or hypoplastic	Absent	Testes	Decreased facial and body hair, no temporal hair recession, prostate not palpable. Will androgenize in puberty	Decreased ratio of 5α/5β C_21- and C_19- steroids in urine, increased T/DHT ratio before and after hCG stim, modest increase in LH, decreased conversion of T to DHT in vitro
Aldo-keto reductase deficiency	Autosomal Recessive AKRC2, AKRC4	Wide range of atypical genitalia including normal female	Normal or hypoplastic	Absent	Testes	Similar features to 5α-reductase-2 deficiency but not expected to androgenize in puberty.	DHT deficiency and apparent 17,20-lyase deficiency but normal CYP17A1 and SRD5A2
Complete androgen insensitivity	X-linked recessive AR	Female with blind vaginal pouch	Often normal or hypoplastic	Absent	Testes	Scant or absent pubic and axillary hair, breast development and female body habitus at puberty, primary amenorrhea	Increased LH and T, increased oestradiol, FSH levels normal or slightly increased, resistance to androgenic and metabolic effects of T (may be normal in some cases)
Partial androgen insensitivity	X-linked recessive AR	Wide range of atypical genitalia including normal male with infertility, sometimes referred to as mild AIS (MAIS)	Often normal	Absent	Testes	Decreased to normal axillary and pubic hair, facial and body hair, gynaecomastia common at puberty	Increased LH and T, increased oestradiol, FSH levels may be normal or slightly increased, partial resistance to androgenic and metabolic effects of T

Table 4. A selection of genes associated with disorders of gonadal development in XX and XY DSD. It is beyond the scope of this table to include all the congenital conditions and syndromes that are associated with atypical genitalia
	Inheritance	46 XX/46 XY/both	Gonadal dysgenesis	Testicular DSD	Ovotesticular DSD	Associated Features
ARX	XLD	XY	+			lissencephaly, epilepsy, learning difficulty
ATRX	XLD:del	XY				learning difficulty, α-thalassemia
BMP15	XLD	XX	+
CBX2	AR	XY	+
DAX1	XL:dup	XY	+
DHH	AR/AD	XY	+			minifascicular neuropathy
DHX37	AD	XY	+
DMRT1	AD:del	XY	+			learning difficulty
EMX2	AD:del	XY	+			learning difficulty, renal agenesis
ESR2	AR/AD	XY	+
FGF9	AD	XX		+
FGFR2	AD	XY	+			craniosynostosis
FOXL2	AD	XX	+			blepharophimosis, epicanthus inversus and ptosis
GATA4	AD	XY	+			congenital heart disease
HHAT	AR	XY	+			short stature, generalized chondrodysplasia, muscle hypertrophy, myopia, intellectual deficiency
MAP3K1	AD	XY	+
NR2F2	AD			+	+	congenital heart defects, congenital diaphragmatic hernia, blepharon-phimosis-ptosis-epicanthus inversus syndrome
NR5A1	AD	XX	+	+	+
NR5A1	AR/AD	XY	+			rarely primary adrenal insufficiency
NUP107	AR	XX	+
RSPO1	AR	XX		+	+	palmoplantar hyperkeratosis, squamous cell carcinoma of skin
SOX3	XL:dup	XX		+	+
SOX8	AD	XY	+			skeletal anomalies, learning difficulty
SOX9	AD:dup	XX		+	+
SOX9	AD	XY	+			campomelic dysplasia
SOX10	AD:dup	XX		+	+	Waardenburg and Hirschsprung syndromes, peripheral neuropathy
SRY	T	XX		+	+
SRY	Del	XY	+
STARD8	XL	XY	+
TSPYL1	AR	XY	+			abnormal brain stem development, sudden infant death
WNT4	AR/AD	XX		+	+	sex reversal dysgenesis of kidneys, adrenals and lung, lethal when biallelic
WNT4	AD:dup	XY	+		+	may also only have ovarian tissue
WT1	AD	XX		+
WT1	variable	XY	+			Deletion—WAGR syndrome, inactivation—Denys Drash syndrome, splicing—Frasier syndrome
WWOX	AD;del	XY	+			epilepsy
ZFPM2	AD	XY	+		+	congenital heart disease
ZNRF3	AD	XY	+

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; del, deletion; dup, duplication; XLD, X-linked dominant.

Authors and Disclosures

S. Faisal Ahmed^1–3, John Achermann⁴, Julie Alderson⁵, Naomi S. Crouch⁶, Sue Elford⁷, Ieuan A. Hughes^8,9, Nils Krone¹⁰, Ruth McGowan^1,11, Talat Mushtaq¹², Stuart O'Toole^2,13, Leslie Perry¹⁴, Martina E. Rodie^2,3,15, Mars Skae¹⁶ and Helen E. Turner¹⁷

¹Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK
²Royal Hospital for Children, NHS Greater Glasgow & Clyde, Glasgow, UK
³Office for Rare Conditions, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK
⁴Genetics & Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, London, UK
⁵Psychological Health Services, University Hospitals Bristol & Weston NHS Foundation Trust, Bristol, UK
⁶Department of Women's Health, St Michael's Hospital, University Hospitals Bristol & Weston NHS Foundation Trust, Bristol, UK
⁷CAH Support Group, Crewe, UK
⁸DSDFamilies, UK
⁹Department of Paediatrics, University of Cambridge, Cambridge, UK
¹⁰Academic Unit of Child Health, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
¹¹West of Scotland Centre for Genomic Medicine, NHS Greater Glasgow & Clyde, Glasgow, UK
¹²Department of Paediatric Endocrinology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
¹³Department of Paediatric Urology, Royal Hospital for Children, NHS Greater Glasgow & Clyde, Glasgow, UK
¹⁴Department of Clinical Biochemistry, Croydon University Hospital, London, UK
¹⁵Department of Neonatology, Queen Elizabeth University Hospital, Glasgow, UK
¹⁶Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester, UK
¹⁷Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

Correspondence
S Faisal Ahmed, Developmental Endocrinology Research Group, School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, UK. Email: faisal.ahmed@glasgow.ac.uk

Conflict of Interest
The authors have no conflicts of interest.

Author Contributions
All authors have contributed to this manuscript and have approved the final version.

Society for Endocrinology UK Guidance on the Initial Evaluation of a Suspected Difference or Disorder of Sex Development (Revised 2021)

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Society for Endocrinology UK Guidance on the Initial Evaluation of a Suspected Difference or Disorder of Sex Development (Revised 2021)

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