intersex

INTERSEX

Disorders of sexual development (DSD), formerly termed intersex conditions, are among the most fascinating conditions encountered by the clinician. The ability to diagnose these conditions has advanced rapidly in recent years. In most cases today, clinicians can promptly make an accurate diagnosis and counsel parents on therapeutic options.

INTERSEX

Intersex covers a diverse range of conditions encompassing: individuals with standard male or female genitalia, who may have a variety of internal genital organs and karyotypes, and also those with ambiguous external genitalia.

“Intersex” is a general term used for a variety of conditions in which a person is born with a reproductive or sexual anatomy that doesn’t seem to fit the typical definitions of female or male.

For example, a person might be born appearing to be female on the outside, but having mostly male-typical anatomy on the inside. Or a person may be born with genitals that seem to be in-between the usual male and female types—for example, a girl may be born with a noticeably large clitoris, or lacking a vaginal opening, or a boy may be born with a notably small penis, or with a scrotum that is divided so that it has formed more like labia. Or a person may be born with mosaic genetics, so that some of her cells have XX chromosomes and some of them have XY.

CLASSIFICATION OF INTERSEXUALITY

Virilization of genetically female foetus Female pseudohemaphroditism Incomplete musculinization of genetically male foetus Male pseudohermaphroditism (XY-FEMALE)

3. The presence of both ovarian and testicular tissue in the same individual True hermaphroditism 4. Chromosomal abnormality Mixed gonadal dysgenesis ( 45,X0 / 46,XY) This terminology mainly reflects the chromosomal sex or the gonadal tissue associated with the disorder.

How many children are born with intersex conditions?

A conservative estimate is that 1 in 2000 children born will be affected by an intersex condition.


Aetiology
Most intersex conditions occur due to a genetic or environmental disruption to the pathway of fetal sexual development. This disruption can be to: Gonadal differentiation or development, Sex steroid production, Sex steroid conversion, Tissue utilization of sex steroid.

FEMALE PSEUDOHERMAPHRODITISM

EXCESS FETAL ANDROGENSCongenital adrenal hyperplasia  21 -hydrxylase deficiency 11-hydroxylase deficiency 3Я-hydroxysteroid dehydrogenase deficiency EXCESS MATERNAL ANDROGENS Maternal androgen secreting tumours (ovary, adrenal) Maternal ingestion of androgenic drugs

Congenital adrenal hyperplasia

The commonest cause of genital ambiguity at birth21-Ohas deficiency is most common formAutosomal reccessiveSalt wasting form may be lethal in neonatesSERUM 17OH-progesterone (21OHase) SERUM deoxycorticosterone, 11-deoxycotisol (11- OHase)Treatment : cortisol replacement and ? Surgery

Background

The term congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive disorders, each of which involves a deficiency of an enzyme involved in the synthesis of cortisol, aldosterone, or both.

Overall, CAH is the most frequent cause of ambiguous genitalia in the newborn, constituting approximately 60% of all intersex cases. Excessive androstenedione production results in a gonadal female with a virilized phenotype.

Pathophysiology

The clinical manifestations of each form of congenital adrenal hyperplasia are related to the degree of cortisol deficiency and/or the degree of aldosterone deficiency. In some cases, these manifestations reflect the accumulation of precursor adrenocortical hormones. When present in supraphysiologic concentrations, these precursors cause abnormalities such as virilization or hypotension.

The basic biochemical defect is an enzymatic block that prevents sufficient cortisol production. Biofeedback via the pituitary gland causes the precursor to accumulate above the block. Clinical manifestation of CAH depends on which enzymatic defect is present.

21-hydrxylase deficiencycongenital adrenal hyperplasia

Pituitary
ACTH
Adrenal cortex
Androgens Cortisol
Cholesterol
Pregnenolone
Progesterone
17-OH progesterone
21-hydroxylase
Androgens
Cortisol


Severe forms of congenital adrenal hyperplasia are potentially fatal if unrecognized and untreated because of the severe cortisol and aldosterone deficiencies that result in salt wasting, hyponatremia, hyperkalemia, dehydration, and hypotension.

Epidemiology

Classic adrenal hyperplasia has an overall prevalence of 1 case per 16,000 population; however, in selected populations (eg, the Yupik of Alaska), the prevalence is as high as 1 case in 400 population. Congenital adrenal hyperplasia caused by 11-beta-hydroxylase deficiency accounts for 5-8% of all congenital adrenal hyperplasia cases.

Clinical Presentation

Sex: Because all forms of congenital adrenal hyperplasia are autosomal recessive disorders, both sexes are affected with equal frequency. However, because accumulated precursor hormones or associated impaired testosterone synthesis impacts sexual differentiation, the phenotypic consequences of mutations or deletions of a particular gene differ between the sexes.

Age Classic congenital adrenal hyperplasia is generally recognized at birth or in early childhood because of ambiguous genitalia, salt wasting, or early virilization. Nonclassic adrenal hyperplasia is generally recognized at or after puberty because of oligomenorrhea or virilizing signs in females.

History: The clinical phenotype of congenital adrenal hyperplasia depends on the nature and severity of the enzyme deficiency. Although the information below is presented according to chromosomal sex, the sex of a neonate with congenital adrenal hyperplasia is often initially unclear because of genital ambiguity.

Clinical presentation in females

Females with severe forms of adrenal hyperplasia due to deficiencies of 21-hydroxylase, 11-beta-hydroxylase or 3-beta-hydroxysteroid dehydrogenase have ambiguous genitalia at birth due to excess adrenal androgen production in utero. This is often called classic virilizing adrenal hyperplasia.

Mild forms of 21-hydroxylase deficiency in females are identified later in childhood because of precocious pubic hair, clitoromegaly, or both, often accompanied by accelerated growth and skeletal maturation due to excess postnatal exposure to adrenal androgens. This is called simple virilizing adrenal hyperplasia. Milder deficiencies of 21-hydroxylase or 3-beta-hydroxysteroid dehydrogenase activity may present in adolescence or adulthood with oligomenorrhea, hirsutism, and/or infertility. This is termed nonclassic adrenal hyperplasia.

Clinical presentation in males

21-hydroxylase deficiency in males is generally not identified in the neonatal period because the genitalia are normal. If the defect is severe and results in salt wasting, these male neonates present at age 1-4 weeks with failure to thrive, recurrent vomiting, dehydration, hypotension, hyponatremia, hyperkalemia, and shock (classic salt-wasting adrenal hyperplasia).


Patients with less severe deficiencies of 21-hydroxylase present later in childhood because of the early development of pubic hair, phallic enlargement, or both, accompanied by accelerated linear growth and advancement of skeletal maturation (simple virilizing adrenal hyperplasia). In male infants, the disease may be misdiagnosed as gastroenteritis or pyloric stenosis, with potentially disastrous consequences due to delayed treatment with glucocorticoids.


Management Of Newborn With Ambiguous GenitaliaGeneral GiudelinesMedical and social emergencyAvoid immediate declaration of sexProper counselling of the parentsTeam management; obstetrician, neonatologist, pediatric endocrinolgist, genetist and paediatric surgeon.DiagnosisHistory : pregnancy; family Detailed examination : abdomen; pelvis; external genitalia; urethral and anal openings. Federman’s rule: a palpable gonad below the inguinal ligament is testes until proven otherwise

Investigations • Rule out cong. Adrenal hyperplasia: Serum electrolytes; 17-OHP level and urinary levels of 17-ketosteroids • Karyotype ( buccal smear; blood)• Pelvic US and sometimes MRI • Skin biopsy; fibroblast culture to measure 5alpha-reductase activity or dihydrotestosterone binding Laproscopy

Male pseudohermaphroditism(XY- FEMALE)Failure to produce testosterone Anatomical testicular failure (Pure XY gonadal dysgenesis (swyer’s syndrome), testicular regression syndrome)Leydig-cell agenesisEnzymatic testicular failure. Failure to utilize testosterone 5-alpha-reductase deficiencyAndrogen receptor deficiency * Complete androgen Insensitivity (TFS) *Incomplete androgen Insensitivity Anatomical testicular failure:Failure of testicular differentiation and development result from sex chromosomes mosaicism or may be associated with normal chromosomes in pure gonadal dysgenesis.These patient have poor musculinization or none, uterus (in contrast to other XY females) ,tubes and vagina are present.

Sawyer ‘s syndrome

Diagnosis of XY female


Turner’s syndrome Karyotype 45XO Phenotype female Oedema of hand & feet Short stature Absent secondary sexual characteristics Wide carrying angle of the arms Webbed neck Broad chest with widely spaced nipples Streak ovaries Normal internal genital organs

Tuner’s syndrome Diagnosis: Karyotype Marked elevation of LH,FSH Reduced Oestrogen US....Cystic hygroma Treatment: Induction of puberty by estrogen. Induction of menstruation by progesterone. Growth hormone Up to one third may have functioning ovaries

Klinefilter's syndrome

-Karyotype 47XXY -Phenotype, male -Small azoospermia testis -Abnormal secondary sexual characteristics -Gynaecomastia Treatment -Androgen -Reduction mammoplasty