Ganapati T*, Chaudhari HK**
(* Ex-resident, ** Associate professor, Department of Obstetrics and Gynecology, Seth GS Medical College and KEM Hospital, Mumbai, India.)
In India, many a time genital ambiguity at birth gets overlooked and these children present later in life with growth disorders or menstrual abnormalities. When a young patient presents with virilization and menstrual abnormality without electrolyte disturbances or hypotension a clinician should suspect simple virilizing type of Congenital Adrenal Hyperplasia (CAH) as one of the differential diagnosis. Patient with CAH presenting with secondary amenorrhea can present a diagnostic challenge to even an experienced gynecologist. We present a case of non-classical CAH presenting with secondary amenorrhea and infertility.
CAH is an autosomal recessive condition. It is a group of disorders resulting from disruption in the balance of adrenal cortical hormone biosynthesis. It is a genetic and an endocrinological disorder that may demand diagnosis and treatment right from the birth. The clinical presentation of CAH is classified as classic, the severe form and non-classic (mild or late-onset) form. Classic CAH can be subdivided into salt-losing or non-salt-losing (simple virilizing), depending on the degree of aldosterone deficiency. In more than 90% of cases of CAH, the inability to synthesize cortisol is due to 21-hydroxylase deficiency. Females with classic 21-hydroxylase deficiency are exposed to excess androgens in the intrauterine period and are born with ambiguous external genitalia. Most patients cannot produce sufficient aldosterone to keep sodium balance and may develop potentially develop disastrous "salt wasting" crises if it remains untreated. Classical CAH occurs in around 1:15,000 live births whereas non-classical or late onset congenital adrenal hyperplasia (LCAD) is more common than classical CAH. The case presented here is a non-classic late-onset CAH.
A 20 year old lady married since 1 year came with history of menses every 3-4 months, lasting for 1 day, for one year. She also complained of severe dyspareunia. She gave history of amenorrhea during the preceding year. She had attained menarche at 15 years of age with past cycles being regular with moderate menstrual flow. She was born of a second-degree consanguineous marriage. She belonged to a lower class of society, had completed schooling and a house wife by occupation. Her mother felt that she had normal female external genitalia at birth, and had not given much importance to it during the adolescent period. There was no history of recurrent vomiting, hyperpigmentation or recurrent hospital admissions in childhood or adolescence or prior abdominal surgery. There were no other signs of virilization like hoarseness of voice, masculinization. She had a younger brother who was otherwise normal. On examination, BMI was 29.3 kg/ m2 and her blood pressure was normal. Axillary hair and pubic hair distribution was Tanner stage 5, while breasts were Tanner stage 3. Local examination showed clitoromegaly with clitoral index of 600 mm2. Vagina was healthy but shallow. Cervix was flush with vagina with external os pin-point. Urethral opening was normal and 3 cm below the clitoris.(Figure 1) Serum FSH, LH, thyroid hormones and electrolytes were within normal limits. Karyotyping showed normal 46XX pattern with no detectable Y element on Fluorescent in situ hybridization.
Figure 1. Virilized external genitalia.
Serum basal 17-hydroxy progesterone was elevated (6.84 ng/ ml) (Normal: 0.11–1.2) and serum testosterone was elevated 2.19 ng/ ml (Normal: 0.1-1.2 ng/ml) and ACTH was 43.5 pg/ ml (Normal: 5-27 pg/ ml) were also elevated. CYP21A1 testing was not done because she could not afford it. MRI was suggestive of adrenal hyperplasia. Diagnostic laparoscopy showed normal size uterus pulled towards right. Both fallopian tubes were normal. Both ovaries were bulky with thickened white glistening capsule suggestive of anovulation. Chromopertubation was attempted with pediatric Foley’s catheter no.8 but no spill was observed. Diagnosis of late-onset Congenital Adrenal Hyperplasia resulting in clitoromegaly and masculinization of external genitalia, with otherwise normal internal reproductive organs was ascertained.
Psychological counseling of family members was done. She attained withdrawal bleeding with tablet medroxyprogesterone acetate 5 mg twice a day for 5 days. She was given tablet dexamethasone 0.5 mg for 5 days followed by oral prednisolone, the dose of which was titrated with 17 hydroxy progesterone, and finalized at 2.5 mg/ day. She was referred to plastic surgeon and she underwent clitoroplasty (figure 2). Perioperatively, she was given injectable steroids, and then switched back to prednisolone 2.5 mg/ day. She achieved spontaneous regular menstruation thereafter.
Figure 2. Picture after clitoroplasty.
CAH is an autosomal recessive condition affecting both genders equally. It is due to mutations of genes required for enzymes mediating the production of cortisol from the adrenal glands. The most common mutation is CYP21A2 gene resulting in 21-hydroxylase deficiency. Depending on the severity of enzyme deficiency, the clinical spectrum varies from mild form of non-classical CAH to severe form. Depending on the time of onset, quantity of androgens and duration of exposure, CAH tends to have varied manifestation. It can range from serious salt wasting type with ambiguous genitalia at birth, due to intrauterine exposure to androgens; to simple virilization in adult. Salt-losing classical CAH approximates nearly 67% of the cases reported, and the non-classical forms the remaining 33%. The patient described here is a case of non-classical CAH presenting with clitoromegaly.
The primary management of the disease is replacing the corticosteroids. Replacement of steroids normalizes the ACTH levels in the body and in turn the levels of other enzymes like 11β-Hydroxylase and 3β- hydroxysteroid dehydrogenase normalize. This administration of steroids resulted in successful, but gradual reversal of virilization in our patient also. However, reconstructive genital surgery was necessary.
Our patient presented at 20 years of age. Lack of knowledge and ignorance about normal genitalia delayed the need for seeking medical care for abnormal genitalia.
Due to intrauterine exposure and abnormality, genital reconstructive surgery may be required in the first few years of life. Studies have shown that despite relatively poor outcome of the initial single-stage surgery in infancy and the inevitable re-operation in puberty, the adult outcome of psychosexual outcome has been positive. The surgical treatment and the subsequent hormonal therapy has bearings on psychological health and sexual life, which should be factored in while managing patients.[7,8].
Our patient presented with infertility. Fertility in a case of CAH is generally reduced usually due to chronic anovulation and in some due to poor surgical results of genital reconstruction. The rate of miscarriages can be reduced with glucocorticoid treatment .
Our patient was phenotypically female at birth and there was no ambiguity in genitalia. The clitoromegaly and subsequent virilization of the genital parts resembling male parts, must have taken place during the teen years of the patient.
However, those which present earlier should be offered genetic testing at the earliest. Genetic testing should be offered to newborns with ambiguous genitalia, positive CAH screening test (elevated 17hydroxy progesterone), those with adrenal insufficiency and those with unexplained electrolyte abnormalities. In women with polycystic ovary syndrome and hirsutism, non-classical CAH could be considered as a rare differential diagnosis. Since the effects on the offspring start within the intrauterine life, pregnant women at risk of having a fetus affected with CYP21A2 mutations should be offered prenatal diagnosis. Adults with detected CAH but preserved fertility should consider genotyping of themselves before planning for children. Some studies have recommend universal screening of all newborns for CAH.
CAH is a multicentric disorder requiring involvement of various specialties such as gynecologist, endocrinologist, urologist, plastic surgeons and psychologist should work together in order to achieve the best results. Treatment challenge is to individualize therapy and effectively control the excess androgen symptoms by using the lowest possible therapeutic dose, in order to avoid glucocorticoid side effects and optimize the reproductive, sexual, and bone health.
Dr Vinita Puri (Head of Plastic surgery department, KEM Hospital) is acknowledged for intraoperative images.
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