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Classic congenital adrenal hyperplasia: A delayed presentation.

Byline: Saima Aziz Siddiqui, Nargis Soomro and Ashraf Ganatra

ABSTRACT

Congenital adrenal hyperplasia (CAH) is a rare congenital disorder, which in cases of female genotype may result in virilization. Specific enzyme deficiencies in adrenocorticoid hormones biosynthetic pathway lead to excess androgen production causing virilization. Classic type presents early in infant life as salt losing or simple virilizing type, whereas non classic form presents late at puberty or in adult life. Depending on the type of classic CAH, type of adrenocorticoid deficiency, extent of virilization and genotype, surgical corrective procedures, glucocorticoid and mineralocorticoid replacement therapy are the mainstay of management. We present here a case of classic congenital adrenal hyperplasia of simple virilizing type, which presented later in childhood.

KEY WORDS: Congenital adrenal hyperplasia, Clitoromegaly, Virilization, Clitoroplasty, Ambiguous genitalia.

INTRODUCTION

Birth of neonate is immediately accompanied by assignment of gender based on features of external genitalia. Gender assignment becomes a dilemma if external genitalia do not conform to the normal male or female appearance. Ambiguous genitalia, the congenital condition in which the external genitalia do not conform to either sex, give rise to extreme anxiety and concern to the parents.

Early but accurate and appropriate diagnostic evaluation is required in such cases. Key feature in physical examination is the presence of gonads in labioscrotal folds or inguinal canal. In the absence of palpable gonads, possibility of female pseudo-hermaphrodite is considered whereas in case of palpable gonads diagnostic evaluation is directed to male pseudohermaphrodite.

Among the variety of causes of ambiguous geni- talia, congenital adrenal hyperplasia (CAH) is the commonest reported cause in the presence of 46XX karyotype.1,2 Virilized females with 46 XX karyo- type have ambiguous external genitalia but normal internal female genitalia. During first seven weeks of gestation external genitalia of male and female genotypes are identical. In the absence of testoster- one and dihydrotestosterone (DHT) external genitalia appear phenotypically female. DHT, the converted form of testosterone under the action of enzyme 5 (alpha) reductase, acts on urogenital sinus and genital anal- gae to affect male differentiation of external genita- lia. 5 (alpha) reductase is present in urogenital analgae in both male and female fetuses. Exposure of abnormal androgen levels cause masculinization of female ex- ternal genitalia. Absence of antimullerian hormone leads to normal female internal genital organs.

Any posterior labial fusion (defined as a ratio of the distance from anus to fourchette/anus to base of clitoris (greater than) 0.5) or clitoromegaly ( (greater than) 1cm clitoral length) constitutes ambiguous genitalia and is indicative of a virilizing process.

CASE REPORT

We report here a case of ambiguous genitalia resulting from congenital adrenal hyperplasia presenting later in childhood.

A 7 and 1/2 years female child was brought in outpatients clinic with history of ambiguous genitalia since birth. She had five siblings including an elder sister. Mother's history did not reveal intake of antiepileptic drugs, progestogens or other drug treatment. There was no history of genital ambiguity in parents or any of the family members. Child was noted to have abnormal genitalia at the time of her birth at home, but medical help was never sought for that. She was in a good state of health with weight 30 kg and height 137 cm. Blood pressure was 100/60 mm of Hg.

Examination revealed no breast development, no axillary hair. On genital examination there were a few pubic hairs, clitoromegaly i.e. stretched phallus size 5cm, labia majora and minora normally developed no fusion abnormality, normal introitus, gonads not palpable, single uretheral opening below the base of phallus. These findings were consistent with Prader stage 1 for ambiguous genitalia.3,4 There was no abnormality on systemic examination. On laboratory investigations, serum Na was 143meq/l, potassium 4meq/l.

Ultrasound pelvis revealed uterus normal size for age, 3.5 cm in length and 2.1cm in transverse diameter, central midline echo, right ovary 2.3 X1.4 cm, left ovary 2.1 X1.4cm. karyotype was 46XX.

On the basis of raised 17 (alpha) hydroxyprogesterone, testosterone, and Dehydraepiandrostanedione Sulphate (DHEAS) and decreased cortisol response to Adrenocortictropic Hormone (ACTH) stimulation in these results, alongwith normal karyotype and clitoromegaly in the presence of normal introitus, labia and female reproductive organs, classic congenital adrenal hyperplasia due to 21 hydroxylase deficiency was diagnosed. Her management comprised surgical correction of enlarged phallus by clitoroplasty with dorsal neurovascular bundle preservation and glucocorticoid replacement therapy. The operation was performed by the team of plastic surgeon and Gynaecologist.

A traction suture of 3/0 poplygalactin, was placed in the glans of clitoris. Circumferential incision was given over base of the glans. Two longitudinal incisions were made lateral to dorsal neurovascular bundle. Corpra cavernosa visualized in entire extent. Excision of a portion of corpoeal tissue with wedge resection of glans was done, preserving neurovascular bundle. Conserved portion of corpora folded and sutured to pubic symphisis. Reconstruction of skin of labia minora and hood of clitoris was done.

Postoperatively she recovered well with no complications. She was also started on replacement therapy with hydrocortisone.

DISCUSSION

Incidence of CAH is reported as 1 in 15000 to 16000 births. These are a group of monogenic autosomal recessive disorders characterized by impaired cortisol synthesis and abnormal adrenal hormonal profile. These disorders are caused

Table-I: Endocrinological assay results.

Investigation###Result###Reference range

17 (alpha) hydroxyprogesterone###100ng/ml###(0-0.6ng/ml)

Serum testosterone###103.7ng/dl###(For 7-12years age; 3-68ng/dl)

DHEAS###212.3 (mu) g/dl###(Prepubertal range19-63ug/dl)

Serum Aldosterone###13.3ng/dl;###(4-31ng/dl)

Short synacthen test###Baseline 3.4 (mu) g/dl###(greater than) 18ug/dl)

###30 minutes 4.8 (mu) g/dl

###60 minutes 5.5 (mu) g/dl

by deficiency of enzymes necessary for the synthesis of adrenal corticosteroids. Spectrum of severity of this condition ranges from severe salt losing type due to aldosterone and cortisol deficiency to a milder form with mild androgen excess. Important steps in the biosynthesis of corticosteroids involve conversion of pregnenolone and 17 hydroxy pregnenolone to progesterone and 17 hydroxy progesterone respectively, mediated by enzyme 3 (beta) hydroxyl steroid dehydrogenase (3 (beta) HSD). These compounds in turn are converted to Deoxycorticosterone (precursor of aldosterone) and 11 deoxycorisol through the action of 21 (alpha) hydroxylase [21 (alpha) OHD] Final conversion of each of these precursors to Corticosterone and cortisol respectively is mediated through 11 (beta) Hydroxylase [11 (beta) OHD]. Enzymes necessary for these steps in biosynthesis, if deficient lead to diversion of this pathway away from corticosterone and Cortisol synthesis to androstanedione and testosterone synthesis.

Cortisol is the only adrenal hormone able to stimulate biofeedback loop. Corticosteroids deficiency leads to raised adrenocorticotrophic hormone (ACTH) which stimulates adrenal cortex to produce more androgenic hormones leading to features of masculinization (development of male characteristics in a genotypical female) of female fetus resulting in ambiguous genitalia. Thus deficiency of any of the three mentioned enzymes may lead to congenital adrenal hyperplasia leading to virilization. Most common enzyme deficiency in causing CAH is 21 (alpha) OHD, accounting for 90% cases of CAH.5 Whereas 11 (beta) OHD accounts for 5-8% cases.4,5 21 (alpha) OHD is a cytochrome P450 enzyme located in endoplasmic reticulum. There are 2 genes encoding for 21 hydroxylase, the structural gene encoding p450c21 (CYP21) and pseudogene CYP21p, both located on chromosome 6p21.3.4 Incidence of 21 (alpha) OH deficiency varies between 1 in 5000 to 1 in 15000 based on neonatal screening programmes.5

A hospital based study from Karachi reported diagnosis of congenital adrenal hyperplasia in 41.44% cases of ambiguous genitalia.6 It also showed that consanguinity of parents was identified in 52% of these cases.

According to time of presentation of androgenization, CAH can be of classic or non classic type. The classic type, presents early in life as salt losing type or simple virilizing type, depending on presence of both cortisol and 11 deoxycorticosterone (DOC) deficiency or sole deficiency of cortisol. Affected females are born with enlarged clitoris, fused labioscrotal folds and a urogenital sinus which may become a phallic urethera. Affected females can present a range of virilization of external genitalia from mild clitoromegaly and posterior fusion to complete labioscrotal fusion and urogenital sinus which may open on perineum or shaft of phallus. 21 (alpha) OHD deficiency leading to failure of conversion of progesterone to 11-deoxycorticosterone may result in aldosterone deficiency which is called "salt losing type" of CAH. It accounts for 75% cases of classic CAH, in which neonate develops dehydration, hypotension and hyponatremia between 7-28 days of life.

In "non salt losing" type there is lesser degree of masculinization as compared to salt losing type,3 11 (beta) OHD deficiency is the second commonest cause of classic CAH. It is the hypertensive form of CAH, as absence of 11 (beta) OHD leads to accumulation of 11 deoxycorticosterone. Though aldosterone levels are decreased but salt retaining properties of 11 deoxycorticosterone result in hypertension.

Non classic type of CAH presents later in childhood or near puberty and is characterized by normal production of cortisol and aldosterone with excess production of androgens. It is always caused by 21 (alpha) OHD and only rarely due to other causes. Non classic CAH is common with an incidence of 1 in 100 to 1 in 300.4,5

Diagnosis of 21 (alpha) OHD is made with raised serum 17 hydroxyprogesterone. In 11 (beta) OHD deficiency, 11 deoxycorticosterone level is raised whereas in 3 (beta) HSD deficiency, serum 17 (alpha) hydoxypregnenolone and DHEAS are raised.7

Management of cases of ambiguous genitalia depends on location of gonads, adequacy of phallus, size and location of vaginal orifice; if present need to be assessed.8 Surgery is tailored according to amount of virilization to best suit the gender role. Early diagnosis and management are likely to yield best possible outcome. For clitoral reduction and recession major corrective surgery is ideally suitable at 3 to 6 months of age.8 Surgical techniques of preservation of neurovascular bundle and glans as well as corporeal preservation including recession dismembered clitoroplasty are increasingly being favoured.8,9 Our case was classic type of CAH but instead of infancy she presented late in childhood despite the abnormality being identified at birth. There are local and Indian reports of CAH presenting in later childhood despite being recognized at birth.10,11

CONCLUSION

Management of CAH is a complex issue due to delayed help seeking and lack of neonatal screening programmes in our set up. Accurate diagnosis of this rare disorder requires specialized endocrinological assays, which are not easily available at public sector set up for poor patients. Expert genital reconstructive surgery tailored to best suit the gender role are prerequisite for proper management so as to enable social and psychological adjustment of affected patients.

REFERENCES

1. Al-Agha AE, Thomsett MJ, Batch JA. The child of uncertain sex: 17 years of experience. J Paediatr Child Health. 2001;37(4):348-351.

2. Joshi RR, Rao S, Desai M. Etiology and clinical profile of ambiguous genitalia an overview of 10 years experience. Indian Pediatr. 2006;43(11):974-979.

3. Prader A. Genital findings in the female pseudo- hermaphroditism of the congenital adrenogenital syndrome; morphology, frequency, development and heredity of the different genital forms. Helv Paediatr Acta. 1954;9(3):231-248.

4. Forest MG, Nicolino M, David M, Morel Y. The virilized female: endocrine background. BJU Int. 2004;93(Suppl 3):35-43.

5. Edmonds DK. Sexual differentiation: normal and abnormal. In: Shaw RW, Leusley D, Monga Ash, editors. Gynaecology. 4th ed. Edinburgh, London: Elsevier; 2011:166-181.

6. Bhanji R, Khan AH, Balouch IL, Sabir S, Nazir Z, Billoo AG. Profile of children with Congenital Adrenal Hyperplasia - a hospital study. J Pak Med Assoc. 2004;54(10):509-512.

7. Ogilvy-Stuart AL, Brain CE. Early assessment of ambiguous genitalia. Arch Dis Child. 2004;89(5):401-407.

8. Newman K, Randolph J, Anderson K. The surgical management of infants and children with ambiguous genitalia. Lesson learned from 25 years. Ann Surg. 1992; 215(6):644-653. Available from:http://www.ncbi.nlm.nih. gov/pmc/articles/PMC1242521/pdf/annsurg00088-0120. pdf.

9. Pippi Salle JL, Braga LP, Macedo N, Rosito N, Bagli D. Corporeal sparing dismembered clitoroplasty: an alternative technique for feminizing genitoplasty. J Urol. 2007;178(4 Pt 2):1796-800; discussion 1801.

10. Mustafa R, Hashmi HA, Shafaatullah. Congenital adrenal hyperplasia causing clitoromegaly. J Coll Physicians Surg Pak. 2008;18(6):378-379.

11. Bajpai A, Kabra M, Menon PS. 21-Hydroxylase deficiency: clinical features, laboratory profile and pointers to diagnosis in Indian children. Indian Pediatr. 2004;41(12):1226-1232.

Authors contribution:

Dr. Saima Aziz Siddiqui did literature search, collected data and prepared initial draft and final draft of manuscript.

Dr. Nargis Soomro critically reviewed, revised first draft, prepared photographs and assisted in preparing final manuscript.

Dr. Ashraf Ganatra made necessary changes in initial draft and critically reviewed the final manuscript.

How to cite this:

Siddiqui SA, Soomro N, Ganatra A. Classic congenital adrenal hyperplasia: A delayed presentation. Pak J Med Sci 2013;29(1):220-223. doi: http://dx.doi.org/10.12669/pjms.291.2830

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Dr. Saima Aziz Siddiqui, MBBS, MCPS, FCPS, Assistant Professor, Department of Obstetrics and Gynaecology,

2. Dr. Nargis Soomro, MBBS, DA, FCPS, FRCOG, Professor, Department of Obstetrics and Gynaecology,

3. Dr. Ashraf Ganatra, MBBS, M.S(Plastic Surgery), Professor, Department of Plastic Surgery,

1-3: Dow University of Health Sciences and Civil Hospital Karachi, Karachi, Pakistan.

Correspondence:

Dr. Saima Aziz Siddiqui, R-19, City Cottages, Gulshan-e-Iqbal Block 4-A, Karachi. Pakistan.

Email: symaaziz@gmail.com

Received for Publication: August 17, 2012

Accepted for Publication: October 16, 2012
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Publication:Pakistan Journal of Medical Sciences
Date:Feb 28, 2013
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