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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2007  |  Volume : 18  |  Issue : 3  |  Page : 405-413
Congenital Adrenal Hyperplasia: Problems with Developmental Anomalies of the External Genitalia and Sex Assignment


Amman 11941, P.O. Box 2324, Jubaiha, Jordan

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   Abstract 

A retrospective study was performed on all patients with congenital adrenal hyperplasia (CAH) who were followed up at the King Hussein Medical Center (KHMC), Amman, Jordan, during the period from January 1996 to June 2006. The aim was to evaluate the clinical features, special problems, and corrective interventions for these patients. The records of 73 children (39 were genetic females and 34 were genetic males) with CAH were reviewed in the study. The age of the patients at last follow-up was between five months and 18 years. Diagnostic criteria for CAH were typical clinical features of the illness (salt loss, dehydration, virilization, macrogenitosomia, ambiguous genitalia, and accelerated growth) and typical hormonal abnormalities (decreased serum cortisol and elevated serum 17-hydroxyprogesterone). There were 62 patients with classical presentation; among them, salt-wasting (SW) form was seen in 41 patients (66%). There were 5 patients with the nonclassic form, while 6 others had cryptic presentation. Seven patients (9%) had hypertension, mostly due to salt-retaining CAH. Among the 39 females with CAH, 27 had developed mental anomalies of the external genitalia; 20 of them underwent surgical interventions of their external genitalia. Fourteen genetically female patients were wrongly diagnosed as 'male sex' at birth due to severe virilization. Seven of them were reassigned 'female sex' socially, legally, and surgically; the parents of one of them (a four-year-old girl) wanted the surgical intervention postponed for two to three years. Hysterectomy and gonadectomy were carried out for 6 of the other 7 patients who chose to keep the male gender. Our study indicates that newborns with developmental anomalies of the external genitalia should be diagnosed as early as possible so that medical, psychological, and social complications are minimized. A neonatal screening program for such a disorder can identify infants at risk for the development of life-threatening adrenal crisis and prevent incorrect sex assignment of affected female infants with intersex.

Keywords: Congenital adrenal hyperplasia, Gender identity, Sex assignment and reassignment

How to cite this article:
Al-Maghribi H. Congenital Adrenal Hyperplasia: Problems with Developmental Anomalies of the External Genitalia and Sex Assignment. Saudi J Kidney Dis Transpl 2007;18:405-13

How to cite this URL:
Al-Maghribi H. Congenital Adrenal Hyperplasia: Problems with Developmental Anomalies of the External Genitalia and Sex Assignment. Saudi J Kidney Dis Transpl [serial online] 2007 [cited 2022 May 23];18:405-13. Available from: https://www.sjkdt.org/text.asp?2007/18/3/405/33760

   Introduction Top


Congenital adrenal hyperplasia (CAH) is an autosomal recessive inherited disorder characterized by loss of activity of one of the enzymes necessary for adrenal steroido­genesis. Deficiency of steroid 21-hydroxylase (21-OHD) accounts for more than 90% of all cases. Complete deficiency of 21-OHD leads to the classical salt-wasting (SW) form, characterized by decreased cortisol and aldosterone production and androgen excess, leading to prenatal virilization of external genitalia in female fetuses and SW in both sexes. Partial 21-OHD deficiency leads to the classical simple virilizing (SV) form, characterized by prenatal virilization of female fetuses but without SW. [1],[2] 11­beta-hydroxylase deficiency accounts for 5 to 8% of cases of CAH [3] ; studies from Saudi Arabian patients show that it accounts for up to 25.6% of all patients with CAH. [4] Deficiency of 11-beta-hydroxylase leads to elevation of 11-deoxycortisol and 11­deoxy cortisterone (DOC) and hyper­andoro genemia, which results in virilization of the external genitalia in females at birth and subsequent hypertension during childhood in both males and females. [5]

Ambiguous genitalia and uncertainty about the sex of a newborn are devastating and often incomprehensible to most parents. [6] It has long been known that the most frequent cause of ambiguous genitalia in a genetically female infant is CAH, which may be life threatening if associated with a SW crisis. [7]

A precise classification of CAH subtypes is sometimes difficult owing to the substantial overlap in clinical manifestations and laboratory findings, resulting in part from compound heterozygosity and thus supporting the concept that CAH is basically a disease continuum. [8] Wrong sex assignment and reassignment of sex in infancy and childhood poses serious psychosocial problems for patients and their families and is a difficult task for physicians. While easier in infancy than after one year of age, [9] the decision about surgery should always be made by the parents, together with the treating team, and the patient himself or herself, if old enough to give consent. All available options should be discussed and an informed consent should be obtained. [10] Long-term satisfaction is controversial with respect to gender, cosmetic appearance, function of genitalia, and surgical procedures. [11],[12]


   Patients and Methods Top


During the period from January 1996 to June 2006, 73 Jordanian children with CAH were seen in the pediatric endocrinology clinic at the King Hussein Medical Center, Amman, and their records were reviewed. The diagnosis was suspected on clinical grounds and confirmed in all patients by demonstrating high plasma levels of adrenocorticotropic hormone (ACTH), testosterone, and 17­hydroxyprogesterone; and low serum concentration of cortisol at several stages of follow-up during treatment period. Chromosomal analysis, bone age, and growth parameters were performed in all patients; and abdominal ultrasound and genitography were performed on patients with ambiguous genitalia. All patients underwent laparoscopic genitoscopy before any scheduled surgery. Blood pressure was measured manually; and if high, it was repeated at several visits. The normal values of the fourth report of the task force 2004 were used. [13] For genetically female patients who had wrong sex assignment and for those with ambiguous genitalia, both parents and/or patients themselves, if old enough to understand their congenital malformation, were involved in evaluation and choice of rearing sex. A joint clinic of pediatric endocrinologist and pediatric surgeon was established for these cases.

Predicted adult height was obtained from the tables of Greulich and Pyle. [14] Mid­parental height was calculated using the manual of evaluation of growth charts. [15] Bone age was determined using the standards of Greulich and Pyle and interpreted by a consultant pediatric radiologist. Patients' heights were plotted on the Centers for Disease Control (CDC) growth chart. [16]


   Results Top


Diagnosis and follow-up

Out of 73 children studied, there were 39 females and 34 males with a female to male ratio of 1.1:1. The age and sex distri­bution at diagnosis are listed in [Table - 1]. Sixty-two patients were regarded as classical, six as nonclassical (symptoms appeared after five years of age) and 5 others as cryptic (detected by patient family tracing) [Table - 2]. Forty-one patients (23 males and 18 females) displayed salt loss at less than six months of age; one of the salt-losing gene­tically male patients presented with ambiguous genitalia, and his hormonal assay showed 3-beta hydroxysteroid dehydro­genase deficiency. Seven patients (9%) had hypertension and hypokalemia, causing muscle weakness. The cause of hypertension could not be determined despite using all available tests; deoxycorticosterone level, which was tested in only 4 patients, was elevated in all four. Patients' plasma renin activity and aldosterone levels were low. The hypertension of these patients responded to potassium-sparing diuretics and calcium-blocking agents but not to angiotensin-converting enzyme inhibitors. [17] Interestingly, 2 of the 7 patients had skeletal anomalies of both feet, with short fourth metatarsal and overriding of the fourth toe over the third and the second toes. [18] Most likely, this group of patients had 11-beta hydroxylase deficiency. The diagnosis in 28 patients (39%) was made after the age of one year, and most of these patients showed growth acceleration.

After the diagnosis of CAH was made, hydrocortisone therapy was started in all patients, and fludrocortisone was given to those with high serum levels of plasma renin activity.

Mortality

Of the 73 patients, 3 - including two boys and a girl - died due to salt-losing crisis at ages 2, 6 and 10 weeks respectively; the first and the second patient had low birth weight and hyperpigmented nipples and external genitalia. These infants were diagnosed as CAH at admission to the pediatric ward, clinically and by hormonal assay; they were given hydrocortisone and normal saline for two days without success. The third had spastic cerebral palsy and died of streptococcal meningitis.

Central nervous system anomalies

Among the 73 patients, 4 had cerebral palsy; 1 died at 10 weeks of age. All four patients had been admitted at infancy with salt-losing crisis, which could be the cause of their neurological handicaps. One of them, a boy, had seizures and mental retardation.

Sex assignment, gender role behavior and surgical intervention

Among the 39 females with CAH, 27 had developmental anomalies of the external genitalia [Table - 3], 20 of whom underwent surgical intervention. Fourteen genetically female patients were wrongly diagnosed as 'male sex' at birth due to severe virili­zation [Table - 3]. Seven patients who kept the rearing sex as male were diagnosed as virilized CAH before 6 weeks of age; the parents of six of these patients asked for hysterectomy and gonadectomy for their children. Four of them had the surgery at our center, and two were referred to us after undergoing the surgery. The seventh patient (the eldest of the group) and his parents refused any surgical intervention. Three out of the 7 patients were referred to our unit at age ranging from 5 to 12 years. Two patients expressed concern and severe sadness about living as a male sex and about getting married with infertility. The parents of these patients, on the other hand, reported that they were not given sufficient input into the treatment decisions for their children. Two patients are living as normal males without apparent gender identity conflict. Another two subjects had marked interest and attitudes that were considered typical of males, while the eldest patient in the group had gender identity conflict and is currently under follow-up by an adult endocrinologist.

The other seven genetically female patients with wrong sex assignment at birth, whose diagnosis at our unit was made at less than eight months of age, were changed from an initial male to a female sex assignment. Surgical intervention was performed on six of them; and for a four-year old child, inter­vention was postponed till early childhood, as requested by the parents. The assigned gender was well accepted by majority of the patients and parents, although five parents complained of tomboyish behavior of their female children. Eight patients underwent only clitoris reduction at different ages from six months to five years; and in five other girls, their feminizing genitoplasty was postponed till pre-adolecent age.

Growth, precocious puberty, and consanguinity

The growth rate in the CAH patients with onset of their disease before one year of age could not be distinguished from the normal Jordanian standards. [19],[20] The majority of patients with CAH, who were diagnosed after the first year of life [Table - 2], had advanced bone age of +1 to +4 years, leading to a reduced final height. Twelve patients were referred to our unit from different health care sectors; the patient's compliance and the mode of hormonal re­placement therapy were not uniform. Both lack of therapy and over-treatment contri­buted to problems in their growth. The final height, which could be estimated in only 30 patients, was lower than that of the control population (mean-1 SD). The final height was achieved between the ages of 11 and 13.5 years. Precocious pseudo-puberty was observed in eight genetically male patients, who had pubic hair and enlargement of the penis early at school-age period. Gonads were of less than 4 ml in volume. Precocious puberty was observed in five genetically female patients at ages ranging from five to eight years, with breast development and acceleration of bone age. They attained menarche by less than eight years of age, most likely due to prolonged exposure to adrenal androgens. They were offered gonadotropin-releasing hormone (GnRH), and three of them accepted the monthly injection and daily growth hormone treatment. Consanguinity was common in our report. First- and second-degree cousin marriages were found in parents of 24 patients. Sixteen patients were siblings.


   Discussion Top


The prevalence of CAH in our study was higher among females than males (39 females: 34 males) rather than the 1:1 ratio reported. It was possible that some of the affected males might have died without a correct diagnosis or that male patients with simple virilizing CAH remained undiagnosed. In our study, female patients presented earlier due to virilization of the external genitalia; in six patients, family tracing of a known affected sibling helped in making the diagnosis. In other reported studies, the discrepancy between diagnosed females and males was higher (83 females: 67 males). 21 One of the weaknesses of our report was the inability to calculate the prevalence of CAH in Jordan as a whole, due to the lack of a screening program at a national level though the existing neonatal screening program for CAH meets the recommended criteria for newborn screening. [22]

There was significant diagnostic delay in both classical and nonclassical groups; 24 cases were diagnosed after the age of three months. The delay did not seem to result in increased mortality or neurological sequelae but had a negative impact on the final height of these patients. A high-risk group is the neonates with an older sibling having this illness; such newborns should be investigated a few days after birth to rule out the 25% risk of CAH. There was a relatively high proportion of patients with affected siblings in the present study population (22%). It was interesting to find that the prevalence of CAH with hypertension in the Jordan River Valley province (4 out of 7 patients) was higher than in the other parts of the country. The population of this geographic region of the country has darker skin than the rest of the Jordanian population. The diagnostic delay was significant in some of the virilized girls of older age group in our study. The care of such cases could be speeded up by the education of physicians and health-care providers for neonates, for earlier detection and referral.

Twenty-seven of the 39 genetically female patients with CAH had developmental anomalies of the external genitalia, and 14 genetically female patients were wrongly diagnosed as 'male sex' at birth. It has been recommended that the management of intersex conditions requires a multi-disciplinary approach, with involvement of appropriate professionals at an early stage to plan management. [23] After several sessions of genetic counseling with parents and patients who were old enough to understand their disorder, only 7 of 14 such patients were reassigned female sex; not surprisingly, they were diagnosed before the age of 4 weeks. Parents were offered several reasons for choosing female sex for their children. These included considering their children as females with a congenital malformation that could be corrected surgically rather than a possible future gender identity confusion and future infertility if their children were assigned as males.

Although five of the seven patients who kept the rearing sex as male were diagnosed before 6 weeks of age, three of them were referred to our hospital after the age of four years. It is known that children learn about their world; and by three years of age, a child can give his/her full name and sex. [24] The decision whether to reassign or not, and the proper age to do so, was very difficult for the parents and the counseling team, and it needed several weeks to reach a final decision. The data on normative development suggest a cut off date, perhaps around nine months of age. [25] However, it is difficult to tell if the assigned sex is going to be acceptable to the child when old enough to understand his or her malformation. Regarding children in whom their male gender was kept, the decision was strongly influenced by the fear of social stigmatization of having a masculinized female in the family. Parents considered the fully formed penile structure and the uncertainty of the surgery with its possible gender identity disorder later on as other causes to strongly oppose any sex reassignment.

Early diagnosis and surgery is considered crucial for parents who ask for feminizing genitoplasty for their children to minimize the period of gender uncertainty and to prevent stigmatization of other family members. The female gender is usually considered ideal for46XX patients with CAH because it is considered as a developmental anomaly of the external genitalia. Genital surgery, when needed,

permits later penovaginal intercourse. [26],[27] Those parents whose children had feminizing genitoplasty indicated that genital surgery should be undertaken in infancy, even at the risk of reducing genital sensitivity, in order to properly reassign the child to a female sex, socially and legally. Those parents, as well as the treating team, are satisfied with the results of surgery and with the female gender identity of the patients. The eldest patients of the group are aged four to five years and they recognize themselves as girls and behave as such, although they are considered by their parents to be little rough and tomboyish. Recent data suggest that women with CAH are psychologically well adjusted when diagnosed and treated early. [28],[29]

Genital surgery is one of the most controversial interventions in current intersex management. [30] The two elements of feminizing genitoplasty are clitoral reduction/recession and vaginoplasty. While clitoral shaft resection with preservation of the glans on its neurovascular bundles seems logical, [31] there is some emerging evidence to the contrary because of the disappointing results of clitoral atrophy, abnormal sensation in the clitoris, and prominent glans clitoris. [32] For these reasons, the North American group of adult patients is dissatisfied with the results of surgery performed some decades ago, suggesting that no surgery should be performed in infancy and that the choice of the gender of patients should be postponed until the age 7 to 10 years, when the child becomes able to self-determine his or her own sex. [33] In our series, all parents preferred swift management of the problem except for parents of a four-year-old genetically female child who decided to postpone the surgery for few years.

In summary, our data indicates that CAH results in significant morbidity and mortality if left undetected, and there is effective treatment that reduces negative outcome, including life-threatening complications, incorrect sex assignments, gender identity disorders, growth disturbance and short final height. Thus, a neonatal screening program for this disorder would be of paramount importance. Until such a program is in place, it is advisable that 17-hydroxy progesterone should be determined in any neonate with suspected CAH. Early counseling and education about possible surgeries and sex assignment is advised.


   Acknowledgment Top


I would like to thank Dr. Mjali Ahmad (pediatric endocrinologist), Dr. Bassam Samawi (pediatric surgeon), and Dr. Emad Habaibeh (pediatric surgeon) for their invaluable help and thoughtful insights throughout all stages of this study.

 
   References Top

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2.New MI. Prenatal treatment of congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30:1-13.  Back to cited text no. 2    
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4.Al-Jurayyan NA. Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency in Saudi Arabia: clinical and biochemical characteristics. Acta Paediatr 1995;84:651-4.  Back to cited text no. 4    
5.Motaghedi R, Betensky BP, Slowinska B, et al. Update on the prenatal diagnosis and treatment of congenial adrenal hyperplasia due to 11 beta hydroxylase deficiency. J Pediatr Endocrinol Metab 2005;18:133-42.  Back to cited text no. 5    
6.Ogilvy-Stuart AL, Brain CE. Early assessment of ambiguous genitalia. Arch Dis Child 2004;89:401-7.  Back to cited text no. 6    
7.Hamilton W, Hutchinson JH, Fraser D, Farquhar JW. Female pseudoher­maphroditism. In: Forfar JO, Arneil GC ed. Text book of pediatric. Third edition. Churchill Livingstone 1984. p.1138.  Back to cited text no. 7    
8.Hughes IA. Congenital adrenal hyperplasia a continuum of disorder. Lancet 1998; 352;752-4.  Back to cited text no. 8    
9.Conte FA, Grumbach MM. Abnormalities of sexual determination and differentiation. In: Basic and clinical endocrinology. McGraw-Hill ed. Sixth edition. Lange Medical Books 2001. PP509-546.  Back to cited text no. 9    
10.Joint LWPES/ESPE CAH Working Group. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology. J Clin Endocrinol Metab. 2002;87:4048-53.  Back to cited text no. 10    
11.Wisniewski AB, Migeon CJ, Malouf MA, Gearhart JP. Psychosexual outcome in women affected by congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Urol. 2004;71:2497-2501.  Back to cited text no. 11    
12.Berenabaum SA, Bailey JM. Effect on gender identity of prenatal androgens and genital appearance: evidence from girls with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2003;88:1102-6.  Back to cited text no. 12    
13.National high blood pressure education program working group on high blood pressure in children and adolescents. The fourth report on the diagnosis evaluation and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114:555-76.  Back to cited text no. 13    
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15.Moell C. Evaluation of growth charts. Growth service Kabi pharmacia. Pp6.  Back to cited text no. 15    
16.CDC growth charts. A revised version (2000) of the 1997 NCHS growth charts. Available on the internet at www.cdcgov/growthcharts.   Back to cited text no. 16    
17.New MI, Crawford C. Low-Renin hyper­tension in childhood. In: Fima Lifshitz. Pediatric Endocrinology. 3 rd .edition. Marcel Dekker, Inc. PP775. 1996.  Back to cited text no. 17    
18.Al-Mograbi H, Abu-Odeh A, Habahbeh Z, et al. Hypertension in children with ambiguous genitalia: Six cases. Saudi J Kidney Dis Transpl 2004;15:157-66.  Back to cited text no. 18    
19.Mawajdeh S, Al-Qutob R, Rawashdeh M, et al. Growth patterns of Jordanian children: a national study. J Family Community Med 1995;2:47-53.  Back to cited text no. 19    
20.Hasan MA, Batieha A, Jadou H, et al. Growth status of Jordanian schoolchildren in military-funded schools. Eur J Clin Nut 2001;555;380-6.  Back to cited text no. 20    
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26.Lee PA, Houk CP. Impact of environment upon gender identity and sexual orientation. J Pediatr Endocrinol Metab 2005;18:625-30.  Back to cited text no. 26    
27.Randecroft L, Surgical management of ambiguous genitalia. Archi Dis Child 2003;88:799-801.  Back to cited text no. 27    
28.Meyer-Bahlurg HF. Gender and sexuality in classic congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30:155-71.  Back to cited text no. 28    
29.Phornphutkul C, Fausto-Sterling A, Philip AG. Gender self-reassignment in an XY adolescent female born with ambiguous genitalia. Pediatrics 2000;106:135-7.  Back to cited text no. 29    
30.Wilcox DT, Creighton S, Woodhouse CR, Mouriquad PD. Urogenital implications of endocrine disorders in children and adolescents. In: Brook CG, Hindmarsh PC eds. Clinical Pediatric Endocrinology 4 th ed. Blackwell Science 2001:222-44.  Back to cited text no. 30    
31.Randecroft L. Surgical management of ambiguous genitalia. Arch Dis Child 2003;88:799-801.  Back to cited text no. 31    
32.Meyer-Bahlurg HF. Gender and sexuality in classic congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2001;30:155-71.  Back to cited text no. 32    
33.Mogeon CJ, Murphy H, Lacey JH, Conway G. Long term psychological outcome for women with congenital adrenal hyperplasia: cross sectional survey. Br Med J 2005; 30:340-1.  Back to cited text no. 33    

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Correspondence Address:
Hussein Al-Maghribi
Amman 11941, P.O.B 2324, Jubaiha
Jordan
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    Tables

  [Table - 1], [Table - 2], [Table - 3]

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