Abstract

Eighty-two children (30 males and 52 females) with congenital adrenal hyperplasia (CAH) were seen at King Khalid University Hospital (KKUH) over a 10-year period. Of these, 74 (90.2%) were Saudis and eight (9.8%) non-Saudis. Fifty-nine (72%) patients were 21-hydroxylase deficient. Of these, 56 (95%) had variable degrees of salt depletion. Nineteen (23.2%) patients had a deficiency of 11-ß-hydroxylase enzyme and four (4.8%) showed deficiency of 3-ß-hydroxysteroid dehydrogenase. The consanguinity rate was high (71.2%) and positive family history was documented in 45.8%. Thirty-nine infant deaths occurred within 25 families. The diagnosis was often delayed. Of the 52 females, 27 (52%) were initially assigned male sex. These results indicate the importance of physicians' awareness and the need for a neonatal screening program for early detection and appropriate management. Ann Saudi Med 1995; 15(5):447-450

Methods

Material and Methods

Records of all infants and children under the age of 12 years who were born in or referred to the Pediatric Endocrine Unit at KKUH, Riyadh during the period from January 1984 to December 1993 with the diagnosis of CAH were reviewed. Data including age, sex, nationality, place of origin, clinical presentation, relevant family history and results of all the laboratory and ancillary investigations were obtained. Information was supplemented when possible by interviewing the families of the patients.

Diagnosis of CAH was suspected on clinical grounds and confirmed in all patients by detailed endocrine investigations. Diagnosis of classic 21-hydroxylase deficiency was confirmed by high plasma concentrations of 17-hydroxyprogesterone. Elevated plasma concentrations of 11 -deoxycortisol with suppressed plasma renin activity are confirming classic 11 -ß-hydroxylase deficiency, while the presence of normal 17-hydroxyprogesterone with increased dehydroepiandrosterone (DHEA) levels associated with low concentrations of androstenedione and testosterone on clinically suspected subjects are confirming the diagnosis of 3-ß-hydroxysteroid dehydrogenase deficiency. A salt-depleting state was confirmed by the presence of hyponatremia, hyperkalemia, natriuresis and raised serum renin activity with low or normal serum aldosterone concentrations.^1,2,9,10 All the hormones were measured commercially by Bio-Scientia Laboratory, Germany. Chromosomal analysis, abdominal ultrasonography and genitography were done when appropriate. The degree of severity of the virilization of the female external genitalia was determined by applying the Prader classification.¹⁴

Results

Eighty-two patients from 59 families were diagnosed to have CAH. Thirty (36.6%) patients were males and 52 (63.4%) were females, giving a male to female ratio of 0.6:1. Of these, 74 (90.2%) patients were Saudis. Their geographic and sex distribution are shown in Figure 1. The remaining eight (9.8%) patients were of various nationalities; three Egyptians, two Ethiopians and one Pakistani, one Yemeni and one Jordanian.

Ten patients from eight families were born at KKUH, while the rest were referred from other hospitals in the Kingdom. Of these, nine patients (three Saud males and four Saudi females and two non-Saudi males) were diagnosed to have 21-hydroxylase deficiency, all salt depleters, while one Saudi male had 3-ß-hydroxysteroid dehydrogenase deficiency. During this period, there were 37,354 live births in our hospital, of which 28,016 were Saudis.

Fifty-nine (72%) of the whole group of patients were diagnosed as 21-hydroxylase deficient. Of these, 56 (95%) had variable degrees of salt depletion. Nineteen (23.2%) patients had deficiency of 11-ß-hydroxylase enzyme and four (4.8%) patients showed deficiency of 3-ß-hydroxysteroid dehydrogenase. Table 1 shows the relationship between the cause, family history, consanguinity and neonatal and infant deaths among the families with CAH. Seventeen (28.8%) families had more than one affected child, one of these having four children. Six had three children while the rest had only two. Family history of a similar disorder was documented in 27 (45.8%) families. Consanguinity was found in 42 (71.2%) of the families. Thirty-nine neonatal and infant deaths occurred within 25 (42.4%) families.

Sixty-nine (84.1%) patients were born in the hospital and 13 (15.9%) were born at home. Table 2 shows the sex distribution and the major clinical manifestations at the time of presentation. Out of the 52 females, 27 (52%) were initially assigned male sex. Of these, only six were home deliveries. Fourteen male patients with 21-hydroxylase deficiency were readmitted at a mean age of 1.8 months (range 0.5 to 6) because of salt-depleting crisis, while another five were diagnosed at an earlier age, a mean of eight days (range 2 to 12), having had a history of other affected siblings. One male child was diagnosed at a later age (8 and 1/2 years) after his younger sibling presented with ambiguous genitalia and was found to have virilization. Of the 39 females with 21-hydroxylase deficiency, the mean age at diagnosis was 0.4 year (range 0 to 6). All except one had abnormal genitalia. This led to wrong sex assignment in 20 (51.3%) patients. Patients with 11-ß-hydroxylase deficiency were diagnosed at an older age; the mean for males was two years (range 0.2 to 4) and for females was 3.6 years (range 0 to 10). There were more severe clinical symptoms (pseudoprecocious puberty in males and ambiguous genitalia ± pseudoprecocious puberty in females). Initially, seven (58.3%) of the females were wrongly assigned male sex. Six (31.6%) patients had moderate to severe hypertension. Three boys presented at birth with hypospadias and were diagnosed to have 3-ß-hydroxysteroid dehydrogenase deficiency at a mean age of nine weeks (range 3 to 18), presenting with salt depletion crisis.

Discussion

Congenital adrenal hyperplasia (CAH) is the most common adrenal disorder in infancy and childhood.^1,2 Its prevalence worldwide shows a marked geographical variation from one in 490 to 67,000 live births.^5,7-10,15 In Europe and North America^5,7-10,15 it has been reported to have a prevalence of one in 5000 to 15,000 live births, while in neighboring Kuwait,⁴ a figure of one in 9000 live births has been reported. In Saudi Arabia, the overall prevalence of the disease is not known; however, the contention that this is not an uncommon disease is readily supported by the high number of patients in this series as well as the high number of neonatal and infant deaths within the families studied. We believe that even more cases have been missed, particularly the male ones as suggested by the abnormal male to female ratio of 0.6:1 in this study. The high parity rate with involvement of multiple siblings and the high rate of consanguinity in this population could be major contributing factors. Al-Meshari et al.¹⁶ and Saedi-Wong et al.¹⁷ showed, in two different studies, a high rate of parity and consanguineous mating among the Saudi population.

Although we are referring to a highly select group, it is of interest to find that the calculated incidence for patients with 21-hydroxylase deficiency who were delivered at KKUH is approximating one in 4000. If we include one sibling of three of our Saudi patients who died in the second day of life and was found to have hyperkalemia and hyponatremia, which suggest salt depletion, the estimated incidence would be even higher at 1:3500. This is further evidence in support of our contention.

The pattern of enzyme deficiency in our series is somewhat different than that reported before.^1,2 While 21 -hydroxylase deficiency remains the most common as in other studies,^{3-5,7-11,13,15,18,19} it only accounts for 72%. Ninety-five percent of these were salt depleters with variable degrees of severity, a figure higher than previous reports.^{3-5,7-11,13,15,18-20} The possibility of missing nonsalt depleters could be a cause. However, this is in contrast to Salman et al.¹³ from another referral center in Riyadh who showed that 92% of his patients were 21-hydroxylase deficient while none were 11-ß-hydroxylase deficient. The pattern of referral might be a contributing factor, as not all cases are referred to our hospital. The incidence of 3-ß-hydroxysteroid dehydrogenase deficiency in this series (4.8%) is similar to that reported from Kuwait⁴ and greater than that reported elsewhere.^3,7-10 Although we were investigating a highly select group, it is of interest that 19 (23.2%) of our patients, who came from 11 families, were 11-ß-hydroxylase deficient, a figure which is far more than what has been quoted in the literature^4,6,7-11,21 and indicated further the importance of proper investigation of nonsalt depleters, as 11-hydroxylase deficiency may cause elevation of 17-hydroxyprogesterone.^1,2 Multiple sibling involvement does not seem to be the only factor. Therefore, detailed genetic studies are needed to highlight the cause.⁶

Early recognition is important to avoid or minimize the unwanted sequelae.^{9-11,13,15,18-20,22} It is of concern that a majority of our male patients and some of the females were diagnosed after they experienced a salt depletion crisis and another 39 siblings of these cases died in infancy who could have been cases of CAH. Severe virilization of external genitalia in female newborns may lead to an incorrect sex assignment for life or sex reassignment in later life with its attendant psychological damage.^13,15,20,22Therefore, ambiguity of the external genitalia should alert the physician to the possible diagnosis of CAH and should be considered a medical and social emergency.¹²Unfortunately, 27 (52%) of our 52 females were initially assigned male sex. Delayed diagnosis may also result in several other complications, including acceleration of skeletal maturation with ultimate short stature, premature development of secondary sexual characteristics in male children and further virilization of females.^3,15 Health education and genetic counseling of parents regarding CAH and its sequelae are of paramount importance. It is also necessary to examine other siblings, even if they are apparently normal, as some of our patients were diagnosed by this method because their siblings presented with obvious symptoms.

In conclusion, though further studies are needed to see the prevalence and pattern of the disease in other parts of the Kingdom, our data support the contention that this is a common problem in this part of the world. It frequently remains undiagnosed in the neonatal period. Rather, children often initially present with precocious puberty, ambiguous genitalia with wrong sex assignment at a later age or, more critically, salt depletion crises, if not infant death. A neonatal screening program for CAH should therefore be established, as there are many reasons to justify it.²³ This can be either mass screening or selective, as has been established elsewhere.^5,15,21 Until then, all physicians should be made aware of the magnitude, clinical presentations and gravity of this condition in order to detect and treat such patients early enough to avoid or minimize the unwanted sequelae.

Acknowledgment

The authors would like to acknowledge Miss Alicia C. Evarola for her secretarial assistance.

References