| Abstract|| |
Congenital adrenal hyperplasia is relatively an uncommon condition, and it is considered a rare event to be associated with hypertension on presentation. In this report we describe six patients with growth acceleration and hypertension occurring in early childhood; three patients had hypertensive encephalopathy. The eldest patient in this report is an 18year old with a genetic female karyotype reared as male. The second and the third patients had skeletal abnormality (short fourth metatarsal), which is a rare combination. The 4th and 5th patients are siblings, a boy and a girl; both of whom had several months of muscle weakness and hypokalemia. The girl had concentric left ventricular hypertrophy and underwent vaginoplasty and clitoral rescission. The sixth patient is an infant with history of neonatal septicemia and convulsions. In all the cases, growth acceleration and features of pseudoprecocious puberty were overlooked. Two patients out of six were reared incorrectly as males.
Keywords: 11 Beta-hydroxylase deficiency, Childhood hypertension, Congenital adrenal hyperplasia.
|How to cite this article:|
Al-Mograbi H, Abu-Odeh A, Habahbeh Z, Al Nader M, Hasan MA. Hypertension in Children with Ambiguous Genitalia: Six Cases. Saudi J Kidney Dis Transpl 2004;15:157-66
|How to cite this URL:|
Al-Mograbi H, Abu-Odeh A, Habahbeh Z, Al Nader M, Hasan MA. Hypertension in Children with Ambiguous Genitalia: Six Cases. Saudi J Kidney Dis Transpl [serial online] 2004 [cited 2021 Apr 15];15:157-66. Available from: https://www.sjkdt.org/text.asp?2004/15/2/157/32899
| Introduction|| |
The recognition of hypertension in children is based on epidemiological rather than pathological studies with prevalence between 2 3%. , In two reviews, endocrine disorders were the cause of hypertension in up to 9% of the cases; adrenal diseases were the cause in1-2%. Although rare, endocrine hypertension is frequently curable. ,
The combination of hypertension and ambiguous genitalia is a rare, and it becomes more so when associated with skeletal malformation; only four cases of 11-beta-hydroxylase deficiency and short fourth metatarsal bones have been reported. ,
The onset of hypertensive encephalopathy may be indolent with headache, drowsiness, nausea, vomiting, blurred vision, cortical blindness and hemiparesis. It may manifest as ataxia, stupor or seizures. 
11-beta-hydroxylase deficiency accounts for 3-8% of the cases of congenital adrenal hyperplasia (CAH) and occurs in approximately 1/100,000 births in the Caucasian population.  In a study from Saudi Arabia, 11-beta hydroxylase deficiency was responsible for 25.6% of cases of CAH.  Approximately two thirds of patients with the severe classic form of 11-beta-hydroxylase deficiency have high blood pressure, often starting in the first few years of life. 
Affected boys with 11-beta-hydroxylase deficiency are usually recognized in later infancy and childhood because of early signs of pseudoprecocious puberty.  It is essential that pediatricians remain alert to the possibility of the condition when features of precocious puberty appear before the patients develop complications of hypertension.
| Case Report|| |
This is an 18-year-old patient, was born to a Jordanian consanguineous parents with 11 siblings. Pregnancy and delivery were uneventful. There was a positive family history of three siblings' deaths in the neonatal period. The patient was reared as a boy due to the appearance of the external genitalia (a big phallus, penile urethra and fused labioscrotal folds). At two years of age, the child developed several episodes of convulsions and managed with anticonvulsants. One-year later, the child started to have darkening of skin, enlargement of phallus and a remarkable increase in height (Ht.) and weight (Wt.). At age of five years, the patient was referred to our hospital, King Hussein Medical Center (KHMC) with a history of shortness of breath on moderate exercise and occasional episodes of vomiting. On admission, the child had hyper-pigmented skin with muscular built; both Ht. and Wt. were at the 90 th percentile, his Ht. age was nine years, whereas mid-parental Ht. was at the 10 th percentile. Blood pressure (BP) at several occasions was above the 95 th percentile. The external genitalia consisted of phallus of seven centimeters in length with meatus opening at its tip and empty fused labioscrotal folds [Figure - 1]. There was an interesting finding of skeletal anomaly at both feet with short fourth metatarsal and overriding of the fourth on the third and the second toes [Figure - 2].
The chromosomal kayo type was consistent with a normal female 46XX pattern. Abdominal ultrasound (US) confirmed the presence of the uterus and both ovaries in the normal anatomical position with normal kidneys, spleen and liver. Renal Doppler sonography was normal.
The brain computerized tomography (CT) Scan showed two old infarcts in the right frontal and parietal regions with right unilateral cerebral atrophy. Electroencephalogram (EEG) showed very high voltage and slow waves of delta pattern over the right side that indicated a focal lesion. Bone age was of eight years at five years of chronological age.
Investigations showed normal complete blood count (CBC), liver function test (LFT), and kidney function tests (KFT) apart from hypokalemia on several occasions. The hormonal assay is shown in Table 1.
A diagnosis of 11-beta-hydroxylase deficiency resulting in CAH was made and at this point we approached both parents and advised them for sexual reassignment of the patient but all the attempts to convince them failed. The patient was discharged on steroid replacement, anticonvulsants and antihypertensive therapy.
On follow-up, the patient's growth velocity slowed down. Due to poor academic performance, he underwent intelligence (IQ) assessment by a senior psychologist at the age of eight and received low score of 59 ± 5.
At the age of ten, the patient started to show progressive features of sexual maturity rating (SMR) with enlargement of both breasts and reaching Tanner stage IV/V [Figure - 3]. The patient's Ht. decelerated achieving a final level of 140 cm (below the 5th percentile) and Wt. of 45kg (at the 5th percentile). A year later, the patient started to have menstrual cycles at which time the parents were consulted again and advised sexual reassignment but refused again to consent for it.
The patient stopped going to school at the age of 12 and started to lead an isolated life, as it was necessary to wear a jacket to cover the enlarged breasts even during summer time. At the age of 16, the patient was referred for follow-up by the internist.
This is an 11-year-old girl who is the third of five sibling sand the result of uneventful pregnancy and delivery. At age of five years, parents noticed that the child started to develop dyspnea on moderate exertion. The patient had heavy facial and axillary hair, acne, seborrhea and increase in clitoris size. On examination, BP was 160/110 mmHg and the Ht. and Wt. were 125 cm and 31 kg, respectively; both were above the 95 th percentile. The patient had well developed muscles and deepening voice with partial fusion of labial folds and clitoris length of 4 cm. Bone age was estimated as seven years. CBC, KFT and LFT were normal except serum potassium level that was low on two occasions. The hormonal assay is shown in Table 1. The patient was treated with hydrocortisone, potassium sparing diuretic and calcium channel blockers. She was poorly compliant with medications and had aggressive behavior with siblings and peers at school. The patient underwent vaginoplasty and clitoral recession at the age of seven years. Follow-up showed deceleration of growth velocity and currently the Ht. and Wt. are at the 50th percentile. The child still attends school with satisfactory performance.
This is an eight and half-year- old patient who is the third of four siblings. The patient was reared as a boy; he was diagnosed to have CAH due to the triad of ambiguous genitalia, accelerated growth and hyper-pigmentation. Treatment was instituted by hormonal replacement therapy at a local hospital, and then referred to our hospital due to hypertensive encephalopathy. Examination showed hyper pigmented skin, short fourth metatarsal, SMR for pubic hair III/V, phallus length of six centimeters and a penile urethra with fused labioscrotal folds. The patient was hypertensive with BP of 150/110 mmHg, and the bone age was estimated as nine years. Cystoscopy showed septated vagina and a common channel for the vagina and urinary bladder. Chromosomal karyotype was 46XX. Cardiac consultation revealed left ventricular hypertrophy, whereas abdominal ultrasound confirmed the presence of a uterus.
Investigations showed normal CBC, BUN and electrolytes. The hormonal assay is shown in Table 1. Treatment included corticosteroids, calcium channel blockers and potassium sparing diuretics. Parents did not wish to change the rearing sex of the child despite the medical advice and counseling.
This is an eight-year-old boy who was the eldest sibling of case number five. The patient was brought to the clinic due to family screening. The patient had dyspnea on mild exertion, as well as excessive gain in Ht. and progressive darkening of skin for the past two years [Figure - 4]. His BP was 150/110 mmHg, and was poorly controlled on angiotensin-converting enzyme (ACE) inhibitor.
The cardiovascular evaluation revealed no cardiomegaly secondary to the patient's hypertension. The Ht. and Wt. were at the 95 th percentile. The SMR showed gonads of seven ml volume, pubic hair Tanner stage II/V and a penis eight centimeters long. The patient's bone age at seven years of chronological age was consistent with 15 years. The patient had ejaculation and wet dreams for the previous several months.
The urinalysis, KFT and LFT were normal. The hormonal assay is shown in [Table - 1].
Potassium sparing diuretics and calcium channel blockers were effective in controlling his blood pressure. The patient was started also on hydrocortisone replacement therapy 20mg/m 2 /day.
This is a six-year-old girl who was born to non-consanguineous parents; she was the third of four children, and a product of uneventful pregnancy and delivery. The patient was found to have enlarged clitoris at birth. The hormonal assay was consistent with non-salt loosing CAH. She was managed for one year with cortisone and then lost for follow-up due to the change in health policy insurance. At age of four years, the patient was referred to our center with history of two episodes of convulsions during the year prior to referral. In addition, the patient had history of shortness of breath, increased pigmentation of skin, acne and hypertension. On examination, the Ht. and Wt. were just above the 95 th percentile. The patient's Ht. age was an average for a seven year-old child. BP was 180/120mmHg, which was poorly controlled on ACE inhibitor. The cardiac assessment showed concentric left ventricular hypertrophy and mild aortic regurgitation. The SMR included pubic hair Tanner stage II/V and clitoris three centimeters in length. The bone age was estimated to be compatible with the same chronological age.
The laboratory studies showed normal CBC, Urinalysis, LFT and KFT. The hormonal assay is shown in [Table - 1]. Abdominal US showed the presence of both ovaries and uterus in the normal anatomical site; kidneys liver and spleen were also normal. Renal Doppler sonography was normal.
Potassium sparing diuretic, calcium blocking blocker and hydrocortisone replacement were effective in controlling her blood pressure and improving the well being and activity of the patient.
This is a three- year-old girl who was the product of full term normal vaginal delivery from a consanguineous marriage. The birth weight was 1.7 kg. She was discovered during the neonatal period to have fused labioscrotal folds and a urogenital sinus with enlarged phallus. The patient had a difficult neonatal period with admission to the neonatal intensive care unit for one month due to neonatal septicemia. The patient was spastic with hyper-flexia of deep tendon reflexes. Biochemical
Investigations proved to have hypokalemia on several occasions. The growth parameters showed length of 84 cm, Wt. of 10 kg and occipitofrontal circumference of 48 cm.; the parameters were at about 50th, 10th and 50th percentile, respectively. The bone age was estimated to be compatible with the patient's chronological age. BP was 140/100 mmHg.
The chromosomal karyotype proved to have normal female 46XX. The hormonal assay is shown in [Table - 1]. The brain CT scan proved the presence of dilatation of the lateral and the 3rd ventricle with mild degree of brain atrophy. The abdominal US showed infantile uterus.
The patient was treated with hydrocortisone and potassium sparing agents. Blood pressure, growth and biochemical assay and hormonal levels are currently within normal level. The parents are unwilling to consent for surgical intervention to the external genitalia.
| Discussion|| |
The deficiency of 11 beta-hydroxylase is one of two hypertensive forms of CAH. The other form is the deficiency of 17 alfa-hydroxylase and results in diminished production of cortisol and also of androgens and estrogens due to more proximal location in the pathway of steroidogenesis.  Our patients had pseudoprecocious puberty, so they are unlikely to have 17 alfa-hydroxylase deficiency, because in this latter disorder male children present with female appearing external genitalia and females do not develop secondary sexual signs at puberty. 
The first and the third cases represent a unique association of skeletal abnormality and 11 beta-hydroxylase deficiency; such anomaly has been reported in previous four Jordanian patients. , The short fourth metatarsal bone is found in pseudohypoparathyroidism, pseudopseudohypoparathyroidism, Turner's syndrome, Gardner's syndrome and other hereditary disorders that are ruled out in our patients on the basis of the clinical picture. 
The presumptive cause of hypertension in our patients was the increased level of deoxycorticosterone (DOC), which was about 426 times of normal level. It has been reported that DOC secretion rates in congenital 11 beta-hydroxylase patients were 30-70 times than those found in normal children.  DOC is a precursor of aldosterone with only 1/30 th the sodium retaining potency of aldosterone. Overproduction of DOC occurs with two distinct defects of adrenal steroidogenesis; impairment of 11-hydroxylation and 17hydroxylation. 
All of our children had high levels or at the upper limits of normal of ACTH and 17-(OH) progesterone concentrations, and normal morning cortisol serum levels. It has been reported that other neural peptides are capable of releasing ACTH from the pituitary. The antidiuretic hormone is probably the most important of these. 
Two of our patients had central nervous system pathology (cases 1 and 6), while other two had left ventricular hypertrophy (cases 3 and 5); they were most likely secondary to hypertension. The presenting features of hypertension during childhood may include headache, nausea, vomiting, tiredness and facial palsy; hypertensive encephalopathy with convulsions and coma has been reported in 10% of the cases. 
Easy fatigability was observed in three patients (2,4 and 5). Easy fatigability is most likely due to heart failure or hypokalemia, the latter feature reflects mineralocorticoid excess. 
The most difficult decisions physicians have to be make includes cases of ambiguous genitalia or markedly traumatized genitalia.  The masculinizing effect of CAH syndrome starts during the first 8 to 12 weeks of fetal life.  Our two genetically female patients (cases no. 1 and 3) were brought up as male gender and parents were difficult to be convinced of the contrary, because the external genitalia were of a male gender a part from empty fused labioscrotal folds. It would be an advantage that all 46XX newborn with Prader genital stage five to be assigned as males.  The fully formed penile structure, which involves a penile urethra, may not require any surgery that may risk the neuronal and vascular supply to the clitorophallus. On the other hand, subsequent ovariectomy and the abolishment of fertility potential with sex hormone replacement therapy are almost unavoidable sequelae to this decision.
To the contrary of the above suggestion, is the argument that assignment as female is usually considered optimal for virilized 46XX patients with CAH because, with adequate glucocorticoid replacement therapy, ovarian sex hormone production can be preserved, sex hormone replacement therapy is unnecessary, and fertility can be retained.  Genital surgery, when needed, permits later penovaginal intercourse. The few attempts at correlating Prader stage with the degree of behavioral masculinization have at best been moderately successful. 
Conventional medical treatment is often a difficult balancing act between the undesirable states of hypercortisolism and hyperandrogenism.  Treatment consists of glucocorticoid administration, which usually replaces deficient cortisol and reduces ACTH secretion, suppressing excessive adrenal androgen production and preventing further virilization. Such therapy should also uppress ACTH-dependent production of mineralocorticoid agonists and ameliorates hypertension. 
There was a variable pattern of response to antihypertensive drugs in our patients; two of them (cases 1 and 6) had normal BP control on potassium sparing agents and the other four needed as well calcium channel blockers. It has been reported that if the hypertension has been long-standing before treatment, additional antihypertensive drugs may be required to lower blood pressure into the normal range. These drugs may include potassium-sparing diuretics such as spironolactone or amiloride with or without calcium channel blocker such a nifedipine. 
Two of our patients (cases 4,5) were treated with ACE inhibitor for their hypertension with poor control. Because the renin-angiotensin system is suppressed in these patients, ACE inhibitors are unlikely to be effective. 
It has been proposed that adrenalectomy in both 21-hydroxylase deficiency and 11-beta hydroxylase deficiency ,, would eliminate the hormones produced in excess, making therapy easier for affected individuals. Such approach does not resolve the difficulty of administering an appropriate dose of replacement cortisol.
It is not known if surgery for those with ambiguous genitalia can be delayed until the patient decides which correction should be performed. Whether this would be a successful practice in our society requires long-term follow-up studies.
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Mjalli Ahmad Hasan
Consultant Pediatrician, P.O. Box 6080, Zarka
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]
[Table - 1]