Two types of aldosterone synthase
deficiency (ASD) are described at the hormonal level: type 1
(ASD1), with undetectable aldosterone levels, while the levels
of 18-hydroxy-11-deoxycorticosterone (18-OHDOC) are increased,
levels of 18-OHB are reduced, and the ratio B/18-OHB is
increased. Type 2 ASD (ASD2) is characterized by low aldosterone
levels, increased 18-OHB and 18-OHDOC levels, as well as an
increased 18-OHB/aldosterone ratio.
Clinical signs for ASD are failure to thrive,
vomiting, and severe dehydration [1,2]. Hyperkalemia,
hyponatremia, metabolic acidosis, elevated plasma renin activity
and low or undetectable aldosterone levels are the main
laboratory characteristics of ASD [1, 3]. Both types of ASD have
not been described to have genital anomalies. Herein we describe
a one year old boy with ASD2 and penile hypospadias.
Case Report
The boy was born after uneventfull pregnancy
and delivered at 39 wk gestation with a birth weight of 3400 g,
and a length of 51 cm. The parents were young, nonconsanguineous
Macedonian Albanians. At the age of 4 weeks, he was admitted to
hospital for vomiting and failure to thrive.
He had blue sclera and penile hypospadias.
The blood pressure was 80/40 mm Hg. He had hyponatremia (serum
sodium, 131mmol/L), hyperkalemia (serum potassium varied between
6.0-6.8 mmol/L), and no metabolic acidosis. Urine osmolality was
normal. Magnesium, chloride, creatinine, urea, uric acid, liver
enzymes, and proteins levels were normal. There were no signs of
salt-wasting nephropathy or enteropathy, urinary tract
infection, or obstruction.
The karyotype was 46, XY. Plasma steroid
hormones were measured by liquid chromatography- tandem mass
spectrometry. Unstimulated progesterone was 0.06 (normal
0.03-0.25ng/mL), 11-desoxycorticosterone 0.06 (0.03-0.63 ng/mL),
corticosterone 3.2 (0.03-2.98 ng/mL), 18-OHB 22.0 ng/mL
(0.20-0.53), 18-OH-DOC 0.4 ng/mL (0.05-0.56), aldosterone <0.03
(0.03-0.82 ng/mL), 17-OH-progesterone <0,03 (0.2-0.63 ng/mL),
11-desoxycortisol 0.58 (0.66-2.46ng/mL), cortisol 62 (47.6-105.7
ng/mL), cortisone 16 (14-28.9 ng/mL). ACTH stimulation test
results were within normal range for 17OH progesterone and 17OH
pregnenolone. The baseline/HCG stimulated testosterone, DHT and
androstenedione levels were done before and after administration
of 3 doses of hCG (1500 ie). Results before stimulation: DHEA-S
31 (15-39) ng/mL, 17-OH-Pregnenolon 0,3 ng/mL, androstendion 3
(2.9- 23) ng/dL, testosteron <2,9 (2,9-20) ng/dL, DHT <2,9
(2,9-38) ng/dL. After hCG administration: androstendion 15 ng/dL,
testosteron 325 ng/dL, DHT 29 ng/dL. DHEA, DHEA-S and
17-OH-Pregnenolone within the normal range. Baseline androgens
were within the normal limits and there was a typical rise after
hCG. Ratio A/T<1 (normal), T/DHT 11 (normal). No evidence was
found for Leydig cell insufficiency, disorder of androgen
biosythesis or action.
Plasma active renin and direct renin were
measured by RIA. Urine renin was 3760 (LIA normal 1.7-23. ng/L),
and plasma renin activity >50 ng/mL/h (RIA <3.5 ng/mL/h). ACTH
and cortisol had normal values on repeated measurements. The
highly elevated 18-OH-B, normal levels of 18-OH DOC and absent
aldosterone confirmed the diagnosis of ASD 2.
Treatment with fludrocortisone (0.1 mg/d)
corrected the failure to thrive.
Karyotype: Karyotype standardized
G-banding was performed. Genomic DNA was extracted and all nine
exons of CYP11B2 of the patient were specifically
amplified by PCR in two fragments (exons 1-5 and exons 6-9).
Direct sequencing on an ABI PRISM 310 DNA sequencer (PE Applied
Biosystems, Foster City, CA) was performed. Informed consent was
obtained from the parents. The amplification of the 9 exons of
the CYP11B2 gene by PCR and direct sequencing identified
a homozygous missense mutation c.554C>T in exon 3 coding for an
aminoacid substitution p.T185I in the index patient.
Informed consent was obtained from the
parents.
Discussion
We describe a previously unreported
association of ASD2 and penile hypospadias in a Macedonian
infant. ASD can be found in congenital adrenal hyperplasia due
to 21-hydroxylase or 3β-hydroxysteroid
dehydrogenase deficiency, congenital adrenal hypoplasia due to a
deficiency of the steroidogenic acute regulatory (StAR) protein
and other forms of primary adrenocortical insufficiency. Basal
and ACTH stimulated steroid levels can differentiate between ASD
and other types of aldosterone deficiency. It is of note that in
ASD genitalia are normal, while congenital adrenal hyperplasia
has various degrees of virilization or undervirilization.
There are two forms of aldosterone synthase
(also termed: corticosterone methyloxidase) deficiency. They
both have identical clinical features but differ in profiles of
secreted steroids: excretion of 18-hydroxycorticosterone is
mildly decreased in type I deficiency, urinary and serum levels
of this steroid are markedly increased in patients with type II
deficiency.
Genetic alterations that encode CYP11B2
enzymes are found to cause ASD2. Consequentely, patients with
ASD2 have efficient 11β-hydroxylase
activity, but markedly reduced or ablated 18-hydroxylase and oxidase activities in vitro. The excess B is converted to
18OHB by the 11β-hydroxylase
activity of the CYP11B2 enzyme [4, 5], therefore increasing the
18OHB/aldosterone ratio and a decreasing the B/18OHB ratio.
Absent aldosterone, increased 18OHB and 18OHDOC levels, and an
increased 18OHB/aldosterone ratio classified our patient as type
2 ASD.
In contrast to ASD2, ASD-1 is caused by
mutations in CYP11B2 that result in a complete loss or total
inactivation of aldosterone synthase activity [5]. Both the
18-hydroxylase and oxidase activities are impaired, but the 11β-hydroxylase
activity is retained [5-7]. Consequently, the production of
18OHB is lower and B/18OHB ratio is increased.
The p.T185I substitution found in our patient
has previously been reported in association with type II
aldosterone synthase deficiency [8] in a consanguineous family
of Middle Eastern European origin [8,9]. In addition, a compound
heterozygous patient (T185I and a T498A substitution) has been
also reported [6]. Interestingly, Macedonian nonconsanguinous
immigrants in Australia were found to have the same genetic
alteration [6]. A compound heterozygote showed a clinical
phenotype of type II deficiency, with both detectable serum
aldosterone and elevated 18-hydroxycorticosterone, but
invitro no residual aldosterone synthase activity [7].
In summary, the hormonal analysis classified
the infant as ASD2. The penile hypoplasia can not, at this time
be linked to any known cause. A coincidental occurrence cannot
be excluded.
Contributors: All authors contributed to
reporting and writing the manuscript.
Competing interests: None stated;
Funding: None.
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