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\begin{document}

\title{Rare cause of a resistant hypertension in a middle-aged man: A case
report}



\author[1]{Renata Marecek}%
\author[1]{Eva De Keyzer}%
\author[1]{Georgiana Taujan}%
\author[1]{Felicia Baleanu}%
\author[1]{Mihaela Rosu}%
\author[1]{Ioanna Papadopoulou}%
\author[1]{Olga Kosmopoulou}%
\author[1]{Laura Iconaru}%
\affil[1]{Brugmann University Hospital - Site Victor Horta}%


\vspace{-1em}



  
  \date{June 09, 2024}


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\selectlanguage{english}
\begin{abstract}
Congenital adrenal hyperplasia associated to 11-beta-hydroxylase
deficiency is a rare cause of secondary hypertension, usually discovered
during childhood; however, a late diagnosis in adults has also been
reported. Despite low cortisol levels, accumulated adrenal steroid
precursors can activate the glucocorticoid receptor, and thus protect
the patient against adrenal crisis.%
\end{abstract}%



\sloppy


\textbf{Rare cause of a resistant hypertension in a middle-aged man: A
case report}

Renata Marecek\textsuperscript{1}, De Keyzer Eva\textsuperscript{2},
Georgiana Taujan\textsuperscript{3}, Felicia Baleanu\textsuperscript{3},
Mihaela Rosu\textsuperscript{3}, Ioanna Papadopoulou\textsuperscript{3},
Olga Kosmopoulou\textsuperscript{3}, Iconaru Laura\textsuperscript{3}

Authors affiliations:

1. Department of Internal Medicine, Centre Hospitalier Universitaire
Brugmann, Universit\selectlanguage{ngerman}é Libre de Bruxelles, Brussels, Belgium 2. Department
of Cardiology, Centre Hospitalier Universitaire Brugmann, Université
Libre de Bruxelles, Brussels, Belgium 3. Department of Endocrinology,
Centre Hospitalier Universitaire Brugmann, Université Libre de
Bruxelles, Brussels, Belgium

Correspondence:

Renata Marecek, Department of Internal Medicine, CHU Brugmann,
Université Libre de Bruxelles, Brussels, Belgium

\emph{mareckova.r@gmail.com}

\textbf{Abstract:} Congenital adrenal hyperplasia associated to
11-beta-hydroxylase deficiency is a rare cause of secondary
hypertension, usually discovered during childhood; however, a late
diagnosis in adults has also been reported. Despite low cortisol levels,
accumulated adrenal steroid precursors can activate the glucocorticoid
receptor, and thus protect the patient against adrenal crisis.

\textbf{KEYWORDS} Secondary hypertension, congenital adrenal
hyperplasia, 11-b-hydroxylase deficiency, testicular adrenal rest tumors

\textbf{1 INTRODUCTION}

Congenital adrenal hyperplasia (CAH) refers to a family of autosomal
recessive disorders of adrenal steroidogenesis, in which each variant is
characterized by a specific enzyme deficiency that impairs cortisol
production by the adrenal cortex. The enzyme most commonly affected is
21- hydroxylase (21-OH)\textsuperscript{1} followed by
11-beta-hydroxylase (11\selectlanguage{greek}β\selectlanguage{english}OH), which accounts for 5--8\% cases of CAH,
with an incidence of approximately 1:100,000.\textsuperscript{2}

\textbf{2 CASE PRESENTATION}

A 43 year-old man was referred to the endocrinology department for the
suspicion of secondary hypertension. The patient had a history of B-cell
non-Hodgkin lymphoma, and in remission for 13 years already after being
treated with chemotherapy for six months. Moreover, he was diagnosed
with arterial hypertension at the age of five, for which he received
bi-therapy by carvedilol 6,25 mg twice daily and lisinopril 20 mg once a
day.

For the last two years before presentation, the patient associated
dyspnea on exertion (NYHA II). The patient has a history of hypertension
in the family. At medical consultation, he reported premature adrenarche
with an early pubic hair development. The physical examination revealed
short stature (158 cm), and a hypertension with a blood pressure (BP) of
190/120 mmHg. The echocardiography showed a moderate left ventricle
concentric hypertrophy, with an ejection fraction of 40\%, with no
valvulopathy nor dyskinesia. The laboratory results (Table 1) showed a
negligible hypokalemia at 3,4 mmol/l (reference value: 3,5--4,5 mmol/l),
an elevated ACTH level of 921 pg/ml (reference value: 6--60 pg/ml), with
low cortisol level at 117 mmol/l (reference value: 166--507 mmol/l),
normal renin level at 9 \selectlanguage{greek}µ\selectlanguage{english}UI/ml (reference value: 4,4--46,1 \selectlanguage{greek}µ\selectlanguage{english}UI/ml) and
low-normal aldosterone level at 22,8 ng/l (reference value: 22,1--353
ng/l). Further investigations demonstrated a minimal elevation of the
testosterone level at 30,4 nmol/l (reference value: 8,64--29 nmol/l) and
elevated values of dehydroepiandrosterone (DHEAS) at 17,8 \selectlanguage{greek}µ\selectlanguage{english}mol/l
(reference value: 2,4--11,6 \selectlanguage{greek}µ\selectlanguage{english}mol/l), androstendione at 31 ng/ml
(reference value \textless{} 3 ng/ml, 17--hydroxyprogesterone (17OHP) at
8 ng/ml (reference value: 0,9--3,4 ng/ml) and 11-DC at 30 ng/ml
(reference value \textless{} 0,5 ng/ml). The results were compatible
with CAH due to 11\selectlanguage{greek}β\selectlanguage{english}OH deficiency. The patient confirmed the absence of
adrenal insufficiency crisis until the moment of presentation. The
abdominal scanner showed bilateral enlarged adrenal glands with
voluminous lesions with lipomatous density (right side: 66 x 53 x 88 mm
and left side: 55 x 40 x 52 mm) (Figure 1). The scrotal ultrasound and
MRI showed bilateral intratesticular lesions compatible with adrenal
intratesticular inclusion (Figure 2). The genetic tests revealed a
homozygote pathogenic variant of the gene CYP11B1, chromosome 8, exon 8,
protein pArg448His.

Treatment by dexamethasone 0,5 mg once per day was initiated with the
improvement of laboratory results after two months (the ACTH level
decreased at 38 pg/ml, with a low cortisol level of 14 mmol/l, potassium
level normalized (4,2 mmol/l) and all the androgens and adrenal
precursors decreased to values in reference ranges: testosterone, 14,3
nmol/l; androstendione, 5,3 ng/ml; DHEAS, 6,08 \selectlanguage{greek}µ\selectlanguage{english}mol/l; 17OHP, 2,1 ng/ml;
11-DC 2,5 ng/ml (Table 1). At the four year-follow-up, his BP was
normalized at 128/84 mmHg under monotherapy (lecarnidipine 20 mg per
day). The echocardiography showed normalization of the left ventricle
ejection fraction. The testicular ultrasound demonstrated a relative
decrease in volume of the testicular lesions. The patient refuses the
testicular biopsy.

\textbf{3 DISCUSSIONS}

The 11\selectlanguage{greek}β\selectlanguage{english}OH deficiency accounts for 5-8\% of patients with
CAH.\textsuperscript{2} The patients are usually diagnosed before the
age of 13 years\textsuperscript{2--5} and mostly before the age of 4
years.\textsuperscript{3} Late diagnosis in adult aged 28-years and
above have been reported; however, it is rare.\textsuperscript{6--8}

The 11\selectlanguage{greek}β\selectlanguage{english}OH converts 11-desoxycortisol (11-DC) to cortisol and
11-deoxycorticosterone (DOC) to corticosterone.\textsuperscript{9} The
decreased cortisol secretion results in elevated adrenocorticotropic
hormone (ACTH) plasma level as well as an overproduction of steroid
precursors and androgens (see the adrenal steroidogenesis pathway
described in Figure 3). Androgen excess produces virilisation and
precocious pseudo-puberty. The mineralocorticoid effect of the elevated
DOC can lead to hypertension in up to two thirds of untreated
patients.\textsuperscript{10} Excessive ACTH production results in
hyperplasia of ACTH-sensitive tissues in adrenal glands and others sites
such as the testes, causing adrenal masses and testicular masses known
as testicular adrenal rest tumors (TARTs).\textsuperscript{11}

The 11\selectlanguage{greek}β\selectlanguage{english}OH deficiency occurs as a classic or non-classic phenotype,
depending on the degree of clinical severity and the percentage loss of
enzyme activity.\textsuperscript{3} Non-classic phenotype present no
abnormalities at birth and later can present mild virilisation,
peripheral precocious puberty, with premature adrenarche and penis
enlargement in boys, and hirsutism as well as menstrual irregularities
in girls.\textsuperscript{12} Patients with non-classic 11\selectlanguage{greek}β\selectlanguage{english}OH deficiency
usually do not develop hypertension.\textsuperscript{6} Untreated
patients may present accelerated skeletal maturation, resulting in short
final stature.\textsuperscript{3} The clinical signs are usually more
evident in female patients than in males.

Engels et al. reported that the accumulated adrenal steroid precursors
in patients with CAH can activate the glucocorticoid receptor and
protect the patients against adrenal crisis.\textsuperscript{13} The
most potent glucocorticoid receptor activating steroid precursors are
11-beta-hydroxylated steroids - 11-DC and
DOC.\textsuperscript{14,15}This mechanism that could explain the late
diagnosis present in several rare cases described in the literature. The
non-inclusion of measurement of 11-DC in dry blood spots in neonatal
screening programs, and the presence of elevated 17OHP that may lead to
the misdiagnosis of 21-OH deficiency, are other two factors that can
contribute to a delay in diagnosis.

Arterial hypertension is another important feature of the classic form
of this deficiency. The exact pathophysiology of hypertension in 11\selectlanguage{greek}β\selectlanguage{english}OH
deficiency remains unclear. Peter et al. discussed the predominant role
of the DOC with intrinsic mineralocorticoid activity as a possible
cause.\textsuperscript{15} However, the DOC levels do not correlate with
the severity of hypertension.\textsuperscript{6} Overall, the
hypertension in 11\selectlanguage{greek}β\selectlanguage{english}OH deficiency is hyporeninemic, without overt
alterations in serum potassium and sodium
concentrations.\textsuperscript{16} Breil et al. reported several
cardiovascular conditions associated with 11\selectlanguage{greek}β\selectlanguage{english}OH deficiency such as left
ventricular hypertrophy, ischemic heart disease, hypertensive
retinopathy, and cerebrovascular accidents\textsuperscript{2} and some
studies have demonstrated that the left ventricular hypertrophy in 11\selectlanguage{greek}β\selectlanguage{english}OH
deficiency can be reversed after bilateral
adrenalectomy.\textsuperscript{17,18}

The intra-testicular inclusions are present in approximately 42\% of
cases of male patients with CAH.\textsuperscript{19} The tumor growth
increases the intra-testicular pressure and reduces blood flow causing
testicular damage with resulting oligo- or
azoospermia.\textsuperscript{2} Despite their benign character,
monitoring of TARTs is important as they are hardly distinguishable from
the Leydig-cell tumours (LCT). Bilateral tumours are more frequently
seen in TARTs with 83\% of cases than LCT with only 2.5\% of
cases.\textsuperscript{20} A testicular biopsy can always be performed
to help in the differential diagnosis. These inclusions are
ACTH-dependent benign tumors and can regress with ACTH suppression in
most cases.

The treatment modalities in 11\selectlanguage{greek}β\selectlanguage{english}OH deficiency consists of glucocorticoid
suppressive therapy and surgical correction of the ambiguous external
genitalia in virilized female patients.\textsuperscript{17} The
glucocorticoids can substitute for the cortisol deficiency and inhibit
ACTH oversecretion, and thus suppress the excessive androgen and
mineralocorticoid production. However, in CAH, an effective suppression
of ACTH sometimes requires high doses of glucocorticoid over a prolonged
period of time,\textsuperscript{21} which explains the difficulty to
maintain a satisfactory adrenal suppression without producing an
unacceptable degree of hypercortisolism. The bilateral adrenalectomy was
proposed as an alternative; nevertheless, the patient compliance is
required for a lifelong hormonal substitution. Nasir et al. opted for it
in the management of a difficult case with failure to suppress androgen
production.\textsuperscript{22} Chabre et al. have applied it in a case
of a patient with severe hypertension who had experienced longterm
difficulties with equilibrium and compliance with the suppressive
therapy.\textsuperscript{17} Finally, Hinz et al. reported bilateral
adrenalectomy in a 15 year-old patient with resistant hypertension
despite good compliance.\textsuperscript{23}

\textbf{4 CONCLUSIONS}

The 11\selectlanguage{greek}β\selectlanguage{english}OH deficiency is a pediatric pathology, which can be rarely
diagnosed even in adulthood. The diagnosis can be delayed due to a poor
clinical presentation, especially in men, and the fact that the patients
with this form of congenital adrenal hyperplasia do not usually develop
adrenal crisis. Once the diagnosis was established, male patients should
be screened for testicular adrenal inclusions.

Despite the late diagnosis and the long evolution of arterial
hypertension, our patient had a good therapeutic response once the
glucocorticoid suppressive therapy was started, with a better control of
arterial pressure by monotherapy only, normalization of left ventricular
ejection fraction, normalization of ACTH, androgens and adrenal
precursors, but with only a minimal decrease in volume of the testicular
adrenal rest tumors.

\textbf{ACKNOWLEDGMENT}

None

\textbf{DATA AVAILABILITY}

Data are available for review on request.

\textbf{CONFLICT OF INTEREST}

All authors state that they have no conflicts of interest.

\textbf{ETHICAL STATEMENT}

The consent has been obtained from patient after full explanation of the
purpose and nature of all procedures used.

\textbf{PATIENT CONSENT STATEMENT}

Written informed consent was obtained from the patient to participate in
this study for the publication of this case report. A copy of the
written consent form is available for review on request.

\textbf{FUNDING}

No funding

\textbf{AUTHORSHIP LIST}

RM: wrote the first draft of the manuscript. LI, FB, ED, GT, IP, OK, MR:
revised subsequent versions of the manuscript. All authors read and
approved the final version of the paper. RM accepts responsibility for
the integrity of the data analyses.

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