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\begin{document}

\title{Apparent Mineralocorticoid Excess Syndrome (AME): A Case Report of Two
Twins}



\author[1]{Abdellah  Kaddour}%
\author[2]{Mohammad Badr Almoshantaf}%
\author[3]{Ahmed  Aljabali}%
\author[4]{Ahmed Houcine  TCHOUAR}%
\author[5]{Amira Yasmine  Benmelouka }%
\affil[1]{EHS Mère \& Enfant Tlemcen}%
\affil[2]{Ibn Al-Nafees Hospital}%
\affil[3]{Jordan University of Science and Technology}%
\affil[4]{Abou Bekr Belkaid University Tlemcen Faculty of Medicine}%
\affil[5]{Faculty of Medicine, University of Algiers}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Ulick syndrome, also called apparent mineralocorticoid excess is an
autosomal recessive disorder that causes severe hypertension with
polyurea, polydipsia , and other symptoms. We report a case report of
two dichorionic diamniotic twins from a first-degree consanguineous
couple who suffered from variable symptoms of Ulick syndrome.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Ulick syndrome (US), also called apparent mineralocorticoid excess
(AME), is a rare autosomal recessive disorder caused by a genetic
mutation of HSD11B2. Chr. 16q22.1. The HSD11B2 enzyme typically converts
active cortisol into its inactive form. The HSD11B2 mutation will cause
a deficiency of the enzyme, which in turn will induce more cortisol
activation of the mineralocorticoid receptor resulting in hypertension
{[}1{]}. However, the US may have an additional unknown enzyme that
correlates with HSD11B2 activity or possibly some cortisol metabolizing
enzyme {[}2{]}.

Patients with the typical US show severe hypertension with both polyurea
and polydipsia, low birth weight, hypokalemia, and low aldosterone. It
is noted that US simulates all findings of primary aldosteronism except
for the contrast low plasma aldosterone concentration. However, the
severity of the symptoms can differ depending on the degree of the gene
mutation {[}3{]}.

US treatment involves decreasing cortisol endogenous synthesis or
blocking the mineralocorticoid (MC) receptor. Dexamethasone 1.5 to 2
mg/day is usually the drug of choice but may not relieve all symptoms
and has unwanted long-term side effects. Spironolactone or eplerenone
-mineralocorticoid receptor blockers- can also be used to treat the US
and correct hypokalemia. Some cases have reported that transplantation
of a kidney with normal HSD11B2 activity had cured the disease {[}4{]}.

\textbf{Case presentation}

We report two dichorionic diamniotic twins from a first-degree
consanguineous couple with no pathological familial medical. The
pregnancy was carried out at term and without incident. The elder sister
is 11 years old and in good health. At 17 months, twin A developed
hemiplegia and blindness for 04 weeks.

Brain imaging showed ischemic stroke, and further etiological
investigation could not identify the origin of this event. Yet, the
evolution was good with restoring the motor function and vision, and the
patient was discharged. Between 17 months and 06 years, both twins were
lost from sight. At the age of 06, the second twin B, was hospitalized
for a severe urinary infection. Investigations showed bilateral
nephrocalcinosis, severe hypokalemia, and elevated blood pressure.
Clinical examination, lab tests, and imaging were carried out for the
second sister (A), who had a history of stroke.

They also revealed hypokalemia, nephrocalcinosis, and the existence of
hypertension. Creatinine clearance for both sisters was under the normal
limit, indicating kidney failure.

The treatment of both patients was based on amiloride,
hydrochlorothiazide, and potassium supplementation.

An echocardiogram and fundus examination were requested to assess the
impact of hypertension, and they were normal in both patients. During
the follow-up, twin B had recurrent urinary tract infections. Retrograde
urethrocystography showed bilateral vesicoureteral reflux (VUR) grade 3.
Renal scintigraphy was recommended, and the patient has been referred to
the surgeon to discuss the necessity of surgical treatment. A genetic
study on twin B was consistent with Ulick syndrome.~\textbf{Figure 1}
~demonstrated the exact pathophysiology of AME, while~\textbf{Figure 2}
~showed the type of AME's inheritance as a family pedigree.

\textbf{Discussion}

In this case report, we described two twins diagnosed with AMES.
Clinical, biochemical, and genetic data confirmed a congenital
deficiency in the HSD11\selectlanguage{greek}β\selectlanguage{english}2 enzyme (twin B). Usually, this syndrome is
encountered early in the first decade of age. It is characterized by a
set of symptoms such as high blood pressure, reduced renin and
aldosterone levels, increased urine output and thirstiness, faltering
growth, hypokalemia with metabolic alkalosis, and often a high level of
calcium deposition in the kidneys. Cerebrovascular stroke is usually
observed before age ten in undiagnosed, lately treated children
{[}5--7{]}. Regarding inheritance of AMES, it is an AR (autosomal
recessive) and caused by specific mutations. Homozygous/ compounds
heterozygous or deletion mutations in a specific gene on chromosome 16
leads to the complete absence or significant decrease in the activity of
the 11-b-HSD2 enzyme that produces cortisone from cortisol. The
unprocessed active cortisol binds to its receptor, mineralocorticoid
(MC) receptors, inducing the after-mentioned clinical features
{[}8,9{]}. Our cases highlight many, if not all, of the features of the
condition. Thus, in addition to the classical findings, they
demonstrated a parent's consanguinity, a strong suspicion of the
affected twin, hypertensive retinopathy, and hypokalemic nephropathy.

These features have been reported in many other cases in the literature.
Al-Harbi and Al-Shaikh reported three cases, two females and one male,
with AMES, who presented with severe hypertension, low aldosterone, low
renin levels, and hypokalemia. Genetic analysis confirmed the AMES
diagnosis in these children. All cases had the typical clinical
presentation of AMES, and their parents were first-degree cousins,
considered consanguineous parents {[}10{]}. Yau et al. reported about a
consanguineous Omani family with six AMES cases. Genetic analysis of
affected family members confirmed a novel homozygous p.T267A mutation in
HSD11B2. The diagnosis was confirmed with clinical signs and symptoms
and biochemical investigations {[}11{]}.

Azara et al. reported a consanguineous family from Iran with three
affected cases. Two females and one male were diagnosed at 14, 11, and
4, respectively. At the time of presentation, low-renin hypertension,
retinopathy, hypertrophy of the left ventricle, and mutation in R337C,
within exon five of the 11\selectlanguage{ngerman}ßHSD2's gene, were found in this family with
AMES {[}12{]}. The mainstay of treatment of our patients were potassium
supplementations, thiazide (hydrochlorothiazide) and potassium
sparing-diuretic (amiloride). We used thiazide diuretics to treat the
nephrocalcinosis and associated hypercalciuria, while urine potassium
loss could occur due to this drug; therefore, potassium supplementations
were used. Amiloride was used as an alternative diuretic for thiazide if
it was needed. Calcium channel blockers, dexamethasone, and other
candidate treatments have been described in many cases with variable
successes {[}13{]}.

\textbf{Conclusion}

The AMES presents in childhood, typically with high blood pressure,
hypokalemia, and low renin and aldosterone levels. The hallmark of the
syndrome is increased cortisol-to-cortisone metabolites in the urine.
Spironolactone, which blocks receptors of cortisol and aldosterone, was
adopted. Adjunctive treatments are supplementation with potassium and a
diet with low sodium. Cortisol formation can be suppressed through ACTH
feedback inhibition using dexamethasone, but a consistent
antihypertensive effect is not guaranteed and has significant long-term
adverse events. To prevent or improve end-organ damage (EOD) morbidity,
diagnosis then treatment should be early.

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.42\columnwidth]{figures/Picture-algeria-case-1/Picture-algeria-case-1}

\end{center}
\end{figure}

\textbf{Figure 1.~}Syndrome of apparent mineralocorticoid excess (AMES).
The exact pathophysiology is shown here in detail.

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.42\columnwidth]{figures/Picture-algeria-case-2/Picture-algeria-case-2}

\end{center}
\end{figure}

\textbf{Figure 2.} Family pedigree.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.42\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3.} Magnetic resonance imaging of the brain that confirm
an established stroke.

\textbf{References:}

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(Oxf)} . 2018;89(4):385-396. doi:10.1111/cen.13741

2. White PC, Obeid J, Agarwal AK, Tannin GM, Nikkila H. Genetic analysis
of 11 beta-hydroxysteroid dehydrogenase. \emph{Steroids} .
1994;59(2):111-115. doi:10.1016/0039-128x(94)90086-8

3. Wilson RC, Dave-Sharma S, Wei JQ, et al. A genetic defect resulting
in mild low-renin hypertension. \emph{Proc Natl Acad Sci U S A} .
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4. Sahay M, Sahay R. Low renin hypertension. \emph{Indian J Endocrinol
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5. Craigie E, Evans LC, Mullins JJ, Bailey MA. Failure to downregulate
the epithelial sodium channel causes salt sensitivity in Hsd11b2
heterozygote mice. \emph{Hypertens (Dallas, Tex 1979)} .
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6. Knops NBB, Monnens LA, Lenders JW, Levtchenko EN. Apparent
Mineralocorticoid Excess: Time of Manifestation and Complications
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doi:10.1542/peds.2010-1928

7. Palermo M, Quinkler M, Stewart PM. Apparent mineralocorticoid excess
syndrome: an overview. \emph{Arq Bras Endocrinol Metabol} .
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8. Kamide K, Kokubo Y, Hanada H, et al. Genetic variations of HSD11B2 in
hypertensive patients and in the general population, six rare
missense/frameshift mutations. \emph{Hypertens Res} .
2006;29(4):243-252. doi:10.1291/hypres.29.243

9. Morineau G, Sulmont V, Salomon R, et al. Apparent Mineralocorticoid
Excess: Report of Six New Cases and Extensive Personal
Experience.\emph{J Am Soc Nephrol} . 2006;17(11):3176-3184.
doi:10.1681/ASN.2006060570

10. Al-Harbi T, Al-Shaikh A. Apparent mineralocorticoid excess syndrome:
report of one family with three affected children. \emph{J Pediatr
Endocrinol Metab} . 2012;25(11-12). doi:10.1515/jpem-2012-0113

11. Yau M, Azkawi HS Al, Haider S, et al. A novel mutation in HSD11B2
causes apparent mineralocorticoid excess in an Omani kindred. \emph{Ann
N Y Acad Sci} . 2016;1376(1):65-71. doi:10.1111/nyas.13162

12. Razzaghy-Azar M, Yau M, Khattab A, New MI. Apparent
mineralocorticoid excess and the long term treatment of genetic
hypertension. \emph{J Steroid Biochem Mol Biol} . 2017;165:145-150.
doi:10.1016/j.jsbmb.2016.02.014

13. Draper N, Stewart PM. 11beta-hydroxysteroid dehydrogenase and the
pre-receptor regulation of corticosteroid hormone action. \emph{J
Endocrinol} . 2005;186(2):251-271. doi:10.1677/joe.1.06019

\textbf{Figure Legends:}

Figure 1. Syndrome of apparent mineralocorticoid excess (AMES). Exact
pathophysiology is shown here in details.

Figure 2. Family pedigree.

Figure 3. Magnetic resonance imaging of the brain that confirm an
established stroke.

\textbf{Declarations:}

*\textbf{Consent for publication}

Written informed consent was obtained from the patients' parents for the
publication of this case report and any accompanying images. A copy of
the written consent will be available for review by the Editor of this
journal if required.

*\textbf{Availability of data and material}

All data generated or analyzed are included in this article

\textbf{*Competing interests}

No conflict of interest exits in the submission of this manuscript.

\textbf{*Funding}

Not applicable

\textbf{*Authors' contributions}

All authors have read and approved the manuscript

*\textbf{Acknowledgements}

Our sincere thanks to Dr Salah Eddine O. Kacimi for providing the
details and the materials of this case report.

\selectlanguage{english}
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