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\begin{document}

\title{An uncommon RBC membranopathy : two case reports}



\author[1]{Ritika Khurana}%
\author[1]{Purva Kanvinde}%
\author[1]{Mukesh Desai}%
\author[1]{Nitin Shah}%
\author[1]{Archana Swami}%
\author[1]{Minnie Bodhanwala}%
\author[1]{Sangeeta Mudaliar}%
\affil[1]{Bai Jerbai Wadia Hospital for Children}%


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  \date{May 27, 2024}


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Title page

Title - \textbf{An uncommon RBC membranopathy : two case reports}

\textbf{Authors}

R Khurana -- Senior resident, Pediatric hematology -- oncology, B.J.
Wadia hospital for children, Mumbai, India

P Kanvinde - Consultant, Pediatric hematology -- oncology, B.J. Wadia
hospital for children, Mumbai, India

M Desai -- Senior Consultant \& head of Immunology, Pediatric hematology
-- oncology, B.J. Wadia hospital for children, Mumbai, India

N Shah - Senior Consultant, Pediatric hematology -- oncology, B.J. Wadia
hospital for children, Mumbai, India

A Swami - Senior Consultant, Pediatric hematology -- oncology, B.J.
Wadia hospital for children, Mumbai, India

M Bodhanwala -- CEO, B.J. Wadia hospital for children, Mumbai, India

S Mudaliar -- Head of the department, Pediatric hematology -- oncology,
B.J. Wadia hospital for children, Mumbai, India

\textbf{Corresponding author} -- Dr Sangeeta Mudaliar

Address -- B. J. Wadia hospital for children, Acharya Donde Marg, Parel,
Mumbai

Phone no -- +91967307272

Email id - mudaliarsangi@rediffmail.com

Word count -- 733

Figures -- 1

Tables -- 1

Key words -- sitosterolemia, Phytosterolemia, stomatocytes,
macrothrombocytopenia, sterols, hemolytic anemia

Abbreviations\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Abbreviations & Full form\tabularnewline
\midrule
\endhead
MCV & Mean Corpuscular Volume\tabularnewline
WBC & White blood cell\tabularnewline
LDH & Lactate Dehydrogenase\tabularnewline
EMA & Eosin 5' Maleimide\tabularnewline
PS & Peripheral smear\tabularnewline
NGS & Next Generation Sequencing\tabularnewline
GC-MS & Gas Chromatography -- Mass spectroscopy\tabularnewline
\bottomrule
\end{longtable}

\textbf{Main text}

\textbf{An uncommon RBC membranopathy : two case reports}

\textbf{R Khurana, P Kanvinde, M Desai, N Shah, A Swami, M Bodhanwala, S
Mudaliar}

Sitosterolemia is a rare autosomal recessive disease of plant sterol
metabolism. Bhattacharyya and Connor first described this disease in
1974 (1). To date, there are only about 100 known cases worldwide (2).

We describe two patients diagnosed with Sitosterolemia at our centre.
Patient A is a 12 year old male, presented with complaints of short
stature, abdominal distension \& gradually progressive paleness since 2
months. He had pallor, hemolytic facies and both weight (25kg) \& height
(130cm) were less than 3\textsuperscript{rd} centile and had
spleno-hepatomegaly.

His investigations (table1) were suggestive of a chronic hemolytic
anemia. Since the child did not have spherocytes on peripheral smear \&
had giant platelets, diagnosis of hereditary spherocytosis seemed
unconvincing. So genetic work up by next generation sequencing was done
which revealed mutation in ABCG8 gene, suggestive of Sitosterolemia. On
review, his peripheral smear showed some stomatocytes (figure1).

Patient B is a 12 year old child who was referred to us for splenectomy.
Child had splenomegaly bicytopenia, diagnosed during work up for a short
febrile illness. There were stomatocytes in his smear too \& sterol
levels were borderline high, hence genetic studies were sent, which
revealed compound heterozygous variants in the ABCG5 gene, suggestive of
Sitosterolemia type 2.

Both the patients are under regular follow up for monitoring diet,
counts \& changes of early atherosclerosis. If dietary changes are not
adequate, we will consider ezitimibe for them.

Discussion

Patients with Sitosterolemia can have a variety of presentations like
short stature, chronic abdominal discomfort, splenomegaly etc indicating
a chronic hemolytic disease. Some may present with tendinous and
cutaneous xanthomas, arthritis, and arthralgias. They have a strong
propensity towards premature coronary atherosclerosis (3).

Laboratory features are suggestive of chronic hemolysis with presence of
stomatocytic red cells and macrothrombocytopenia on blood films. Eosin
5' maleimide test by flow cytometry (EMA) is usually abnormal. Plasma
levels of plant sterols (sitosterol, cholestanol, and stigmasterol)
measured by GC-MS (gas chromatography-mass spectrometry) are elevated.
The identified homozygous or compound heterozygous mutations in ABCG5
and ABCG8 genes further confirm the diagnosis.

Treatment predominantly involves dietary changes \& pharmacological
adjuncts. All sources of vegetable fats like vegetable oils, nuts,
seeds, olives, avocados etc. should be eliminated. Food derived from
animal sources with cholesterol as the dominant source should be allowed
(4). Bile acid resins like cholestyramine may be useful, statins have no
role (5). Ezetimibe was US FDA approved in 2002 for use in patients with
sitosterolemia. Ezetimibe alone or in combination with cholestyramine
effectively reduces plant sterol levels by around 50\%(6). Some patients
may require surgical interventions like ileal bypass to effectively
reduce sterol levels.

We feel that this condition is under reported as many may remain
misdiagnosed as hereditary spherocytosis or hyperlipidemias. Measures as
simple as dietary modification can control this condition \& prevent a
splenectomy(which will be detrimental in patients with Sitosterolemia).
Hence, stomatocytes should be actively searched for in patients with
large platelets and unexplained mild hemolysis. Consider early NGS to
determine diagnosis.

References

\begin{enumerate}
\tightlist
\item
  Bhattacharyya AK, Connor WE. Beta-sitosterolemia and xanthomatosis. A
  newly described lipid storage disease in two sisters. J Clin Invest.
  1974;53(4):1033-1043.
\item
  Kidambi S, Patel SB. Sitosterolaemia: pathophysiology, clinical
  presentation and laboratory diagnosis. J Clin Pathol. 2008;
  61(5):588-594.
\item
  Merkens LS, Myrie SB, Steiner RD, Mymin D.~\emph{Sitosterolemia.
  GeneReviews {[}Internet{]}} ~Seattle (WA): University of Washington;
  2016. {[}updated 2013 Apr 4{]}.
\item
  EscolaGil JC, Quesada H, Julve J, MartinCampos JM, Cedo L,
  BlancoVaca F. Sitosterolemia: diagnosis, investigation, and
  management. Curr Atheroscler Rep 2014;16:424.
\item
  Parsons HG, Jamal R, Baylis B, Dias VC, Roncari D. A marked and
  sustained reduction in LDL sterols by diet and cholestyramine in
  betasitosterolemia. Clin Invest Med 1995;18:389400.
\item
  Lutjohann D, von Bergmann K, Sirah W, Macdonell G, JohnsonLevonas AO,
  Shah A, et al. Longterm efficacy and safety of ezetimibe 10 mg in
  patients with homozygous sitosterolemia: a 2year, openlabel
  extension study. Int J Clin Pract 2008;62:1499510.
\end{enumerate}

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