# Connecting the dots: Xanthoma, haemolytic anaemia, stomatocytosis and macrothrombocytopenia point to phytosterolaemia

Jean-baptiste Rieu, Thibaut Jamme, Léonardo Astudillo, Lamisse

Mansour-hendili, Thierry Levade, Pierre Cougoul

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## To cite this version:

Jean-baptiste Rieu, Thibaut Jamme, Léonardo Astudillo, Lamisse Mansour-hendili, Thierry Levade, et al.. Connecting the dots: Xanthoma, haemolytic anaemia, stomatocytosis and macrothrombocytopenia point to phytosterolaemia. eJHaem, 2023, 4 (4), pp.1166 - 1167. 10.1002/jha2.777. inserm-04994245

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# Connecting the dots: Xanthoma, haemolytic anaemia, stomatocytosis and macrothrombocytopenia point to phytosterolaemia

Jean-Baptiste Rieu<fnref n="1" /> ID

Thibaut Jamme<fnref n="2" /> ID

Léonardo Astudillo<fnref n="3" />

Lamisse Mansour-Hendili<fnref n="4" />

Thierry Levade<fnref n="2" />,<fnref n="5" />

Pierre Cougoul<fnref n="6" />

**Correspondence**

Jean-Baptiste Rieu, Laboratoire d'Hématologie, Institut Universitaire du Cancer - Oncopole, 1 avenue Irène Joliot-Curie 31100 Toulouse, France.

Email: rieu.jeanbaptiste@iuct-oncopole.fr

**Funding information**

Centre Hospitalier Universitaire de Toulouse

**KEYWORDS**

acute leukaemia, biology, blood morphology, bone marrow pathology

A 20-year-old Caucasian woman was referred to the internal medicine department for investigation of unexplained chronic haemolytic anaemia (haemoglobin: 100 g/L) with negative direct anti-globulin test, thrombocytopaenia (102 × 10⁹/L) and xanthelasma palpebrarum (Figure 1A). Clinical examination showed mild splenomegaly. Blood film examination (Figure 1B, May-Grünwald-Giemsa, original magnification ×100) revealed marked stomatocytosis and large platelets. Plasma cholesterol and triglyceride levels were normal but the levels of plant sterols measured by gas chromatography were elevated for sitosterol (500 µmol/L, control value < 3.2 µmol/L) and campesterol (196 µmol/L, control value < 6.5 µmol/L). Next-generation sequencing revealed a new splicing homozygous variant in the ABCG5 gene (NM_022436):c.904+5G > C), confirming the diagnosis of phytosterolaemia. Treatment with 10 mg/day ezetimibe, a selective inhibitor of the Niemann-Pick C1-Like 1 protein, was prescribed in addition to specific dietary restriction banning plant fats and limiting foods rich in plant sterols. Investigation of family members was also recommended.

Phytosterolaemia (also known as sitosterolaemia) is an autosomal recessive disorder resulting from biallelic pathogenic ABCG5 (mainly found in Caucasians) or ABCG8 (more common among Asian populations) variants, characterized by excessive absorption of dietary sterols (cholesterol but also plant sterols). Cutaneous infiltration by lipid-loaded macrophages leads to the formation of xanthomas. The incorporation of plant sterols in the membranes of blood cells leads to structural and functional abnormalities that can cause macrothrombocytopenia and haemolytic anaemia. Thus, an association of mild haemolytic anaemia, macrothrombocytopenia, stomatocytosis and xanthoma is highly suggestive of this rare and probably underdiagnosed inherited condition [1, 2], especially when the standard lipid profile is normal. Knowledge of clinical and haematological manifestations of phytosterolaemia is of great importance since treatment with ezetimibe can reduce haemolysis, improve haemoglobin level and platelets count and lead to regression of xanthomas. Most importantly, it can help prevent disease complications such as premature atherosclerosis [3].

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.

<footnote n="1">¹Hematology Laboratory, University Hospital of Toulouse, Cancer University Institute of Toulouse Oncopole, Toulouse, France</footnote>

<footnote n="2">²Biochemistry Laboratory, University Hospital of Toulouse, Federative Institute of Biology, Toulouse, France</footnote>

<footnote n="3">³Department of Internal Medicine, Saint Exupéry Nephrology Clinic, Toulouse, France</footnote>

<footnote n="4">⁴Chemistry and Molecular Biology Laboratory, AP-HP, University Hospital Henri Mondor, Créteil, France</footnote>

<footnote n="5">⁵INSERM UMR1037 Unit, Cancer Research Center of Toulouse, Paul Sabatier University, Toulouse, France</footnote>

<footnote n="6">⁶Department of Internal Medicine, University Hospital of Toulouse, Cancer University Institute of Toulouse Oncopole, Toulouse, France</footnote>
<figure><img src="image_3.png" /><figcaption>**FIGURE 1** Clinical and blood film examination. (A) Clinical examination showing xanthelasma palpebrarum, (B) Blood film examination showing marked stomatocytosis and large platelets (May-Grünwald-Giemsa, original magnification ×100).</figcaption></figure>

## AUTHOR CONTRIBUTIONS

Jean-Baptiste Rieu wrote the paper; Jean-Baptiste Rieu took the pictures; JBR performed the blood film examination; Thibaut Jamme and Thierry Levade performed gas chromatography studies, Lamisse Mansour-Hendili performed molecular studies, Léonardo Astudillo and Pierre Cougoul performed clinical examination and follow-up of the patient. Written permission for reproduction from the copyright owners will be provided if the submission is accepted.

## CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

## DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

## ETHICS STATEMENT

This manuscript respects the ethical policy of CHU Toulouse for the treatment of human research participants.

## PATIENT CONSENT STATEMENT

The authors did not obtain written informed consent from the patient but the patient did not object to his data being used for research purposes (as required by the ethical policy of CHU Toulouse).

## CLINICAL TRIAL REGISTRATION

The authors have confirmed clinical trial registration is not needed for this submission.

## ORCID

Jean-Baptiste Rieu https://orcid.org/0000-0002-0950-979X

Thibaut Jamme https://orcid.org/0009-0000-4437-3448

## REFERENCES

1. Wang Z, Cao L, Su Y, Wang G, Wang R, Yu Z, et al. Specific macrothrombocytopenia/hemolytic anemia associated with sitosterolemia. Am J Hematol. 2014;89(3):320-4. https://doi.org/10.1002/ajh.23619

2. Bain BJ, Chakravorty S. Phytosterolemia. Am J Hematol. 2016; 91(6):643. https://doi.org/10.1002/ajh.24343

3. Tada H, Nohara A, Inazu A, Sakuma N, Mabuchi H, Kawashiri MA. Sitosterolemia, hypercholesterolemia, and coronary artery disease. J Atheroscler Thromb. 2018;25(9):783-9. https://doi.org/10.5551/jat.RV17024

**How to cite this article:** Rieu J-B, Jamme T, Astudillo L, Mansour-Hendili L, Levade T, Cougoul P. Connecting the dots: Xanthoma, haemolytic anaemia, stomatocytosis and macrothrombocytopenia point to phytosterolaemia. eJHaem. 2023;4:1166-1167. https://doi.org/10.1002/jha2.777