X-MAID international registry/X-MAIDReg
An international, multicentre, retrospective study of patients with X-linked moesin-associated immunodeficiency
X-MAID international registry/X-MAIDReg
The moesin (MSN) deficiency initially described in 7 male patients aged 4 to 69 years is characterized by lymphopenia in three cell lines (T, B and NK cells) and moderate neutropenia that responds to treatment with granulocyte colony stimulating factor. The T cell lymphopenia is similar to that observed in patients suffering from severe combined immune deficiency (SCID) (CD3+ count ≤ 300/µl). The patients’ T lymphocytes proliferate poorly after activation (less than 10% of the normal rate) and present signs of senescence and altered migration/adhesion very early in life. Serum immunoglobulin levels are significantly lower than in age-matched healthy controls. On the genetic level, 6 of the 7 patients presented the same c.511C>T missense mutation in the MSN gene located on the X chromosome, leading to an amino acid substitution (R171W) in the MSN protein. The 7th patient presented a c.1657C>T mutation, leading to the introduction of a stop codon at amino acid 553 (R553*). We have evidenced total inactivation of the X chromosome bearing the mutation in lymphocytes from the mothers and sisters (healthy carriers) of 3 patients - reinforcing the supposition whereby these mutations are harmful for lymphocytes.
Moesin belongs to the ezrin-radixin-moesin (ERM) family of proteins. Although these proteins are expressed ubiquitously, the expression level is tissue-dependent. All 3 proteins have a FERM domain (which binds to surface proteins, phospholipids, and cytosolic adaptor proteins), an alpha helical domain, and an actin-F-binding domain. All have a significant mechanistic role in cell migration, adhesion and deformation. Although the 3 proteins (moesin, radixin and ezrin) are partially redundant, each has unique functions by virtue of the expression patterns and physical-chemical properties (1). Prior to the publication of our study results in 2016, an inherited disease linked to mutations in the genes coding for the ERM proteins had never been described.
On the clinical level, all 7 patients suffering from X-linked moesin-associated immunodeficiency (X-MAID) presented with recurrent bacterial infections of the respiratory, gastro-intestinal or urinary tracts, and some had severe, late-resolving chicken pox. Eczema was observed in several patients. One of the patients developed an auto-immune disease (against ADAMTS13), which led to thrombotic thrombocytopenic purpura and a stroke at the age of 13 months. In the absence of a molecular diagnosis and in view of the SCID-type phenotype, one patient underwent allogeneic, genoidentical haematopoietic stem cell transplantation (HSCT). The other patients were not treated or received immunoglobulin replacement therapy and/or antibiotic prophylaxis (2). An Australian study recently described a patient bearing a p.R171W mutation in the MSN gene and who presented with much the same characteristics as our patients, i.e. recurrent bacterial infections and severe chicken pox (3).
Since this study, the MSN gene sequence has been included in the DNA chips used for the molecular diagnosis of immunodeficiencies in several countries. To date, physicians in Australia, the United States, Japan, and Europe have contacted us about a total of 16 patients. A certain number of these physicians have alerted us to the fact that the patients suffering from X-MAID had been diagnosed at birth after neonatal T-cell-receptor-excision-circle-based screening for SCIDs (4, 5, 6). Given the very low T lymphocyte count, 2 patients in the United States underwent allogeneic HSCT but experienced severe post-transplantation complications (7). The management of patients with X-MAID thus varies greatly as a function of the country, the age at diagnosis, and the clinical picture. It ranges from no treatment (associated with recurrent infections and skin manifestations) to intravenous immunoglobulin replacement therapy and/or antibiotic prophylaxis (with low toxicity and good apparent effectiveness) and allogeneic transplantation (with all the associated risks: graft-related toxicity, graft-versus-host disease, rejection, and a risk of infection). We therefore considered that is was important to review the diagnosis, clinical presentation, and management of patients with X-MAID. The study set out here will (i) provide a better understanding of the presentation of patients with X-MAID, (ii) help to establish guidelines, and (ii) help to provide the best possible treatment for each patient as a function of the clinical picture.
1- Fehon, R.G. et al. Organizing the cell cortex: the role of ERM proteins. Nat Rev Mol Cell Biol. (2010), 11: 276–287
2- Lagresle-Peyrou C, et al. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene. J Allergy Clin Immunol, (2016), 138 :1681-9
3- Bradshaw G., et al. Exome Sequencing Diagnoses X-Linked Moesin-Associated Immunodeficiency in a Primary Immunodeficiency Case. Frontiers Immunol (2018), 9: 420-39
4- Delmonte O.M., et al. First Case of X-Linked Moesin Deficiency Identified After Newborn Screening for SCID. J. Clin. Immuno (2017),37 (4) : 336-338
5- Kwan A, et al. Newborn screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States. JAMA (2014) 312: 729-38
6- Dvorak CC, et al. The genetic landscape of severe combined immunodeficiency in the United Stats and Canada in the current era (2010-2018). JACI (2019 Jan), 143 (1) :405-407
7- Henrickson SE, et al. Hematopoietic Stem Cell Transplant for the Treatment of X-MAID Front Pediatr. (2019 May) 14 ; 7 :170
Imagine Institute (24 boulevard du Montparnasse 75015 Paris, France)
- Human Lymphohematopoiesis laboratory
Dr Isabelle André, lab head
Dr Jean- Sébastien Diana, pediatrician
Alexandrine Garrigue, project officer