Inherited MST1 Deficiency Underlies Susceptibility to EV-HPV Infections

Amandine Crequer,Etienne Patin,Marianne Debré,Gérard Orth,Martine Munzer,Emmanuelle Jouanguy,Geneviève De Saint-Basile,Capucine Picard,Jean-Laurent Casanova,Laurent Abel,Aurelia D’Amico,Alain Fischer,Shen-Ying Zhang,Avinash Abhyankar,Mark M Wurfel

doi:10.1371/journal.pone.0044010

Abstract

Epidermodysplasia verruciformis (EV) is characterized by persistent cutaneous lesions caused by a specific group of related human papillomavirus genotypes (EV-HPVs) in otherwise healthy individuals. Autosomal recessive (AR) EVER1 and EVER2 deficiencies account for two thirds of known cases of EV. AR RHOH deficiency has recently been described in two siblings with EV-HPV infections as well as other infectious and tumoral manifestations. We report here the whole-exome based discovery of AR MST1 deficiency in a 19-year-old patient with a T-cell deficiency associated with EV-HPV, bacterial and fungal infections. MST1 deficiency has recently been described in seven patients from three unrelated kindreds with profound T-cell deficiency and various viral and bacterial infections. The patient was also homozygous for a rare ERCC3 variation. Our findings broaden the clinical range of infections seen in MST1 deficiency and provide a new genetic etiology of susceptibility to EV-HPV infections. Together with the recent discovery of RHOH deficiency, they suggest that T cells are involved in the control of EV-HPVs, at least in some individuals.

Highlights

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent cutaneous lesions caused by a specific group of related human betapapillomavirus genotypes (EV-HPVs) in otherwise healthy individuals [1,2]
Histological analysis of one of the lymph nodes removed showed a fibrous thickening of the capsule associated with an increase in the abundance of plasmocytes and the presence of a few HHV8+ cells and a few cells labeled with the Epstein-Barr-encoded RNA (EBER) probe
We report here the first patient with susceptibility to EV-HPV lesions due to MST1 deficiency

Summary

Introduction

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by persistent cutaneous lesions caused by a specific group of related human betapapillomavirus genotypes (EV-HPVs) in otherwise healthy individuals [1,2]. Many cases of EV are familial, and 10% of patients come from consanguineous families [2] This observation led Cockayne et al to hypothesize in 1933 that EV resulted from autosomal recessive (AR) inborn errors of immunity against EV-HPVs [3]. This hypothesis was confirmed by the discovery of the first two genetic etiologies of EV in 2002, mutations in EVER1 and EVER2 [4], which added EV to the list of primary immunodeficiencies [5,6,7,8]. We recently identified two siblings with RHOH deficiency, EV-HPV infections, other cutaneous viral infections, a bronchopulmonary disease of unclear pathogenesis, and a Burkitt lymphoma [17]

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