Expanding the Nude SCID/CID Phenotype Associated with FOXN1 Homozygous, Compound Heterozygous, or Heterozygous Mutations

Giuliana Giardino, Svetlana O. Sharapova, Peter Ciznar, Fatima Dhalla, Luca Maragliano, Akella Radha Rama Devi, Candan Islamoglu, Aydan Ikinciogullari, Sule Haskologlu, Figen Dogu, Rima Hanna-Wakim, Ghassan Dbaibo, Janet Chou, Emilia Cirillo, Carla Borzacchiello, Alexandra Y. Kreins, Austen Worth, Ioanna A. Rota, José G. Marques, Muge SayitogluSinem Firtina, Moaffaq Mahdi, Raif Geha, Bénédicte Neven, Ana E. Sousa, Fabio Benfenati, Georg A. Hollander, E. Graham Davies, Claudio Pignata

Research output: Contribution to journalArticlepeer-review

Abstract

Human nude SCID is a rare autosomal recessive inborn error of immunity (IEI) characterized by congenital athymia, alopecia, and nail dystrophy. Few cases have been reported to date. However, the recent introduction of newborn screening for IEIs and high-throughput sequencing has led to the identification of novel and atypical cases. Moreover, immunological alterations have been recently described in patients carrying heterozygous mutations. The aim of this paper is to describe the extended phenotype associated with FOXN1 homozygous, compound heterozygous, or heterozygous mutations. We collected clinical and laboratory information of a cohort of 11 homozygous, 2 compound heterozygous, and 5 heterozygous patients with recurrent severe infections. All, except one heterozygous patient, had signs of CID or SCID. Nail dystrophy and alopecia, that represent the hallmarks of the syndrome, were not always present, while almost 50% of the patients developed Omenn syndrome. One patient with hypomorphic compound heterozygous mutations had a late-onset atypical phenotype. A SCID-like phenotype was observed in 4 heterozygous patients coming from the same family. A spectrum of clinical manifestations may be associated with different mutations. The severity of the clinical phenotype likely depends on the amount of residual activity of the gene product, as previously observed for other SCID-related genes. The severity of the manifestations in this heterozygous family may suggest a mechanism of negative dominance of the specific mutation or the presence of additional mutations in noncoding regions.

Original languageEnglish
JournalJournal of Clinical Immunology
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • alopecia
  • compound heterozygous
  • EBV-related lymphoproliferative disease
  • FOXN1
  • heterozygous
  • homozygous
  • nail dystrophy
  • Nude SCID
  • Omenn syndrome

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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