1 - Primary Immunodeficiencies Unit, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central EPE, Lisbon, Portugal
2 - Centro de investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Universitário Egas Moniz, Caparica, Portugal
3 - Pediatric Reumatology Unit, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central EPE, Lisbon, Portugal
4 - NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisbon, Portugal
5 - CHRC, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisbon, Portugal
6 - Immunology Department, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, Lisbon, Portugal
7 - Centro de Genética Preditiva e preventiva, Instituto de Biologia Molecular e Celular, Instituto de Investigação e Inovação em Saúde, Porto, Portugal
8 - Auto-inflammatory syndromes Clinics, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central EPE, Lisbon, Portugal
9 - Pediatric Infectious Diseases Unit, Hospital Dona Estefânia, Centro Hospitalar Universitário Lisboa Central EPE, Lisbon, Portugal
- Publication as Clinical Letter to the Author in the Pediatric Allergy and Immunology Journal (PAI) DOI: 10.1111/pai.14020
Introduction: Mutations in the nucleotide-binding leucine-rich repeat-containing receptor 12 (NLRP12) gene are known to cause Familial Cold Autoinflammatory Syndrome 2 (FCAS2), a rare systemic autoinflammatory syndrome. It is described a case of an adolescent with a novel NLRP12 variant presenting with recurrent febrile episodes, cold urticaria and hemophagocytic lymphohistiocytosis, never reported in patients harbouring NLRP12 mutations.
Clinical case: A 14-year-old boy presented to emergency department with a three-week history of a pruritic, generalized maculo-papular rash, and 1-day of bilateral conjunctival hyperemia, headache, and myalgia. He had a previous medical history of growth hormone deficiency; myositis at 8 years old, and an episode of cold urticaria at 10 years old. His father had a previous diagnosis of cold urticaria and migraine. At hospital admission he showed elevated C-reactive protein (CRP) of 113.4 mg/L, with neutrophilia and lymphopenia. He was admitted and started intravenous ceftriaxone. On the following day he developed dyspnea and hypoxemia. The chest CT-scan showed a diffuse “cotton-like” infiltrate and bilateral pleural effusion. Invasive streptococcal disease was suspected, and he was started on antibiotics and intravenous immunoglobulin (1gr/kg/day) with clinical improvement although negative infectious investigation. On day 15, he presented again with high fever, rash and hepatosplenomegaly. Laboratory evaluation and splenomegaly fulfilled 5/8 criteria for hemophagocytic lymphohistiocytosis (HLH). He was started on daily methylprednisolone pulses (30 mg/kg) for five days, followed by oral prednisolone, with progressive improvement. When clinically stable, he was discharged with a tapering steroid scheme. Four weeks after stopping steroids, following exposure to cold water, he again developed fever, elevated inflammatory markers, and rash. He was then started on anakinra for one year when he had a new relapse. Anakinra was then substituted by canakinumab.. The analysis of a whole-exome sequencing (WES) for auto-inflammatory syndromes, found a novel nonsense heterozygous variant in the NLRP12 gene (c.1952C>A; p.(Ser651*)), inherited from his father.
Conclusion: It is described a novel NLRP12 variant, identified in an adolescent with HLH and recurrent episodes of cold-induced rash and fever. This report expands the range of disease-causing variants in the NLRP12 gene and further illustrates the complexity of phenotypes associated with this gene dysfunction.
Palavras Chave: adolescent, anakinra, autosomal dominant, canakinumab, familial cold autoinflammatory syndrome, NLRP12.