RESUMO
Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.
Assuntos
Agamaglobulinemia/genética , Linfócitos B/patologia , Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Síndromes de Imunodeficiência/genética , Linfopenia/genética , Adulto , Animais , Linfócitos B/metabolismo , Criança , Pré-Escolar , Cromossomos Humanos Par 5/genética , Códon sem Sentido , Consanguinidade , Doença de Crohn/genética , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/genética , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Cardiopatias Congênitas/genética , Humanos , Infecções/etiologia , Mutação com Perda de Função , Masculino , Camundongos , Neutropenia/genética , Linhagem , Dissomia Uniparental , Sequenciamento do ExomaAssuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/tratamento farmacológico , Terapia de Reposição de Enzimas/métodos , Complicações na Gravidez/tratamento farmacológico , Imunodeficiência Combinada Severa/tratamento farmacológico , Adenosina Desaminase/administração & dosagem , Adenosina Desaminase/imunologia , Adulto , Agamaglobulinemia/imunologia , Esquema de Medicação , Feminino , Humanos , Gravidez , Complicações na Gravidez/imunologia , Imunodeficiência Combinada Severa/imunologia , Resultado do TratamentoRESUMO
Wells' syndrome is a rare disease that is even more uncommon in childhood. This case report illustrates the potential devastating extent of the disease and highlights the unusual presentation of bullae in a child. It is imperative to consider Wells' syndrome in patients with presumed cellulitis and eosinophilia who fail to respond to antibiotics.