RESUMO
BACKGROUND: Children's interstitial lung diseases (chILD) comprise a broad spectrum of diseases. Besides the genetically defined surfactant dysfunction disorders, most entities pathologically involve the alveolar surfactant region, possibly affecting the surfactant proteins SP-B and SP-C. Therefore, our objective was to determine the value of quantitation of SP-B and SP-C levels in bronchoalveolar lavage fluid (BALF) for the diagnosis of chILD. METHODS: Levels of SP-B and SP-C in BALF from 302 children with chILD and in controls were quantified using western blotting. In a subset, single-nucleotide polymorphisms (SNPs) in the SFTPC promoter were genotyped by direct sequencing. RESULTS: While a lack of dimeric SP-B was found only in the sole subject with hereditary SP-B deficiency, low or absent SP-C was observed not only in surfactant dysfunction disorders but also in patients with other diffuse parenchymal lung diseases pathogenetically related to the alveolar surfactant region. Genetic analysis of the SFTPC promoter showed association of a single SNP with SP-C level. CONCLUSION: SP-B levels may be used for screening for SP-B deficiency, while low SP-C levels may point out diseases caused by mutations in TTF1, SFTPC, ABCA3, and likely in other genes involved in surfactant metabolism that remain to be identified. We conclude that measurement of levels of SP-B and SP-C was useful for the differential diagnosis of chILD, and for the precise molecular diagnosis, sequencing of the genes is necessary.
Assuntos
Líquido da Lavagem Broncoalveolar/química , Doenças Pulmonares Intersticiais/diagnóstico , Proteína B Associada a Surfactante Pulmonar/análise , Proteína C Associada a Surfactante Pulmonar/análise , Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Bronquite/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Comorbidade , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Feminino , Heterogeneidade Genética , Genótipo , Humanos , Síndromes de Imunodeficiência/genética , Lactente , Doenças Pulmonares Intersticiais/genética , Masculino , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Precursores de Proteínas/genética , Proteolipídeos/genética , Proteinose Alveolar Pulmonar/diagnóstico , Proteinose Alveolar Pulmonar/genética , Proteína B Associada a Surfactante Pulmonar/deficiência , Proteína B Associada a Surfactante Pulmonar/genética , Proteína C Associada a Surfactante Pulmonar/química , Proteína C Associada a Surfactante Pulmonar/deficiência , Proteína C Associada a Surfactante Pulmonar/genética , Análise de Sequência de DNA , Fatores de Transcrição , Adulto JovemRESUMO
BACKGROUND: The majority of cases with severe pulmonary alveolar proteinosis (PAP) are caused by auto-antibodies against GM-CSF. A multitude of genetic and exogenous causes are responsible for few other cases. Goal of this study was to determine the prevalence of GATA2 deficiency in children and adults with PAP and hematologic disorders. METHODS: Of 21 patients with GM-CSF-autoantibody negative PAP, 13 had no other organ involvement and 8 had some form of hematologic disorder. The latter were sequenced for GATA2. RESULTS: Age at start of PAP ranged from 0.3 to 64 years, 4 patients were children. In half of the subjects GATA2-sequence variations were found, two of which were considered disease causing. Those two patients had the typical phenotype of GATA2 deficiency, one of whom additionally showed a previously undescribed feature - a cholesterol pneumonia. Hematologic disorders included chronic myeloic leukemia, juvenile myelo-monocytic leukemia, lymphoblastic leukemia, sideroblastic anemia and two cases of myelodysplastic syndrome (MDS). A 4 year old child with MDS and DiGeorge Syndrome Type 2 was rescued with repetitive whole lung lavages and her PAP was cured with heterologous stem cell transplant. CONCLUSIONS: In children and adults with severe GM-CSF negative PAP a close cooperation between pneumologists and hemato-oncologists is needed to diagnose the underlying diseases, some of which are caused by mutations of transcription factor GATA2. Treatment with whole lung lavages as well as stem cell transplant may be successful.