Pediatric population with cystic fibrosis in the centre of Portugal: candidates for new therapies

Abstract Objectives: Cystic fibrosis (CF) is a severe autosomal recessive disease that results from mutations in a gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, a chloride channel. This study aims to characterize the clinical and genetic features of a cohort of pediatric people with CF (PwCF) in the center of Portugal and to determine which ones are candidates for the new drugs modulating the CFTR channel. Methods: A review of the demographic, genetic and clinical characteristics of PwCF undergoing follow-up at a CF reference center was carried out. Results: Twenty-three PwCF (12 male), with a median age of 12 years, were followed up. All patients carry the F508del mutation in at least one allele. Fifteen PwCF were F508del-homozygous, median BMI z-score was -0.13, all are pancreatic insufficient and median FEV1 value was 78.1%. These PwCF are eligible for dual therapy (lumacaftor/tezacaftor+ivacaftor) and for triple therapy (tezacaftor+ivacaftor+elexacaftor). PwCF with 711 +1G->T (n = 2), 2184insA (n = 1) mutations and a novel mutation c.3321dup (n = 1) have minimal function mutation and patients with a residual function mutation: R334W (n = 3) and P5L (n = 1) have a less severe phenotype. All these patients, because they also carry F508del mutation, are elegible to triple therapy. Conclusions: Genetic and molecular characterization of PwCF poses an important step not just for CF diagnosis and prognosis which is tightly correlated with the clinical phenotype, but also for the eligibility of CFTR modulator drugs.

Pediatric population with cystic fibrosis in the centre of Portugal: candidates for new therapies.

OBJECTIVES: Cystic fibrosis (CF) is a severe autosomal recessive disease that results from mutations in a gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, a chloride channel. This study aims to characterize the clinical and genetic features of a cohort of pediatric people with CF (PwCF) in the center of Portugal and to determine which ones are candidates for the new drugs modulating the CFTR channel. METHODS: A review of the demographic, genetic and clinical characteristics of PwCF undergoing follow-up at a CF reference center was carried out. RESULTS: Twenty-three PwCF (12 male), with a median age of 12 years, were followed up. All patients carry the F508del mutation in at least one allele. Fifteen PwCF were F508del-homozygous, median BMI z-score was -0.13, all are pancreatic insufficient and median FEV1 value was 78.1%. These PwCF are eligible for dual therapy (lumacaftor/tezacaftor+ivacaftor) and for triple therapy (tezacaftor+ivacaftor+elexacaftor). PwCF with 711 +1G->T (n = 2), 2184insA (n = 1) mutations and a novel mutation c.3321dup (n = 1) have minimal function mutation and patients with a residual function mutation: R334W (n = 3) and P5L (n = 1) have a less severe phenotype. All these patients, because they also carry F508del mutation, are elegible to triple therapy. CONCLUSIONS: Genetic and molecular characterization of PwCF poses an important step not just for CF diagnosis and prognosis which is tightly correlated with the clinical phenotype, but also for the eligibility of CFTR modulator drugs.

Severe iron-deficiency anemia as initial manifestation of pulmonary hemosiderosis in a child.

Idiopathic pulmonary hemosiderosis is a potentially fatal disease that results from episodes of alveolar hemorrhage of unknown origin. The clinical spectrum is varied, and anemia may constitute the only manifestation of illness, preceding other signs and symptoms by several months. We present the case of a 4 year-old child presenting with fever, vomiting and prostration, associated with pallor. He had microcytic and hypochromic anemia refractory to iron therapy. Gastrointestinal bleeding was ruled out after negative extensive etiological investigation. Subsequently, pulmonary infiltrates suggestive of alveolar hemorrhage were observed in the chest radiography. The cytological exam of the bronchoalveolar lavage showed hemosiderin-laden macrophages. After the etiological study, the diagnosis of idiopathic pulmonary hemosiderosis was made by exclusion. He was initiated on corticosteroid therapy, later associated to an immunosuppressive agent, with subsequent correction of anemia and of the radiological pattern. The patient is currently asymptomatic.

Cystic Fibrosis Newborn Screening in Portugal: PAP Value in Populations with Stringent Rules for Genetic Studies.

Newborn screening (NBS) for cystic fibrosis (CF) has been shown to be advantageous for children with CF, and has thus been included in most NBS programs using various algorithms. With this study, we intend to establish the most appropriate algorithm for CF-NBS in the Portuguese population, to determine the incidence, and to contribute to elucidating the genetic epidemiology of CF in Portugal. This was a nationwide three-year pilot study including 255,000 newborns (NB) that were also screened for congenital hypothyroidism (CH) and 24 other metabolic disorders included in the Portuguese screening program. Most samples were collected in local health centers spread all over the country, between the 3rd and 6th days of life. The algorithm tested includes immunoreactive trypsinogen (IRT) determination, pancreatitis associated protein (PAP) as a second tier, and genetic study for cases referred to specialized clinical centers. Thirty-four CF cases were confirmed positive, thus indicating an incidence of 1:7500 NB. The p.F508del mutation was found in 79% of the alleles. According to the results presented here, CF-NBS is recommended to be included in the Portuguese NBS panel with a small adjustment regarding the PAP cut-off, which we expect to contribute to the improvement of the CF-NBS performance. According to our results, this algorithm is a valuable alternative for CF-NBS in populations with stringent rules for genetic studies.

Severe iron-deficiency anemia as initial manifestation of pulmonary hemosiderosis in a child / Anemia ferropriva grave como manifestaçao inicial de hemossiderose pulmonar em criança

ABSTRACT Idiopathic pulmonary hemosiderosis is a potentially fatal disease that results from episodes of alveolar hemorrhage of unknown origin. The clinical spectrum is varied, and anemia may constitute the only manifestation of illness, preceding other signs and symptoms by several months. We present the case of a 4 year-old child presenting with fever, vomiting and prostration, associated with pallor. He had microcytic and hypochromic anemia refractory to iron therapy. Gastrointestinal bleeding was ruled out after negative extensive etiological investigation. Subsequently, pulmonary infiltrates suggestive of alveolar hemorrhage were observed in the chest radiography. The cytological exam of the bronchoalveolar lavage showed hemosiderin-laden macrophages. After the etiological study, the diagnosis of idiopathic pulmonary hemosiderosis was made by exclusion. He was initiated on corticosteroid therapy, later associated to an immunosuppressive agent, with subsequent correction of anemia and of the radiological pattern. The patient is currently asymptomatic.

RESUMO A hemossiderose pulmonar idiopática é uma doença potencialmente fatal que cursa com episódios de hemorragia alveolar de etiologia desconhecida. As manifestações clínicas são variadas, e a anemia pode constituir o único sinal de doença, precedendo em vários meses os outros sinais e sintomas. Apresenta-se o caso de criança de 4 anos, com febre, vômitos e prostração, associados à palidez. Apresentava anemia microcítica e hipocrômica, refratária à terapêutica com ferro. A hipótese diagnóstica de sangramento gastrintestinal foi excluída, após investigação etiológica extensa, inconclusiva. Posteriormente, em radiografia torácica, foram observados infiltrados sugestivos de hemorragia alveolar. O exame citológico do lavado broncoalveolar mostrou macrófagos com depósitos de hemossiderina. Após estudo etiológico, assumiu-se, por exclusão, o diagnóstico de hemossiderose pulmonar idiopática. Foi iniciada terapêutica com corticoides, associada posteriormente a imunossupressor, com correção subsequente da anemia e do padrão radiológico, encontrando-se, atualmente, assintomático.