Selected exon sequencing detects at least one mutated allele in over a half of our patients who have PCD due to DNAH5 or DNAI1 mutations. To lower the costs of the genetic testing, targeted step-wise genetic testing may be a reasonable approach to detect mutations in PCD patients, especially if their phenotype is taken into account.

Background: The most frequently used parameters for assessing bronchoconstriction and bronchodilation are forced expiratory volume in 1 s (FEV₁) and peak expiratory flow (PEF). Objectives: To assess the sensitivity of other parameters after induced bronchoconstriction and bronchodilation. Methods: From maximum expiratory flow-volume (MEFV) curves, forced vital capacity, FEV₁, PEF, maximum expiratory flows (MEF) at 25, 50 and 75% of vital capacity and the area under the MEFV curve (A_ex) were measured in two groups of asthmatic children after induced bronchoconstriction and bronchodilation, and in children with cystic fibrosis (CF) after bronchodilation. Results: In 142 asthmatics without airway obstruction, bronchoconstriction was induced by inhalation of 1% histamine aerosol. The 20% fall in A_ex compared to baseline was found in all asthmatics, while the 20 and 15% falls in FEV₁ were noted in 36 and 65% of the patients, respectively. Other parameters were less sensitive or interpretation was problematic. Another110 asthmatics with mild-moderate airway obstruction were treated with various bronchodilators. The 20% increase in A_ex was observed in all asthmatics, while the 20% increase in FEV₁ was found in only 33% of the patients and the 15% increase in FEV₁ in 51%. In 9CF children, the pattern of changes in A_ex and FEV₁ after bronchodilation was similar to that in asthmatics. Conclusions: A_ex was a sensitive and less problematic parameter in the evaluation of airway patency in comparison with FEV₁ and other parameters measured from the MEFV curve in our study patients.

We present a combination of Sanger sequencing with an NGS panel for known and candidate PCD genes, implemented in a moderate-size national collection of patients. This strategy has proven to be cost-effective, rapid and reliable, and was able to detect the causative gene in two thirds of our PCD patients.

BackgroundGATA-2 transcription factor deficiency has recently been described in patients with a propensity towards myeloid malignancy associated with other highly variable phenotypic features: chronic leukocytopenias (dendritic cell-, monocyto-, granulocyto-, lymphocytopenia), increased susceptibility to infections, lymphatic vasculature abnormalities, and sensorineural deafness. Patients often suffer from opportunistic respiratory infections; chronic pulmonary changes have been found in advanced disease.Case presentationWe present a case of a 17-year-old previously healthy Caucasian male who was admitted to the hospital with fever, malaise, headache, cough and dyspnea. A chest X-ray revealed bilateral interstitial infiltrates and pneumonia was diagnosed. Despite prompt clinical improvement under antibiotic therapy, interstitial changes remained stable. A high resolution computer tomography showed severe diffuse parenchymal lung disease, while the patient’s pulmonary function tests were normal and he was asymptomatic. Lung tissue biopsy revealed chronic reparative and resorptive reaction with organizing vasculitis. At the time of the initial presentation to the hospital, serological signs of acute infection with Epstein-Barr virus (EBV) were present; EBV viremia with atypical serological response persisted during two-year follow up. No other infectious agents were found. Marked monocytopenia combined with B-cell lymphopenia led to a suspicion of GATA-2 deficiency. Diagnosis was confirmed by detection of the previously published heterozygous mutation in GATA2 (c.1081 C > T, p.R361C). The patient’s brother and father were both carriers of the same genetic defect. The brother had no clinically relevant ailments despite leukocyte changes similar to the index patient. The father suffered from spondylarthritis, and apart from B-cell lymphopenia, no other changes within the leukocyte pool were seen.ConclusionWe conclude that a diagnosis of GATA-2 deficiency should be considered in all patients with diffuse parenchymal lung disease presenting together with leukocytopenia, namely monocyto-, dendritic cell- and B-lymphopenia, irrespective of severity of the clinical phenotype. Genetic counseling and screening for GATA2 mutations within the patient’s family should be provided as the phenotype is highly variable and carriers without apparent immunodeficiency are still in danger of developing myeloid malignancy. A prompt recognition of this rare condition helps to direct clinical treatment strategies and follow-up procedures.

Primary ciliary dyskinesia (PCD) leads to recurrent/chronic respiratory infections, resulting in chronic inflammation and potentially in chronic pulmonary disease with bronchiectasis. We analyzed longitudinal data on body length/height and body mass index (BMI) for 29 children and young adults with PCD aging 1.5–24 years (median, 14.5) who had been diagnosed at the age of 0.5–17 years (median, 8). Of these, 10 carried pathogenic mutations in either DNAH5 or DNAI1. In children with PCD, body length/height progressively decreased from +0.40 ± 0.24 SDS (the 1st birthday), +0.16 ± 0.23 SDS (3 years old), and −0.13 ± 0.21 SDS (5 years old) to −0.54 ± 0.19 SDS (7 years old; P = 0.01 versus 0), −0.67 ± 0.21 SDS (9 years old; P = 0.005 versus 0), −0.52 ± 0.24 SDS (11 years old; P = 0.04 versus 0), and −0.53 ± 0.23 SDS (13 years old; P = 0.03 versus 0). These results reflect low growth rates during the childhood growth period. Thereafter, heights stabilized up to the age of 17 years. The growth deterioration was not dependent on sex or disease severity but was more pronounced in DNAH5 or DNAI1 mutation carriers. BMI did not differ from population standards, which suggests that nutritional deficits are not the cause of growth delay. We conclude that PCD leads to chronic deprivation with significant growth deterioration during childhood.