Truncating mutations in exons 20 and 21 of OFD1 can cause primary ciliary dyskinesia without associated syndromic symptoms.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a motile ciliopathy, whose symptoms include airway infections, male infertility and situs inversus. Apart from the typical forms of PCD, rare syndromic PCD forms exist. Mutations of the X-linked OFD1 gene cause several syndromic ciliopathies, including oral-facial-digital syndrome type 1, Joubert syndrome type 10 (JBTS10), and Simpson-Golabi-Behmel syndrome type 2, the latter causing the X-linked syndromic form of PCD. Neurological and skeletal symptoms are characteristic for these syndromes, with their severity depending on the location of the mutation within the gene. OBJECTIVES: To elucidate the role of motile cilia defects in the respiratory phenotype of PCD patients with C-terminal OFD1 mutations. METHODS: Whole-exome sequencing in a group of 120 Polish PCD patients, mutation screening of the OFD1 coding sequence, analysis of motile cilia, and magnetic resonance brain imaging. RESULTS: Four novel hemizygous OFD1 mutations, in exons 20 and 21, were found in men with a typical PCD presentation but without severe neurological, skeletal or renal symptoms characteristic for other OFD1-related syndromes. Magnetic resonance brain imaging in two patients did not show a molar tooth sign typical for JBTS10. Cilia in the respiratory epithelium were sparse, unusually long and displayed a defective motility pattern. CONCLUSION: Consistent with the literature, truncations of the C-terminal part of OFD1 (exons 16-22) almost invariably cause a respiratory phenotype (due to motile cilia defects) while their impact on the primary cilia function is limited. We suggest that exons 20-21 should be included in the panel for regular mutation screening in PCD.

Organization of Patient Management and Fungal Epidemiology in Cystic Fibrosis.

The achievement of a better life for cystic fibrosis (CF) patients is mainly caused by a better management and infection control over the last three decades. Herein, we want to summarize the cornerstones for an effective management of CF patients and to give an overview of the knowledge about the fungal epidemiology in this clinical context in Europe. Data from a retrospective analysis encompassing 66,616 samples from 3235 CF patients followed-up in 9 CF centers from different European countries are shown.

Common variable immune deficiency in children--clinical characteristics varies depending on defect in peripheral B cell maturation.

Common variable immune deficiency (CVID) is a heterogeneous disease associated with ineffective production of antibodies. It is usually diagnosed in adulthood, but a variable proportion of children develop CVID. Early identification of patients with potentially worse prognosis may help to avoid serious complications. The goal of this study was to associate the clinical phenotype of patients with early onset CVID with peripheral B-cell maturation profile. Four color flow cytometry was used to define distribution of peripheral B-cell subsets in 49 children with early-onset CVID. All clinical data were extracted from medical records. A proportion of patients demonstrated diminishing with time total B-lymphocytes pool, beyond physiological age-related changes. Irrespective from duration of the follow-up period the B-cell maturation profile in individual patients remained unchanged. We identified six different aberrant peripheral B cell maturation profiles associated with different clinical characteristics. Patients with an early B-cell maturation block earlier required replacement therapy and were at significantly greater risk of enteropathy, granuloma formation, cytopenia, and lymphoproliferation. B-cell maturation inhibited at the natural effector stage was associated with higher risk of autoimmune manifestations other than autoimmune cytopenia. Prevalence of male patients was observed among patients with B-cell maturation inhibited at naïve B-cell stage. In conclusion, the diagnostic process in patients with suspected early-onset CVID shall include routine analysis of peripheral B-cell maturation to provide surrogate markers identifying patients at greater risk of developing certain complications.

Novel de novo large deletion in cystic fibrosis transmembrane conductance regulator gene results in a severe cystic fibrosis phenotype.

We identified c.1521_1523delCTT and c.1679+94_2619+986del8118 in trans in a 6-year-old boy with a severe cystic fibrosis phenotype. The first deletion was inherited maternally, but the latter had arisen de novo.

Progressive bronchiectasis and CMC in a patient with STAT1 GOF - a rare case of primary immunodeficiency.

Bronchiestasis is a common complication developing in patients with primary immunodeficiency disorders. AD GOF STAT1 defi-ciency is characterized by CMC, repeated infections, and autoimmunity. It is the most frequently diagnosed entity in a group of PIDs with CMC. Here, we present the first Polish case of a female patient with early-onset bronchiestasis accompanied by CMC and a severe course of infections who was genetically diagnosed with AD GOF1 STAT1 mutation at the age of 15.

Interstitial Lung Disease in Children With Selected Primary Immunodeficiency Disorders-A Multicenter Observational Study.

Primary immunodeficiencies (PIDs) are rare disorders of the immune system encompassing inborn errors of immunity. Primary antibody deficiencies constitute the largest group of PID with common variable immunodeficiency (CVID) being the most common symptomatic form. Combined immunodeficiencies (CID) accompanied by antibody deficiency can mimic CVID and these patients need the verification of the final diagnosis. Respiratory involvement, especially interstitial lung disease (ILD), poses a relevant cause of morbidity and mortality among patients with PID and in some cases is the first manifestation of immunodeficiency. In this study we present a retrospective analysis of a group of children with primary immunodeficiency and ILD - the clinical, radiological, histological characteristics, treatment strategies and outcomes. Eleven children with PID-related ILD were described. The majority of them presented CVID, in three patients CID was recognized. All patients underwent detailed pulmonary diagnostics. In eight of them histological analysis of lung biopsy was performed. We noted that in two out of 11 patients acute onset of ILD with respiratory failure was the first manifestation of the disease and preceded PID diagnosis. The most common histopathological diagnosis was GLILD. Among the analyzed patients three did not require any immunosuppressive therapy. All eight treated children received corticosteroids as initial treatment, but in some of them second-line therapy was introduced. The relevant side effects in some patients were observed. The study demonstrated that the response to corticosteroids is usually prompt. However, the resolution of pulmonary changes may be incomplete and second-line treatment may be necessary.

[The analyze of capability of biofilm synthesis by Staphylococcus aureus strains isolated from children with cystic fibrosis]. / Ocena wytwarzania biofilmu przez szczepy Staphylococcus a ureus izolowane od dzieci chorych na mukowiscydoze.

The aim of this study was to analyse the capability of biofilm synthesis by S. aureus isolates obtained from the respiratory tract of CF (cystic fibrosis) patients. A total of 297 S. aureus strains isolated from 33 CF patients, and 40 isolates obtained from healthy control children, were analysed. Extracellular slime production was determined using phenotypical methods (Congo red agar, and crystal violet) and molecular techniques (icaA and icaD genes amplification). All S. aureus strains possessed the icaA and icaD genes belonging to the operon responsible for slime synthesis. The isolates obtained from the respiratory tract of CS patients more frequently showed the ability to produce a biofilm than those from healthy individuals.

[The frequency of small colony variants of Staphylococcus aureus strains isolated from children with cystic fibrosis]. / Czestosc wystepowania fenotypów small colony variants wsród szczepów Staphylococcus aureus izolowanych od dzieci chorych na mukowiscydoze.

The aim of this study was to determine the frequency of spontaneous and inducible SCV formation in S. aureus isolates obtained from CF patients. A total of 297 S. aureus strains isolated from 33 CF patients, and 40 isolates obtained from healthy control children, were analysed. S. aureus was cultured on Columbia blood agar, Schaedler agar and Chapman agar under aerophilic and microaerophilic conditions. Subinhibitory gentamicin concentrations (1 mg/L) were used to test S. aureus ability to form SCVs. The study showed that the characteristic feature of S. aureus strains, persistently colonizing the airways of CS patients, was the formation of small colony variants. In the subinhibitory gentamicin concentration, S. aureus strains from CS patients formed SCVs more frequently (55%) than isolates from healthy subjects (20%). SCV formation in CF patients was associated with treatment with inhaled aminoglycosides.

[The analysis of the isolated microorganisms from the respiratory tract of cystic fibrosis patients treated in Children's Memorial Health Institute 1999-2002]. / Analiza drobnoustrojów izolowanych z dróg oddechowych chorych na mukowiscydoze leczonych w IP-CZD w latach 1999-2002.

The aim of the study was, to analyze the microorganisms cultured from materials from the airways of children with cystic fibrosis treated in the Children's Memorial Health Institute in Warsaw during 1999-2002. A total of 411 samples were tested, obtained from the airways of 58 patients with diagnosed mucoviscidosis. The age of the treated patients was within the range of 1 month and 20 years. The bacteriological tests were taken during routine visits in the Consultation and Pulmonology Clinic, which took place 3-4 times a year. The most often isolated strain was Staphylococcus aureus--48%. 17% of the isolates of Haemophilus influenzae and 13% of Pseudomonas aeruginosa were obtained. Most S. aureus, P. aeruginosa and H. infiuenzae isolates showed high susceptibility to tested antimicrobial agents. About 6% of all S. aureus isolates were resistant to methicillin (MRSA). S. aureus was occurring in all age groups with the same frequency. The rods H. influenzae were cultured more often from children under 10 years, while P. aeruginosa more often from older patients.

Apparent X-linked primary ciliary dyskinesia associated with retinitis pigmentosa and a hearing loss.

Three brothers, one 10-year-old and a pair of 14-year-old dizygotic twins--expressed the classical, early-onset retinitis pigmentosa (RP) with typical ophthalmoscopic findings, night blindness, visual field constricted to 10 degrees and flat ERG response. All three brothers were also diagnosed with primary ciliary dyskinesia (PCD) and had recurrent respiratory infections, chronic sinusitis and bronchiectasis. In all of them, resection of the middle lobe of the right lung was performed. A similar clinical picture of coexisting RP and PCD was noted in the brother of the probands' mother. All probands displayed situs solitus. Consistent with the X-linked mode of RP inheritance, there were also three obligatory female carriers of the disorder in this family: the mother of the affected boys, her mother and a daughter of her brother. In all of them, retinitis pigmentosa "sine pigmento" was found with milder but clinically significant symptoms (mild night blindness, visual field constricted to 30 degrees, and scotopic and photopic ERG responses reduced to 30-60%). No extraocular symptoms were detected in any of the heterozygous female carriers. This family presents an example of two rare phenomena: X-linked dominant retinitis pigmentosa (with milder expression in females) and a rare combination of RP with recurrent respiratory infections due to PCD.

Mutations in radial spoke head genes and ultrastructural cilia defects in East-European cohort of primary ciliary dyskinesia patients.

Primary ciliary dyskinesia (PCD) is a rare (1/20,000), multisystem disease with a complex phenotype caused by the impaired motility of cilia/flagella, usually related to ultrastructural defects of these organelles. Mutations in genes encoding radial spoke head (RSPH) proteins, elements of the ciliary ultrastructure, have been recently described. However, the relative involvement of RSPH genes in PCD pathogenesis remained unknown, due to a small number of PCD families examined for mutations in these genes. The purpose of this study was to estimate the involvement of RSPH4A and RSPH9 in PCD pathogenesis among East Europeans (West Slavs), and to shed more light on ultrastructural ciliary defects caused by mutations in these genes. The coding sequences of RSPH4A and RSPH9 were screened in PCD patients from 184 families, using single strand conformational polymorphism analysis and sequencing. Two previously described (Q109X; R490X) and two new RSPH4A mutations (W356X; IVS3_2-5del), in/around exons 1 and 3, were identified; no mutations were found in RSPH9. We estimate that mutations in RSPH4A, but not in RSPH9, are responsible for 2-3% of cases in the East European PCD population (4% in PCD families without situs inversus; 11% in families preselected for microtubular defects). Analysis of the SNP-haplotype background provided insight into the ancestry of repetitively found mutations (Q109X; R490X; IVS3_2-5del), but further studies involving other PCD cohorts are required to elucidate whether these mutations are specific for Slavic people or spread among other European populations. Ultrastructural defects associated with the mutations were analyzed in the transmission electron microscope images; almost half of the ciliary cross-sections examined in patients with RSPH4A mutations had the microtubule transposition phenotype (9+0 and 8+1 pattern). While microtubule transposition was a prevalent ultrastructural defect in cilia from patients with RSPH4A mutations, similar defects were also observed in PCD patients with mutations in other genes.

[Longitudinal study of children with bronchopulmonary dysplasia treated with disodium cromoglycate]. / Dlugofalowe obserwacje kliniczne dzieci z dysplazja oskrzelowo-plucna leczonych kromoglikanem dwusodowym.

In order to improve the quality of life of children born prematurely, who developed chronic lung disease, clinical trials of drugs of different origin are undertaken. The aim of the work was the evaluation of the efficacy of disodium cromoglycate in the treatment of bronchopulmonary dysplasia in children. We retrospectively studied 15 infants with bronchopulmonary dysplasia (BPD) hospitalised in the Infant Care Department of Children's Health Memorial Institute from 01.01.1997 to 01.02.2000. All babies were premature (25-30 weeks of gestation) with LBW or VLBW A control group of 11 babies with BPD, matched for birth weight and gestational age, who did not have disodium cromoglycate therapy were also studied. Recurrent obturative bronchitis and bronchial hyperresponsiveness were stated in all cases in both groups. Disodium cromoglycate was administered in all babies in the study group. Inhaled corticosteroid (Budesonide mite) was given in 10 cases, for a short period of time, due to severe obturative bronchitis. Babies in the control group were treated with systemic and inhaled corticosteroids. Results of our trial compared with the log-rank and chi2 test show statistically, significant differences in the regression of obturative bronchitis (log-rank = 4.35, p < 0.0001) and normalization of capillary blood-gas examination (log-rank = 3.777, p < 0.0002) in favour of the studied group, treated with disodium cromoglycate.