A Study on the Genetics of Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is a poorly understood disorder. It is primarily autosomal recessive and is prevalent in tribal communities of the United Arab Emirates due to consanguineous marriages. This retrospective study aimed to assess the pathogenicity of the genetic variants of PCD in indigenous patients with significant clinical respiratory problems. Pathogenicity scores of variants obtained from the chart review were consolidated using the Ensembl Variant Effect Predictor. The multidimensional dataset of scores was clustered into three groups based on their pathogenicity. Sequence alignment and the Jensen-Shannon Divergence (JSD) were generated to evaluate the amino acid conservation at the site of the variation. One-hundred and twelve variants of 28 genes linked to PCD were identified in 66 patients. Twenty-two variants were double heterozygous, two triple heterozygous, and seven homozygous. Of the thirteen novel variants, two, c.11839 + 1G > A in dynein, axonemal, heavy chain 11 (DNAH11) and p.Lys92Trpfs in dynein, axonemal, intermediate chain 1 (DNAI1) were associated with dextrocardia with situs inversus, and one, p.Gly21Val in coiled-coil domain-containing protein 40 (CCDC40), with absent inner dynein arms. Homozygous C1orf127:p.Arg113Ter (rs558323413) was also associated with laterality defects in two related patients. The majority of variants were missense involving conserved residues with a median JSD score of 0.747. Homology models of two deleterious variants in the stalk of DNAH11, p.Gly3102Asp and p.Leu3127Arg, revealed structural importance of the conserved glycine and leucine. These results define potentially damaging PCD variants in the region. Future studies, however, are needed to fully comprehend the genetic underpinnings of PCD.

Epidemiology of Bronchiolitis in Hospitalized Infants at Tawam Hospital, Al Ain, United Arab Emirates.

BACKGROUND: Bronchiolitis is the commonest lower respiratory tract infection, found worldwide in children < 2 years of age. Over sixty percent of cases are caused by Respiratory Syncytial Virus (RSV). The disease is known to have significant morbidity, mortality and health care costs. Its seasonal variability, manifestations and complications vary between countries. The aim of this study was to determine the epidemiological and clinical characteristics of infants hospitalized with bronchiolitis in Al Ain City, United Arab Emirates. METHODS: Retrospective observational chart review was made of an unselected cohort of infants ≤ 2 years admitted to the pediatric department of Tawam hospital over a 3-year period and discharged with the diagnosis of bronchiolitis. Epidemiological data and risk factors were analyzed. RESULTS: RSV was the commonest pathogen (51%). Hospitalizations occurred year-round but increased significantly in December and January. The patients' median age was 5.8 months with a male predominance (male:female ratio of 1.5:1.0). The mean age at admission was 6.6 months and presentation occurred, on average, 2.9 days after the onset of the symptoms. The majority (94%) had respiratory distress on presentation. Chest x-ray was performed in 80% of the patients. Most children received bronchodilator therapy and oxygen therapy was administered to 42%. The mean duration of hospital stay was 3 days. CONCLUSION: Bronchiolitis remains a common reason for hospital admission and carries significant morbidity. RSV is the primarily responsible virus for hospital admissions and morbidity.A better understanding of the burden of bronchiolitis in our setting would enable better planning and use of hospital resources to minimize its short and long-term sequelae.

Genetic variants of small airways and interstitial pulmonary disease in children.

Genetic variants of small airways and interstitial pulmonary disease have not been comprehensively studied. This cluster of respiratory disorders usually manifests from early infancy ('lung disease in utero'). In this study, 24 variants linked to these entities are described. The variants involved two genes associated with surfactant metabolism dysfunction (ABCA3 and CSF2RB), two with pulmonary fibrosis (MUC5B and SFTP), one with bronchiectasis (SCNN1B), and one with alpha-1-antitrypsin deficiency (SERPINA1). A nonsense variant, MUC5B:c.16861G > T, p.Glu5621*, was found in homozygous state in two siblings with severe respiratory disease from birth. One of the siblings also had heterozygous SFTPA1:c.675C > G, p.Asn225Lys, which resulted in a more severe respiratory disease. The sibling with only the homozygous MUC5B variant had lung biopsy, which showed alveolar simplification, interstitial fibrosis, intra-alveolar lipid-laden macrophages, and foci of foreign body giant cell reaction in distal airspaces. Two missense variants, MUC5B:c.14936 T > C, p.Ile4979Thr (rs201287218) and MUC5B:c.16738G > A, p.Gly5580Arg (rs776709402), were also found in compound heterozygous state in two siblings with severe respiratory disease from birth. Overall, the results emphasize the need for genetic studies for patients with complex respiratory problems. Identifying pathogenic variants, such as those presented here, assists in effective family counseling aimed at genetic prevention. In addition, results of genetic studies improve the clinical care and provide opportunities for participating in clinical trials, such as those involving molecularly-targeted therapies.

Genetic variants in children with chronic respiratory diseases.

Founder mutations and autosomal recessive (AR) disorders are common in the Arabian Peninsula due to frequent consanguineous marriages. As a result, the pulmonary service at Tawam Hospital (Al Ain, UAE) routinely requests genetic testing for children with persistent (unexplained) respiratory problems. The main purpose of this report was to underscore the usefulness of these tests. Ten children with severe respiratory diseases due to complex genetic findings are described here. Forty-one variants (six novel) were detected, averaging four per patient (range: 1-9). Seven (17%) variants were homozygous and 34 (83%) heterozygous; some variants were known to show monoallelic expression. Using binomial probability distribution, the fetal-risk for having AR disorder(s) as a function of the number of shared variants by a couple ranged from 0.25 (having one shared variant) to 0.9249 (having nine shared variants). In cultures where increased size of homozygous genomic segments is common, children often have multiple variants that could cause complex clinical phenotypes. Identifying pathogenic variants assists in clinical care, family counseling, and disease prevention through genetic screening.

Cross-sectional study assessing the performance of the Arabic translated childhood asthma control test.

The standard Arabic version of the Childhood Asthma Control Test (C-ACT) has never been previously evaluated in Arab countries. We studied its correlation in Arabic speaking children in the United Arab Emirates (UAE), with both the GINA assessment of asthma control and the resulting changes in asthma management. The Arabic C-ACT was completed by the children or by their parents when needed. A GINA based level of asthma control score was assigned by their managing physician. The correlation between the different cut- scores of the C-ACT and GINA were studied. A total of 105 eligible children with asthma (aged between 4 and 11.8 years, 61% boys) were enrolled. The Arabic translated C-ACT had a high reliability (Cronbach alpha 81%) and validity (as it correlated well with the GINA level of control). We found that using it with the traditional cut-score of 19 overestimated the degree of asthma control. Instead, a calculated optimal cut-score of 20 estimated more accurately the level of asthma control as assessed both by the GINA assessment and also by changes in asthma management. The current Arabic version of the C-ACT has a good reliability and validity. By using a single optimal cut-point of 20, it can be used to assess both the level of asthma control and of treatment control. It does not, however, accurately define asthma control when using the originally proposed cut-score of 19. Physicians need to recognise that the C-ACT cut-points may vary in different populations. We suggest that cut-scores of translated versions need to be modified in different geographical settings.

Hypotonia, developmental delay and features of scalp-ear-nipple syndrome in an inbred Arab family.

We report two children from an inbred Arab family with features suggestive of scalp-ear-nipple syndrome who in addition had severe hypotonia and developmental delay. Also addition, other features seen in scalp-ear-nipple syndrome such as camptodactyly, syndactyly and dry skin were absent in these children. We suggest the children in this report have a severe recessive form of this syndrome.

Gas trapping in normal infants and in infants with cystic fibrosis.

Two different methods for estimating trapped gas volume have been described in the literature. The purpose of this study was to use both of these methods to estimate and compare trapped gas volumes in normal infants and infants with cystic fibrosis (CF). Thirty normal infants and 29 infants with CF, ages 1 month to 3 years, were studied. Pulmonary function tests, including raised volume forced expiratory flows, plethysmographic functional residual capacity (FRC(pleth)), and fractional lung volumes, were measured. Then functional residual capacity was measured by nitrogen washout (FRC(nitrogen)). Following nitrogen washout, lungs were then inflated three times to 30 cm H(2)O, using 100% oxygen. This process was repeated until no further nitrogen could be washed from the lungs. The volume of trapped gas (tg) was calculated from the total additional amounts of nitrogen expired following lung inflations. The difference between FRC(pleth) and FRC(nitrogen) provided a second estimate of trapped gas volume (delta V). Mean tg and delta V values for normal infants were 2.5 +/- 3.5 ml and 15.6 +/- 30.4 ml, respectively. Mean tg and delta V values for infants with CF were 5.8 +/- 7.7 ml and 33.2 +/- 43.8 ml, respectively. Both tg and delta V did not differ significantly between normal infants and infants with CF. Measured following raised volume forced expiratory maneuvers, delta V and tg do not distinguish infants with CF from normal infants as well as do other currently available tests of infant lung function.