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Primary ciliary dyskinesia (PCD) is a rare disorder of motile cilia associated with situs abnormalities. At least 12% of patients with PCD have situs ambiguus (SA), including organ laterality defects falling outside normal arrangement (situs solitus [SS]) or mirror image inversion (situs inversus totalis [SIT]). Do patients with PCD and SA achieve worse clinical outcomes compared with those with SS or SIT? This cross-sectional, multicenter study evaluated participants aged 21 years or younger with PCD. Participants were classified as having SA, including heterotaxy, or not having SA (SS or SIT). Markers of disease severity were compared between situs groups, adjusting for age at enrollment and severe CCDC39 or CCDC40 genotype, using generalized linear models and logistic and Poisson regression. In 397 participants with PCD (mean age, 8.4 years; range, 0.1-21), 42 patients were classified as having SA, including 16 patients (38%) with complex cardiovascular malformations or atrial isomerism, 13 patients (31%) with simple CVM, and 13 patients (31%) without cardiovascular malformations. Of these, 15 patients (36%) underwent cardiac surgery, 24 patients (57%) showed an anatomic spleen abnormality, and seven patients (17%) showed both. The remaining 355 participants did not have SA, including 152 with SIT and 203 with SS. Overall, 70 participants (17%) harbored the severe CCDC39 or CCDC40 genotype. Compared with participants without SA, those with SA showed lower median BMI z scores (P =.03), lower FVC z scores (P =.01), and more hospitalizations and IV antibiotic courses for acute respiratory infections during the 5 years before enrollment (P <.01). Participants with cardiovascular malformations requiring surgery or with anatomic spleen abnormalities showed lower median BMI z scores and more hospitalizations and IV therapies for respiratory illnesses compared with participants without SA. Children with PCD and SA achieve worse nutritional and pulmonary outcomes with more hospitalizations for acute respiratory illnesses than those with SS or SIT combined. Poor nutrition and increased hospitalizations for respiratory infections in participants with SA and PCD are associated with cardiovascular malformations requiring cardiac surgery, splenic anomalies, or both. ClinicalTrials.gov; Nos.: NCT02389049 and NCT00323167; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Otitis media with effusion (OME) in children with primary ciliary dyskinesia (PCD) is recurrent and persistent and presents a complex clinical problem for otolaryngologists. We sought to review the otological presentation of children with PCD treated medically and surgically and to compare audiological outcomes and complications of surgical and medical management in children with PCD and correlate these findings with known PCD ultrastructural ciliary phenotype. Methods: A retrospective review was performed of all patients with PCD and OME presenting from 1991 to 2009. Patients were grouped into “medical management” and “ventilation tube (VT) insertion” groups to observe changes in hearing and post-operative complications. Results: Of 31 patients with PCD and OME, 20 received VTs and 11 were treated by medical management strategies. A median of one set of VTs (range 1–5) were inserted per patient. Hearing thresholds improved to normal (<25dB HL) in 80% ears with VTs (mean improvement from 27.1dB to 22.1dB (p =0.034)), whereas patients managed medically had stable thresholds (22.7–23.6dB (p =0.397) over the study period. At least one episode of post-operative otorrhea occurred in eight (42.1%) VT insertion patients during the study period, and four had multiple episodes. We could not demonstrate any differences in post-surgical outcomes between patient groups based on ultrastructural ciliary phenotype. Otorrhea was well controlled with medical therapy with only one requiring tube removal. Bilateral cholesteatoma was found in two patients. Conclusions: Our data support the use of VT insertion as an option for patients with PCD and OME with mild to moderate hearing loss. Patients should be counseled on the possibility of multiple insertions and the likelihood of post-operative otorrhea, although this was not very troublesome in our group. Ultrastructural ciliary phenotype did not appear to alter the likelihood of post-operative otorrhea in our series. Cholesteatoma should be considered as a potential cause of otorrhea in PCD. [Copyright &y& Elsevier]

Primary ciliary dyskinesia (PCD) is an autosomal-recessive disorder resulting from loss of normal ciliary function. Symptoms include neonatal respiratory distress, chronic sinusitis, bronchiectasis, situs inversus, and infertility. Clinical features may be subtle and highly variable, making the diagnosis of PCD challenging. The diagnosis can be confirmed with ciliary ultrastructure analysis and/or molecular genetic testing of 32 PCD-associated genes. However, because of this genetic heterogeneity, comprehensive molecular genetic testing is not considered the standard of care, and the most efficient molecular approach has yet to be elucidated. Here, we propose a cost-effective and time-efficient molecular genetic algorithm to solve cases of PCD. We conducted targeted copy number variation (CNV) analysis and/or whole-exome sequencing on 20 families (22 patients) from a subset of 45 families (52 patients) with a clinical diagnosis of PCD who did not have a molecular genetic diagnosis after Sanger sequencingof12PCD-associatedgenes. This combined molecular genetic approach led to the identification of 4 of 20 (20%) families with clinically significant CNVs and 7 of 20 (35%) families with biallelic pathogenic mutations in recently identified PCD genes, resulting in an increased molecular genetic diagnostic rate of 55% (11/20). In patients with a clinical diagnosis of PCD, whole-exome sequencing followed by targeted CNV analysis results in an overall molecular genetic yield of 76% (34/45). [ABSTRACT FROM AUTHOR]

Motile cilia are cellular beating machines that play a critical role in mucociliary clearance, cerebrospinal fluid movement, and fertility. In the airways, hundreds of motile cilia present on the surface of a multiciliated epithelia cell beat coordinately to protect the epithelium from bacteria, viruses, and harmful particulates. During multiciliated cell differentiation, motile cilia are templated from basal bodies, each extending a basal foot—an appendage linking motile cilia together to ensure coordinated beating. Here, we demonstrate that among the many motile cilia of a multiciliated cell, a hybrid cilium with structural features of both primary and motile cilia is harbored. The hybrid cilium is conserved in mammalian multiciliated cells, originates from parental centrioles, and its cellular position is biased and dependent on ciliary beating. Furthermore, we show that the hybrid cilium emerges independently of other motile cilia and functions in regulating basal body alignment. • Multiciliated cells contain a hybrid cilium with features of primary and motile cilium • The hybrid cilium originates from parental centriole • The hybrid cilium position is biased toward the cilia beating direction • The hybrid cilium functions in basal body alignment Liu, Nguyen et al. show that among hundreds of cilia of a multiciliated cell, there is one that differs from the others in structure, origin, and cellular position, and it participates in basal body alignment. [ABSTRACT FROM AUTHOR]