Susan L. Minnix

Congenital Heart Disease and Other Heterotaxic Defects in a Large Cohort of Patients With Primary Ciliary Dyskinesia

Background— Primary ciliary dyskinesia (PCD) is a recessive genetic disorder that is characterized by sinopulmonary disease and reflects abnormal ciliary structure and function. Situs inversus totalis occurs in ≈50% of PCD patients (Kartagener’s syndrome in PCD), and there are a few reports of PCD with heterotaxy (situs ambiguus), such as cardiovascular anomalies. Advances in diagnosis of PCD, such as genetic testing, allow the systematic investigation of this association. Methods and Results— The prevalence of heterotaxic defects was determined in 337 PCD patients by retrospective review of radiographic and ultrasound data. Situs solitus (normal situs) and situs inversus totalis were identified in 46.0% and 47.7% of patients, respectively, and 6.3% (21 patients) had heterotaxy. As compared with patients with situs solitus, those with situs abnormalities had more ciliary outer dynein arm defects, fewer inner dynein arm and central apparatus defects (P<0.001), and more mutations in ciliary outer dynein arm genes (DNAI1 and DNAH5; P=0.022). Seven of 12 patients with heterotaxy who were genotyped had mutations in DNAI1 or DNAH5. Twelve patients with heterotaxy had cardiac and/or vascular abnormalities, and most (8 of 12 patients) had complex congenital heart disease. Conclusions— At least 6.3% of patients with PCD have heterotaxy, and most of those have cardiovascular abnormalities. The prevalence of congenital heart disease with heterotaxy is 200-fold higher in PCD than in the general population (1:50 versus 1:10 000); thus, patients with PCD should have cardiac evaluation. Conversely, mutations in genes that adversely affect both respiratory and embryological nodal cilia are a significant cause of heterotaxy and congenital heart disease, and screening for PCD is indicated in those patients.

High-Resolution CT of Patients with Primary Ciliary Dyskinesia

OBJECTIVE High-resolution CT is an important tool in the detection and management of bronchiectasis, but there is little information about high-resolution CT findings in primary ciliary dyskinesia (PCD). We analyzed all high-resolution CT studies of the chest available for a cohort of PCD patients to identify an associated pattern of high-resolution CT changes. MATERIALS AND METHODS High-resolution CT studies were available for 45 PCD patients from 42 families with ranges of age and disease severity. The images were assessed for severity and distribution of bronchiectasis, peribronchial thickening, mucous plugging, and other findings. A bronchiectasis severity score was calculated. CT findings were correlated with phenotypic findings, including situs type, ciliary ultrastructural defect, nasal level of nitric oxide, forced expiratory volume in 1 second, and microbiologic findings in the airways. RESULTS Twenty-nine adults (mean age, 42 +/- 15 years; age range, 21-73 years) and 16 children (mean age, 8 +/- 4 years; age range, 1-14 years) were included; 26 (58%) of the patients were women or girls. Situs inversus totalis (38%) or heterotaxy (18%) was identified in 56% of the patients. A high (9%) prevalence of pectus excavatum was identified. High-resolution CT of all of the adult and 56% of the pediatric patients showed bronchiectasis in a predominantly middle and lower lobe distribution. The right middle lobe was most commonly involved. Bronchiectasis severity score correlated with older age and worse pulmonary function. CONCLUSION High-resolution CT shows that pulmonary disease related to PCD predominantly involves the middle and lower lobes of the lungs. In adults, high-resolution CT findings negative for bronchiectasis may have a role in excluding the diagnosis of PCD. Correlation of severity of disease on high-resolution CT with patient phenotype gives further insight into the diversity and natural history of PCD.

Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure

Rationale Primary ciliary dyskinesia (PCD) is an autosomal recessive, genetically heterogeneous disorder characterised by oto-sino-pulmonary disease and situs abnormalities (Kartagener syndrome) due to abnormal structure and/or function of cilia. Most patients currently recognised to have PCD have ultrastructural defects of cilia; however, some patients have clinical manifestations of PCD and low levels of nasal nitric oxide, but normal ultrastructure, including a few patients with biallelic mutations in dynein axonemal heavy chain 11 (DNAH11). Objectives To test further for mutant DNAH11 as a cause of PCD, DNAH11 was sequenced in patients with a PCD clinical phenotype, but no known genetic aetiology. Methods 82 exons and intron/exon junctions in DNAH11 were sequenced in 163 unrelated patients with a clinical phenotype of PCD, including those with normal ciliary ultrastructure (n=58), defects in outer and/or inner dynein arms (n=76), radial spoke/central pair defects (n=6), and 23 without definitive ultrastructural results, but who had situs inversus (n=17), or bronchiectasis and/or low nasal nitric oxide (n=6). Additionally, DNAH11 was sequenced in 13 subjects with isolated situs abnormalities to see if mutant DNAH11 could cause situs defects without respiratory disease. Results Of the 58 unrelated patients with PCD with normal ultrastructure, 13 (22%) had two (biallelic) mutations in DNAH11; and two patients without ultrastructural analysis had biallelic mutations. All mutations were novel and private. None of the patients with dynein arm or radial spoke/central pair defects, or isolated situs abnormalities, had mutations in DNAH11. Of the 35 identified mutant alleles, 24 (69%) were nonsense, insertion/deletion or loss-of-function splice-site mutations. Conclusions Mutations in DNAH11 are a common cause of PCD in patients without ciliary ultrastructural defects; thus, genetic analysis can be used to ascertain the diagnosis of PCD in this challenging group of patients.