Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy

Abstract

Background: Motile cilia dysfunction causes primary ciliary dyskinesia (PCD), situs inversus totalis (SI), and a spectrum of laterality defects, yet the prevalence of laterality defects other than SI in PCD has not been prospectively studied.

Methods: In this prospective study, participants with suspected PCD were referred to our multisite consortium. We measured nasal nitric oxide (nNO) level, examined cilia with electron microscopy, and analyzed PCD-causing gene mutations. Situs was classified as (1) situs solitus (SS), (2) SI, or (3) situs ambiguus (SA), including heterotaxy. Participants with hallmark electron microscopic defects, biallelic gene mutations, or both were considered to have classic PCD.

Results: Of 767 participants (median age, 8.1 years, range, 0.1-58 years), classic PCD was defined in 305, including 143 (46.9%), 125 (41.0%), and 37 (12.1%) with SS, SI, and SA, respectively. A spectrum of laterality defects was identified with classic PCD, including 2.6% and 2.3% with SA plus complex or simple cardiac defects, respectively; 4.6% with SA but no cardiac defect; and 2.6% with an isolated possible laterality defect. Participants with SA and classic PCD had a higher prevalence of PCD-associated respiratory symptoms vs SA control participants (year-round wet cough, P < .001; year-round nasal congestion, P = .015; neonatal respiratory distress, P = .009; digital clubbing, P = .021) and lower nNO levels (median, 12 nL/min vs 252 nL/min; P < .001).

Conclusions: At least 12.1% of patients with classic PCD have SA and laterality defects ranging from classic heterotaxy to subtle laterality defects. Specific clinical features of PCD and low nNO levels help to identify PCD in patients with laterality defects.

Trial registry: ClinicalTrials.gov; No.: NCT00323167; URL: www.clinicaltrials.gov.

Figures

Figure 1 –

Examples of laterality defects on radiology imaging in various situs groups in the study population. A, A participant with situs solitus, or normal organ arrangement, with left cardiac apex, left-sided stomach bubble, and right-sided liver. B, A patient with situs inversus totalis, or mirror-image organ arrangement, with right-sided cardiac apex, right-sided stomach bubble, and left-sided liver. C, A patient with situs ambiguus with left-sided cardiac apex, right-sided stomach bubble, right-sided liver, and intestinal malrotation who also has right-sided polysplenia visualized on CT scan. C = cardiac apex; L = liver; M = intestinal malrotation; S = stomach.

Figure 2 –

Distribution of participants across laterality defect groups and situs ambiguus subgroups. CVM = cardiovascular malformation, EM = electron microscopic; nNO = nasal nitric oxide; PCD = primary ciliary dyskinesia.

Figure 3 –

Measurements of nNO in participants by final diagnosis group. Shown are nNO values by velum closure in participants with SA. Box plots show interquartile range, with median denoted by bold line. Whiskers denote minimum to maximum values. See Figure 2 legend for expansion of abbreviations.

Figure 4 –

Measurements of nNO in SA subgroups with classic primary cilia dyskinesia. Shown are nNO values by velum closure in participants with SA according to SA subgroup. Box plots show interquartile range, with median denoted by bold line. Whiskers denote minimum to maximum values. SA = situs ambiguus. See Figure 2 legend for expansion of other abbreviations.