Expanding spectrum of ciliopathy beyond the airway
Andrew Bush MB BS (Hons) MA MD FRCP FRCPCH
Professor of Paediatric Respirology, Imperial School of Medicine at National Heart and Lung
Institute; and Honorary Consultant Paediatric Chest Physician, Royal Brompton Hospital.
Correspondence: Department of Paediatric Respiratory Medicine, Royal Brompton Hospital,
Sydney Street, London SW3 6NP, UK.
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Tel: -207-351-8232
Fax: -207-351-8763
e mail:- a.bush@rbh.nthames.nhs.uk
Abstract Primary ciliary dyskinesia (PCD)is characterised by chronic upper and lower respiratory tract
infection, and in nearly 50% of cases, mirror image arrangement. This is the archetypal ciliary
disease, but it is now clear that it is part of a wide spectrum. Clinical features now recogised as
intrinsic components of PCD include heterotaxy and complex congenital heart disease, oesophageal
disease and primary ciliary dyskinesia. It is dysfunction of motile cilia that is responsible for the
clinical manifestations of PCD, but malfunction of primary and nodal cilia is also important. The
complexities of ciliary structure and function are only beginning to be appreciated; primary cilia may
have mechano- and chemosensory functions as well as possibly secretory, through the illunderstood process of intraflagellar transport. Dysfunction of nodal cilia is implicated in cystic
disease in particular of the kidneys and liver. Ciliary dysfunction is important in the pathophysiology
of retinitis pigmentosa, Jeune’s asphyxiating thoracic dystrophy, and complex neurodevelopmental,
sketal and other multisystem syndromes. This review covers PCD, as well as acting as an introduction
to the many complex conditions caused by underlying ciliary dysfunction.
Keywords: cilia, heterotaxy, bronchiectasis, congenital heart disease, polycystic kidney disease,
retinitis pigmentosa
The initial description of ciliopathy was the triad of sinusitis, bronchiectasis and situs inversus
(Kartagener’s syndrome). The structure and genetics of cilia, and the upper and lower airway
manifestations of ciliopathy (primary ciliary dyskinesia, PCD) have been described in previous
presentations and elsewhere [1,2]. It is clear that PCD is only the tip of the iceberg of ciliary diseases.
The purpose of this presentation is briefly to review the standard manifestations of PCD; to review
the expanding spectrum of other manifestations of PCD; and to discuss other diseases related to
ciliary dysfunction. If nitric oxide was the molecule of the 1990s, cilia are clearly the structures of the
new millennium.
Nomenclature of the different types of cilia
Primary cilia (which confusingly are not the root cause of PCD) are solitary structures widely
distributed in epithelial cells. Their primary structure is nine outer doublets, but no inner pair. The
structure may vary along the axoneme, and there may be regions with central singlets. They are
probably mechano- or chemo-sensors, and are not motile. They arise from a proximal and distal
centriole. They are found on the vast majority of non-mitotic cells in the body [3].
Nodal cilia overlap between primary and motile cilia. They are responsible for determining situs in
the developing embryo [4]. They are structurally primary in type (no central pairs), but unlike other
primary cilia, some are motile. There are also sensory cilia within the embryonic node.
Motile cilia are responsible either for propelling unicellular organisms through liquids (e.g.
chlamydomonas) or moving mucus along epithelial surfaces. These are the cilia which are abnormal
in PCD. They are complex structure, with nine outer doublets and an inner pair, containing more
than 200 proteins [5]. Key structures are the inner and outer dynein arms, which are
mechanochemical ATPases, similar in function to myosin and kynesin, and radial spokes and nexin
links. The complexity of these structures means that there are likely many PCD genes. Human
locations of cilia are listed at http://members.global2000.net/bowser/cilialist.htm/; they are widely
distributed in the plant and animal kingdoms. The human rods and cones of the retina, sperm tails
and olfactory cells are related human structures.
Intraflagellar transport
In addition to the functions described above, the complex processes of intraflagellar transport are
being discovered. The purpose of this complex process is not clear, but may relate to ciliary nutrition
[6,7]. It has been suggested this may be a ciliary secretory function [8]. It is linked to ciliary signalling
pathways via sonic hedgehog in particular [9], but this is also not well defined. ‘A’ and ‘B’ rafts are
moved anterogradely to the ciliary tip, and retrogradely to the base of the cilia. Mutations in A and B
raft genes lead to short, stumpy cilia. There is a link to Jeune’s asphyxiating thoracic dystrophy
(below).
PCD: airway manifestations
The classical phenotype of PCD is of upper and lower airway disease, with, in around 50% of cases,
mirror image arrangement. The presentation and diagnosis of PCD have been reviewed in detail
[1,2], and are summarised in Tables 1 and 2 respectively. Absolutely essential in the diagnostic
process is to ensure that ciliary abnormalities secondary to infection are not mis-diagnosed as PCD. If
there is any doubt, and in atypical cases, testing should be repeated a few months later. Typically
there are combinations of upper and lower airway disease; isolated cough is rarely due to PCD. The
diagnosis is frequently delayed into adult life [10], probably because many of the symptoms (cough,
rhinitis, chronic serous otitis media) are very common in otherwise normal children [11]. There is a
spectrum; mild disease may be diagnosed in apparently well siblings after the finding of PCD in an
index case [10]. This means that there is often substantial impairment of lung function [12];
stabilisation can be achieved [12, 13], but significant and sustained improvement is rare. Established
bronchiectasis is frequently found in children diagnosed late. Thus diagnostic vigilance is essential,
and this usually has to rely on a carefully focussed history and clinical examination.
Treatment is empirical, and largely based on cystic fibrosis (CF) protocols. This is not logical, given
the different pathophysiology (ciliary dysfunction versus airway surface dehydration [14]), and
indeed, treatments such as rhDNase which are very effective in CF, may be useless or even harmful
in other chronic chest conditions [15]. Lower respiratory tract treatment is by combinations of
airway clearance techniques [13]; early on Staphylococcus aureus and Haemophilus influenza are
common. Isolates of these orhanisms are treated with a 2-4 week course of an appropriate oral
antibiotic such as Augmentin. Repeated isolates merit consideration of prophylactic antibiotics, and
symptoms non-responsive to oral therapy are treated with intravenous antibiotic. Mucoid and nonmucoid strains of Pseudomonas aeruginosa and atypical Mycobacteris species are not usually seen
until adult life. Most centres use eradication protocols for Pseudomonas similar to CF, and also use
chronic suppressive nebulised antibiotics if infection has become established. Intravenous antibiotics
are used as needed, usually a combination of an aminoglycoside and a third generation
cephalosporin. The management of atypical Mycobacteria is complex in CF; there is even less
evidence in PCD.
The treatment of the upper airway complications is significantly different from what might be
expected [16]. Secretory otitis media is treated conservatively – the placement of tympnostomy
tubes almost invariably leads to prolonged otorrhea with no improvement of hearing. Long-term,
improvement can be anticipated, and hearing loss is minimal [17]. If hearing is problematic in PCD
patients, then a short period of the use of hearing aids may be needed, but these are usually able to
be discarded in the teenage years. Sinusitis is also managed conservatively where possible. Nasal
polyps are very rare in PCD, in my experience. The management of PCD has recently been reviewed
in detail [1, 2].
PCD: more than just an airway disease
The spectrum of PCD has been extended to include hydrocephalus (a rare manifestation), infertility,
and heterotaxy and complex congenital heart disease [18]. Hydrocephalus is seen more commonly in
animal models of PCD; there are cilia bathed in cerebrospinal fluid, but their function is not clear.
Sperm tails may be immotile in men with PCD, but this is not inevitable [19]. There is said to be a
higher prevalence of ectopic pregnancy in women with PCD due to immotility of cilia in the Fallopian
tubes [20]. In terms of heterotaxy, a large series (n=337) of PCD patients [18], 46% had usual organ
arrangement, 48% had mirror image, and 6% (21/337) had disorders of heterotaxy (including n=1
right isomerism with asplenia, n=11 left isomerism with polyspenia). Complex congenital heart
disease was seen in 8 patients, and there was a 200-fold higher prevalence than normal of complex
congenital heart diease in PCD with heterotaxy, an overall prevalence of one in fifty. Complex
congenital heart disease was particularly common in the presence of outer dynein arm defects
(especially DNAH1 and DNAI5). Therefore it is essential to remember PCD in the context of
congenital heart disease with laterality disorder, and screen for PCD if there is the least suspicion of
associated respiratory disorders.
Taken together, the facts that nodal cilia are responsible for situs, and ciliary dysfunction affects
cardiac structure, presumably due to motility effects during the development of the heart, one could
speculate that other organ malpositions, in particular gastrointestinal malrotation, may be an effect
of ciliary dysfunction. Indeed, malrotation is associated with right and left isomerism [21], and we
have described malrotation and a gastrointestinal motility disorder in a cilipathy related condition,
Jeune’s asphyxiating thoracic dystrophy (below). In this regard, the finding of disordered neural crest
migration and Hirschprung’s disease in Bardet-Biedl syndrome lends support to the hypothesis that
gastrointestinal motility disorders may in part be cilia related [22].
Another co-morbidity, which should prompt exclusion of PCD, is biliary atresia [23]. Although mild to
moderate gastro-oesophageal reflux is common in many respiratory diseases, there seems to be an
increased risk of really severe reflux, and other oesophageal disease, in PCD [24]. Whether there is
an oesophageal motility disorder in PCD has yet to be determined.
Spectrum of disorders of primary cilia
As might be expected given their wide distribution, there are many manifestations of disorders of
primary cilia. There is a wide spectrum of liver and kidney cystic syndromes [25], of varying disease
severity, and retinal involvement, anosmia, obesity, ataxia and other central nervous system
abnormalities, and skeletal dysplasias are all described as part of this spectrum. Many syndromes
are rare and beyond the scope of this manuscript, the more important will briefly be described
below and see Table [26].
Renal manifestations of ciliopathy include adult and juvenile onset polycystic kidney disease, and
nephronophthisis. The mechanisms linking ciliary dysfunction and cyst formation are unknown,
although the WNT signalling pathway is implicated [27]. There is also a fascinating link between
kidney disease and bronchiectasis [28]. Polycystin is found in the human respiratory epithelium,
although its function there is not known. In a comparison between nearly 100 adult polycystic kidney
patients and 100 other renal disease patients, the prevalence of bronchiectasis was 37% in the
polycystics versus 1: in the non-cystic kidney patients, p=0.0022. However, 13% prevalence of
bronchiectasis in the control group is much higher than could be expected by chance. It has been
suggested that this might be related to the newly described primary cilia in airway smooth muscle
cells [29]. Whatever the explanation, it is suggested that bronchiectasis should be excluded in any
renal patient with respiratory symptoms. Cilia connect the inner and outer retinal photoreceptor
neurones. There are many syndromes which include retinitis pigmentosa, with involvement of other
organ systems common. We are following a family in which the father has retinitis pigmentosa and
the two children have PCD. A number of similarly poly-phenotypic kindreds have been described
[30-2]. Jeune asphyxiating thoracic dystrophy is an autosomal-recessive chondrodysplasia
characterized by short ribs and a narrow thorax, short long bones, inconstant polydactyly, and
trident acetabular roof. It is closely related to the short rib polydactyly syndrome (SRP) type III,
which is a more severe condition characterized by early prenatal expression and lethality and
variable malformations. Jeune’s asphyxiating thoracic dystrophy has been known to be associated
with abnormalities of situs. Recently, Jeune’s was found to be associated with abnormalities in the
IFT80 gene on chromosome 3 [33]. This is a poorly understood gene, which is concerned in
intraflagellar transport. More recently, a Jeune’s gene to was mapped to chromosome 11q14.3q23.1 in a 20.4 Mb region and identified as the cytoplasmic dynein 2 heavy chain 1 (DYNC2H1) gene
[34]. DYNC2H1 is a component of a cytoplasmic dynein complex and is directly involved in the
generation and maintenance of cilia. Polydactyly, renal degeneration and renal cysts have also been
described in this condition. We have described a child with Jeune’s syndrome, malrotation and gut
dysmotility, hypothesising that these last two features may be a feature of ciliopathy [35].
Ciliopathy: the future
Clearly, ciliary disease has come a long way from the days of Kartagener! Ciliopathy is a rapidly
expanding multisystem condition. We are good at investigating the function of motile cilia in the
respiratory tract, but it cannot be assumed that anormalities in primary and nodal cilia are
necessarily related to motile cilia. Indeed, patients with PCD and motile sperm have been described,
underscoring the variability within cilia-like structures. We urgently need new tests of ciliary
function, particularly primary cilia. In the meantime, when seeing a child with a multisystem disease,
it is worth asking ‘could this be another ciliopathy?’
Table 1. Clinical manifestations of PCD
Age
Classical Manifestations
Antenatal
Mirror image arrangement on antenatal
ultrasound (not diagnostic)
Newborn
period
Respiratory distress
Rhinitis
Positive family history
Childhood
Atypical ‘asthma’
Chronic productive cough
Bronchiectasis
Severe gastro-oesophageal reflux
Rhinosinusitis
Chronic secretory otitis media
After diagnosis in a relative
As for childhood
Male infertility
Ectopic pregnancy
Adulthood
Non-Classical Manifestations
Heterotaxy on antenatal ultrasound
Complex congenital heart disease on
ultrasound
Heterotaxy
Complex congenital heart disease
Biliary atresia
Oesophageal disease
Table 2. Summary of diagnostic testing for PCD
Screening for PCD
Ciliary function
Ciliary structure
Ciliary culture [42]
Genetic studies [5]
Immunohistochemistry [43]
Saccharine test [36]
Radionuclide scanning [37]
Nasal nitric oxide (less well established in young
children) [38-40]
Ciliary beat frequency and pattern [2]
Transmission electron microscopy [2, 41]
Only needed if clinical doubt
Many genes as yet undiscovered
Only limited availability
Table 3: The common associations of clinical features in five ciliary dysfunction syndromes [44, 45]
Disease
Retinitis pigmentosa
Renal cystic disease
Polydactyly
Situs inversus/isomerism
Mental retardation/developmental delay
Hypoplasia of the corpus callosum
Dandy-Walker mallformation
Posterior encephalocele
Hepatic disease
Total number of phenotypes in each disorder
* In mice.
BBS
√
√
√
√
√
√
√
√*
√
8
OFD1
√
√
Senior-Loken
√
√
√
√
√
√
√*
5
√
5
Meckel Joubert
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
9
9
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