Severe disease due to CCDC40 gene variants and the perils of late diagnosis in primary ciliary dyskinesia

Abstract

Primary ciliary dyskinesia (PCD) can manifest in the neonatal period with severe respiratory distress. We describe a child with PCD who presented at term with severe neonatal respiratory distress, persistent right upper lobe collapse and failure to thrive who underwent lobectomy prior to the diagnosis of PCD at the age of 3 years. This case report illustrates the severe spectrum of lung disease associated with coiled-coil domain containing protein 40 (CCDC40) gene variants in patients with PCD.

Background

Primary ciliary dyskinesia (PCD) is a rare genetic disease affecting the ciliary structures and/or function. The inheritance pattern is autosomal recessive, with rare cases described to have X linked inheritance. To date, there are over 40 genes known to cause PCD, and more genes are expected to be discovered.^{1 2}

The spectrum of lung disease severity varies by the causative gene. Five genes, dynein axonemal heavy chain 5 and 11 (DNAH5 and DNAH11), dynein intermediate chain 1 (DNAI1), coiled- coil domain containing protein 39 and 40 (CCDC39 and CCDC40) cause more than 50% of genetically defined PCD in North America and Europe.³ Patients with PCD caused by pathogenic variants in the CCDC39 and CCDC40 genes count for about 12% of PCD cases and have more severe lung disease in comparison to patients with PCD caused by other genes.

The clinical manifestations usually present early in life with unexplained neonatal respiratory distress, lobar collapse and oxygen requirement.⁴ Chronic wet cough and rhinorrhoea develop during infancy.⁵ During childhood, recurrent pneumonia, otitis media, sinusitis and hearing loss occurs frequently. About half of children with PCD are born with organ laterality defects. By adulthood, most subjects with PCD have bronchiectasis, and male infertility is common. Progressive bronchiectasis is a major cause of morbidity and mortality, with some patients requiring lung transplantation for end-stage lung disease by mid-adulthood.

We present a child with PCD due to a homozygous pathogenic variant in the CCDC40 gene, who presented with unexplained term neonatal respiratory distress, no laterality defects, failure to thrive and persistent right upper lobe collapse. A delayed diagnosis of PCD resulted in no PCD management strategy being initiated, and a lobectomy being performed in infancy. Paediatricians should recognise the clinical manifestations of PCD in the neonatal period and early childhood in order to diagnose the condition early, to initiate therapy, prevent progression of lung disease and to avoid unnecessary interventions such as lobectomy.

Case presentation

A full-term female infant was born to a 29-year-old G3P2 Pakistani consanguineous parents after regular perinatal care in a community hospital. The pregnancy and delivery were uncomplicated; birth weight was 2745 g, and Appearance, Pulse, Grimace, Activity and Respiration (APGAR) scores were 9 at both 5 and 10 min. At 2 hours of life, she was noted to be tachypneic and hypoxic. Oxygen therapy was initiated (28%–40% FiO2), and eventually she needed continuous positive airway pressure for respiratory failure. Her chest X-ray showed right upper lobe collapse as well as hyperinflation and infiltrates in the left upper lobe (figure 1). She was treated with intravenous ampicillin and gentamicin for congenital pneumonia with no improvement. On day 3 of life, she had required intubation and mechanical ventilation for hypoxic respiratory failure. A chest CT scan done while intubated showed marked atelectasis of the right upper lobe and posterior–basilar segments of left lower lobe. Bronchoscopy was done, and a right-sided accessory bronchus (tracheal bronchus) was reported. Sweat chloride and an alpha-1-antitrypsin testing were negative. Congenital heart disease was ruled out with a normal echocardiogram.

Figure 1.

Chest X-ray at 11 days of age showing right upper lobe collapse, diffuse hyperinflation and infiltrates in the left upper lobe. Note that infant is intubated for respiratory failure with proper positioning of endotracheal tube.

She had severe gastro-oesophageal reflux disease and was not gaining weight appropriately, and hence a gastrostomy tube was inserted for supplemental feeding. She needed respiratory support for 32 days and was discharged home on day 51 of life.

During infancy, she was hospitalised multiple times for pneumonia, and her chest X-ray showed persistent right upper lobe collapse. As the lung finding was localised to the right upper lobe, and the rest of both lungs were normal on imaging and bronchoscopy, a decision was made to proceed with right upper lobectomy at 10 months of age instead of a lung biopsy. Intraoperatively, the right upper lobe was consolidated, with normal airway branching (no tracheal bronchus), and the bronchus was slit-like but with patent lumen. Histopathology of the right upper lobe showed non-specific changes of minor airspace acute inflammation and follicular bronchiolitis (figure 2).

Figure 2.

Histopathology of the right upper lobe showing non-specific changes of minor airspace acute inflammation and follicular bronchiolitis (arrow).

Due to persistent daily wet cough and nasal congestion, a diagnosis of PCD was eventually considered at 3 years of age; a nasal scrape biopsy was done which showed ciliary ultrastructure abnormalities of reduced inner dynein arm count with tubular disorganisation (figure 3). Genetic testing revealed homozygous pathogenic variants in the CCDC40 gene.

Figure 3.

Normal ciliary ultrastructure under electron microscopy (A) and inner dynein arm defect with axonemal disorganisation seen in patients with pathogenic variants in the coiled- coil domain containing protein 40 gene (B).

Investigations

Sweat chloride and an alpha-1-antitrypsin testing were negative.

Chest X-ray in the neonatal period showed right upper lobe collapse.

Chest CT scan in the neonatal period showed marked atelectasis of the right upper lobe and posterior–basilar segments of left lower lobe.

Bronchoscopy on day 20 of life was reported as showing a right-sided accessory bronchus/tracheal bronchus.

Echocardiography showed situs solitus, normal heart anatomy and function with no signs of pulmonary hypertension.

Abdominal ultrasound revealed normal splenic, abdominal organs and vascular anatomy.

Histopathology of the right upper lobe showed non-specific changes of minor airspace acute inflammation and follicular bronchiolitis (figure 2).

Nasal ciliary biopsy examined under transmission electron microscopy showed a classic ciliary ultrastructural defect of reduced inner dynein arm count with tubular disorganisation.

Genetic testing revealed homozygous frameshift mutation (c.1416delG) in the CCDC40 gene.

Chest CT scan at 16 years of age showed bilateral bronchiectasis and chest wall asymmetry.

Differential diagnosis

Initially, respiratory distress syndrome (RDS) and congenital pneumonia were the working diagnoses in the neonatal period; however, she was a full-term baby and had no risk factors for RDS. She also had no signs of sepsis, and respiratory symptoms did not improve with antibiotic treatment, making neonatal pneumonia unlikely. Furthermore, bilateral alveolar infiltrates with air bronchograms are characteristic of neonatal pneumonia.⁶ Interstitial lung diseases, such as surfactant protein deficiency and alveolar capillary dysplasia, could present in the neonatal period; however, these diseases usually present with profound respiratory failure, pulmonary hypertension and diffuse changes on chest imaging. After the bronchoscopy, congenital lung malformation with a tracheal bronchus was erroneously presumed to be the cause of the persistent right upper lobe collapse, however, the subsequent chest CT scan and thoracotomy procedure excluded that.

Cystic fibrosis and immunodeficiency syndromes are high on the differential diagnosis of an infant with recurrent chest infections and failure to thrive, however, sweat chloride testing and immune workup were negative, ruling out these aetiologies.

Treatment

Right upper lobectomy was done at 10 months of age due to the persistent right upper lobe collapse. After the PCD diagnosis was confirmed, she started regular follow-up for chronic disease management in the PCD clinic and was established on daily chest physiotherapy and antibiotics as needed.

Outcome and follow-up

At 16 years of age, despite active PCD management, she has moderately severe air flow obstruction on spirometry with the forced expiratory volume in 1 s of 58% predicted. Her chest CT shows severe bronchiectasis and right-sided chest wall asymmetry (figure 4), and ongoing malnutrition with body mass index of 13.

Figure 4.

Chest CT scan at mid-thoracic level showing bilateral bronchiectasis, mucous plugging and tree-in-bud changes (A). Chest CT scan at upper thoracic level showing anterior-posterior diameter of the right side is 20.5 mm narrower in comparison to the left side (B).

Discussion

Patients with PCD can present with unexplained neonatal respiratory distress, recurrent otosinopulmonary infection, organ laterality defects and infertility. Bronchiectasis is almost universal by adulthood and it is a major cause of mortality.⁵

While the prevalence worldwide is estimated to be 1:10 000–1:15 000, it may be much higher in certain communities, especially where consanguinity is more prevalent. In the British South Asian community, for example, the prevalence has been estimated at 1:2450, similar to that of cystic fibrosis among white Europeans.^{7 8}

The neonatal clinical manifestations of this case were typical for PCD, but more severe than usual. The usual neonatal respiratory symptoms start at a median of 12 hours of life and usually they need oxygen for up to 2 weeks. In our case, the neonatal respiratory distress started at 2 hours of life and she needed oxygen and respiratory support for 32 days.^{4 9} The lack of organ laterality defects made it more difficult to suspect PCD.

There is no single ‘gold standard’ diagnostic test for PCD, and the diagnosis requires a number of technically demanding, sophisticated investigations including the examination of ciliary ultrastructure under electron microscopy, measuring the nasal nitric oxide level, genetic testing, ciliary beat frequency and ciliary waveform analysis.⁵

The lung disease severity can vary by causative gene, with more severe lung involvement in patients with disease caused by the CCDC40 and CCDC39 genes. CCDC40 is a cytoplasmic transporter gene required for assembly of the dynein regulatory complex and inner dynein arm complexes, which are responsible for ciliary beat regulation. Pathogenic variants in this gene are associated with a distinct ciliary ultrastructural pattern which includes the absence of inner dynein arms in conjunction with central apparatus defects and microtubular disorganisation. CCDC40 interacts with CCDC39 to form a molecular ruler that determines the 96 nm repeat length and arrangements of components in cilia and flagella.^{9 10} These ultrastructural defects were initially described in children with PCD in Toronto in 1979 and labelled as ‘radial spoke defects’.¹¹ We now know that this was a misnomer, since radial spoke head protein defects cause a much more subtle ciliary ultrastructural defect.¹² PCD caused by pathogenic mutations in the CCDC39 and CCDC40 genes are known to be associated with worse pulmonary function, significantly more lobes of consolidation and impaired growth parameters in comparison to patients with PCD due to other genes.⁹ The reason for the more severe lung disease is not yet completely understood, but hypothesised to be related to the loss of the 96 nm repeat ruler in the dynein arm organisation which is crucial for ciliary function.¹³

The aetiology for the impaired growth parameters is also not fully understood, it could be due to the chronic respiratory illness and recurrent infection which put the body under stress and hypermetabolic state or other yet uncovered mechanisms.^{9 14} Other common causes such as severe gastro-oesophageal reflux and secondary food refusal need to be thought of. In our patient, workup for failure to thrive when she was an infant suggested that it was not an absorption issue, and calorimetry study indicated normal resting energy expenditure suggesting that it was an intake issue.

The histopathology of the removed lung lobe showed follicular bronchiolitis and non-specific inflammatory changes. Similar changes were found in a previous reported case of a 27-year-old Caucasian woman with PCD who had recurrent pneumonia and underwent transbronchial biopsies revealing follicular bronchiolitis, and lack of outer dynein arms demonstrated on transmission electron microscopy.¹⁵

Lobectomy is not recommended for patients with PCD, however it may be considered as a therapy in select patients with severe localised lung disease that does not respond to standard PCD management; this decision should be carefully considered after discussion with the pulmonologist, paediatric surgeon and intensivist. Care should be taken in the postoperative period as airway clearance is limited by pain and immobility, and patients with PCD are at risk of pulmonary deterioration.⁵

The chest wall asymmetry in this case is significant and is associated with anxiety, distress and lack of confidence in this young adolescent. In our case, the chest wall deformity is likely secondary to the early life thoracotomy intervention. A recent retrospective review of 74 children who underwent lung resection (either thoracotomy or thoracoscopic procedures) for congenital lung disease reported that thoracic and spinal deformities developed in 37%. One of the proposed mechanisms is that during infancy, the skeletal muscles are developing and cutting the latissimus dorsi muscle and/or the serratus anterior muscle during posterolateral thoracotomy can result in postoperative muscular atrophy, which can then cause the development of thoracic and/or spinal deformities.¹⁶

This case illustrates the severe spectrum of lung disease that can develop in patients with PCD, and also the importance of considering PCD in the differential diagnosis of a newborn presenting with unexplained respiratory distress and oxygen needs.

Learning points.

• Primary ciliary dyskinesia (PCD) is a rare disease and should be considered in a neonate with unexplained respiratory distress.

• To date, there are more than 40 genes known to cause PCD, and commercial PCD genetic testing panels are available that are estimated to diagnose 60% to 70% of PCD cases.

• There is currently no single ‘gold standard’ diagnostic test for PCD, and the diagnosis requires a number of technically demanding, sophisticated investigations.

• Failure to identify PCD early could lead to delayed diagnosis, which in addition to delaying disease management strategies such as daily airway clearance therapies, may also put these children at potential risk of unnecessary treatment and/or surgical procedures.

• This case also illustrates the severe spectrum of respiratory disease that can be seen in patients with PCD caused by pathogenic variants in the coiled- coil domain containing protein 40 (CCDC40) gene.