OVERVIEW

What is Primary Ciliary Dyskinesia Syndrome?

Primary ciliary dyskinesia syndrome is a genetic disorder in which the structure or function of cilia is defective. The cilia cannot perform rhythmic movements normally or are completely absent, losing functions such as clearing mucus and bacteria. This disease mainly affects organs such as the lungs, nasal cavity, sinuses, and ears, and reproductive function may also be impaired.

Cilia are highly specialized structures primarily found in epithelial tissues of the lungs, ear canals, sinuses, nasal cavity, ependyma, and fallopian tubes. The flagella at the tail of sperm are also a specialized type of cilium.

Normally, cilia continuously propel mucus on tissue surfaces through coordinated beating to clear bacteria and other foreign particles. In the fallopian tubes of females, the beating of cilia helps move eggs or fertilized eggs toward the uterus.

Is Primary Ciliary Dyskinesia Syndrome common?

It is not common. The incidence rate is approximately between 0.01% and 0.0045% ^[1].

What are the types of Primary Ciliary Dyskinesia Syndrome?

A special subtype is called Kartagener Syndrome. In addition to common manifestations such as bronchiectasis and chronic sinusitis, patients with Kartagener Syndrome also exhibit situs inversus totalis, where the left-right distribution of internal organs is the opposite of normal individuals. Situs inversus totalis does not affect the normal function of the organs ^[2].

Is Primary Ciliary Dyskinesia Syndrome hereditary?

Primary ciliary dyskinesia syndrome is hereditary, but it does not mean that a child born to an affected parent will necessarily inherit the disease. They may only carry the pathogenic gene without developing symptoms. The details are as follows:

• Most pathogenic genes for primary ciliary dyskinesia follow an autosomal recessive inheritance pattern, meaning that the disease only manifests when two pathogenic genes are present. Having one pathogenic gene does not cause the disease.

  Children of affected individuals will inherit at least one pathogenic gene. If they also inherit a pathogenic gene from the other parent, they will develop the disease. If they inherit a normal gene from the other parent, they will not develop symptoms.

  If both parents are carriers of the pathogenic gene, even if they appear normal, their child still has a 1/4 risk of developing the disease.

• In rare cases, pathogenic genes follow a dominant inheritance pattern, meaning that having just one pathogenic gene will cause the disease, resulting in a higher risk. Additionally, some pathogenic genes are located on the X chromosome, making the risk of inheritance dependent on the child's sex ^[1,3,4].

SYMPTOMS

What are the common manifestations of primary ciliary dyskinesia syndrome?

Primary ciliary dyskinesia syndrome presents with diverse clinical manifestations, affecting multiple organs and systems, often involving the lungs, nasal passages, sinuses, and ear canals. The cilia in these areas, along with surface mucus, facilitate "mucociliary clearance," which traps and removes waste and foreign particles. In patients with primary ciliary dyskinesia syndrome, this function is impaired, preventing timely clearance of pathogens like bacteria and viruses, leading to recurrent infections in the respiratory tract, sinuses, and middle ear. Specific manifestations include:

1. Pulmonary symptoms:

   • Neonatal respiratory distress: Manifested as rapid breathing or low blood oxygen levels. Most full-term newborns may experience mild respiratory distress after birth and may require supplemental oxygen ^[2].

   • Chronic cough and sputum production: Nearly all patients develop persistent coughing and mucus production in infancy. This cough can last for months or even years, with sputum typically being white and mucoid. During respiratory infections, it may become thick or bloody ^[3].

   • Recurrent or chronic respiratory infections: Infections worsen coughing and sputum production, leading to thick or bloody sputum, possibly accompanied by fever, chills, or chest pain. Infections may recur after treatment or persist as chronic conditions ^[3,4].

   • Impaired lung function: Lung function abnormalities, such as reduced vital capacity, may appear in childhood, primarily due to recurrent lung infections. Long-term impairment can progress to chronic obstructive pulmonary disease (COPD) ^[5].

   • Bronchiectasis: Bronchiectasis and recurrent lung infections exacerbate each other. Some patients may cough up blood, and a few adults may develop clubbing (abnormal enlargement of finger or toe tips). Over half of patients show signs of bronchiectasis in infancy, and nearly all adults with the condition exhibit it ^[1-4].

2. Nasal and sinus symptoms:

   • Nasal congestion: Persistent year-round congestion with nasal discharge. Some patients may develop nasal polyps, often in early childhood ^[3].

   • Sinusitis symptoms: Include nasal congestion, facial pain or pressure, and persistent mucopurulent discharge. Chronic sinusitis may cause headaches or loss of smell ^[1,4].

3. Ear symptoms: Children are prone to acute or chronic secretory otitis media, presenting as ear pain, pus discharge, and sometimes fever or chills. Severe cases may damage middle ear structures, leading to conductive hearing loss or deafness. Ear symptoms are rare in adulthood ^[1,4].

4. Central nervous system symptoms: Headaches are common. Hydrocephalus may cause nausea, vomiting, or vision impairment, and severe cases can hinder physical and intellectual development in children, requiring vigilance ^[1]. Hydrocephalus results from abnormal ependymal cilia function, disrupting cerebrospinal fluid circulation.

5. Infertility: Related to reproductive dysfunction, as follows:

   • Males: Most have sperm with impaired flagellar motility, preventing natural fertilization. Some produce no sperm (azoospermia), while very few have normal sperm motility ^[3,4].

   • Females: Cilia on fallopian tube surfaces aid egg and embryo movement. Abnormal cilia impair fertility, though ~50% of female patients can conceive naturally ^[1,3,4].

6. Other abnormalities: Higher incidence of congenital heart disease, pectus excavatum, and scoliosis ^[1].

What complications can primary ciliary dyskinesia syndrome cause?

Primary ciliary dyskinesia syndrome can lead to multi-organ complications, including:

• Lungs: Neonatal respiratory distress, recurrent/chronic lung infections, bronchiectasis, COPD.

• Ears: Acute/chronic secretory otitis media, middle ear effusion, conductive hearing loss.

• Nose: Acute/chronic sinusitis, nasal polyps.

• Central nervous system: Hydrocephalus.

• Reproductive system: Azoospermia, ectopic pregnancy, infertility.

CAUSES

What is the cause of primary ciliary dyskinesia syndrome?

Genetic mutations: This type of mutated gene (i.e., pathogenic gene) in patients with primary ciliary dyskinesia syndrome leads to the absence of cilia; or allows the formation of cilia, but the structure or function of the cilia is abnormal.

DIAGNOSIS

When should a patient with Primary Ciliary Dyskinesia Syndrome seek medical attention?

Medical attention is required in the following situations:

• Regular pulmonary function tests are needed to assess lung function.

• Symptoms such as respiratory infections, rhinosinusitis, or otitis media occur.

• Adult patients, especially male patients, have fertility plans.

Which department should a patient with Primary Ciliary Dyskinesia Syndrome visit?

The choice of department depends on the symptoms, as follows:

• For cough, sputum, or recurrent lung infections, visit the Respiratory Medicine Department.

• For nasal, sinus, or ear symptoms, visit the Otolaryngology Department.

• For headaches or hydrocephalus symptoms, visit the Neurology or Neurosurgery Department.

• For fertility plans, it is advisable to first consult the Genetic Counseling Department to assess the risk of inheritance in offspring. If natural conception is difficult, visit the Assisted Reproductive Department to explore suitable assisted reproductive technologies.

How is Primary Ciliary Dyskinesia Syndrome diagnosed?

Currently, there is no unified diagnostic standard for Primary Ciliary Dyskinesia Syndrome. Diagnosis requires evaluating the patient's clinical manifestations and medical history to assess the risk of the disease. A detailed medical history is necessary, and for pediatric patients, parents must provide a comprehensive birth and past medical history.

1. The following manifestations strongly suggest Primary Ciliary Dyskinesia Syndrome:

   • Unexplained neonatal respiratory distress at birth, chronic cough with sputum, recurrent pneumonia, persistent nasal congestion or discharge, otitis media, or even hearing loss, and physical examination findings such as dextrocardia.

   • Male patients with infertility due to sperm motility disorders, accompanied by pulmonary symptoms.

   • Female patients with unexplained reduced fertility (failure to conceive naturally within 2 years) or infertility (failure to conceive naturally for over 2 years), especially when accompanied by other symptoms related to the disease.

2. When clinical manifestations strongly suggest Primary Ciliary Dyskinesia Syndrome, further diagnostic tests include:

   • Nasal Nitric Oxide (nNO) Test: Patients with this condition have very low or no nasal nitric oxide. This is a highly effective screening method for patients aged 5 and above ^[1,4].

   • Ciliary Motility and Ultrastructure Analysis: High-speed video microscopy analysis (HSVA or HSVM) and transmission electron microscopy (TEM) are used to directly observe ciliary movement and ultrastructure, identifying abnormalities in ciliary function and structure. Combining HSVA and TEM can achieve a sensitivity of up to 100% for diagnosing this condition ^[5]. This test involves brushing ciliated epithelial cells from the nasal cavity or bronchi via bronchoscopy for observation.

   • Genetic Testing: This can detect the presence of disease-causing genes and identify the genotype. It may also uncover new pathogenic genes. Results may include: homozygous (identical pathogenic mutations on both chromosomes), compound heterozygous (different pathogenic mutations on the same gene locus), or multiple pathogenic gene variants (mutations at different gene loci).

TREATMENT

How to Treat Primary Ciliary Dyskinesia Syndrome?

The treatment of primary ciliary dyskinesia syndrome mainly focuses on symptomatic management and controlling complications. Current medical approaches cannot restore normal ciliary function. Specific treatments include:

• Treatment during remission: Expectorants may be administered to promote mucus clearance from the lungs. Prophylactic antibiotics are not recommended during remission, but immunomodulators such as bacterial lysates may be considered for patients with recurrent respiratory infections ^[4].

• Treatment of pulmonary symptoms:

  1. Lung infections: Acute infections require prompt antibiotic therapy. The choice of antibiotics should be guided by bacterial culture and sensitivity testing. For recurrent lung infections, expectorants (e.g., N-acetylcysteine, fudosteine, or carbocisteine) may be used. Chest percussion and postural drainage can also aid mucus clearance ^[1,4].

  2. Bronchiectasis: Medical management is the first-line treatment. Surgery may be considered if infections persist despite medical therapy or if recurrent massive hemoptysis is unresponsive to medical or interventional treatments. Lung transplantation may be an option for end-stage patients ^[1,2,4].

• Treatment of rhinosinusitis: Patients with chronic rhinitis or sinusitis may benefit from daily nasal irrigation. Intranasal corticosteroids can be used for those with nasal polyps ^[1,4].

• Treatment of ear symptoms: Otitis media requires antibiotic therapy as prescribed. Recurrent secretory otitis media may necessitate tympanostomy tube insertion to improve hearing. Young patients should undergo regular hearing and speech assessments, with hearing aids provided if needed ^[1,2,4].

• Infertility and genetic counseling:

  1. Adult male patients should be informed of infertility risks and advised to undergo semen analysis. For those with viable sperm but difficulty conceiving naturally, assisted reproductive technologies (e.g., intracytoplasmic sperm injection) may be considered ^[2].

  2. Female patients should be informed of reduced fertility and ectopic pregnancy risks, with assisted reproductive technologies offered if necessary ^[2,4].

  3. Parents concerned about passing the disease to offspring may seek genetic counseling. Preimplantation genetic diagnosis (genetic testing of embryos before implantation) can reduce transmission risks.

• Regular follow-up monitoring: Patients require long-term clinical follow-up to assess lung function. Those aged 6 and above should undergo 1–3 evaluations annually ^[2].

DIET & LIFESTYLE

What should be noted in daily life/diet for Primary Ciliary Dyskinesia Syndrome?

• Prevent respiratory infections, minimize exposure to polluted air, and wear masks during daily outings.
• Avoid smoking and secondhand smoke, as smoking can worsen lung function deterioration.
• Patients or caregivers should monitor daily health. Seek early medical attention if symptoms like coughing or phlegm worsen.

PREVENTION

Can primary ciliary dyskinesia syndrome be prevented? How to prevent it?

Primary ciliary dyskinesia syndrome can be prevented through the following two approaches:

• Genetic counseling and pre-pregnancy diagnosis: Couples with a family history of primary ciliary dyskinesia syndrome have a higher probability of carrying the disease-causing gene and passing it on to their offspring. They can undergo genetic counseling before pregnancy or use assisted reproductive technologies for preimplantation genetic diagnosis to reduce the risk of the disease in their descendants.

• Preventing complications: Patients should actively prevent and treat complications, especially bronchiectasis. They should take protective measures to reduce the likelihood of respiratory infections and seek prompt medical treatment if infections occur to prevent worsening of the condition.

Can individuals with primary ciliary dyskinesia syndrome have their own children?

Individuals with primary ciliary dyskinesia syndrome can have their own children.

Males: While most patients have sperm with impaired motility, the sperm remain viable. They can father children through in vitro fertilization.

Females: Some patients can conceive naturally. If natural conception is difficult, they can achieve pregnancy through in vitro fertilization and embryo transfer ^[2].