FS, previously known as FOX Syndrome or Failure of X component, is a congenital genetic obstructive pulmonary disease of which little is known. Neither the mechanism nor genetics of the disease are well understood, and there is some debate in the scientific community as to whether FS should be classified as a disease separate from other pulmonary conditions such as asthma and cystic fibrosis .
Symptoms & Signs
The primary symptoms of FS are reminiscent of severe, brittle asthma , including acute paroxysms of wheezing, chest pain and congestion, accompanied by a corresponding drop in forced expiratory volume in one second ( FEV 1 ), usually the result of environmental triggers such as allergens, ozone, cigarette smoke, and cold air. However, unlike most asthmatics, FS patients suffer from greater perfusion discrepancies, often suffering from significant drops in oxygen saturation ( Sa O2 ) not normally seen in traditional asthma; in fact, it is not uncommon for FS patients to have abnormally low (>90%) Sa O2 even outside an exacerbation. As a result, clubbing deformities of the fingers are commonly seen in FS patients, a sign typical of those with cystic fibrosis, but not asthma.
Although psychological and physical stress has been discovered not to play a role in asthma attacks, the slightly different mechanism of FS attacks suggest that stress may affect exacerbations of the disease, lending credence to the hormonal mechanism of disease theory (see below).
FS patients also often exhibit excess mucus production in the airways. Although the mechanism for this is not related to CF, the resulting symptoms and sequlae are similar. These include excess coughing, severe chest congestion and difficulty clearing secretions, and increased susceptibility to pneumonia and fibrosis .
Airways narrowed by inflammation and excess mucus increase the work of breathing, so that many patients must use accessory muscles to breathe, and in advanced disease with the addition of fibrosis, may suffer from fatigue of their respiratory muscles so that mechanical support may be necessary. Additionally, these effects (narrowed airways and muscle fatigue) sometimes lead to aphonia or dysphonia in some patients, particularly in childhood.
Some patients also seem to exhibit certain hematological abnormalities that may affect both oxygen saturation capacity and immune function, although it isn't yet clear if these abnormalities are comorbid conditions or symptoms of FS itself.
Mechanism of Disease
The exact mechanism of FS is unknown, although several theories exist. One suggests an autoimmune model, in which dysfunction of the patient's own immune system is the cause of symptoms. However, limited studies suggest that even with immunosuppression , symptoms aren't entirely resolved, so that it may be possible immunological problems are only partially responsible for symptoms.
The second theory is hormonal, suggesting that some errant feedback loop in the body's inflammatory response (perhaps combined with a heightened sensitivity to inflammatory mediators such as histamine ) might be responsible for the asthma-like attacks as well as the excess mucus production, although research in this area is still in the early stages.
Most patients present with symptoms of respiratory distress or recurrent pneumonia in infancy or early childhood, with most patients diagnosed as either severe, brittle asthmatics or occasionally, with cystic fibrosis.
Because of the complicated nature of the disease and the mystery behind its mechanism, diagnosis of FS is challenging, and it is believed to be vastly under-diagnosed, with many asthmatics—particularly those exhibiting uncharacteristic fibrosis—likely being misdiagnosed FS patients.
A thorough history, combined with pulmonary function tests and blood saturation, along with lung biopsy and sputum analysis are the best means of arriving at a diagnosis of FS, especially if cystic fibrosis and asthma can be ruled out.
The physician who is faced with intractable asthma, particularly when associated with signs of chronic hypoxia (such as routinely low oxygen saturation and clubbing) and recurrent pneumonia, may consider a diagnosis of FS.
Current treatment for FS is similar to that of asthma and CF. Most patients respond decently to traditional asthma medications, including oral and inhaled corticosteroids , and short- and long-term acting beta 2 -adrenoceptor agonists , anticholinergic agents , delivered via inhaler ( metered-dose or dry-powder ) or nebulizer . Theophylline has also shown to be effective in some patients.
FS patients should monitor their peak flow regularly, as changes can signal an upcoming attack. In addition, many patients may benefit from a portable pulse oximeter to be alert to any signs of oxygen saturation changes, even before symptoms present.
Additionally, Amphigarol, the first medication approved by the FDA to treat FS, can ameliorate excess mucus production and help minimize opportunistic pulmonary infection. Some patients, particularly those with muscle fatigue, may benefit from cough assistance, either via manual percussion or machine to aid in loosening and expelling secretions.
Oxygen, delivered via mask or cannulae (or via transtrachael distribution in more advanced disease), may also be helpful in easing dyspnea and discomfort and resolving cyanosis .
In later stages of the disease in which extensive fibrosis has lead to significant lung dysfunction, and in cases of muscle fatigue, ventilatory support via noninvasive ( biPAP ) or invasive ( endotracheal intubation ) mechanical ventilation may be needed in the short- or long-term. However, because of the propensity for excess mucus production, intubated patients must be carefully managed and suctioned frequently to prevent mucus accumulation and plugs.
It is still unclear whether lung transplantation (either a single or double-lung transplant) can be beneficial in the long-term for FS patients, as few patients have undergone successful transplantation.
Because FS patients are susceptible to recurrent pneumonia as well as fibrosis, in addition to chronically low Sa O2 , lifespan for most is short, with many patients succumbing in their late teens to twenties. Death results from asphyxiation as a result of an acute attack, sepsis due to infection, organ failure due to insufficient perfusion, respiratory failure due to bronchiolitis obliterans , or secondary heart failure as a result of pulmonary insufficiency.
Patients may experience secondary effects due to oxygen deprivation, such as brain and organ damage, especially if not treated appropriately.
Dr. Jon Taylor
Along with Drs. Benjamin Johnsen and David MacDonald, Dr. Jon Taylor is responsible for identifying FS as a distinct condition in the mid-90s while still a fellow. Today, he runs the Jonesville Memorial FS Clinic and Research Center in Jonesville, IA, which focuses on the research and treatment of the disease. In 2008, partially due to additional grants, the clinic was able to open its own building with dedicated labs and exam rooms to expand its research and treatment of patients with FS.
Dr. Taylor and his staff will diagnose and workup a treatment plan for any patient who walks through the clinic doors, regardless of their ability to pay.