Case In Point: Cystic fibrosis in an elderly woman

The diagnosis of cystic fibrosis (CF) is typically made in childhood. However, there is increasing evidence that a mild and atypical form of this disease can present in adulthood. The author describes a patient who received the diagnosis of CF when she was 74 years old.

THE CASE

A 74-year-old white woman was evaluated for CF because of her family history. She had a history of sinusitis but no other recurrent infections. The patient had no GI symptoms, such as symptoms of malabsorption or steatorrhea. She had recently received diagnoses of hypertension, rheumatoid arthritis (RA), and osteoporosis.

The patient was married, had had uncomplicated pregnancies, and had delivered 10 healthy children. With the exception of 1 daughter with asthma, her children and grandchildren had no significant respiratory or GI symptoms.

On physical examination, the patient's height was 137 cm and her weight was 82 kg. There were no nasal polyps. Chest examination did not reveal any adventitious breath sounds. Heart sounds were also normal, as were results of the abdominal examination. There was RA involvement of the small joints of the hands but no digital clubbing.

The patient's family history included 2 nieces with CF. Her youngest niece received the diagnosis of CF at age 35 years as a result of a combination of suggestive findings.In the other niece, the diagnosis was made by genotyping when she was 42 years old. The nieces had different genotypes (G542X/ W1282X and R117H/W1282X, respectively), but they had the same father. This observation prompted an evaluation of their 63-year-old mother, who had minimal respiratory symptoms. The mother had 2 known CF mutations, R117H and G542X.

The patient'sglucose levels and the results of liver and renal function tests were normal. Pulmonary function tests revealed a forced vital capacity (FVC) of 142% of predicted, forced expiratory volume in 1 second (FEV₁) of 108% of predicted, FEV₁:FVC ratio of 76%, forced expiratory volume at 25% to 75% of FVC of 68% of predicted, and a ratio of residual volume to total lung capacity of 98%.

The patient's chest radiograph and CT scans of the sinuses and chest revealed normal findings. Duplicate sweat tests indicated a chloride value of 61 mEq/L. Sputum culture yielded normal respiratory flora. The patient was found to be heterozygous with the genotype R117H/G542X.

DISCUSSION

CF is the most common autosomal recessive life-threatening disorder in white populations.¹ Epidemiologic studies suggest an incidence of 1 in 2500 births among whites.² CF is characterized by the classic diagnostic triad of chronic sinopulmonary disease, pancreatic insufficiency, and elevated sweat electrolyte concentration.³

CF is generally regarded as a disease of childhood. More than 90% of patients with CF receive the diagnosis by age 12 years.⁴ Advances in treatment have extended the life span of patients with CF, and the median survival is now 32.9 years.⁵ Lung transplantation is offered to many patients with advanced pulmonary disease and has extended their survival. As a result, many nonpediatric pulmonologists now are providing care to young adults with CF.

Occasional cases of CF presenting in adults have been described,⁶ and over the past 2 decades, it has become evident that CF includes a wider spectrum of disease severity than was previously recognized. This includes mild and atypical disease that can present in adulthood. Many physicians are unaware that CF can present later in life, potentially leading to delayed or missed diagnosis.⁷ The initial diagnosis of CF after the age of 50 years is extremely unusual.

The genetic basis of CF

The cause of CF is a defect in a single gene on chromosome 7 that encodes a cyclic adenosine monophosphate-regulated chloride channel, termed the "CF transmembrane conductance regulator" (CFTR). The CFTR resides on the apical membrane of epithelial cells lining the airways, pancreatic ducts, sweat ducts, vas deferens, intestines, and hepatobiliary system. It also down-regulates the activity of the epithelial sodium channel in the airways. In the absence of CFTR function, this down-regulation is relieved, and sodium reabsorption increases, contributing to reduced fluid volume and probably to the airway pathophysiology.⁸

CFTR also transports bicarbonate or regulates its transport through the epithelial cell membrane. When the chloride ion cannot be transported by CFTR at these sites, fluid secretion is insufficient, and the protein portions of the secretions may become more viscid or precipitate and obstruct the ducts, leading to plugging and dysfunction at the organ level.⁹ How the chloride transport defect causes abnormal secretions is still unclear.

The diagnosis of CF is based on the identification of 1 or more characteristic phenotypic clinical features or a history of CF in a sibling plus laboratory evidence of a CFTR abnormality, as documented by elevated sweat chloride concentrations (greater than 60 mEq/L), the identification of 2 known CF mutations, or in vivo demonstration of raised potential difference in nasal epithelia.¹⁰

More than 1000 CFTR mutations have been identified. The most common mutation in the CFTR is a 3 base-pair deletion, which results in deletion of the phenylalanine residue at amino acid position 508 (DF508). This mutation accounts for approximately 70% of the CF chromosomes reported worldwide.¹¹

The relationship between the type of mutation in the CFTR (genotype) and the severity of clinical disease (phenotype) is not clear-cut in most situations.¹² Studies have shown that pancreatic insufficiency correlates well with a few specific classes of mutations. Also, sequence alterations have been associated with congenital bilateral absence of vas deferens (CBAVD), which is considered a CF-related disorder. Other clinical signs and symptoms are less predictable by the CFTR genotype. There is no obvious correlation between CFTR genotype and CF lung disease.

Many variables can modify the clinical expression of CF, particularly the lung disease. These variables may include genetic modifiers that are outside the CFTR locus, differences in treatment, exposure to infectious (particularly viral) diseases, and other environmental influences.

Several studies have shown that other genetic variations can influence the consequences of certain CFTR mutations. The best example is the T-tract polymorphism adjacent to the splice junction in front of exon.⁹ It has been well documented that the less efficient 5T variant renders R117H a more severe allele than the 7T variant. Consequently, R117H (5T) is associated with typical CF with pancreatic sufficiency. In contrast, men carrying R117H (7H) may present with CBAVD but not CF-related lung disease and have normal or borderline sweat chloride values.¹³

The patient reported here was found to be a compound heterozygote for the R117H and G542X mutations. The R117H mutation exhibited 7T and 9T variants. This patient's apparent pancreatic sufficiency probably explains her normal development and the delayed diagnosis.

Some female patients identified by CF carrier screening tests have no pulmonary disease and are otherwise asymptomatic despite an R117H/F508 genotype. The range of phenotypes that may be attributed to the R117H mutation now includes typical CF with pancreatic sufficiency, CBAVD, and the absence of symptoms.¹⁴

Clinical manifestations

This case illustrates that while CF most commonly presents in infancy or early childhood, the diagnosis of CF should be considered even in adults who present with recurrent pulmonary infections. The lungs of patients with CF tend to be colonized by organisms such as Staphylococcus aureus,Haemophilus influenzae and, most characteristically, Pseudomonas aeruginosa. The recovery of mucoid P aeruginosa from sputum is so characteristic of CF that it is considered by some to be a sign of CF in adults with chronic pulmonary disease.¹⁵

Chest radiographic abnormalities, such as bronchiectasis, atelectasis, pulmonary infiltrates, and hyperinflation, are common in CF, and involvement of the upper lobes is an unexplained characteristic of CF. A significantly increased frequency of CF mutations has been found in patients with idiopathic disseminated bronchiectasis.¹⁶

The possibility of CF should also be considered in adults with nasal polyps, particularly if they also have symptoms of severe sinusitis.¹⁷

Adults with CF are much less likely to present with GI or hepatobiliary symptoms than with pulmonary disease.¹⁸ Recurrent, isolated chronic pancreatitis with no respiratory symptoms is a rare presentation of CF that has been reported in adults.¹⁹ At least one third of patients with CF have abnormal results on liver function tests. Fatty infiltration is reported in up to 70% of patients; this progresses to biliary cirrhosis in fewer than 10%.

There are a few case reports of CF presenting in adults with abnormal liver function, portal hypertension with esophageal varices,²⁰ and jaundice.²¹ CF should be considered as a cause of cirrhosis of the liver after the more common causes have been excluded.

Over 98% of male patients with CF are infertile, with aspermia secondary to atretic or absent vas deferens and dilated or absent seminal vesicles. Several studies have confirmed that CFTR gene mutations are associated with CBAVD.²² It is important to determine whether an infertile patient with CBAVD has CFTR gene mutations, particularly if his partner is of European ancestry, to assess the risk of having a child with CF. Reproductive function is generally normal in women with CF, although cervical mucus can be dehydrated, which may impair fertility.

DiSant'Agnese and associates²³ noted a significantly high number of children with CF among those admitted to the hospital with heat prostration during a heat wave. This observation led to the finding of high concentrations of sodium and chloride in the sweat of patients with CF and development of the diagnostic sweat test. Heat prostration, hyponatremic dehydration, and metabolic alkalosis are well-recognized complications of CF in children and may even be the initial presentation. This presentation has also been reported in a few adults.^24,25

Genetic testing

Identification of CFTR mutations in patients with atypical presentations can support the diagnosis of CF in the absence of the classic CF phenotype. In view of the size of the CFTR gene and the large number of mutations identified, failure to detect such mutations does not preclude the diagnosis of CF.

Genetic testing is also useful in screening close relatives of patients with CF to detect carriers and to give appropriate genetic counseling. As newer therapies for CF become available, earlier case recognition should lead to an improved prognosis.

References:

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