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6 The patient with cystic fibrosis
Tarek El‐Toukhy
Assisted Conception Unit, Guy’s and St Thomas’ Hospital, London, UK
Case History 1: A couple (both 28 years old) consulted their general practitioner because of a 2‐year history of infertility. Semen analysis showed azoospermia on two occasions. Therefore, the couple were referred to the local fertility center, where the male partner was found to be a “carrier” of cystic fibrosis.
Case History 2: A 32‐year‐old woman and her 35‐year‐old husband were seen in the regional genetics center for genetic counseling after their 5‐month‐old daughter had recently died from acute pneumonia. The daughter was diagnosed with cystic fibrosis at age 2 weeks. Both parents were confirmed carriers of the delta‐F508 cystic fibrosis mutation.
Background
Cystic fibrosis is the most common life‐threatening autosomal recessive condition in Caucasians, with an estimated carrier rate of 1 in 25 and incidence of 1 in 2,500. Common manifestations of cystic fibrosis are recurrent chest infections, chronic sinusitis and digestive problems leading to chronic diarrhea, malnutrition, poor growth and weight loss. Due to contemporary advances in medical treatment of the disease, the average lifespan of an affected person now extends well into the fourth decade of life, whereas in the past the disease was fatal in childhood or early adolescence.
Over 800 mutations in the cystic fibrosis transmembrane regulator (CFTR) gene have been identified, with a wide range of clinical phenotypes related to those mutations. The most common mutation in Western Europe is the delta‐F508 mutation, present in about 75% of affected individuals [1].
Approximately, 98% of men affected with cystic fibrosis are azoospermic, due to congenital bilateral absence of the vas deferens (CBAVD), blocking the transport of sperm from the proximal epididymis to the urethra [2]. CBAVD accounts for 6% of cases of obstructive azoospermia. In some otherwise healthy men, CBAVD could be the only phenotypic manifestation of cystic fibrosis. These men are now recognized as compound heterozygotes for a common (severe) mutation and a rare (but mild) mutation or carry two mild cystic fibrosis mutations. This condition is known as “genital cystic fibrosis” [3,4]. The male partner in Case History 1 belongs to this group, underscoring the importance of extensive molecular screening for cystic fibrosis mutations in men with obstructive azoospermia and CBAVD. Most (>95%) of men with only one cystic fibrosis mutation (true carriers) don’t exhibit CBAVD and are generally fertile as in the case of the male partner of the couple described in Case History 2.
Management options
Management of the two couples in Case Histories 1 and 2 require the collaborative expertise of fertility specialists and a genetics center with advanced molecular diagnostic facilities.
Diagnosis and counseling
Clinical diagnosis of CBAVD is easily made via palpation. Secondary sexual characteristics are normally developed. Testicular size is usually normal, and the epididymis may be engorged and distended on palpation depending on whether it is involved in the process of atresia or not. Typically, the vas deferens on either side is absent, although occasionally testicular ultrasound is required for confirmation of diagnosis. Renal ultrasound is indicated to rule out associated renal tract anomalies. In addition to azoospermia, the semen analysis exhibits normal or reduced volume, increased acidity and low concentration of fructose. Serum hormone levels show normal FSH, LH, testosterone and prolactin levels.
Molecular genetic confirmation is obtained via extended mutation analysis typically involving over 100 different cystic fibrosis mutations to identify not only the 32 most common mutations, but also to detect the less common mutations responsible for the CBAVD condition. This detailed mutation testing is particularly indicated if only one mutation was detected in either partner on routine cystic fibrosis screening in the presence of a history of recurrent respiratory or digestive disease, as could be in Case History 2, for example. Screening of the female partner of men with CBAVD is crucial to fully understand the future reproductive risks for the couples such as in Case History 1.
After
