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Cystic Fibrosis (CF) and Infertility

Cystic Fibrosis is an autosomal recessive condition in Caucasians and affects 1/2500 live births. 1/25 people are carriers. The typical form has chronic pulmonary obstruction/infection, exocrine pancreatic insufficiency (85% of patients), and elevated sweat chloride concentrations. (>60 mmole/l) Other symptoms include neonatal meconeum ileus , liver disease, diabetes mellitus, and male infertility (>95%). Females may have infertility, albeit at a lower frequency. The Cystic Fibrosis Transmembrane Receptor (CFTR) gene encodes a 1480 amino acid protein that transports Cl- across membranes, and has more than 700 mutations. 27 Exons are over 250 kb of DNA on chromosome 7. The most common mutation (70%) is the deletion of a Phe at position 508 (F508). Mutations are functionally divided into 5 classes: 1, no synthesis, of known cases, non-sense, frame shift, and aberrant splicing; 2, block in processing mutations, delta F508, secondary to improper folding protein is mislocated on epithelial cell and not protease resistant; 3, block in regulation of Cl- channel; 4, altered conductance of the Cl- conductor or gate; and 5, reduced synthesis of functional CFTR protein (1). Only 2-3 % of CF patients are fertile. Almost all have congenital bilateral absence of the vas deferens (CBAVD). The body and tail of the epididymis are rudimentary or absent. Seminal vesicles may be anomalous with aplasia, hypoplastia, or cystic dilatation (2). Spermatogenesis may be impaired (3). Most are autosomal recessive. Some pedigrees have an X-linked recessive pattern or autosomal dominant, male limited. Penetrance is approximately 60 % (2). From a developmental standpoint, the CFTR protein must play some role in embryonic vas deferens development.

Atypical forms of CF, monosymptomatic, including congenital unilateral absence of the vas deferens, bilateral ejaculatory duct obstruction, bilateral obstruction w/in the epididymis, idiopathic pancreatitis, bronchiectasis, and nasal polyps (2). R117H and 5T are other common alleles found. The presence or absence of renal malformations is important to ascertain. If the patient has CBAVD and renal anomalies no CFTR mutations have been identified. Therefore, his spouse does not need testing for this. Three out of five patients with congenital unilateral absence of the vas deferens had mutations and 2/7 with azoospermia with normal vas deferens (2).

Only 80 % of the potential mutations can be determined. Renal ultrasound is performed. If anomalies are not present, both partners should be screened for mutations. Lewis-Jones et al (4) tested for 8 mutations (detection rate 90 %). If the female was negative the risk of having an affected child would be 1:960. Of course, if the male is positive, the female must be tested given this high carrier frequency. The risk could be if both were positive. MESA/ICSI followed by PGD has resulted in the birth of a health female screened for CF (5). This technology is becoming generally available. First PCR and now reports of micro-arrays (6) using multiple probes may make diagnosis more accurate.

Thus, CF mutation testing should be offered when performing ICSI for the above indications.

References:

1. Zielenski J, Tsui L-C. Cystic fibrosis: genotypic and phenotypic variations. 1995. Ann. Rev. Genet. 29:777-807.

2. Stuhrmann M, Dork T. CFTR gene mutation testing and male infertility. 2000. Adrologia 32(2):71-83.

3. Meng M, Black L, Cha I, ljung B-M, Pera R, Turey P. Impaired spermatogenesis in men with congenital absence of the vas deferens. 2001. Hum Reprod. 16 (3):529-33. Stuhrmann M, Dork T. CFTR gene mutations and male infertility. 2000. Andrologia 32:71-83.

4. Lewis-Jones DI, Gazvani MR, Mountford R. Cystic fibrosis in infertility: screening before assisted reproduction. 2000. Hum. Repro. 15(11)2415-17.

5. Handyside AH, Lesko JG, Tarin JJ, Winston RML, Hughes MR. Birth of a normal girl after in vitro fertilization and pre-implantation diagnostic testing for cystic fibrosis. NEJM 327:905-909.

6. Salvado CS, Cram DS. Towards preimplantation diagnosis of cystic fibrosis ising microarrays. 2004. RBM Online 8(1):107-114.
 

 

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