delta F508 and R1070W

Question

My boy 3yo has been diagnosed with CF heterosigotus of delta F508 (7T-9T polimorfism) and R1070W (in exon 17b).
This mutation R1070W alters an arginine into a tryptophane on amino acid position 1070 of the resulting protein (p.Arg1070Trp).

He never had pulmonary infections and is pancreatic sufficient (faecal elastase is normal). He is 100 cm and 15,5 kg. He has been diagnosed as result of several severe dehydration through perspiration, at the age of 7-11 monts. The sweat test had three different values(but was 68 after several days of NaCl perfusions, then 59 done 3 weeks after the perfusion was stopped, and 49 - few months later). He now receives Humana Electrolytes with every glass of water and daily aerosols 4 ml of 3,5 concentration of NaCl.

He has normal abdominal echography. We have investigated, and at the echography and surgeon control (hand touch), it seems like he might have deferent vases.
What would be the prognosis in his case? How can I realize his lungs are affected over time?
Thank you.

Answer

Dear Parent
Thank you for your question regarding your child with CF genetics delta F508/R1070W.
The question of the severity of symptoms with these two mutations has already been dealt with in previous answers.
This answer will therefore concentrate on the congenital bilateral absence of the vas deferens (CBAVD).
Studies report that around 98% males with CF have CBAVD leading to infertility. The R1070W mutation is usually associated with CBAVD.
The defect in the CFTR protein affects formation of the ejaculatory ducts, seminal vesicles, vas deferens and the distal 2/3 of the epididymis.
Clinical findings on examination of the testes should reveal normal testicular volume, enlarged/hardened epididymis, nodules in the epididymis or vas deferens and absence or partial atresia of the vas deferens.
Ultrasound scan (USS) of the scrotum can help look for signs of obstruction/ absence of the vas deferens. Transrectal USS can be performed in adults if a more distal obstruction is suspected but would not usually performed in children.
Confirmation of a diagnosis of CBAVD in adulthood is made by assessing a combination of factors
• a small volume of ejaculate
• absence of spermatozoa (however spermatogenesis {production of sperm}is usually intact)
• increased acidity of the seminal fluid (pH less than 7)
• absence/decreased concentration of fructose (type of sugar) in the seminal fluid
• normal blood levels of FSH (follicular stimulating hormone)

Males with CF can now still go on to have children with assistance using ICSI (intracytoplasmic sperm injection).

Sperm is collected by direct aspiration of the epididymis/testicle by fine needle under local anaesthetic. The female partner has ovarian stimulation to allow collection of eggs, which are collected under sedation with USS guidance. A single sperm is injected into an egg and after several days replaced into the womb.
Fertilisation rate of up to 60% have been reported but successful outcomes are lower. Success rates of 30-50% have been reported in some studies (Callum et al 2000, Dohle et al 1998). Success rates for ICSI in the UK are currently quoted to be around 28% per cycle.

Prior to assisted conception the couple should be counselled about the risks of the embryos being affected by CF. The female partner should be carrier tested , if she is a carrier for a know CF gene then there is a 50% chance that an embryo would be affected. Couples can opt for pre-implantation diagnostic genetic testing so that only embryos not affected would be replaced. A single cell is taken from the embryo and tested for CF prior to implantation.

If the female partner has no identified mutations there is still 0.4% risk of being a carrier of an unidentified mutation. The risk of having a child with CF is then 1:400.

ICSI and PGD are expensive treatments and are not available in all areas. You should discuss this with your CF centre as they will be able to give you information as to what is available locally.
It is important to remember when counselling males with CF about fertility also to discuss the risks of sexually transmitted diseases.

Dr Laura Jenkins

Literature:
Fertility in men with CF. Update on current surgical practice and outcomes. Callum T et al; CHEST 2000, 118:1059-1062

Genetic risk factors in infertile men with severe oligozoospermia & azoospermia. Dohle GR et al Human Reproduction Vol117 No. 1 pp13-16. 2002

European Guidelines on male infertility. European Urology 48(2005)703-711

Cystic fibrosis transmembrane conductance regulator gene mutations in infertile males with CBAVD. Tohoku. J Exp Med 2005 Dec 207(4) 279-85

www.cfmedicine.com

28.02.2012