Case history

Mr and Mrs A attend your paediatric clinic with their 18 month old daughter. She has a history of repeated chest infections, failure to thrive, and steatorrhoea (fatty stools). As part of the consultation you take a family history and draw the pedigree (family tree) (fig 1).

Fig 1 Family tree

Questions

(1) What does the double line between Mr and Mrs A represent?

(2) You suspect an inherited disorder. Examining the pedigree, what is the most likely pattern of inheritance--sex linked, autosomal dominant, or autosomal recessive?

(3) What is the most likely diagnosis?

(4) Given that Mr and Mrs A's first child--an 8 year old boy--is fit and well, what is the probability that he is a carrier of the inherited disorder?

(5) While at clinic, Mrs A tells you that she is pregnant and is worried that the child could also be affected by the same condition. Who would you refer her to and why?

Answers

(1) Consanguinity, which means "of the same blood." Mr and Mrs A are genetically related as they share a common set of grandparents--they are first cousins.

(2) Autosomal recessive. The affected child is a girl, which makes a sex linked pattern of inheritance unlikely as this usually affect males. Neither of the parents appears to be affected, which makes an autosomal dominant pattern also unlikely. Most probably, both Mr and Mrs A are carriers of an autosomal recessive condition, having both inherited the faulty gene from a shared common ancestor. Consanguinity increases the chances of autosomal recessive diseases in offspring.

(3) Cystic fibrosis.

(4) Two thirds. If both parents are carriers of an autosomal recessive condition then there is a one in four chance in each pregnancy that the child will be affected--in other words, inherit both copies of the faulty gene. There is a two in four (one in two) chance that the child will be a carrier--thus inherit one copy of the faulty gene. And there is a one in four chance that the child will be neither affected nor a carrier--inherit neither copies of the "faulty" gene. However, in this case we already know that Mr and Mrs A's 8 year old son is fit and well. As cystic fibrosis usually presents early in childhood, we can therefore deduce that he is unlikely to be affected. Hence we have eliminated one of the possibilities. Therefore there is a 2 in 3 chance (instead of a 2 in 4 chance) that he is a carrier for the condition. Carriers of autosomal recessive conditions are usually asymptomatic (see fig 2).

(5) Clinical geneticist for genetic counselling--see discussion--and to discuss prenatal testing. Prenatal testing for cystic fibrosis is possible and can be done either through chorionic villous biopsy at 10-11 weeks of pregnancy or amniocentesis at 15-16 weeks.

Fig 2 Autosomal recessive inheritance.If a child is not affected then there is a two in three chance that the child is a carrier

Discussion

Cystic fibrosis

Cystic fibrosis is one of the commonest autosomal recessive conditions, with an incidence of 1 in 2000. The carrier (heterozygote) frequency for this condition is quite high in the general population at about 1 in 20. The cystic fibrosis gene is located on the long arm of chromosome 7, and codes for a protein that regulates chloride ion channels. The most common mutation--in 66% of cases--is a phenylalanine codon deletion, known as F508. Affected individuals produce secretions that are highly viscous, which results in multi-organ dysfunction. The lungs are prone to recurrent infections, and disturbance of pancreatic secretions leads to disordered digestion, with steatorrhoea and failure to thrive. Neonates can also present with meconium ileus (intestinal obstruction).

Genetic counselling

Genetic counselling refers to the process by which information relating to an inheritable condition is shared with an individual or several members of a family. Topics covered can include confirming the diagnosis of the condition in the family; ascertaining the risks to family members of being carriers or affected by the condition and offering genetic testing when appropriate; and discussing the course of the disease, the treatment options, and management strategies, including support groups. Genetic counselling might also involve discussing diagnostic tests, including predictive DNA testing of other, currently asymptomatic, family members. The latter, however, can raise ethical issues relating to whose interests are best served by carrying out such tests.

Fig 1 Family tree Fig 2 Autosomal recessive inheritance. If a child is not affected then there is a two in three chance that the child is a carrier Further reading

• Bonthron D, FitzPatrick D, Porteous M, Trainer A. Clinical genetics: a case-based approach. London: WB Saunders, 1998
• Passarge E. Color atlas of genetics: with 194 color plates by Jurgen Wirth. 2nd ed. Stuttgart: Thieme, 2001
• Leung W-C, Mariman ECM, van der Wouden JC, van Amerongen H, Weijer C. Ethical debate: results of genetic testing: when confidentiality conflicts with a duty to warn relatives. BMJ 2000;321:1464-6
• Mallia P. Biomedical ethics: genetics. studentBMJ 2003;11:320-1 (September.)

Well the daughter could get Cystic Fibrosis. Mr and Mrs A are genetically attracted so that means the daughter could be a carrier.

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