VOLUME 16 NUMBER 6 November/December 2003

Cystic Fibrosis in India: [PDF]

Cystic fibrosis (CF) was first described as a clinically distinct entity in 1938 by Anderson. Initially, it was considered a rare and lethal disease of infancy. Over the past six decades, major advances in the understanding of CF have resulted in an increase in the median age of survival to 30 years.1

Cystic fibrosis is the most common life-limiting genetic disorder in Caucasians with an incidence of approximately 1 in 2500 children born in the UK.2 It is less common in African Americans (1 in 15 000) and Asian Americans (1 in 31 000). It also affects other ethnic groups such as Blacks with an incidence of 1 in 17 000 and native Americans with an approximate incidence of 1 in 80 000.3,4

Cystic fibrosis was thought to be extremely rare in India and was first reported in 1968.5,6 However, a recent review of all cases of CF reported in the literature indicates that the disease is probably far more common in people of Indian origin than previously thought, but its diagnosis is missed in the majority of cases.7 The precise incidence of CF among Indians is unknown. The estimated incidence of CF in the migrant population from the Indian subcontinent in the USA is 1 in 40 000,8 and that in the UK is 1 in 10 000–12 000.9,10 A recent study on 955 cord blood samples reported a carrier rate of the common mutation DF 508 (DF 508) as 0.4%.11 By using the same data the incidence of CF in India is estimated to be 1 in 40 000.

The CF gene was identified in 1989. It is located on the long arm of chromosome number 7 at position 7qI3,12,13 and more than a thousand mutations in the gene have been recognized.14 The basic defect in CF is a mutation in the gene for the chloride conductance channel, i.e. cystic fibrosis transmembrane conductance regulator. This results in an abnormality of cyclic adenosine monophosphate regulated chloride conductance by epithelial cells on the mucosal surface. The failure of chloride conductance leads to dehydration of secretions that become viscid and are difficult to clear.15 The prevalence of genetic mutations varies from one population to another. The commonest mutation is DF 508, which constitutes about 70% of the total cases.16 The frequency of this mutation in Indian children is reported to be between 19% and 44%.7,8,10,17–20 In a report of 120 Indian children with CF,20 the DF 508 mutation was identified in 45 chromosomes (19%) out of the 240 tested; 19 patients (16%) were homozygous and 7 (6%) were heterozygous for the mutation. The frequency of DF 508 mutation was higher in patients whose parental origins were from Pakistan. Out of 23 patients whose origin was traced to Pakistan, 13 (56%) were positive for the DF 508 mutation. The figure for patients originating from other parts of India was 13 (13%) out of 97 patients. In a report from Pakistan describing mutations in 15 patients, the DF 508 mutation was found in 60% of the patients.21 The spectrum of mutations other than DF 508 in Indian patients is highly variable and some rare and new mutations have also been described.17

It has been reported from other Asian countries. that there are fewer children with DF 508 mutations as compared with the Caucasian population. Desgeorges et al.22 identified 20 families living in Lebanon for several generations who had at least one child with CF. They showed that 10 different DNA alterations—including two novel mutations—accounted for 88% of the CF alleles. The DF 508 mutation was found in 37.5% of the CF alleles.

The clinical features of CF are variable, and depend on the age at diagnosis, supportive care and treatment. It has been suggested that CF is more severe in Asians.10 There are not many studies which document the clinical features in Indian children. A review of 20 Asian children diagnosed with CF till 1994 in the USA suggests that the mean age at diagnosis was delayed to 12 months as compared to 6 months in their American counterparts. In a study of 18 children from Chandigarh, the mean age at diagnosis was 4.8 years and the mean duration of symptoms was 4.1 years, suggesting a delayed diagnosis.23

In a recent report of 120 patients with CF20 from the All India Institute of Medical Sciences, New Delhi it was observed that most of the clinical manifestations at the time of presentation were similar to those reported from the West and included recurrent or persistent pneumonia, failure to thrive, malabsorption, rectal prolapse, history of dehydration in the past, meconium ileus, salt craving, salty taste on kissing and skin rashes. The clinical manifestations that were different from the western series on CF included: vitamin A and D deficiencies, lower CF clinical scores suggesting advanced stage of illness at the time of diagnosis, hypochloraemic alkalosis, higher colonization rate with Pseudomonas and lower rates of common mutations.20

It has also been reported that the frequency of different morphotypes of Pseudomonas aeruginosa as well as the antibiotic resistance in these strains were higher in Indian children with CF, and some of them were colonized by phenotypically and genotypically distinct strains of Pseudomonas aeruginosa, which has an implication for the management of these patients.24

The diagnosis of CF is based on clinical features and demonstration of high sweat chloride values. To avoid false-positive and false-negative results, the sweat test should be done by experienced laboratories and must be repeated 2–3 times.25 After the identification of CF mutations in 1989, it was believed that the diagnosis would be easy. However, because of the large number of known mutations (>1000) and their geographic variability, diagnosis by mutations alone is not easy. In the USA, testing for 64 mutations provided a sensitivity of 70%–95% in all ethnic groups except Asians and at least 81% when the US population was considered as a whole.26 The wider mutation profile in Indian patients has not been investigated. In a study on 24 patients in whom 18 exons of the CF gene were screened using single strand conformational polymorphism (SSCP) it was observed that DF 508 was present in 40% and the remaining mutations were multiple in accordance with the multi-ethnic background of the patient population.17

Facilities for the identification of CF mutations are not readily available in India. The sweat test remains the best diagnostic tool. However, attempts should be made to identify mutations for further evaluation, patient counselling and prenatal testing.

In the absence of sweat chloride estimation and mutation analysis at most centres in India, CF may be suspected on the basis of supportive investigations. These include low or low normal serum sodium and potassium, metabolic alkalosis and hypochloraemia, isolation of Pseudomonas aeruginosa or Burkholdelia cepacia from sputum or cough swabs, exocrine pancreatic deficiency below 20 years of age or azoospermia in postpubertal patients.

While CF does occur in Indian children, its precise magnitude is not known; but the clinical features are typical. The diagnosis is often delayed and at presentation the disease is therefore advanced in most patients. They may have evidence of fat-soluble vitamin deficiency and laboratory evidence of hypochloraemic metabolic alkalosis with hypokalaemia. A major proportion of these patients are colonized with Pseudomonas aeruginosa at the time of diagnosis. The common mutation DF 508 is less frequently seen in Indians than in Caucasians. Apart from creating an awareness about CF among healthcare workers, it is also necessary to develop diagnostic and treatment facilities for such patients.

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s. k. kabra
Paediatric Pulmonology Division
madhulika kabra
Genetics Division
Department of Paediatrics
All India Institute of Medical Sciences
New Delhi


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