Amjad Fathi Hussein El-ShantiMD, MPH, Doctorate of Public Health (Epidemiology)

Medical director of CFFC-Gaza

April-2014

Contents

• Introduction:Definition of Cystic fibrosis (CF)Epidemiology of CF ( Magnitude and Genotype Distribution)Pathogenesis of CFClinical Manifestations of CFDiagnosis of CFTreatment

• CF in Gaza Strip• Conclusion• Recommendations

What is cystic fibrosis (CF)?• A multisystem disease• Autosomal recessive inheritance• Cause: mutations in the cystic fibrosis

transmembrane conductance regulator (CFTR)– chromosome 7 – codes for a c-AMP regulated chloride channel

Rosenstein, BJ and Zeitlin, PL. Cystic fibrosis. The Lancet. 351: 277-82.

•A multisystem disease

•Autosomal recessive inheritance

What is cystic fibrosis (CF)?

Rosenstein, BJ and Zeitlin, PL. Cystic fibrosis. The Lancet. 351: 277-82.

Definition

Autosomal recessive inheritance in CF

Let C= normal CFTRLet c= mutant CFTRIf mom and dad are both

carriers then:

• With mom and dad carriers, then:– 50% chance of having

child who is a carrier– 25% chance of child

being affected– 25% of child with no

mutant copies of CFTRCC

Cc

Cc

cc

C c

C

c

Definition• Cystic Fibrosis (CF) or mucoviscidosis is an

inherited disease of the exocrine glands, primarily affecting the GI and respiratory systems, and usually characterized by COPD, exocrine pancreatic insufficiency, and abnormally high sweat electrolytes, causing progressive disability and often, early death.

• It is caused by a mutation in a gene called the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).

Epidemiology of Cystic Fibrosis

• Birth prevalence is traditionally cited as 1 in 2,000 to 1 in 2,500 live births in Caucasian populations.

• For Non-Caucasian countries, the problem of estimating birth prevalence of CF is even greater, and good estimates are lacking.

Magnitude and genotypic distribution

• In UK, in 2003, the prevalence of CF was of 11.7 per 100,000.

• In Canada, the prevalence was 10.5 per 100,000 (based on 2002 patient registry data and 2005 population estimates).

Magnitude and genotypic distribution

• The incidence of CF among Arabs is estimated to range from rare to as common as the Caucasian populations.

• Reports indicated frequencies ranging from 1:5800 in Bahrain, to 1:2650 in Jordan.

• In Egypt, CF is more common than previously anticipated with an incidence rate of 1:2664.

Magnitude and Genotypic Distribution

• The commonest mutation identified in the world is DF508, which comprises 66% of global mutations, followed by G451X and G551D which are responsible for 2.4% and 1.6% of the mutations respectively.

Magnitude and Genotypic Distribution

• Survival and mortality rate are useful indicators of clinical outcome, and are likely to be influenced by a variety of factors.

• The CDR for CF in 2003 in the UK is only 0.17 per 100,000 general population.

• In USA, standardized mortality has been shown to vary significantly with genotype, being as low as 4.4 per 1000 person-years at risk for certain genotype combination and as high as 25 per 1000 for others.

Magnitude and genotypic distribution:

• Non genetic factors:1. Gender2. Skin color and race3. Birth weight4. Consanguinity5. Socioeconomic status6. Environmental factors7. Patient adherence to prescribed medical regimens

• Genetic Factors:1. CFTR gene mutations2. Modifying genes

Risk factors & determinants

Pathogenesis of CF

Pathogenesis

• The CFTR gene is found in region q31.2 on the long (q) arm of human chromosome 7.

Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

CFTR Gene and Protein

Pathogenesis• The CFTR protein transports chloride ions (Cl-) ions

across the membranes of cells of the lungs, liver, pancreas, digestive tract, reproductive tract, and skin.

• It is made up of five domains:

Types of mutations in CFTR• Class I

– Defective protein production• Class II

– Defects in processing• ΔF508

• Class III– CFTR reaches cell surface but

regulation is defective (channel not activated)

• Class IV– CFTR in membrane with

defective conduction• Class V

– Decreased synthesis of CFTRhttp://www.cysticfibrosismedicine.com/htmldocs/CFText/genetics.htm

Pathogenesis

• Mutations in the CFTR gene have been classified into five different groups according to the mechanism by which they disrupt CFTR function.

ClassEffect on CFTR proteinExample of mutation

IShortened proteinW1282X

IIProtein fails to reach cell membrane

ΔF508

IIIChannel cannot be regulated properly

G551D

IVReduced chloride conductance

R117H

VReduced due to incorrect splicing of gene

3120+1G>A

5 Classes of CFTR Mutations

20

II

Defective

Processing

III

Defective

Regulation

IV

Defective

Conductance

V

Reduced

Amounts

I

Defective

Production

CFTR and Airway Surface Liquid

Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.

Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

Airway surface liquid low volume hypothesis

• Mucus---helps clear airway of bacteria• Clearance of mucus depends on

– Ciliary function– Mucin secretion – Volume of airway surface liquid (ASL)

• Forms periciliary liquid layer• Dilutes mucus---facilates entrapment of bacteria and

clearance• Optimal volume of ASL regulated by Na+ absorption

and Cl- secretionDonaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.

Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

• Normal CFTR inhibits a sodium channel (ENaC)– Mutant CFTR----ENaC not inhibited

• Sodium absorption is increased• Water follows sodium• ASL volume decreases

• Normal CFTR will cause Cl- ions to be secreted if the ASL fluid is low– Mutant CFTR Cl- ions not secreted

Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

Airway surface liquid low volume hypothesis

• Cilia do not beat well when PCL volume is depleted

• Mucins are not diluted and cannot be easily swept up the airway

• Mucus becomes concentrated• Results in increased adhesion to airway surface• Promotes chronic infection

Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.

Airway surface liquid low volume hypothesis

25

The mutant form of CFTR prevents chloride transport, causing mucus build-up

Mucus clogs the airwaysMucus clogs the airways

and disrupts the function ofand disrupts the function of

the pancreas & intestinesthe pancreas & intestines . .

From Mutation To Disease

Pathophysiology of CF

CFTR Dysfunction

Disease manifestations

– Lungs

– Sinuses

– Pancreas

– Liver

– Bones

– Vas deferens

??

Clinical Manifestations of CF

• Chronic Sino-Pulmonary Disease• Nutritional deficiency/GI abnormality• Obstructive Azoospermia• Electrolyte abnormality • CF in a first degree relative

Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.

Chronic Sino-Pulmonary Disease

• Chronic infection with CF pathogens • Endobronchial disease

– Cough/sputum production– Air obstruction---wheezing; evidence of obstruction on

PFTs– Chest x-ray anomalies– Digital Clubbing

• Sinus disease– Nasal Polyps– CT or x-ray findings of sinus disease

Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.

Infection

Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

Prevalence of Infections in CF Patients

00

2020

4040

6060

8080

100100

00 to 1to 1 22 to 5to 5 66 to 10to 10 1111 to 17to 17 1818 to 24to 24 2525 to 34to 34 3535 to 44to 44 4545++

Age (years)Age (years)

Per

cen

tP

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nt

Cystic Fibrosis Foundation Patient Registry Data. 2005

P. aeruginosaP. aeruginosa

S. aureusS. aureus

MRSAMRSA

H. influenzaH. influenza

S. maltophiliaS. maltophilia B. cepaciaB. cepacia

CF Infections---Pseudomonas aeruginosa

• 80% CF patients eventually infected with pseudomonas

• Association between acquiring pseudomonas and clinical status deterioration

• Form biofilms• Relatively large genome

– Pseudomonae collected from sputa of CF patients have been noted to have larger genomes than lab strains

Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.

Pseudomonas genome

http://www.pseudomonas.com/

Burkholderia cepacia complex

• B. cepacia syndrome: fevers, rapidly progressive necrotizing pneumonia, death

• Chronic cepacia infection decreased lung function and increased mortality

• Several closely related species termed genomovars1

Holmes, A, Govan, J, and Goldstein, R. Agricultural Use of Burkholderia (Pseudomonas) cepacia: A Threat to Human Health?Emerging Infectious Diseases. 4(2):221-227; 1998

1. Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.

Endobronchial disease

• Hyperinflation• Peribronchial cuffing• Bronchiectasis• Diffuse fibrosis • Atelectasis

From: http://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htm

Nasal Polyps

• Benign lesions in nasal airway

• If large enough, can be associated with significant nasal obstruction, drainage, headaches, snoring

• Likely associated with chronic inflammation

• May need surgical intervention

• High recurrence rate

From :http://www.emedicine.com/ped/topic1550.htm

Digital Clubbing

• Bulbous swelling at end of fingers

• Normal angle between nail and nail bed lost (Schamroth sign)

• Can be associated with pulmonary disease, cardiac disease, ulcerative colitis, and malignancies

From: Fawcett et al., 2004

Nutritional deficiency• Pancreatic insufficiency

• Pancreatic enzymes stay in ducts and are activated intraductally

– Autolysis of pancreas– Inflammation, calcification, plugging of ducts,

fibrosis

• Malabsorption– Failure to thrive– Fat soluble vitamin deficiency

1. Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press. Doi: 10.1164/rccm.200505-840OE; 2005.2. Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22, 1999.

GI disease

• Intestinal abnormality– Meconium ileus– Distal intestinal obstruction syndrome (DIOS)– Rectal prolapse

• Hepatobiliary disease– Focal biliary cirrhosis– Multilobular cirrhosis

• Pancreatic endocrine dysfunction– Cystic fibrosis related diabetes

Cystic fibrosis related liver disease• Focal inspissation of bile

– Obstructs biliary ductules

• Second leading cause of death in CF1

• Prevalence 9-37%1

• Spectrum of disease – increased liver enzymes – biliary cirrhosis – portal hypertension

1. Efrati, O et al., Liver Cirrhosis and portal hypertension in CF. European Journal of Gastroenterology and Hepatology. 15(10): 1073-1078; 2003.

Cystic fibrosis related diabetes mellitus

• Screening– Oral glucose tolerance test (OGTT)

• Every two years in patients 10-16 years• Any patient with random plasma glucose >180

• Fasting>=140 mg/dl– initiate insulin treatment

• Fasting<140 and OGTT at 2 hrs>200 mg/dl– Home glucose monitoring; consider insulin

• Fasting <140 and 2 hour 140-200– Impaired glucose tolerance

• OGTT annually• Fasting and 2 hour <140

– Normal glucose tolerance

Infertility

• Men– Abnormal embryologic development of the

epididymal duct and vas deferens---may be incomplete of absent1

– Congential bilateral absence of the vas deferens—97-98% of men with CF 1

1. Lewis-Jones et al, Cystic fibrosis in infertility: screening before assisted reproduction: Opinion. Human Reproduction 15(11): 2415-2417.

Infertility• Women

– Lower fertility rate than non-CF women– Viscid mucoid cervical secretions of low volume in

women with CF 1

• Pregnancy and CF: – Goss et al, 2003---no significant difference in

survival in women who became pregnant with CF compared to women who did not become pregnant (after adjusting for disease severity)2

1.Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22, 19992.Goss, CH, Rubenfeld, GD, Otto, K and Aitken, ML. The effect of pregnancy on survival in women with cystic fibrosis. Chest 124(4):1460-68; 2003.

Electrolyte abnormality---history• Dr. Paul di Sant’ Agnese

– 1949 NYC heat wave----noted CF infants to have a higher rate of heat prostration than non-CF

• Showed that sodium and chloride concentration in CF patients’ sweat was 5 times higher than in non-CF1

– Became basis for sweat chloride test

.1Davis, P. Cystic Fibrosis Since 1938. American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 475-482, (2006)

Electrolyte abnormality

• Clinically---hypochloremic metabolic alkalosis– CFTR on luminal side of sweat duct

• Chloride goes in from lumen via CFTR and out to blood by other transporters

• Sodium goes in via ENaC• Defective CFTR---Na and Cl- movement and

reabsoprtion into lumen impeded

Goodman, B and Percy, WH..CFTR in Teaching Membrane Transport. Adv Physiol Educ. 29 (79-82); 2005

Genetic Determinants of severity of disease

• The variability in disease severity in patients with CF is not a consequence of relative preservation of pancreatic function but is a result of different gene mutants, together with additional factors, genetic and /or environmental.

• The location of a mutation along the CFTR gene has no direct effect on severity of CF disease.

• One or more clinical manifestations of CF PLUS• Two CF mutations OR• Two positive quantative pilocarpine

iontophoresis sweat chloride values OR• An abnormal nasal transepithelial potential

difference value

Diagnosis of Cystic Fibrosis

Diagnostic criteria for cystic fibrosis

Part 1: Clinical Manifestation of Disease• At least one of the following:

1) One or more clinical manifestations of CF• Meconium ileus• Chronic bronchitis / bronchiectasis• Chronic infection of the paranasal sinuses• Pancreatic insufficiency• Salt loss syndromes• Male infertility due to congenital bilateral absence of the vas deferens

2) Positive newborn screening test3) History of CF in a sibling

Diagnostic Criteria for Cystic FibrosisPart 2: Laboratory evidence of CFTR abnormality

• At least one of the following: 1) Elevated sweat chloride test

2) Identification of a mutation in each CFTR gene known to cause CF

3) In vivo demonstration of characteristic abnormalities in ion transport across nasal epithelium (not widely available)

Sweat Test

Sweat Test for Diagnosis of CF

0 20 40 60 80 100 120 140 160 180

mEq/L

0

300

600

900

1200

1500

1800

0

600

120

180

240

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Shwachman H, Mahmoodian A. Mod Prob Pediatr 1967;10:158

A perspective on the Sweat Test• The “sweat test” provides laboratory confirmation

of the clinical diagnosis of Cystic Fibrosis.

• This occurs because of an abnormally high salt concentration in their eccrine sweat, ranging from 3-5 times higher than that of normal children.

A perspective on the Sweat Test• The sweat Test was first described in 1959 by

Gibson & Cooke and remains the “ Gold Standard” for the diagnosis of cystic fibrosis.

• In the majority of CF patients with typical features and identified CFTR mutations, the sweat test is diagnostic.

• In atypical forms, the sweat chloride levels may fall into the intermediate range and there are rare examples of patients with CF, confirmed on genetic testing, who have a normal sweat test.

SWEAT TESTING PROCEDURE WESCOR MACRODUCT

Sweat Stimulus & Collection

Sweat Analysis

Sweat chloride

–Positive Sweat chloride: 60-165 meq/L

–Borderline sweat chloride: 40-60 meq/L

–Normal sweat chloride: 0-40

Sweat chloride• False positives:

– Anorexia Nervosa– Autonomic dysfunction– Addison disease– Ectodermal dysplasia– Eczema– Edema– Fucosidosis– Glucose-6-Phosphate dehydrogenase deficiency– Glycogen storage disease Type 1– Hypothyroidism– Hypoparathyroidism– Malnutrition from various causes including HIV infection– Nephrogenic diabetes insipidus– Nepohrosis– Lab error (evaporation or contamination of sample)

Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press. Doi: 10.1164/rccm.200505-840OE; 2005.

Sweat Chloride• False negatives:

– Edema– Malnutrition– Some CF mutations– Sample diluted

Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press. Doi: 10.1164/rccm.200505-840OE; 2005.

Use of Genotyping to Diagnose CF

• 1601 CFTR mutations known to cause CF

• Only 25 mutations have a frequency > 0.1%

FrequencyFrequency% ,% ,

00 1010 2020 3030 4040 5050 6060 7070

R347PR347P3849+10kbC 3849+10kbC T T

ΔΔ I507 I507R117HR117H

R1162XR1162X1717-1G 1717-1G A A

R553XR553X621+1G 621+1G T T

W1282XW1282XN1303KN1303KG551DG551DG542XG542XΔΔF508F508

CF Genetic Analysis Consortium

Population Frequency of Specific CFTR Mutations Causing CFPopulation Frequency of Specific CFTR Mutations Causing CF

Genotyping for CF Diagnosis

• Current commercial screening tests

– Look for presence of between 25 - 100 mutations

– These will detect a CF allele only ~90% of time

• For a group of patients with known CF, genotyping would be diagnostic in only ~81% of patients

• Screening for most common mutations is not as sensitive as sweat testing (98%) to diagnose classic CF

Genetic Diagnosis of CF

• Tests becoming commercially available for detecting mutations more broadly– PCR used to amplify all exons and surrounding

splice sites– Heteroduplex formation screening and/or

sequencing– Analysis for large deletions and duplications

Treatment

It gets more complicated......

Treatment

•The only way to cure CF would be to use gene therapy to replace the defective gene or to give the patient the normal form of the protein before symptoms cause permanent damage.

• The major goal in treating CF is:1. to clear the abnormal and excess secretions and 2. to control infections in the lungs, and3. to prevent obstruction in the intestines.

• For patients with advanced stages of the disease, a lung transplant operation may be necessary.

• Although treating the symptoms does not cure the disease, it can greatly improve the quality of life for most patients and has, over the years, increased the average life span of CF patients to 30 years.

Treatment of Acute Exacerbations of CF Lung Disease

• Antibiotic treatment– Oral antibiotics

• If symptoms are mild, and• Bacteria are susceptible

– Intravenous antibiotics otherwise

Management of Chronic Lung Disease in Cystic Fibrosis

Aerosolized Antibiotics

• High dose tobramycin proven for chronic infection–TOBI® 300 mg in 5 ml bid every other month

Ramsey B, et al. NEJM 1999;340:23-30

Mucolytic Therapy for CF

• DNase (Pulmozyme ®)–Chronic use improves FEV1 and causes fewer exacerbations

Fuchs HJ, et al. NEJM 1994;331:637-642

Bronchodilators in CF

• No studies in acute exacerbations but routinely given

• Chronic use -- FEV1 improves acutely in some patients– -adrenergic agonists (e.g. albuterol, salmeterol)– Anticholinergic agents (ipratroprium bromide,

tiotroprium)

Anti-Inflammatory Treatment in CF

• Glucocorticoids– Oral (prednisone)

• Preserves lung function, but too many adverse effects

– Inhaled• Used for subgroup of with bronchial hyperreactivity

(asthma) symptoms

• Ibuprofen– Beneficial for young patients– No evidence for improvement in adults

Macrolide Therapy for CF

• Azithromycin in CF– Improved FEV1– Fewer exacerbations of CF

lung disease– Uncertain mechanism of

action• Anti-inflammatory?• Bacterial toxin or biofilm

production? 00 44 1212 2424 2828

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Saiman L, et al. JAMA. 2003;290:1749-56

Nebulized Hypertonic Saline (7%)

Elkins MR et al. N Engl J Med 2006;354:229-240

• Effect on FEV1

– Randomized, double-blind, placebo controlled trial

– N = 164

– Inhalation of 4 ml of 7% vs. 0.9% saline bid for 48 weeks

Effect of 7% Saline on Frequency of Pulmonary Exacerbations

Elkins MR et al. N Engl J Med 2006;354:229-240

Physiotherapy for CF

• No studies in acute exacerbations– But “standard of care” treatment

• Beneficial for chronic management

Gastrointestinal Treatment Modified diet • Due to pancreatic disorders, children with CF

require a modified diet, including vitamin supplements (vitamins A, D, E, and K) and pancreatic enzymes.

• Maintaining adequate nutrition is essential. The diet calls for a high-caloric content (twice what is considered normal for the child's age), which is typically low in fat and high in protein.

• Patients or their caregivers should consult with their health care providers to determine the most appropriate diet.

Gene Therapy

• Gene therapy is the use of normal DNA to "correct" for the damaged genes that cause disease.

• In the case of CF, gene therapy involves inhaling a spray that delivers normal DNA to the lungs.

• The goal is to replace the defective CF gene in the lungs to cure CF or slow the progression of the disease.

• The average annual incidence rate of CF disease through the last ten years (2000-2010) in the Gaza strip was 1.26 case per 5000 live births.

Magnitude of CF disease in GS

Incidence rates of cystic fibrosis disease (Gaza, 2000- 2010)

• The average annual prevalence of CF disease through the last ten years in Gaza strip was 3.72 cases per 100,000 population.

Magnitude of CF disease in GS

Prevalence rates of cystic fibrosis disease (Gaza, 2000- 2010)

Mortality

• The average annual mortality rate due to CF in the Gaza Strip through the last ten years (2000-2010) was 0.26 case per 100,000 populations.

• The average annual CFR of CF through the last ten years was 9.18%.

Magnitude of CF disease in GS

CF diagnosis• The mean age of CF cases at diagnosis was 6.05+6.57 months. (98%

of cases were infants at time of diagnosis).

Magnitude of CF disease in GS

Clinical manifestations and hospitalizations of CF patients• All cases were recurrently admitted to hospital, The average

admission times was 3.51+1.63 times/year among cases.

Magnitude of CF disease in GS

Distribution of cystic fibrosis cases by the affected systems (Gaza,2010)

Nutritional indicators of CF cases and controls

Magnitude of CF disease in GS

Variable

Cases (n= 100) Controls (n= 100)T-Test

AverageS.DAverageS.DTP

Height (cm)99.6420.10112.1016.6

2-4.780.000*

HAZ-2.42

1.800.07

2.09-9.010.000*

Weight (kg)14.70

5.8419.89

7.44-5.480.000*

WAZ-2.48

1.05-0.26

1.67-11.280.000*

WHZ-1.67

1.82-0.02

2.06-5.980.000*

Average anthropometric measurements and nutritional indicators of cystic fibrosis cases and controls (Gaza, 2010)

*Statistically significant

Nutritional indicators of CF cases and controls• This difference was a statistically significant (t=-13.71, p =0.00).

Magnitude of CF disease in GS

Average hemoglobin level of CF cases and controls (Gaza, 2010)

• Male Gender (OR=2.35, 95% CI=1.26, 4.04, p=0.004). • Fair Skin Color (OR=5.43, 95% CI=2.11, 14.50, p=0.000).• Consanguinity (OR=13.20, 95% CI=5.94, 29.95, p=0.000). • North Gaza Governorate (OR=2.006,95%CI=1.04,3.853, p=0.035).

Risk factors associated with CF disease in GS

Distribution of cases and controls by sociodemographic factors (Gaza, 2010)

Sociodemographic factors

Genetic determinants of CF disease in GS

• The results of mutation testing revealed that 61% of known mutation-CF cases have at least single allele of F508.

• Also 12.2% of known mutation-CF cases were of homo 3120+1kb CFTR mutation.

• Also 14.7% of known mutation-CF cases were of homo N1303k CFTR mutation, homo G85E CFTR mutation, and homo 3120del 18.6kb CFTR mutation equally.  

Genetic determinants of CF disease in GS

CF disease ClassesCF Cases

No%

Class I24.9

Class II2151.2

Class III00

Class IV12.4

Class V819.5

Compound922

Total41100

• The majority of the cases was diagnosed during infantile age and was diagnosed in Governmental Pediatric Hospitals by both manifestations and sweat test.

• The anthropometric measurements and hemoglobin level of CF cases in the GS reflected that short stature, underweight, wasting and anemia were very common.

• About two thirds of known mutation of CF cases have at least a single allele of DF508, which is considered of severe type of CFTR mutations.

RECOMMENDATIONS

Recommendations concerning CF services

• Neonatal screening programs for CF disease should be set up.

• The importance of establishing a reliable diagnosis of CF using a properly conducted sweat test. In addition, diagnostic radiology, and laboratory facilities.

• Integration of genetic counseling and services for CF cases’ families into primary health care.

• Setting an expanded comprehensive health educational program for families of CF cases’, old CF cases, and general public about CF and strengthening the nutrition program for the public.

• Supplies of pancreatic enzymes and basic antibiotics, including anti-Pseudomonas agents for CF patients free of charge .

• It is essential for health authorities to know the magnitude of the problem if they are to make appropriate provisions for CF care.

• It is important to establish and maintain a national CF registry in order to identify and predict the need for services and to monitor survival trends.

Recommendations for improving socioeconomic & environmental status

• Increasing the situation of women in the community by encouraging the high education of girls, and involving the women in all fields and works.

• Increasing community awareness and counseling concerning the effect of early marriage and consanguineous marriage.

• Campaigns aiming at educating families on the importance of clean drinking water as well as advising mothers to take compensatory measures such as additional nutrition intakes.

• Local authorities should inform the public about local concentrations of air pollutants, possible effects on health, and the action taken to minimize any health risks.