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From the Children’s Institute, Hospital dasClínicas, Faculty of Medicine, University ofSão Paulo – São Paulo/SP, Brazil; GenetikaLaboratory – Paraná, Brazil and FederalUniversity of Medicine, São Paulo/SP, Brazil.

Received for publication onAugust 30, 2002.

CYSTIC FIBROSIS WITH NORMAL SWEATCHLORIDE CONCENTRATION – CASE REPORT

Luiz Vicente Ferreira da Silva Filho, Maria Helena de Carvalho Ferreira Bussamra,Cleyde Miriam Aversa Nakaie, Fabíola Villac Adde, Joaquim Carlos Rodrigues,Salmo Raskin and Tatiana Rozov

SILVA FILHO LVF et al. - Cystic fibrosis with normal sweat chloride concentration – case report. Rev. Hosp. Clín. Fac. Med.S. Paulo 58 (5):260-262, 2003.

Cystic fibrosis is a genetic disease usually diagnosed by abnormal sweat testing. We report a case of an 18-year-oldfemale with bronchiectasis, chronic P. aeruginosa infection, and normal sweat chloride concentrations who experiencedrapid decrease of lung function and clinical deterioration despite treatment. Given the high suspicion ofcystic fibrosis,broad genotyping testing was performed, showing a compound heterozygous with ∆F508 and 3849+10kb C→T mutations,therefore confirming cystic fibrosis diagnosis. Although the sweat chloride test remains the gold standard for the diagnosisof cystic fibrosis, alternative diagnostic tests such as genotyping and electrophysiologic measurements must be performedif there is suspicion of cystic fibrosis, despite normal or borderline sweat chloride levels.

DESCRIPTORS: Cystic fibrosis. Atypical. Diagnosis. Sweat chloride. Mutations.

Cystic fibrosis (CF) is the mostcommon lethal genetic disease in Cau-casians and is characterized by chronicand recurrent lung infections, pancre-atic insufficiency, and high chloridelevels in the sweat. Inheritance is au-tosomal recessive, and the disease iscaused by mutations in the cystic fi-brosis transmembrane conductanceregulator (CFTR) gene, located in thelong arm of chromosome 7. As formany other human monogenic dis-eases, high variability in disease ex-pression is found among patients. Thesweat test has been the diagnostic“gold standard” for CF since its de-scription in the late 1950s, but now itis clear that a few patients (1% to 2%)may have normal or borderline sweatchloride concentrations, a conditionassociated with some specific muta-tions. Such patients have mild CF vari-ants that include atypical clinical

manifestations; therefore, it is recom-mended that they should be referredfor CFTR genotyping1,2. Althoughnowadays this is common knowledgeamong CF caregivers, there are fewpublications of case reports of CF withnormal sweat chloride levels, and gen-eral pediatricians are usually not awareof this possibility. Searching PubMedusing the following keywords: [cysticfibrosis] and [normal] and [sweat chlo-ride] and [case report] we found 21 en-tries. Of these entries, 8 were case re-ports that share some similarity to ours,but 2 cases were not confirmed by ge-netic testing.

In Brazil, CF is an underdiagnosedcondition that is primarily treated atspecialized centers, usually universityhospitals. The Pediatric PulmonologyUnit of the Children’s Institute is a gen-eral pediatric pulmonology clinic thattreats approximately 120 CF patients.Cystic fibrosis is routinely diagnosedby clinical symptoms and sweat test-ing; genotyping was not routinely per-formed before 1998 except for selectedor atypical cases. We report a case of afemale with symptoms suggesting CFbut with normal sweat chloride levelswho underwent genotype testing thatconfirmed the CF diagnosis.

CASE REPORT

An 18-year-old female was referredto our service in 1997 with a previoushistory of atopic symptoms, such as al-

CASE REPORT

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lergic rhinitis and angioneuroticedema, as well as nasal polypectomyat age 9. There was no history of pneu-monia, although she presented severalupper airway infections, treated withantibiotics, expectorants, and antihis-tamines. Her brother was healthy, andno relative had experienced similarsymptoms. She was well until age 16,when adynamia, chronic cough, anddyspnea during exercise ensued. Herpulmonary symptoms worsened, andthe cough became productive. Duringthis period, salivary gland lithiasis wasdiagnosed, with spontaneous resolu-tion. The patient was referred for evalu-ation showing mild malnutrition with-out clinical steatorrhea, finger club-bing, and diffuse inspiratory cracklesat pulmonary auscultation. A chest X-ray revealed hyperinflation and bron-chiectasis, confirmed by chest CT scan.Sweat chloride measurements by pilo-carpine iontophoresis ranged from 23to 47.5 mEq/liter (5 samples). A spu-tum culture was positive for Staphylo-coccus aureus. Pulmonary functiontesting revealed an obstructive disor-der, with a forced vital capacity (FVC)of 2.28 L (68%) and a forced expira-tory volume in the first second (FEV

1)

of 1.71 L (52%). Genotyping identi-fied a ∆F508 mutation in 1 allele. Pan-creatic function was assessed by a 72-hour fecal fat study and was found tobe preserved.

The patient developed chronic S.aureus and intermittent Pseudomonasaeruginosa pulmonary infection. Acutepulmonary exacerbations were treatedwith oral or intravenous antibiotictherapy. Despite aggressive treatment,pulmonary function testing revealed amassive decrease in FVC and FEV1(0.82 L (25%) and 1.30 L (32%), re-spectively) after 2 years. A new chestCT scan was performed and showedwidespread bronchiectasis and largecysts, mainly in the upper lobes (Fig.1). Since the clinical presentation sug-gested CF, in spite of repeatedly nor-

mal sweat chloride values, a newbroader genetic testing including in-frequent mutations was performed. Thenew genotyping showed that the pa-tient was a compound heterozygous,with ∆F508 and 3849+10kb C→T mu-tations, which confirmed the diagno-sis of CF. The basic treatment of CFwas maintained with nutritional sup-port, frequent courses of systemic an-tibiotics, and continuous inhaledgentamycin; however, lung functiondecline persisted, and the patient isnow waiting for a lung transplantation.

DISCUSSION

The concept of “mild” and “se-vere” mutations was proposed byKerem et al.3 as an explanation for theclinical heterogeneity of CF. However,because of the high clinical variabil-ity and the large number of identifiedmutations, it is very difficult to char-acterize genotype-phenotype correla-tions in CF, except for the most com-mon mutations. The ∆F508 mutationis usually associated with a more se-vere clinical presentation and highersweat chloride levels, while a few othermutations are associated with a mildphenotype. Patients carrying at least 1mild mutation may present symptomswith later onset, better nutritional sta-

tus, pancreatic sufficiency, and lowersweat chloride levels 2.

Highsmith et al.4, studying 23 pa-tients with pulmonary disease charac-teristic of CF but with normal sweattesting, identified a point mutation inintron 19 of the CFTR gene, termed3849+10kb C→T. Published datashow mild phenotypic characteristicsamong CF patients who are ho-mozygous for this mutation. The on-set of pulmonary disease was delayedin most of them, but then became se-vere in some, as was the case for ourpatient. Male patients can have normalsperm count, sweat Cl- values are usu-ally in the intermediate or normalrange, and sufficient exocrine pancre-atic function is reported1,5. The CysticFibrosis Genetic Analysis Consortiumreports the relative frequency of the3849+10kb C→T mutation to be1.4%1.

A classification system accordingto the functional properties of the geneproduct was proposed by Welsh andSmith6. Class V mutations result in re-duced synthesis of normally function-ing CFTR because of defectiveprocessing or alternative splicing sites,resulting in decrease of normal mes-senger ribonucleic acid (mRNA) tran-scripts7. The 3849+10kb C→T muta-tion produces an alternative splicingsite, and decreased amounts of CFTR

Figure 1 - High resolution computer tomography scans showing diffuse bronchiectasis andlarge cysts in upper lobes.

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mRNA can be detected4. Minor diseasemanifestations are probably associatedwith some production of normallyfunctional protein. Patients with the3849+10kb C→T mutation appear tohave less significant pulmonary dis-ease than patients homozygous for∆F508, although lung disease is themost severe clinical manifestation re-ported1,4. In compound heterozygouspatients, the presence of the ∆F508 al-

lele does not necessarily confer a moresevere prognosis3.

Although in most patients with CFall major diagnostic criteria are present,variation in severity of involvement ofthe different organs is well known.Chronic pulmonary disease, even in theabsence of pancreatic insufficiency andabnormal sweat electrolyte values, cansuggest CF if other clinical manifesta-tions like nasal polyposis, azoospermia,

or mucoid P. aeruginosa colonizationis present. For more than 30 years, thesweat chloride test has been used toconfirm the diagnosis of CF and re-mains the gold standard8. However,once there is a clinical suspicion of CFbut normal or borderline sweat chloridelevels, alternative diagnostic tests suchas genotyping and electrophysiologicmeasurements must be performed toconfirm diagnosis.

RESUMO

SILVA FILHO LVF e col. - Fibrosecística com dosagem de cloro nosuor normal – relato de caso. Rev.Hosp. Clín. Fac. Med. S. Paulo 58(5):260-262, 2003.

A fibrose cística é uma doença ge-nética usualmente diagnosticada atra-vés de teste anormal de dosagem decloro no suor. Os autores descrevem ocaso de uma paciente de 18 anos combronquiectasias e infecção crônica por

P. aeruginosa mas com dosagens decloro no suor normais que evoluiu comrápido declínio da função pulmonar epiora clínica, a despeito do tratamen-to. Dada a forte suspeita de fibrosecística, realizou-se um teste de genoti-pagem amplo, evidenciando a presen-ça de mutações ∆F508 e 3849+10kbC→T, deste modo confirmando o di-agnóstico de fibrose cística . Apesar dadosagem de cloro no suor ainda serconsiderada o padrão ouro para o di-

agnóstico de fibrose cística , testes di-agnósticos alternativos como geno-tipagem e medidas eletrofisiológicasdevem ser empregados se há suspeitade fibrose cística , mesmo com níveisnormais ou limítrofes de níveis de clo-ro no suor.

DESCRITORES: Fibrose cística.Atípica. Diagnóstico. Cloro no suor.Mutações.

REFERENCES

1. STEWART B, ZABNER J, SHUBER AP et al. - Normal sweatchloride values do not exclude the diagnosis of cystic fibrosis.Am J Respir Crit Care Med 1995; 151(3 Pt 1):899-903.

2. KEREM E, KEREM B - Genotype-phenotype correlations incystic fibrosis. Pediatr Pulmonol 1996; 22(6):387-395.

3. LESTER LA, KRAUT J, LLOYD-STILL J et al. - Delta F508genotype does not predict disease severity in an ethnicallydiverse cystic fibrosis population. Pediatrics 1994; 93(1):114-118.

4. HIGHSMITH WE, BURCH LH, ZHOU Z et al. - A novel mutationin the cystic fibrosis gene in patients with pulmonary diseasebut normal sweat chloride concentrations. N Engl J Med 1994;331(15):974-980.

5. STERN RC, DOERSHUK CF, DRUMM ML - 3849+10kb C®Tmutation and disease severity in cystic fibrosis. Lancet 1995;346(8970):274-276.

6. WELSH MJ, SMITH AE - Molecular mechanisms of CFTRchloride channel dysfunction in cystic fibrosis. Cell 1993;73(7):1251-1254.

7. WILSCHANSKI M, ZIELENSKI J, MARKIEWICZ D et al. -Correlation of sweat chloride concentration with classes of thecystic fibrosis transmembrane conductance regulator genemutations. J Pediatr 1995; 127(5):705-710.

8. DAVIS PB, HUBBARD VS, DI SANT’AGNESE PA - Low sweatelectrolytes in a patient with cystic fibrosis. Am J Med 1980;69(4):643-646.