Lebanese Medical Journal 2006 • Volume 54 (1) 45

CAS CLINIQUE/CASE REPORTFAMILIAL IDIOPATHIC PULMONARY FIBROSIS IN THREE LEBANESE SIBLINGSCase report with long-term follow-up

Nadim KANJ1, Mouhamad ABDALLAH1, Ayman TAWIL2

The true prevalence of idiopathic pulmonary fibrosis isnot known. According to an epidemiologic report from theUS, there are up to 20 cases per 100,000 individuals witha male to female ratio of 1.5 to 1 [1]. Only about 0.5 to 2%of all cases of IPF are thought to have a genetic basis [2].We describe three siblings from a village in southernLebanon who were evaluated and followed up at theAmerican University of Beirut Medical Center (AUBMC)for chronic respiratory complaints between 1989 and 2002.All three were diagnosed with pulmonary fibrosis by openlung biopsy. The patients gave no history of exposure tochemical or environmental fibrogenic agents. A literaturereview shows no previously reported cases of familial IPFin Lebanon. To date, about 110 families have been report-ed to have this disease worldwide [3-6].

C A S E S

Case # 1A 35-year-old woman, nonsmoker, with no signifi-

cant prior medical history presented to AUBMC in 1989complaining of progressive shortness of breath, cough,and chest pain of one year duration. She had been start-ed on antituberculous medication for suspected tubercu-

losis by a physician elsewhere. Physical examinationrevealed end-expiratory wheezes and basilar crackles.Chest X-ray revealed a pneumothorax and generalizedfibrosis in all lung fields (Fig. 1). Pulmonary functiontests revealed a restrictive pattern. Blood tests were nor-mal except for positive ANA and RA latex tests. Anopen lung biopsy showed interstitial pneumonitis withfibrosis consistent with usual interstitial pneumonitis(UIP) (Fig. 2). The patient was placed on oral steroidsfor several months with some symptomatic improve-ment, however, she later discontinued treatment andexperienced progressive respiratory deterioration. Shedied in 1994 at the age of 40.

Kanj N, Abdallah M, Tawil A. Familial idiopathic pulmonaryfibrosis in three Lebanese siblings : Case report with long-termfollow-up. Leb Med J 2006 ; 54 (1) : 45-49.

Kanj N, Abdallah M, Tawil A. Fibrose pulmonaire idiopa-thique chez deux sœurs et un frère libanais : A propos d’uneobservation avec long suivi. J Méd Lib J 2006 ; 54 (1) : 45-49.

Departments of 1Internal Medicine, 2Pathology and LaboratoryMedicine, American University of Beirut, Lebanon.

Corresponding author : Nadim Kanj, MD. American Uni -versity of Beirut. Dept. of Internal Medicine. POBox 11-0236.Riad El- Solh St. Beirut. Lebanon.

Tel. : (961) 1 350 000 ext. 5356 E-mail : dk01@aub.edu.lb

ABSTRACT : This is the first report of a familialcluster of idiopathic pulmonary fibrosis (IPF) inLebanon. This rare variant of IPF has an autosomaldominant mode of inheritance with variable expres-sivity, and is commonly associated with a mutation of the surfactant protein C gene. The patients areyounger at diagnosis but have otherwise identicalclinical, radiological, and histological features as the more common non-familial cases. IPF is aninvariably fatal disease with no effective treatment.Lung transplantation remains the only chance formore prolonged survival and must be considered inyoung patients.

RÉSUMÉ : C’est la première publication de fibrosepulmonaire idiopathique (FPI) familiale rapportée au Liban. Cette variante rare de FPI suit un mode detransmission génétique autosomal dominant à expres-sivité variable. Elle est fréquemment associée à unemutation du gène de la protéine C du surfactant. Lespatients sont plus jeunes lors du diagnostic mais sontcliniquement, radiologiquement et histologiquementidentiques comparativement aux cas non familiaux pluscommuns. La FPI est une maladie inéluctablementfatale sans traitement efficace. La transplantation pul-monaire reste la seule option thérapeutique pour unesurvie prolongée chez les jeunes patients.

FIGURE 1. CXR with generalized fibrosis.

46 Lebanese Medical Journal 2006 • Volume 54 (1) N. KANJet al. – Familial idiopathic pulmonary fibrosis

FIGURE 2Left : Low magnification showing a patch of interstitial fibrosis (arrows)

with relatively normal lung tissue in the right upper corner (H & E stain, x 20). Right : Higher magnification showing an area of fibrosis with a fibroblastic focus

denoting the presence of active disease (black arrow)and an adjacent lymphocytic infiltrate (white arrow) (H & E stain, x 100).

FIGURE 3CXR with bilateral reticulonodular infiltrates.

FIGURE 5CXR with diffuse interstitial infiltrates.

FIGURE 4A b o v e : A peripheral focus of prominent interstitial fibrosis

with subpleural cystic change (H & E stain, x 20). B e l o w : Expansion of the interstitium by fibrosis

and chronic inflammation on the right with less involved alveolar septa on the left. (H & E stain, x 100)

FIGURE 6A b o v e : An area of extensive fibrosis with slightly dilated alveolar spaces

in the upper part of the field (H & E stain x 20).Below : A fibrotic area with a lymphoid follicle

in the lower right. (H & E stain x 100)

48 Lebanese Medical Journal 2006 • Volume 54 (1) N. KANJet al. – Familial idiopathic pulmonary fibrosis

Case # 2In 1994, the patient’s sister presented to AUBMC at

the age of 25 with abnormal chest X-ray findings (Fig. 3).An open lung biopsy from the right upper and middlelobes revealed wide areas of interstitial fibrosis withchronic inflammation in both lobes, also consistent withUIP (Fig. 4). Her condition worsened progressively andshe died in 2003 at the age of 34.

Case # 3In 1996, their 33-year-old brother presented with

symptoms of fatigue, cough, and dyspnea on exertion ofone year’s duration. Chest X-ray revealed diffuse inter-stitial infiltrates (Fig. 5). An open lung biopsy revealedpulmonary fibrosis and interstitial pneumonitis with apattern that is consistent with UIP (Fig. 6). Most of theleft lower lobe biopsy and all of the lingular sample wereinvolved. He died in 1999 at the age of 36 while waitingfor lung transplantation.

The clininical presentations of all three cases are sum-marized in table I.

DISCUSSION

Idiopathic pulmonary fibrosis (IPF), also termedcryptogenic fibrosing alveolitis or usual interstitial pneu-monia (UIP), is a rare disease of unknown etiology. Thepathogenesis of IPF stipulates that there is an injury tothe lung parenchyma which results in the formation ofimmune complexes. These complexes stimulate alveolarmacrophages to produce a variety of factors including

chemotactic factors that attract neutrophils into the inter-stitium. The inflammatory cells, together with activatedresident cells are thought to release polypeptide media-tors that stimulate fibroblast proliferation and matrix col-lagen synthesis [7-8]. There is mounting evidence thatthere are genetic influences that are also involved in thepathogenesis of IPF. The evidence includes the existenceof familial clusters, and the recent discovery of caseswith mutated surfactant proteins [9-10]. These geneticinfluences could play a role by altering surfactant pro-teins, by affecting the immunological response to injury,or by modulating collagen metabolism in the lung [11-12]. Genetically altered pulmonary surfactant is nowproven to play a role in the pathogenesis of some inter-stitial lung diseases, particularly in familial cases of IPF.Pulmonary surfactant, a complex mixture of phospho-lipids and proteins present in alveolar lining fluid, con-tains proteins designated as surfactant proteins A, B, C,and D [13]. Mutations in surfactant protein C (SP-C)have been well documented in familial IPF, but are rarein sporadic cases [3, 13-15]. These mutations may lead tothe production of structurally abnormal proSP-C or SP-Cprotein. In severe lung disease, there may be completeabsence of SP-C and proSP-C [1, 4, 6]. The pattern ofinheritance of familial IPF suggests an autosomal domi-nant inheritance with variable expressivity [3, 10, 14, 20].

Patients with either sporadic or familial forms of IPFinvariably die within 6 to 8 years after diagnosis. Con-ventional treatment with steroids has been unsatisfacto-ry in altering the natural history of the disease. Somaticcell gene therapy, which has played a role in the man-

TABLE ICLINICAL PICTURE AT DIAGNOSIS

DATA Case 1 Case 2 Case 3

SEX Female Female Male

AGE 35 24 33

SMOKING HISTORY None None None

CLUBBING No No Yes

LUNG SOUNDS End expiratory wheezes and Bilateral inspiratory crackles End expiratory wheezes and basal crackles basal crackles

CXR Pneumothorax & Generalized fibrosis Bilateral reticulonodular infiltrates Diffuse interstitial infiltrates

Bilateral infiltrates in upper lung Bilateral reticular infiltrates andCT SCAN Not done fields and interlobular septal pleural thickening

thickening at the base of the right lung

EKG Normal Normal Normal

ESR 37 25 7

PPD Negative Negative Negative

ANA Positive (1:5) Negative Negative

RA Latex Reactive Non-reactive Non-reactive

OTHER FINDINGS None None Uveitis

agement of some monogenic human disorders, is ineffec-tive in IPF. This is probably because the disease is poly-genic and involves complex interactions between geneticsusceptibility and environmental factors. Experiments inanimal models attempted at reducing the expression oftransforming growth factor-ß (TGF-ß), the most impor-tant growth factor involved in inflammatory fibrosis, andat enhancing fibrinolytic activity. Epigenetic approachesusing antisense oligonucleotides to suppress collagensynthesis have also been tried, but no gene therapy yetexists for IPF [7]. Lung transplantation, despite its majormedical complications [16], remains the only therapeuticoption shown to improve survival in IPF [17], and it mustbe considered early on in younger patients [18].

Patients with sporadic IPF are usually 50 to 70 of ageat the time of diagnosis [19], while familial cases areusually younger. Apart from this and the common occur-rence of SP-C gene mutations, familial cases are indis-tinguishable from non-familial cases [21].

CONCLUSION

This is the first documented familial cluster of idio-pathic pulmonary fibrosis in Lebanon. It includes threesiblings with similar clinical courses, radiographic pic-tures, and histopathologic features. The occurrence offamilial cases of IFP has stimulated the search for spe-cific genetic mutations, and is beginning to unravel somemolecular aspects in the pathogenesis of IPF in general.Mutations in SP-C gene were identified in some, but notall, patients with IPF. Further insight into the molecularbasis of IPF is necessary in order to develop new modal-ities of treatment. Currently, the only effective treatmentavailable is lung transplantation.

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N. KANJet al. – Familial idiopathic pulmonary fibrosis Lebanese Medical Journal 2006 • Volume 54 (1) 49