Chest
Volume 89, Issue 2, February 1986, Pages 206-210
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Genetic Studies in Familial Fibrosing Alveolitis: Possible Linkage with Immunoglobulin Allotypes (Gm)

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A family containing 12 subjects spanning three generations and including six cases with clinical evidence of definite or probable fibrosing alveolitis has been investigated. Histologic confirmation was available for three cases. The subjects were between 15 and 54 years of age at diagnosis. Although the size of the sample is small, the mode of inheritance of fibrosing alveolitis within this family appeared to be dominant with incomplete penetrance. HLA typing showed that at least one of the affected siblings did not share any HLA haplotypes with other affected siblings in the third generation. This makes it unlikely that a disease gene would be in association with HLA genes on chromosome 6. In contrast, all affected siblings, as well as two as yet unaffected siblings, carried the immunoglobulin haplotype Gm L These studies indicate that familial fibrosing alveolitis in this family may be inherited by a dominantly inherited gene located on chromsome 14 close to the loci encoding for Gm.

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MATERIALS AND METHODS

All available subjects underwent the following investigations: (1) routine posteroanterior chest x-ray film; and (2) testing of pulmonary function, which included measurement of ventilatory capacity, pulmonary volumes by plethysmography,15 and diffusing capacity by the single-breath transfer factor for carbon monoxide.16 Predicted values were those determined by Cotes.15

In four of the subjects with clinical evidence of disease, the following additional studies were performed: (1) bronchoscopy

RESULTS

Twelve members from three generations of the family were studied (Fig 1). Four of the 12 studied subjects fulfilled all of the clinical criteria for definite fibrosing alveolitis (Table 1). Three of these subjects had histologic confirmation of the diagnosis. One further subject (case 4) fulfilled all clinical criteria except that no crackles were heard in his lungs, and one other subject (case 5) had no definite abnormality on the plain chest roentgenogram but had crackles on auscultation of

CASE 1 (III [2])

The index case was a patient who first presented at the age of 15 years when a routine chest x-ray film was said to show diffuse shadowing of upper and middle zones, possibly due to fibrosing alveolitis. There was a delay of one year in instigating further investigation, but at the age of 16 years, further chest x-ray films confirmed the abnormality, and review of his pediatric case notes revealed that a chest x-ray film (no longer available) had been performed at the age of four years when he

GENETIC STUDIES

It was possible to determine the HLA genotype of all siblings in the third generation of the family (Fig 1; Table 2). Case III(1) had the HLA haplotypes ad, and these were also found in cases III(3), III(5) and III(6). Case III(2) did not share any haplotypes with case III(l), having the bc haplotypes, while case III(4) had the ac haplotype, sharing one with each of cases III(1) and III(2). The lack of sharing of HLA haplotypes between diseased siblings indicates that linkage of fibrosing

DISCUSSION

Definite or probable idiopathic pulmonary fibrosis has been found in six members of this family. The diagnosis has been based on accepted clinical, radiographic, and physiologic criteria and was confirmed histologically in three subjects. The results of bronchoalveolar lavage and gallium scanning suggest low-grade disease activity in all subjects tested.17

In this family, fibrosing alveolitis extended through three generations. The disease appeared to be inherited in an autosomal dominant

ACKNOWLEDGMENTS

The helpful criticism and comments of Dr. Heath Kelly and the assistance of Mrs. Ailsa Miller and Miss Elizabeth Bingle in preparation of the manuscript are gratefully acknowledged.

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Manuscript received February 5; revision accepted July 30.

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