We describe two siblings with a progressive unrelenting and unique syndrome of bilateral fibrosing pleuritis of unknown cause occurring in association with Fanconi's syndrome (renal tubular acidosis). The parents of the siblings were second cousins. Both siblings had identical pleural histologic characteristics and identical urinary metabolic defects. This condition resulted in the development of severe respiratory failure in both patients and ultimately the death of the older sibling at the age of 21 years. (Chest 1995; 107.576-78)
Key words: fibrosis; pleura; renal tubular acidosis
lateral pleural disease may be associated with a number of disorders. In most cases, the cause is clear and rarely progressive. We describe a brother and sister, the parents of whom were second cousins, who developed bilateral fibrosing pleuritis in conjunction with the renal tubular defect, Fanconi's syndrome. Despite a number of therapeutic interventions, this resulted in the slow but unrelenting development of chronic respiratory failure and the death of the older patient. A third male sibling has Fanconi's syndrome but no pleural disease and a fourth male sibling has neither disorder. An association between this congenital renal condition and pleural disease has not been previously described. However, in common with the only previous report of cryptogenic fibrosing pleuritis, the histocompatibility antigen HLA B44 was found in both siblings.
In 1980, an 18-year-old man was noted to have proteinuria and glycosuria on routine urinalysis and was referred to this hospital. There was no previous relevant medical history. Clinical examination disclosed no abnormalities at this time, but the patient was below the third percentile for height and weight. On further assessment, he was found to have glycosuria with a normal glucose tolerance test, proteinuria, and aminoaciduria, hyperealciuria, and hypophosphatemia. The serum alkaline phosphatase level was elevated. Skeletal bone survey showed that bone age was retarded by 2 years and a bone biopsy confirmed the presence of osteomaiacia. Hypouricemia was also noted, but there was no hypokalemia, and urinary acidification was normal. In 1985, he presented with symptoms of malaise and fatigue. A chest x-ray film revealed right pleural shadowing. Pleural aspirate confirmed an exudative effusion but was otherwise noncontributory. Pulmonary function tests showed a restrictive pattern of disease but with an above normal coefficient of gas transfer: percent predicted [FEV.sub1], 19; forced vital capacity (FVC), 21; diffusing capacity for carbon monoxide (single-breath), 25; coefficient of gas transfer (KCO) 124. There was no pathologic evidence of focal bacterial, fungal or tuberculous infection, asbestos-related disease, thromboembolic disease, autoimmune disorder, or malignancy. He had smoked 20 cigarettes a day for 5 years. Prescriptions for medications known to be associated with fibrosing syndromes had never been given to the patient. Bronchoalveolar lavage differential cell counts were normal. The computed tomography (CT) scan of the thorax revealed right-sided pleural thickening. He underwent a right-sided pleural decortication which did not significantly improve his pulmonary function. Pleural histologic findings revealed marked pleural fibrosis with organizing fibrin on the surface with focal lymphocytic collections at the fibrofatty junctions. No asbestos bodies were noted. Subsequently, he developed a pleural rub on the left side of his chest and a CT scan of the thorax showed the emergence of extensive bilateral pleural thickening (Fig 1). He was given therapeutic trials of a number of anti-inflammatory agents including orally administered corticosteroids, penicillamine, and colchicine. However, his condition deteriorated and he died 3 years after presentation owing to respiratory failure secondary to progressive bilateral pleural thickening.
The 23-year-old sister of the previously reported patient presented with a history of dyspnea and vague chest pain in 1986. A chest x-ray film showed bilateral pleural thickening which was confirmed by a CT scan of the thorax (Fig 2). Pulmonary function tests confirmed a restrictive defect with an above normal coefficient of gas transfer: percent predicted [FEV.sub.1], 32; FVC, 36; diffusing capacity for carbon monoxide (single-breath), 29; KCO, 118. Bronchoalveolar lavage differential cell count was normal. There was no evidence of any associated pathologic condition. An open left pleural biopsy was performed which showed an identical histologic pattern to that of her brother. Again, no asbestos bodies were found. Urinary biochemistry revealed glycosuria, proteinuria, aminoaciduria, hypercalciuria, and normal urinary acidification. Hypophosphatemia and hypouricemia but no hypokalemia also were noted. The skeletal bone survey was normal. These serum and urinary biochemical abnormalities were identical to that of her brother. This patient was treated with oral corticosteroids, but over a 6-year period she has demonstrated a slow decline in vital capacity. Similarly, repeated CT scans of the thorax show increasing pleural fibrosis. The HLA typing was carried out and revealed identical haplotypes in both siblings (Table 1).
There are two other male siblings in the family. Although one of these siblings has been found to have classic Fanconi's syndrome, neither has any evidence of pleural disease after 8 years of follow up. The unaffected sibling carries HLA B44, but the sibling with Fanconi's syndrome does not.
We describe two siblings, a brother and sister, who developed progressive fibrosing pleuritis of unknown origin in conjunction with Fanconi's syndrome (renal tubular acidosis). Pleural fibrosis may commonly occur with a number of clinical conditions including bacterial, fungal, or tuberculous infection, thromoembolic disease, malignancy, autoimmune disorders, asbestos-related disease and some medications. Often the diagnosis is obvious and the pleural fibrosis is not progressive. Additionally, the syndrome of cryptogenic fibrosing pleuritis has been described in four unrelated patients. Although the histologic appearances are similar in our two patients, they differ in that our two patients did not respond to oral corticosteroids. Fanconi's syndrome may be a primary inherited condition or associated with a number of systemic or renal disorders. Despite extensive assessment over an 8-year period, we have found no evidence of any associated conditions in any of the affected siblings. Characteristics of our patients differ slightly from the usual biochemical abnormalities associated with this condition in that urinary acidification is normal. The fact that our patients have an identical biochemical abnormality is consistent with an inherited defect. The coexistence of Fanconi's syndrome and progressive fibrosing pleuritis has not been previously described. It is difficult to explain what relationship, if any, there may be between these two conditions in our patients. Although a common environmental factor cannot be fully excluded, it is possible that both conditions are genetically linked disorders. It is interesting to note that our patients with pleural fibrosis both have HLA B44 in common with the four patients previously described, and one sibling found to have Fanconi's syndrome but not to have pleural fibrosis does not express HLA B44. Although this is a common histocompatability antigen (25% of the Irish population), its association with our two cases suggests a possible association between this antigen and pleural fibrosis.
 Sahn SA. The pleura: state of the art. Am Rev Respir Dis 1988; 138:184-234
 Buchanan DR, Johnstone IDA, Kerr IH, Hetzel MR, Corrin B, Turner-Warwick M. Cryptogenic bilateral fibrosing pleuritis. Br J Dis Chest 1988; 82:186-93  Brenton DP, Isenberg DA, Cusworth DC, Garrod P, Krywawych S, Stamp TCB. The adult presenting idiopathic Fanconi's syndrome. J Inherit Met Dis 1984; 4:211-15
(*) From the Department of Respiratory Medicine (Drs. Hayes, Ward, and FitzGerald) and Department of Metabolic Medicine (Dr. Muldowney), St. Vincent's Hospital/University College Dublin, Dublin, Ireland; and the Department of Medicine (Dr. Wiggins), Wexham Park Hospital, Slough, Berkshire, England. Reprint requests: Dr. Fitzgerald, St Vincent's Hospital, Dublin 4, Ireland
COPYRIGHT 1995 American College of Chest Physicians
COPYRIGHT 2004 Gale Group