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Fanconi's anemia

Fanconi anemia (FA) is a rare genetic disease that affects children and adults from all ethnic backgrounds. Named for the Swiss pediatrician who originally described this disorder, Guido Fanconi, FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C. more...

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Causes

FA is primarily a autosomal recessive genetic condition. There are at least 8 genes for which mutations in are known to cause FA: A, C, D1, D2, F, G, L, and B. FANCB is the one exception to FA being autosomal recessive, as this gene is on the X chromosome. For an autosomal recessive disorder, both parents must be carriers in order for a child to inherit the condition. If both parents are carriers, there is a 25% risk with each pregnancy for the mother to have an affected child. Approximately 1,000 persons worldwide presently suffer from the disease. The carrier frequency in the Ashkenazi Jewish population is about 1/90. Genetic counseling and genetic testing is recommended for families that may be carriers of Fanconi anemia.

Because of the failure of the components of the blood - white and red blood cells and platelets - the body cannot successfully combat infection, fatigue or spontaneous hemorrhage or bleeding. Bone marrow transplantation is the accepted treatment to repair the hematological problems associated with FA. Patients face an increased risk of acquiring cancer and other serious health problems throughout their lifetime.

Prognosis

Many patients eventually develop acute myelogenous leukemia (AML). Older patients are extremely likely to develop head and neck, esophageal, gastrointestinal, vulvar and anal cancers. Patients who have had a successful bone marrow transplant and, thus, are cured of the blood problem associated with FA still must have regular examinations to watch for signs of cancer. Many patients do not reach adulthood.

The overarching medical challenge that Fanconi patients face is a failure of their bone marrow to produce blood cells. In addition, Fanconi patients normally are born with a variety of birth defects. For instance, 90% of the Jewish children born with Fanconi's have no thumbs. A good number of Fanconi patients have kidney problems, trouble with their eyes, developmental retardation and other serious defects.

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Pulmonary alveolar proteinosis in association with Fanconi's anemia and psoriasis: a possible common pathogenetic mechanism
From CHEST, 8/1/92 by Rodney D. Steens

A Possible Common Pathogenetic Mechanism

We report a case of PAP which proved to be fatal despite whole lung lavage. The need for early BAL and transbronchial biopsies in diffuse infiltrative lung disorders of unknown etiology is highlighted. The occurrence of PAP in association with Fanconi's anemia and psoriasis raises the possibility of a common pathogenetic defect which may be related to abnormal cytokine metabolism. Investigation of cytokine metabolism in PAP is warranted.

Pulmonary alveolar proteinosis is an uncommon diffuse lung disease of unknown etiology which is characterized by the dense accumulation of lipoproteinaceous material in the alveolar spaces. This material is similar to surfactant and stains positively with PAS. We report a patient with PAP associated with Fanconi's anemia and psoriasis, which was fatal despite whole lung lavage, and postulate a common pathogenetic basis for the concurrence of these disorders.

CASE REPORT

A 28-year-old woman with Fanconi's congenital hypoplastic anemia and psoriasis (with arthropathy) was admitted to another hospital with a diagnosis of "atypical pneumonia." She gave a two-week history of fever, dry cough, exertional dyspnea, myalgia, general malaise, anorexia and weight loss. She smoked 10 cigarettes daily.

A chest x-ray film showed diffuse bilateral symmetrical reticular and alveolar infiltrates most concentrated in the mid-zones without lymphadenopathy or cardiomegaly. She was treated with antibiotics (initially erythromycin and then doxycycline) for a month. There was minimal symptomatic improvement and no change in the radiographs. During the ensuing month she deteriorated and was transferred to our institution.

On transfer, two and half months following onset of her illness, she weighed 35 kg. She had widespread psoriatic plaques, had cyanosis and was dyspneic on speaking. There was no clubbing or lymphadenopathy. She had a temperature of 38[degrees]C, respiratory rate of 26 breaths per minute, a pulse rate of 130 beats per minute and blood pressure of 110/80 mm Hg. There were profuse fine bilateral mid-zone end-inspiratory crackles. The remainder of the examination disclosed no other abnormalities.

Arterial blood gas values while she was breathing room air revealed pH, 7.45; [PaCO.sub.2], 27 mm Hg; [PaO.sub.2], 46 mm Hg; and the alveolar-arterial oxygen gradient was 72 mm Hg (normal, < 15). The hemoglobin level was 105 g/L; MCV, 119 fl; MCH, 39.0 pg; white blood cell count, 6.9 x [10.sup.9]/L (neutrophils, 5.52; lymphocytes, 1.17; monocytes, 0.13; and eosinophils, 0.06), and the platelet count was normal. The ESR was 100 mm/h. Electrolyte levels, creatinine value and liver function tests were normal. A chest x-ray film showed some increase in the right mid-zone infiltrate in comparison with previous films. Lung function testing revealed an [FEV.sub.1] of 1.40 L (predicted, 2.89 [+ or -] 0.47); FVC, 1.85 L (3.62 [+ or -] 0.52); FRC, 1.96 1 (3.00 [+ or -] 0.47); TLC, 2.82 1 (4.74 [+ or -] 0.55); DCO, 6.6 ml/min/mm Hg (26.3 [+ or -] 3.6); and KCO 2.4 (5.6 [+ or -] 0.6).

One and a half weeks following transfer, sputum and blood cultures showed no growth and paired serologic titers for atypical organisms were negative. There had been no response to a course of broad-spectrum antibiotics (cefamandol, sulfamethoxazole-trimethoprim and doxycycline). Bronchoscopy was performed and was anatomically normal. The BAL fluid was grossly opaque and contained profuse lipoproteinaceous material but no organisms or malignant cells. Culture of BAL fluid was negative. Light microscopic examination of transbronchial biopsies showed copious PAS-positive material in the interstitium and alveoli both free and within macrophages, with minimal fibrosis. Subsequent electron microscopy revealed that these PAS-positive areas comprised the typical concentric lamellar bodies seen in PAP.

At 2-1/2 and 3-1/2 weeks following transfer, right lung and sequential segmental left lung lavage were attempted in succession but were both abandoned prematurely (after only 0.65 and 2 L were instilled, respectively) because of arterial oxygen desaturation and hypotension. After the second procedure there was some symptomatic improvement but the degree of hypoxemia and the chest x-ray film findings were unchanged. Her clinical condition stabilized for the next 11 days but terminated in sudden deterioration in the form of respiratory and asystolic cardiac arrests from which the patient was successfully resuscitated.

At this time (now five weeks after transfer), whole lung lavage (left lung, 10 L; right lung, 13L) was performed under cardiopulmonary bypass. Subsequently the patient required ventilatory and inotropic support died five days later. Tracheal aspirates and blood cultures taken prior to death subsequently grew an opportunistic fungus, Pseudalloscheria boydii. Postmortem examination confirmed the presence of widespread fungal infection and PAP.

DISCUSSION

The utility of various diagnostic procedures in PAP recently has been reviewed[1] and it is apparent that BAL with or without transbronchial biopsies examined by light microscopy, with electron microscopy if necessary, would be sufficient in most cases. In our patient, recourse to open-lung biopsy and its attendant risks was not necessary. Given the relative ease with which this diagnosis can be made, and the fact that the diagnosis of PAP frequently is significantly delayed,[2] clinicians should consider the use of BAL and transbronchial biopsies early in the course of diffuse infiltrative lung disorders without apparent etiology.

To our knowledge, only one case of PAP associated with Fanconi's anemia has been reported previously.[3] We estimate that the probability of these two uncommon disorders occurring in one patient by chance alone is of the order of 1 in 2 x 10.[10] This figure is based upon estimates of the prevalence of Fanconi's anemia being 1 in 348,000[4] and the frequency of PAP being 5,000 in 250,000,000.[5] The occurrence of PAP in a patient with Fanconi's anemia and psoriasis raises the possibility of a common pathogenetic defect in these disorders. Psoriasis is characterized by keratinocyte hyperplasia, and disturbances in cytokine production are recognized.[6] Although cytokine abnormalities are also well described in aplastic anemia,[7,8] and there is now evidence of defective monocyte-to-macrophage maturation in this disorder,[9] we have not found studies addressing these aspects in Fanconi's anemia. There are no data on cytokine metabolism in PAP, but impaired alveolar macrophage function has been documented[10-12] and is thought to be a major feature in the pathophysiology of this disorder.[10,13,14] Various cytokines not only stimulate the proliferation of phagocyte precursors in bone marrow, but also probably enhance monocyte-to-macrophage maturation and activation of these cells.[15] A primary defect in cytokine metabolism might explain the concurrence of these three disorders or, alternatively, may represent a common feature in the pathophysiologic process in each disorder. Further investigation of cytokine metabolism in PAP is warranted.

Bronchoalveolar lavage is of proven value in the treatment of PAP[2,16-18] and alveolar macrophage function improves after such therapy.[19] A primary monocytic defect, whether or not related to cytokine abnormality, in Fanconi's anemia could account for the lack of response to therapeutic lavage in our patient and may have predisposed to the occurrence of septicemia with an opportunistic fungus infection.

REFERENCES

[1] Rubinstein I, Mullen JBM, Hoffstein V. Morphologic diagnosis of idiopathic pulmonary alveolar lipoproteinosis-revisted. Arch Intern Med 1988; 148:813-16

[2] Du Bois RM, McAllister WAC, Branthwaite MA. Alveolar proteinosis: diagnosis and treatment over a 10 year period. Thorax 1983; 38:360-63

[3] Eldar M, Schoefeld Y, Zaizov R, Fogel R, Asherov J, Liban E, et al. Pulmonary alveolar proteinosis associated with Fanconi's anaemia. Respiration 1979; 38:177-79

[4] Swift M. Fanconi's anaemia in the genetics of neoplasia. Nature 1971; 230:370-73

[5] Wasserman K, Mason GR. Pulmonary alveolar proteinosis. In: Murray JF, Nadel JA, eds. Textbook of respiratory medicine. Philadelphia: WB Saunders, 1988:1535-47

[6] Krueger JG, Krane JF, Carter DM, Gottlieb AB. Role of growth factors, cytokines, and their receptors in the pathogenesis of psoriasis. J Invest Dermatol 1990; 94(suppl):135-40

[7] Young NS, Leonard E, Platanias L. Lymphocytes and lymphokines in aplastic anaemia: pathogenic role and implications for pathogenesis. Blood Cells 1987; 13:87-100

[8] Gascon P, Scala G. Decreased interleukin-1 production in aplastic anaemia. Am J Med 1988; 85:668-74

[9] Andreesen R, Brugger W, Thomssen C, Rehm A, Speck B, Lohr GW. Defective monocyte-to-macrohage maturation in patients with aplastic anaemia. Blood 1989; 74:2150-56

[10] Harris JO. Pulmonary alveolar proteinosis: abnormal in vitro function of alveolar macrophages. Chest 1979; 76:156-59

[11] Nugent KM, Pesanti EL. Macrophage function in pulmonary alveolar proteinosis. Am Rev Respir Dis 1983; 127:780-81

[12] Gonzalez-Rothi RJ, Harris JO. Pulmonary alvelolar proteinosis: further evaluation of abnormal alveolar macrophages. Chest 1986; 90:656-61

[13] Bedrossian CWM, Luna MA, Conklin RH, Miller WC. Alveolar proteinosis as a consequence of immunosuppression: a hypothesis based on clinical and pathologic observations. Hum Pathol 1980; 11(suppl):527-35

[14] Prakash UBS, Barham SS, Carpenter HA, Dines DE, Marsh HM. Pulmonary alveolar phospholipoproteinosis: experience with 34 cases and a review. Mayo Clin Proc 1987; 62:499-518

[15] Sullivan R. Hemopoietic colony-stimulating factors: biologic functions and clinical potentials. Am J Respir Cell Mol Biol 1990; 3:283-84

[16] Freedman AP, Pelias A, Johnston RF, Joel IP, Hakki I, Oslick T, et al. Alveolar proteinosis lung lavage using partial cardiopulmonary bypass. Thorax 1981; 36:543-45

[17] Kariman K, Kylstra JA, Spock A. Pulmonary alveolar proteinosis: prospective clinical experience in 23 patients for 15 years. Lung 1984; 162:223-31

[18] Jansen HM, Zuurmond WWA, Roos CM, Schreuder JJ, Bakker DJ. Whole-lung lavage under hyperbaric oxygen conditions for alveolar proteinosis with respiratory failure. Chest 1987; 91:829-32

[19] Hoffman RM, Dauber JH, Rogers RM. Improvement in alveolar macrophage migration after therapeutic whole lung lavage in pulmonary alveolar proteinosis. Am Rev Respir Dis 1989; 139:1030-2

COPYRIGHT 1992 American College of Chest Physicians
COPYRIGHT 2004 Gale Group

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