Lung interstitial diseases and bullae are described as possible complications of neurofibromatosis type-1 (NF-1), a genetic disorder inherited as a autosomal-dominant trait. We report the case of a 16-year-old male non-smoker with NF-1, who presented with pneumothorax caused by ruptured lung bullae. The case of this young patient, successfully treated by video-assisted thoracoscopic resection of bullae, supports the concept that pulmonary alterations may be part of the NF-1 syndrome, rather than as an unrelated complication

Castiglioni M

Di Natale D

Imperatori A

Nardecchia E

Perfetti L

Rotolo N.

NARDECCHIA, ELISA

IMPERATORI, ANDREA SELENITO

ROTOLO, NICOLA

Archivio istituzionale della ricerca - Università dell'Insubria

Monaldi Arch Chest Dis2012; 77: 2, 105-107 CASE REPORTBullous lung disease and neurofibromatosis type-1E. Nardecchia1, L. Perfetti2, M. Castiglioni1, D. Di Natale1, A. Imperatori1, N. Rotolo1IntroductionVon Recklinghausen’s disease (VRD), alsoknown as neurofibromatosis-1 (NF-1) is an auto-somal-dominant disease that occurs with a preva-lence of 1:2500-3000, independently from ethnyand gender. Approximately 50% of cases are dueto mutation of chromosome 17. Clinically, NF-1 isrecognised by the presence of numerous “café-au-lait” skin macules, but 25% of affected patients de-velop multiple cutaneous and central nervous sys-tem (CNS) tumors that are histologically charac-terized as neurofibroma, pheochromocytoma or fi-brosarcoma [1, 2].To establish the diagnosis of NF-1, moleculardefinition of the disease is not necessary. Clinicalcriteria for the diagnosis of NF-1 were defined in1997 and confirmed in 2007 [3]; two or more ofthe following criteria must be met:– six or more café-au-lait spots >5 mm in diam-eter before puberty, or >15 mm after puberty;– two or more typical neurofibromas of any type,or one plexiform neurofibroma;– frackles/hyperpigmentation spots in area inac-cessible to sunlight (axilla, groin);– two ore more iris hamartomas (Lisch nodules);– typical bone abnormalities (see below);– first-degree relative meeting the above criteria.The thoracic manifestations of NF-1 are mostcommonly cutaneous, but they can also be skeletaland pulmonary [4]. The most common thoracicskeletal manifestations of NF-1 involve the spineand ribs. Characteristic deformities of the ribs in-clude well-marginated erosions of one or moreribs, and the separation of adjacent ribs due toplexiform neurofibromas. Spinal abnormalitiescan present as kyphoscoliosis, posterior scallopingof the vertebral bodies and enlargement of neuralforamina [2]. Lung manifestations, that usually in-clude interstitial lung disease (ILD) and thin-walled bullae, are reported in as many as 10-20%of adult patients with NF-1. Although these find-ings may be incidental, sometimes patients presentwith dyspnea that may also result from lung mes-enchymal abnormalities [5]. Pulmonary fibrosis isusually bilateral and simmetric, predominantlybasal [6]. Typically, ILD occurs in association withbullae that are thin-walled, located in the upperlobes, and usually asymmetric [1, 6].Case reportA 16-year-old male non-smoker, with ecto-morph body build, affected by VRD was referredto our hospital complaining of chest pain and pal-pitations. His vitals signs and haemoglobin oxygensaturation were normal. Chest X-ray examinationshowed left pneumothorax (fig. 1). The patientpast medical history was unremarkable, except forthe diagnosis of VRD made in 2004. This diagno-sis was based on physical examination, which re-vealed multiple (>6) large café-au-lait macules onthe chest skin and in cutaneous areas of the ab-domen usually not exposed to sunlight (fig. 2).Other clinical manifestations of VRD (CNS, skele-tal, neurological) were absent. The pneumothoraxKeywords: Neurofibromatosis, Pneumothorax, Emphysema, Lung bullae.1 Department of Surgical and Morphological Sciences, Thoracic Surgery Unit, Varese University Hospital, University ofInsubria, Varese;2 Respiratory Unit, Varese University Hospital, University of Insubria, Varese, Italy.Correspondence: Nicola Rotolo, Department of Surgical and Morphological Sciences, Thoracic Surgery Unit, Varese UniversityHospital, University of Insubria, Via Guicciardini 9, 21100 Varese, Italy; e-mail: nicola.rotolo@uninsubria.itABSTRACT: Bullous lung disease and neurofibromatosistype-1. E. Nardecchia, L. Perfetti, M. Castiglioni, D. Di Natale,A. Imperatori, N. Rotolo.Lung interstitial diseases and bullae are described aspossible complications of neurofibromatosis type-1 (NF-1),a genetic disorder inherited as a autosomal-dominanttrait. We report the case of a 16-year-old male non-smok-er with NF-1, who presented with pneumothorax causedby ruptured lung bullae. The case of this young patient,successfully treated by video-assisted thoracoscopic resec-tion of bullae, supports the concept that pulmonary alter-ations may be part of the NF-1 syndrome, rather than asan unrelated complication.Monaldi Arch Chest Dis 2012; 77: 2, 105-107.106E. NARDECCHIA ET AL.was treated by tube drainage of the left pleuralspace. Since pulmonary air leakage persisted forseveral days, high-resolution computed tomogra-phy (HRCT) of the chest was obtained. Chestscans revealed bilateral apical lung bullae, with di-ameter up to 1.5 cm (fig. 3). Surgical treatment ofpersistent pneumothorax was decided. With a left3-port video-thoracoscopic approach, the apicallung bullae were resected and successful pleurode-sis was obtained by partial parietal pleurectomy.Histological examination of the resected pul-monary bullae revealed emphysematous parenchy-ma with sub-pleural bullae. The post-operativecourse was uneventful and after seven days the pa-tient was discharged in good condition. At 30-dayfollow-up the patient was asymptomatic.DiscussionNF-1 is a neurogenetic disorder with wide-spread involvement of neuroectodermal and meso-dermal tissues [7, 8]. Lung involvement consistingof ILD and/or bullae is not infrequent in the con-text of NF-1. The association between NF-1 andILD was first reported in 1963 by Davies [9], andseveral authors described coexisting lung diseasesin 10-20% of patients with NF-1 [5, 9]. A reviewof the pertinent literature revealed many differenttypes of lung lesions detected by radiologicalimaging in VRD patients, as summarized in table1. Associated pulmonary manifestations mostcommonly include bilateral fibrosis with basal pre-dominance, associated or not with thin-walled bul-lae that typically occur in the upper lobes [1, 2, 5,9-16]. Less frequently intra thoracic tumour andcystic disorders have been described [1, 2, 5].However, it is uncertain whether the developmentof ILD is a peculiar phenotypic manifestation ofNF-1. A recent article questioned such association,reporting that the evidence supporting a causativerelationship between NF-1 and interstitial diseasesis poor, and suggested that the latter are mainlysmoking-induced manifestations [15]. However,Zamora et al. proposed that NF-1 in associationwith ILD represents a distinct clinical entity [1].The pathogenesis of ILD in patients with NF-1 isuncertain. Patchefsky et al. suggested that pul-monary fibrosis in NF-1 may be determined by in-creased deposition of collagen in the lung, causinga fibrotic environment [12]. Fabricant et al. postu-lated a similar pathogenetic mechanism, attribut-ing the cause of ILD to myofibroblast activationby increased nerve growth factor levels in NF-1patients [17].In our case, the patient had a pre-existing clin-ical diagnosis of NF-1, documented by café-au-lait macules on the chest and lower abdomen skin,and presented with pneumothorax caused by rup-tured lung bullae. His chest HRCT showed bilat-eral apical lung bullae, without signs of fibrosis,and histology of the resected bullous parenchymarevealed emphysematous lung. Differently fromprevious reports of lung bullous disease associat-ed with VRD, that occurred after the fourthdecade of life [11, 13, 14, 16], the case here de-scribed occurred in a non-smoker young male,and supports the concept that NF-1 with bullousFig. 1. Chest X-ray exam on admission, showing left-sided pneu-mothorax.Fig. 2. Café-au-lait cutaneous macules on the chest and abdomen.Fig. 3. High resolution computed tomography scan of the chest, show-ing pulmonary bullous disease bilaterally, and left-sided pneumothorax.107BULLOUS DISEASE AND NEUROFIBROMATOSIS TYPE-1lung disease may be a distinct clinical entity, un-related to smoking [1, 5, 9].References1. Zamora AC, Collard HR, Wolters PJ, Webb WR, KingTE. Neurofibromatosis associated lung disease: a case se-ries and literature review. Eur Respir J 2007; 29: 210-14.2. Rossi SE, Erasmus JJ, Page McAdams H, Donelly LF.Thoracic manifestations of neurofibromatosis-I. Am JRoentgenol 1999; 173: 1631-8.3. Ferner RE, Huson SM, Thomas N et al. Guidelines forthe diagnosis and management of individuals with neu-rofibromatosis 1. J Med Genet 2007; 44: 81-88.4. Riccardi VM. Von Recklinghausen neurofibromatosis.N Engl J Med 1981; 305: 1617-27.5. Oikonomou A, Vadikolias K, Birbilis T, Bouros D, Pras-sopoulos P. HRCT findings in the lungs of non smokerswith neurofibromatosis. Eur J Radiol 2011; 80: 520-23.6. Miyamoto K. Pulmonary manifestations in Von Reck-linghausen’s disease. Intern Med 1997; 36: 381.7. Arun D, Gutmann DH. Recent advances in neurofibro-matosis type 1. Curr Opin Neurol 2004; 17: 101-5.8. Karmes PS. Neurofibromatosis: a common neurocuta-neous disorder. Mayo Clin Proc 1998; 73: 1071-76.9. Davies PDB. Diffuse pulmonary involvement in VonRecklinghausen’s disease: a new syndrome. Thorax1963; 18: 198.10. Israel-Asselain R, Chebat J, Sors CH, Basset F, Le Rol-land A. Diffuse interstitial pulmonary fibrosis in amother and son with von Recklinghausen’s disease.Thorax 1965; 20: 153-57.11. Massaro D, Katz S. Fibrosing alveolitis: its occurrence,roentgenographic and pathologic features in von Reck-linghausen’s neurofibromatosis. Am Rev Respir Dis1966; 93: 934-42.12. Patchefsky AS, Atkinson WG, Hoch WS, Gordon G,Lipshitz HI. Interstitial pulmonary fibrosis and vonRecklinghausen’s disease. An ultrastructural and im-munofluorescent study. Chest 1973; 64: 459-64.13. Volpini E, Convertino G, Fulgoni P, Savasta S, VituloP. Pulmonary changes in a man affected by von Reck-linghausen’s disease. Monaldi Arch Chest Dis 1996;51: 123-24.14. Yokoyama A, Kohno N, Sakai K, Kondo K, HirasawaY, Hiwada K. Distal acinar emphysema and interstitialpneumonia in a patient with von Recklinghausen’s dis-ease: five-year observation following quitting smoking.Intern Med 1997; 36: 413-16.15. Ryu JH, Parambil JG, McGrann PS, Aughenbaugh GL.Lack of evidence for an association between neurofi-bromatosis and pulmonary fibrosis. Chest 2005; 128:2381-86.16. Zanobetti M, Del Taglia B, Conti A, Innocenti F, PiniR. Chest ultrasonography to detect lung involvement invon Recklinghausen’s disease. Intern Emerg Med 2012;DOI 10.1007/s11739-012-0779-8.17. Fabricant RN, Todaro GJ. Increased serum levels ofnerve growth factor in von Recklinghausen’s disease.Arch Neurol 1981; 38: 401-5.Table 1. - Chest radiographic findings of lung abnormalities associated with NF-1Cases of thoracic Radiographic Predominant RespiratoryAuthor abnormalities appearance lung site symptomsin VRD* patientsDavies PDB, 1963 [9] 9 Mottled opacities Lower lobe Breathlessnes, dyspnoeaIsrael-Asselain R, 1965 [10] 2 Reticular/linear opacities Upper lobe Dyspnoea, coughNodular opacities Lower lobeMassaro D, 1966 [11] 20 Bullae Upper lobe Not AvailableMottled and linear infiltrate DiffusePatchefsky A, 1973 [12] 1 Diffuse interstitial infiltrations Lower lobe DyspnoeaVolpini E, 1995 [13] 1 Severe bullous emphysema Upper lobe BreathlessnesYokoyama A, 1997 [14] 1 Bullae and acinar emphysema Upper lobe NoRossi SE, 1999 [2] Not Available Thin-walled bullae Upper lobe Not AvailableLung fibrosis Lower lobePulmonary nodulesRyu JH, 2005 [15] 22 Cystic airspace Not Available Not AvailableBullaeInterstitial infiltrateThin-walled bullae Upper lobeZamora AC, 2007 [1] 64 Linear opacities Lowe lobe Dyspnoea, cough, chest painBullous emphysema Upper lobeThin-walled cyst Upper lobeOikonomou A, 2010 [5] 6 Thin-walled cyst Upper lobe NoZanobetti M, 2012 [16] 1 Small thin-walled cyst Lower lobe Dyspnoea, cough* VRD = Von Recklinghausen’s disease.

Bullous lung disease and neurofibromatosis type-1.

Bullous lung disease and neurofibromatosis type-1.

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