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Pulmonary infiltrates in Costello Syndrome

¹ Dept of Pulmonary and Intensive Care Medicine, ² Institute of Immunology, and ³ Institute of Pathology, Otto-von-Guericke-University, Magdeburg, Germany

CORRESPONDENCE: N. Waldburg, Klinik für Pneumologie und Intersivmedizin, Universitätsklinikum Magdeburg, Leipziger Str. 44, 39112 Magdeburg, Germany. Fax: 49 3916715420. E-mail: tobias.welte@medizin.uni-magdeburg.de

Keywords: Costello, infiltrate, lipid pneumonia, lung

Received: June 27, 2003
Accepted October 6, 2003

Abstract

This paper reports on a patient with diffuse pulmonary infiltrates directly related to Costello Syndrome.

This congenital disorder is characterised by multiple congenital abnormalities, such as psychomotor retardation, short stature, redundant skin, papillomata, curly hair, relative macroencephaly, distinctive face and various defects of internal organs.

This study is the first to document the histopathological findings in the lungs.

Most conspicuous was the depositing of abnormal collagen and elastic fibres and the development of endogenous lipid pneumonia.

In 1971, Costello described a new syndrome that involves multiple congenital abnormalities, such as psychomotor retardation, short stature, redundant skin, papillomata, curly hair, relative macroencephaly, distinctive face and various defects of internal organs 1–3. In addition, patients with the Costello Syndrome tend to develop benign and malignant tumours 4–6. This paper now reports on a patient with diffuse pulmonary infiltrates that are directly related to this condition.

Case history

History
The 37-yr-old male patient was born after uneventful pregnancy (birth weight 3,240 g; length 49 cm), with unremarkable family history. A gastroduodenal tube was required at the age of 9 months. Upon his last examination, at 37 yrs of age, he described exclusively progredient dyspnoea. He showed a happy outgoing nature, short stature (153 cm) and mental subnormality.

Physical findings
Characteristically, his skin was dark, with loose and redundant skin on the hands and feet. The palms were hyperkeratotic and the fingers hyperextensible with dystrophic nails. Papillomas were noted on his cheeks and fingers. His ears were low-set, protuberant and posteriorly rotated. He had curly hair, relative macroencephaly, depressed nasal bridge, pectus carinatum, long nipples and lymphedema (fig. 1).

View larger version (67K): [in this window] [in a new window]   Fig. 1.— A 37-yr-old male patient with Costello Syndrome (short stature (153 cm), redundant dark skin, curly hair, relative macroencephaly, distinctive face, pectus carinatum, long nipples and lymphedema).

Chest examination
Chest radiographs showed bilateral diffuse interstitial infiltration predominating in lower lung zones (fig. 2). Chest CT scans displayed bilateral, diffuse areas of ground-glass attenuation, with a basal predominance (figs 3 and 4). The bronchoalveolar lavage fluid contained increased amounts of granulocytes and CD8-positive lymphocytes.

View larger version (110K): [in this window] [in a new window]   Fig. 2.— Chest radiographs showed bilateral diffuse interstitial infiltration predominating in lower lung zones.

View larger version (118K): [in this window] [in a new window]   Fig. 3.— Basal chest CT scans displayed bilateral, diffuse areas of ground-glass attenuation, with a basal predominance.

View larger version (100K): [in this window] [in a new window]   Fig. 4.— Apical Chest CT scans without significant pathologies.

Histopathological examination
Histopathological examination revealed endogenous lipid pneumonia consisting of numerous intra-alveolar foamy macrophages, cholesterol clefts, surrounding giant cell reaction and hyperplasia of type II pneumocytes. Atypical collagen fibres were deposited in the pleura and septal connective tissue, particularly in the adventitia of medium-sized pulmonary veins and arteries, leading to marked thickening and compression (fig. 5). Most conspicuous was the increased deposition of atypical, fragmented, thickened, sometimes loosely organised elastic fibres in the alveolar walls (fig. 6). Continuous aspiration of lipids, virus pneumonia and malignancy were excluded.

View larger version (144K): [in this window] [in a new window]   Fig. 5.— Atypical collagen fibres in the adventitia of pulmonary vessels. Elastica van Gieson. Scale bar=310 µm.

View larger version (129K): [in this window] [in a new window]   Fig. 6.— Atypical elastic fibres in alveolar walls. Elastica van Gieson Scale bar=40 µm.

Since its first description in 1971, >45 cases of Costello Syndrome have been reported, suggesting that this congenital disorder is more common than previously thought. Aetiology and genetics still need to be clarified. The clinical findings of this patient are consistent with those described previously. Some patients suffered from respiratory distress, upper respiratory infection and aspiration syndrome. Most patients died at a very young age because of cardiac complications, failure to thrive or unspecified causes 2, 7, 8.

To the best of the current authors' knowledge, this is the first histologically proven affection of the lung structure in Costello Syndrome. However, abnormal elastic fibres in the skin are a common feature 9, 10. In addition, autopsy cases revealed an impaired deposition of elastic fibres in the tongue, pharynx and upper oesophagus 11. The authors believe that the respiratory problems seen in this patient result from an impaired clearance of the airspaces from lipoproteins, caused by a structural damage of the lung parenchyma. Therefore, a direct relationship to the primary disease, which could have been revealed only by histopathological examination, seems to exist. There might be a causal link between the functional deficiency of the 67-kD elastin-binding protein, as previously described for Costello Syndrome 10, the depositing of abnormal collagen and elastic fibres, and the development of endogenous lipid pneumonia.

Future examinations of patients with Costello Syndrome may reveal organ manifestations that are unknown at present but may be clinically relevant or even play a decisive role for prognosis, as in the case presented here.

References

1. Assadi FK, Scott CI Jr, McKay CP, et al. Hypercalciuria and urolithiasis in a case of Costello syndrome. Pediatr Nephrol 1999;13:57–59.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. Der KV, Moroz B, McIntosh N, Watters AK, Blaichman S. Costello syndrome. Am J Med Genet 1991;41:69–73.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Siwik ES, Zahka KG, Wiesner GL, Limwongse C. Cardiac disease in Costello syndrome. Pediatrics 1998;101:706–709.[Free Full Text]
4. Gripp KW, Scott CI Jr, Nicholson L, et al. Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for a tumor screening protocol. Am J Med Genet 2002;108:80–87.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Sigaudy S, Vittu G, David A, et al. Costello syndrome: report of six patients including one with an embryonal rhabdomyosarcoma. Eur J Pediatr 2000;159:139–142.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Urakami S, Igawa M, Shiina H, Shigeno K, Kikuno N, Yoshino T. Recurrent transitional cell carcinoma in a child with the Costello syndrome. J Urol 2002;168:1133–1134.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
7. Kaji M, Kurokawa K, Hasegawa T, et al. A case of Costello syndrome and glycogen storage disease type III. J Med Genet 2002;39:E8.
8. Szalai S, Becker K, Torok E. Costello syndrome with decreased glucose tolerance. Eur J Dermatol 1999;9:533–536.[Web of Science][Medline] [Order article via Infotrieve]
9. Hatamochi A, Nagayama H, Kuroda K, et al. Costello syndrome with decreased gene expression of elastin in cultured dermal fibroblasts. Dermatology 2000;201:366–369.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
10. Hinek A, Smith AC, Cutiongco EM, Callahan JW, Gripp KW, Weksberg R. Decreased elastin deposition and high proliferation of fibroblasts from Costello syndrome are related to functional deficiency in the 67-kD elastin-binding protein. Am J Hum Genet 2000;66:859–872.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Mori M, Yamagata T, Mori Y, et al. Elastic fiber degeneration in Costello syndrome. Am J Med Genet 1996;61:304–309.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

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