Top

Published in:

Open Access 01-12-2024 | Pulmonary-Function Tests | Research

Quantification of Proteus syndrome-associated lung disease

Authors: Christopher A. Ours, Anna Buser, Mia B. Hodges, Marcus Y. Chen, Julie C. Sapp, Bernadette R. Gochuico, Leslie G. Biesecker

Published in: Orphanet Journal of Rare Diseases | Issue 1/2024

Abstract

Background

Proteus syndrome is an ultra-rare mosaic overgrowth disorder. Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention. This retrospective study seeks to quantify the radiographic features of Proteus syndrome-associated lung disease using computed tomography (CT) of the chest. The first method derives a Cystic Lung Score (CLS) by using a computer-aided diagnostic tool to quantify the fraction of cystic involvement of the lung. The second method yields a Clinician Visual Score (CVS), an observer reported scale of severity based on multiple radiographic features. The aim of this study was to determine if these measurements are associated with clinical symptoms, pulmonary function test (PFT) measurements, and if they may be used to assess progression of pulmonary disease.

Results

One hundred and thirteen imaging studies from 44 individuals with Proteus syndrome were included. Dyspnea and oxygen use were each associated with higher CLS (p = 0.001 and < 0.001, respectively) and higher CVS (p < 0.001 and < 0.001). Decreases in percent predicted FVC, FEV₁, and DLCO each correlated with increased CLS and CVS. The annual increase of CLS in children, 5.6, was significantly greater than in adults, 1.6. (p = 0.03). The annual increase in CVS in children, 0.4, was similar to adults, 0.2 (p = 0.36).

Conclusions

Proteus syndrome-associated lung disease is progressive. The rate of cystic progression is increased in children. Increased scores in CLS and CVS were associated with clinical symptoms and decreased pulmonary function. Both methods were able to detect change over time and were associated with clinically meaningful outcomes which may enable their use in interventional studies.

Brody AS, Klein JS, Molina PL, Quan J, Bean JA, Wilmott RW. High-resolution computed tomography in young patients with cystic fibrosis: distribution of abnormalities and correlation with pulmonary function tests. J Pediatr. 2004;145(1):32–8. https://doi.org/10.1016/j.jpeds.2004.02.038.CrossRefPubMed

Goddard PR, Nicholson EM, Laszlo G, Watt I. Computed tomography in pulmonary emphysema. Clin Radiol. 1982;33(4):379–87. https://doi.org/10.1016/s0009-9260(82)80301-2.CrossRefPubMed

Gopalakrishnan V, Yao J, Steagall WK, Avila NA, Taveira-DaSilva AM, Stylianou M, Chen MY, Moss J. Use of CT imaging to quantify progression and response to treatment in lymphangioleiomyomatosis. Chest. 2019;155(5):962–71. https://doi.org/10.1016/j.chest.2019.01.004.CrossRefPubMedPubMedCentral

Irion KL, Hocchegger B, Marchiori E, Holemans JA, Smith RA, Raja RC, Singanayagam S. Proteus syndrome: high-resolution CT and CT pulmonary densitovolumetry findings. J Thorac Imaging. 2009;24(1):45–8. https://doi.org/10.1097/RTI.0b013e31818b20cd.CrossRefPubMed

Kaduthodil MJ, Prasad DS, Lowe AS, Punekar AS, Yeung S, Kay CL. Imaging manifestations in Proteus syndrome: an unusual multisystem developmental disorder. Br J Radiol. 2012;85(1017):e793-799. https://doi.org/10.1259/bjr/92343528.CrossRefPubMedPubMedCentral

Keppler-Noreuil KM, Burton-Akright J, Kleiner DE, Sapp JC, Lindhurst MJ, Han CG, Biesecker LG, Gochuico BR. Phenotypic features of cystic lung disease in Proteus syndrome: a clinical trial. Ann Am Thorac Soc. 2022;19(11):1871–80. https://doi.org/10.1513/AnnalsATS.202111-1214OC.CrossRefPubMedPubMedCentral

Keppler-Noreuil KM, Lozier J, Oden N, Taneja A, Burton-Akright J, Sapp JC, Biesecker LG. Thrombosis risk factors in PIK3CA-related overgrowth spectrum and Proteus syndrome. Am J Med Genet C Semin Med Genet. 2019;181(4):571–81. https://doi.org/10.1002/ajmg.c.31735.CrossRefPubMedPubMedCentral

Li CY, Chang YL, Chen WC, Lee YC. Pulmonary manifestations and management of proteus syndrome. J Formos Med Assoc. 2010;109(5):397–400. https://doi.org/10.1016/s0929-6646(10)60069-1.CrossRefPubMed

Lim GY, Kim OH, Kim HW, Lee KS, Kang KH, Song HR, Cho TJ. Pulmonary manifestations in Proteus syndrome: pulmonary varicosities and bullous lung disease. Am J Med Genet A. 2011;155(4):865–9. https://doi.org/10.1002/ajmg.a.33926.CrossRef

10.

Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O’Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011;365(7):611–9. https://doi.org/10.1056/NEJMoa1104017.CrossRefPubMedPubMedCentral

11.

Lynch DA, Al-Qaisi MA. Quantitative computed tomography in chronic obstructive pulmonary disease. J Thorac Imaging. 2013;28(5):284–90. https://doi.org/10.1097/RTI.0b013e318298733c.CrossRefPubMedPubMedCentral

12.

McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC, National Institutes of Health Rare Lung Diseases Consortium, The MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011;364(17):1595–606. https://doi.org/10.1056/NEJMoa1100391.CrossRefPubMedPubMedCentral

13.

Mirmomen SM, Arai AE, Turkbey EB, Bradley AJ, Sapp JC, Biesecker LG, Sirajuddin A. Cardiothoracic imaging findings of Proteus syndrome. Sci Rep. 2021;11(1):6577. https://doi.org/10.1038/s41598-021-86029-0.ADSCrossRefPubMedPubMedCentral

14.

Nakane M, Sato M, Hattori H, Matsumoto Y, Otsuki M, Murakawa M. Perioperative respiratory complications caused by cystic lung malformation in Proteus syndrome. J Anesth. 2006;20(1):26–9. https://doi.org/10.1007/s00540-005-0353-x.CrossRefPubMed

15.

Nathan NR, Patel R, Crenshaw MM, Lindhurst MJ, Olsen C, Biesecker LG, Keppler-Noreuil KM, Darling TN. Pathogenetic insights from quantification of the cerebriform connective tissue nevus in Proteus syndrome. J Am Acad Dermatol. 2018;78(4):725–32. https://doi.org/10.1016/j.jaad.2017.10.018.CrossRefPubMed

16.

Newman B, Urbach AH, Orenstein D, Dickman PS. Proteus syndrome: emphasis on the pulmonary manifestations. Pediatr Radiol. 1994;24(3):189–93. https://doi.org/10.1007/bf02012188.CrossRefPubMed

17.

Pal R, Bhattacharjee R, Bhansali A. Protean manifestations of Proteus syndrome. Postgrad Med J. 2018;94(1113):416. https://doi.org/10.1136/postgradmedj-2018-135731.CrossRefPubMed

18.

Rosenow T, Oudraad MC, Murray CP, Turkovic L, Kuo W, de Bruijne M, Ranganathan SC, Tiddens HA, Stick SM. PRAGMA-CF. A quantitative structural lung disease computed tomography outcome in young children with cystic fibrosis. Am J Respir Crit Care Med. 2015;191(10):1158–65. https://doi.org/10.1164/rccm.201501-0061OC.CrossRefPubMed

19.

Sapp JC, Buser A, Burton-Akright J, Keppler-Noreuil KM, Biesecker LG. A dyadic genotype-phenotype approach to diagnostic criteria for Proteus syndrome. Am J Med Genet C Semin Med Genet. 2019;181(4):565–70. https://doi.org/10.1002/ajmg.c.31744.CrossRefPubMedPubMedCentral

20.

Schielzeth H, Dingemanse NJ, Nakagawa S, Westneat DF, Allegue H, Teplitsky C, Reale D, Dochtermann NA, Garamszegi LZ, Araya-Ajoy YG. Robustness of linear mixed-effects models to violations of distributional assumptions. Methods Ecol Evol. 2020;11(9):1141–52. https://doi.org/10.1111/2041-210x.13434.CrossRef

21.

Shin SM, Kim WS, Cheon JE, Kim HS, Lee W, Jung AY, Kim IO, Choi JH. Bronchopulmonary dysplasia: new high resolution computed tomography scoring system and correlation between the high resolution computed tomography score and clinical severity. Korean J Radiol. 2013;14(2):350–60. https://doi.org/10.3348/kjr.2013.14.2.350.CrossRefPubMedPubMedCentral

22.

Taveira-DaSilva AM, Gopalakrishnan V, Yao J, Chen MY, Julien-Williams P, Jones AM, Pacheco-Rodriguez G, Moss J. Computer grading of lung disease severity in patients with lymphangioleiomyomatosis referred for transplantation. BMC Pulm Med. 2022;22(1):362. https://doi.org/10.1186/s12890-022-02123-7.CrossRefPubMedPubMedCentral

23.

Tiddens H, Andrinopoulou ER, McIntosh J, Elborn JS, Kerem E, Bouma N, Bosch J, Kemner-van de Corput M. Chest computed tomography outcomes in a randomized clinical trial in cystic fibrosis: Lessons learned from the first ataluren phase 3 study. PLoS ONE. 2020;15(11): e0240898. https://doi.org/10.1371/journal.pone.0240898.CrossRefPubMedPubMedCentral

24.

Turner JT, Cohen MM Jr, Biesecker LG. Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases. Am J Med Genet A. 2004;130(2):111–22. https://doi.org/10.1002/ajmg.a.30327.CrossRef

25.

Zusan E, Smith JM, Parker T. Proteus syndrome: a case report. Am Surg. 2009;75(9):853–6.CrossRefPubMed

Title: Quantification of Proteus syndrome-associated lung disease
Authors: Christopher A. Ours
Anna Buser
Mia B. Hodges
Marcus Y. Chen
Julie C. Sapp
Bernadette R. Gochuico
Leslie G. Biesecker
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Pulmonary-Function Tests
Computed Tomography
Computed Tomography
Published in: Orphanet Journal of Rare Diseases / Issue 1/2024
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-023-03013-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Quantification of Proteus syndrome-associated lung disease

Abstract

Background

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2024

Phenylketonuria from the perspectives of patients in Türkiye

Healthcare provider recognition of pregnancy related risks and management considerations in patients with tuberous sclerosis complex

Abnormal biochemical indicators of neonatal inherited metabolic disease in carriers

Brain perfusion changes in beta-thalassemia

Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods

Comparative study of different extendable intramedullary rods combined with surgery in the treatment of congenital pseudarthrosis of the tibia