X-linked Cardiomyopathy Presenting as Contracted Endocardial Fibroelastosis Gunnar Sjoberg, MD, PhD,a Chung Wo Chow, MBBS,b Stephen Cooper, MBBS,c and Robert G. Weintraub, MBBSa We report a case of familial contracted endocardial fibroelastosis (EFE) in a young boy presenting at 14 months of age with severe heart failure. A previous echocardiogram showed normal left ventricular (LV) size and systolic function. The family history was suggestive of X-linked cardiomyopathy. These findings are assessed in light of earlier reports of contracted EFE. J Heart Lung Transplant 2007;26:293–5. Copyright © 2007 by the International Society for Heart and Lung Transplantation.
Endocardial fibroelastosis (EFE) is a rare disorder characterized by fibrotic thickening of the mural endocardium, most often affecting the left ventricle.1 Many different forms of EFE have been described. EFE can be divided by etiology into primary and secondary forms, and by ventricular size into dilated and contracted forms. Secondary forms include EFE associated with different cardiac anomalies, in particular left ventricular outflow tract obstructions such as critical aortic stenosis and hypoplastic left heart syndrome. The primary form of contracted EFE is characterized by a thickened endocardium and small- or normal-sized left ventricle (LV) without associated cardiac anomaly. The inheritance has been reported as X-linked,2 or as suggestive of an autosomal-recessive status.3 We describe a case of contracted EFE where the family history indicates an X-linked form of inheritance. CASE REPORT
and the heart was still available for review. It showed a slightly small LV with features of mitral stenosis and diffuse endocardial fibroelastosis. No autopsy was performed on the second uncle. In view of the family history, the index patient (Figure 1, III-3) had an echocardiogram performed at 4 months of age, which showed normal LV dimensions and systolic function (Figure 2A). There was no evidence of left ventricular non-compaction. Ten months later the boy presented with severe congestive heart failure. Repeat echocardiography (Figure 2B) showed severe LV hypoplasia. The LV free wall and interventricular septum were hypertrophic and the mitral valve was stenotic (Figure 2B, C). The right ventricle was markedly dilated and contracted poorly. At cardiac catheterization the pulmonary artery pressures were suprasystemic, with a resting transpulmonary gradient of 34 mm Hg and an indexed pulmonary vascular resistance index (PVRI) of 15 U.msq, falling to 18 mm Hg and 8 U/msq, respectively, with a
The patient described herein was referred for cardiac transplantation at 14 months of age. The pedigree of the family shows two paternal uncles (Figure 1, II-1 and II-2), who died at 11 and 14 months of age in the 1950s, shortly after developing congestive heart failure. An autopsy performed on the oldest uncle was performed
From the Departments of aCardiology and bPathology, Royal Children’s Hospital, Melbourne, Australia; and cDepartment of Cardiology, Children’s Hospital at Westmead, Sydney, Australia. Submitted August 3, 2006; revised November 26, 2006; accepted December 12, 2006. Supported by grants from Stiftelsen Samariten and Sallskapet Barnavard (to G.S.). Reprint requests: Robert Weintraub, MBBS, Department of Cardiology, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia. Telephone: ⫹61-3-6345-5718. Fax: ⫹61-3-6345-6001. E-mail:
[email protected] Copyright © 2007 by the International Society for Heart and Lung Transplantation. 1053-2498/07/$–see front matter. doi:10.1016/ j.healun.2006.12.001
Figure 1. This pedigree shows the index patient (III-3) who died of heart failure secondary to contracted EFE at 15 months of age. His paternal uncles (II-1 and II-2) both died of congestive heart failure at 11 and 14 months of age, respectively. 293
294
Sjoberg et al.
The Journal of Heart and Lung Transplantation March 2007
Figure 2. (A–C) Echocardiographic 2D imaging and pathology specimen (D) of the heart of the index patient. (A) Echocardiogram was performed at 4 months of age, showing normal left atrial and left and right ventricular sizes. (B) On subsequent echocardiogram, performed at 15 months of age, the LV is severely hypoplastic and LA and RV enlarged. Note the increased echogenicity of the LV inner wall. (C) Color Doppler of mitral inflow shows severe mitral stenosis. (D) Pathologic specimen shows severe LV hypoplasia and endocardial fibroelastosis. There is a thrombus at the apex of the RV. LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle.
combination of inhaled nitric oxide and 100% oxygen. Detailed chromosomal analysis did not reveal any mutation in the G4.5 (TAZ) gene of the X-chromosome (Barth gene coding for tafazzin). Both the urine metabolic screen and serum carnitine profile were normal. Electrocardiograms and echocardiograms in both parents were normal. The patient was listed for urgent cardiac transplantation but died from refractory congestive heart failure shortly afterward. Examination of the heart at autopsy (Figure 2D) confirmed the echocardiographic findings. The left ventricle was small. A dense layer of endocardial fibroelastosis, which also involved the mitral leaflets and chordal apparatus, resulting in mitral stenosis, covered the entire left atrium and ventricle. Histologic examination showed irregular myocyte hypertrophy in association with features of endocardial fibroelastosis (Figure 3). There was organized thrombus at the apex of the right ventricle. No abnormality of mitochondrial
structure was noted on electron microscopy of the heart, skeletal muscle or liver. DISCUSSION We have described a form of contracted EFE in the setting of probable X-linked cardiomyopathy. A small number of cases of hereditary contracted EFE have been reported previously.2–7 Fixler et al described a family in whom contracted EFE was found in three boys over two generations and the pedigree also favored a sex-linked recessive inheritance.2 In this family the affected boys, similar to our case, presented with cardiac failure at around 1 year of age. Familial contracted EFE has also been reported to affect girls.3 EFE can be associated with structural heart disease such as severe neonatal aortic stenosis and hypoplastic left heart syndrome as well as intrauterine mumps infection. Ursell and co-workers described three unrelated children with contracted EFE who died within 3
The Journal of Heart and Lung Transplantation Volume 26, Number 3
Sjoberg et al.
295
our knowledge, the contracted form has not been described in families with known mutations in the TAZ gene. In conclusion, our report has demonstrated the postnatal evolution of contracted fibroelastosis in the setting of X-linked cardiomyopathy where TAZ gene mutations have been excluded. REFERENCES
Figure 3. Histologic section of myocardial tissue from the left ventricle of the index patient. Note irregular marked thickening of endocardium (arrow) containing prominent elastic fibers (Miller elastic stain).
days of birth, and for whom onset of the disease must also have been intrauterine.6 This contrasts to our case in which post-natal evolution of contracted fibroelastosis progressed over a period of only 10 months. In the past 15 years, several mutations causing X-linked cardiomyopathy have been discovered. The first gene to be discovered causing a primary cardiomyopathy was dystrophin, as the cause of X-linked dilated cardiomyopathy.8,9 Other genes located on the X-chromosome coding for emerin, LAMP-2, -galactosidase and tafazzin have been shown to cause the cardiomyopathy-associated syndromes of X-linked Emery–Dreifuss muscular dystrophy,10 Danon disease,11 Fabry disease12 and Barth syndrome,13 respectively. The latter, Barth syndrome, is characterized by muscular weakness, neutropenia, growth retardation and dilated cardiomyopathy, often associated with endocardial fibroelastosis.14 However, a more cardiac-specific phenotype has also been described, which is caused by mutation in the same gene (TAZ) as Barth syndrome, characterized by left ventricular non-compaction and endocardial fibroelastosis15 but without the other characteristic findings of Barth syndrome. A recent review by Barth and co-workers indicated that the different forms of X-linked endocardial fibroelastosis described before genetic analysis was possible, such as that described by Fixler and co-workers, would be within the spectrum of Barth syndrome.16 We have shown that the gene causing Barth syndrome, the TAZ gene, was not mutated in this case of contracted EFE and involvement of another genetic mechanism is most likely. This may be specific to the contracted form of X-linked EFE, because, to
1. Sellers FJ, Keith JD, Manning JA. The diagnosis of primary endocardial fibroelastosis. Circulation 1964;29:49 –59. 2. Fixler DE, Cole RB, Paul MH, Lev M, Girod DA. Familial occurrence of the contracted form of endocardial fibroelastosis. Am J Cardiol 1970;26:208 –13. 3. Akiba T, Nakasato M, Suzuki H, Sato S, Sato T. Contracted form of endocardial fibroelastosis in two siblings. Pediatr Int 1999;41: 379 – 81. 4. Blieden LC, Schneeweiss A, Deutsch V, Neufeld HN. Contracted form of endocardial fibroelastosis: angiographic diagnosis and necropsy confirmation. Pediatr Cardiol 1983;4:281–3. 5. Hashimoto T, Yano K, Matsumoto Y, Hashiba K. Contracted form of primary endocardial fibroelastosis in a young adult without congestive heart failure. Jpn Heart J 1988;29: 121– 6. 6. Ursell PC, Neill CA, Anderson RH, Ho SY, Becker AE, Gerlis LM. Endocardial fibroelastosis and hypoplasia of the left ventricle in neonates without significant aortic stenosis. Br Heart J 1984;51: 492–7. 7. Okuni M, Saito Y, Okada R, Nakanishi A. A case of constrictive endocardial sclerosis accompanied with congenital Lutembacher’s syndrome. Jpn Heart J 1962;3:275– 83. 8. Towbin JA, Hejtmancik JF, Brink P, et al. X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation 1993;87:1854 – 65. 9. Muntoni F, Cau M, Ganau A, et al. Brief report: deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Engl J Med 1993;329:921–5. 10. Bione S, Small K, Aksmanovic VM, et al. Identification of new mutations in the Emery–Dreifuss muscular dystrophy gene and evidence for genetic heterogeneity of the disease. Hum Mol Genet 1995;4:1859 – 63. 11. Nishino I, Fu J, Tanji K, et al. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 2000;406:906 –10. 12. Bernstein HS, Bishop DF, Astrin KH, et al. Fabry disease: six gene rearrangements and an exonic point mutation in the alphagalactosidase gene. J Clin Invest 1989;83:1390 –9. 13. Bione S, D’Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D. A novel X-linked gene, G4.5. is responsible for Barth syndrome. Nat Genet 1996;12:385–9. 14. Barth PG, Scholte HR, Berden JA, et al. An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes. J Neurol Sci 1983;62:327–55. 15. Bleyl SB, Mumford BR, Thompson V, et al. Neonatal, lethal noncompaction of the left ventricular myocardium is allelic with Barth syndrome. Am J Hum Genet 1997;61:868 –72. 16. Barth PG, Valianpour F, Bowen VM, et al. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update. Am J Med Genet A 2004;126:349 –54.
