Sections

Angiokeratoma Corporis Diffusum (Fabry Disease)

Sections Angiokeratoma Corporis Diffusum (Fabry Disease)
Overview
Presentation
DDx
Workup
Treatment
Medication
Media Gallery
References

Workup

Laboratory Studies

Alpha-galactosidase assays are used to diagnose Fabry disease in males. Enzyme activity can be measured using patient's serum, leukocytes, tears, or cultured fibroblasts. The technique of using samples eluted from a dried blood spot collected on filter paper has allowed for high-throughput screening.^[32]However, enzyme assays only identify two thirds of heterozygote females. Thus, genetic testing is preferred for diagnosis of females. Holzl et al^[33]reported in 2010 on a fast and simple (yet sensitive) test to identify enzyme deficiencies in patients with angiokeratoma corporis diffusum Fabry disease).

Albuminuria/proteinuria are the main markers of renal dysfunction in Fabry disease. Urine sediment contains cells with birefringent lipid globules termed Maltese crosses. A few studies have shown that measuring biomarkers of glomerular (transferrin and type IV collagen) and tubular (α1-microglobulin, N-acetyl-β-glucosaminidase, and alanine aminopeptidase) dysfunction may be more accurate than albuminuria in identifying Fabry nephropathy.^[34]

Papaxanthos-Roche et al^[35]noted that azoospermia can be a feature of Fabry disease.

Novel Gb(3) isoforms can be found in patients with Fabry disease.^[36]

Pereira et al^[37]found the lysosome-associated membrane proteins (LAMP) 1 and 2 are normal in normal controls and normalize with treatment with alpha-galactosidase. This helps to measure the effective of enzyme replacement therapy.

Using a mouse model, Shu et al^[38]found that 3-nitrotyrosine can function as a marker for Fabry disease–related vasculopathy.

Imaging Studies

A variety of imaging studies can be used to evaluate Fabry disease. These include cardiac, body, and brain imaging tests.

Neurological

In a group of young Fabry disease patients with normal MRI findings, a significant increment of greater than 12% in apparent diffusion coefficient values in the corona radiata occurred compared with age-matched controls. The difference might demonstrate increased interstitial water in tissue after the Starling equilibrium under raised cerebral blood flow. This increase water content has been previously defined as a manifestation of Fabry disease. Thus, increased apparent diffusion coefficient values might occur before conventional MRI changes in persons with Fabry disease. Increased apparent diffusion coefficient values seem to be a sensitive marker of disease progression and the healing effect of enzymatic replacement therapy.^[39]

Cardiac

Echocardiography can disclose left ventricular hypertrophy and systolic anterior motion of the mitral leaflets. Cardiac catheterization can show marked gradient loss in the left ventricular peak systolic outflow gradient, which indicates the presence of left ventricular outflow obstruction. Cardiac MRI might play a role in evaluating the effectiveness of enzyme therapy for Fabry disease.^[40]

Other Tests

Slit-lamp examination of the eyes of patient with Fabry disease can reveal a whorl-like keratopathy.^[41]Thus, ophthalmic examination can be useful in defining Fabry disease.

A variety of neurological tests can be done to detect small-fiber neuropathy in Fabry disease and other small-fiber diseases that involve neuropathy.^[42]

Procedures

Slit-lamp ophthalmologic examination demonstrates characteristic corneal opacity. Also, look for the unique spokelike cataracts in the posterior capsule.

Tissue biopsy can aid in diagnosis.

Histologic Findings

Histology shows numerous, dilated, thin-walled, endothelial-lined, blood-engorged capillaries in the papillary dermis, with an overlying hyperkeratotic epidermis. Careful inspection may reveal cytoplasmic vacuoles containing lipid in the endothelial cells, fibroblasts, and pericytes. However, in most patients, histologic findings essentially are identical to those of other angiokeratomas.

Endomyocardial biopsy findings of the heart can demonstrate sarcoplasmic vacuolization of cardiac muscle cells under light microscopy and lamellated zebra bodies in the cytoplasm under electron microscopy.

Electromicroscopy investigation can show stromal cells in hemizygous tissue and endothelial and smooth muscle cells in heterozygous tissue; cells contain membrane-bound inclusions with a lamellar structure (ie, inclusion bodies with a zebralike appearance).

Treatment & Management

U.S. National Library of Medicine, part of the National Institutes of Health,. GLA. Genetics Home Reference. Available at http://ghr.nlm.nih.gov/gene=gla. Accessed: June 21, 2009.
Zampetti A, Orteu CH, Antuzzi D, Bongiorno MR, Manco S, Gnarra M, et al. Angiokeratoma: decision-making aid for the diagnosis of Fabry disease. Br J Dermatol. 2012 Apr. 166 (4):712-20. [Medline].
Kelly B, Kelly E. Angiokeratoma corporis diffusum in a patient with no recognizable enzyme abnormalities. Arch Dermatol. 2006 May. 142 (5):615-8. [Medline].
Calzavara-Pinton PG, Colombi M, Carlino A, Zane C, Gardella R, Clemente M, et al. Angiokeratoma corporis diffusum and arteriovenous fistulas with dominant transmission in the absence of metabolic disorders. Arch Dermatol. 1995 Jan. 131 (1):57-62. [Medline].
Lu YY, Lu CC, Wu CS, Wu CH. Familial angiokeratoma corporis diffusum without identified enzyme defect. Indian J Dermatol Venereol Leprol. 2015 Jan-Feb. 81 (1):46-9. [Medline].
Zampetti A, Gnarra M, Borsini W, et al. Vascular Endothelial Growth Factor (VEGF-a) in Fabry disease: Association with cutaneous and systemic manifestations with vascular involvement. Cytokine. 2013 Jan 16. [Medline].
Molho-Pessach V, Bargal R, Abramowitz Y, et al. Angiokeratoma corporis diffusum in human beta-mannosidosis: Report of a new case and a novel mutation. J Am Acad Dermatol. 2007 Sep. 57(3):407-12. [Medline].
Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet Med. 2009 Nov. 11 (11):790-6. [Medline].
Orteu CH, Jansen T, Lidove O, Jaussaud R, Hughes DA, Pintos-Morell G, et al. Fabry disease and the skin: data from FOS, the Fabry outcome survey. Br J Dermatol. 2007 Aug. 157 (2):331-7. [Medline].
Mehta A, Clarke JT, Giugliani R, et al. Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey. J Med Genet. 2009 Aug. 46(8):548-52. [Medline].
Larralde M, Boggio P, Amartino H, Chamoles N. Fabry disease: a study of 6 hemizygous men and 5 heterozygous women with emphasis on dermatologic manifestations. Arch Dermatol. 2004 Dec. 140(12):1440-6. [Medline].
Lidove O, Zeller V, Chicheportiche V, Meyssonnier V, Sené T, Godot S, et al. Musculoskeletal manifestations of Fabry disease: A retrospective study. Joint Bone Spine. 2015 Dec 14. [Medline].
Møller AT, Jensen TS. Neurological manifestations in Fabry's disease. Nat Clin Pract Neurol. 2007 Feb. 3(2):95-106. [Medline].
Nance CS, Klein CJ, Banikazemi M, et al. Later-onset Fabry disease: an adult variant presenting with the cramp-fasciculation syndrome. Arch Neurol. 2006 Mar. 63(3):453-7. [Medline].
Eng CM, Fletcher J, Wilcox WR, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis. 2007 Apr. 30(2):184-92. [Medline].
Cole AL, Lee PJ, Hughes DA, Deegan PB, Waldek S, Lachmann RH. Depression in adults with Fabry disease: a common and under-diagnosed problem. J Inherit Metab Dis. 2007 Nov. 30(6):943-51. [Medline].
Dominguez RO, Michref A, Tanus E, Amartino H. [Restless legs syndrome in Fabry disease: clinical feature associated to neuropathic pain is overlooked]. Rev Neurol. 2007 Oct 16-31. 45(8):474-8. [Medline].
Choudhury S, Meehan S, Shin HT. Fabry disease: an atypical presentation. Pediatr Dermatol. 2005 Jul-Aug. 22(4):334-7. [Medline].
Happle R. Capillary malformations: a classification using specific names for specific skin disorders. J Eur Acad Dermatol Venereol. 2015 Dec. 29 (12):2295-305. [Medline].
Jung S, Kim YC. Hypohidrosis: an early clue in the diagnosis of Fabry disease. Clin Exp Dermatol. 2014 Dec 24. [Medline].
Germain DP, Atanasiu OI, Akrout-Marouene J, Benistan K. Raynaud's phenomenon associated with Fabry disease. J Inherit Metab Dis. 2014 Dec 16:[Medline].
Linhart A, Kampmann C, Zamorano JL, et al. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J. 2007 May. 28(10):1228-35. [Medline].
Sadick N, Thomas L. Cardiovascular manifestations in Fabry disease: a clinical and echocardiographic study. Heart Lung Circ. 2007 Jun. 16(3):200-6. [Medline].
Sadick N, Thomas L. Cardiovascular manifestations in Fabry disease: a clinical and echocardiographic study. Heart Lung Circ. 2007 Jun. 16(3):200-6. [Medline].
Palla A, Hegemann S, Widmer U, Straumann D. Vestibular and auditory deficits in Fabry disease and their response to enzyme replacement therapy. J Neurol. 2007 Oct. 254(10):1433-42. [Medline].
Wasik JS, Simon RW, Meier T, Steinmann B, Amann-Vesti BR. Nailfold capillaroscopy: Specific features in Fabry disease. Clin Hemorheol Microcirc. 2009. 42(2):99-106. [Medline].
Lidove O, Chauveheid MP, Benoist L, Alexandra JF, Klein I, Papo T. Chronic meningitis and thalamic involvement in a woman: Fabry disease expanding phenotype. J Neurol Neurosurg Psychiatry. 2007 Sep. 78(9):1007. [Medline].
Germain DP, Benistan K, Boutouyrie P, Mutschler C. Osteopenia and osteoporosis: previously unrecognized manifestations of Fabry disease. Clin Genet. 2005 Jul. 68(1):93-5. [Medline].
Mersebach H, Johansson JO, Rasmussen AK, et al. Osteopenia: a common aspect of Fabry disease. Predictors of bone mineral density. Genet Med. 2007 Dec. 9(12):812-8. [Medline].
Hoffmann B, Schwarz M, Mehta A, Keshav S. Gastrointestinal symptoms in 342 patients with Fabry disease: prevalence and response to enzyme replacement therapy. Clin Gastroenterol Hepatol. 2007 Dec. 5(12):1447-53. [Medline].
Callegaro D, Kaimen-Maciel DR. Fabry's disease as a differential diagnosis of MS. Int MS J. 2006 Jan. 13(1):27-30. [Medline].
Chamoles NA, Blanco M, Gaggioli D. Fabry disease: enzymatic diagnosis in dried blood spots on filter paper. Clin Chim Acta. 2001 Jun. 308 (1-2):195-6. [Medline].
Holzl MA, Gartner M, Kovarik JJ, et al. Quantification of alpha-galactosidase activity in intact leukocytes. Clin Chim Acta. 2010 Jun 25. [Medline].
Riccio E, Sabbatini M, Capuano I, Pisani A. Early Biomarkers of Fabry Nephropathy: A Review of the Literature. Nephron. 2019 Oct 15. 1-8:1-8. [Medline].
Papaxanthos-Roche A, Deminiere C, Bauduer F, Hocke C, Mayer G, Lacombe D. Azoospermia as a new feature of Fabry disease. Fertil Steril. 2007 Jul. 88(1):212.e15-8. [Medline].
Auray-Blais C, Boutin M. Novel Gb(3) Isoforms Detected in Urine of Fabry Disease Patients: A Metabolomic Study. Curr Med Chem. 2012 May. [Medline].
Pereira EM, do Monte SJ, do Nascimento FF, de Castro JA, Sousa JL, Filho HC, et al. Lysosome-associated protein 1 (LAMP-1) and Lysosome-associated protein 2 (LAMP-2) in a larger family carrier of Fabry disease. Gene. 2014 Feb 15. 536(1):118-22. [Medline].
Shu L, Vivekanandan-Giri A, Pennathur S, Smid BE, Aerts JM, Hollak CE, et al. Establishing 3-nitrotyrosine as a biomarker for the vasculopathy of Fabry disease. Kidney Int. 2014 Jan 8. [Medline].
Politei JM, Capizzano AA. Magnetic resonance image findings in 5 young patients with Fabry disease. Neurologist. 2006 Mar. 12(2):103-5. [Medline].
Messalli G, Imbriaco M, Avitabile G, Russo R, Iodice D, Spinelli L, et al. Role of cardiac MRI in evaluating patients with Anderson-Fabry disease: assessing cardiac effects of long-term enzyme replacement therapy. Radiol Med. 2011 Jul. [Medline].
Sivley MD. Fabry disease: a review of ophthalmic and systemic manifestations. Optom Vis Sci. 2013 Feb. 90(2):e63-78. [Medline].
Lefaucheur JP, Wahab A, Planté-Bordeneuve V, Sène D, Ménard-Lefaucheur I, Rouie D, et al. Diagnosis of small fiber neuropathy: A comparative study of five neurophysiological tests. Neurophysiol Clin. 2015 Dec. 45 (6):445-55. [Medline].
Politei JM. Can we use statins to prevent stroke in Fabry disease?. J Inherit Metab Dis. 2009 Aug. 32(4):481-7. [Medline].
Imbriaco M, Pisani A, Spinelli L, et al. Effects of enzyme-replacement therapy in patients with Anderson-Fabry disease: a prospective long-term cardiac magnetic resonance imaging study. Heart. 2009 Jul. 95(13):1103-7. [Medline].
Linthorst GE, Vedder AC, Aerts JM, Hollak CE. Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers. Clin Chim Acta. 2005 Mar. 353(1-2):201-3. [Medline].
Fuller M, Sharp PC, Rozaklis T, et al. Urinary lipid profiling for the identification of fabry hemizygotes and heterozygotes. Clin Chem. 2005 Apr. 51(4):688-94. [Medline].
Clarke JT. Narrative review: Fabry disease. Ann Intern Med. 2007 Mar 20. 146(6):425-33. [Medline].
Suzuki K, Miura N, Kitagawa W, Suzuki S, Komatsuda A, Nishikawa K, et al. Progressive renal failure despite long-term biweekly enzyme replacement therapy in apatient with Fabry disease secondary to a new alpha-galactosidase mutation of Leu311Arg(L311R). Clin Exp Nephrol. 2011 Jul. [Medline].
Lidove O, Joly D, Barbey F, et al. Clinical results of enzyme replacement therapy in Fabry disease: a comprehensive review of literature. Int J Clin Pract. 2007 Feb. 61(2):293-302. [Medline].
Lin HY, Huang YH, Liao HC, Liu HC, Hsu TR, Shen CI, et al. Clinical observations on enzyme replacement therapy in patients with Fabry disease and the switch from agalsidase beta to agalsidase alfa. J Chin Med Assoc. 2013 Dec 30. S1726-4901(13)00312-2. [Medline].
Kim W, Pyeritz RE, Bernhardt BA, Casey M, Litt HI. Pulmonary manifestations of Fabry disease and positive response to enzyme replacement therapy. Am J Med Genet A. 2007 Feb 15. 143(4):377-81. [Medline].
Germain DP, Giugliani R, Hughes DA, et al. Safety and pharmacodynamic effects of a pharmacological chaperone on a-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies. Orphanet J Rare Dis. 2012 Nov 24. 7:91. [Medline]. [Full Text].

Media Gallery

Angiokeratomas are commonly observed as dense cluster of lesions on the flank and private areas.
Angiokeratoma is the small punctate reddish-to-bluish angiectases on the umbilicus.
Corneal verticillata, commonly seen in patients with Fabry disease, detectable by slit lamp examination

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Author

Fnu Nutan, MD, FACP Assistant Professor, Department of Dermatology, Virginia Commonwealth University School of Medicine

Fnu Nutan, MD, FACP is a member of the following medical societies: American College of Physicians, Indian Association of Dermatologists, Venereologists and Leprologists, Society of General Internal Medicine, Society of Hospital Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Zixuan Yi Eastern Virginia Medical School

Zixuan Yi is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael J Wells, MD, FAAD Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Rosalie Elenitsas, MD Herman Beerman Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System

Rosalie Elenitsas, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society of Dermatopathology, Pennsylvania Academy of Dermatology

Disclosure: Received royalty from Lippincott Williams Wilkins for textbook editor.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.

Additional Contributors

Timothy McCalmont, MD Director, UCSF Dermatopathology Service, Professor of Clinical Pathology and Dermatology, Departments of Pathology and Dermatology, University of California at San Francisco; Editor-in-Chief, Journal of Cutaneous Pathology

Timothy McCalmont, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, American Society of Dermatopathology, California Medical Association, College of American Pathologists, United States and Canadian Academy of Pathology

Disclosure: Received consulting fee from Apsara for independent contractor.

Noah S Scheinfeld, JD, MD, FAAD † Assistant Clinical Professor, Department of Dermatology, Weil Cornell Medical College; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Assistant Attending Dermatologist, New York Presbyterian Hospital; Assistant Attending Dermatologist, Lenox Hill Hospital, North Shore-LIJ Health System; Private Practice

Noah S Scheinfeld, JD, MD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Anusuya Mokashi, MD, MS Resident Physician, Department of Radiology, Staten Island University Hospital

Disclosure: Nothing to disclose.

Acknowledgements

Arnold R Oppenheim, MD Assistant Professor, Department of Internal Medicine, Division of Dermatology, Eastern Virginia School of Medicine

Arnold R Oppenheim, MD is a member of the following medical societies: American Academy of Dermatology and American Society for Clinical Pathology

Disclosure: Nothing to disclose.

Sections Angiokeratoma Corporis Diffusum (Fabry Disease)
Overview
Presentation
DDx
Workup
Treatment
Medication
Media Gallery
References

Angiokeratoma Corporis Diffusum (Fabry Disease) Workup

Laboratory Studies

Imaging Studies

Neurological

Cardiac

Other Tests

Procedures

Histologic Findings

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