Angiokeratoma Corporis Diffusum (Fabry Syndrome) Workup: Laboratory Studies, Imaging Studies, Other Tests

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Angiokeratoma Corporis Diffusum (Fabry Syndrome)

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

Workup

Laboratory Studies

Urine sediment contains cells with birefringent lipid globules termed Maltese crosses.

Serum, leukocytes, tears, skin biopsy samples, and cell cultures demonstrate alpha-galactosidase deficiency. These tests are the most definitive means of diagnosis.

Papaxanthos-Roche et al^[30]noted that azoospermia can be a feature of Fabry disease.

Holzl et al reported in 2010 on a fast and simple (yet sensitive) test to identify enzyme deficiencies in patients with angiokeratoma corporis diffusum Fabry disease).^[31]

Novel Gb(3) isoforms can be found in patients with Fabry disease.^[32]

Pereira et al found the lysosome-associated membrane proteins (LAMP) 1 and 2 are normal in normal controls and normalize with treatment with alpha-galactosidase.^[33]This helps to measure the effective of enzyme replacement therapy.

Using a mouse model, Shu et al found that 3-nitrotyrosine can function as a marker for Fabry disease–related vasculopathy.^[34]

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.^[35]

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.^[36]

Other Tests

Slit-lamp examination of the eyes of patient with Fabry disease can reveal a whorl-like keratopathy.^[37]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.^[38]

Procedures

The characteristic angiokeratoma of Fabry disease is found diffusely and is not limited to the scrotum as it is in Fordyce angiokeratoma. Mibelli angiokeratoma is observed primarily on the dorsum of the hands and feet. Angiokeratoma circumscriptum is a rare type of angiokeratoma with a unilateral distribution of discrete papules and nodules localized to a small area of the legs or trunk.

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

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.
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Nguyen Dinh Cat A, Escoubet B, Agrapart V, et al. Cardiomyopathy and response to enzyme replacement therapy in a male mouse model for fabry disease. PLoS One. 2012 May 4. 2012:e33743. [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].
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].
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Choudhury S, Meehan S, Shin HT. Fabry disease: an atypical presentation. Pediatr Dermatol. 2005 Jul-Aug. 22(4):334-7. [Medline].
Han AF, Wang P, Li Z, et al. Angiokeratoma corporis diffusum in a patient with Hodgkin's lymphoma: a new paraneoplastic skin manifestation?. Br J Dermatol. 2012 Dec 22. [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].
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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].
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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].
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].
Holzl MA, Gartner M, Kovarik JJ, et al. Quantification of alpha-galactosidase activity in intact leukocytes. Clin Chim Acta. 2010 Jun 25. [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].
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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].
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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].
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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].
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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

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.

Coauthor(s)

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

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.

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 Syndrome)
Overview
Presentation
DDx
Workup
Treatment
Medication
Media Gallery
References

Angiokeratoma Corporis Diffusum (Fabry Syndrome) Workup

Laboratory Studies

Imaging Studies

Neurological

Cardiac

Other Tests

Procedures

Histologic Findings

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Angiokeratoma Corporis Diffusum (Fabry Syndrome) Workup

Laboratory Studies

Imaging Studies

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Other Tests

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Histologic Findings

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