Pediatric Dermatology

Vol. 22 No. 4 334–337, 2005

334

Address correspondence to Helen T. Shin, M.D., Ronald O.Perelman Department of Dermatology, New York University School ofMedicine, 560 First Avenue, H-100, New York, NY 10016, or e-mail:shin01@med.nyu.edu.

Blackwell Publishing, Ltd.

Fabry Disease: An Atypical Presentation

Sourab Choudhury, D.O.,* Shane Meehan, M.D.,† and Helen T. Shin, M.D.†‡

*

Department of Pediatrics, Long Island College Hospital, Brooklyn, New York,

†

Ronald O. Perelman Department of Dermatology, and

‡

Department of Pediatrics, New York University Medical Center, New York, New York

Abstract:

Fabry disease is a rare X-linked recessive lysosomal storagedisease. Patients typically have angiokeratomas distributed betweenthe umbilicus and knees, painful crises of the hands and feet, and renal,ophthalmologic, and cardiac abnormalities. An 11-year-old boy presentedwith a 6-year history of widespread petechial-like lesions and painful crisesof the hands and feet. On physical examination, he had numerous erythema-tous, nonblanching pinpoint macules and rare papules with an overlyingcrust. These lesions were widely distributed on his trunk, palms, and soles,while sparing the area between the umbilicus and knees. Histologic evalua-tion of one of these lesions found several dilated, blood-filled vessels in theupper dermis beneath a thinned epidermis. The patient also had markedlydecreased αααα

galactosidase A levels. Although the distribution of the angio-keratomas was atypical, the clinical and histologic findings were consistent

with a diagnosis of Fabry disease.

Fabry (1) described a 13-year-old boy with albuminuriaand cutaneous lesions that he later called angiokeratomacorporis diffusum in 1898. Around the same time, Andersondescribed a patient with similar features in England (2).Fabry disease is an X-linked recessive inborn error ofglycosphinogolipid catabolism resulting from the defi-cient activity of

α

-galactosidase A (

α

-Gal A) in affectedhemizygous males (3,4). This defect leads to the sys-temic deposition of glycosphingolipids affecting multipleorgan systems. The typical hemizygous male presentswith angiokeratomas between the umbilicus and theknees, painful crises of the hands and feet, and renal,ophthalmologic, and cardiac abnormalities. Fabry diseaseconfined to the heart or kidneys without any other symp-toms has been reported (5,6). Our patient presented at ayoung age with an atypical, widespread distribution ofangiokeratomas.

CASE REPORT

An 11-year-old Hispanic boy was referred to thepediatric dermatology clinic with a 6-year history of apetechial rash. A previous hematologic work-up, includinga complete blood count and coagulation studies hadnormal results. The petechia-like lesions had increasedin number and distribution over the years but wereasymptomatic. On physical examination, the patient hadnumerous pinpoint, erythematous, nonblanching maculeson his chest, back, and palms (Figs. 1 and 2). Rare pinpoint,erythematous, nonblanching papules, some with fine scale,were also present in these locations.

During the previous 2 years, the patient had com-plained of 1-hour episodes of pain involving his palmsand soles. The pain was described as a needle-like sen-sation exacerbated by cold temperatures and exercise.

Choudhury et al: Fabry Disease 335

He obtained some relief with ibuprofen but none withacetominophen. At times, he was unable to walk and wouldawaken at night because of severe pain. The patient hadbeen hospitalized twice for management and evaluationof this pain.

Antinuclear antibody (ANA), erythrocyte sedimenta-tion rate (ESR), C-reactive protein, rapid plasma reagin(RPR), protein electrophoresis, IgA, IgG, and IgM levelswere all normal. His medical history was unremarkableexcept for a history of a positive purified protein derivative(PPD) and 6 months of treatment with isoniazid (INH).

A biopsy specimen from a lesion on the lower backexhibited several dilated blood-filled vessels in the upperdermis lying beneath a thinned epidermis, consistent withan angiokeratoma (Fig. 3). Laboratory tests showed adeficiency of leukocyte

α

-Gal A at 6 U (normal > 30 U)and a plasma

α

-Gal A of 2.6 U (normal 8

−

12 U). Theseclinical and histologic findings were consistent with adiagnosis of angiokeratoma corporis diffusum (Fabrydisease).

In 1981, the patient’s mother, a 35-year-old womanfrom Colombia, experienced episodes of pain in bothfeet that have now resolved. Her values for the samelaboratory tests were 16 U and 3.8 U, respectively. DNAanalysis showed a point mutation of the X chromosome.No other family members are symptomatic.

The boy had normal renal and cardiac function. Anophthalmologic examination was normal. He is currentlyreceiving symptomatic care, including phenytoin 100 mgonce a day as needed for pain.

DISCUSSION

Fabry disease is a rare X-linked recessive lysosomalstorage disorder caused by a deficiency of leukocyte

α

-Gal A. It presents with complete penetrance and variableclinical expression in homozygous males and occasionalmild penetrance in heterozygous females. The deficiencyof leukocyte

α

-Gal A is present in the lysosomes of awide range of cell types including endothelial, vascularsmooth muscle, pericytes, renal epithelial, and dorsalroot ganglion neurons. The substrate of

α

-Gal A,globotriaosylceramide (Gb3), accumulates in these cellsand results in the characteristic dermatologic, renal,cardiovascular, and nervous system manifestations (3,4).

Figure 1. Pinpoint erythematous, nonblanching maculesand rare papules on the back.

Figure 2. Erythematous, nonblanching macules on thepalms.

Figure 3. A punch biopsy specimen from the back showsseveral dilated thin-walled vessels in the papillary dermis(magnification 40×).

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Pediatric Dermatology Vol. 22 No. 4 July/August 2005

The disease presents in childhood or adolescencewith multiple angiokeratomas and pain and paresthesiasin the extremities. The angiokeratomas typically occurbetween the umbilicus and knees and increase in size andnumber with age. They are erythematous, nonblanchingmacules, which, despite their name, often have little orno hyperkeratosis. Angiokeratomas may initially beconfused with petechiae, causing a delay in diagnosis.The majority of our patient’s angiokeratomas were locatedon the palms, upper chest and back, which is an unusualdistribution for Fabry disease.

Patients with Fabry disease experience agonizingattacks of pain and paresthesias of the hands and feet. Thepain is described as a needle-like sensation associatedwith low-grade fever. Attacks appear to be associatedwith vasomotor disturbances. The symptoms may be subtleand are often discounted as malingering or are mis-takenly attributed to other disorders such as rheumatic feveror erythromyalgia. The joint pain and erythema mar-ginatum of rheumatic fever are not observed in patientswith Fabry disease. Other acute symptoms of rheumaticfever that are absent include carditis, polyarthritis, chorea,and subcutaneous nodules. Patients do not experiencethe warmth and redness of the hands and feet associatedwith pain that is seen with erythromyalgia.

Those with Fabry disease are more susceptible tothrombosis. Neurologic symptoms such as seizures,hemiplegia, and aphasia have been reported. Cardiacdiseases include myocardial infarction, heart failure, val-vular disease, and arrhythmia. Proteinuria, hypertension,elevated creatinine levels, and disturbances in tubularreabsorption and secretion are potential renal manifesta-tions of the disease. Cardiac and renal symptoms are theusual causes of death, often at a young age, in malepatients (4).

The disease course in heterozygous females tends tobe less severe. However, they may have angiokeratomas,cataracts, acral pain, and visceral involvement. Our patient’smother had a history of attacks of pain involving herfeet, and serum and DNA testing confirmed her as acarrier of the disease.

The diagnosis of Fabry disease can be confirmed byskin biopsy. Histopathology examination of a petechial-like lesion shows several dilated thin-walled vessels inthe superficial dermis with variable degrees of acanthosisand hyperkeratosis. Electron microscopy may show typi-cal inclusions in vascular endothelium, fibroblasts, andpericytes (7). On slit-lamp examination, the presence ofwhorled corneal and lenticular opacities may assist indiagnosis. In addition, urine can be examined for bire-fringent lipid globules (Maltese crosses) on polarizingmicroscopy. The disease can be further classified bydetermining the level of leukocyte and plasma leukocyte

α

-Gal A and demonstration of the defect on the Xchromosome, locus

X q22

by DNA analysis (8).The variable presentation of Fabry disease often leads

to a delay in diagnosis. The average age of diagnosis ina group of patients with Fabry disease in one study was29 years old (9).

Prior to 2003, treatment of Fabry disease was prima-rily symptomatic. Hand and foot pain can be treated bycarbamazepine, phenytoin, or low-dose morphine (10–12).The angiokeratomas are amenable to laser treatment,although this is not a realistic treatment option ifinvolvement is extensive (13).

In 2003, enzyme replacement therapy with recombinanthuman

α

-Gal A (r-h

α

GalA, agalsidase beta [Fabrazyme,Genzyme Corp., Cambridge, Massachusetts]) was approvedby the Food and Drug Administration for the treatmentof patients with Fabry disease. Clinical trials evaluatedintravenous infusion of r-h

α

GalA and gene-activatedhuman

α

-Gal A (ga-h

α

GalA, agalsidase alfa [Replagal,Transkaryotic Therapies, Inc., Cambridge, Massachusetts])(14–17). These studies showed that enzyme replacementtherapy was effective both in the reduction of painfulcrises and in clearing the microvascular deposits ofGb3 in the kidneys, heart, and skin. Reports of enzymereplacement therapy in children is limited to a smallnumber of adolescents (15,18,19).

Although enzyme replacement therapy is the firstdisease-specific treatment available for Fabry disease,additional clinical trials to further determine its safety,efficacy, and optimal dosing, especially in children, arenecessary.

Enzyme replacement therapy and a better understand-ing of the various clinical presentations of Fabry diseasewill improve our ability to diagnose and treat this chronic,rare, and progressive disease.

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