Misdiagnosis in Fabry Disease

Cintia L. Marchesoni, MD, Norma Roa, Ana Marıa Pardal, MD, Pablo Neumann, MD, Guillermo Caceres, MD,

Pablo Martınez, Bioch, Isaac Kisinovsky, MD, Silvia Bianchi, MD, Ana Lıa Tarabuso, MD, and Ricardo C. Reisin, MD

Objective To evaluate the most frequent diagnostic errors in patients with Fabry disease and the types of special-ists most often consulted before diagnosis.Study design We evaluated 45 consecutive symptomatic patients with Fabry disease confirmed by enzymatictests in males and genetic studies in females. We interviewed the patients, their mothers, or both regarding symp-toms, age at onset, medical consultations, and recommended treatments.Results Neuropathic pain was the most frequent initial complaint, and rheumatic fever was the most common di-agnosis. Seven patients were treated with penicillin for many years. Ten patients sought medical consultation be-cause of abdominal pain and were diagnosed with food intoxication or nonspecific pain. Six patients soughtconsultation because of anhidrosis, considered of unclear cause, and angiokeratomas diagnosed as petechiae. In-ternists and pediatricians were the most frequently consulted specialists. The correct diagnosis was obtained aftera mean of 19.7 years.Conclusions Pediatricians as well as internists commonly misdiagnose Fabry disease. Neuropathic pain, hypo-hidrosis, and recurrent abdominal pain in childhood or adolescence should include Fabry disease in the differentialdiagnosis to facilitate earlier diagnosis and treatment of these patients. (J Pediatr 2010;156:828-31).

See related article, p 832

Fabry disease is an X-linked lysosomal storage disease caused by inherited deficiency of the lysosomal enzyme a-galacto-sidase A. The resultant inability to catabolize glycosphingolipids causes progressive multisystemic accumulation of glo-botriaosylceramide1 and globotriaosylsphingosine.2 Symptoms typically begin in childhood and adolescence with pain

and gastrointestinal complaints appearing first, followed by cardiac, renal, and cerebral damage in early adulthood. Most un-treated males usually die within the fifth decade of life.3 Most females experience milder symptoms, but their life expectancy isalso reduced, by about 15 years compared with the unaffected population.4 The long delay between the onset of symptoms inFabry disease and the correct diagnosis is likely due to the poor recognition of the disease’s manifestations.5 Enzyme replace-ment therapy (ERT) has proven safe and effective in treating Fabry disease and may be most useful when administered early inthe course of the disorder.6,7 The objective of the present study was to evaluate the most frequent diagnostic errors in patientswith Fabry disease and to identify the medical specialists who were initially consulted, with the aim of raising the awareness ofFabry disease and to improve recognition and patient management.

AADELFA Asociacion Argentina de

ERT Enzyme replacement ther

828

Methods

We evaluated 55 consecutive patients with Fabry disease referred to our hospital for neurologic assessment by the AsociacionArgentina de Enfermedad de Fabry y Otras Enfermedades Lisosomales (AADELFA), a national association devoted to the di-agnosis and evaluation of patients with lysosomal disorders in Argentina. These 55 patients are a subset of the 107 patients withFabry disease identified by AADELFA since 2001. The 55 patients that we evaluated between 2006 and 2008 belonged to 4 un-related families, the mutations and index case recognition of which are summarized in Table I. The study group included 25

From the Neurology Department, Hospital Britanico deBuenos Aires, Buenos Aires, Argentina (C.M., A.M.P.,R.R.); Hematology Service, Instituto Medico Quilmes,Quilmes, Argentina (N.R., I.K.); Nephrology Department,Hospital Italiano, La Plata, Argentina (P.N.); BiochemistryLaboratory, Hospital Interzonal Pinamar, Pinamar,Argentina (G.C.); Pediatric Service, Hospital Interzonal deBahıa Blanca, Bahıa Blanca, Argentina (P.M.); PediatricService, Centro Fabry de Tucuman, Tucuman, Argentina(S.B.); and Dermatology Service, CEAL Centro Medico,Chubut, Trelew, Argentina (A.L.T.)

males (mean age, 27.5 years; range, 10-43 years) and 30 females (mean age, 38.03years; range, 15-73 years). Two women were excluded because they wereasymptomatic, and another 8 symptomatic patients were excluded becausethey had never consulted a physician for symptoms related to Fabry disease.Of the 45 patients considered in the study (6 of them under age 18 years), 39were currently receiving ERT. The diagnosis of Fabry disease was confirmed byenzymatic tests in males and by genetic studies in females. We interviewed thepatients, their parents, or both regarding signs and symptoms, age at onset,medical consultations, and recommended treatments before the diagnosis of

This work was presented in part at the 60th annualmeeting of the American Academy of Neurology,Chicago, IL, April, 2008. The authors declare no conflictsof interest.

0022-3476/$ - see front matter. Copyright � 2010 Mosby Inc.

All rights reserved. 10.1016/j.jpeds.2010.02.012

Enfermedad de Fabry y Otras Enfermedades Lisosomales

apy

Table I. Alpha-galactosidase A gene mutations from affected families

Family cDNA Exon Protein Index case detected by Age at onset of symptoms, years Age at diagnosis, years

1 c.C679T 5 p.R227X Nephrologist* Not evaluated 242 c.G463C 3 p.D155H Dermatologist 10 233 c.T1244C 7 p.L415P Dermatologist 5 324 c.G281A 2 p.C94Y Nephrologist 8 26

*An index case was not included in this study.

Vol. 156, No. 5 � May 2010

Fabry disease was established. The study was approved by theInstitutional Review Board of the Hospital Britanico deBuenos Aires. The study patients came primarily froma nonurban population in which generalists (ie, internistsor pediatricians) are usually consulted before subspecialists.

Results

Fabry disease was suspected in the 4 male index patients be-cause of renal or dermatologic findings. Three of these 4 pa-tients were included in our study; the fourth had not yet beenreferred to our hospital for evaluation (Table I). Thediagnosis of Fabry disease in the remaining patients wasconfirmed by testing enzyme activity and/or molecular

Table II. Misdiagnosis in Fabry disease

Symptom(number of patients)

Diagnosis(number of patients)

Treatment(number of patients)

Acroparesthesias (34) Rheumatic fever (12) Analgesics (10)Cryptogenic (10) None (8)Viral disorders (5) Penicillin (7)Psychogenic (3) Insoles (4)Rheumatism (3) Antibiotics (3)Gout (3) Rest (2)Flat feet (2) Allopurinol +

colchicine (1)Growing pains (2)‘‘Bone problems’’ (2)Circulatory

problems (1)Arthritis (1)Brucellosis (1)Raynaud’s

phenomenon (1)Abdominal pain (10) Food intoxication (4) Diet (4)

Nonspecific pain (2) Cholecystectomy (1)Gallstones (1) Parenteral hydration (1)Hepatic

insufficiency (1)Ranitidine-metoclopramide (1)

Dyspepsia (1) Psycotherapy (1)Gastroesophageal

reflux (1)Parasites (1)Bulimia (1)

Angiokeratomas (5) Humidity (2) Avoidance of coldtemperatures andhigh humidity (2)

Vascular fragility (2)Petechia (1)Leeches (1)

Hypohidrosis (3) Glandular block (1)Cryptogenic (1)‘‘Normal’’ (1)

Stroke (1) Cryptogenic (1) None (1)Vertigo (1) Alcohol

intoxication (1)Gastric lavage (1)

analysis in relatives within several weeks after identificationof the index patient. Signs, symptoms at initial consultationare summarized in Table II. In 40 patients (88.9%), thedisease manifested before age 18 years.

Neuropathic pain was the most frequent initial complaint,reported by 34 patients, and rheumatic fever was the mostcommon misdiagnosis, in 12 of 34 patients. Seven of these12 patients erroneously received penicillin for many years.Abdominal pain was the second most common reason forconsulting a physician in 10 patients (22.2%), and as a resultof misdiagnosis 1 patient underwent gall bladder surgerywithout improvement. Internists and pediatricians were themost frequently consulted specialists (Figure 1). The meanage of symptom onset was 9.8 years in males and 10.9 yearsin females, and the mean delay to the diagnosis of Fabrydisease was 15.3 years in males (range, 3 months to 32years) and 24.7 years in females (range, 1-52 years). Thestudy patients underwent clinical examination between1951 and 2004; most of them did so during 1984. Only 8patients received their first consultation after ERT becameavailable. Currently, 39 patients receive ERT due tocardiac manifestations (ie, hypertrophic cardiomyopathy,arrythmias, or heart failure) in 7 patients, renal involvement(ie, proteinuria or reduced glomerular filtration rate) in 6patients, combined cardiac and renal manifestations in 11patients, and severe neuropathic pain, either isolated (in

Figure 1. Number of patients who consulted with differentspecialists.

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Figure 2. Angiokeratomas in Fabry disease.

THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 156, No. 5

5 patients) or associated with cardiac or renal manifestations(in 10 patients).

Discussion

Neuropathic pain in Fabry disease occurs most commonlywithin the first decade in the soles and palms and may presentas crises with excruciating pain in hands and feet possiblypersisting from minutes to days.8,9 Recurrent painful epi-sodes may be spontaneous or frequently triggered by cold,heat, fever, exercise, stress, or fatigue.10,11 Pain may be ofsuch severity so as to lead to suicidal ideation.12-14 Thepain is due to small-fiber neuropathy, and its pathophysiol-ogy may include an accumulation and maldistribution of so-dium channels on injured axons, leading to increasedmechanical excitability and repetitive nerve firing, patholog-ical sympatho-afferent coupling, central or peripheral noci-ceptive sensitization, and ischemia.15,16 In our patients,rheumatic fever was the most frequent misdiagnosis of Fabrydisease–associated pain, as was found in the Fabry OutcomeSurvey.5 Moreover, 7 of 12 patients who received this diagno-sis in our study received unnecessary and prolonged treat-ment with penicillin. Joint pain has been reported in 24.1%of females and 27.2% of males with Fabry disease.17 In ourstudy population, joint pain was present in 10 of 45 patients(22.2%), and 5 of these patients had only joint pain withoutacroparesthesias. Occasionally pain attacks are accompaniedby fever, malaise, and elevated erythrocyte sedimentationrate, leading to an erroneous diagnosis of rheumatic feveror rheumatoid arthritis.18

The presentation of rheumatic fever is distinct from that ofFabry disease and is characterized by migratory polyarthritisaffecting the ankles, wrists, knees, and elbows, often associ-ated with swelling. It usually spares the small joints of thehands and feet. Fabry disease, not rheumatic fever, shouldbe suspected in the presence of paresthesias, intolerance toheat or cold exposure, hypohidrosis, angiokeratoma, abdom-inal cramps or diarrhea, cornea verticillata, or a compatiblefamily history.19

Growing pains are recurrent, self-limited pains in the lowerextremities occurring mostly at the end of the day and atnight. Physical examination and ancillary study findings arenormal. The pain may be relieved with massage, analgesics,or heat. The etiology is unclear. The disorder is benign andusually resolves within a year or two.20 Neuropathic pain isfrequently associated with hypohidrosis, which exacerbatesthe exercise intolerance suffered by these patients. Moreover,considering that 75.5% of our patients sought initial consul-tation for this complaint, and the fact that small-fiberneuropathy is uncommon in childhood, a systematic evalua-tion for Fabry disease in these children would markedlyreduce the rate of misdiagnosis in this disorder.

The mean age of symptom onset in males of our group (9.8years) was similar to the findings of MacDermot et al (10.1years).3 In females, the mean age at onset was intermediatebetween studies that evaluated girls (8.4 years)21 and adults(15 years).4

830 Marchesoni et a

Gastrointestinal complaints (ie, abdominal pain, diarrhea,constipation, nausea, vomiting) have been reported in 52%of patients with Fabry disease.22 Chronic and recurrent ab-dominal pain poses a diagnostic challenge23 because it is com-monly found in children without Fabry disease, witha prevalence of 9%-15%.24-28 Although gastrointestinal symp-toms are nonspecific in Fabry disease, 90% of our children alsomanifested acroparesthesias, a pairing of symptoms thatmight have suggested the correct diagnosis. Only 1 patientpresented exclusively with gastrointestinal manifestations.

Cutaneous lesions of Fabry disease usually appear between5 and 13 years of age as telangiectasias and angiokeratomas.Angiokeratomas are red-purple macules or papules <5 mmin diameter that do not bleach with pressure and may exhibithyperkeratosis. Most of these lesions are in the area betweenthe umbilicus and knees (Figure 2). Angiokeratomas aretypical but not pathognomonic of Fabry disease, and mustbe differentiated from other childhood forms ofangiokeratomas.29 Other lysosomal diseases also maypresent with angiokeratoma corporis diffusum, anddiagnosis requires biochemical and genetic analysis of theunderlying enzyme defect.30,31 Frequent misdiagnoses ofskin lesions of Fabry disease in children include pyogenicgranuloma, hereditary hemorrhagic telangiectasia, andataxia telangiectasia. Pyogenic granuloma is a solitary softnodule that bleeds easily and commonly appears in areassubject to trauma (eg, hands, fingers, lips). Hereditaryhemorrhagic telangiectasia (Osler-Weber-Rendu’s disease)is an autosomal dominant inherited disease characterized bytelangiectasias involving the skin, mucous membranes, andinternal organs, with recurrent epistaxis during adolescence.Cutaneous and conjunctival telangiectasias are present inautosomal recessive inherited ataxia-telangiectasia (Louis-Bar syndrome); it involves skin exposed to light, but theclinical picture is dominated by neurologic symptoms.32

The misdiagnosis of patients with Fabry disease led toa long delay in recognition and treatment in both the presentstudy and previous studies.5,33 Moreover, poor recognition

l

May 2010 ORIGINAL ARTICLES

of the earliest manifestations of the disease, including neuro-pathic pain and gastrointestinal symptoms, leads to late iden-tification of these patients, after heart, brain, or kidneyinvolvement has developed.

Limitations of the present study include patient recall bias.Consequently, we always interviewed at least one parent.Moreover, because our study population was drawn mainlyfrom rural areas, the patients had limited access to medicalspecialists. This underscores the importance of both pediatri-cians and internists increasing their awareness of the initialsymptoms of this lethal but potentially treatable disorder.Our patients rarely consulted neurologists despite the highfrequency of neuropathic complaints, because the nature ofthe pain was commonly misinterpreted as being due to an or-thopedic, rheumatologic, or infectious cause. Moreover, car-diologists and nephrologists were usually consulted in moreadvance stages of the disease.

Why is Fabry disease so difficult to diagnose? Most likelybecause it is an uncommon disorder with nonspecific initialsymptoms and a wide range of differential diagnosis. Clues torecognition, in addition to higher awareness, include identi-fication of the combination of early signs, recurrent com-plaints, and suggestive family history. Educational programswith more intensive training in treatable lysosomal disordersmay lead to earlier recognition. n

We thank Dr Markus Ries (an employee of Shire Human Genetic Ther-apies until June 2009) for a critical review of the manuscript and DrPaula Rozenfeld (who received research grants from Shire HGT) forgenetic testing. We also thank the AADELFA. (Asociacion Argentinapara el estudio de la Enfermedad de Fabry y otras enfermedades liso-somales)

Submitted for publication Apr 19, 2009; last revision received Dec 2, 2009;

accepted Feb 8, 2010.

Reprint requests: Ricardo C. Reisin, Neurology Department, Hospital

Britanico, Perdriel 74, Buenos Aires 1280, Argentina. E-mail: rcreisin@

intramed.net.

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