Normal enzyme function in a suspected case of Fabry disease—A rare entity

INTRODUCTION

Fabry disease (FD), also called Anderson-FD, is the most common of the lysosomal storage disorders and is caused by mutations in the alpha-galactosidase A gene on the X chromosome (Xq22.1) due to decreased activity of the enzyme alpha-galactosidase A, leading to progressive lysosomal deposition of globotriaosylceramide (GL3) and its deacylated forms in vascular endothelial cells, leading to cardiovascular, renal, gastrointestinal, neuropathic, lenticular, and dermatological manifestations. It classically affects males with a reported incidence of 1/40,000 males, while 10%–15% of female heterozygote carriers may get affected.^1,2

The classic form has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesia), angiokeratomas, anhidrosis, hypohidrosis or rarely hyperhidrosis, characteristic corneal and lenticular opacities, and gradual deterioration of kidney function to end-stage kidney disease by the third to fifth decade. Cardiac and/or cerebrovascular disease is a major cause of morbidity and mortality.¹ The subtype of angiokeratomas called angiokeratoma corporis diffusum is the cutaneous hallmark of FD.

CASE REPORT

We report a case of a 20-year-old male who was referred to the Dermatology Outpatient Department (OPD) from the Neurology OPD in view of red, raised skin lesions. The patient complained of asymptomatic, shiny, red lesions on his chest, back, arms, thighs, and buttocks since 8 years, which initially appeared on the chest and gradually involved the other areas, such as the back, bilateral arms, bilateral thighs, and bilateral buttocks. The patient also had history of episodic burning sensations in both hands and feet since 10 years, for which he had sought treatment from various practitioners and experienced partial relief. The episodes resolved spontaneously. There was no history of hypohidrosis or anhidrosis, visual disturbance, seizures, consanguinity, or similar complaints among family members. On cutaneous examination, multiple well-defined, non-blanchable angiomatous papules of sizes ranging from 1 mm × 2 mm to 2 mm × 3 mm were present over the chest, back, both buttocks, and both arms, some of which coalesced to form larger lesions [Figure 1-3]. Oral and genital mucosa were normal. Dermoscopic examination revealed well-defined, round lacunae representing dilated dermal vessels and a whitish haze signifying epidermal hyperkeratosis [Figure 4]. A skin biopsy was further done, which showed localized proliferation of thin-walled vascular channels filling dermal papillae in the papillary dermis impinging on the epidermis. The deep dermis did not show any vascular abnormality. Focal mild perivascular lymphocytic infiltration was seen. These findings were suggestive of angiokeratomas [Figure 5]. On the basis of history, examination, dermoscopy, and histopathology, a diagnosis of Angiokeratoma Corporis Diffusum (ACD) was established. Given the co-existence of acroparesthesias, further investigations were conducted to evaluate the possibility of Fabry’s disease. All biochemical and hematological laboratory investigations were within normal limits. Electrocardiogram (ECG), 2D Echocardiography (2D ECHO), and ophthalmological examination including slit lamp examination, showed no abnormalities. Enzyme assay for alpha-galactosidase enzyme activity was within normal range. The patient was referred to the department of medical genetics for further evaluation and was advised gene testing, which the patient refused due to financial constraints. The patient was counselled regarding the nature of his illness and was advised regular check-ups for internal organ involvement. For his cutaneous lesions, radiofrequency ablation of prominent lesions was planned for cosmetic concerns.

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Figure 1:

Multiple well defined angiomatous papules present over chest.

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Figure 2:

Multiple well defined angiomatous papules present over back.

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Figure 3:

Multiple well defined angiomatous papules present over right arm.

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Figure 4:

Dermoscopy shows well-defined, round lacunae representing dilated dermal vessels and a whitish haze which signifies epidermal hyperkeratosis (Yellow star).

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Figure 5:

Histopathology showed papillary dermis with localized proliferation of thin-walled vascular channels filling dermal papillae and impinging on the epidermis (Yellow star). Deep dermis did not show any vascular abnormality. Focal mild perivascular lymphocytic infiltration was seen (Black arrow) [Hematoxylin and Eosin stain, original magnification x40].

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DISCUSSION

Fabry’s disease is an X-linked recessive disease that involves accumulation of glycosphingolipids in endothelial cells. The affected males in FD usually present in childhood with the first symptoms being severe burning pain in palms and soles (acroparaesthesia). ACD occurs in 65%–70% of male patients, which appears after puberty and is usually clustered around the umbilicus or bathing suit areas. Anhidrosis or hypohidrosis results from autonomic neuropathy. Gradually renal function also deteriorates, and end-stage renal disease is reached by 40–50 years of age.³

The most prevalent cerebrovascular events in Fabry’s disease are ischemic strokes and transient ischemic attacks. A few other cases of intracerebral hemorrhages, subarachnoid hemorrhage, microbleeds, cerebral venous thrombosis, and cervical carotid dissection have also been reported. Stroke shows a higher incidence in Fabry’s disease compared to the general population across all age categories. Among various studies, the first stroke was most commonly observed in the second or third decade of life. MRI is recommended approximately every 3 years for patients with stable Fabry’s disease; however, it should be performed in the event of signs suggestive of cerebrovascular involvement.⁴

Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death.⁵ Most of the cardiovascular signs of Fabry’s disease develop from the third decade of life onwards. After confirming the diagnosis of Fabry’s disease, the patient is evaluated for cardiac involvement by assessing symptoms, ECG, and 2D ECHO. If the evaluation is within normal limits, then we re-evaluate annually in males and biannually in females.⁶

CONCLUSION

We present this case for its uniqueness, as our patient exhibited symptoms consistent with Fabry’s disease despite normal enzyme levels and no family history. Early diagnosis becomes essential to monitor regularly for the development of other systemic manifestations of the disease, which may have life-threatening consequences.