|Year : 2020 | Volume
| Issue : 4 | Page : 319-322
Fabry's disease manifesting as familial angiokeratoma corporis diffusum in an indian family – A rare occurrence!
Ishmeet Kaur, Archana Singal, Deepak Jakhar, Deepika Pandhi
Department of Dermatology and STD, University College of Medical Sciences and GTB Hospital (University of Delhi), Delhi, India
|Date of Submission||02-Apr-2019|
|Date of Decision||14-Apr-2019|
|Date of Acceptance||21-Apr-2020|
|Date of Web Publication||30-Sep-2020|
Dr. Archana Singal
University College of Medical Sciences and GTBH, Dilshad Garden, Delhi - 110 095
Source of Support: None, Conflict of Interest: None
Fabry's disease is a rare X-linked dermatosis, resulting from alpha-galactosidase deficiency and presents with both cutaneous (angiokeratoma, acral paresthesia, and hypohidrosis) and extracutaneous manifestations (ocular, cardiac, renal, and neurological). We report two brothers age 16 and 14 years that presented with multiple angiokeratoma in a bathing suit distribution on the trunk and the scrotum. The younger brother had acral paresthesia too. On systemic screening, ocular involvement was noted in both. Alpha-galactosidase assay in both brothers, revealed a deficiency of 19.2 nmol/h/mg (reference value <60), confirming the diagnosis of Fabry's disease. Cutaneous manifestations such as angiokeratoma and acral paraesthesia can be clues to the diagnosis of Fabry's disease. The case report is accompanied by a brief review of the literature.
Keywords: Alpha-galactosidase A, angiokeratoma corporis diffusum, dermoscopy, Fabry's disease, genodermatosis, lysosomal storage disease
|How to cite this article:|
Kaur I, Singal A, Jakhar D, Pandhi D. Fabry's disease manifesting as familial angiokeratoma corporis diffusum in an indian family – A rare occurrence!. Indian J Paediatr Dermatol 2020;21:319-22
|How to cite this URL:|
Kaur I, Singal A, Jakhar D, Pandhi D. Fabry's disease manifesting as familial angiokeratoma corporis diffusum in an indian family – A rare occurrence!. Indian J Paediatr Dermatol [serial online] 2020 [cited 2020 Oct 19];21:319-22. Available from: https://www.ijpd.in/text.asp?2020/21/4/319/296857
| Introduction|| |
Fabry's disease is a rare X-linked lysosomal storage disorder caused due to deficiency of enzyme alpha-galactosidase A. This causes the accumulation of glycosphingolipids in various cells, especially endothelial cells leading to a progressive and life-threatening manifestations. Fabry's disease may present as a triad of angiokeratoma corporis diffusum, acral paresthesia, and hypohidrosis. It may be associated with various comorbidities such as cardiac dysfunction, renal insufficiency, ocular, and cerebrovascular anomalies. Fabry's disease appears to be underdiagnosed from India, as only handful of cases have been reported in the literature.,, Of these, in fewer cases, the clinical diagnosis has been collaborated with enzyme assay due to a lack of required facilities. Hereby, we report two brothers and their two first-degree relatives presenting with Fabry's disease and review the pertinent literature.
| Case Report|| |
Two brothers 16 and 14 years of age, born out of a consanguineous marriage, presented with multiple pin-point to pin-head sized red raised lesions over the trunk and scrotum for the past 5 years. The lesions were asymptomatic and were gradually progressive in size as well as number. The younger brother also had a history of burning sensation and pain over bilateral palms for the past 2 years. There was no history of sweating abnormalities or any systemic involvement in the form of chest pain, palpitations, dyspnea, urinary, abdominal or ocular complaints, persistent headache, or seizures in either of them. On detailed history and physical examination, similar lesions were observed in their maternal aunt and her son without any evidence of systemic complaints [Figure 1].
Both brothers had characteristics and distinctive facial features such as bushy eyebrows, prominent supraorbital ridge, wide nasal bridge, and thickening of the lips [Figure 2]. On cutaneous examination, multiple angiokeratomas were noted in a bathing trunk distribution with predominant involvement of periumbilical and scrotal regions in both. Similar lesions were also present over the palms and lip mucosa [Figure 3]a-c]. In addition, the younger brother had multiple purpuric lesions over bilateral palms [Figure 3]d. Dermoscopy of the skin lesions and palm lesions revealed multiple well-demarcated dark red lacunae with whitish veils suggestive of angiokeratoma [Figure 4]a and [Figure 4]b. Nail fold dermoscopy revealed similar dark red lacunae suggestive of macular angioma [Figure 4]c. Angiokeratoma over the upper eyelids [Figure 4]d was noted on ocular examination along with dilated and tortuous conjunctival vessels [Figure 4]e, and the presence of corneal opacities in a characteristic whorled pattern referred as cornea verticillata [Figure 4]f.
|Figure 2: Facial features of the affected brothers such as bushy eyebrows, prominent supraorbital ridge, wide nasal bridge, and thickening of the lips (Fabry facies)|
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|Figure 3: (a-d) Cutaneous manifestations showing angiokeratoma corporis diffusum affecting the trunk and periumbilical area (a), scrotum (b), lip mucosa (c) in all the affected members and macular angiomas over palms in younger brother (d)|
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|Figure 4: (a-f) Dermoscopy of cutaneous lesions showing red lacunae with “veil-like” structures suggestive of angiokeratoma on the trunk (a); ×200 and digit (b); ×50 and nail fold suggestive of macular angiomas (c); ×200.(Dinolite AM 413 ZT; Polarising). Ocular examination (d-f) showing angiokeratoma on the upper eyelid (d), tortuous conjunctival vessels (e) and whorled corneal opacities known as cornea verticillata (f)|
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Histopathology from the skin lesion on the trunk revealed the presence of hyperkeratosis, acanthosis, and proliferation of dilated blood vessels encroaching into the upper dermis consistent with angiokeratoma [Figure 5]. Baseline hematological investigations, urine microscopy, X-ray chest posteroanterior view, electrocardiogram (ECG), and two-dimensional-ECHO did not reveal any abnormalities. Alpha-galactosidase A enzyme assay showed markedly deficient values of 19.20 nmol/h/mg (cutoff = 60) in both the brothers. The assay was not performed in other two family members.
Based on the clinical, dermoscopic, histological, and biochemical profile, a diagnosis of Fabry's disease was established. Patients and their parents were counseled regarding the disease course, prognosis, and the need for periodic systemic evaluation. Various modalities for angiokeratoma were offered, but they did not feel the need for a cosmetic intervention at this point of time. The younger brother was prescribed gabapentin 300 mg daily for acral paraesthesia, resulting in significant symptomatic relief in 4 weeks' time.
| Discussion|| |
Fabry's disease is a rare multisystem progressive lysosomal storage disorder with X-linked inheritance. The worldwide incidence ranges from 1 in 476,000 to 1 in 117,000 with higher frequency reported from the Czech Republic and Taiwan. The prevalence in the Indian population is quite low, as evident from the absence of Fabry's disease during the screening of 1110 children during 2002–2012, of which 387 were diagnosed with lysosomal storage defects., Another descriptive study done in North India detected two cases of Fabry's disease in 68 children diagnosed with lysosomal storage disorder.
Fabry's disease is caused due to deficiency/absence of enzyme alpha-galactosidase A, which causes accumulation of globotriaosylceramides (GB3 and GL3) in lysosomes of various cells such as endothelial, epithelial, smooth muscle, nephron, myocardial, corneal epithelial, and ganglion cells of the autonomic nervous system causing ischemia and dysfunction of various systems.,
Fabry's disease typically manifests early in childhood, around 10 years of age, with cutaneous manifestations such as angiokeratoma, followed by neurological symptoms like acral paresthesia. Systemic involvement in the form of renal, cardiac, and gastrointestinal dysfunction occurs in adulthood, which worsens with time. Characteristic facial features (Fabry facies) is predominantly seen in males as present in our cases, and include coarse features, frontal bossing, bushy eyebrows, prominent supraorbital ridge, widened nasal ridge, thickening of lips, and prognathism.
Angiokeratoma is the characteristic cutaneous marker of Fabry's disease seen in 66% of males and 36% of females affected by Fabry's disease. They appear between 5 and 13 years of age, as multiple nonblanchable red-purple lesions with or without a hyperkeratotic surface in a bathing suit distribution, especially in the periumbilical region (angiokeratoma corporis diffusum). These can also be found over palms and soles, scrotum, and oral and conjunctival mucosa. The lesions tend to be more in number and progressive in males., Dermoscopy shows the presence of sharply demarcated red-brown lacunae with whitish veil-like structures, which can help distinguish it from other differential diagnoses such as cherry angioma and pyogenic granuloma. It can also aid in detecting lesions not visible to the naked eye, like in the present case where they were detected in the acral parts of the elder brother. Histopathology shows the presence of benign proliferation of dilated vessels in the dermis encroaching on the upper dermis with variable amounts of hyperkeratosis and acanthosis. Electron microscopy shows lamellated intracytoplasmic vacuolar inclusions called “Zebra bodies.” These inclusion bodies usually disappear with successful enzyme replacement therapy.
Other cutaneous manifestations include telangiectasia presenting over the photoexposed areas such as face and “V” of the neck, hypohidrosis, and anhidrosis. Hyperhidrosis can also be present, which could be either a compensatory mechanism to hypohidrosis or due to damage to the hypothalamic nuclei., Edema, including lymphedema of the arms, legs, and upper eyelids, may also be present. These features are not seen, or they have not yet evolved in our patients. Various system involvements are tabulated in [Table 1].,,
|Table 1: Various organ systems involvement in Fabry's disease,,|
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Due to the usual course of the disease, the diagnosis of Fabry's disease is often missed at an early stage when the patient presents with only cutaneous manifestations, and systemic involvement is yet to set in. [Figure 6] shows an outline of the diagnostic approach to Fabrys' disease. Diagnosis can be confirmed by alpha-galactosidase A enzyme assay, which detects enzyme activity in plasma, leukocytes, fibroblasts, or even renal cells.
Management of Fabry's disease requires periodic monitoring for early detection of systemic involvement and thus, a multidisciplinary approach. Screening of family and genetic counseling is important. Follow-up should be done every 6–12 months, including a two yearly creatinine clearance test, echocardiography, and ECG., Enzyme replacement therapies are the most specific treatment, which is done with recombinant human alpha-galactosidase A given at a dose of 1 mg/kg every 2 weeks as infusion. Various studies have shown improvement in neuropathic pain and renal and cardiac involvement; however, its role in cerebrovascular involvement is not yet clear.,, For neuropathic pain, non-steroidal anti-inflammatory drugs are usually ineffective; however, drugs such as carbamazepine, gabapentin, tricyclic antidepressants, and topiramate can be used. Treatment of angiokeratoma may be required when they are symptomatic or causing cosmetic distress to the patient. Various modalities such as excision and electrocoagulation can be used. Lasers such as copper vapor laser, neodymium: yttrium-aluminium-garnet laser, the flashlamp-pumped pulsed dye laser, and the potassium titanyl phosphate 532-nm laser have shown to be successful. However, it does not prevent the recurrence of the lesions.,
Fabry's disease is a rare and underdiagnosed disease, more so in India. In the Indian population, very few cases of Fabry's disease have been reported.,, While only a small proportion of them have collaborated the diagnosis with enzyme assay, due to lack of facilities. We report a rare case affecting four members of the same family. Angiokeratoma, with its diffuse or atypical distribution, may help to reach an early diagnosis of Fabry disease, where dermoscopy can be a helpful aid for diagnosing angiokeratoma and acral involvement. Periodic evaluation to look for systemic associations in the patient as well as the family members is of utmost importance.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]