Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy.

Introduction

Fabry’s disease is a rare hereditary lysosomal storage disorder linked to the X chromosome, resulting from a deficiency of the enzyme α-galactosidase A.

This deficiency leads to the accumulation of the neutral glycosphingolipid globotriaosylceramide (GL-3) in various organs.¹

Diagnosis of Fabry disease (FD) is established through clinical evaluation, reduced activity of α-galactosidase A (GALA), and sequencing of cDNA or genomic DNA (gDNA). The c.644A > G mutation has predominantly been identified in patients with the cardiac variant of FD. This mutation was linked to renal involvement without cardiac symptoms in one case of homozygosity and in two other family members.²

ANCA-associated vasculitides (AAVs) are a type of inflammatory disease that affects small blood vessels throughout the body. People with AAVs have autoantibodies (abnormal proteins) that attack their own neutrophils, a type of white blood cell. This can lead to inflammation and damage in various organs, including the lungs and kidneys.³

This report describes an unusual case of Fabry’s disease (c.644A > G mutation) in conjunction with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) occurring in the context of atopy

Case report

A 65-year-old patient with a personal history of arterial hypertension and family history revealed that his mother, sister and brother were being followed for polycystic kidney disease, and his grandson was being followed for Fabry disease discovered during the investigation of an autism spectrum disorder as expressed on pedigree ( Figure 1).

Figure 1. Pedigree.

In February 2024, the patient was admitted to the general surgery department for the management of acute pancreatitis, stage E of lithiasis origin. An allergy to ertapenem has been detected.

During the hospitalization, renal insufficiency was discovered with a creatinine level of 150 micromol/l, for which she was referred to the nephrology consultation.

Three months after the episode of acute pancreatitis, the patient developed a skin rash and uremic syndrome, with creatinine levels reaching 1000 micromol/l. A recent intake of allopurinol was noted.

The diagnosis of immuno-allergic nephropathy was made, and the patient was started on corticosteroid therapy at 0.5 mg/kg/day, leading to a return to baseline creatinine levels within one month. When renal function failed to improve, an immunological work-up revealed pANCA vasculitis, The patient was referred to us for a kidney biopsy. She was admitted to our nephrology department.

The clinical examination revealed a blood pressure of 160/100 mmHg with the presence of a skin rash without oedema of the lower limbs. The neurological examination was without anomalies. The diuresis was preserved.

The patient’s clinical progression included the development of headaches, photophobia, and gait disturbances, characterized by a cautious ataxic gait and a multidirectional positive Romberg sign. Brain MRI showed multiple FLAIR signal abnormalities in the superficial white matter, presenting as punctiform and nodular lesions, as well as confluent periventricular patches, consistent with vascular leukoencephalopathy classified as Fazekas 2 associated with diffuse pachymeningitis and an old ischemic lesion in the right cerebellum (Figures 1, 2, 3). These findings are all indicative of vasculitis.

Figure 2. Diffuse pachymeningitis.

Figure 3. Old ischemic lesion in the right cerebellum and regular and thin pachymeningeal contrast enhancement.

Urinalysis revealed hematuria and proteinuria (3.8 g/day).

A renal biopsy was performed, and treatment with corticosteroid therapy (3 boluses of Solumedrol followed by oral prednisone at 1 mg/kg/day) and cyclophosphamide (600 mg/m² on days 0, 15, and 30) was initiated.

The renal biopsy showed cellular crescents and cytoplasmic vacuolization in podocytes and tubular cells ( Figures 4, 5, 6, 7).

Figure 4. Vascular leukoencephalopathy.

Figure 5. The renal biopsy showed cytoplasmic vacuolization in tubular cells.

Figure 6. The renal biopsy showed cytoplasmic vacuolization in podocytes.

Figure 7. The renal biopsy showed cellular crescents.

Immunofluorescence revealed no IgG, IgA, IgM, C3, or C1q deposition.

A bronchoscopy with bronchoalveolar lavage was performed, which ruled out alveolar hemorrhage.

The patient had experienced anhidrosis, acroparesthesia, and hearing loss since childhood, raising early suspicion of Fabry disease due to the presence of these characteristic symptoms. A genetic investigation was conducted, confirming the GLA gene mutation (heterozygous for the c.644A>G,p. Asn215Ser mutation). This mutation primarily leads to cardiac involvement.

No treatement for FD was initiated because of the concomitant discovery of vasculitis which prompted us to urgently treat the vasculitis.

The echocardiogram revealed left ventricular hypertrophy (LVH), with normal systolic function.

The patient underwent two courses of cyclophosphamide and during the second course, she developed symptoms of fever, chills, vomiting, and a generalized skin rash, which resolved after discontinuing the infusion, administering Unidex, and taking antihistamines.

A pharmacovigilance investigation confirmed allergies to ertapenem, allopurinol, and cyclophosphamide.

Unfortunately, before the Rituximab treatment could be initiated, the patient developed acute respiratory distress syndrome due to pneumonia, necessitating admission to the intensive care unit and mechanical ventilation. Sadly, the patient did not survive.

Discussion

We present a rare and intriguing case of the coexistence of Fabry’s disease (FD) and ANCA-associated vasculitis in the context of atopy. Fabry’s disease was suspected due to the patient’s history of anhidrosis, acroparesthesia, and hypoacusis, as well as the family history of Fabry’s disease in her grandson, who was diagnosed through genetic testing conducted as part of an autism evaluation and treated with enzyme replacement therapy. Histological examination of the renal involvement in our patient revealed in addition to the presence of cellular crescents associated with vasculitis, cytoplasmic vacuolization in podocytes and tubular cells. Immunofluorescence was negative.

Although the c.644A>G (p.Asn215Ser) mutation in the GLA gene is recognized as pathogenic and primarily associated with the cardiac variant of Fabry disease, it cannot fully account for the renal involvement observed in our patient. However, it is important to note that several patients carrying this mutation have been reported to develop renal manifestations even in the absence of significant cardiac symptoms.⁴ This highlights the phenotypic variability associated with this mutation and suggests that renal involvement cannot be entirely excluded based on its typical cardiac association.

The European Society of Cardiology has established clear guidelines for Fabry disease.

Cardiovascular involvement often manifests as LVH, myocardial fibrosis, inflammation, heart failure, and arrhythmias, which can significantly affect quality of life and are the primary cause of death. Regular clinical monitoring is vital to track disease progression and necessitates a multidisciplinary approach.

Indeed, fabry disease should be considered in patients presenting with cardiac warning signs, such as left ventricular hypertrophy (LVH), a short PQ interval in young individuals, bradycardia, atrioventricular blocks in adults, chronotropic incompetence on the electrocardiogram (ECG), LVH with normal systolic function, hypertrophy of the papillary muscles, thickening of the mitral and aortic valves with mild-to-moderate regurgitation, and reduced global longitudinal strain on the echocardiogram. Laboratory tests typically show elevated high-sensitivity troponin and NT-proBNP levels.⁵

In our case, ECG showed a left ventricular hypertrophy (LVH). Troponin and NT-proBNP levels was normal.

These findings may be related to the history of hypertension.

In the same context, Singh and Hanaoka reported 3 cases of patients with combined FD and pauci-immune necrotizing and crescentic glomerulonephritis but the pathogenic relationship between these two conditions is still unclear. Low peripheral leukocyte α-Gal-A activity was observed in all the cases.^6,7

Pauci-immune glomerulonephritis was confirmed in the three cases. Notably, only the case of Hanaoka tested positive for PR3-ANCA and was definitively diagnosed with granulomatosis with polyangiitis (GPA).⁷

All the patients received high-dose prednisolone, with cyclophosphamide added. No deaths have been reported.

The possible explanation for the association between FD and ANCA-associated vasculitis could be linked to immune system dysregulation caused by lysosomal dysfunction, which may lead to abnormal immune responses. The accumulation of galactocerebroside in Fabry’s disease may be immunogenic, potentially triggering immune-mediated disease processes. This immune imbalance could potentially trigger the development of autoimmune conditions such as ANCA-associated vasculitis in patients with Fabry disease.⁸

On the other hand, an association between atopic conditions and ANCA-associated vasculitis has been reported in the literature.

Indeed, neutrophils play a central role in the pathology of vasculitis. Proinflammatory cytokines can prime neutrophils, leading to the translocation of ANCA antigens from lysosomal compartments to the cell surface during the early stages of inflammation. When ANCA antigens on the cell surface engage with their antibodies and interact with Fc receptors, it activates the neutrophils.⁹

Gómez and al. reported the case of a patient followed since childhood for allergic reactions, including allergic eczema, who developed ANCA-associated vasculitis in adulthood. This case underlines the potential link between a background of atopy and the later development of ANCA vasculitis, highlighting the importance of close monitoring in such patients as they grow older.¹⁰

In our patient, a history of atopy preceded the onset of ANCA-associated vasculitis. Specifically, the patient had multiple allergic reactions to treatments such as ertapenem, allopurinol, and cyclophosphamide. However, the blood tests did not reveal any associated hyper-eosinophilia.

A study on serum IgE and clinical symptomatology of atopy in patients with FD, a lysosomal storage disorder, explores how this condition impacts IgE levels and the manifestation of atopic symptoms. The research aims to understand the relationship between lysosomal dysfunction and the prevalence of atopic disorders, which may include conditions such as asthma, eczema, and allergic rhinitis.

Among patients (both male and female) with FD, whether receiving enzyme replacement therapy or not, clinical symptoms of atopic asthma, allergic rhinitis, and atopic eczema were observed. Some patients, including 2 out of 12 men and 6 out of 19 women, had total IgE concentrations exceeding 100 kU/L.¹¹

The study concluded that patients with FD may exhibit an increased total serum IgE concentration and may present with symptoms of atopic disorders at rates similar to those observed internationally in individuals without FD.¹¹

As for the association between Fabry disease and polycystic kidney disease, this case report describes a 60-year-old man with both Fabry disease and polycystic kidney disease, underscoring the significance of considering multiple kidney conditions in patient evaluation. Such comorbidity is particularly relevant in families with a history of either disease. To better understand the complex interplay between these conditions and the role of genetic factors, further research is imperative. This knowledge could have significant implications for patient diagnosis, management, and prognosis.¹²

Conclusion

The coexistence of Fabry’s disease with other renal diseases is rarely reported in the same patient.

This case demonstrates the simultaneous occurrence of Fabry’s disease and ANCA-associated vasculitis in a patient with an atopic predisposition.

A causal relationship between the different pathologies can be explained by the pathophysiological and immunological mechanisms involved in these diseases.