Multiple adult-onset xanthogranulomas associated with skin dysbiosis: A presenting sign of common variable immune deficiency, supported by next-generation sequencing

Introduction

Multiple adult-onset xanthogranuloma (MAXG) is a rarely reported, late-onset variant of xanthogranuloma (XG). Associations with hematologic neoplasia were recorded in most cases.¹ However, only 1 case was associated with common variable immunodeficiency syndrome (CVID).² CVID is the most common primary immunodeficiency in adults. It is characterized by B-cell dysfunction, with subsequent pan-hypogammaglobinemia, resulting in increased susceptibility to infections and lack of protective response to vaccinations.² Herein, we describe the second association of MAXG with CVID that coincided with patches of vitiligo and coalescing macules of pityriasis versicolor (PV). We conjecture that this entity might be a reactive process, possibly related to underlying primary or acquired immune dysfunction. We highlight the importance of comprehensive screening of patients presenting with MAXG.

Case report

A 66-year-old man with no history of chronic infections or immunodeficiency presented with numerous asymptomatic papules on the head, neck, and upper portion of the trunk. The patient reported having similar lesions 5 years prior. Biopsy at that time revealed a xanthoma. More recently, the condition progressed from “a handful” of lesions to dozens, over several months. Examination revealed multiple small pink-orange papules (Fig 1) and vitiliginous patches on lower portion of the back (Fig 2). Additionally, several hypopigmented, coalescent scaly macules of PV were observed on his chest and upper portion of the back. Microscopic examination showed a nodular infiltrate of histiocytes, lymphocytes, and Touton giant cells in the papillary reticular dermis, which were negative for S100, CD1a, and langerin, consistent with XG (Fig 3). Given the patient’s age and normal lipid profile, a diagnosis of MAXG was made. Extensive testing, including complete blood cell count and metabolic profile, serum protein electrophoresis, thyroid-stimulating hormone, human immunodeficiency, and presence of hepatitis B and C viruses, was unremarkable, except for deficiencies of IgG, IgA, and immunoglobulin M (79%, 33%, and 32.5% of normal values, respectively). Given reported associations with malignancies and lymphoproliferative disorders, computed tomography scan of the head, chest, abdomen, and pelvis along with flow cytometry of peripheral blood were obtained and no abnormalities were found. The patient had pan-hypogammaglobinemia, without lymphocyte deficiency, suggestive of CVID. Immunohistochemistry studies revealed decreased CD19 expression by B lymphocytes (Fig 4). Next-generation sequencing performed on skin biopsy for 106 genes in a custom immunodeficiency-targeted panel revealed 2 rare compound heterozygous variants: c.[602A>T;614G>A] (p.[Tyr201Phe;Gly205Glu]), in AK2 (OMIM: 267500). Expanded analysis of the whole exome detected a deleterious splice region variant in IRF7 (Fig 5). All putative germline variants occurred in genes related to immunodeficiency phenotypes—findings further supporting the diagnosis of CVID. The patient gave consent for his photographs and medical information to be published in print and online and with the understanding that this information may be publicly available.

Fig 1.

Multiple xanthogranuloma and pityriasis versicolor (PV). The figure shows 2 types of lesions. The first is the small orange-brown papules of xanthogranuloma distributed on the head, neck, and upper portion of the trunk. The second is lesions of PV, where multiple, hypopigmented and light pink scaly macules sometimes coalesce into patches and are found mainly on the chest and neck in close proximity to xanthogranuloma.

Fig 2.

Vitiligo. The figure shows multiple vitiliginous patches and macules on the back.

Fig 3.

Xanthogranuloma. A, Biopsy from the chest revealed a well-circumscribed but unencapsulated nodule in the dermis. There was a mixed cellular infiltrate of histiocytes, lymphocytes, eosinophils, and occasional neutrophils and plasma cells (not shown). B, Multiple giant cells that have a wreath-like arrangement of nuclei, that is, Touton giant cells, are characteristic of XG. (A and B, Hematoxylin-eosin stain; original magnifications: A, ×40; B, ×200.)

Fig 4.

Staining with CD20 (B) and CD19 (A) in the same region. Normally, the number of cells expressing CD20 and CD19 should be essentially identical. Here, there is a decrease in CD19 expression, not attributable to artifacts such as sectioning. (A, CD19 stain; B, CD20 stain; original magnifications: A and B, ×80.)

Fig 5.

Read pile up of a germline splice region heterozygous small deletion, NM_001572.5 (IRF7):c.847+4delA, is shown at a read depth of 58× and variant allele fraction of 0.38. IRF7 is implicated in a form of immunodeficiency (OMIM: 616345) and this variant is predicted to result in the loss of function of an authentic 5′ donor splice site; leading to exon skipping.

Discussion

XG is a form of non-Langerhans cell histiocytosis of unclear etiopathogenesis, mostly involving the skin.³ It is subclassified into juvenile and adult forms on the basis of age of onset. MAXG is defined as the presence of more than 5 XG arising after 14 years of age.⁴

MAXG should be differentiated from other forms of xanthomas using clinical, laboratory, and histologic findings to ensure the understanding of disease prognosis and provide proper screenings and monitoring. For example, eruptive xanthoma is most frequently located on patient’s hands, feet, and buttocks and, unlike MAXG, is typically associated with hypertriglyceridemia.⁵ Xanthoma disseminatum is mainly distributed in interfacial and flexional regions and is commonly associated with extracutaneous symptoms.⁶ Similarly, Erdheim-Chester disease is a rare multisystemic histocytosis with skin involvement in only 25% of cases, the majority of which are xanthelasma-like lesions.⁷ Lack of constitutional symptoms, systemic involvement, and BRAF mutation makes Erdheim-Chester disease less likely.⁷ Absence of both deep histiocytic infiltrates and large multinucleated giant cells excludes the diagnosis of necrobiotic XG.²

MAXG is a rare entity, with <50 cases reported in the English literature. Benign and malignant hematologic disorders are the most frequent comorbidities, suggesting MAXG as a possible marker of blood dyscrasias.¹ One publication described MAXG in a patient with CVID, making the current case the second reporting of this association, to our knowlegde.² Our patient, additionally, has the cutaneous findings of vitiligo and PV.

Interestingly, despite their immune-deficient condition, more than half of patients with CVID have concomitant autoimmune and inflammatory disorders. Coincidence of MAXG and vitiligo with CVID in our patient could be explained by several hypotheses.⁸ For example, his immunodeficiency may result in insufficient clearance of pathogens, leading to continuous exposure to foreign antigens. This may trigger anomalous proliferation of histiocytes seen in MAXG and autoimmune process of vitiligo.⁸ In this case, it is possible that PV was this offending trigger. With PV now being considered a manifestation of skin dysbiosis, this association could indeed point to a critical role of dysbiosis in immune dysregulation commonly seen in CVID.⁹

Another hypothesis would be that both immunodeficient status of CVID and immune dysregulation of the patient’s skin findings originally stemmed from hyperplastic germinal centers occupied with polyclonal/self-reactive B-cell clones. Lack of regulatory T-cells has been postulated to explain these associations.⁸

Likely due to the scarcity of published cases, there is no agreement on management of MAXG. Treatments such as intralesional steroids, light therapy, CO₂ laser, simple excision, and cryotherapy are used with variable success.^1,2 Spontaneous regression is uncommon, except in cases with concomitant blood dyscrasias, in which resolution is observed upon treating the associated neoplasms.¹ In the single case previously reported with CVID, the patient was treated with monthly intravenous immunoglobulins to address both her CVID and XGs.² This resulted in normalization of her immunoglobulin levels but less than 30% improvement in XGs.² Surprisingly, treatment of CVID with intravenous immunoglobulins was linked to de-novo eruption of plane xanthomas in a single pediatric case report.¹⁰ Our patient opted for treatment of his PV, with monitoring of XG and vitiligo. He was also scheduled for immunology follow-up to manage his CVID. Three months later, the patient reported slight improvement in his XG lesions.

We aim, through this case description, to emphasize the importance of similar reporting to better understand the etiopathogenesis of MAXG and find plausible explanations for disease associations. In agreement with other studies, we believe that MAXG may be a cutaneous manifestation of a systemic disorder. Previous cases associated MAXG with blood dyscrasias. Analyzing our patient’s findings, we propose that MAXG may be a reactive process to an underlying immune dysfunction. As such, comprehensive assessment is critical for early diagnosis and proper management of underlying conditions.

Conflicts of interest

None disclosed.