Occurrence of eruptive cutaneous capillary haemangiomas in a teenager with hyper IgM syndrome

Dear Editor,

Hyper IgM syndrome, also known as immunoglobulin class switch recombination (Ig-CSR) deficiencies, is a rare type of inherited primary immunodeficiency disorder that presents with normal or high serum levels of IgM and low serum levels or absence of IgG, IgA, and IgE. In most cases, this disorder is inherited in an X-linked pattern and caused by a mutation in the CD40 ligand (CD40L) gene. Clinically, it is characterised by recurrent, severe, and prolonged infections and increased risk of opportunistic infections, neutropenia, autoimmune diseases, and cancers. Immunoglobulin replacement therapy with intravenous or subcutaneous immunoglobulin, specific anti-microbial therapy, prophylactic antibiotic therapy, recombinant granulocyte colony-stimulating factor (G-CSF), stem cell transplantation, and immunosuppressants are used for its management.¹

A 13-year-old male child with known hyper IgM syndrome was referred to the Department of Dermatology, Farhangian Clinic, Arak, Iran with disseminated multiple macules and nodules that appeared to have a vascular component. The lesions began 2 years prior with the appearance of a tumoral vascular lesion on the volar surface of the left forearm. Thereafter, multiple vascular lesions progressively developed and disseminated on the face, upper trunk, and upper limbs [Figure 1]. A biopsy was done with differential diagnoses of capillary haemangioma and Kaposi sarcoma. Histologically, the tumour demonstrated organised and anastomosing vascular channels lined by endothelial cells with increased deposition of fibrous tissue between the channels, consistent with the diagnosis of capillary haemangioma [Figure 2].

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Figure 1:

Multiple vascular macules and nodular lesions on a) trunk, b) upper limb and c) face (black arrows).

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Figure 2:

Anastomosing vascular channels lined by endothelial cells with increased deposition of fibrous tissue between the channels (black arrows) (Haematoxylin & eosin). a) 40x, b) 200x c) 400x.

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Hyper IgM syndrome was diagnosed initially when the patient was 3 years old. He was frequently admitted to the hospital for severe and recurrent pulmonary infections. In these years, he also experienced recurrent courses of neutropenia. He has been under treatment with Intravenous immunoglobulin (IVIG), prophylactic co-trimoxazole, and recombinant G-CSF after confirmation of diagnosis.

Capillary haemangiomas are the most common subtype of vascular proliferation. In its pathogenesis, an abnormal angiogenic stimulation has a role. Circulating endothelial progenitor cells, originating from the bone marrow and not normally present in the circulation, have a role in the postnatal growth of haemangiomas. Rapid growth of a haemangioma can be stimulated by the mobilisation of endothelial progenitor cells.^2,3 Growth factors, chemokines, and cytokines, such as Vascular endothelial growth factor (VEGF), interleukin 8, CXCL2 (Groβ), G-CSF, stromal cell-derived factor 1 alpha, somatic cell-derived factor, and osteopontin, also play a role in the pathogenesis of haemangiomas through mobilisation and activation of circulating endothelial progenitor cells. In addition to the aforementioned factors, other non-cytokine facilitators include nitric oxide, erythropoietin, inflammatory agents, and pharmacological modulation (such as anti-TNF agents, angiotensin converting enzymes).³

Reactive capillary haemangiomas are a group of benign vascular proliferations, among which eruptive cherry angiomas, pyogenic granuloma, papillary endothelial hyperplasia, bacillary angiomatosis, epithelioid haemangioma, and glomeruloid haemangioma are the most important. They are manifested by capillary proliferations sometimes in association with infection, medication, and trauma.⁴ Eruptive cherry angiomas have rarely been reported in relation to VEGF-inhibitors, cyclosporine, nitrogen mustard,⁵ HHV-8,⁶ and lymphoproliferative disorders.⁷ In a case report, multiple capillary haemangiomas were reported as a distinctive feature of multicentric Castleman’s disease and polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome.⁸

Vascular conditions have been seen as side effects of medications. Multiple capillary haemangiomas,⁹ recurrent scrotal haemangiomas,¹⁰ and periungual pyogenic granuloma¹¹ have been reported as side effects of tyrosine kinase inhibitors in treating cancers. It appears that tyrosine kinase inhibitors act by increasing the number of circulating endothelial cells and the levels of VEGF, G-CSF, stromal cell-derived factor 1 alpha, somatic cell-derived factor, and osteopontin in the induction of haemangioma formation.¹⁰ In a case report, two patients with reactive capillary haemangiomas following administration of amrelizumab (SHR-1210), an anti-PD-1 agent for the treatment of Hodgkin’s lymphoma and lung adenocarcinoma, respectively, were described. It was postulated that a shift in the balance of receptor/receptor-ligand interactions with increased levels of vascular proliferative proteins, such as VEGF, is the pathogenetic mechanism of amrelizumab in inducing reactive capillary haemangiomas.⁴ Pyogenic granuloma, particularly with the involvement of the oral mucosa, sometimes develops in pregnancy or following oral contraceptive (OCP) ingestion. A case of multiple disseminated cutaneous pyogenic granulomas has been reported following OCP ingestion. Cessation of OCP and delivery can normalise the hormonal imbalance and may result in regression of the lesions.¹²

To the best of our knowledge, our case was the first to demonstrate a comorbidity of eruptive capillary haemangiomas and hyper IgM syndrome. As a hypothesis, in our case, administration of recombinant G-CSF and recurrent infections (through increasing cytokines and chemokines) might play a role in the pathogenesis of eruptive capillary haemangioma through mobilisation and activation of the endothelial progenitor cells. Further studies will be necessary to confirm or refute this hypothesis.