What Caused This Infant to Develop Numerous Expanding Red Lesions?

What led a 3-month-old boy to become covered in red skin lesions? That was the question facing Catherine Reilly, BS, of Georgetown University School of Medicine in Washington, D.C., and colleagues, as they report in JAMA Dermatology.

When the infant was referred for evaluation, clinicians learned that he showed multiple red skin papules at birth, and these increased in number and size during the next few months. The child’s head and neck, trunk, arms and legs, right palm, mons pubis, and buttocks were affected. When the condition was at its most severe, there was 39 lesions, some of which were ulcerated and bleeding.

The child’s birth at full-term and vaginal delivery had been unremarkable, and the birth mother did not receive prenatal care. Neither mother nor infant had any known exposure to hazardous substances. Regarding family medical history, the mother’s was unknown, and the father’s revealed nothing of note.

On physical examination, case authors noted “numerous bright red macules, papules, and plaques ranging in size from 1.0 × 1.0 mm to 2.2 × 2.3 cm, many of which had hemorrhagic crust and dark scale.” They also noted retrognathia, thickened maxillary frenulum, and anterior ankyloglossia.

Case authors considered various possible diagnoses, including multifocal infantile hemangioma, bacillary angiomatosis, multifocal lymphangioendotheliomatosis with thrombocytopenia, and congenital disseminated pyogenic granuloma (CDPG). Based on immunochemistry findings and the clinical progression, the team diagnosed the patient with the latter.

Microscopic Findings and Clinical Course

Clinicians confirmed the diagnosis of CDPG with hematoxylin-eosin staining, which revealed an upper dermal lobulated capillary proliferation that was positive for CD31 and smooth muscle actin (SMA), and negative for D2-40 and GLUT-1.

A complete blood cell count and metabolic panel and an abdominal ultrasound all returned normal results. At 4 months of age, the patient underwent an MRI of the brain; this revealed an enhancing nodule measuring 7 × 5 × 6 mm located “along the posterior temporal dural surface, [along with] enhancing exophytic soft tissue polyps in the neck and scalp,” case authors noted. They also observed “mild hypogenesis or dysgenesis of the corpus callosum… with evidence of prior pineal hemorrhage.” Results of a neurological assessment suggested the patient’s risk of stroke was low.

At a 7-month follow-up visit, clinicians noted an increase in the number of pyogenic granulomas (PGs), which were also growing in size. The patient had a large friable PG on his left elbow which his guardians noted bled frequently, so this was surgically removed. He had several smaller PGs that were also causing problems – these were removed using shave biopsy.

At 8 months of age, the patient had another MRI which showed that a dural nodule had decreased in size (3 mm) and there were no other important changes.

When the patient reached 9 months old, the PGs began to involute, and most were resolved by the time he reached 16 months, case authors noted. As well, “results of genetic testing were negative for genes previously reported to be involved in PGs (ATR, BRAF, FLT4, GNA14, HRAS, KDR, KRAS, and NRAS).”

Discussion

First described in 2009 by Browning and colleagues, CDPG “is a rare, multisystemic disorder” with only 13 cases reported in the medical literature, case authors wrote.

The histopathologic tests revealed “capillary proliferation with enlarged endothelial nuclei and highly vascular granulation tissue,” findings suggestive of CDPG, they noted; the positive CD31 and negative GLUT-1 and D2-40 staining confirm the diagnosis.

While the causes of CDPG remain unclear, case authors theorized that imbalances between pro- and antiangiogenic pathways may be associated with the rapid growth of new blood vessels and capillary proliferation that characterize pyogenic granuloma. The cited paper also states that pyogenic granuloma stains positive for vascular markers like CD31, CD34, and factor VIII antigen, but unlike infantile hemangioma, results are negative for glucose transporter-1 (GLUT-1).

The condition develops during infancy, causing multiple vascular macules and papules which may be bright pink to red, with a smooth or lobulated surface. The lesions may become ulcerated and/or crusted, and may bleed with or without contact or provocation. Typically, these proliferate and increase in size during the first few months after birth, and then gradually resolve over the course of infancy.

Pyogenic granulomas “can develop in the brain, musculoskeletal system, and visceral organs,” case authors wrote, and can cause potentially life-threatening hemorrhaging. They may also cause temporary coagulopathy, which in some cases may be severe.

The skin condition has been linked to the use of certain types of medications, including antiretrovirals such as indinavir, antineoplastics such as imatinib, immunosuppressants such as etanercept, and retinoids.

Reilly and coauthors described aspects of CDPG that help distinguish it from similar-appearing conditions, such as multifocal infantile hemangioma (MIH): while both conditions move through neonatal phases of proliferation and then involution, MIH does not develop at birth, but rather after the first weeks of life, thus typically does not involve the cranium. Histopathologically, MIH is characterized by tightly packed vascular channels lined by a single endothelial layer, and in contrast to CDPG, staining is GLUT-1 positive.

Another condition, bacillary angiomatosis (BA), which occurs due to Bartonella henselae or B. quintana infection, is rarely seen in infants; it tends to affect immunocompromised individuals. Histologically, BA findings are similar to those seen in PG, case authors noted, “except for clumps of bacterial rods revealed by Warthin-Starry staining.

Finally, progressive multifocal lymphangioendotheliomatosis with thrombocytopenia presents at birth with multiple “red-brown and blue macules or thin broad plaques that can involute in the gastrointestinal tract,” potentially resulting in thrombocytopenia and gastrointestinal hemorrhage, authors noted. “Its histopathologic findings appear as dermal and subcutaneous proliferation of dilated thin-walled vessels lined by hobnailed endothelial cells with intraluminal papillary projections. The endothelial cells label with vascular stains (e.g., CD31, LYVE-1), although other lymphatic markers are reportedly negative, as is GLUT-1,” they explained.

Patients with CDPG require timely diagnosis and multisystemic evaluation, and should be monitored frequently with complete blood cell count and metabolic panels, as well as lab tests of clotting function when that is a concern, case authors wrote. While standard treatment guidelines do not exist, “given the risk of catastrophic intracranial hemorrhage and the relative accessibility of imaging, brain MRI and abdominal ultrasonography should be performed,” the group concluded. Future treatment approaches may benefit from genetic testing to guide use of targeted therapy.