Analysis of cytokine profiles in sera of single and multiple infantile hemangioma.

Infantile hemangiomas (IH) are benign vascular tumors that are common in infancy. They vary in growth, size, location, and depth, and although most lesions are relatively small, approximately one fifth of patients have multiple lesions. Risk factors for IH include female sex, low birth weight, multiple gestation, preterm birth, progesterone therapy, and family history, but the mechanism that causes multiple lesions is unclear. We hypothesized that blood cytokines are involved as a cause of multiple IHs, and tried to prove this using sera and membrane arrays from patients with single and multiple IHs. Serum samples were obtained from five patients with multiple lesions and four patients with a single lesion, none of which had received any treatment. Serum levels of 20 cytokines were measured using human angiogenesis antibody membrane array. Four of the 20 cytokines (bFGF, IFN-γ, IGF-I, and TGF-ß1) were higher in the patients with multiple lesions than in those with single lesion, with statistically significant difference (p < 0.05). Notably, signal for IFN-γ was evident in all cases with multiple IHs, but was absent in cases with single IH. Although not significant, there was mild correlation between IFN-γ and IGF-I (r = 0.64, p = 0.065), and between IGF-I and TGF-ß1 (r = 0.63, p = 0.066). bFGF levels were strongly and significantly correlated with the number of lesions (r = 0.88, p = 0.0020). In conclusion, blood cytokines could act as a cause of multiple IHs. This is a pilot study with a small cohort, so further large-scale studies are necessary.

Anti-desmoglein 1 antibody-positive mother and antibody-negative child with Darier's disease.

We report a mother and an adult son with Darier's disease. The mother, 76 years old and Japanese, had positivity for anti-desmoglein (Dsg)1 antibodies. She had erythema with hyperkeratosis and seborrheic and interstitial blistering. A high level of anti-Dsg1 antibodies was detected in the serum. Histopathological examination showed acantholysis and direct immunofluorescence testing revealed intercellular IgG and C3 deposition of the epidermis. Although she was diagnosed as having pemphigus foliaceus, the skin lesions slightly improved with immunosuppressive therapy. Her son, 47 years old, had similar skin lesions on the seborrheic and interstitial parts, but the anti-Dsg1 antibodies were negative in his serum. Histopathological examination showed acantholysis and dyskeratotic cells. Although Hailey-Hailey disease was first suspected, no mutation in the ATP2C1 was detected in either patient. Trio-exome analysis including the father showed a heterozygous c.2027C>A transition on exon 14 of ATP2A2, causing a replacement at amino acid 676 (p.Ala676Asp) in the mother and son only. The two patients were then diagnosed as having Darier's disease. Exome analysis further showed that a novel heterozygous missense mutation of DSG1 was identified only in the affected mother. Anti-Dsg1 antibody-positive Darier's disease is reported here for the first time. Very rare coexistence of Darier's disease and anti-Dsg1 antibody-positivity might be associated with this novel heterozygous DSG1 mutation. Experimental evidence is required to validate this hypothesis.

Dupilumab Improves Pruritus in Netherton Syndrome: A Case Study.

The patient was a 26-year-old male. He had red and scaling skin of the entire body since birth, as well as an elevated level of serum IgE. Genetic testing revealed a mutation in the SPINK5 gene, which had confirmed the diagnosis with Netherton syndrome. He has had significant pruritis since birth, and subsequently had symptoms of sleeping disorders and concentration difficulty throughout the day. Since treatment with various antihistamines were not effective, we administered dupilumab and found that it was effective in immediate elimination of pruritus and gradual reduction of the rash. Dupilumab has been administered for one year without any adverse events or recurrence of symptoms. Although studies have previously described cases who used dupilumab for Netherton syndrome, reported effects have been limited or transient. Additional studies are needed to confirm the effect of dupilumab for Netherton syndrome, which currently lack any effective treatment strategies.

Analysis of onset and clinical characteristics in Japanese patients with infantile hemangioma.

Infantile hemangioma (IH) is a common benign tumor during infancy, although the detailed mechanism behind it has not been fully elucidated. Based on previous studies, we hypothesized that formation of hemangioma might be triggered by secondary physiological events (perinatal hypoxia or mechanical stress during delivery) in patients carrying germline risk mutations. We aimed to clarify the mechanism by evaluating whether head and neck lesions were more frequent in patients in who IH appeared after birth compared with those in who it was present at birth. Clinical data of 62 lesions in 51 patients with IH were collected. All patients were analyzed for correlation of onset with gender, localization, family histories, gestational age, birth weight, and clinical subtypes. Distribution of lesions on the head and neck was slightly more frequent in the after-birth IH group, compared with those with IH present at birth, but without significant difference (47.6% vs. 40.0%, p = 0.32). On the other hand, the ratio of superficial and deep type IH at birth was significantly altered compared with that in IH after birth (19:0 vs. 26:7, p = 0.039). In addition, IHs appearing after birth tended to more commonly have multiple lesions than those with IH present at birth, with statistically significant difference (25.8% vs. 0%, p = 0.0164). There may therefore be different triggers for IHs at birth and IH after birth. Further studies with greater number of patients are necessary to validate these findings.

Distribution analysis of infantile hemangioma or capillary malformation on the head and face in Japanese patients.

Infantile hemangioma is one of the most common tumors in infancy. Delivery may be a clue for the trigger of infantile hemangioma formation in the head and face areas. In this study, we tried to plot localization of infantile hemangioma as well as capillary malformation on the head and face, and compared them to identify their characteristics and risk factors. The distribution of 104 lesions in 100 patients with infantile hemangioma was as follows: 32 lesions on the head, 12 on the forehead, 57 on the cheek and three in the jaw area. We could not find a statistically significant correlation of the distribution with three clinical subtypes (superficial, deep and mixed), sex or size of the lesions. However, the lesions in the jaw or chin areas were significantly less frequent than other areas (P = 0.0008 or 0.03, respectively). This tendency was not found in 40 patients with capillary malformation. Mechanical stress to jaw or chin areas may be less than other areas in normal cephalic delivery. Considering the emergence after birth and age-dependent involution of infantile hemangioma, we speculate that physiological events including perinatal hypoxia or mechanical stress during delivery as the trigger of hemangioma formation. Taken together, our results may reveal the contribution of mechanical stress to the trigger of infantile hemangioma, not capillary malformation, and may facilitate clinical differentiation between the two diseases by their localization. Further studies with an increased number of patients will be necessary to validate the finding.