Infantile hemangiomas (IHs) are common benign vascular and soft-tissue tumors in children (1). The pathological characteristics typically include aberrant endothelial growth and an abnormal blood vessel structure (2). However, the pathogenesis and origin of IHs remain unclear. Many studies have demonstrated that IH formation is a result of a somatic mutation of one or more genes related to endothelial cell proliferation, leading to tumor formation (3). IHs may include single, multiple, segmental, and intermediate types and can also be divided into superficial, deep, and mixed according to the location. In addition, IHs can be complicated by other complications. Therefore, the correct and timely diagnosis of IHs and complications is particularly important in clinical practice.

IHs are usually diagnosed on the basis of medical history and clinical and imaging findings. More than 90% of tumors can be detected by local ultrasound examination. A small number of tumors located in the scalp, sacrocaudal region, and around important organs require magnetic resonance imaging (MRI) examination to understand whether the surrounding tissues and organs are involved and the degree of invasion. Echocardiography can be performed to determine the presence of cardiac insufficiency, cardiac or aortic structural abnormalities in some large or multiple hepatic hemangiomas, and other complications. IHs are mainly treated with systemic and topical drugs supplemented by laser or local injection, which aim to inhibit the proliferation of vascular endothelial cells, promote tumor regression, reduce tumor residue, and prevent functional damage. These therapeutic methods have made great progress; however, in clinical diagnosis and treatment, there are still some unavoidable complications due to systemic administration (4). Multiple studies have established the evidence of IHs; however, we still do not fully understand the pathogenesis and treatment mechanism of IHs. The most urgent requirement for IH treatment is to use the current data to diagnose and classify each child to set up individualized or personalized therapy.

Generally, IHs often occur in sporadic cases from various regions and racial/ethnic groups, although a few familial aggregations that are considered to be genetically related may exist (5). Recently, a multicenter study found an increased risk of IHs in siblings of patients with IHs, which is considered to be due to the familial clustering of prenatal risk factors (6).

The etiology of IHs is not exactly clear. However, many studies have clarified and confirmed several important risk factors for the development of IHs. They occur more commonly in infants, including low birth-weight babies (7), premature babies, female infants, multiparous pregnancies, estrogen use during pregnancy, a positive family history or genetic evidence, and the Caucasian race. Additional associations included in vitro fertilization, maternal smoking, older maternal age, placental anomalies, gestational diabetes, gestational hypertension, vaginal bleeding in the first trimester, amniocentesis, and chorionic villus sampling (8).

The pathogenesis of IHs may be multifactorial, and although scholars have proposed many hypotheses at present, it is still not clearly defined. The pathogenesis of IHs consists mainly of the following:

Understanding the pathogenesis of IHs lays the foundation for identifying and developing new treatments and for reducing adverse reactions during treatment.

IHs are characterized by a predictable course and experience three stages: proliferation, a plateau phase, and involution (16). The morphology of IHs mainly depends on their location. IHs can be classified as deep, superficial, or combined IHs according to their clinical depth. IHs are usually not observed or are often preceded by pale or pink precursor lesions when infants are born. The most rapid proliferation of IHs was completed within 8 weeks after birth. IHs usually grow to their maximum size when the infants are approximately 9–12 months (17); however, the proliferative phase may last longer and take longer to regress in segmental or deep IHs. After a short plateau phase, IHs gradually regress after 1 year of age, and most may be in complete involution when the child is 4 years old (18). In this phase, some cases present with skin problems such as significant permanent scarring, dilation of the capillaries, and other changes.

Although IHs are usually small and harmless, in a significant proportion of patients, they can lead to serious complications during the rapid proliferation phase, including pain, ulceration, functional impairment, cosmetic disfigurement, and potentially serious visceral abnormalities. Furthermore, a few cases of IHs can be associated with additional abnormalities. PHACE(S) and LUMBAR are considered the two most recognized syndromes.

PHACE(S) is characterized by posterior fossa vascular malformation, segmental hemangiomas of the face, arterial anomalies, coarctation of the aorta, cardiac anomalies, eye abnormalities, and, insome cases, sternal defects or supraumbilical raphe defects. The LUMBAR syndrome is usually characterized by lower-body hemangioma, urogenital abnormalities, ulceration, myelopathy, bony deformities, and anorectal malformations (19).

IHs are diagnosed clinically; the evaluation of infants with IHs should include a detailed history and a full-body physical examination, and large or potentially problematic lesions should be confirmed by a specialist after presenting a systematic analysis. The rapidly proliferating nature of IHs can lead to misdiagnosis in patients with malignancy, as they may mimic dermatofibrosarcoma and infantile fibrosarcoma (15). Nevus simplex and port wine stains are flat, hyperpigmented capillary malformations, typically on the head and neck regions of newborns, that may resemble IHs. If the lesion was present at birth and has not grown, it may be a congenital hemangioma rather than IHs. Other benign vascular tumors include spindle-cell, epithelioid, intramuscular, and pyogenic granulomas (20).

IHs in a beard distribution/location should prompt an evaluation of the airway, despite IHs rarely causing airway blockage. Five or more cutaneous hemangiomas are associated with the presence of IHs involving the liver, and ultrasound can be helpful in diagnosis. Moreover, large or multiple IHs in the liver increase the risk of high-output cardiac failure, as well as acquired hypothyroidism (21).

PHACE(S) syndrome is not always large, and smaller segmental IHs on the face should increase the possibility of associated anomalies (22). Many studies have suggested that head and neck MRI with magnetic resonance angiography should be performed in infants with segmental facial hemangiomas of ≥5 cm. In addition to MRI/magnetic resonance angiography, patients with PHACE(S) syndrome should undergo echocardiography and ophthalmologic assessment. Patients with LUMBAR syndrome also need to undergo an MRI of the pelvic and lower spine (23, 24).

Treatment should be considered comprehensively after the diagnosis of IHs. Most IHs do not require active treatment because of their natural course but do require regular follow-up. However, high-risk IHs are identified according to their size, nature, or location; therefore, active interventions are needed. Urgent referral and early intervention are recommended for infants with high-risk IHs, including lesions associated with life-threatening complications, functional impairment, ulceration or bleeding, structural abnormalities (PHACE or LUMBAR syndrome), and permanent disfigurement (25).

Various systemic and topical therapies have been investigated for IHs treatment. The current systemic therapy for IHs can safely start with propranolol. Other systemic treatments for IHs have been reported to include corticosteroids and other β-blockers (26).

With a better understanding of the natural course of IHs and related complications, the efficacy of propranolol and its mechanism of action are clearer, which helps enhance further research on them as well as the treatment of IHs. In many cases, treatment decisions are based on the presence or absence of complications. Infants who may develop complications and other risks should be considered and treated by a specialist clinic as soon as possible. After a comprehensive evaluation by a specialist, appropriate and individualized approaches should be used to treat or prevent complications. Propranolol is the mainstay of treatment, and combination treatment has unique advantages. Promising results have been reported during the exploration of new treatment options.

XW: conceptualization, methodology, data curation, and writing—original draft preparation. HZ: validation and writing—review and editing. All authors have read and agreed to the published version of the manuscript.

This work was supported by the Shandong Medical Trade Union Committee (SDYWZGKCJH2022002) and the Qingdao Municipal Health Commission (2022-zyym42).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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