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Anogenital warts in pediatric population*

The approach to children with anogenital warts in the context of sexual abuse is a challenge in clinical practice. This study aims to review the current knowledge of anogenital warts in children, the forms of transmission, and the association with sexual abuse and to propose a cross-sectional approach involving all medical specialties. A systematic review of the literature was conducted in Portuguese and English from January 2000 to June 2016 using the ISI Web of Knowledge and PubMed databases. Children aged 12 years or younger were included. The ethical and legal aspects were consulted in the Declaration and Convention on the Rights of Children and in the World Health Organization. Non-sexual and sexual transmission events of human papillomavirus in children have been well documented. The possibility of sexual transmission appears to be greater in children older than 4 years. In the case of anogenital warts in children younger than 4 years of age, the possibility of non-sexual transmission should be strongly considered in the absence of another sexually transmitted infection, clinical indicators, or history of sexual abuse. The importance of human papillomavirus genotyping in the evaluation of sexual abuse is controversial. A detailed medical history and physical examination of both the child and caregivers are critical during the course of the investigation. The likelihood of an association between human papillomavirus infection and sexual abuse increases directly with age. A multidisciplinary clinical approach improves the ability to identify sexual abuse in children with anogenital warts.


INTRODUCTION
Anogenital infection caused by human papillomavirus (HPV) is the most common sexually transmitted infection (STI).
Clinically, HPV may manifest as anogenital warts (AWs), also known as condyloma acuminata, in cases in which it infects mucous membranes. However, AW and condyloma acuminata are often used as synonyms.
The incidence of AWs in children has increased in recent decades. 1,2 This increase has renewed the interest in understanding the mode of transmission of AWs, its social and legal impacts in cases of sexual abuse, and possible long-term complications.
The association between AWs in children and the occurrence of sexual abuse has been discussed. According to the World Health Organization, child abuse is defined as the abuse and neglect of all children younger than 18 years and includes all types of physical, psychological, and sexual abuse, as well as neglect and commercial exploitation. 3 More specifically, sexual abuse of minors involves the sexual contact of a child by an adult or older child, with an age difference of at least 5 years and a significant difference in cognitive-affective development. This type of abuse also involves the participation of the minor in practices aimed at the gratification and satisfaction of an adult or older child who is in a position of power or authority over the child. 4,5 The forms of sexual abuse considered in most studies are orogenital contact, genital-genital contact, genital-anal contact, caressing, digital penetration of the vagina or anus, and the introduction of objects into the vagina or anus. 6 The difficulty in addressing suspicions of sexual abuse in children with AWs is due to the vulnerability of the child and the caregivers and to the ethical, medical, and legal aspects involved in the suspicion of this crime. Therefore, most healthcare professionals do not feel comfortable consulting potential victims or performing a detailed medical history and physical examination. This study aims to review the current knowledge of AWs in children, its form of transmission, and the association with sexual abuse and to propose a cross-sectional approach involving all medical specialties, without disregarding the children and caregivers. The tropism of a particular HPV type to specific regions of the cutaneous or mucosal tegument is known, although this tropism is not absolute (Table 1). 7,8,11 Certain viral subtypes are usually found in specific locations, but overlap is common, particularly in the pediatric population. High-risk HPV types 16 and 18 and cutaneous HPV types 1 to 4, among others, can also be identified in AWs.

Epidemiology
The incidence of AWs in children has increased, which may be reflected in the concomitant increase in adults, an increased awareness of the diagnosis of AWs in the general and pediatric population, and increased development and investment in vaccines against HPV. 1,2,6 Girls are more frequently affected than boys, at a ratio of 3:1.7. 1 However, little is known about the epidemiology of the virus in the pediatric population. 12 A recent review has shown that the sexual abuse of minors is highly prevalent worldwide, with prevalence rates of 8-31% for girls aged less than 18 years and 3-17% for boys in the same age group, and that 9 out of 100 girls and 3 out of 100 boys are victims of forced sex. 13 Sexual abuse accounts for approximately 10% of official cases of child maltreatment in the United States. 14 Several studies have concluded that 80% to 90% of the abused children are girls, with a mean age of 7 to 8 years, and that 75% to 85% of children have been abused by a male aggressor known to the child and, above all, by family members, with several episodes of abuse over time. Other studies reported that 20% to 50% of the cases of sexual abuse involving children and adolescents are committed by minors. 16 .
The identification of AWs in children often raises suspicions of sexual abuse. In children with AWs, the reports of sexual abuse range from 0 to 80%. 1,2,9,17,18 The association with sexual abuse increases with age; however, the age below which the hypothesis of sexual abuse can be excluded has not been defined. 2,17 Sinclair et al.
found that the likelihood of AWs due to sexual abuse was 37% in children aged 4 to 8 years and 70% in children older than 8 years. 17 Another study concluded that children with AWs aged 4 years, 8 years, and more than 8 years had, respectively, 2-, 9-, and 12-fold increased likelihoods of having been sexually abused than children

Transmission
The prenatal transmission (during pregnancy), and (iii) perinatal transmission (during and immediately after birth). Therefore, the detailed gynecological history of the mother, including episodes of AWs and abnormal cytological examinations, is crucial. 6 Vertical transmission is estimated to occur in approximately 20% of cases. 6 Periconception transmission can theoretically occur via infected oocytes or spermatozoa. 6 Although studies have detected HPV DNA in samples of sperm and sperm cells and in biopsy specimens of the vas deferens and upper female genital tract, it is still controversial whether these cases indicate true forms of transmission in clinical practice. [21][22][23] In addition, no studies have evaluated the presence of HPV in oocytes. 23 Some authors argue that the viral contamination of embryos may occur immediately after fertilization. 6 The detection of HPV DNA in amniotic fluid, fetal membranes, umbilical cord blood, and placental trophoblastic cells suggests in utero infection, i.e., prenatal transmission. 24,25 Perinatal transmission may occur during childbirth by the direct contact with the infected genital tract of the mother. 6 Furthermore, there is evidence that the mothers who transmitted the infection by perinatal transmission had a significantly higher viral load in the cervix than those who did not transmit it. 26 The frequent detection of HPV DNA in children a few days after birth may also be associated with transient mucosal colonization. 27 Horizontal transmission may occur by autoinoculation or heteroinoculation. 6 Autoinoculation refers to the contamination of a body site that was not infected by an infected body site. 28,29 Heteroinoculation involves transmission by third parties, particularly by the parents or caregivers of the child, by direct contact. 8 Transmission via fomites, including the sharing of personal hygiene products, bathing, or even underwear, is suggested but appears to have little impact on the development of active infections. 9,30 Pathophysiology HPV infection can be asymptomatic, transient, or characterized by epithelial proliferation, commonly known as warts. HPV primarily infects the differentiated squamous cellular epithelium, and basal keratinocytes are the target sites on the skin and mucous membranes. The virus remains in the nucleus as a double-stranded DNA episome. 10 HPV can remain in a latent phase, and the incubation period after infection may last several months. Therefore, lesions may not become clinically evident for months to years after the initial exposure. This unpredictable latent period makes determination of the mode of transmission problematic.
The genome of HPV contains the proteins E1 and E2, which bind to DNA, promote its replication, and activate messenger RNA (mRNA) synthesis to allow its integration into the host genome. 31 The E5 oncoprotein activates the epidermal growth factor receptor and promotes cell growth by increasing cell sensitization to growth signals. The E4 oncoprotein leads to cytokeratin breakdown. The oncogenes E6 and E7 encode oncoproteins that target the p53 and Rb proteins, which are encoded by tumor-suppressor genes. 31 The genes E6 and E7 induce cell division and prevent apoptosis by binding to p53 and Rb, respectively, which are degraded and inactivated. This mechanism causes genetic instability, with unregulated cell replication and accumulation of aberrant chromosomal mutations, which cause dysplasia of varying degrees. The lesions may evolve into invasive carcinomas if left untreated. [31][32][33] The proteins encoded by the viral E genes stimulate cell proliferation, which facilitates replication of the viral genome by the host cell DNA polymerase as the cells divide. 10 The warts grow via a virally induced increase in cell number, leading to the thickening of the basal, spinous, and granular layers of the epidermis (Figure 1).
Utilizing the keratinization process, the virus crosses the skin layers and is released with dead cells from the upper layer. 10 The average period of wart development is 3 to 4 months. 31 A good cellular and innate immune response is fundamental for the control and reso- The genotyping of HPV DNA in children and adolescents suspected of sexual abuse without clinical evidence of AWs is discouraged because the infection is transient and the virus is eliminated by a healthy immune system, and it appears that a few specific genital HPV types are associated with sexual abuse. 18 However, no consistent evidence has been established between the type of HPV and the mode of transmission, and additional research is needed to elucidate this association. 2,11 Serological tests with the detection of anti-HPV antibodies are not routine. These tests are used for epidemiological studies and do not represent a valid diagnostic test in clinical practice. In addi-

FIgure 2: A)
Perianal a n o g e n i t a l warts in a female child. B) Perianal anogenital warts in the intergluteal fold of a female child Although they represent a benign pathology, condylomas are a cause of anxiety and involve the use of many human and financial resources. 36,37 There is no single treatment for this condition.
Multiple sessions and combinations of different techniques and treatments are usually required to achieve healing.

Prognosis
The viral infection is usually localized and regresses spontaneously, possibly because of the immune response, and may recur.
In healthy children, approximately 70% of the AWs resolve spontaneously within 1 year, and 90% resolve within 2 years. 27 Immunocompromised patients have higher numbers of recurrences and aggressive infections and a lower probability of spontaneous remission. 10 The identification of HPV types known to have a unique oncogenic potential (e.g., types 16, 18, 31, 33, 35, 39, 45,  Vaccination should preferably be administered to adolescents before sexual initiation. 41 Recent studies have reported the occurrence of several subclinical high-risk HPV infections in the prepuce of boys, a region that is considered a large reservoir for viral diseases and has not received enough attention to date. 43 These results support the interest in the vaccination against HPV in male subjects. 44 Tetravalent and nonavalent vaccines are recommended to males starting at ages 11 to 12 years and may be administered until the age of 26, as in females. 41 In sexually abused children, the administration of HPV vaccines is recommended at age 9. behavior should be evaluated. 36 The support of the psychologist and/or child psychiatrist is fundamental to this approach.

Approach To Children With Aws
Identifying cases of sexual abuse is difficult given the various routes of HPV transmission, its long period of latency after infection (approximately 3 months in adolescents and adults, unknown in children), and the fact that HPV genotyping does not elucidate its mode of transmission. Most sexually abused children have no identifiable lesions, or these lesions are completely healed before clinical evaluation. 9 The physical findings during anogenital examination in approximately 60% of children with STIs are unremarkable or non-specific. 35,45 Therefore, the period from sexual abuse to clinical examination by the specialist is critical. Furthermore, an urgent evaluation is crucial in cases in which sexual abuse is suspected. 46 Considering that one of the main obstacles is the lack of knowledge of the anatomy of the female genitalia before menarche, the implementation of standardized approaches and training of health professionals are necessary to evaluate potential victims of sexual abuse, ensuring a high level of accuracy in these assessments. 45,46 Studies have shown that the rate of diagnosis of sexual abuse by the combination of medical and social assessments reached 22% and increased to 71% when an interdisciplinary investigation was used. 35 The prevalence of cases of abuse is underestimated because there are few complaints and cases that actually go to court, especially when they involve intrafamily abuse and high socioeconomic status where these cases are more easily hidden. Furthermore, children do not have adequate communication skills to report these events or to provide details, cannot recognize the action as inappropriate, and repress unpleasant memories. 45 Most investigated cases involve, as a rule, abusers with lower socioeconomic status, and these social groups have higher prevalence rates of teenage pregnancy, drug abuse, poverty, unemployment, prostitution, and promiscuity, i.e., contexts that promote dysfunctional behaviors. 2

CONCLUSION
The presence of AWs or only HPV DNA in the genital region, without collection of clinical information and determination of the social context, is not a diagnostic criterion of sexual abuse. It should be noted that the age below which the hypothesis of sexual abuse can be excluded has not been defined. However, in children younger than 4 years, the non-sexual transmission of HPV should be strongly con-