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Acne in childhood
OCCASIONAL REVIEW
Acne in childhood
Pre-pubertal acne defined according to age Acne type
Age
Neonatal Infantile Mid-childhood
Birth to 6 weeks 6 weeks up to 12 months 1e7 years
Lea Solman Alison M Layton
Abstract
Table 1
Acne is a common, chronic inflammatory disease of the skin. While it is primarily a skin disorder of adolescence, acne also occurs, less commonly, in children who have not yet reached puberty. This specific group of acne patients can be categorised into four categories, based on the time of onset; neonatal, infantile, mid-childhood and prepubertal acne. The presentation of acne in this younger population may be associated with systemic pathologies different from those in adolescent acne. Clinical assessment should focus on securing symptoms and signs of virilisation and early referral to a paediatric endocrinologist should be considered if these are identified. Treatment regimens should be adopted such that they target the underlying pathophysiology of acne as well as the presenting clinical lesions. Antibiotics should be used judiciously to avoid the emergence of antibiotic resistant bacteria as this can impact on treatment response and may also contribute to resistance in commensal bacteria beyond the skin.
papulopustular acneiform conditions, such as neonatal cephalic pustulosis or transient neonatal pustular melanosis, may masquerade as neonatal acne challenging a definitive diagnosis. The relationship between neonatal acne and neonatal cephalic pustulosis remains controversial; some authors consider them to be two different entities, while others consider them a spectrum of the same disease. True neonatal acne triggered by androgens can present at birth through to the age of 4e6 weeks and is reported as being more frequent in boys. Cases of neonatal acne present with comedonal lesions with or without small inflammatory, erythematous papules and pustules. The acne usually occurs symmetrically on the cheeks, forehead and chin. The inflammatory lesions usually resolve spontaneously by 12 weeks and rarely result in any permanent sequelae such as scarring. The pathogenesis of neonatal acne is unclear. Several factors have been described including increased sebum excretion through stimulation of the sebaceous glands by maternal or neonatal androgens and/or colonization of sebaceous glands by Malassezia species. The main differential is Neonatal Cephalic Pustulosis. This is characterised by an erythematous papulopustular eruption mainly on the cheeks, but also on the forehead, chin, eyelids, upper chest and back. It has been postulated that neonatal cephalic pustulosis develops in association with Malassezia sympodialis and Malassezia globosa; however, the exact aetiological role of Malassezia is uncertain, as the organism is part of the normal flora of neonatal skin. Another explanation is that Neonatal Cephalic Pustulosis relates to an overgrowth of lipophilic yeasts at birth that results in an inflammatory reaction leading to monomorphic papules and pustules in predisposed neonates with elevated sebum production resulting from the influence of maternal androgens. Treatment is usually not required in neonatal acne as it is a self-limiting condition that resolves without scarring in 1e3 months. Daily cleansing may be all that is required. If treatment is deemed necessary in more severe cases, topical 2% ketoconazole cream can be used once daily. There are a number of other differential diagnoses that should be considered as a potential cause of an acneiform eruption in the neonate including bacterial folliculitis, herpes simplex virus, varicella zoster virus, secondary syphilis, congenital candidiasis, erythema toxicum neonatorum, transient neonatal pustular melanosis, and milia.
Keywords acne; childhood; infantile; pubertal; virilisation
Introduction Acne is a very common inflammatory disease seen in children and adolescents. It centres on the pilosebaceous unit and as a result is seen most prominently at skin sites with a high density of sebaceous glands, which include the face back and chest. However, the clinical presentation, differential diagnosis and underlying pathophysiology differs with age. Acne before the onset of puberty is uncommon. A recent classification of acne in children based on expert consensus included 5 subtypes according to age i.e. neonatal, infantile, mid childhood, preadolescent and adolescent. The distinction between pre-adolescence and adolescence by age is challenging as epidemiological studies have shown that acne is presenting earlier in boys and girls. This earlier presentation aligns with earlier menarche in girls. The term “pubertal” acne has been adopted to represent both preadolescent and adolescent in this text. Table 1 outlines the ages of presentation in early childhood acne pre- puberty.
Neonatal acne Neonatal acne may affect up to 20% of neonates, however, there is debate as to whether this reflects an overestimate, as
Lea Solman MD MRCP FRCPCH is a Consultant Paediatric Dermatologist, in the Department of Dermatology, Great Ormond Street Hospital for Children, London, UK. Conflict of Interest: none declared.
Infantile acne
Alison M Layton MBChB FRCP is a Consultant Dermatologist with Harrogate and District NHS Foundation Trust, Harrogate, UK. Conflict of Interest: none declared.
PAEDIATRICS AND CHILD HEALTH 29:2
Infantile acne may present from around 6 weeks and may last for up to 12 months or in some rare cases even longer. It is reported
85
Ó 2019 Published by Elsevier Ltd.
OCCASIONAL REVIEW
of adrenarche around the age of 7 years. In this age group, causes of hyperandrogenism should be ruled out. Mid-childhood acne presents most frequently on the face and less often on the chest and back. It includes open and closed comedones, inflammatory papules, pustules, cysts, and nodules. Scarring can also ensue as a result of the inflammation. The differential diagnosis of mid-childhood acne includes keratosis pilaris and milia alongside endocrinopathies and conditions relating to hyperandrogenism. There should be strong consideration of an underlying endocrine disorder in midchildhood acne, and a workup is usually warranted to exclude congenital adrenal hyperplasia, malignant adrenal or gonadal tumors, true precocious puberty and premature adrenarche. Clinical examination should focus on signs of virilisation: growth assessment, testicular growth, clitoromegaly, hirsutism and increased muscle mass. Bone age should be determined with radiologic imaging of the left hand and wrist. Other investigations should include total and free serum testosterone levels, DHEAS, luteinizing hormone, follicle stimulating hormone, prolactin, and 17-hydroxyprogesterone levels. If congenital adrenal hyperplasia is suspected, an Adrenocorticotropic Hormone (ACTH) stimulation test with a full range of the androgenic steroids, which are precursors to cortisol, should be measured.
more commonly in boys. Lesions are more heterogeneous and inflammatory then neonatal acne and embrace both open and closed comedones, papules, pustules as well as more deep seated inflammatory lesions including nodules which are can predispose to scarring (see Figure 1). Patients with infantile acne have been shown to have a higher likelihood of developing adolescent acne, with associated risks of more refractory, severe disease and scarring. The aetiology of infantile acne also remains poorly understood. Similar to neonatal acne, it may be associated with increased levels of androgens produced by adrenal glands in both sexes and by the testes in boys. Dehydroepiandrosterone (DHEA) from the adrenal glands stimulates sebum production for up to a year of age or until the DHEA levels drop at about 6e12 months. It is important to consider underlying systemic disease including an adrenocortical tumour in the case of persistent infantile acne with signs of virilisation and rapid development. The differential diagnosis of infantile acne includes neonatal acne, acne venerata infantum, chloracne and hyperandrogenism. Most cases of infantile acne resolve by the age of 4e5 years, but a few may remain active until puberty. Physical examination should focus on the signs of virilisation; genital and breast development, excessive hair growth, body odour and abnormal growth. If endocrinopathy is suspected, referral to a paediatric endocrinologist is recommended. Assessment of bone age, alongside blood tests to confirm luteinizing hormone, follicle stimulating hormone, total and free testosterone, prolactin, 17hydroxyprogesterone and dehydroepiandrosterone sulfate (DHEAS) levels should be considered. A recent study indicated that there is a relatively low risk of underlying endocrinopathy in preadolescent children with acne in the context of no other symptoms or signs of androgen excess. No further workup is necessary for the majority of cases in the absence of hormonal abnormalities.
Pubertal acne Acne is extremely common in and around puberty and may precede signs of pubertal maturation. Investigation other than a medical history and physical examination is generally unnecessary unless the acne is severe or there are other signs of androgen excess and/or other systemic abnormalities. Table 2 summarises examination and possible investigations required if an underlying systemic cause is suspected in acne that presents in childhood. At puberty a rising output of DHEAS and adrenal androgens in both sexes drives the onset of sebum production and increases hyperkeratinisation in the intrafollicular duct. Acne is therefore often the first sign of pubertal maturation. Acne at this age usually presents with increased sebum and comedonal lesions with or without some inflammatory papules. Lesions usually present on the forehead and central face and the trunk is often affected later in the course of the disease. Early presentation may include comedones of the ear as well as a significant number of midfacial comedones (see Figure 2). Lesions located in a midfacial distribution at the onset may precede any other signs of maturation and are considered a predictor of acne severity as a teenager. As adrenarche and menarche are occurring at an earlier age, acne is also presenting earlier. However, the development of acne in childhood along with premature adrenarche may represent be an initial sign of polycystic ovarian syndrome and this should be considered. Additional factors that may play a role in early onset pubertal acne are low birth weight and family history of acne. The differential diagnosis of pubertal acne includes keratosis pilaris, childhood granulomatous periorifacial dermatitis, lupus miliaris disseminatus faciei and childhood granulomatous
Mid-childhood acne Mid-childhood acne presents between the ages of 1e7 years and is extremely rare. Production of androgens from the neonatal adrenal glands ceases around the first year of life until the onset
Figure 1 Infantile acne.
PAEDIATRICS AND CHILD HEALTH 29:2
86
Ó 2019 Published by Elsevier Ltd.
OCCASIONAL REVIEW
Identifying the morphology of clinical lesions allow treatments to be selected to specifically target the lesions. Characteristic lesions include comedonal lesions (Blackheads and Whiteheads) and inflammatory lesions (papules, pustules and nodules). Pigment changes and scarring arise from inflammation, therefore treating acne early and effectively is important as a means of avoiding these disfiguring sequelae. At a microscopic level, the microcomedo is seen. This is the precursor of both non-inflammatory and inflammatory lesions. Treatment aimed at clearing and preventing the microcomedo from developing will treat established clinical lesions and prevent new ones occurring. Prevention and maintenance is an important part of treatment in children as acne is a chronic disease often lasting for 5e6 years. Selecting therapy should take into account the extent and severity of the disease as well as the psychological impact. Acne is generally divided into mild, moderate and severe disease based on clinical appearance. Table 3 outlines descriptions of each severity. Most acne therapies are approved for children of 12 years and older. The exceptions include erythromycin, adapalene/benzoyl peroxide gel approved from 9 years and tretinoin approved for patients 10 years and older. Tetracycline derivatives should be avoided in patients below 8e12 years of age (this difference in age depends on individual country recommendations). The age restrictions relates to the risk of permanent discolouration of enamel and altered bone growth in children. Most acne treatments are not contraindicated in younger children, but if being used off licence, it is important to ensure the parents are appropriately informed. Mild disease, which may include comedonal acne or mixed inflammatory/comedonal disease, should be treated with topical therapies. These may include topical retinoids and/or topical benzoyl peroxide as individual agents or fixed dose combination products including retinoids, antibiotics and benzoyl peroxide. Topical retinoids are the treatment of choice for comedonal acne.
Examination and investigations that should be considered to rule out the endocrinopathy in childhood acne History and examination C Growth assessment and plotting of height and weight charts C Age of menarche in girls C Tanner stage Endocrine work-up C Bone age (left hand and wrist X-ray for those with high growth parameters) C Free and total testosterone C DHEAS, luteinizing hormone, follicle-stimulating hormone C Prolactin C 17 hydroxy-progesterone (to rule out congenital adrenal hyperplasia) Table 2
rosacea alongside endocrinopathies and disorders associated with an androgen excess.,
Treatment The principles of treating acne in children involve adopting simple regimens, avoiding adverse effects and targeting the clinical lesions and pathophysiological factors implicated in acne. These include the interplay between four main factors, firstly sebogenesis which results from an increase in androgen levels at adrenarche, changes in follicular growth and differentiation within the intrafollicular duct, colonisation of the follicles with P. acnes (syn: C. acnes), with the consequent innate and adaptive immune responses which lead to inflammation.
Defining the severity of acne Severity
Description
Clear or almost clear Residual hyperpigmentation and erythema may be present. A few scattered comedones and a few small papules Mild Easily recognisable: less than half the face is involved. Some comedones, papules and pustules. Moderate More than half the face involved. Many comedones, papules and pustules. One nodule may be present. Severe Entire face involved. Covered with comedones, papules and pustules. More than one nodule/ cyst present. Table 3
Figure 2 Midfacial comedones are a predictor of acne severity.
PAEDIATRICS AND CHILD HEALTH 29:2
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Ó 2019 Published by Elsevier Ltd.
OCCASIONAL REVIEW
If more extensive, topical agents can be used safely. Parents should be given clear explanation about the proper application of topical treatments; a pea size amount should be applied to the entire acne-prone area in contrast to local treatment of the individual lesions. To avoid excessive dryness of the skin, topical treatments may be used for a short period of time (i.e. starting with 30 minutes) and slowly titrated up or can be used alternate days to good effect. Night time application is often the most practical. If topical benzoyl peroxide is used, parents should be warned about bleaching of the clothing, linens and towels. If response if poor it is important to check adherence ensuring that the treatment is practical to use and not causing any adverse effects. For moderate disease, a fixed dose topical therapy should be used, this could include a combination of retinoid plus BPO and/or antibiotics. If not responding a macrolide systemic antibiotic such as erythromycin should be considered as part of a combination regime. Antibiotics as monotherapy should be avoided to prevent the development of antibiotic resistant bacteria. If antibiotics are used they should be combined with benzoyl peroxide to reduce the likelihood of antimicrobial resistance occurring in the Propionibacterium acnes (syn. Cutibacterium acnes). Treatment should aim to reduce new lesions forming by including a topical retinoid and risk of scarring by adopting the use of effective anti-inflammatory agents. Systemic trimethoprim can be used off license as an alternative antibiotic to erythromycin if the latter is contraindicated or not tolerated. Systemic tetracyclines should be restricted in children according to age as outlined above. When antibiotics are prescribed, topical benzoyl peroxide should be used as part of a treatment regimen to reduce the risk of bacterial resistance to Propionibacterium acnes (syn. with Cutibacterium acnes) emerging. In recent years intensive antibiotic use has contributed to the development of antimicrobial resistance, and emerging strains of antibiotic-resistant bacterial strains are now a major global health concern. Recently, recommendations suggest the duration of oral antibiotics should be limited to three to six months in the treatment of acne whenever possible to avoid the consequent emergence of antibiotic resistant bacterial strains. Resistant strains can be transferred between close contacts which could result in younger siblings with acne having resistant bacterial strains before they have received any treatment. There is an association between resistant bacterial strains and poor clinical response to treatment. Adolescent females with acne may benefit from hormonal therapy. All combined oral contraceptives can help acne through their oestrogenic effect. However, it is important to consider the exact progesterone used as some progestins are less androgenic than others. Third generation testosterone derived progesterones are less androgenic than first and second generation progesterones. The anti-androgenic progestins cyproterone acetate and drospirenone found in some combined oral contraceptives are particularly effective in acne. The risk of venous thromboembolism should be considered if prescribing combined oral contraceptives, this risk is higher in combined oral contraceptives containing third generation progesterones and anti-androgens. For severe disease and/or risk of scarring, referral to a dermatologist is recommended. Successful treatment with oral isotretinoin at the dose of 0.3e2 mg/kg/day for 4e6 months in
PAEDIATRICS AND CHILD HEALTH 29:2
Relapse rates in children successfully treated with isotretinoin Age in years
10e12 (n¼20) 12e14 (n¼47) 14e16 (n¼66)
Number relapsing over time 6 months
1 year
2 years
3 years
2 3 2
12 18 21
6 19 23
3 9
Table 4
children younger than 5 years has been reported in the literature. Isotretinoin has only been adopted in a treatment regime when other more conventional therapies have failed and the risk of scarring has been considered a significant issue. Severe acne should initially be treated with a combination of oral antibiotics and a fixed dose retinoid/antimicrobial agent but on-going referral to a dermatologist should be considered early in the course of the disease if response is poor and/or there is evidence of scarring. Hormonal treatments can also be considered in girls if they have an established menstrual cycle. Relapse rates are high in patients with severe acne in this age group. One study demonstrated that 100% of patients between 12 and 16 years would have relapsed at three years after being successfully treated with isotretinoin Table 4. This may be explained by the fact sebaceous follicles have been shown in a longitudinal study to switch on asynchronously over time. As relapse rates are high in this age group with severe acne, maintenance therapy should be considered. Topical retinoids or fixed dose topical retinoids/benzoyl peroxide are considered the best maintenance therapies following successful treatment with isotretinoin. Isolated deep inflammatory nodules can be treated with a potent topical steroid for 5e7 days and if not responding injected with a low concentration of intralesional triamcinolone acetonide (2.5 mg/ml). A FURTHER READING Eichenfield LF, Krakowski AC, Piggott C, et al. Evidence-Based recommendations for the Diagnosis and Treatment if Pediatric Acne. Paediatrics 2013; 131: S163e86. Layton AM, Eady EA, Zouboulis CC. Chapter 90, Acne. In: Rook’s Textbook of Dermatology. 9th edn, 2016. John Wiley & Sons Ltd; 59e65, www.rooksdermatology.com. Lee KC, Lio PA. Evidence-based recommendations for the diagnosis and treatment of paediatric acne. Arch Dis Child Educ Pract Ed 2014; 99: 135e7. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group D. J Am Acad Dermatol 2009; 60(suppl 5): S1e50. no B, Abanmi A, et al. Practical management of Thiboutot DM, Dre acne for clinicians: an international consensus from the global alliance to improve outcomes in acne. J Am Acad Dermatol 2018; 78(2 suppl 1): S1e23. Yeo L, Ormerod AD. Treatment of acne in children. Am J Clin Dermatol 2014; 15: 77e86. https://doi.org/10.1007/S40257-013-0057-1.
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Ó 2019 Published by Elsevier Ltd.
OCCASIONAL REVIEW
Practice points C C
C
C
C
C
C
C
Acne can develop in neonates, infants and young children Neonatal acne is usually mild and no treatment is required. If more extensive and thought to be associated with Malassezia, 2% ketoconazole cream can be applied once daily. If severe and persisting, a workup for an underlying endocrine disorder including congenital adrenal hyperplasia or a virilising tumour should be considered. Most cases of infantile acne are self-limiting and not associated with underlying endocrine disease or systemic pathology. However, if there are signs and symptoms to suggest virilisation referral to an endocrinologist and a more extensive investigation should be considered. Mid-childhood acne is very rare; underlying systemic causes should always be considered and referral to a paediatric endocrinologist is warranted Management should aim to treat established lesions and also reduce the likelihood of new lesions developing. Treatment should address the inflammatory component of acne as a means of reducing likelihood of scarring. Antibiotics should be used judiciously as a means of avoiding antimicrobial resistance. Acne is a chronic disease and relapse rates are high in children with severe pubertal acne; maintenance therapy should be considered.
PAEDIATRICS AND CHILD HEALTH 29:2
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Ó 2019 Published by Elsevier Ltd.
Acne in childhood
Pre-pubertal acne defined according to age Acne type
Age
Neonatal Infantile Mid-childhood
Birth to 6 weeks 6 weeks up to 12 months 1e7 years
Lea Solman Alison M Layton
Abstract
Table 1
Acne is a common, chronic inflammatory disease of the skin. While it is primarily a skin disorder of adolescence, acne also occurs, less commonly, in children who have not yet reached puberty. This specific group of acne patients can be categorised into four categories, based on the time of onset; neonatal, infantile, mid-childhood and prepubertal acne. The presentation of acne in this younger population may be associated with systemic pathologies different from those in adolescent acne. Clinical assessment should focus on securing symptoms and signs of virilisation and early referral to a paediatric endocrinologist should be considered if these are identified. Treatment regimens should be adopted such that they target the underlying pathophysiology of acne as well as the presenting clinical lesions. Antibiotics should be used judiciously to avoid the emergence of antibiotic resistant bacteria as this can impact on treatment response and may also contribute to resistance in commensal bacteria beyond the skin.
papulopustular acneiform conditions, such as neonatal cephalic pustulosis or transient neonatal pustular melanosis, may masquerade as neonatal acne challenging a definitive diagnosis. The relationship between neonatal acne and neonatal cephalic pustulosis remains controversial; some authors consider them to be two different entities, while others consider them a spectrum of the same disease. True neonatal acne triggered by androgens can present at birth through to the age of 4e6 weeks and is reported as being more frequent in boys. Cases of neonatal acne present with comedonal lesions with or without small inflammatory, erythematous papules and pustules. The acne usually occurs symmetrically on the cheeks, forehead and chin. The inflammatory lesions usually resolve spontaneously by 12 weeks and rarely result in any permanent sequelae such as scarring. The pathogenesis of neonatal acne is unclear. Several factors have been described including increased sebum excretion through stimulation of the sebaceous glands by maternal or neonatal androgens and/or colonization of sebaceous glands by Malassezia species. The main differential is Neonatal Cephalic Pustulosis. This is characterised by an erythematous papulopustular eruption mainly on the cheeks, but also on the forehead, chin, eyelids, upper chest and back. It has been postulated that neonatal cephalic pustulosis develops in association with Malassezia sympodialis and Malassezia globosa; however, the exact aetiological role of Malassezia is uncertain, as the organism is part of the normal flora of neonatal skin. Another explanation is that Neonatal Cephalic Pustulosis relates to an overgrowth of lipophilic yeasts at birth that results in an inflammatory reaction leading to monomorphic papules and pustules in predisposed neonates with elevated sebum production resulting from the influence of maternal androgens. Treatment is usually not required in neonatal acne as it is a self-limiting condition that resolves without scarring in 1e3 months. Daily cleansing may be all that is required. If treatment is deemed necessary in more severe cases, topical 2% ketoconazole cream can be used once daily. There are a number of other differential diagnoses that should be considered as a potential cause of an acneiform eruption in the neonate including bacterial folliculitis, herpes simplex virus, varicella zoster virus, secondary syphilis, congenital candidiasis, erythema toxicum neonatorum, transient neonatal pustular melanosis, and milia.
Keywords acne; childhood; infantile; pubertal; virilisation
Introduction Acne is a very common inflammatory disease seen in children and adolescents. It centres on the pilosebaceous unit and as a result is seen most prominently at skin sites with a high density of sebaceous glands, which include the face back and chest. However, the clinical presentation, differential diagnosis and underlying pathophysiology differs with age. Acne before the onset of puberty is uncommon. A recent classification of acne in children based on expert consensus included 5 subtypes according to age i.e. neonatal, infantile, mid childhood, preadolescent and adolescent. The distinction between pre-adolescence and adolescence by age is challenging as epidemiological studies have shown that acne is presenting earlier in boys and girls. This earlier presentation aligns with earlier menarche in girls. The term “pubertal” acne has been adopted to represent both preadolescent and adolescent in this text. Table 1 outlines the ages of presentation in early childhood acne pre- puberty.
Neonatal acne Neonatal acne may affect up to 20% of neonates, however, there is debate as to whether this reflects an overestimate, as
Lea Solman MD MRCP FRCPCH is a Consultant Paediatric Dermatologist, in the Department of Dermatology, Great Ormond Street Hospital for Children, London, UK. Conflict of Interest: none declared.
Infantile acne
Alison M Layton MBChB FRCP is a Consultant Dermatologist with Harrogate and District NHS Foundation Trust, Harrogate, UK. Conflict of Interest: none declared.
PAEDIATRICS AND CHILD HEALTH 29:2
Infantile acne may present from around 6 weeks and may last for up to 12 months or in some rare cases even longer. It is reported
85
Ó 2019 Published by Elsevier Ltd.
OCCASIONAL REVIEW
of adrenarche around the age of 7 years. In this age group, causes of hyperandrogenism should be ruled out. Mid-childhood acne presents most frequently on the face and less often on the chest and back. It includes open and closed comedones, inflammatory papules, pustules, cysts, and nodules. Scarring can also ensue as a result of the inflammation. The differential diagnosis of mid-childhood acne includes keratosis pilaris and milia alongside endocrinopathies and conditions relating to hyperandrogenism. There should be strong consideration of an underlying endocrine disorder in midchildhood acne, and a workup is usually warranted to exclude congenital adrenal hyperplasia, malignant adrenal or gonadal tumors, true precocious puberty and premature adrenarche. Clinical examination should focus on signs of virilisation: growth assessment, testicular growth, clitoromegaly, hirsutism and increased muscle mass. Bone age should be determined with radiologic imaging of the left hand and wrist. Other investigations should include total and free serum testosterone levels, DHEAS, luteinizing hormone, follicle stimulating hormone, prolactin, and 17-hydroxyprogesterone levels. If congenital adrenal hyperplasia is suspected, an Adrenocorticotropic Hormone (ACTH) stimulation test with a full range of the androgenic steroids, which are precursors to cortisol, should be measured.
more commonly in boys. Lesions are more heterogeneous and inflammatory then neonatal acne and embrace both open and closed comedones, papules, pustules as well as more deep seated inflammatory lesions including nodules which are can predispose to scarring (see Figure 1). Patients with infantile acne have been shown to have a higher likelihood of developing adolescent acne, with associated risks of more refractory, severe disease and scarring. The aetiology of infantile acne also remains poorly understood. Similar to neonatal acne, it may be associated with increased levels of androgens produced by adrenal glands in both sexes and by the testes in boys. Dehydroepiandrosterone (DHEA) from the adrenal glands stimulates sebum production for up to a year of age or until the DHEA levels drop at about 6e12 months. It is important to consider underlying systemic disease including an adrenocortical tumour in the case of persistent infantile acne with signs of virilisation and rapid development. The differential diagnosis of infantile acne includes neonatal acne, acne venerata infantum, chloracne and hyperandrogenism. Most cases of infantile acne resolve by the age of 4e5 years, but a few may remain active until puberty. Physical examination should focus on the signs of virilisation; genital and breast development, excessive hair growth, body odour and abnormal growth. If endocrinopathy is suspected, referral to a paediatric endocrinologist is recommended. Assessment of bone age, alongside blood tests to confirm luteinizing hormone, follicle stimulating hormone, total and free testosterone, prolactin, 17hydroxyprogesterone and dehydroepiandrosterone sulfate (DHEAS) levels should be considered. A recent study indicated that there is a relatively low risk of underlying endocrinopathy in preadolescent children with acne in the context of no other symptoms or signs of androgen excess. No further workup is necessary for the majority of cases in the absence of hormonal abnormalities.
Pubertal acne Acne is extremely common in and around puberty and may precede signs of pubertal maturation. Investigation other than a medical history and physical examination is generally unnecessary unless the acne is severe or there are other signs of androgen excess and/or other systemic abnormalities. Table 2 summarises examination and possible investigations required if an underlying systemic cause is suspected in acne that presents in childhood. At puberty a rising output of DHEAS and adrenal androgens in both sexes drives the onset of sebum production and increases hyperkeratinisation in the intrafollicular duct. Acne is therefore often the first sign of pubertal maturation. Acne at this age usually presents with increased sebum and comedonal lesions with or without some inflammatory papules. Lesions usually present on the forehead and central face and the trunk is often affected later in the course of the disease. Early presentation may include comedones of the ear as well as a significant number of midfacial comedones (see Figure 2). Lesions located in a midfacial distribution at the onset may precede any other signs of maturation and are considered a predictor of acne severity as a teenager. As adrenarche and menarche are occurring at an earlier age, acne is also presenting earlier. However, the development of acne in childhood along with premature adrenarche may represent be an initial sign of polycystic ovarian syndrome and this should be considered. Additional factors that may play a role in early onset pubertal acne are low birth weight and family history of acne. The differential diagnosis of pubertal acne includes keratosis pilaris, childhood granulomatous periorifacial dermatitis, lupus miliaris disseminatus faciei and childhood granulomatous
Mid-childhood acne Mid-childhood acne presents between the ages of 1e7 years and is extremely rare. Production of androgens from the neonatal adrenal glands ceases around the first year of life until the onset
Figure 1 Infantile acne.
PAEDIATRICS AND CHILD HEALTH 29:2
86
Ó 2019 Published by Elsevier Ltd.
OCCASIONAL REVIEW
Identifying the morphology of clinical lesions allow treatments to be selected to specifically target the lesions. Characteristic lesions include comedonal lesions (Blackheads and Whiteheads) and inflammatory lesions (papules, pustules and nodules). Pigment changes and scarring arise from inflammation, therefore treating acne early and effectively is important as a means of avoiding these disfiguring sequelae. At a microscopic level, the microcomedo is seen. This is the precursor of both non-inflammatory and inflammatory lesions. Treatment aimed at clearing and preventing the microcomedo from developing will treat established clinical lesions and prevent new ones occurring. Prevention and maintenance is an important part of treatment in children as acne is a chronic disease often lasting for 5e6 years. Selecting therapy should take into account the extent and severity of the disease as well as the psychological impact. Acne is generally divided into mild, moderate and severe disease based on clinical appearance. Table 3 outlines descriptions of each severity. Most acne therapies are approved for children of 12 years and older. The exceptions include erythromycin, adapalene/benzoyl peroxide gel approved from 9 years and tretinoin approved for patients 10 years and older. Tetracycline derivatives should be avoided in patients below 8e12 years of age (this difference in age depends on individual country recommendations). The age restrictions relates to the risk of permanent discolouration of enamel and altered bone growth in children. Most acne treatments are not contraindicated in younger children, but if being used off licence, it is important to ensure the parents are appropriately informed. Mild disease, which may include comedonal acne or mixed inflammatory/comedonal disease, should be treated with topical therapies. These may include topical retinoids and/or topical benzoyl peroxide as individual agents or fixed dose combination products including retinoids, antibiotics and benzoyl peroxide. Topical retinoids are the treatment of choice for comedonal acne.
Examination and investigations that should be considered to rule out the endocrinopathy in childhood acne History and examination C Growth assessment and plotting of height and weight charts C Age of menarche in girls C Tanner stage Endocrine work-up C Bone age (left hand and wrist X-ray for those with high growth parameters) C Free and total testosterone C DHEAS, luteinizing hormone, follicle-stimulating hormone C Prolactin C 17 hydroxy-progesterone (to rule out congenital adrenal hyperplasia) Table 2
rosacea alongside endocrinopathies and disorders associated with an androgen excess.,
Treatment The principles of treating acne in children involve adopting simple regimens, avoiding adverse effects and targeting the clinical lesions and pathophysiological factors implicated in acne. These include the interplay between four main factors, firstly sebogenesis which results from an increase in androgen levels at adrenarche, changes in follicular growth and differentiation within the intrafollicular duct, colonisation of the follicles with P. acnes (syn: C. acnes), with the consequent innate and adaptive immune responses which lead to inflammation.
Defining the severity of acne Severity
Description
Clear or almost clear Residual hyperpigmentation and erythema may be present. A few scattered comedones and a few small papules Mild Easily recognisable: less than half the face is involved. Some comedones, papules and pustules. Moderate More than half the face involved. Many comedones, papules and pustules. One nodule may be present. Severe Entire face involved. Covered with comedones, papules and pustules. More than one nodule/ cyst present. Table 3
Figure 2 Midfacial comedones are a predictor of acne severity.
PAEDIATRICS AND CHILD HEALTH 29:2
87
Ó 2019 Published by Elsevier Ltd.
OCCASIONAL REVIEW
If more extensive, topical agents can be used safely. Parents should be given clear explanation about the proper application of topical treatments; a pea size amount should be applied to the entire acne-prone area in contrast to local treatment of the individual lesions. To avoid excessive dryness of the skin, topical treatments may be used for a short period of time (i.e. starting with 30 minutes) and slowly titrated up or can be used alternate days to good effect. Night time application is often the most practical. If topical benzoyl peroxide is used, parents should be warned about bleaching of the clothing, linens and towels. If response if poor it is important to check adherence ensuring that the treatment is practical to use and not causing any adverse effects. For moderate disease, a fixed dose topical therapy should be used, this could include a combination of retinoid plus BPO and/or antibiotics. If not responding a macrolide systemic antibiotic such as erythromycin should be considered as part of a combination regime. Antibiotics as monotherapy should be avoided to prevent the development of antibiotic resistant bacteria. If antibiotics are used they should be combined with benzoyl peroxide to reduce the likelihood of antimicrobial resistance occurring in the Propionibacterium acnes (syn. Cutibacterium acnes). Treatment should aim to reduce new lesions forming by including a topical retinoid and risk of scarring by adopting the use of effective anti-inflammatory agents. Systemic trimethoprim can be used off license as an alternative antibiotic to erythromycin if the latter is contraindicated or not tolerated. Systemic tetracyclines should be restricted in children according to age as outlined above. When antibiotics are prescribed, topical benzoyl peroxide should be used as part of a treatment regimen to reduce the risk of bacterial resistance to Propionibacterium acnes (syn. with Cutibacterium acnes) emerging. In recent years intensive antibiotic use has contributed to the development of antimicrobial resistance, and emerging strains of antibiotic-resistant bacterial strains are now a major global health concern. Recently, recommendations suggest the duration of oral antibiotics should be limited to three to six months in the treatment of acne whenever possible to avoid the consequent emergence of antibiotic resistant bacterial strains. Resistant strains can be transferred between close contacts which could result in younger siblings with acne having resistant bacterial strains before they have received any treatment. There is an association between resistant bacterial strains and poor clinical response to treatment. Adolescent females with acne may benefit from hormonal therapy. All combined oral contraceptives can help acne through their oestrogenic effect. However, it is important to consider the exact progesterone used as some progestins are less androgenic than others. Third generation testosterone derived progesterones are less androgenic than first and second generation progesterones. The anti-androgenic progestins cyproterone acetate and drospirenone found in some combined oral contraceptives are particularly effective in acne. The risk of venous thromboembolism should be considered if prescribing combined oral contraceptives, this risk is higher in combined oral contraceptives containing third generation progesterones and anti-androgens. For severe disease and/or risk of scarring, referral to a dermatologist is recommended. Successful treatment with oral isotretinoin at the dose of 0.3e2 mg/kg/day for 4e6 months in
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Relapse rates in children successfully treated with isotretinoin Age in years
10e12 (n¼20) 12e14 (n¼47) 14e16 (n¼66)
Number relapsing over time 6 months
1 year
2 years
3 years
2 3 2
12 18 21
6 19 23
3 9
Table 4
children younger than 5 years has been reported in the literature. Isotretinoin has only been adopted in a treatment regime when other more conventional therapies have failed and the risk of scarring has been considered a significant issue. Severe acne should initially be treated with a combination of oral antibiotics and a fixed dose retinoid/antimicrobial agent but on-going referral to a dermatologist should be considered early in the course of the disease if response is poor and/or there is evidence of scarring. Hormonal treatments can also be considered in girls if they have an established menstrual cycle. Relapse rates are high in patients with severe acne in this age group. One study demonstrated that 100% of patients between 12 and 16 years would have relapsed at three years after being successfully treated with isotretinoin Table 4. This may be explained by the fact sebaceous follicles have been shown in a longitudinal study to switch on asynchronously over time. As relapse rates are high in this age group with severe acne, maintenance therapy should be considered. Topical retinoids or fixed dose topical retinoids/benzoyl peroxide are considered the best maintenance therapies following successful treatment with isotretinoin. Isolated deep inflammatory nodules can be treated with a potent topical steroid for 5e7 days and if not responding injected with a low concentration of intralesional triamcinolone acetonide (2.5 mg/ml). A FURTHER READING Eichenfield LF, Krakowski AC, Piggott C, et al. Evidence-Based recommendations for the Diagnosis and Treatment if Pediatric Acne. Paediatrics 2013; 131: S163e86. Layton AM, Eady EA, Zouboulis CC. Chapter 90, Acne. In: Rook’s Textbook of Dermatology. 9th edn, 2016. John Wiley & Sons Ltd; 59e65, www.rooksdermatology.com. Lee KC, Lio PA. Evidence-based recommendations for the diagnosis and treatment of paediatric acne. Arch Dis Child Educ Pract Ed 2014; 99: 135e7. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group D. J Am Acad Dermatol 2009; 60(suppl 5): S1e50. no B, Abanmi A, et al. Practical management of Thiboutot DM, Dre acne for clinicians: an international consensus from the global alliance to improve outcomes in acne. J Am Acad Dermatol 2018; 78(2 suppl 1): S1e23. Yeo L, Ormerod AD. Treatment of acne in children. Am J Clin Dermatol 2014; 15: 77e86. https://doi.org/10.1007/S40257-013-0057-1.
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Practice points C C
C
C
C
C
C
C
Acne can develop in neonates, infants and young children Neonatal acne is usually mild and no treatment is required. If more extensive and thought to be associated with Malassezia, 2% ketoconazole cream can be applied once daily. If severe and persisting, a workup for an underlying endocrine disorder including congenital adrenal hyperplasia or a virilising tumour should be considered. Most cases of infantile acne are self-limiting and not associated with underlying endocrine disease or systemic pathology. However, if there are signs and symptoms to suggest virilisation referral to an endocrinologist and a more extensive investigation should be considered. Mid-childhood acne is very rare; underlying systemic causes should always be considered and referral to a paediatric endocrinologist is warranted Management should aim to treat established lesions and also reduce the likelihood of new lesions developing. Treatment should address the inflammatory component of acne as a means of reducing likelihood of scarring. Antibiotics should be used judiciously as a means of avoiding antimicrobial resistance. Acne is a chronic disease and relapse rates are high in children with severe pubertal acne; maintenance therapy should be considered.
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