Cutis

Epidemiology

Rosacea in childhood is most likely underreported because of its clinical similarity to other erythematous facial disorders.¹ Rosacea is generally thought of as a disease of fair-skinned, young to middle-aged adults, though it has been noted to affect people of other complexions and ages.² Most full-blown cases in the pediatric population have been in light-skinned children ranging from infants to adolescents.

Etiology

The etiology of rosacea is unknown, though certain exacerbating factors undoubtedly have a role in predisposed individuals.^3,4 Emotions such as anger, anxiety, and embarrassment can lead to flushing. Environmental conditions such as wind, cold, humidity, or heat from any source (eg, sun, sauna, whirlpool, vigorous exercise) can do the same. Vasodilators such as alcohol or vasodilatory medications can lead to flushing, though these are not likely causes in children. Spicy foods such as chili, curry, and peppers, as well as hot foods and beverages including coffee, tea, and hot chocolate, may contribute to symptoms. Irritants such as alcohol-based cleansers, astringents, perfume, shaving lotion, certain soaps, sunscreen, and facecloths may aggravate rosacea.^3,4 Saprophytic mites (Demodex folliculorum and Demodex brevis) may cause an inflammatory or allergic reaction by either blocking hair follicles or acting as vectors for microorganisms that some believe may be responsible for or may trigger rosacea.⁵ Immunodeficiency, as in patients with human immunodeficiency virus, also may contribute to the development of rosacea.⁶

Genetics plays an uncertain role in the development of blushing and ultimately rosacea. If vasodilator substances or mediators are implicated in the development of rosacea as postulated, the disease may have a genetic basis because such mediators are often under the control of single genes.⁷ In one study, 20% of children with rosacea were found to have a history of rosacea in their immediate families, though this number may be an underestimate because only one parent of each patient was examined and half of the parents clinically diagnosed with rosacea reported no familial involvement.⁸ A family history of perioral dermatitis also may be important, as this condition may be related to rosacea.⁹

Pathophysiology

Chronic transient vasodilation, as occurs with blushing, is the earliest representation of rosacea. The warmth and redness associated with flushing is caused by vasodilation, allowing excess blood flow, and by engorgement of the subpapillary venous plexus.² Flushing without sweating is typically seen in children and is likely due to circulating vasodilator substances or mediators such as bradykinin, catecholamines, cytokines, endorphins, gastrin, histamine, neuropeptides, serotonin, substance P, and vascular endothelial growth factor.¹⁰ A flaw in the autonomic innervation of the cutaneous vasculature also is a likely mechanism.¹⁰

Clinical Description

The first stage of rosacea consists of blushing, in which the face becomes bright red in response to certain stimuli (Figure). Episodes of erythema are recurrent and last longer than normal physiologic flushing, which typically subsides within minutes.¹¹ Telangiectasias can become apparent over time. Children in this early stage of the condition may complain of burning or irritation.

Please refer to the PDF to view the figure

In the second, or intermediate, stage of rosacea, the rash consists of papules and pustules on a background of erythema with telangiectasias confined to the child's face. Although peripheral involvement of the back, upper chest, and scalp may be seen in adults, these areas seem to be spared in the pediatric population.¹²

The third, or late, stage of rosacea involves coarse skin, inflammatory nodules, or gross enlargement of facial features.¹¹ Such chronic changes do not occur in children as they do in adults, presumably because the disease process takes more time to evolve.¹³

Eye involvement can occur in children.¹⁴ It may include manifestations such as blepharoconjunctivitis, episcleritis, keratitis, meibomianitis, chalazia, hordeola, and hyperemic conjunctivae.^15,16 Although any of these eye conditions can potentially occur in children, meibomian gland inflammation and keratitis are the common findings noted.¹⁷ Peripheral vascularization followed by subepithelial infiltrates can lead to scarring or perforation in the lower two thirds of the cornea. The disease may be unilateral, but most commonly it affects both eyes.¹⁷

Steroid-induced rosacea also has been termed iatrosacea because of its mode of acquisition.¹⁸ Topical fluorinated and low-dose corticosteroids can cause a rosacealike dermatitis of the face consisting of persistent erythema with papules, pustules, telangiectasias, and sometimes atrophy.^19-22 Corticosteroids may be an exacerbating factor leading to classic rosacea rather than the cause of an independent disease.² The distribution of steroid rosacea to the eyelids and lateral face may help distinguish it from the centrally located typical rosacea.²³ A case of pediatric rosacea associated with the use of topical fluorinated glucocorticosteroids was identified in a 9-month-old boy and 16-year-old girl, both with erythematous patches and papules on the cheeks, paranasal areas, and chin.^18,23 Forty-six boys and 60 girls, ranging in age of onset from 6 months to 13 years (average, 7 years), were diagnosed with steroid rosacea. Nearly all of the children had perinasal and perioral involvement of erythematous skin interspersed with papules and/or pustules. The lower eyelids were affected in roughly half of the patients.⁸ 

Diagnosis

Consistent flushing in children may be a sign of vasomotor instability and early rosacea. These children may blush more frequently and with greater intensity for longer periods than their peers exposed to the same stimuli.²⁴ Thus, blushing in the early stage of rosacea may be an accentuation of the body's normal physiologic response system. A diagnosis of pediatric rosacea beyond the initial stage should be considered when a healthy child has acuminate papules and small pustules of the face, especially if there also exists flushing, telangiectasias, or a family history of rosacea.¹⁴ 

Differential Diagnosis

The earliest form of rosacea, facial blushing, may be difficult to distinguish from flushing due to other causes. Blushing due to emotions such as embarrassment or anger and to exercise-induced flushing are both appropriate reactions to such stimuli, whereas blushing in the first stage of rosacea may be an exaggeration of this phenomenon.² The main pathway for thermoregulatory and emotional flushing is the cervical sympathetic outflow tract.²⁵ Gustatory blushing, as occurs with consumption of spicy foods, is mediated by autonomic neurons via a branch of the trigeminal nerve.² Sweating often occurs in conjunction with the aforementioned causes of flushing, but it is rarely associated with rosacea flushing. Thus, sweating may be helpful in reaching a diagnosis; however, exceptions exist.² Frey syndrome (auriculotemporal syndrome), which is characterized by warmth and sweating in the malar region caused by aberrant autonomic fiber connections after damage in the parotid region, may mimic the early stage of rosacea.

The intermediate stage of pediatric rosacea may be confused with other papulopustular disorders such as acne vulgaris, perioral dermatitis, and lupus erythematosus (Table). Careful attention to symptoms, distribution of facial lesions, and potential biopsy results are warranted to distinguish between the conditions. Steroid rosacea and perioral dermatitis may be variants of rosacea or completely separate conditions.^9,26

Please refer to the PDF to view the table

Perioral dermatitis is a rosacealike dermatitis characterized by erythematous papules and pustules usually confined to the perioral region, though the perinasal and periocular areas may be involved.²⁷ A granulomatous perioral dermatitis with tiny, closely spaced, flesh-colored papules in the perioral, perinasal, and periorbital areas was described in children aged 3 to 11 years.²⁸ All cases had spontaneous resolution of symptoms regardless of treatment. The patients did not exhibit flushing or telangiectasias.²⁸

The classic butterfly rash, consisting of erythema and telangiectasia of the malar region and associated with systemic lupus erythematosus, also can be confused with rosacea. Histopathologic examination and direct immunofluorescence of the lesion may help to differentiate lupus from rosacea.¹⁴ 

Laboratory Diagnosis

There is no specific histologic change unique to rosacea.¹² The most common findings are telangiectasia, edema, elastosis, a variable amount of superficial and deep perivascular lymphohistiocytic inflammatory infiltrate loosely arranged around the hair follicles, and especially architectural disruption of the upper dermis.^12,28 Depending on the variant of rosacea, there may be an exaggeration of one or more histopathologic signs.¹² For example, granulomatous rosacea may contain collections of granulomas with multinucleated giant cells.²⁸

Treatment

Treatment is gradual and largely determined by the clinical type of rosacea. Children with early or intermediate stages of rosacea are encouraged to avoid their individual local triggers to prevent flares. Topical corticosteroids, especially fluorinated medications, should be discouraged, because even low-potency steroids, including over-the-counter preparations and hydrocortisone 1%, have been shown to cause worsening of the condition.⁸

Traditional therapy for rosacea includes topical and systemic antibiotics, topical metronidazole, and topical retinoids. Oral tetracycline can be used for adolescents in doses similar to those prescribed for adults. It should not be used in children younger than approximately 9 years¹⁷ because it is known to cause dental staining and to be deposited in the skeletal system where it can cause temporary depression in bone growth.^29,30 Azithromycin or a low dose of doxycycline can be used with good results.^31,32 For younger children, oral erythromycin is safe and effective to eliminate the erythema, papules, and pustules of rosacea.³² Topical erythromycin and clindamycin have been used with varying results. Azelaic acid and isotretinoin also may be effective.³³ Topical metronidazole 0.75% gel has proven effective in clinical trials.^34,35 A combination of systemic antibiotics and topical treatment may lead to a substantial reduction in inflammatory lesions, erythema, and the size and diameter of telangiectatic vessels.³²

Eyelid hygiene and erythromycin or bacitracin ointment, to improve meibomian gland function, are appropriate initial treatments for the ocular manifestations of childhood rosacea.^17,36 A low dose of steroid drops can manage significant irritation when needed. Systemic therapy with tetracycline or other oral pharmaceuticals used to treat the face also may work for ocular symptoms.¹⁷

The treatment of steroid rosacea is a slow process often involving antiacne agents such as benzoyl peroxide and oral or topical antibiotics.²³ Abrupt discontinuation of topical steroids followed by administration of antibiotics is a suitable treatment option. Prior recommendation has been to taper all topical steroids to prevent rebound flare; however, one study found clearing of symptoms by week 3 in 22% of patients, by week 4 in 86% of patients, and by week 8 in 100% of patients following abrupt cessation of topical steroids and a regimen of oral erythromycin stearate or topical clindamycin phosphate in children with erythromycin allergy or intolerance.⁸ Thus, a gradual withdrawal of topical nonfluorinated steroids may not be necessary. However, it is more common than not for children to experience an initial flare of their condition upon withdrawal from topical fluorinated steroids. This is followed by a slow and steady fading.²³ 

Epidemiology

Rosacea in childhood is most likely underreported because of its clinical similarity to other erythematous facial disorders.¹ Rosacea is generally thought of as a disease of fair-skinned, young to middle-aged adults, though it has been noted to affect people of other complexions and ages.² Most full-blown cases in the pediatric population have been in light-skinned children ranging from infants to adolescents.

Etiology

The etiology of rosacea is unknown, though certain exacerbating factors undoubtedly have a role in predisposed individuals.^3,4 Emotions such as anger, anxiety, and embarrassment can lead to flushing. Environmental conditions such as wind, cold, humidity, or heat from any source (eg, sun, sauna, whirlpool, vigorous exercise) can do the same. Vasodilators such as alcohol or vasodilatory medications can lead to flushing, though these are not likely causes in children. Spicy foods such as chili, curry, and peppers, as well as hot foods and beverages including coffee, tea, and hot chocolate, may contribute to symptoms. Irritants such as alcohol-based cleansers, astringents, perfume, shaving lotion, certain soaps, sunscreen, and facecloths may aggravate rosacea.^3,4 Saprophytic mites (Demodex folliculorum and Demodex brevis) may cause an inflammatory or allergic reaction by either blocking hair follicles or acting as vectors for microorganisms that some believe may be responsible for or may trigger rosacea.⁵ Immunodeficiency, as in patients with human immunodeficiency virus, also may contribute to the development of rosacea.⁶

Genetics plays an uncertain role in the development of blushing and ultimately rosacea. If vasodilator substances or mediators are implicated in the development of rosacea as postulated, the disease may have a genetic basis because such mediators are often under the control of single genes.⁷ In one study, 20% of children with rosacea were found to have a history of rosacea in their immediate families, though this number may be an underestimate because only one parent of each patient was examined and half of the parents clinically diagnosed with rosacea reported no familial involvement.⁸ A family history of perioral dermatitis also may be important, as this condition may be related to rosacea.⁹

Pathophysiology

Chronic transient vasodilation, as occurs with blushing, is the earliest representation of rosacea. The warmth and redness associated with flushing is caused by vasodilation, allowing excess blood flow, and by engorgement of the subpapillary venous plexus.² Flushing without sweating is typically seen in children and is likely due to circulating vasodilator substances or mediators such as bradykinin, catecholamines, cytokines, endorphins, gastrin, histamine, neuropeptides, serotonin, substance P, and vascular endothelial growth factor.¹⁰ A flaw in the autonomic innervation of the cutaneous vasculature also is a likely mechanism.¹⁰

Clinical Description

The first stage of rosacea consists of blushing, in which the face becomes bright red in response to certain stimuli (Figure). Episodes of erythema are recurrent and last longer than normal physiologic flushing, which typically subsides within minutes.¹¹ Telangiectasias can become apparent over time. Children in this early stage of the condition may complain of burning or irritation.

Please refer to the PDF to view the figure

In the second, or intermediate, stage of rosacea, the rash consists of papules and pustules on a background of erythema with telangiectasias confined to the child's face. Although peripheral involvement of the back, upper chest, and scalp may be seen in adults, these areas seem to be spared in the pediatric population.¹²

The third, or late, stage of rosacea involves coarse skin, inflammatory nodules, or gross enlargement of facial features.¹¹ Such chronic changes do not occur in children as they do in adults, presumably because the disease process takes more time to evolve.¹³

Eye involvement can occur in children.¹⁴ It may include manifestations such as blepharoconjunctivitis, episcleritis, keratitis, meibomianitis, chalazia, hordeola, and hyperemic conjunctivae.^15,16 Although any of these eye conditions can potentially occur in children, meibomian gland inflammation and keratitis are the common findings noted.¹⁷ Peripheral vascularization followed by subepithelial infiltrates can lead to scarring or perforation in the lower two thirds of the cornea. The disease may be unilateral, but most commonly it affects both eyes.¹⁷

Steroid-induced rosacea also has been termed iatrosacea because of its mode of acquisition.¹⁸ Topical fluorinated and low-dose corticosteroids can cause a rosacealike dermatitis of the face consisting of persistent erythema with papules, pustules, telangiectasias, and sometimes atrophy.^19-22 Corticosteroids may be an exacerbating factor leading to classic rosacea rather than the cause of an independent disease.² The distribution of steroid rosacea to the eyelids and lateral face may help distinguish it from the centrally located typical rosacea.²³ A case of pediatric rosacea associated with the use of topical fluorinated glucocorticosteroids was identified in a 9-month-old boy and 16-year-old girl, both with erythematous patches and papules on the cheeks, paranasal areas, and chin.^18,23 Forty-six boys and 60 girls, ranging in age of onset from 6 months to 13 years (average, 7 years), were diagnosed with steroid rosacea. Nearly all of the children had perinasal and perioral involvement of erythematous skin interspersed with papules and/or pustules. The lower eyelids were affected in roughly half of the patients.⁸ 

Diagnosis

Consistent flushing in children may be a sign of vasomotor instability and early rosacea. These children may blush more frequently and with greater intensity for longer periods than their peers exposed to the same stimuli.²⁴ Thus, blushing in the early stage of rosacea may be an accentuation of the body's normal physiologic response system. A diagnosis of pediatric rosacea beyond the initial stage should be considered when a healthy child has acuminate papules and small pustules of the face, especially if there also exists flushing, telangiectasias, or a family history of rosacea.¹⁴ 

Differential Diagnosis

The earliest form of rosacea, facial blushing, may be difficult to distinguish from flushing due to other causes. Blushing due to emotions such as embarrassment or anger and to exercise-induced flushing are both appropriate reactions to such stimuli, whereas blushing in the first stage of rosacea may be an exaggeration of this phenomenon.² The main pathway for thermoregulatory and emotional flushing is the cervical sympathetic outflow tract.²⁵ Gustatory blushing, as occurs with consumption of spicy foods, is mediated by autonomic neurons via a branch of the trigeminal nerve.² Sweating often occurs in conjunction with the aforementioned causes of flushing, but it is rarely associated with rosacea flushing. Thus, sweating may be helpful in reaching a diagnosis; however, exceptions exist.² Frey syndrome (auriculotemporal syndrome), which is characterized by warmth and sweating in the malar region caused by aberrant autonomic fiber connections after damage in the parotid region, may mimic the early stage of rosacea.

The intermediate stage of pediatric rosacea may be confused with other papulopustular disorders such as acne vulgaris, perioral dermatitis, and lupus erythematosus (Table). Careful attention to symptoms, distribution of facial lesions, and potential biopsy results are warranted to distinguish between the conditions. Steroid rosacea and perioral dermatitis may be variants of rosacea or completely separate conditions.^9,26

Please refer to the PDF to view the table

Perioral dermatitis is a rosacealike dermatitis characterized by erythematous papules and pustules usually confined to the perioral region, though the perinasal and periocular areas may be involved.²⁷ A granulomatous perioral dermatitis with tiny, closely spaced, flesh-colored papules in the perioral, perinasal, and periorbital areas was described in children aged 3 to 11 years.²⁸ All cases had spontaneous resolution of symptoms regardless of treatment. The patients did not exhibit flushing or telangiectasias.²⁸

The classic butterfly rash, consisting of erythema and telangiectasia of the malar region and associated with systemic lupus erythematosus, also can be confused with rosacea. Histopathologic examination and direct immunofluorescence of the lesion may help to differentiate lupus from rosacea.¹⁴ 

Laboratory Diagnosis

There is no specific histologic change unique to rosacea.¹² The most common findings are telangiectasia, edema, elastosis, a variable amount of superficial and deep perivascular lymphohistiocytic inflammatory infiltrate loosely arranged around the hair follicles, and especially architectural disruption of the upper dermis.^12,28 Depending on the variant of rosacea, there may be an exaggeration of one or more histopathologic signs.¹² For example, granulomatous rosacea may contain collections of granulomas with multinucleated giant cells.²⁸

Treatment

Treatment is gradual and largely determined by the clinical type of rosacea. Children with early or intermediate stages of rosacea are encouraged to avoid their individual local triggers to prevent flares. Topical corticosteroids, especially fluorinated medications, should be discouraged, because even low-potency steroids, including over-the-counter preparations and hydrocortisone 1%, have been shown to cause worsening of the condition.⁸

Traditional therapy for rosacea includes topical and systemic antibiotics, topical metronidazole, and topical retinoids. Oral tetracycline can be used for adolescents in doses similar to those prescribed for adults. It should not be used in children younger than approximately 9 years¹⁷ because it is known to cause dental staining and to be deposited in the skeletal system where it can cause temporary depression in bone growth.^29,30 Azithromycin or a low dose of doxycycline can be used with good results.^31,32 For younger children, oral erythromycin is safe and effective to eliminate the erythema, papules, and pustules of rosacea.³² Topical erythromycin and clindamycin have been used with varying results. Azelaic acid and isotretinoin also may be effective.³³ Topical metronidazole 0.75% gel has proven effective in clinical trials.^34,35 A combination of systemic antibiotics and topical treatment may lead to a substantial reduction in inflammatory lesions, erythema, and the size and diameter of telangiectatic vessels.³²

Eyelid hygiene and erythromycin or bacitracin ointment, to improve meibomian gland function, are appropriate initial treatments for the ocular manifestations of childhood rosacea.^17,36 A low dose of steroid drops can manage significant irritation when needed. Systemic therapy with tetracycline or other oral pharmaceuticals used to treat the face also may work for ocular symptoms.¹⁷

The treatment of steroid rosacea is a slow process often involving antiacne agents such as benzoyl peroxide and oral or topical antibiotics.²³ Abrupt discontinuation of topical steroids followed by administration of antibiotics is a suitable treatment option. Prior recommendation has been to taper all topical steroids to prevent rebound flare; however, one study found clearing of symptoms by week 3 in 22% of patients, by week 4 in 86% of patients, and by week 8 in 100% of patients following abrupt cessation of topical steroids and a regimen of oral erythromycin stearate or topical clindamycin phosphate in children with erythromycin allergy or intolerance.⁸ Thus, a gradual withdrawal of topical nonfluorinated steroids may not be necessary. However, it is more common than not for children to experience an initial flare of their condition upon withdrawal from topical fluorinated steroids. This is followed by a slow and steady fading.²³ 

Epidemiology

Rosacea in childhood is most likely underreported because of its clinical similarity to other erythematous facial disorders.¹ Rosacea is generally thought of as a disease of fair-skinned, young to middle-aged adults, though it has been noted to affect people of other complexions and ages.² Most full-blown cases in the pediatric population have been in light-skinned children ranging from infants to adolescents.

Etiology

The etiology of rosacea is unknown, though certain exacerbating factors undoubtedly have a role in predisposed individuals.^3,4 Emotions such as anger, anxiety, and embarrassment can lead to flushing. Environmental conditions such as wind, cold, humidity, or heat from any source (eg, sun, sauna, whirlpool, vigorous exercise) can do the same. Vasodilators such as alcohol or vasodilatory medications can lead to flushing, though these are not likely causes in children. Spicy foods such as chili, curry, and peppers, as well as hot foods and beverages including coffee, tea, and hot chocolate, may contribute to symptoms. Irritants such as alcohol-based cleansers, astringents, perfume, shaving lotion, certain soaps, sunscreen, and facecloths may aggravate rosacea.^3,4 Saprophytic mites (Demodex folliculorum and Demodex brevis) may cause an inflammatory or allergic reaction by either blocking hair follicles or acting as vectors for microorganisms that some believe may be responsible for or may trigger rosacea.⁵ Immunodeficiency, as in patients with human immunodeficiency virus, also may contribute to the development of rosacea.⁶

Genetics plays an uncertain role in the development of blushing and ultimately rosacea. If vasodilator substances or mediators are implicated in the development of rosacea as postulated, the disease may have a genetic basis because such mediators are often under the control of single genes.⁷ In one study, 20% of children with rosacea were found to have a history of rosacea in their immediate families, though this number may be an underestimate because only one parent of each patient was examined and half of the parents clinically diagnosed with rosacea reported no familial involvement.⁸ A family history of perioral dermatitis also may be important, as this condition may be related to rosacea.⁹

Pathophysiology

Chronic transient vasodilation, as occurs with blushing, is the earliest representation of rosacea. The warmth and redness associated with flushing is caused by vasodilation, allowing excess blood flow, and by engorgement of the subpapillary venous plexus.² Flushing without sweating is typically seen in children and is likely due to circulating vasodilator substances or mediators such as bradykinin, catecholamines, cytokines, endorphins, gastrin, histamine, neuropeptides, serotonin, substance P, and vascular endothelial growth factor.¹⁰ A flaw in the autonomic innervation of the cutaneous vasculature also is a likely mechanism.¹⁰

Clinical Description

The first stage of rosacea consists of blushing, in which the face becomes bright red in response to certain stimuli (Figure). Episodes of erythema are recurrent and last longer than normal physiologic flushing, which typically subsides within minutes.¹¹ Telangiectasias can become apparent over time. Children in this early stage of the condition may complain of burning or irritation.

Please refer to the PDF to view the figure

In the second, or intermediate, stage of rosacea, the rash consists of papules and pustules on a background of erythema with telangiectasias confined to the child's face. Although peripheral involvement of the back, upper chest, and scalp may be seen in adults, these areas seem to be spared in the pediatric population.¹²

The third, or late, stage of rosacea involves coarse skin, inflammatory nodules, or gross enlargement of facial features.¹¹ Such chronic changes do not occur in children as they do in adults, presumably because the disease process takes more time to evolve.¹³

Eye involvement can occur in children.¹⁴ It may include manifestations such as blepharoconjunctivitis, episcleritis, keratitis, meibomianitis, chalazia, hordeola, and hyperemic conjunctivae.^15,16 Although any of these eye conditions can potentially occur in children, meibomian gland inflammation and keratitis are the common findings noted.¹⁷ Peripheral vascularization followed by subepithelial infiltrates can lead to scarring or perforation in the lower two thirds of the cornea. The disease may be unilateral, but most commonly it affects both eyes.¹⁷

Steroid-induced rosacea also has been termed iatrosacea because of its mode of acquisition.¹⁸ Topical fluorinated and low-dose corticosteroids can cause a rosacealike dermatitis of the face consisting of persistent erythema with papules, pustules, telangiectasias, and sometimes atrophy.^19-22 Corticosteroids may be an exacerbating factor leading to classic rosacea rather than the cause of an independent disease.² The distribution of steroid rosacea to the eyelids and lateral face may help distinguish it from the centrally located typical rosacea.²³ A case of pediatric rosacea associated with the use of topical fluorinated glucocorticosteroids was identified in a 9-month-old boy and 16-year-old girl, both with erythematous patches and papules on the cheeks, paranasal areas, and chin.^18,23 Forty-six boys and 60 girls, ranging in age of onset from 6 months to 13 years (average, 7 years), were diagnosed with steroid rosacea. Nearly all of the children had perinasal and perioral involvement of erythematous skin interspersed with papules and/or pustules. The lower eyelids were affected in roughly half of the patients.⁸ 

Diagnosis

Consistent flushing in children may be a sign of vasomotor instability and early rosacea. These children may blush more frequently and with greater intensity for longer periods than their peers exposed to the same stimuli.²⁴ Thus, blushing in the early stage of rosacea may be an accentuation of the body's normal physiologic response system. A diagnosis of pediatric rosacea beyond the initial stage should be considered when a healthy child has acuminate papules and small pustules of the face, especially if there also exists flushing, telangiectasias, or a family history of rosacea.¹⁴ 

Differential Diagnosis

The earliest form of rosacea, facial blushing, may be difficult to distinguish from flushing due to other causes. Blushing due to emotions such as embarrassment or anger and to exercise-induced flushing are both appropriate reactions to such stimuli, whereas blushing in the first stage of rosacea may be an exaggeration of this phenomenon.² The main pathway for thermoregulatory and emotional flushing is the cervical sympathetic outflow tract.²⁵ Gustatory blushing, as occurs with consumption of spicy foods, is mediated by autonomic neurons via a branch of the trigeminal nerve.² Sweating often occurs in conjunction with the aforementioned causes of flushing, but it is rarely associated with rosacea flushing. Thus, sweating may be helpful in reaching a diagnosis; however, exceptions exist.² Frey syndrome (auriculotemporal syndrome), which is characterized by warmth and sweating in the malar region caused by aberrant autonomic fiber connections after damage in the parotid region, may mimic the early stage of rosacea.

The intermediate stage of pediatric rosacea may be confused with other papulopustular disorders such as acne vulgaris, perioral dermatitis, and lupus erythematosus (Table). Careful attention to symptoms, distribution of facial lesions, and potential biopsy results are warranted to distinguish between the conditions. Steroid rosacea and perioral dermatitis may be variants of rosacea or completely separate conditions.^9,26

Please refer to the PDF to view the table

Perioral dermatitis is a rosacealike dermatitis characterized by erythematous papules and pustules usually confined to the perioral region, though the perinasal and periocular areas may be involved.²⁷ A granulomatous perioral dermatitis with tiny, closely spaced, flesh-colored papules in the perioral, perinasal, and periorbital areas was described in children aged 3 to 11 years.²⁸ All cases had spontaneous resolution of symptoms regardless of treatment. The patients did not exhibit flushing or telangiectasias.²⁸

The classic butterfly rash, consisting of erythema and telangiectasia of the malar region and associated with systemic lupus erythematosus, also can be confused with rosacea. Histopathologic examination and direct immunofluorescence of the lesion may help to differentiate lupus from rosacea.¹⁴ 

Laboratory Diagnosis

There is no specific histologic change unique to rosacea.¹² The most common findings are telangiectasia, edema, elastosis, a variable amount of superficial and deep perivascular lymphohistiocytic inflammatory infiltrate loosely arranged around the hair follicles, and especially architectural disruption of the upper dermis.^12,28 Depending on the variant of rosacea, there may be an exaggeration of one or more histopathologic signs.¹² For example, granulomatous rosacea may contain collections of granulomas with multinucleated giant cells.²⁸

Treatment

Treatment is gradual and largely determined by the clinical type of rosacea. Children with early or intermediate stages of rosacea are encouraged to avoid their individual local triggers to prevent flares. Topical corticosteroids, especially fluorinated medications, should be discouraged, because even low-potency steroids, including over-the-counter preparations and hydrocortisone 1%, have been shown to cause worsening of the condition.⁸

Traditional therapy for rosacea includes topical and systemic antibiotics, topical metronidazole, and topical retinoids. Oral tetracycline can be used for adolescents in doses similar to those prescribed for adults. It should not be used in children younger than approximately 9 years¹⁷ because it is known to cause dental staining and to be deposited in the skeletal system where it can cause temporary depression in bone growth.^29,30 Azithromycin or a low dose of doxycycline can be used with good results.^31,32 For younger children, oral erythromycin is safe and effective to eliminate the erythema, papules, and pustules of rosacea.³² Topical erythromycin and clindamycin have been used with varying results. Azelaic acid and isotretinoin also may be effective.³³ Topical metronidazole 0.75% gel has proven effective in clinical trials.^34,35 A combination of systemic antibiotics and topical treatment may lead to a substantial reduction in inflammatory lesions, erythema, and the size and diameter of telangiectatic vessels.³²

Eyelid hygiene and erythromycin or bacitracin ointment, to improve meibomian gland function, are appropriate initial treatments for the ocular manifestations of childhood rosacea.^17,36 A low dose of steroid drops can manage significant irritation when needed. Systemic therapy with tetracycline or other oral pharmaceuticals used to treat the face also may work for ocular symptoms.¹⁷

The treatment of steroid rosacea is a slow process often involving antiacne agents such as benzoyl peroxide and oral or topical antibiotics.²³ Abrupt discontinuation of topical steroids followed by administration of antibiotics is a suitable treatment option. Prior recommendation has been to taper all topical steroids to prevent rebound flare; however, one study found clearing of symptoms by week 3 in 22% of patients, by week 4 in 86% of patients, and by week 8 in 100% of patients following abrupt cessation of topical steroids and a regimen of oral erythromycin stearate or topical clindamycin phosphate in children with erythromycin allergy or intolerance.⁸ Thus, a gradual withdrawal of topical nonfluorinated steroids may not be necessary. However, it is more common than not for children to experience an initial flare of their condition upon withdrawal from topical fluorinated steroids. This is followed by a slow and steady fading.²³ 

Acne is predominantly a disorder of late childhood and adolescence, despite the fact that it may persist into, recur, or begin during adulthood. Although acne has been reported in otherwise healthy children as young as 8 years,¹ and even earlier in those with abnormal virilization or precocious puberty,² most cases occur between the ages of 14 and 19 years.¹ The prevalence of acne was assessed among 6768 boys and girls aged 12 to 17 years in the National Health Examination Survey of 1966 to 1970.³ Based on physical examinations, only an estimated 27.7% of children were found to have essentially normal skin, whereas 68.1% had lesions diagnosed as facial acne (minimal requirement for diagnosis was sparse comedones with no inflammatory reaction). Prevalence increased with age more rapidly among younger than older youths, from 39% at age 12 years to 86.4% at age 17 years, and the increase in prevalence with age was more rapid and consistent among boys than girls. Although facial acne was about as prevalent among girls as boys in the 12- to 17-year age range (69.8% and 66.4%, respectively), the onset occurred somewhat earlier in girls, and the severity tended to be greater in boys. More severe facial acne (defined in the survey as at least comedones, small pustules, and a tendency toward inflamed lesions deeper than the follicular orifice) was present in a much smaller proportion of youths.

More recently, estimates from the National Health Interview Survey of 1996, which included 24,371 households containing 63,402 persons, identified "chronic" acne (acne with a duration >3 months) in 2.44% of those 17 years and younger,⁴ which corresponds approximately with the prevalence of "more severe facial acne" in the earlier survey. These results suggest a relationship between the onset of puberty and the pathophysiology of acne. This article reviews recent advances in our understanding of acne in children and adolescents, with an emphasis on the triggering role of adrenarche. Part 2 of this article will review treatment options. 

Pathophysiology of Acne

A number of pathophysiologic factors contribute to the development of acne, beginning with increased prepubertal androgen production, followed in a generally sequential manner by abnormal pilosebaceous follicular keratinization and desquamation; increased proliferation of sebocytes, enlarged sebaceous glands, and augmented secretion of sebum; obstruction of sebaceous follicles; colonization of pilosebaceous units by Propionibacterium acnes; and perifollicular inflammation.^5-13 Follicular hyperkeratinization, sebocytic hyperplasia, and seborrhea are all dependent on androgens.^14-16

Role of Adrenarche

The pathogenetic process appears to commence with androgenic hormonal stimulation of pilosebaceous units, the density of which is greatest on the face and scalp (400–800 glands/cm²) and least on the extremities (50 glands/cm²).⁵ Before levels of circulating androgens increase, pilosebaceous units consist of soft, fine, unpigmented vellus hairs and small sebaceous glands.¹⁷ Circulating androgens bind to androgen receptors that are localized to the basal layer of the outer-root–sheath keratinocytes of the hair follicle and to sebaceous glands.¹⁵ In sexual hair areas, such as the axilla, pilosebaceous units begin to differentiate into large terminal hair follicles. In sebaceous areas, such as the face, pilosebaceous units become sebaceous follicles while the hair remains vellus.¹⁷ Without a source of circulating androgens, the sebaceous glands remain small.⁶

The adrenals and the gonads produce the majority of circulating androgens.¹⁵ During the prepubertal period, adrenal androgens appear to be the major determinant of sebaceous gland activity.¹⁸ In both boys and girls, plasma concentrations of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) normally begin to increase at adrenarche, or adrenal puberty, which typically occurs at about age 8 years, and continue to rise through puberty.¹⁹ Conditions such as adrenal hyperplasia or polycystic ovary disease are associated with hyperandrogenism; sudden onset of acne or treatment-resistant acne may be associated with these conditions.¹⁵

Androgen stimulation drives the changes in both follicular keratinocytes and sebocytes that lead to the formation of microcomedones,¹⁰ which are not visible but are already present in 40% of children aged 8 to 10 years.¹⁷ Microcomedones develop when desquamated cornified cells of the upper canal of the sebaceous follicle become highly adherent and obstruct the lumen in the presence of increased sebum production (retention hyperkeratosis).

The onset of adrenal production of DHEA and DHEAS is followed by a rise in plasma levels of adrenal androstenedione 1 to 2 years later, which approximately coincides with an increase in gonadal testosterone production—the so-called gonadarche or pubarche. It is at this time that microcomedones begin to enlarge and become visible, forming open and closed comedones, which are noninflammatory lesions.¹⁰ This comedogenesis may be driven in part by increased levels of interleukin 1α, which is derived from ductal keratinocytes.²⁰ Colonization of the follicular canal with P acnes, an anaerobic, aerotolerant, lipophilic diphtheroid that thrives in triglyceride-rich sebum, follows comedogenesis.²¹ Inflammatory acne appears to be the result of the host response to P acnes and the proinflammatory cytokines released by immunocompetent cells that are recruited by this bacterium and its metabolic by-products.^11,13,21,22 Depending on the intensity of the inflammatory process and its localization within the follicle, erythema, superficial pustules, papules, and/or nodules (cysts) may develop.⁷ Most patients have a variety of noninflammatory and inflammatory lesions, though some have predominantly one type or the other.⁸ It is currently believed that hypersensitivity to P acnes determines the magnitude of the immunologic response and, accordingly, the severity of inflammatory acne in individual patients.²³

It has been proposed that peptidoglycan and lipoteichoic acid from the cell wall of P acnes can amplify the immune activity of androgen-stimulated keratinocytes and sebocytes. This occurs predominantly through toll-like receptors with an increased release of cytokines such as IL-1α, IL-8, and tumor necrosis factor α from these cells.¹³ Abnormal lipids in sebum also may affect the immune activity of keratinocytes and sebocytes, thereby directly influencing their proliferation and differentiation and the release of various cytokines. These cytokines, in turn, can activate endothelial cells and immunocompetent cells, such as neutrophils and T lymphocytes, which then participate in the inflammatory process.

Pilosebaceous units are targets for circulating androgens; in addition, they can synthesize the relatively weak androgens DHEA and DHEAS de novo from cholesterol.²⁴ Pilosebaceous units also are able to convert DHEAS to androstenedione through the action of 3 β-hydroxysteroid dehydrogenase (3 β-HSD) and to convert androstenedione to the more potent androgen testosterone through the action of 17 β-HSD.²⁵ Testosterone, in turn, can be converted by the action of 5 α-reductase to dihydrotestosterone (DHT)—the most active androgen metabolite in the pilosebaceous unit²⁶—with an affinity for the androgen receptor that is 5- to 10-fold greater than that of testosterone.¹⁵ DHT is primarily responsible for androgen receptor binding and end-organ effects in the skin,²⁷ and excessive DHT formation in the skin has been implicated in the pathogenesis of acne, suggesting that activity of 5 α-reductase may be a contributory factor.¹⁷ For example, Imperato-McGinley and colleagues²⁸ showed that patients with an inherited 5 α-reductase deficiency and decreased DHT produced no sebum, just as preadrenarchal children produce no sebum. In a 5-year longitudinal study of adolescent girls, Lucky and colleagues²⁹ observed a correlation between early onset of acne, androgen levels, and more severe comedonal acne later. Girls who experienced early onset of acne had higher levels of DHEAS, testosterone, and free testosterone. The researchers speculated that DHEAS appears to be involved in the initiation of acne.²⁹

Concentrations of testosterone and DHT can be decreased by local conversion to estrogens; to weaker androgens such as 3 α-androstenediol; or to glucuronide conjugates such as 3 α-androstanediol glucuronide, which are more rapidly cleared from the circulation. Fritsch and coworkers³⁰ studied messenger RNA expression patterns of the androgen receptor and androgen-metabolizing enzymes in human skin cells and found that sebocytes are the key regulators of androgen homeostasis. These investigators observed that sebocytes were able to both synthesize testosterone from adrenal precursors and inactivate it to maintain local concentrations of androgen, whereas keratinocytes only inactivate androgen.³⁰ 

Plasma Levels of Androgens Versus Androgen Sensitivity

The severity of facial acne increases with the degree of development of secondary sex characteristics among boys aged 12 to 16 years and girls aged 12 to 15 years, suggesting a relationship with circulating sex hormones.³ Some patients with facial acne have increased levels of circulating androgens, and serum levels of DHEAS are significantly higher in prepubertal girls with both comedonal and inflammatory acne compared with those without acne.¹⁵ In most cases, however, measurable variations in circulating androgens do not differentiate those persons with either mild or severe acne from those without acne.⁷ Rather, the development of acne appears to depend primarily on end-organ sensitivity, or hyperresponsiveness, to normal levels of circulating androgens.1 For example, the activity of 5 α-reductase and 17 β-HSD in skin varies in different regions of the body¹⁵; specifically, the activity of 5 α-reductase in sebaceous glands of facial skin is greater than that in sebaceous glands of skin that is not prone to acne. The enzyme 5 α-reductase catalyzes the conversion of testosterone to the more potent DHT, thereby suggesting a relationship between increased local concentrations of this potent androgen and facial acne. In contrast, the oxidative activity of 17 β-HSD is greater in sebaceous glands of skin that is not prone to acne. The principal activity of this enzyme is to convert testosterone back to the less active androstenedione, suggesting that local concentrations of testosterone remain higher in facial skin than in skin that is not prone to acne. 

Effect of Androgen on the Epidermal Barrier and Keratinocyte Proliferation/Differentiation

The stratum corneum is a rate-limiting semipermeable barrier to the passage of water, electrolytes, and other molecules between the external environment and internal milieu.³¹ It is composed of keratinocytes and a lipid-rich intercellular matrix of sphingolipids, cholesterol, and free fatty acids.³² Lipid synthesis occurs in all nucleated layers of the epidermis, and epidermal lamellar bodies then deliver the newly synthesized lipids to the interstices of the stratum corneum, leading to water barrier formation. In addition to androgen's effects on the pilosebaceous unit, androgens modulate epidermal growth and differentiation, including important influences on the intercellular matrix of the stratum corneum, which mediates both transcutaneous water loss and absorption and percutaneous absorption of foreign substances such as pharmaceuticals.³³

Interestingly, the stratum corneum of a full-term human neonate possesses a normal barrier function, whereas the stratum corneum of a preterm neonate is thinner and has an insufficiently developed barrier function.³¹ Androgens delay the development of this cutaneous permeability barrier in utero, while estrogens accelerate barrier development. A gender difference with respect to fetal development of barrier function also has been noted³⁴; male murine fetuses have demonstrated slower barrier development compared with female littermates, an effect that was reversible with the prenatal administration of the androgen receptor antagonist flutamide. Flutamide exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgens in target tissues.

Based on these observations in fetal skin, Kao and colleagues³⁵ evaluated the effects of testosterone on barrier homeostasis in adult murine and human skin. Hypogonadal (due to castration or systemic flutamide) male mice displayed significantly faster barrier recovery at 3, 6, and 12 hours following sequential cellophane tape stripping compared with controls; topical testosterone replacement slowed barrier recovery in castrated male mice. Topical, as well as systemic, flutamide accelerated barrier recovery in controls, indicating that testosterone directly affects the skin. The investigators also found that barrier recovery was slower in young adult male mice compared with prepubertal male mice. The researchers attributed this difference to the fact that serum testosterone levels are 60% to 70% lower in prepubertal male mice than in postpubertal male mice. The investigators also demonstrated repeated changes in barrier recovery that paralleled peaks and nadirs in serum testosterone levels during intermittent hormone replacement in a hypopituitary human subject. Finally, the investigators studied the ultrastructure of the skin of subject animals. Kao et al noted no difference in sebaceous lipid synthesis but did observe that the thickness of the stratum corneum decreased in testosterone-replete animals because of decreased lamellar body formation and secretion.³⁵

The clinical implications of these findings are unclear because skin diseases that may be associated with compromised barrier homeostasis appear to be as common in women as men. However, gender may influence the severity rather than the prevalence of some dermatologic disorders, such as acne, through its impact on barrier function. For example, it has been postulated that follicular hyperkeratosis in acne may result from a linoleic acid deficiency in the follicular epithelium³⁶ and that retention of desquamated cornified cells in the follicular canal is caused by an imbalance of free sterol and cholesterol sulfate in comedonal lipids.³⁷ In addition, acute or chronic disturbances of barrier function may stimulate epidermal DNA synthesis, leading to epidermal hyperplasia, which also might contribute to follicular hyperkeratosis in acne.³²

Yamamoto and coworkers³⁸ examined the role of the sebum secretion rate and the lipid content and barrier function of the stratum corneum in 36 patients with acne and 29 controls. The sebum secretion rate over 3 hours was significantly greater in patients with moderate acne, but not mild acne, compared with controls. Sphingolipids (ceramides and free sphingosine) in the stratum corneum were significantly different among patients with moderate acne, mild acne, and controls, with the lowest concentrations in patients with moderate acne. Similarly, barrier function was reduced to the greatest extent in patients with moderate acne, with lower levels of sphingolipids corresponding to diminished barrier function. These results suggest that an impaired barrier function caused by decreased amounts of ceramides may be responsible for the formation of comedones because barrier dysfunction is accompanied by hyperkeratosis of the follicular epithelium.³⁸ 

Conclusion

Acne is a disorder of childhood and adolescence, and increasing levels of circulating androgens of adrenal and gonadal origin seem to trigger the condition. The pathophysiology of acne includes, in a somewhat sequential manner, retention hyperkeratosis, sebaceous gland hyperplasia and increased sebum production, colonization of the follicles by P acnes, and perifollicular inflammation. The goals of therapy are to reverse these pathogenetic events and thereby minimize or prevent acne lesions.

Part 2 of this article will discuss treatment options for children and adolescents based on the pathophysiology of acne.

Acne is predominantly a disorder of late childhood and adolescence, despite the fact that it may persist into, recur, or begin during adulthood. Although acne has been reported in otherwise healthy children as young as 8 years,¹ and even earlier in those with abnormal virilization or precocious puberty,² most cases occur between the ages of 14 and 19 years.¹ The prevalence of acne was assessed among 6768 boys and girls aged 12 to 17 years in the National Health Examination Survey of 1966 to 1970.³ Based on physical examinations, only an estimated 27.7% of children were found to have essentially normal skin, whereas 68.1% had lesions diagnosed as facial acne (minimal requirement for diagnosis was sparse comedones with no inflammatory reaction). Prevalence increased with age more rapidly among younger than older youths, from 39% at age 12 years to 86.4% at age 17 years, and the increase in prevalence with age was more rapid and consistent among boys than girls. Although facial acne was about as prevalent among girls as boys in the 12- to 17-year age range (69.8% and 66.4%, respectively), the onset occurred somewhat earlier in girls, and the severity tended to be greater in boys. More severe facial acne (defined in the survey as at least comedones, small pustules, and a tendency toward inflamed lesions deeper than the follicular orifice) was present in a much smaller proportion of youths.

More recently, estimates from the National Health Interview Survey of 1996, which included 24,371 households containing 63,402 persons, identified "chronic" acne (acne with a duration >3 months) in 2.44% of those 17 years and younger,⁴ which corresponds approximately with the prevalence of "more severe facial acne" in the earlier survey. These results suggest a relationship between the onset of puberty and the pathophysiology of acne. This article reviews recent advances in our understanding of acne in children and adolescents, with an emphasis on the triggering role of adrenarche. Part 2 of this article will review treatment options. 

Pathophysiology of Acne

A number of pathophysiologic factors contribute to the development of acne, beginning with increased prepubertal androgen production, followed in a generally sequential manner by abnormal pilosebaceous follicular keratinization and desquamation; increased proliferation of sebocytes, enlarged sebaceous glands, and augmented secretion of sebum; obstruction of sebaceous follicles; colonization of pilosebaceous units by Propionibacterium acnes; and perifollicular inflammation.^5-13 Follicular hyperkeratinization, sebocytic hyperplasia, and seborrhea are all dependent on androgens.^14-16

Role of Adrenarche

The pathogenetic process appears to commence with androgenic hormonal stimulation of pilosebaceous units, the density of which is greatest on the face and scalp (400–800 glands/cm²) and least on the extremities (50 glands/cm²).⁵ Before levels of circulating androgens increase, pilosebaceous units consist of soft, fine, unpigmented vellus hairs and small sebaceous glands.¹⁷ Circulating androgens bind to androgen receptors that are localized to the basal layer of the outer-root–sheath keratinocytes of the hair follicle and to sebaceous glands.¹⁵ In sexual hair areas, such as the axilla, pilosebaceous units begin to differentiate into large terminal hair follicles. In sebaceous areas, such as the face, pilosebaceous units become sebaceous follicles while the hair remains vellus.¹⁷ Without a source of circulating androgens, the sebaceous glands remain small.⁶

The adrenals and the gonads produce the majority of circulating androgens.¹⁵ During the prepubertal period, adrenal androgens appear to be the major determinant of sebaceous gland activity.¹⁸ In both boys and girls, plasma concentrations of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) normally begin to increase at adrenarche, or adrenal puberty, which typically occurs at about age 8 years, and continue to rise through puberty.¹⁹ Conditions such as adrenal hyperplasia or polycystic ovary disease are associated with hyperandrogenism; sudden onset of acne or treatment-resistant acne may be associated with these conditions.¹⁵

Androgen stimulation drives the changes in both follicular keratinocytes and sebocytes that lead to the formation of microcomedones,¹⁰ which are not visible but are already present in 40% of children aged 8 to 10 years.¹⁷ Microcomedones develop when desquamated cornified cells of the upper canal of the sebaceous follicle become highly adherent and obstruct the lumen in the presence of increased sebum production (retention hyperkeratosis).

The onset of adrenal production of DHEA and DHEAS is followed by a rise in plasma levels of adrenal androstenedione 1 to 2 years later, which approximately coincides with an increase in gonadal testosterone production—the so-called gonadarche or pubarche. It is at this time that microcomedones begin to enlarge and become visible, forming open and closed comedones, which are noninflammatory lesions.¹⁰ This comedogenesis may be driven in part by increased levels of interleukin 1α, which is derived from ductal keratinocytes.²⁰ Colonization of the follicular canal with P acnes, an anaerobic, aerotolerant, lipophilic diphtheroid that thrives in triglyceride-rich sebum, follows comedogenesis.²¹ Inflammatory acne appears to be the result of the host response to P acnes and the proinflammatory cytokines released by immunocompetent cells that are recruited by this bacterium and its metabolic by-products.^11,13,21,22 Depending on the intensity of the inflammatory process and its localization within the follicle, erythema, superficial pustules, papules, and/or nodules (cysts) may develop.⁷ Most patients have a variety of noninflammatory and inflammatory lesions, though some have predominantly one type or the other.⁸ It is currently believed that hypersensitivity to P acnes determines the magnitude of the immunologic response and, accordingly, the severity of inflammatory acne in individual patients.²³

It has been proposed that peptidoglycan and lipoteichoic acid from the cell wall of P acnes can amplify the immune activity of androgen-stimulated keratinocytes and sebocytes. This occurs predominantly through toll-like receptors with an increased release of cytokines such as IL-1α, IL-8, and tumor necrosis factor α from these cells.¹³ Abnormal lipids in sebum also may affect the immune activity of keratinocytes and sebocytes, thereby directly influencing their proliferation and differentiation and the release of various cytokines. These cytokines, in turn, can activate endothelial cells and immunocompetent cells, such as neutrophils and T lymphocytes, which then participate in the inflammatory process.

Pilosebaceous units are targets for circulating androgens; in addition, they can synthesize the relatively weak androgens DHEA and DHEAS de novo from cholesterol.²⁴ Pilosebaceous units also are able to convert DHEAS to androstenedione through the action of 3 β-hydroxysteroid dehydrogenase (3 β-HSD) and to convert androstenedione to the more potent androgen testosterone through the action of 17 β-HSD.²⁵ Testosterone, in turn, can be converted by the action of 5 α-reductase to dihydrotestosterone (DHT)—the most active androgen metabolite in the pilosebaceous unit²⁶—with an affinity for the androgen receptor that is 5- to 10-fold greater than that of testosterone.¹⁵ DHT is primarily responsible for androgen receptor binding and end-organ effects in the skin,²⁷ and excessive DHT formation in the skin has been implicated in the pathogenesis of acne, suggesting that activity of 5 α-reductase may be a contributory factor.¹⁷ For example, Imperato-McGinley and colleagues²⁸ showed that patients with an inherited 5 α-reductase deficiency and decreased DHT produced no sebum, just as preadrenarchal children produce no sebum. In a 5-year longitudinal study of adolescent girls, Lucky and colleagues²⁹ observed a correlation between early onset of acne, androgen levels, and more severe comedonal acne later. Girls who experienced early onset of acne had higher levels of DHEAS, testosterone, and free testosterone. The researchers speculated that DHEAS appears to be involved in the initiation of acne.²⁹

Concentrations of testosterone and DHT can be decreased by local conversion to estrogens; to weaker androgens such as 3 α-androstenediol; or to glucuronide conjugates such as 3 α-androstanediol glucuronide, which are more rapidly cleared from the circulation. Fritsch and coworkers³⁰ studied messenger RNA expression patterns of the androgen receptor and androgen-metabolizing enzymes in human skin cells and found that sebocytes are the key regulators of androgen homeostasis. These investigators observed that sebocytes were able to both synthesize testosterone from adrenal precursors and inactivate it to maintain local concentrations of androgen, whereas keratinocytes only inactivate androgen.³⁰ 

Plasma Levels of Androgens Versus Androgen Sensitivity

The severity of facial acne increases with the degree of development of secondary sex characteristics among boys aged 12 to 16 years and girls aged 12 to 15 years, suggesting a relationship with circulating sex hormones.³ Some patients with facial acne have increased levels of circulating androgens, and serum levels of DHEAS are significantly higher in prepubertal girls with both comedonal and inflammatory acne compared with those without acne.¹⁵ In most cases, however, measurable variations in circulating androgens do not differentiate those persons with either mild or severe acne from those without acne.⁷ Rather, the development of acne appears to depend primarily on end-organ sensitivity, or hyperresponsiveness, to normal levels of circulating androgens.1 For example, the activity of 5 α-reductase and 17 β-HSD in skin varies in different regions of the body¹⁵; specifically, the activity of 5 α-reductase in sebaceous glands of facial skin is greater than that in sebaceous glands of skin that is not prone to acne. The enzyme 5 α-reductase catalyzes the conversion of testosterone to the more potent DHT, thereby suggesting a relationship between increased local concentrations of this potent androgen and facial acne. In contrast, the oxidative activity of 17 β-HSD is greater in sebaceous glands of skin that is not prone to acne. The principal activity of this enzyme is to convert testosterone back to the less active androstenedione, suggesting that local concentrations of testosterone remain higher in facial skin than in skin that is not prone to acne. 

Effect of Androgen on the Epidermal Barrier and Keratinocyte Proliferation/Differentiation

The stratum corneum is a rate-limiting semipermeable barrier to the passage of water, electrolytes, and other molecules between the external environment and internal milieu.³¹ It is composed of keratinocytes and a lipid-rich intercellular matrix of sphingolipids, cholesterol, and free fatty acids.³² Lipid synthesis occurs in all nucleated layers of the epidermis, and epidermal lamellar bodies then deliver the newly synthesized lipids to the interstices of the stratum corneum, leading to water barrier formation. In addition to androgen's effects on the pilosebaceous unit, androgens modulate epidermal growth and differentiation, including important influences on the intercellular matrix of the stratum corneum, which mediates both transcutaneous water loss and absorption and percutaneous absorption of foreign substances such as pharmaceuticals.³³

Interestingly, the stratum corneum of a full-term human neonate possesses a normal barrier function, whereas the stratum corneum of a preterm neonate is thinner and has an insufficiently developed barrier function.³¹ Androgens delay the development of this cutaneous permeability barrier in utero, while estrogens accelerate barrier development. A gender difference with respect to fetal development of barrier function also has been noted³⁴; male murine fetuses have demonstrated slower barrier development compared with female littermates, an effect that was reversible with the prenatal administration of the androgen receptor antagonist flutamide. Flutamide exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgens in target tissues.

Based on these observations in fetal skin, Kao and colleagues³⁵ evaluated the effects of testosterone on barrier homeostasis in adult murine and human skin. Hypogonadal (due to castration or systemic flutamide) male mice displayed significantly faster barrier recovery at 3, 6, and 12 hours following sequential cellophane tape stripping compared with controls; topical testosterone replacement slowed barrier recovery in castrated male mice. Topical, as well as systemic, flutamide accelerated barrier recovery in controls, indicating that testosterone directly affects the skin. The investigators also found that barrier recovery was slower in young adult male mice compared with prepubertal male mice. The researchers attributed this difference to the fact that serum testosterone levels are 60% to 70% lower in prepubertal male mice than in postpubertal male mice. The investigators also demonstrated repeated changes in barrier recovery that paralleled peaks and nadirs in serum testosterone levels during intermittent hormone replacement in a hypopituitary human subject. Finally, the investigators studied the ultrastructure of the skin of subject animals. Kao et al noted no difference in sebaceous lipid synthesis but did observe that the thickness of the stratum corneum decreased in testosterone-replete animals because of decreased lamellar body formation and secretion.³⁵

The clinical implications of these findings are unclear because skin diseases that may be associated with compromised barrier homeostasis appear to be as common in women as men. However, gender may influence the severity rather than the prevalence of some dermatologic disorders, such as acne, through its impact on barrier function. For example, it has been postulated that follicular hyperkeratosis in acne may result from a linoleic acid deficiency in the follicular epithelium³⁶ and that retention of desquamated cornified cells in the follicular canal is caused by an imbalance of free sterol and cholesterol sulfate in comedonal lipids.³⁷ In addition, acute or chronic disturbances of barrier function may stimulate epidermal DNA synthesis, leading to epidermal hyperplasia, which also might contribute to follicular hyperkeratosis in acne.³²

Yamamoto and coworkers³⁸ examined the role of the sebum secretion rate and the lipid content and barrier function of the stratum corneum in 36 patients with acne and 29 controls. The sebum secretion rate over 3 hours was significantly greater in patients with moderate acne, but not mild acne, compared with controls. Sphingolipids (ceramides and free sphingosine) in the stratum corneum were significantly different among patients with moderate acne, mild acne, and controls, with the lowest concentrations in patients with moderate acne. Similarly, barrier function was reduced to the greatest extent in patients with moderate acne, with lower levels of sphingolipids corresponding to diminished barrier function. These results suggest that an impaired barrier function caused by decreased amounts of ceramides may be responsible for the formation of comedones because barrier dysfunction is accompanied by hyperkeratosis of the follicular epithelium.³⁸ 

Conclusion

Acne is a disorder of childhood and adolescence, and increasing levels of circulating androgens of adrenal and gonadal origin seem to trigger the condition. The pathophysiology of acne includes, in a somewhat sequential manner, retention hyperkeratosis, sebaceous gland hyperplasia and increased sebum production, colonization of the follicles by P acnes, and perifollicular inflammation. The goals of therapy are to reverse these pathogenetic events and thereby minimize or prevent acne lesions.

Part 2 of this article will discuss treatment options for children and adolescents based on the pathophysiology of acne.

Acne is predominantly a disorder of late childhood and adolescence, despite the fact that it may persist into, recur, or begin during adulthood. Although acne has been reported in otherwise healthy children as young as 8 years,¹ and even earlier in those with abnormal virilization or precocious puberty,² most cases occur between the ages of 14 and 19 years.¹ The prevalence of acne was assessed among 6768 boys and girls aged 12 to 17 years in the National Health Examination Survey of 1966 to 1970.³ Based on physical examinations, only an estimated 27.7% of children were found to have essentially normal skin, whereas 68.1% had lesions diagnosed as facial acne (minimal requirement for diagnosis was sparse comedones with no inflammatory reaction). Prevalence increased with age more rapidly among younger than older youths, from 39% at age 12 years to 86.4% at age 17 years, and the increase in prevalence with age was more rapid and consistent among boys than girls. Although facial acne was about as prevalent among girls as boys in the 12- to 17-year age range (69.8% and 66.4%, respectively), the onset occurred somewhat earlier in girls, and the severity tended to be greater in boys. More severe facial acne (defined in the survey as at least comedones, small pustules, and a tendency toward inflamed lesions deeper than the follicular orifice) was present in a much smaller proportion of youths.

More recently, estimates from the National Health Interview Survey of 1996, which included 24,371 households containing 63,402 persons, identified "chronic" acne (acne with a duration >3 months) in 2.44% of those 17 years and younger,⁴ which corresponds approximately with the prevalence of "more severe facial acne" in the earlier survey. These results suggest a relationship between the onset of puberty and the pathophysiology of acne. This article reviews recent advances in our understanding of acne in children and adolescents, with an emphasis on the triggering role of adrenarche. Part 2 of this article will review treatment options. 

Pathophysiology of Acne

A number of pathophysiologic factors contribute to the development of acne, beginning with increased prepubertal androgen production, followed in a generally sequential manner by abnormal pilosebaceous follicular keratinization and desquamation; increased proliferation of sebocytes, enlarged sebaceous glands, and augmented secretion of sebum; obstruction of sebaceous follicles; colonization of pilosebaceous units by Propionibacterium acnes; and perifollicular inflammation.^5-13 Follicular hyperkeratinization, sebocytic hyperplasia, and seborrhea are all dependent on androgens.^14-16

Role of Adrenarche

The pathogenetic process appears to commence with androgenic hormonal stimulation of pilosebaceous units, the density of which is greatest on the face and scalp (400–800 glands/cm²) and least on the extremities (50 glands/cm²).⁵ Before levels of circulating androgens increase, pilosebaceous units consist of soft, fine, unpigmented vellus hairs and small sebaceous glands.¹⁷ Circulating androgens bind to androgen receptors that are localized to the basal layer of the outer-root–sheath keratinocytes of the hair follicle and to sebaceous glands.¹⁵ In sexual hair areas, such as the axilla, pilosebaceous units begin to differentiate into large terminal hair follicles. In sebaceous areas, such as the face, pilosebaceous units become sebaceous follicles while the hair remains vellus.¹⁷ Without a source of circulating androgens, the sebaceous glands remain small.⁶

The adrenals and the gonads produce the majority of circulating androgens.¹⁵ During the prepubertal period, adrenal androgens appear to be the major determinant of sebaceous gland activity.¹⁸ In both boys and girls, plasma concentrations of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) normally begin to increase at adrenarche, or adrenal puberty, which typically occurs at about age 8 years, and continue to rise through puberty.¹⁹ Conditions such as adrenal hyperplasia or polycystic ovary disease are associated with hyperandrogenism; sudden onset of acne or treatment-resistant acne may be associated with these conditions.¹⁵

Androgen stimulation drives the changes in both follicular keratinocytes and sebocytes that lead to the formation of microcomedones,¹⁰ which are not visible but are already present in 40% of children aged 8 to 10 years.¹⁷ Microcomedones develop when desquamated cornified cells of the upper canal of the sebaceous follicle become highly adherent and obstruct the lumen in the presence of increased sebum production (retention hyperkeratosis).

The onset of adrenal production of DHEA and DHEAS is followed by a rise in plasma levels of adrenal androstenedione 1 to 2 years later, which approximately coincides with an increase in gonadal testosterone production—the so-called gonadarche or pubarche. It is at this time that microcomedones begin to enlarge and become visible, forming open and closed comedones, which are noninflammatory lesions.¹⁰ This comedogenesis may be driven in part by increased levels of interleukin 1α, which is derived from ductal keratinocytes.²⁰ Colonization of the follicular canal with P acnes, an anaerobic, aerotolerant, lipophilic diphtheroid that thrives in triglyceride-rich sebum, follows comedogenesis.²¹ Inflammatory acne appears to be the result of the host response to P acnes and the proinflammatory cytokines released by immunocompetent cells that are recruited by this bacterium and its metabolic by-products.^11,13,21,22 Depending on the intensity of the inflammatory process and its localization within the follicle, erythema, superficial pustules, papules, and/or nodules (cysts) may develop.⁷ Most patients have a variety of noninflammatory and inflammatory lesions, though some have predominantly one type or the other.⁸ It is currently believed that hypersensitivity to P acnes determines the magnitude of the immunologic response and, accordingly, the severity of inflammatory acne in individual patients.²³

It has been proposed that peptidoglycan and lipoteichoic acid from the cell wall of P acnes can amplify the immune activity of androgen-stimulated keratinocytes and sebocytes. This occurs predominantly through toll-like receptors with an increased release of cytokines such as IL-1α, IL-8, and tumor necrosis factor α from these cells.¹³ Abnormal lipids in sebum also may affect the immune activity of keratinocytes and sebocytes, thereby directly influencing their proliferation and differentiation and the release of various cytokines. These cytokines, in turn, can activate endothelial cells and immunocompetent cells, such as neutrophils and T lymphocytes, which then participate in the inflammatory process.

Pilosebaceous units are targets for circulating androgens; in addition, they can synthesize the relatively weak androgens DHEA and DHEAS de novo from cholesterol.²⁴ Pilosebaceous units also are able to convert DHEAS to androstenedione through the action of 3 β-hydroxysteroid dehydrogenase (3 β-HSD) and to convert androstenedione to the more potent androgen testosterone through the action of 17 β-HSD.²⁵ Testosterone, in turn, can be converted by the action of 5 α-reductase to dihydrotestosterone (DHT)—the most active androgen metabolite in the pilosebaceous unit²⁶—with an affinity for the androgen receptor that is 5- to 10-fold greater than that of testosterone.¹⁵ DHT is primarily responsible for androgen receptor binding and end-organ effects in the skin,²⁷ and excessive DHT formation in the skin has been implicated in the pathogenesis of acne, suggesting that activity of 5 α-reductase may be a contributory factor.¹⁷ For example, Imperato-McGinley and colleagues²⁸ showed that patients with an inherited 5 α-reductase deficiency and decreased DHT produced no sebum, just as preadrenarchal children produce no sebum. In a 5-year longitudinal study of adolescent girls, Lucky and colleagues²⁹ observed a correlation between early onset of acne, androgen levels, and more severe comedonal acne later. Girls who experienced early onset of acne had higher levels of DHEAS, testosterone, and free testosterone. The researchers speculated that DHEAS appears to be involved in the initiation of acne.²⁹

Concentrations of testosterone and DHT can be decreased by local conversion to estrogens; to weaker androgens such as 3 α-androstenediol; or to glucuronide conjugates such as 3 α-androstanediol glucuronide, which are more rapidly cleared from the circulation. Fritsch and coworkers³⁰ studied messenger RNA expression patterns of the androgen receptor and androgen-metabolizing enzymes in human skin cells and found that sebocytes are the key regulators of androgen homeostasis. These investigators observed that sebocytes were able to both synthesize testosterone from adrenal precursors and inactivate it to maintain local concentrations of androgen, whereas keratinocytes only inactivate androgen.³⁰ 

Plasma Levels of Androgens Versus Androgen Sensitivity

The severity of facial acne increases with the degree of development of secondary sex characteristics among boys aged 12 to 16 years and girls aged 12 to 15 years, suggesting a relationship with circulating sex hormones.³ Some patients with facial acne have increased levels of circulating androgens, and serum levels of DHEAS are significantly higher in prepubertal girls with both comedonal and inflammatory acne compared with those without acne.¹⁵ In most cases, however, measurable variations in circulating androgens do not differentiate those persons with either mild or severe acne from those without acne.⁷ Rather, the development of acne appears to depend primarily on end-organ sensitivity, or hyperresponsiveness, to normal levels of circulating androgens.1 For example, the activity of 5 α-reductase and 17 β-HSD in skin varies in different regions of the body¹⁵; specifically, the activity of 5 α-reductase in sebaceous glands of facial skin is greater than that in sebaceous glands of skin that is not prone to acne. The enzyme 5 α-reductase catalyzes the conversion of testosterone to the more potent DHT, thereby suggesting a relationship between increased local concentrations of this potent androgen and facial acne. In contrast, the oxidative activity of 17 β-HSD is greater in sebaceous glands of skin that is not prone to acne. The principal activity of this enzyme is to convert testosterone back to the less active androstenedione, suggesting that local concentrations of testosterone remain higher in facial skin than in skin that is not prone to acne. 

Effect of Androgen on the Epidermal Barrier and Keratinocyte Proliferation/Differentiation

The stratum corneum is a rate-limiting semipermeable barrier to the passage of water, electrolytes, and other molecules between the external environment and internal milieu.³¹ It is composed of keratinocytes and a lipid-rich intercellular matrix of sphingolipids, cholesterol, and free fatty acids.³² Lipid synthesis occurs in all nucleated layers of the epidermis, and epidermal lamellar bodies then deliver the newly synthesized lipids to the interstices of the stratum corneum, leading to water barrier formation. In addition to androgen's effects on the pilosebaceous unit, androgens modulate epidermal growth and differentiation, including important influences on the intercellular matrix of the stratum corneum, which mediates both transcutaneous water loss and absorption and percutaneous absorption of foreign substances such as pharmaceuticals.³³

Interestingly, the stratum corneum of a full-term human neonate possesses a normal barrier function, whereas the stratum corneum of a preterm neonate is thinner and has an insufficiently developed barrier function.³¹ Androgens delay the development of this cutaneous permeability barrier in utero, while estrogens accelerate barrier development. A gender difference with respect to fetal development of barrier function also has been noted³⁴; male murine fetuses have demonstrated slower barrier development compared with female littermates, an effect that was reversible with the prenatal administration of the androgen receptor antagonist flutamide. Flutamide exerts its antiandrogenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgens in target tissues.

Based on these observations in fetal skin, Kao and colleagues³⁵ evaluated the effects of testosterone on barrier homeostasis in adult murine and human skin. Hypogonadal (due to castration or systemic flutamide) male mice displayed significantly faster barrier recovery at 3, 6, and 12 hours following sequential cellophane tape stripping compared with controls; topical testosterone replacement slowed barrier recovery in castrated male mice. Topical, as well as systemic, flutamide accelerated barrier recovery in controls, indicating that testosterone directly affects the skin. The investigators also found that barrier recovery was slower in young adult male mice compared with prepubertal male mice. The researchers attributed this difference to the fact that serum testosterone levels are 60% to 70% lower in prepubertal male mice than in postpubertal male mice. The investigators also demonstrated repeated changes in barrier recovery that paralleled peaks and nadirs in serum testosterone levels during intermittent hormone replacement in a hypopituitary human subject. Finally, the investigators studied the ultrastructure of the skin of subject animals. Kao et al noted no difference in sebaceous lipid synthesis but did observe that the thickness of the stratum corneum decreased in testosterone-replete animals because of decreased lamellar body formation and secretion.³⁵

The clinical implications of these findings are unclear because skin diseases that may be associated with compromised barrier homeostasis appear to be as common in women as men. However, gender may influence the severity rather than the prevalence of some dermatologic disorders, such as acne, through its impact on barrier function. For example, it has been postulated that follicular hyperkeratosis in acne may result from a linoleic acid deficiency in the follicular epithelium³⁶ and that retention of desquamated cornified cells in the follicular canal is caused by an imbalance of free sterol and cholesterol sulfate in comedonal lipids.³⁷ In addition, acute or chronic disturbances of barrier function may stimulate epidermal DNA synthesis, leading to epidermal hyperplasia, which also might contribute to follicular hyperkeratosis in acne.³²

Yamamoto and coworkers³⁸ examined the role of the sebum secretion rate and the lipid content and barrier function of the stratum corneum in 36 patients with acne and 29 controls. The sebum secretion rate over 3 hours was significantly greater in patients with moderate acne, but not mild acne, compared with controls. Sphingolipids (ceramides and free sphingosine) in the stratum corneum were significantly different among patients with moderate acne, mild acne, and controls, with the lowest concentrations in patients with moderate acne. Similarly, barrier function was reduced to the greatest extent in patients with moderate acne, with lower levels of sphingolipids corresponding to diminished barrier function. These results suggest that an impaired barrier function caused by decreased amounts of ceramides may be responsible for the formation of comedones because barrier dysfunction is accompanied by hyperkeratosis of the follicular epithelium.³⁸ 

Conclusion

Acne is a disorder of childhood and adolescence, and increasing levels of circulating androgens of adrenal and gonadal origin seem to trigger the condition. The pathophysiology of acne includes, in a somewhat sequential manner, retention hyperkeratosis, sebaceous gland hyperplasia and increased sebum production, colonization of the follicles by P acnes, and perifollicular inflammation. The goals of therapy are to reverse these pathogenetic events and thereby minimize or prevent acne lesions.

Part 2 of this article will discuss treatment options for children and adolescents based on the pathophysiology of acne.