Dermatopathology

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 

Trachyonychia (“rough nails”) is best considered a reaction or morphologic pattern with a variety of clinical presentations and etiologies. It may involve only 1 or as many as 20 nails (20-nail dystrophy). It can be a manifestation of lichen planus, psoriasis, alopecia areata, immunoglobulin A deficiency, atopic dermatitis, and ichthyosis vulgaris. Nail matrix biopsy results and physical examination findings help in establishing the cause of this condition, though often trachyonychia is an isolated finding. When trachyonychia occurs in childhood as a manifestation of lichen planus, it tends to resolve with time. We review a case of trachyonychia, its association, its diagnostic evaluation, and treatment options.

Trachyonychia means "rough nails." This condition may involve only 1 or as many as 20 nails. It is best considered a reaction or morphologic pattern with a variety of clinical presentations and etiologies. Clinical presentations are rough nails with a sandpapered appearance and numerous small superficial pits that make the nails shiny1; onychorrhexis, onychoschizia, distal chipping, and yellow onychauxis of the great toenail; and closely arranged longitudinal ridges, distal notching, and layered splitting.2,3 Nail matrix biopsy results combined with clinical findings have linked trachyonychia with lichen planus generally,4 lichen planus in children,5 psoriasis,6 alopecia areata,7 IgA deficiency,8 atopic dermatitis,9 and ichthyosis vulgaris.10 The term 20-nail dystrophy of childhood11 refers to a trachyonychia variant likely caused by lichen planus. Some who consider the term a misnomer—in part because not all nails are necessarily involved—think that perhaps it should be abandoned.12 back to top

Case Report A 10-year-old girl presented with a 1-year history of worsening nail dystrophy. The patient had no history of psoriasis, atopic dermatitis, alopecia, or other skin disease, and family history was unremarkable. Except for dystrophy and hyperkeratosis identified on nails of both hands and both feet (Figure), physical examination findings were normal. Results of a fungal nail culture were negative, and the nail matrix biopsy specimen showed a bandlike lymphocytic infiltrate in the superficial dermis, with vacuolar alteration of the basal level. The diagnosis was trachyonychia secondary to lichen planus. Daily use of flurandrenolone tape and monthly intralesional injections of triamcinolone 2.5 mg/mL did not improve this patient's condition. After 4 months of injections in the distal nail folds, she was lost to follow-up.

back to top

Comment Often, the onset of trachyonychia is insidious. The condition usually develops on all nails simultaneously. Trachyonychia also can occur on individual nails over many months. Peak age of onset is 3 to 12 years. Trachyonychia occurs, however, in multigenerational families,13 in all age groups, in twins in the United States14 and Europe,15 in both sexes, and in all ethnic groups. This condition has been associated with ichthyosis vulgaris combined with alopecia universalis,16 ungual lichen planus and alopecia areata,17 koilonychia,18 primary biliary cirrhosis,19 and vitiligo.20 In chronic graft versus host (GVH) disease, trachyonychia can be an isolated finding21 or part of a constellation of cutaneous symptoms.22 It may be associated with dystrophy, atrophy, and, often, ulceration of the lunula.23 In the proper setting, the nail findings and clinical presentation of chronic GVH disease can resemble those of dyskeratosis congentia.24 A mother and her 7-year-old daughter with chronic GVH disease had balanced translocation 46, XX, t(6q13;10p13).25 A 15-year-old white boy with chronic GVH disease had recurrent episodes of immune thrombocytopenic purpura, autoimmune hemolytic anemia, and mild depression of immunoglobulin levels.26

Nail matrix biopsy results and physical examination findings help in establishing the cause of trachyonychia, though this condition often is an isolated finding.27 In the case of lichen planus,28 some patients also have flat polished purple papules on the body and white lacy or reticulated plaques in the mouth.29 Nail biopsy specimens can show hyperkeratosis, hypergranulosis, and acanthosis in the ventral portion of the proximal nail fold and in the nail matrix; a bandlike lymphocytic infiltrate in the superficial dermis; and vacuolar alterations in the basal layer. Nail abnormalities can develop in 1% to 10% of patients with lichen planus.30 In the case of psoriasis, psoriasiform plaques sometimes develop on other body areas, and nail biopsy specimens can show psoriasis evidence such as psoriasiform hyperplasia and neutrophils. In the case of atopic dermatitis, spongiosis31 (intercellular edema of the epidermis) also can occur in nail matrix biopsy specimens.32 In the case of alopecia areata, lymphocytes can be present in the nail matrix, patches of nonscarring alopecia can develop on the scalp, and nail pits can develop in a gridlike pattern (giving a pounded brass appearance) on the nail plates. Evaluation of trachyonychia should include a check for fungus—a fungal culture or periodic acid–Schiff staining of a nail clipping. Some authors have suggested that longitudinal nail biopsy may be a useful diagnostic tool in certain cases of acquired nail dystrophy.33

Hazelrigg et al11 stated that trachyonychia is self-limited and self-resolving in children. Specifically, trachyonychia tends to resolve with time when it occurs in childhood as a manifestation of lichen planus. Rarely, there is nail destruction in 20-nail dystrophy. If destruction occurs, the diagnosis is lichen planus—a form not restricted to the proximal nail fold but extended to the matrix. If the matrix is involved in lichen planus, a pterygium can develop—a manifestation rarely seen in 20-nail dystrophy.

Treatments for trachyonychia include intralesional injections of triamcinolone 2.5 to 3 mg/mL into the proximal nail folds.2,34 Injections are painful and thus difficult in children. Medications for systemic treatment include prednisolone,35 antimalarials,36 and etretinate.37 Seven-month therapy with topical psoralen and UVA light is reported effective.38 In treating psoriatic nail disease, topical 5-fluorouracil39 and cyclosporine40 are useful. Clear nail hardeners can be applied to nails to improve their appearance.

In a study of 15 children, intramuscularly injected triamcinolone acetonide 0.5 to 1 mg/kg per month was prescribed for children with typical nail lichen planus.41 Therapy duration was increased from 3 to 6 months, until the proximal half of the nail was normal. No treatment was prescribed for patients with 20-nail dystrophy or idiopathic atrophy of the nails. Treatment with systemic corticosteroids was effective in curing typical nail lichen planus. For 2 children, the disease recurred during follow-up. Recurrences were always responsive to therapy. Two children with 20-nail dystrophy improved without any therapy. Nail lesions caused by idiopathic atrophy of the nails remained unchanged during follow-up.

Trachyonychia and 20-nail dystrophy continue to present difficulties in classification, diagnosis, and treatment. With the advent of new immunomodulators, it is hoped that more effective treatments will be developed. Prompt diagnosis of these conditions aids in patient education and therapy. back to top

Trachyonychia (“rough nails”) is best considered a reaction or morphologic pattern with a variety of clinical presentations and etiologies. It may involve only 1 or as many as 20 nails (20-nail dystrophy). It can be a manifestation of lichen planus, psoriasis, alopecia areata, immunoglobulin A deficiency, atopic dermatitis, and ichthyosis vulgaris. Nail matrix biopsy results and physical examination findings help in establishing the cause of this condition, though often trachyonychia is an isolated finding. When trachyonychia occurs in childhood as a manifestation of lichen planus, it tends to resolve with time. We review a case of trachyonychia, its association, its diagnostic evaluation, and treatment options.

Trachyonychia means "rough nails." This condition may involve only 1 or as many as 20 nails. It is best considered a reaction or morphologic pattern with a variety of clinical presentations and etiologies. Clinical presentations are rough nails with a sandpapered appearance and numerous small superficial pits that make the nails shiny1; onychorrhexis, onychoschizia, distal chipping, and yellow onychauxis of the great toenail; and closely arranged longitudinal ridges, distal notching, and layered splitting.2,3 Nail matrix biopsy results combined with clinical findings have linked trachyonychia with lichen planus generally,4 lichen planus in children,5 psoriasis,6 alopecia areata,7 IgA deficiency,8 atopic dermatitis,9 and ichthyosis vulgaris.10 The term 20-nail dystrophy of childhood11 refers to a trachyonychia variant likely caused by lichen planus. Some who consider the term a misnomer—in part because not all nails are necessarily involved—think that perhaps it should be abandoned.12 back to top

Case Report A 10-year-old girl presented with a 1-year history of worsening nail dystrophy. The patient had no history of psoriasis, atopic dermatitis, alopecia, or other skin disease, and family history was unremarkable. Except for dystrophy and hyperkeratosis identified on nails of both hands and both feet (Figure), physical examination findings were normal. Results of a fungal nail culture were negative, and the nail matrix biopsy specimen showed a bandlike lymphocytic infiltrate in the superficial dermis, with vacuolar alteration of the basal level. The diagnosis was trachyonychia secondary to lichen planus. Daily use of flurandrenolone tape and monthly intralesional injections of triamcinolone 2.5 mg/mL did not improve this patient's condition. After 4 months of injections in the distal nail folds, she was lost to follow-up.

back to top

Comment Often, the onset of trachyonychia is insidious. The condition usually develops on all nails simultaneously. Trachyonychia also can occur on individual nails over many months. Peak age of onset is 3 to 12 years. Trachyonychia occurs, however, in multigenerational families,13 in all age groups, in twins in the United States14 and Europe,15 in both sexes, and in all ethnic groups. This condition has been associated with ichthyosis vulgaris combined with alopecia universalis,16 ungual lichen planus and alopecia areata,17 koilonychia,18 primary biliary cirrhosis,19 and vitiligo.20 In chronic graft versus host (GVH) disease, trachyonychia can be an isolated finding21 or part of a constellation of cutaneous symptoms.22 It may be associated with dystrophy, atrophy, and, often, ulceration of the lunula.23 In the proper setting, the nail findings and clinical presentation of chronic GVH disease can resemble those of dyskeratosis congentia.24 A mother and her 7-year-old daughter with chronic GVH disease had balanced translocation 46, XX, t(6q13;10p13).25 A 15-year-old white boy with chronic GVH disease had recurrent episodes of immune thrombocytopenic purpura, autoimmune hemolytic anemia, and mild depression of immunoglobulin levels.26

Nail matrix biopsy results and physical examination findings help in establishing the cause of trachyonychia, though this condition often is an isolated finding.27 In the case of lichen planus,28 some patients also have flat polished purple papules on the body and white lacy or reticulated plaques in the mouth.29 Nail biopsy specimens can show hyperkeratosis, hypergranulosis, and acanthosis in the ventral portion of the proximal nail fold and in the nail matrix; a bandlike lymphocytic infiltrate in the superficial dermis; and vacuolar alterations in the basal layer. Nail abnormalities can develop in 1% to 10% of patients with lichen planus.30 In the case of psoriasis, psoriasiform plaques sometimes develop on other body areas, and nail biopsy specimens can show psoriasis evidence such as psoriasiform hyperplasia and neutrophils. In the case of atopic dermatitis, spongiosis31 (intercellular edema of the epidermis) also can occur in nail matrix biopsy specimens.32 In the case of alopecia areata, lymphocytes can be present in the nail matrix, patches of nonscarring alopecia can develop on the scalp, and nail pits can develop in a gridlike pattern (giving a pounded brass appearance) on the nail plates. Evaluation of trachyonychia should include a check for fungus—a fungal culture or periodic acid–Schiff staining of a nail clipping. Some authors have suggested that longitudinal nail biopsy may be a useful diagnostic tool in certain cases of acquired nail dystrophy.33

Hazelrigg et al11 stated that trachyonychia is self-limited and self-resolving in children. Specifically, trachyonychia tends to resolve with time when it occurs in childhood as a manifestation of lichen planus. Rarely, there is nail destruction in 20-nail dystrophy. If destruction occurs, the diagnosis is lichen planus—a form not restricted to the proximal nail fold but extended to the matrix. If the matrix is involved in lichen planus, a pterygium can develop—a manifestation rarely seen in 20-nail dystrophy.

Treatments for trachyonychia include intralesional injections of triamcinolone 2.5 to 3 mg/mL into the proximal nail folds.2,34 Injections are painful and thus difficult in children. Medications for systemic treatment include prednisolone,35 antimalarials,36 and etretinate.37 Seven-month therapy with topical psoralen and UVA light is reported effective.38 In treating psoriatic nail disease, topical 5-fluorouracil39 and cyclosporine40 are useful. Clear nail hardeners can be applied to nails to improve their appearance.

In a study of 15 children, intramuscularly injected triamcinolone acetonide 0.5 to 1 mg/kg per month was prescribed for children with typical nail lichen planus.41 Therapy duration was increased from 3 to 6 months, until the proximal half of the nail was normal. No treatment was prescribed for patients with 20-nail dystrophy or idiopathic atrophy of the nails. Treatment with systemic corticosteroids was effective in curing typical nail lichen planus. For 2 children, the disease recurred during follow-up. Recurrences were always responsive to therapy. Two children with 20-nail dystrophy improved without any therapy. Nail lesions caused by idiopathic atrophy of the nails remained unchanged during follow-up.

Trachyonychia and 20-nail dystrophy continue to present difficulties in classification, diagnosis, and treatment. With the advent of new immunomodulators, it is hoped that more effective treatments will be developed. Prompt diagnosis of these conditions aids in patient education and therapy. back to top

Trachyonychia (“rough nails”) is best considered a reaction or morphologic pattern with a variety of clinical presentations and etiologies. It may involve only 1 or as many as 20 nails (20-nail dystrophy). It can be a manifestation of lichen planus, psoriasis, alopecia areata, immunoglobulin A deficiency, atopic dermatitis, and ichthyosis vulgaris. Nail matrix biopsy results and physical examination findings help in establishing the cause of this condition, though often trachyonychia is an isolated finding. When trachyonychia occurs in childhood as a manifestation of lichen planus, it tends to resolve with time. We review a case of trachyonychia, its association, its diagnostic evaluation, and treatment options.

Trachyonychia means "rough nails." This condition may involve only 1 or as many as 20 nails. It is best considered a reaction or morphologic pattern with a variety of clinical presentations and etiologies. Clinical presentations are rough nails with a sandpapered appearance and numerous small superficial pits that make the nails shiny1; onychorrhexis, onychoschizia, distal chipping, and yellow onychauxis of the great toenail; and closely arranged longitudinal ridges, distal notching, and layered splitting.2,3 Nail matrix biopsy results combined with clinical findings have linked trachyonychia with lichen planus generally,4 lichen planus in children,5 psoriasis,6 alopecia areata,7 IgA deficiency,8 atopic dermatitis,9 and ichthyosis vulgaris.10 The term 20-nail dystrophy of childhood11 refers to a trachyonychia variant likely caused by lichen planus. Some who consider the term a misnomer—in part because not all nails are necessarily involved—think that perhaps it should be abandoned.12 back to top

Case Report A 10-year-old girl presented with a 1-year history of worsening nail dystrophy. The patient had no history of psoriasis, atopic dermatitis, alopecia, or other skin disease, and family history was unremarkable. Except for dystrophy and hyperkeratosis identified on nails of both hands and both feet (Figure), physical examination findings were normal. Results of a fungal nail culture were negative, and the nail matrix biopsy specimen showed a bandlike lymphocytic infiltrate in the superficial dermis, with vacuolar alteration of the basal level. The diagnosis was trachyonychia secondary to lichen planus. Daily use of flurandrenolone tape and monthly intralesional injections of triamcinolone 2.5 mg/mL did not improve this patient's condition. After 4 months of injections in the distal nail folds, she was lost to follow-up.

back to top

Comment Often, the onset of trachyonychia is insidious. The condition usually develops on all nails simultaneously. Trachyonychia also can occur on individual nails over many months. Peak age of onset is 3 to 12 years. Trachyonychia occurs, however, in multigenerational families,13 in all age groups, in twins in the United States14 and Europe,15 in both sexes, and in all ethnic groups. This condition has been associated with ichthyosis vulgaris combined with alopecia universalis,16 ungual lichen planus and alopecia areata,17 koilonychia,18 primary biliary cirrhosis,19 and vitiligo.20 In chronic graft versus host (GVH) disease, trachyonychia can be an isolated finding21 or part of a constellation of cutaneous symptoms.22 It may be associated with dystrophy, atrophy, and, often, ulceration of the lunula.23 In the proper setting, the nail findings and clinical presentation of chronic GVH disease can resemble those of dyskeratosis congentia.24 A mother and her 7-year-old daughter with chronic GVH disease had balanced translocation 46, XX, t(6q13;10p13).25 A 15-year-old white boy with chronic GVH disease had recurrent episodes of immune thrombocytopenic purpura, autoimmune hemolytic anemia, and mild depression of immunoglobulin levels.26

Nail matrix biopsy results and physical examination findings help in establishing the cause of trachyonychia, though this condition often is an isolated finding.27 In the case of lichen planus,28 some patients also have flat polished purple papules on the body and white lacy or reticulated plaques in the mouth.29 Nail biopsy specimens can show hyperkeratosis, hypergranulosis, and acanthosis in the ventral portion of the proximal nail fold and in the nail matrix; a bandlike lymphocytic infiltrate in the superficial dermis; and vacuolar alterations in the basal layer. Nail abnormalities can develop in 1% to 10% of patients with lichen planus.30 In the case of psoriasis, psoriasiform plaques sometimes develop on other body areas, and nail biopsy specimens can show psoriasis evidence such as psoriasiform hyperplasia and neutrophils. In the case of atopic dermatitis, spongiosis31 (intercellular edema of the epidermis) also can occur in nail matrix biopsy specimens.32 In the case of alopecia areata, lymphocytes can be present in the nail matrix, patches of nonscarring alopecia can develop on the scalp, and nail pits can develop in a gridlike pattern (giving a pounded brass appearance) on the nail plates. Evaluation of trachyonychia should include a check for fungus—a fungal culture or periodic acid–Schiff staining of a nail clipping. Some authors have suggested that longitudinal nail biopsy may be a useful diagnostic tool in certain cases of acquired nail dystrophy.33

Hazelrigg et al11 stated that trachyonychia is self-limited and self-resolving in children. Specifically, trachyonychia tends to resolve with time when it occurs in childhood as a manifestation of lichen planus. Rarely, there is nail destruction in 20-nail dystrophy. If destruction occurs, the diagnosis is lichen planus—a form not restricted to the proximal nail fold but extended to the matrix. If the matrix is involved in lichen planus, a pterygium can develop—a manifestation rarely seen in 20-nail dystrophy.

Treatments for trachyonychia include intralesional injections of triamcinolone 2.5 to 3 mg/mL into the proximal nail folds.2,34 Injections are painful and thus difficult in children. Medications for systemic treatment include prednisolone,35 antimalarials,36 and etretinate.37 Seven-month therapy with topical psoralen and UVA light is reported effective.38 In treating psoriatic nail disease, topical 5-fluorouracil39 and cyclosporine40 are useful. Clear nail hardeners can be applied to nails to improve their appearance.

In a study of 15 children, intramuscularly injected triamcinolone acetonide 0.5 to 1 mg/kg per month was prescribed for children with typical nail lichen planus.41 Therapy duration was increased from 3 to 6 months, until the proximal half of the nail was normal. No treatment was prescribed for patients with 20-nail dystrophy or idiopathic atrophy of the nails. Treatment with systemic corticosteroids was effective in curing typical nail lichen planus. For 2 children, the disease recurred during follow-up. Recurrences were always responsive to therapy. Two children with 20-nail dystrophy improved without any therapy. Nail lesions caused by idiopathic atrophy of the nails remained unchanged during follow-up.

Trachyonychia and 20-nail dystrophy continue to present difficulties in classification, diagnosis, and treatment. With the advent of new immunomodulators, it is hoped that more effective treatments will be developed. Prompt diagnosis of these conditions aids in patient education and therapy. back to top

α1-Antitrypsin deficiency panniculitis (A1ADP) is a rare form of panniculitis that affects children and adults. Clinical and histologic features, precipitating actors, and treatments are discussed.

α1-Antitrypsin, a serine protease inhibitor synthesized in the liver, regulates the action of proteolytic enzymes including trypsin, collagenase, elastase, factor VIII, chymotrypsin, and kallikrein. A deficiency of this protein is hypothesized to lead to
inadequate inhibition of proteases released by neutrophils and monocytes, which in turn results in unchecked inflammation and tissue necrosis.1 The systemic sequelae of this phenomenon include panacinar emphysema, hepatitis, cirrhosis, hemorrhagic diathesis, and panniculitis.2 Panniculitis most commonly occurs in patients with the severe homozygous deficiency PiZZ phenotype, resulting in serum α1-antitrypsin levels that are 10% of normal. The lesions may mimic cellulitis and are most frequently found on the trunk and proximal extremities. Characteristic microscopic features include neutrophils between collagen bundles in
reticular dermis, septal panniculitis with liquefactive necrosis, and collagenolysis with large areas of normal fat lobules adjacent to necrotic fat.3

Case Report
After falling down the stairs at home, a previously healthy 40-year-old woman presented to the emergency department with a tender edematous 25-cm hematoma on the right lateral thigh. The patient was treated empirically for an infected hematoma; use of oral antibiotics resulted in partial improvement. Subsequently, atraumatic indurated plaques and nodules developed on the
extremities; these plaques and nodules were minimally responsive to oral and intravenous antibiotics. The hematoma was incised and drained. Culture results were negative for bacterial and fungal growth. Serous fluid drained from a left-buttock nodule that had spontaneously ulcerated. The patient was admitted to our hospital for further diagnosis and management.

The patient was comfortable and nontoxic. Her temperature was 99.8ºF, and her heart rate was 88 bpm. Distributed over the right axilla, the medial area of the left elbow, the left ankle, the distal area of the right tibia, and the lateral area of the right thigh were multiple, deep, red, tender, indurated, 4- to 25-cm nodules and plaques (Figure 1). On the left buttock was an ulcerated 5-cm nodule.

A biopsy of the right axillary lesion was performed. Results of histologic examination showed normal epidermis and dermis. Mixed lobular and septal panniculitis included normal fat lobules adjacent to necrotic fat lobules (Figure 2). The infiltrate was composed of lymphocytes, histiocytes, and pools of neutrophils with suppuration, liquefactive necrosis, and collagenolysis (Figure 3). Neutrophils were splayed between collagen bundles (Figure 4). Granulomata were not evident, and there was no evidence of vasculitis. Periodic acid–Schiff, Gram, and acid-fast bacillus stains were negative for microorganisms. Refractile material was not evident under polariscopic examination. The microscopic differential diagnosis included infections, factitial panniculitis, subcutaneous Sweet syndrome, pancreatic fat necrosis, and α1-antitrypsin deficiency panniculitis (A1ADP).

Levels of antineutrophil cytoplasmic antibodies (p-ANCA, c-ANCA), C3, C4, and CH50 were normal. Cryoglobulins were not detected. Complete blood cell count and amylase and lipase levels were normal. Erythrocyte sedimentation rate was
elevated (52 mm/h).

Serum α1-antitrypsin level was 37.0 mg/dL (reference range, 84–218 mg/dL) with a ZZ phenotype. Results of a chest radiograph, liver function tests, and pulmonary function tests were normal. Given the clinical and pathologic findings and the results from the genetic α1 phenotyping, α1-antitrypsin deficiency was diagnosed. The patient, treated with dapsone, improved dramatically.

Comment
α1-Antitrypsin, a polypeptide glycoprotein synthesized by hepatocytes, inhibits collagenase, elastase, factor VIII, chymotrypsin, and kallikrein.1 α1-Antitrypsin is an acute-phase reactant that increases in serum concentration with stress from illness or trauma. Protease activation in the absence of α1-antitrypsin may trigger a cascade of inflammatory events that ultimately damage the tissues they are
meant to protect.2 Speculation is that absence of α1-antitrypsin allows inflammation to continue unabated and thus leads to panniculitis.

α1-Antitrypsin deficiency most frequently causes severe and rapidly progressive panacinar emphysema. This deficiency also is associated with hepatitis, cirrhosis,
vasculitis, acquired angioedema, Marshall syndrome, and severe psoriasis.4 Recently, α1-antitrypsin deficiency was used as a model for conformational
diseases (including liver cirrhosis) and neurodegenerative disorders (including Alzheimer disease and spongiform encephalopathies).5

Serum concentration of α1-antitrypsin is determined by inheritance of autosomal codominant alleles—M, S, and Z being the most common.6 Most cases of A1ADP occur in individuals with a severe homozygous deficiency (ZZ phenotype).3
Ninety-five percent of the US population shares the normal protease inhibitor MM phenotype designated type M. SZ heterozygotes have one third of the normal inhibitor level and a relatively low risk of developing emphysema.6 Prevalence of
the SZ phenotype ranges from 1 in 180 to 1 in 2500 individuals, depending on geographic location.7 Type Z, an α1-antitrypsin variant, differs from the M protein by a single amino acid substitution (lysine for glutamic acid).1 This substitution
results in a changed conformation leading to inhibition of α1-antitrypsin release from hepatocytes and decreased serum levels in patients with the protease inhibitor ZZ phenotype. Homozygous deficiency occurs in about 1 in 2500 individuals; heterozygous deficiency occurs in about 1 in 50.

The case reported here demonstrates many important features of A1ADP. First, our patient linked the onset of her symptoms to her fall down the stairs and her resulting injury of the right lower extremity. Another reviewer found that 6 of
18 cases of A1ADP were precipitated by trauma,8 and an investigator reported the case of a patient who had subclinical 1-antitrypsin deficiency and who developed panniculitis after trauma induced by cryosurgery.9

Second, our case demonstrates the typical clinical characteristics of A1ADP, including location on the proximal area of the lower extremities and axilla
and drainage of serous fluid. Lesions of this disease begin as tender, erythematous, indurated subcutaneous nodules that may be widely disseminated on the trunk or extremities. These lesions spontaneously ulcerate and drain oily, serosanguineous fluid.1 As reported in a review, 16 patients developed such lesions predominantly on the trunk and proximal area of the extremities.8

Third, our patient was diagnosed with a secondarily infected hematoma and cellulitis; repeated trials of antibiotics failed. Antibacterial treatment is completely ineffective in the management of A1ADP. Failure of multiple trials of oral antibiotics
and intravenous antibiotics exemplifies the difficulties encountered in making the diagnosis of A1ADP.

Integral to the diagnosis of our patient’s condition was the right axillary skin biopsy and laboratory evaluation of serum α1-antitrypsin level. Foci of fat necrosis adjacent to large areas of normal fat and acute lobular panniculitis with a large number of neutrophils are characteristic findings.

Other histologic findings should be addressed. Geller and Su3 described the earliest histopathologic findings of A1ADP as splaying of neutrophils between collagen bundles in the reticular dermis. Degeneration of collagen within the dermis, progressive dermal necrosis, and subsequent involvement of fibrous septa and subcutaneous fat are additional features of A1ADP. Therefore, histologic examination is an important diagnostic tool.

The cornerstone of the diagnosis in our patient’s case was the finding of a low level of α1-antitrypsin (37.0 mg/dL) and P1 typing of ZZ. Given the availability of the assay and the prolonged diagnostic challenge marked by multiple unsuccessful trials of antibiotics, running the assay earlier in the workup may be beneficial in cases with a high index of suspicion.

Treatment of A1ADP should include avoidance of trauma and surgical debridements—frequent precipitating factors of panniculitis.10 Dapsone, seemingly the treatment of choice, has been anecdotally effective in a number of cases of A1ADP.
For homozygous patients who have severe forms of the disease and who present with severe emphysema and liver failure, supplemental infusion of exogenous α1 protease inhibitor concentrate has been suggested as the most important therapeutic possibility.9

A1ADP is difficult to diagnose but should be considered when a patient with recurrent painful indurated plaques presents after sustaining a localized trauma.

α1-Antitrypsin deficiency panniculitis (A1ADP) is a rare form of panniculitis that affects children and adults. Clinical and histologic features, precipitating actors, and treatments are discussed.

α1-Antitrypsin, a serine protease inhibitor synthesized in the liver, regulates the action of proteolytic enzymes including trypsin, collagenase, elastase, factor VIII, chymotrypsin, and kallikrein. A deficiency of this protein is hypothesized to lead to
inadequate inhibition of proteases released by neutrophils and monocytes, which in turn results in unchecked inflammation and tissue necrosis.1 The systemic sequelae of this phenomenon include panacinar emphysema, hepatitis, cirrhosis, hemorrhagic diathesis, and panniculitis.2 Panniculitis most commonly occurs in patients with the severe homozygous deficiency PiZZ phenotype, resulting in serum α1-antitrypsin levels that are 10% of normal. The lesions may mimic cellulitis and are most frequently found on the trunk and proximal extremities. Characteristic microscopic features include neutrophils between collagen bundles in
reticular dermis, septal panniculitis with liquefactive necrosis, and collagenolysis with large areas of normal fat lobules adjacent to necrotic fat.3

Case Report
After falling down the stairs at home, a previously healthy 40-year-old woman presented to the emergency department with a tender edematous 25-cm hematoma on the right lateral thigh. The patient was treated empirically for an infected hematoma; use of oral antibiotics resulted in partial improvement. Subsequently, atraumatic indurated plaques and nodules developed on the
extremities; these plaques and nodules were minimally responsive to oral and intravenous antibiotics. The hematoma was incised and drained. Culture results were negative for bacterial and fungal growth. Serous fluid drained from a left-buttock nodule that had spontaneously ulcerated. The patient was admitted to our hospital for further diagnosis and management.

The patient was comfortable and nontoxic. Her temperature was 99.8ºF, and her heart rate was 88 bpm. Distributed over the right axilla, the medial area of the left elbow, the left ankle, the distal area of the right tibia, and the lateral area of the right thigh were multiple, deep, red, tender, indurated, 4- to 25-cm nodules and plaques (Figure 1). On the left buttock was an ulcerated 5-cm nodule.

A biopsy of the right axillary lesion was performed. Results of histologic examination showed normal epidermis and dermis. Mixed lobular and septal panniculitis included normal fat lobules adjacent to necrotic fat lobules (Figure 2). The infiltrate was composed of lymphocytes, histiocytes, and pools of neutrophils with suppuration, liquefactive necrosis, and collagenolysis (Figure 3). Neutrophils were splayed between collagen bundles (Figure 4). Granulomata were not evident, and there was no evidence of vasculitis. Periodic acid–Schiff, Gram, and acid-fast bacillus stains were negative for microorganisms. Refractile material was not evident under polariscopic examination. The microscopic differential diagnosis included infections, factitial panniculitis, subcutaneous Sweet syndrome, pancreatic fat necrosis, and α1-antitrypsin deficiency panniculitis (A1ADP).

Levels of antineutrophil cytoplasmic antibodies (p-ANCA, c-ANCA), C3, C4, and CH50 were normal. Cryoglobulins were not detected. Complete blood cell count and amylase and lipase levels were normal. Erythrocyte sedimentation rate was
elevated (52 mm/h).

Serum α1-antitrypsin level was 37.0 mg/dL (reference range, 84–218 mg/dL) with a ZZ phenotype. Results of a chest radiograph, liver function tests, and pulmonary function tests were normal. Given the clinical and pathologic findings and the results from the genetic α1 phenotyping, α1-antitrypsin deficiency was diagnosed. The patient, treated with dapsone, improved dramatically.

Comment
α1-Antitrypsin, a polypeptide glycoprotein synthesized by hepatocytes, inhibits collagenase, elastase, factor VIII, chymotrypsin, and kallikrein.1 α1-Antitrypsin is an acute-phase reactant that increases in serum concentration with stress from illness or trauma. Protease activation in the absence of α1-antitrypsin may trigger a cascade of inflammatory events that ultimately damage the tissues they are
meant to protect.2 Speculation is that absence of α1-antitrypsin allows inflammation to continue unabated and thus leads to panniculitis.

α1-Antitrypsin deficiency most frequently causes severe and rapidly progressive panacinar emphysema. This deficiency also is associated with hepatitis, cirrhosis,
vasculitis, acquired angioedema, Marshall syndrome, and severe psoriasis.4 Recently, α1-antitrypsin deficiency was used as a model for conformational
diseases (including liver cirrhosis) and neurodegenerative disorders (including Alzheimer disease and spongiform encephalopathies).5

Serum concentration of α1-antitrypsin is determined by inheritance of autosomal codominant alleles—M, S, and Z being the most common.6 Most cases of A1ADP occur in individuals with a severe homozygous deficiency (ZZ phenotype).3
Ninety-five percent of the US population shares the normal protease inhibitor MM phenotype designated type M. SZ heterozygotes have one third of the normal inhibitor level and a relatively low risk of developing emphysema.6 Prevalence of
the SZ phenotype ranges from 1 in 180 to 1 in 2500 individuals, depending on geographic location.7 Type Z, an α1-antitrypsin variant, differs from the M protein by a single amino acid substitution (lysine for glutamic acid).1 This substitution
results in a changed conformation leading to inhibition of α1-antitrypsin release from hepatocytes and decreased serum levels in patients with the protease inhibitor ZZ phenotype. Homozygous deficiency occurs in about 1 in 2500 individuals; heterozygous deficiency occurs in about 1 in 50.

The case reported here demonstrates many important features of A1ADP. First, our patient linked the onset of her symptoms to her fall down the stairs and her resulting injury of the right lower extremity. Another reviewer found that 6 of
18 cases of A1ADP were precipitated by trauma,8 and an investigator reported the case of a patient who had subclinical 1-antitrypsin deficiency and who developed panniculitis after trauma induced by cryosurgery.9

Second, our case demonstrates the typical clinical characteristics of A1ADP, including location on the proximal area of the lower extremities and axilla
and drainage of serous fluid. Lesions of this disease begin as tender, erythematous, indurated subcutaneous nodules that may be widely disseminated on the trunk or extremities. These lesions spontaneously ulcerate and drain oily, serosanguineous fluid.1 As reported in a review, 16 patients developed such lesions predominantly on the trunk and proximal area of the extremities.8

Third, our patient was diagnosed with a secondarily infected hematoma and cellulitis; repeated trials of antibiotics failed. Antibacterial treatment is completely ineffective in the management of A1ADP. Failure of multiple trials of oral antibiotics
and intravenous antibiotics exemplifies the difficulties encountered in making the diagnosis of A1ADP.

Integral to the diagnosis of our patient’s condition was the right axillary skin biopsy and laboratory evaluation of serum α1-antitrypsin level. Foci of fat necrosis adjacent to large areas of normal fat and acute lobular panniculitis with a large number of neutrophils are characteristic findings.

Other histologic findings should be addressed. Geller and Su3 described the earliest histopathologic findings of A1ADP as splaying of neutrophils between collagen bundles in the reticular dermis. Degeneration of collagen within the dermis, progressive dermal necrosis, and subsequent involvement of fibrous septa and subcutaneous fat are additional features of A1ADP. Therefore, histologic examination is an important diagnostic tool.

The cornerstone of the diagnosis in our patient’s case was the finding of a low level of α1-antitrypsin (37.0 mg/dL) and P1 typing of ZZ. Given the availability of the assay and the prolonged diagnostic challenge marked by multiple unsuccessful trials of antibiotics, running the assay earlier in the workup may be beneficial in cases with a high index of suspicion.

Treatment of A1ADP should include avoidance of trauma and surgical debridements—frequent precipitating factors of panniculitis.10 Dapsone, seemingly the treatment of choice, has been anecdotally effective in a number of cases of A1ADP.
For homozygous patients who have severe forms of the disease and who present with severe emphysema and liver failure, supplemental infusion of exogenous α1 protease inhibitor concentrate has been suggested as the most important therapeutic possibility.9

A1ADP is difficult to diagnose but should be considered when a patient with recurrent painful indurated plaques presents after sustaining a localized trauma.

α1-Antitrypsin deficiency panniculitis (A1ADP) is a rare form of panniculitis that affects children and adults. Clinical and histologic features, precipitating actors, and treatments are discussed.

α1-Antitrypsin, a serine protease inhibitor synthesized in the liver, regulates the action of proteolytic enzymes including trypsin, collagenase, elastase, factor VIII, chymotrypsin, and kallikrein. A deficiency of this protein is hypothesized to lead to
inadequate inhibition of proteases released by neutrophils and monocytes, which in turn results in unchecked inflammation and tissue necrosis.1 The systemic sequelae of this phenomenon include panacinar emphysema, hepatitis, cirrhosis, hemorrhagic diathesis, and panniculitis.2 Panniculitis most commonly occurs in patients with the severe homozygous deficiency PiZZ phenotype, resulting in serum α1-antitrypsin levels that are 10% of normal. The lesions may mimic cellulitis and are most frequently found on the trunk and proximal extremities. Characteristic microscopic features include neutrophils between collagen bundles in
reticular dermis, septal panniculitis with liquefactive necrosis, and collagenolysis with large areas of normal fat lobules adjacent to necrotic fat.3

Case Report
After falling down the stairs at home, a previously healthy 40-year-old woman presented to the emergency department with a tender edematous 25-cm hematoma on the right lateral thigh. The patient was treated empirically for an infected hematoma; use of oral antibiotics resulted in partial improvement. Subsequently, atraumatic indurated plaques and nodules developed on the
extremities; these plaques and nodules were minimally responsive to oral and intravenous antibiotics. The hematoma was incised and drained. Culture results were negative for bacterial and fungal growth. Serous fluid drained from a left-buttock nodule that had spontaneously ulcerated. The patient was admitted to our hospital for further diagnosis and management.

The patient was comfortable and nontoxic. Her temperature was 99.8ºF, and her heart rate was 88 bpm. Distributed over the right axilla, the medial area of the left elbow, the left ankle, the distal area of the right tibia, and the lateral area of the right thigh were multiple, deep, red, tender, indurated, 4- to 25-cm nodules and plaques (Figure 1). On the left buttock was an ulcerated 5-cm nodule.

A biopsy of the right axillary lesion was performed. Results of histologic examination showed normal epidermis and dermis. Mixed lobular and septal panniculitis included normal fat lobules adjacent to necrotic fat lobules (Figure 2). The infiltrate was composed of lymphocytes, histiocytes, and pools of neutrophils with suppuration, liquefactive necrosis, and collagenolysis (Figure 3). Neutrophils were splayed between collagen bundles (Figure 4). Granulomata were not evident, and there was no evidence of vasculitis. Periodic acid–Schiff, Gram, and acid-fast bacillus stains were negative for microorganisms. Refractile material was not evident under polariscopic examination. The microscopic differential diagnosis included infections, factitial panniculitis, subcutaneous Sweet syndrome, pancreatic fat necrosis, and α1-antitrypsin deficiency panniculitis (A1ADP).

Levels of antineutrophil cytoplasmic antibodies (p-ANCA, c-ANCA), C3, C4, and CH50 were normal. Cryoglobulins were not detected. Complete blood cell count and amylase and lipase levels were normal. Erythrocyte sedimentation rate was
elevated (52 mm/h).

Serum α1-antitrypsin level was 37.0 mg/dL (reference range, 84–218 mg/dL) with a ZZ phenotype. Results of a chest radiograph, liver function tests, and pulmonary function tests were normal. Given the clinical and pathologic findings and the results from the genetic α1 phenotyping, α1-antitrypsin deficiency was diagnosed. The patient, treated with dapsone, improved dramatically.

Comment
α1-Antitrypsin, a polypeptide glycoprotein synthesized by hepatocytes, inhibits collagenase, elastase, factor VIII, chymotrypsin, and kallikrein.1 α1-Antitrypsin is an acute-phase reactant that increases in serum concentration with stress from illness or trauma. Protease activation in the absence of α1-antitrypsin may trigger a cascade of inflammatory events that ultimately damage the tissues they are
meant to protect.2 Speculation is that absence of α1-antitrypsin allows inflammation to continue unabated and thus leads to panniculitis.

α1-Antitrypsin deficiency most frequently causes severe and rapidly progressive panacinar emphysema. This deficiency also is associated with hepatitis, cirrhosis,
vasculitis, acquired angioedema, Marshall syndrome, and severe psoriasis.4 Recently, α1-antitrypsin deficiency was used as a model for conformational
diseases (including liver cirrhosis) and neurodegenerative disorders (including Alzheimer disease and spongiform encephalopathies).5

Serum concentration of α1-antitrypsin is determined by inheritance of autosomal codominant alleles—M, S, and Z being the most common.6 Most cases of A1ADP occur in individuals with a severe homozygous deficiency (ZZ phenotype).3
Ninety-five percent of the US population shares the normal protease inhibitor MM phenotype designated type M. SZ heterozygotes have one third of the normal inhibitor level and a relatively low risk of developing emphysema.6 Prevalence of
the SZ phenotype ranges from 1 in 180 to 1 in 2500 individuals, depending on geographic location.7 Type Z, an α1-antitrypsin variant, differs from the M protein by a single amino acid substitution (lysine for glutamic acid).1 This substitution
results in a changed conformation leading to inhibition of α1-antitrypsin release from hepatocytes and decreased serum levels in patients with the protease inhibitor ZZ phenotype. Homozygous deficiency occurs in about 1 in 2500 individuals; heterozygous deficiency occurs in about 1 in 50.

The case reported here demonstrates many important features of A1ADP. First, our patient linked the onset of her symptoms to her fall down the stairs and her resulting injury of the right lower extremity. Another reviewer found that 6 of
18 cases of A1ADP were precipitated by trauma,8 and an investigator reported the case of a patient who had subclinical 1-antitrypsin deficiency and who developed panniculitis after trauma induced by cryosurgery.9

Second, our case demonstrates the typical clinical characteristics of A1ADP, including location on the proximal area of the lower extremities and axilla
and drainage of serous fluid. Lesions of this disease begin as tender, erythematous, indurated subcutaneous nodules that may be widely disseminated on the trunk or extremities. These lesions spontaneously ulcerate and drain oily, serosanguineous fluid.1 As reported in a review, 16 patients developed such lesions predominantly on the trunk and proximal area of the extremities.8

Third, our patient was diagnosed with a secondarily infected hematoma and cellulitis; repeated trials of antibiotics failed. Antibacterial treatment is completely ineffective in the management of A1ADP. Failure of multiple trials of oral antibiotics
and intravenous antibiotics exemplifies the difficulties encountered in making the diagnosis of A1ADP.

Integral to the diagnosis of our patient’s condition was the right axillary skin biopsy and laboratory evaluation of serum α1-antitrypsin level. Foci of fat necrosis adjacent to large areas of normal fat and acute lobular panniculitis with a large number of neutrophils are characteristic findings.

Other histologic findings should be addressed. Geller and Su3 described the earliest histopathologic findings of A1ADP as splaying of neutrophils between collagen bundles in the reticular dermis. Degeneration of collagen within the dermis, progressive dermal necrosis, and subsequent involvement of fibrous septa and subcutaneous fat are additional features of A1ADP. Therefore, histologic examination is an important diagnostic tool.

The cornerstone of the diagnosis in our patient’s case was the finding of a low level of α1-antitrypsin (37.0 mg/dL) and P1 typing of ZZ. Given the availability of the assay and the prolonged diagnostic challenge marked by multiple unsuccessful trials of antibiotics, running the assay earlier in the workup may be beneficial in cases with a high index of suspicion.

Treatment of A1ADP should include avoidance of trauma and surgical debridements—frequent precipitating factors of panniculitis.10 Dapsone, seemingly the treatment of choice, has been anecdotally effective in a number of cases of A1ADP.
For homozygous patients who have severe forms of the disease and who present with severe emphysema and liver failure, supplemental infusion of exogenous α1 protease inhibitor concentrate has been suggested as the most important therapeutic possibility.9

A1ADP is difficult to diagnose but should be considered when a patient with recurrent painful indurated plaques presents after sustaining a localized trauma.