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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

Acne vulgaris in infants and children often triggers extensive laboratory evaluation out of concern about associated endocrinopathy. Clinical parameters to help guide evaluation of these children have not been defined. This was a retrospective chart review of 24 preadolescent patients with acne and a review of related medical literature. Two age-related subsets were identified: 12 patients who developed acne before the age of 15 months, 75% male, with comedonal and inflammatory lesions; and 12 patients who developed acne between the ages of 2 and 7 years, 75% female, with primarily comedonal lesions. Laboratory evaluation in 13 of the patients was unremarkable. Bone age was advanced in 1 of the 11 children imaged. Premature adrenarche was diagnosed in four patients; all four had additional clinical signs of puberty and growth parameters >90th percentile. None required additional treatment. Our cohort of preadolescent children presenting with acne included an equal number of patients in two distinct subsets: infantile and childhood-onset acne. Literature review identified a rare third subset presenting with acne, signs of advanced puberty, and associated endocrinopathy. There was no evidence of endocrinopathy in our patients with infantile acne. Two-thirds of our patients with childhood-onset acne had no additional clinical signs of puberty and no evidence of endocrinopathy. A focused history and physical examination is sufficient to evaluate the majority of infants and children with acne. Hand X-ray for bone age is a useful screening test. Further evaluation and endocrinology referral are warranted in preadolescents with acne and advanced bone age or additional clinical evidence of early puberty.

Acne vulgaris affects up to 95% of teenagers and young adults [1] but can begin in infancy and early childhood. Acne neonatorum was first reported in 1913, followed by a review on the subject of infantile acne in 1945 [2]. A comprehensive search of the medical literature for relevant data on this acne subset yielded fewer than 25 papers, largely descriptive. The most recent classification of pediatric acne based on expert consensus includes five subgroups defined largely according to age of onset: neonatal, infantile, midchildhood, preadolescent, and adolescent [3]. Neonatal acne has been defined as onset in infants younger than 6 weeks old. In most cases, neonatal acne is not typically true acne vulgaris but a transient acneiform eruption, with the most common of these being neonatal cephalic pustulosis, which is thought to be caused by colonization of Malassezia [4]. An important concern for older infants and children with infantile or midchildhood acne vulgaris is that it may be a presenting sign of a treatable endocrinopathy [3, 5, 6]. Timely diagnosis and treatment of androgen excess can prevent sequelae, including accelerated bone maturation, which may result in short adult stature. Recognition of this entity may also lead to detection of rare, but life-threatening, androgen-secreting tumors, although a classification system based simply on age of onset does not help distinguish children with androgen excess.

The goal of this study was to establish an approach to the evaluation of infants and children presenting with acne based on a retrospective analysis of a cohort of preadolescent patients seen over 5 years at an academic dermatology clinic as well as a critical review of the literature.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

We performed a retrospective chart review of 24 infants and children with a diagnosis of acne vulgaris evaluated over a 5-year period at Saint Louis University. Subjects were chosen from patients evaluated during that period who were ages 0 to 14 years old who developed acne at the age of 7 years or younger and who had a full history and physical examination documenting pertinent positive and negative findings. For included subjects, a complete medical history had been obtained, including age of acne onset and duration of disease, type of treatment, growth, developmental milestones, menarche, breast development, and presence of body odor and axillary or pubic hair. Pertinent physical examination parameters included height, weight, types and location of acne, and signs of puberty (body odor, axillary and pubic hair, breast buds, genital development). Diagnostic testing, performed on 13 of the 24 subjects, which was not based on uniform clinical characteristics, may have included dehydroepiandrosterone sulfate, free and total testosterone, urine 17-ketosteroids, cortisol, 17-hydroxyprogesterone, androstenedione, estradiol, and in some cases cosyntropin stimulation test, dexamethasone suppression test, and hand X-ray for bone age.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

Twenty-four patients (12 female, 50%) were included in the analysis. All were Caucasian. The age of acne onset ranged from 1 week to 7 years. Further analysis of the type and distribution of lesions identified two separate, age-related subsets. The first subset consisted of 12 patients (50%) with an onset of acne between 1 week and 14 months of age, 75% of whom were male. Their lesions were predominantly mixed comedonal and inflammatory, and in all 12 (100%), lesions were limited to the cheeks (Fig. 1A). The second subset consisted of 12 patients (50%) whose acne began between 2 and 7 years of age, 75% of whom were female (75%). The majority of their lesions were comedonal and were distributed on the forehead, nose, and cheeks (Fig. 1B). Weight in those that had been weighed was greater than the 75th percentile in 89% of the first group and 67% of the second group, and height in those measured was greater than the 75th percentile in 42% of the first group and 67% of the second group (Table 1). None of the patients in the first group and six in the second group (50%) exhibited pubarche, body odor, thelarche, or menarche. Blood work was performed in 7 (29%) patients and bone age was determined in 11 (46%). The only abnormal diagnostic test identified in this cohort was bone age, with one patient in the second subset (8%) having advanced bone age. There were no identified cases of congenital adrenal hyperplasia, androgen-secreting tumor, or central precocious puberty in the 13 patients who had a diagnostic evaluation, and these conditions were not suspected in the remaining 11 because they did not have other signs of advanced puberty. There were no diagnosed endocrinopathies in the first group, but four female subjects in the second group had premature adrenarche. All four of these girls (100%) had other clinical signs of advanced puberty; four had growth parameters above the 90th percentile, two had body odor, three had breast development, three had pubic hair, and one was postmenarchal. One was also noted to have acanthosis nigricans.

Table 1. Clinical Characteristics of the Preadolescent Study Patients with Acne
SubjectAge of onsetSexLesion typeAdditional signs of advanced pubertyHeightWeightEndocrinologic evaluation and examination
Percentile
  1. C, comedonal; I, inflammatory (papules and pustules); N, nodules; ND, not determined.

12 mosMaleC, INoneND>95No
22 wksFemaleINoneND80No
36.5 yrsFemaleCBody odor, thelarcheNDNDNo
45 yrsFemaleCAxillary hair, body odor>95>95Normal laboratory results, advanced bone age, premature adrenarche
51 moMaleC, INone5580Normal laboratory results and bone age
63 mosMaleC, INone90>95No
76 yrsMaleCNoneNDNDNo
82 mosMaleINone7580No
910 mosFemaleINoneNDNDNo
107 yrsFemaleC, INoneNDNDNo
1113 mosMaleI, NNoneNDNDNormal bone age
126 yrsFemaleC, INone4555Normal bone age
131 yrFemaleI, NNoneNDNDNo
1414 mosMaleC, I, NNone10>95Normal laboratory results
157 yrsMaleINone9050Normal bone age
162 wksMaleC, INone1080Normal bone age
1729 mosFemaleINone7090Normal laboratory results
186 yrsFemaleCBody odor, pubarche, thelarche9590Normal laboratory results and bone age, premature adrenarche
192 mosMaleCNone10<5Delayed bone age
206 yrsFemaleCBody odor7575Normal bone age
211 wkMaleINone9575No
226 yrsMaleCNone6060No
232 yrsFemaleC, IAxillary hair, pubarche, thelarche>9595Normal laboratory results and bone age, premature adrenarche
246 yrsFemaleC, IAxillary hair, pubarche, thelarche, menarche90>95Normal laboratory results and bone age, premature adrenarche
image

Figure 1. (A) A 9-month-old boy with comedonal and inflammatory lesions on the cheeks, typical of infantile acne. (B) A 3-year-old boy with primarily comedonal acne on the midface, typical of midchildhood onset. (Photo courtesy of Andrea Zaenglein.)

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Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References

The most recent classification of pediatric acne is an age-based, descriptive, five-group categorization: neonatal, infantile, midchildhood, preadolescent, and adolescent [3]. The existing classification systems are based on collective expert opinion or long-standing observations that have been propagated in the literature [3, 6]. Therefore they fail to distinguish which children with early onset acne are truly at risk of treatable forms of virilizing endocrinopathy and therefore should undergo a more extensive examination.

Puberty, with a mean onset of 10.2 years in Caucasian girls and 9.6 years in African American girls [5], is characterized by a variable combination of several signs: adrenarche, pubarche, gonadarche, thelarche, and menarche. Adrenarche represents maturation of the adrenal gland, characterized by adrenal androgen production and increases in return of the zona reticularis and acquisition of the enzymes that facilitate synthesis of androgens from cholesterol. This increase in androgen production is measured by an increase in the serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate [7]. Pubarche is defined according to the appearance of pubic hair, which is causally related to adrenarche, and clinically may mark true pubertal maturation [8]. Premature pubarche is defined by the presence of pubic hair before the age of 8 years in girls and before the age of 9 years in boys [7, 9]. Gonadarche is the activation of the hypothalamic–pituitary–gonadal axis, which manifests as thelarche in girls and testicular enlargement in boys [9]. Thelarche is demonstrated by the presence of palpable breast tissue below the areola. The average age of onset is 9 to 10 years (range 8–13 yrs) [9]. Finally, menarche is defined as the first menses, with the average onset of 12.5 years in Caucasians (range 10–16 yrs), and 12.0 years in African Americans [5, 9].

Adrenal androgens play an important role in the pathogenesis of acne vulgaris, but the precise nature of this role has been elusive [10, 11]. The most common identifiable androgenic abnormality associated with acne vulgaris is a marginal, but statistically significant, increase in adrenal androgens, usually within a normal defined range [12, 13]. Studies suggest that rising levels of ovarian androgens at adrenarche may be responsible for early onset acne in girls [14], whereas adrenal and testicular androgens trigger acne in pubertal boys [15, 16].

Any of the signs of puberty can occur prematurely as an isolated abnormality. The diagnosis of precocious puberty, precocious pseudopuberty, and premature adrenarche can be controversial because clinical signs may not be associated with measurable standard biochemical markers, and published definitions differ, with many not including acne as a sign of these conditions [17]. Low birthweight has been implicated as a risk factor for premature adrenarche, but others have not confirmed this correlation, although there is some evidence that low birthweight is associated with higher androgen levels in childhood[17]. Other associations with premature adrenarche include impaired insulin sensitivity, possible dyslipidemia, and proinflammatory shift of the adipokine profile that is commonly seen in polycystic ovarian syndrome [17].

There is also debate regarding the long-term risks and follow-up of children with isolated signs of advanced puberty [7, 9, 10, 14, 18], but recent literature supports following patients with signs of early onset androgen excess, including those with premature adrenarche, because they appear to have a risk of metabolic syndrome [17]. This spectrum of disorders, including polycystic ovarian syndrome and metabolic syndrome (or syndrome X) [10, 12], has been best characterized in adults, but premature adrenarche may be the first sign of these conditions in childhood [17]. Although it is important to recognize this phenotype, current treatment recommendations are not based on laboratory abnormalities or pharmacotherapy, but focus on a healthy diet and regular exercise whereas in girls with a history of low birth weight and precocious pubarche, early metformin therapy seemed to prevent or delay the development of hirsutism, androgen excess, and oligomenorrhea [19].

One report of two toddlers and two case series including 45 infants and toddlers with acne found no evidence of androgen excess or other clinical signs of virilization [20-22]. Isolated case reports such as that of a 23-month-old boy with infantile acne and an occult adrenocortical tumor have offset these reassuring numbers, although this patient also had several other signs of androgen excess, including large hands, large phallus, and facial, axillary, and pubic hair [23]. Another case series focused on 25 girls diagnosed with virilization who all had multiple signs of androgen excess, including seven with acne [24]. Three of the seven were diagnosed with isolated adrenarche. Two had congenital adrenal hyper-plasia and two had virilizing tumors, and all four of these girls with associated endocrinopathy had above average height and advanced bone age in addition to multiple virilizing signs. A report of fifteen 5- to 10-year-old children who presented with acne before age 8 years emphasized the importance of hormonal evaluation [7]. Extensive laboratory evaluation confirmed congenital adrenal hyperplasia in two girls, but both of these girls also had pubarche and advanced bone age. All of the children with acne but without pubic hair had normal endocrine evaluation.

Our study identified two subsets of patients with preadolescent acne vulgaris based on clinical characteristics. The first subset, which closely correlates to the recent classification of infantile acne [3], is characterized by onset of acne before 18 months of age, male predominance, mixed comedonal and inflammatory lesions involving only the cheeks, and no other clinical signs of androgen excess. There were no children identified with underlying endocrinopathy in the infantile group. The second subset, which closely correlates to the recent classification of midchildhood acne [3], is characterized by onset after 18 months of age, female predominance, and a high proportion of comedones located on the forehead, cheeks, and chin; half of the patients in this subset had additional signs and symptoms of puberty. There were four cases of premature adrenarche in this childhood group, but all had growth parameters greater than the 90th percentile and additional signs of advanced puberty (Table 2).

Table 2. Subsets of Acne Vulgaris in Preadolescent Children
FactorInfantile onsetChildhood onsetEndocrinopathy associated
OnsetBefore 18 mos oldAfter 18 mos oldAny age
Sex predominanceMaleFemaleNone
Primary lesion typeMixed comedones and inflammatory lesionsComedonesAll types
DistributionCheeks onlyForehead, nose, cheeksFace, chest, back
Average height, percentile<50th>75Typically advanced
Average body mass index, kg/m2>2015Typically high
Associated clinical findingsNoneMay have advanced signs of pubertyAlways has advanced signs of puberty
Possible pathophysiologyTesticular and adrenal androgen secretionAccelerated adrenarche—a possible early sign of polycystic ovarian syndromeUnderlying endocrine abnormality

Therefore most cases of preadolescent acne, similar to children with premature pubarche [25], are not associated with virilizing endocrinopathies. They may instead represent a functional hyperandrogenism that could be the earliest sign of polycystic ovarian syndrome or a metabolic syndrome phenotype. In these cases, the children are not at risk for advanced gonadarche or compromised final height [9, 24], but are at risk of more severe or prolonged acne in adolescence or adulthood [18]. Infants and children with pathologic forms of acne always have other clinical signs of androgen excess—most often accelerated height velocity, body odor, pubic hair, and enlarged genitalia. Deadly adrenocortical tumors are rare, accounting for only 0.02% of pediatric neoplasms [23].

We feel that a bias toward publishing isolated, memorable cases has overemphasized the risk of endocrinopathy in children with acne vulgaris. These cases have led some authors to recommend extensive laboratory evaluation and endocrine consultation for all children with midchildhood and prepubertal acne [6, 26], but our study and review of the literature indicates a low risk of true endocrinopathy in infants and children with acne vulgaris who have no other signs of androgen excess. Concern about preventable sequelae of precocious puberty is often disproportionate to the risk in children with early onset acne. In these cases, additional investigative examination is often superfluous and provokes needless parental angst.

Based on our data and review of prior reports in the literature, we recommend a focused history and physical examination, which should include a growth curve, for all children age 7 years and younger with acne (Fig. 2). A left hand and wrist X-ray for bone age is a sufficient initial screening test for those with high growth parameters. If there is evidence of advanced bone age, or if there are any additional symptoms or signs of advanced puberty, pediatric endocrinology referral is recommended because this is the subset of children who seem to be at risk of possible underlying endocrinopathy. The development of acne in childhood, along with premature adrenarche, may be the initial sign of polycystic ovarian syndrome or metabolic syndrome [2, 3, 12, 17, 27], so anticipatory guidance and follow-up is indicated in all cases of acne vulgaris in preadolescent children.

image

Figure 2. Evaluation algorithm for a preadolescent child presenting with early onset acne vulgaris. BMI, body mass index; WNL, within normal limits; SD, standard deviation.

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References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References