Revista Adolescência e Saúde

Revista Oficial do Núcleo de Estudos da Saúde do Adolescente / UERJ

NESA Publicação oficial
ISSN: 2177-5281 (Online)

Vol. 16 nº 1 - Jan/Mar - 2019

Case Report Imprimir 

Páginas 113 a 119


When acne is the tip of the iceberg

Cuando el acné es la punta del iceberg

Quando a acne é a ponta do iceberg

Autores: Joana Costa Soares1; Sofia Alexandra Pereira Pires2; Pascoal Moleiro1

1. Department of Pediatrics. Hospital Center of Leiria, Portugal
2. Department of Pediatrics - Pediatric Hospital of Coimbra, Hospital and University Center of Coimbra. Coimbra, Portugal

Joana Costa Soares
Departamento de Pediatria. R. de Santo André, 2410-197
Leiria, Portugal
joana_soares@msn.com

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Keywords: Adrenal Hyperplasia, Congenital; Acne Vulgaris; Acne Keloid; Hyperandrogenism; Child.
Palabra Clave: Hiperplasia Suprarrenal Congénita; Acné Vulgar; Acné Queloide; Hiperandrogenismo; Niño.
Descritores: Hiperplasia Suprarrenal Congênita; Acne Vulgar; Acne Queloide; Hiperandrogenismo; Criança.

Abstract:
OBJECTIVE: Acne is a common pathology in adolescence. The severe acne, therapeutically resistant or associated with systemic symptoms may be a sign of a systemic disease. We report a case of non-classic congenital adrenal hyperplasia (NCAH), in which the main sign was severe and refractory acne.
CASE DESCRIPTION: Describes the case of an eleven-years old female referred to an outpatient consult due to exuberant, progressive and refractory acne since  eight years old, which didn´t responded to treatment. There were no signs of precocious puberty, accelerated growth or hirsutism. She had elevated levels of total testosterone, delta-4-androstenedione and 17-hydroxyprogesterone and no changes in the adrenal gland or polycystic ovarian criteria. A genetic study confirmed the suspicious diagnosis of NCAH, when she was then medicated with hydrocortisone and had a good response.
COMMENTS: In NCAH there is a partial enzymatic blockade, and cortisol deficiency does not occur. Therefore, it may have a late presentation with signs and/or symptoms caused by hyperandrogenism. Oral corticosteroids are recommended in symptomatic cases. Severe and treatment-resistant acne should be investigated and NCAH hypothesis should be considered. The diagnosis of NCAH is also important because it is a possible cause of infertility and because prenatal counseling is recommended.

Resumen:
OBJETIVO: El acné es una patología común en la adolescencia. El acné grave, resistente a la terapia o asociada a señales sistémicas puede ser la manifestación de una enfermedad sistémica. Se describe un caso de hiperplasia congénita de la suprarrenal, forma no clásica (HCSR-NC), que se manifestó como un caso de acné grave y refractario.
DESCRIPCIÓN DEL CASO: Se presenta el caso de una adolescente evaluada en consulta a los once años por acné exuberante de agravamiento progresivo desde los ocho años, con mala respuesta al tratamiento. No había señales de pubertad precoz, aceleración del crecimiento o hirsutismo. Analíticamente, presentaba aumento de testosterona total, de delta-4-androstenediona y de 17-hidroxiprogesterona, sin alteraciones ecográficas en la suprarrenal y sin criterios de ovario poliquístico. Un estudio genético confirmó el diagnóstico sospechoso de HCSR-NC, cuando fue entonces medicada con hidrocortisona y tuvo buena respuesta.
COMENTARIOS: En esta forma clínica existe bloqueo enzimático parcial, no ocurriendo deficiencia de cortisol. Así, se puede presentar de forma tardía a través de señales y/o síntomas causados por el hiperandrogenismo. En los casos sintomáticos es recomendada la corticoterapia oral. El acné grave y refractario al tratamiento debe ser investigado y considerarse la hipótesis de HCRS-NC. El diagnóstico de HCRS-NC es todavia más importante por ser una posible causa de infertilidad y por estar recomendado el acompañamiento prenatal.

Resumo:
OBJETIVO: A acne é uma patologia comum na adolescência. A acne grave, resistente à terapêutica ou associada a sinais sistémicos pode ser a manifestação de uma doença sistémica. Descreve-se um caso de hiperplasia congénita da suprarrenal, forma não clássica (HCSR-NC), que se manifestou como um caso de acne grave e refratária.
DESCRIÇÃO DO CASO: Apresenta-se o caso de uma adolescente avaliada em consulta aos onze anos por acne exuberante de agravamento progressivo desde os oito anos, com má resposta ao tratamento. Não havia sinais de puberdade precoce, aceleração do crescimento ou hirsutismo. Analiticamente, ela apresentava elevação da testosterona total, da delta-4-androstenediona e da 17-hidroxiprogesterona, sem alterações ecográficas na suprarrenal e sem critérios de ovário policístico. Um estudo genético confirmou o diagnóstico suspeito de HCSR-NC, quando foi então medicada com hidrocortisona e teve boa resposta.
COMENTÁRIOS: Nesta forma clínica existe bloqueio enzimático parcial, não ocorrendo deficiência do cortisol. Assim, pode apresentar-se de forma tardia através de sinais e/ou sintomas causados pelo hiperandrogenismo. Nos casos sintomáticos é recomendada a corticoterapia oral. A acne grave e refratária ao tratamento deve ser investigada e considerarse a hipótese de HCRS-NC. O diagnóstico de HCRS-NC é ainda importante por ser uma possível causa de infertilidade e por estar recomendado o aconselhamento pré-natal.

INTRODUCTION

Acne is a very common skin disease, reaching a prevalence of 70-87% of the population in adolescence.1 Its multifactorial nature reflects the role of infection, abnormal keratinization and immunological reaction, as well as hormonal influences in the pilosebaceous unit.2 It can also be a manifestation of hyperandrogenism since androgens induce the production of sebum and in excess may cause or aggravate acne.3 Hyperandrogenism has several causes, such as androgen producing tumors, polycystic ovarian syndrome, or adrenal congenital hyperplasia.3

Despite the high prevalence of acne in adolescence, this may be an isolated sign of systemic diseases. Acne cases should be suspected in children between one and seven years of age and adolescents, such as severe and / or treatment-resistant acne, associated with other signs of hyperandrogenism (example, signs of precocious puberty, virilization, hirsutism, menstrual irregularities, infertility), or other systemic symptoms (example, joint complaints such as SAPHO syndrome - synovitis, acne, pustulosis, hyperostosis, inflammatory osteitis, and signs of hypercortisolism such as Cushing's syndrome) 1-6.

The present study describes a case of congenital adrenal hyperplasia of the non-classical adrenal (HCRS-NC) in an 11-year-old adolescent whose presentation was exuberant acne and with poor treatment response. This case is considered relevant because acne was the only sign of hyperandogenism, leading to the diagnosis of an endocrinological disease with potential long-term consequences.


CASE DESCRIPTION

Adolescent of the feminine gender, referred to the Consultation of Medicine of the Adolescent to the eleven years for exuberant acne with three years of evolution. It presented a regular staturo-ponderal growth, without increase of the speed of growth and normal psychomotor development. She had no family history of infertility, genital ambiguity or unexplained neonatal death, and didn´t take chronic medication.

At age eight the patient started acne lesions, at the age of nine pubic pilosity appeared and the telarche occurred at the age of ten. She first used the Dermatology consultation at the age of ten and was medicated with minocycline and erythromycin, without acne improvement, and was referred to the Adolescent Medicine clinic. In this consultation, at the age of 11 years and 2 months, the objective examination was the exuberant acne with cicatricial lesions on the face, cervical region and thorax (Figure 1). She presented a M3 / P5 pubertal stage, still without menarche, without hirsutism or signs of genital virilization, or cutaneous striae. The main hypotheses for diagnosis were HCRS-NC and polycystic ovarian syndrome.


Figure 1. Exuberant acne in the patient analyzed at age 11 (Image courtesy of the family).



The adolescent presented an increase in total testosterone (81.18ng / dl), delta-4-androstenedione (5.52 μg / L) and 17-OHP (11.2ng / ml) and the rest of the normal analytical evaluation including LH , FSH, estradiol, progesterone and DHEA-SO4 (Table 1). In pelvic and adrenal ultrasound didn´t show masses in the adrenal, ovaries had normal dimensions presenting some cystic structures of probable functional nature. A genetic study was performed that revealed a mutation g. 1683G> T in homozygosity, which is compatible with a partial deficiency of 21-hydroxylase, confirming the diagnosis of HCRS-NC.




The adolescent patient was followed up in consultation with Pediatric Endocrinology and Dermatology and was medicated with oral isotretinoin, topical benzoyl peroxide and methylprednisolone, which was later replaced by hydrocortisone (15 mg / m2 / day). It presented good clinical evolution, keeping acne stable (Figure 2). He had menarche at twelve with regular cycles. Post-treatment periodic laboratory examination, including evaluation at the last consultation at the age of thirteen, revealed a trend towards normalization of the analytical parameters (Table 1).


Figure 2. Improvement of the patient's acne picture analyzed after treatment (Image courtesy of the family).



DISCUSSION

Congenital adrenal hyperplasia (HCSR) encompasses a group of autosomal recessive diseases, with mutation of genes encoding the enzymes involved in cortisol synthesis.7  The production of cortisol and mineralocorticoids is compromised leading to excessive production of androgens. The most common form is the 21-hydroxylase deficiency (90-95% of cases), coded by the CYP21A21 gene, which is responsible for the conversion of 17-OHP (17-OHP) to 11-deoxycortisol7,8 (Figure 3).


Figure 3. Changes in the cortisol synthesis pathway by the 21-hydroxylase deficit.



The disease can have two clinical presentations: classic form, subdivided in loss of salt and simply virilizing; and the non-classical or late expression form.8  The latter is much more frequent, with an incidence of 1: 10,000-20,000 births.9

In the non-classical form, enzyme blockade is partial (20-50%), leading to adrenal stimulation with excessive androgen production.10 People with HCSR-NC are normally asymptomatic at birth with no signs of virilization. However, they may later show signs of androgen excess or remain asymptomatic. In infancy the disease can manifest itself as precocious puberty with accelerated growth, with the risk of compromising the final height, due to the early closure of the epiphyses. In adolescence and adulthood it can be manifested as hirsutism (59%), acne (33%), menstrual irregularities (54%), infertility (13%) and alopecia (8%) 7,8,10,11,12

Exuberant and refractory acne may be the first or even the only symptom, as pictured in this case; hence it is important to maintain a level of suspicion in atypical cases of acne or with poor response to treatment.

The diagnosis may be suggested by the clinic, but it is confirmed by hormonal changes. Elevation of 17-OHP is the biochemical marker of 21-hydroxylase deficiency. Levels of 17-OHP (morning harvest)> 82ng / dl (2.5nmol / l) in children are very suggestive of HCSR-NC.13 However, individuals with the non-classical form may have normal values of 17- OHP (2-11%) 10, where the gold standard method for diagnosis is the ACTH stimulation test, with 17-OHP assay 60 minutes after administration of 250gr tetracosactide (synthetic ACTH) .7,10 Values of 17 -OHP at 60 minutes between 2-10ng / mL (6-30nmol / L) may correspond to heterozygous carriers, values between 10-100ng / mL (30-300nmol / L) are suggestive of HCSR-NC and values greater than 100ng / mL (300 nmol / L) are suggestive of the classical form of the disease.7 As in the case presented, other hormonal changes are also frequently present, such as elevation of total testosterone and delta-4-androstenedione. There may also be an increase in the urinary excretion of 17-OHP metabolites, such as preganetriol.7 The genetic study allows confirmation of the diagnosis in cases of 17-OHP elevation.

In the differential diagnosis of HCSR-NC should be considered other pathologies that occur with excess production of androgens, namely Polycystic Ovarian Syndrome, adrenal tumors or gonads and Cushing's syndrome.

Treatment is only necessary if there are symptoms, since unlike the classic form, oral corticosteroid therapy isn´t essential for survival. Thus, children whose diagnosis was made by genetic screening have no indication for treatment. Treatment is only initiated in children by early pubarche with rapid progression, accelerated growth velocity with advanced bone age and in adolescents/adults due to exuberant acne, hirsutism and/or oligomenorrhea/infertility.

The dose of corticosteroids used is as minimal as possible to suppress excess androgens. The first line corticosteroid in pediatric age is hydrocortisone (10-20mg / m2 / day) divided into two to three daily doses. Prednisolone and dexamethasone are also used in adults, which, however, should be avoided at pediatric age because of the risk of compromising growth.7,8,13

Regular clinical and analytical follow-up with 17-OHP, delta-4-androstenedione and testosterone assay should be performed to obtain a standardization of delta-4-androstenedione and testosterone. Adrenal secretion of androgens should not be completely stopped, since suppressed levels of 17-OHP may indicate excess treatment.13 In pediatric age, growth monitoring and pubertal development are essential.

In couples who have had a child with HCSR or when one of the parents has the disease, genetic counseling is important because of the increased risk of fetuses with the classic form of the disease, whose salt-losing form causes life-threatening associated hydroelectrolytic disorders. However, prenatal diagnosis is only possible from the 9th to 11th weeks of gestation by biopsy of the chorionic villi, or from 15 to 18 weeks of gestation by amniocentesis.7,8

Given that it is an autosomal recessive disease, preconception genetic counseling allows the identification of risk families in which both parents have the mutation. The calculated probability of a couple, in which one is a non-classical and one in the general population, of having a child with the classic form is 1: 480, which is significantly greater than the risk calculated on the basis of the incidence of population. 8 On the other hand, prenatal diagnosis and the identification of parents with severe mutations allow the institution of prenatal treatment with dexamethasone at 20 μg/kg/day (based on pre-pregnancy weight), divided in three doses (maximum dose of 1.5mg / day) .7,8 This therapy aims to normalize the levels of 17-OHP in the amniotic fluid and thus avoid virilization and genital ambiguity. Treatment should be instituted before the 8th week of gestation in all women whose fetuses are at risk of having the classic form of the disease. This therapy should be discontinued when the fetus is male or when prenatal diagnosis excludes the classical form of the disease.7

HCSR-NC is one of the most common autosomal recessive pathologies, with frequent clinical signs in the general population. Its presentation may be monosymptomatic, which implies a high clinical suspicion for its diagnosis. Women with HCSR-NC who are severely mutated should have access to genetic counseling.


THANKS

To all the colleagues who followed this case and who collaborated in the diagnosis and subsequent therapeutic orientation. To the parents for the availability of their daughter's images.


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