ISSN: 1679-9941 (Print), 2177-5281 (Online)
Official website of the journal Adolescencia e Saude (Adolescence and Health Journal)

Vol. 16 nº 1 - Jan/Mar - 2019

When acne is just the tip of the iceberg

Authors: Joana Costa Soares1, Sofia Alexandra Pereira Pires2, Pascoal Moleiro1
1Departamento de Pediatria. Centro Hospitalar de Leiria, Portugal
2Departamento de Pediatria – Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra. Coimbra, Portugal
Correspondence:

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

Keywords: Adrenal Hyperplasia, Congenital; Acne Vulgaris; Acne Keloid; Hyperandrogenism; Child.
Abstract

OBJECTIVE: Acne is a common pathology in adolescence. Severe acne, resistant to therapy or associated with systemic signs may be the manifestation of a systemic disease. We describe a case of congenital adrenal hyperplasia, non-classical form (CHRS-NC), which manifested as a case of severe and refractory acne.
CASE DESCRIPTION: We present the case of an adolescent who was evaluated in a consultation at the age of eleven for exuberant acne that had been progressively worsening since the age of eight, with poor response to treatment. There were no signs of precocious puberty, growth acceleration or hirsutism. Laboratory tests showed elevated total testosterone, delta-4-androstenedione and 17-hydroxyprogesterone, with no ultrasound alterations in the adrenal gland and no criteria for polycystic ovary. A genetic study confirmed the suspected diagnosis of CHRS-NC, at which point she was treated with hydrocortisone and had a good response.
COMMENTS: In this clinical form, there is partial enzyme blockade, and there is no cortisol deficiency. Therefore, it may present late through signs and/or symptoms caused by hyperandrogenism. In symptomatic cases, oral corticosteroid therapy is recommended. Severe acne that is refractory to treatment should be investigated and the hypothesis of HCRS-NC should be considered. The diagnosis of HCRS-NC is also important because it is a possible cause of infertility and prenatal counseling is recommended.

INTRODUCTION

Acne is a very common skin disease, with a prevalence of 70 to 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 on the pilosebaceous unit. 2 It can also be a manifestation of hyperandrogenism, since androgens induce sebum production and, in excess, can cause or aggravate acne. 3 Hyperandrogenism has several causes, such as androgen-producing tumors, polycystic ovary syndrome or congenital adrenal hyperplasia. 3

Despite the high prevalence of acne in adolescence, it can be an isolated sign of systemic diseases. Acne cases in children aged between one and seven years and adolescents should be suspected as severe and/or treatment-resistant acne, associating this with other signs of hyperandrogenism (e.g., signs of precocious puberty, virilization, hirsutism, menstrual irregularities, infertility) or other systemic symptoms (e.g., joint complaints as in SAPHO syndrome – Synovitis, Acne, Pustulosis, Hyperostosis, Inflammatory Osteitis; and signs of hypercortisolism as in Cushing’s syndrome). 1-6

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

CASE DESCRIPTION

A female adolescent was referred to the Adolescent Medicine Consultation at the age of eleven due to exuberant acne that had been developing for three years. She had regular height growth, with no increase in growth velocity, and normal psychomotor development. She had no family history of infertility, ambiguous genitalia, or unexplained neonatal death, and was not taking chronic medication.

At the age of eight, the patient began to develop acne lesions, pubic hair appeared at the age of nine, and thelarche occurred at the age of ten. She first sought dermatology consultation at the age of ten and was medicated with minocycline and erythromycin, without improvement of the acne, and was referred to the Adolescent Medicine consultation. At this consultation, at the age of eleven and two months, physical examination revealed exuberant acne with scarring lesions on the face, neck, and chest (Figure 1). She presented pubertal stage M3/P5, without menarche, hirsutism or signs of genital virilization, or cutaneous striae. The main diagnostic hypotheses were HCRS-NC and polycystic ovary syndrome.

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

Laboratory tests showed elevated total testosterone (81.18 ng/dL), delta-4-androstenedione (5.52 µg/L) and 17-OHP (11.2 ng/ml) levels, and the rest of the laboratory tests were normal, including LH, FSH, estradiol, progesterone and DHEA-SO4 (Table 1). Pelvic and adrenal ultrasound showed no adrenal masses, the ovaries were normal in size and presented some cystic structures of a probable functional nature. A genetic study was performed, which revealed a homozygous mutation g. 1683G>T, which is compatible with a partial deficiency of 21-hydroxylase, confirming the diagnosis of HCRS-NC.

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

Figure 2. Improvement in the patient’s acne after treatment (Image provided by the family).

DISCUSSION

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

Figure 3. Changes in the cortisol synthesis pathway due to 21-hydroxylase deficiency.

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

In the non-classical form, the enzyme blockade is partial (20-50%), leading to adrenal stimulation with excessive androgen production. 10 People with NC-HCR are usually asymptomatic at birth, with no signs of virilization. However, they may later manifest signs of androgen excess or remain asymptomatic. In childhood, the disease may manifest as precocious puberty with accelerated growth, with a risk of compromising final height due to early closure of the epiphyses. In adolescence and adulthood, it may manifest 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 depicted in this case, hence it is important to maintain a level of suspicion in atypical cases of acne or those with poor response to treatment.

The diagnosis may be suggested clinically, but is confirmed by hormonal changes. Elevated 17-OHP is the biochemical marker of 21-hydroxylase deficiency. 17-OHP levels (morning collection) > 82ng/dl (2.5nmol/l) in children are highly suggestive of NC-HCR. 13 However, individuals with the non-classical form may have normal 17-OHP values ​​(2-11%) 10 , where the gold-standard method for diagnosis is the ACTH stimulation test, with 17-OHP measurement 60 minutes after administration of 250g tetracosactide (synthetic ACTH). 7,10 17-OHP levels 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 NC-HCR, and values ​​above 100ng/mL (300nmol/L) are suggestive of the classic form of the disease. 7 As in the case presented, other hormonal changes are also frequently present, such as elevated total testosterone and delta-4-androstenedione. There may also be an increase in urinary excretion of 17-OHP metabolites, such as preganetriol. 7 Genetic testing allows confirmation of the diagnosis in cases of elevated 17-OHP.

In the differential diagnosis of HCSR-NC, other pathologies that occur with excess androgen production must be considered, namely Polycystic Ovary Syndrome, adrenal or gonadal tumors and Cushing’s Syndrome.

Treatment is only necessary if symptoms are present, since unlike the classic form, oral corticosteroid therapy is not essential for survival. Therefore, children whose diagnosis was made by genetic screening are not indicated for treatment. Treatment is only initiated in children due to precocious pubarche with rapid progression, accelerated growth rate with advanced bone age and in adolescents/adults due to exuberant acne, hirsutism and/or oligomenorrhoea/infertility.

The dose of corticosteroids used is the minimum 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, but should be avoided in pediatric age due to the risk of compromising growth. 7,8,13

Regular clinical and analytical monitoring should be carried out, with measurement of 17-OHP, delta-4-androstenedione and testosterone, with the aim of achieving normalization of delta-4-androstenedione and testosterone. Adrenal secretion of androgens should not be completely stopped, since suppressed levels of 17-OHP may indicate overtreatment. 13 In pediatric age, monitoring of growth and pubertal development is essential.

In couples who have already had a child with HCSR or when one of the parents has the disease, genetic counseling is important due to the greater risk of fetuses with the classic form of the disease, whose salt-wasting form is life-threatening due to associated hydroelectrolytic disorders. However, prenatal diagnosis is only possible from the 9th to 11th week of gestation by chorionic villus sampling, or from the 15th to 18th week of gestation by amniocentesis. 7,8

Given that this is an autosomal recessive disease, preconception genetic counseling allows the identification of families at risk in which both parents have the mutation. The calculated probability of a couple, in which one is a carrier of the non-classical form and the other belongs to the general population, of having a child with the classical form is 1:480, which is significantly higher than the risk calculated based on the incidence in the general population. 8 On the other hand, prenatal diagnosis and identification of parents with a severe mutation allows the institution of prenatal treatment with dexamethasone at 20 µg/kg/day (based on pre-pregnancy weight), divided into three doses (maximum dose of 1.5 mg/day). 7,8This therapy aims to normalize 17-OHP levels in the amniotic fluid and thus prevent virilization and genital ambiguity. Treatment should be started 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 classic 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 carry a severe mutation should have access to genetic counseling.

ACKNOWLEDGMENTS

To all colleagues who followed this case and who collaborated in the diagnosis and subsequent therapeutic guidance.

To the parents for their willingness to provide images of their daughter.

Bibliographic References

1. Eichenfield LF, Krakowski AC, Piggott C, Del Rosso J, Baldwin H, Friedlander SF et al. Evidencebased recommendations for the diagnosis and treatment of pediatric acne. Pediatrics. 2013 May;131 (Suppl3):S163-86.

2. Lucky AW. Hormonal correlates of acne and hirsutism. AM J Med 1995 Jan 16;98(1A):89S-94S.

3. Degitz K, Placzek M, Arnold B, Schmidt H, Plewig G. Congenital adrenal hyperplasia and acne in male patients. Br J Dermatol. 2003 Jun; 148(6):1263-6.

4. Freira S, Fonseca H, Ferreira PD, Vasconcelos P, Fonseca JE. SAPHO syndrome in an adolescent: a clinical case with unusual severe systemic impact. J Adolesc Health. 2014 Aug;55(2):304-6.

5. Caputo V, Fiorella S, Curiale S, Caputo A, Niceta M. Refractory acne and 21-hydroxylase deficiency in a selected group of female patients. Dermatology. 2010, 220:121-127.

6. Uzuncakmak TK, Karadag AS, Akdeniz N. Acne and systemic diseases. EMJ Dermatol. 2015, 3:73-78.

7. Azevedo T, Martins T, Lemos MC, Rodrigues F. Nonclassical congenital adrenal hyperplasia – relevant aspects for clinical practice. Rev Port Endocrinol Diabetes Metab. 2014,9:59-64.

8. Vieira A, Paiva S, Baptista C, Ruas L, Silva J, Conçalves J et al. Late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Review of the literature and preconception genetic study of five couples. Acta Med Port. 2011, 24:099-110.

9. Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. 2010. J Clin Endocrinol Metab Sep;95(9):4133-60.

10. Falhammar H, Nordenstrom A. Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment and outcome. Endocrine. 2015, 50:32-50.

11. Cordinha C, Morais S, Cardoso R, Ramos L, Taborda A, Mirante A. Congenital adrenal hyperplasia: when the same genotype has different phenotypes. Port Endocrinol Diabetes Metab. 2011, 1:41-46.

12. Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency. [Accessed in August/2017]. Available at: https://www.uptodate.com/contents/genetics-and-clinical-presentation-of-nonclassic-late-onset-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency?source=search_result&search;=Nonclassic%20congenital%20adrenal%20hyperplasia&selectedTitle;=2~27 .

13. Diagnosis and treatment of non-classic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency [Accessed in August/2017]. Available at: https://www.uptodate.com/contents/diagnosis-and-treatment-of-nonclassic-late-onset-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency?source=search_result&search;=Nonclassic%20congenital%20adrenal%20hyperplasia&selectedTitle;=1~27 .

14. Esoterix Laboratory Services [updated 2015; Accessed 6 August 2018]. Available at: https://www.esoterix.com/sites/esoterix/files/L5167.pdf