Endocrine Abstracts

Introduction: Precocious puberty in boys is the development of secondary sexual characteristics before 9 years of age. Peripheral precocious puberty (PPP), as opposed to central precocious puberty (CPP), is caused by autonomous secretion of androgens or human chorionic gonadotropin (hCG). Testicular volume, penis size, growth velocity, gonadotropin and androgen levels, and bone age readings aid in diagnosing precocious puberty and in identifying its cause. Distinguishing CPP from PPP is rather straightforward and based on the gonadotrophin levels, which are pubertal or prepubertal respectively. However, the differential diagnosis of PPP is challenging and includes several neoplastic causes, such as Leydig cell tumors, hCG-producing germ cell tumors, and androgen-secreting adrenocortical tumors (ACT) (1). ACT are rare in childhood with a reported annual incidence of 0.2-0.3 new cases per million per year. In children, as opposed to adults, most ACT are functioning and secrete cortisol, frequently in combination with androgens. Pure androgen-secreting adrenocortical tumors (PASACT) are extremely rare, they are usually sporadic and benign, but sometimes associated with tumor syndromes, such as Beckwith-Wiedemann syndrome and Li-Fraumeni syndrome (LFS) (2). We present a 2-year-old boy who presented with isosexual PPP due to a PASACT, as the first presentation of LFS. This case illustrates the differential diagnosis of PPP in young boys and highlights the importance of the histopathological and genetic analysis of PASACT.

Case report: A 2 ½ -year-old boy presented with a 6-month history of penile enlargement, pubic hair, frequent erections, and rapid linear growth. No exposure to exogenous testosterone was evident. The boy’s personal and family history was unremarkable. On physical examination his weight was at +2.5 SD, and height at +1.7 SD. He was at Tanner stage Al P4 G3, penile length was 6.8 cm, and he had symmetrical prepubertal testes without palpable abnormalities. He had hypertension with repeated blood pressures above the 95th percentile. His skeletal maturation was advanced by 1 year. Serum gonadotrophin levels were prepubertal, while testosterone (9.9 µg/1) and dehydroepiandrosterone-sulphate (DHEA-S) levels (1.49 mg/1) were elevated. Serum electrolytes, 17-OH-progesterone, androstenedione, ACTH, renin, aldosterone, and cortisol levels were normal, as were 24-h urinary free cortisol excretion and urinary catecholamine levels. The testes were normal upon ultrasound examination, but in the left adrenal a hypo-echogenic lesion was found. Magnetic resonance imaging (MRI) confirmed a well-defined 26x23x3 lmm nodule with limited, but homogenous contrast accumulation, and no evidence of invasion into adjacent organs or vessels. Based on the hormonal findings and imaging features, we decided for tumor resection by laparoscopic adrenalectomy. The tumor was found to be benign based on its histological characteristics (Wieneke criteria, score: 0): tumor weight < 200g, no capsular invasion or tumor necrosis, mitotic activity < 15/20 HPF, and Ki67 index < 15%.Genetic tumor profiling included comparative genomic hybridization, which revealed complex chromosome rearrangements, and capture-based massively parallel sequencing, which identified a previously reported disease-causing variant of TP53 (R158H). This variant was subsequently found as a heterozygous de novo germline missense mutation in a leukocyte sample, confirming the diagnosis ofLFS.

Discussion: Penile growth without testicular enlargement in boys under 9 years of age is a sign of PPP. The differential diagnosis of PPP in boys is broad and includes exposure to exogenous testosterone, testotoxicosis, genetic syndromes, and neoplastic causes. A detailed history and repeated physical examination are needed to document the stage and progression rate of puberty, and sometimes suffice to identify the cause of PPP. Initial screening should include bone age, measurement of gonadotropins, testosterone, hCG, DHEA-S, 17-0H-progesterone, cortisol, and aldosterone levels. PASACT is a rare neoplastic cause of PPP and represent a diagnostic challenge (3). We report on a boy presenting with isosexual PPP caused by a PASACT in the context of LFS. The selective secretion of testosterone and DHEA-S, the absence of invasion into adjacent tissues, and the small tumor size established by MRI were suggestive of an adrenocortical adenoma, as opposed to a carcinoma, and were decisive for a laparoscopic resection. Androgen secretion by ACTs is often accompanied by aldosterone secretion causing hypertension, but in this patient the hypertension was not related to an excess of aldosterone, cortisol, or catecholamines. Of note, blood pressures in children should always be measured using correct cuff sizes and interpreted using percentiles by age and height. The histology of PASACT is also challenging and a distinct scale, the Wieneke criteria, is used to grade pediatric ACT, as opposed to the Weiss criteria in adults (4). Germline TP53 mutations causing LFS have been identified in more than half of children with ACT (5). Here, the absence of a positive family history of cancer is in line with the de novo nature of the TP53 mutation. A high rate of de novo germline TP53 mutations and a variable expression and penetrance make families with LFS prone be missed. The R158H missense mutation reported here has previously been reported in children with ACT (5). This mutation hits the functional part of the DNA-binding domain of P53 and imparts a transcriptional activity comparable to null mutations. A strict surveillance protocol, including annual total body and brain MRI is therefore warranted in this patient and exposure to ionizing radiation should be minimized.

References: 1. Carel JC, Leger J. Clinical practice. Precocious puberty. N Engl J Med. 2008;358(22):2366-77.

2. Pinto EM, Zambetti GP, Rodriguez-Galindo C. Pediatric adrenocortical tumours. Best Pract Res Clin Endocrinol Metab. 2020;34(3):101448.

3. Tong A, Jiang J, Wang F, Li C, Zhang Y, Wu X. Pure Androgen-Producing Adrenal Tumor: Clinical Features and Pathogenes is . Endocr Pract. 2017;23(4):399-407.

4. Chatterjee G, DasGupta S, Mukherjee G, Sengupta M, Roy P, Arun I, Datta C, Mishra PK, Banerjee S, Chatterjee U. Usefulness of Wieneke criteria in assessing morphologic characteristics of adrenocortical tumors in children. Pediatr Surg Int. 2015;31(6):563-71.

5. Varley JM, McGown G, Thorncroft M, James LA, Margison GP, Forster G, Evans DG, Harris M, Kelsey AM, Birch JM. Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors. Am J Hum Genet. 1999;65(4):995-1006.