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Endocrine-related Cancer Jan 2016Five syndromes share predominantly hyperplastic glands with a primary excess of hormones: neonatal severe primary hyperparathyroidism, from homozygous mutated CASR,... (Review)
Review
Five syndromes share predominantly hyperplastic glands with a primary excess of hormones: neonatal severe primary hyperparathyroidism, from homozygous mutated CASR, begins severely in utero; congenital non-autoimmune thyrotoxicosis, from mutated TSHR, varies from severe with fetal onset to mild with adult onset; familial male-limited precocious puberty, from mutated LHR, expresses testosterone oversecretion in young boys; hereditary ovarian hyperstimulation syndrome, from mutated FSHR, expresses symptomatic systemic vascular permeabilities during pregnancy; and familial hyperaldosteronism type IIIA, from mutated KCNJ5, presents in young children with hypertension and hypokalemia. The grouping of these five syndromes highlights predominant hyperplasia as a stable tissue endpoint and as their tissue stage for all of the hormone excess. Comparisons were made among this and two other groups of syndromes, forming a continuum of gland staging: predominant oversecretions express little or no hyperplasia; predominant hyperplasias express little or no neoplasia; and predominant neoplasias express nodules, adenomas, or cancers. Hyperplasias may progress (5 of 5) to neoplastic stages while predominant oversecretions rarely do (1 of 6; frequencies differ P<0.02). Hyperplasias do not show tumor multiplicity (0 of 5) unlike neoplasias that do (13 of 19; P<0.02). Hyperplasias express mutation of a plasma membrane-bound sensor (5 of 5), while neoplasias rarely do (3 of 14; P<0.002). In conclusion, the multiple distinguishing themes within the hyperplasias establish a robust pathophysiology. It has the shared and novel feature of mutant sensors in the plasma membrane, suggesting that these are major contributors to hyperplasia.
Topics: Adenoma; Adult; Child; Endocrine Glands; Female; Hormones, Ectopic; Humans; Hyperplasia; Hyperthyroidism; Male; Parathyroid Glands; Parathyroid Neoplasms; Pregnancy; Puberty, Precocious
PubMed: 26407873
DOI: 10.1530/ERC-15-0171 -
The Journal of Clinical Endocrinology... Nov 2022The purpose of this study is to report development of a malignant testicular germ cell tumor (GCT) in 2 young adult males with familial male-limited precocious puberty... (Review)
Review
OBJECTIVE
The purpose of this study is to report development of a malignant testicular germ cell tumor (GCT) in 2 young adult males with familial male-limited precocious puberty (FMPP) because of LHCGR pathogenic variants in 2 families. Secondarily, to study the possible relation between FMPP and testicular tumors and to investigate whether FMPP might predispose to development of malignant testicular tumors in adulthood a literature review is conducted.
METHODS
Data on 6 cases in 2 families are obtained from the available medical records. In addition, a database search is performed in Cochrane, PubMed, and Embase for studies that report on a possible link between FMPP and testicular tumors.
RESULTS
The characteristics of 6 males with FMPP based on activating LH receptor (LHCGR) germline pathogenic variants are described, as are details of the testicular GCTs. Furthermore, a literature review identified 4 more patients with signs of FMPP and a (precursor of) testicular GCT in adolescence or adulthood (age 15-35 years). Additionally, 12 patients with signs of precocious puberty and, simultaneously, occurrence of a Leydig cell adenoma or Leydig cell hyperplasia are reported.
CONCLUSION
There is a strong suggestion that FMPP might increase the risk of development of testicular GCTs in early adulthood compared with the risk in the general population. Therefore, prolonged patient monitoring from mid-pubertal age onward including instruction for self-examination and periodic testicular ultrasound investigation in patients with a germline LHCGR pathogenic variant might contribute to early detection and thus early treatment of testicular GCT.
Topics: Adolescent; Adult; Humans; Male; Young Adult; Puberty, Precocious; Testicular Neoplasms
PubMed: 36071555
DOI: 10.1210/clinem/dgac516 -
Best Practice & Research. Clinical... Jun 2019Peripheral precocious puberty results from peripheral production of sex steroids independent of activation of the hypothalamic-pituitary gonadal axis. It is much less... (Review)
Review
Peripheral precocious puberty results from peripheral production of sex steroids independent of activation of the hypothalamic-pituitary gonadal axis. It is much less common than central precocious puberty. Causes are variable and can be congenital or acquired. In this review, we will discuss the diagnosis and management of the most common etiologies including congenital adrenal hyperplasia, McCune Albright syndrome, familial male-limited precocious puberty, and adrenal and gonadal tumors.
Topics: Adrenal Gland Neoplasms; Adrenal Hyperplasia, Congenital; Female; Fibrous Dysplasia, Polyostotic; Humans; Male; Puberty, Precocious
PubMed: 31027974
DOI: 10.1016/j.beem.2019.04.007 -
Frontiers in Endocrinology 2022The long-term follow-up in children with familial male-limited precocious puberty (FMPP) who were treated with letrozole, triptorelin, and spironolactone is limited,...
BACKGROUND
The long-term follow-up in children with familial male-limited precocious puberty (FMPP) who were treated with letrozole, triptorelin, and spironolactone is limited, especially considering the efficiency and safety.
OBJECTIVE
We describe the clinical characteristics and long-term treatment with letrozole on adult height of a boy diagnosed with FMPP, confirmed by analysis of the LHCGR gene.
METHODS
Physical examinations, bone age (BA), testosterone, and gonadotropin levels were measured as well as gene sequencing of the proband and parents.
RESULTS
The boy was referred to the hospital at 3.1 years of age due to peripheral precocious puberty. His height was 116.8cm (+5.1SD) and BA was 9 years. Genetic analysis revealed a patrilineal c.1703C>T.(p.Ala568Val) mutation of the LHCGR gene. After treating with letrozole for 1.6 years, the height according to BA went from -3.52SD to -2.82SD. Triptorelin was added at age 4.7 years based on both the evidence of central puberty and his growth velocity according to BA. During the 6.9 years of treatment, he had a height gain of 51.9cm, and BA increased 5.2 years. At age 10, his present height is 168.7cm (0.05SD) and BA is 14.7 years. No adverse effects of treatment were encountered.
CONCLUSION
A patrilineal mutation of the LHCGR gene has been identified in a boy with FMPP. His height is 168.7cm (-0.05SD) which is approaching his adult height after long-term treatment with letrozole, triptorelin, and spironolactone.
Topics: Adult; Child; Child, Preschool; Humans; Letrozole; Male; Puberty, Precocious; Spironolactone; Triptorelin Pamoate
PubMed: 35909557
DOI: 10.3389/fendo.2022.906852 -
Journal of Medical Case Reports May 2023Pure androgen-secreting adrenocortical tumors are a rare but important cause of peripheral precocious puberty. (Review)
Review
INTRODUCTION
Pure androgen-secreting adrenocortical tumors are a rare but important cause of peripheral precocious puberty.
CASE PRESENTATION
Here, we report a pure androgen-secreting adrenocortical tumor in a 2.5-year-old boy presenting with penile enlargement, pubic hair, frequent erections, and rapid linear growth. We confirmed the diagnosis through laboratory tests, medical imaging, and histology. Furthermore, genetic testing detected a pathogenic germline variant in the TP53 gene, molecularly confirming underlying Li-Fraumeni syndrome.
DISCUSSION
Only 15 well-documented cases of pure androgen-secreting adrenocortical tumors have been reported so far. No clinical or imaging signs were identified to differentiate adenomas from carcinomas, and no other cases of Li-Fraumeni syndrome were diagnosed in the four patients that underwent genetic testing. However, diagnosing Li-Fraumeni syndrome is important as it implies a need for intensive tumor surveillance and avoidance of ionizing radiation.
CONCLUSION
In this article, we emphasize the need to screen for TP53 gene variants in children with androgen-producing adrenal adenomas and report an association with arterial hypertension.
Topics: Male; Child; Humans; Child, Preschool; Li-Fraumeni Syndrome; Genes, p53; Androgens; Puberty, Precocious; Adrenal Cortex Neoplasms
PubMed: 37179382
DOI: 10.1186/s13256-023-03889-y -
Postgraduate Medical Journal Mar 1992In this era of rapidly developing investigational tools and pharmacology, the pathophysiology of precocious puberty is becoming well defined. What was previously thought...
In this era of rapidly developing investigational tools and pharmacology, the pathophysiology of precocious puberty is becoming well defined. What was previously thought to be a form of gonadotrophin releasing hormone (GNRH)-dependent central precocious puberty is now classified as GNRH-independent familial testotoxicosis. We present two such cases and review the clinical features, pathophysiology and treatment of testotoxicosis.
Topics: Child; Child, Preschool; Genitalia, Male; Humans; Male; Puberty, Precocious; Testosterone
PubMed: 1589386
DOI: 10.1136/pgmj.68.797.225 -
Journal of Clinical Research in... Sep 2015Testotoxicosis is a rare disorder which presents as isosexual peripheral precocious puberty in males. Despite the pattern of autosomal dominant inheritance, sporadic...
Testotoxicosis is a rare disorder which presents as isosexual peripheral precocious puberty in males. Despite the pattern of autosomal dominant inheritance, sporadic cases also may occur. Due to activating mutation in luteinizing hormone (LH))/choriogonadotropin receptor (LHCGR) gene, early virilization and advancement in bone age are common with increased serum testosterone levels above adult ranges, despite low LH and follicular-stimulating hormone (FSH) levels. There are different treatment regimens, such as combination of bicalutamide (antiandrogen agent) and a third-generation aromatase inhibitor, that are reported to be well-tolerated and successful in slowing bone age advancement and preventing progression of virilization. We report here two patients who presented with peripheral precocious puberty and an activating mutation in the LHCGR gene: one with a family history and previously determined mutation and the other without family history and with a novel mutation (c.830G>T). Combination of bicalutamide+anastrozole was ineffective in slowing pubertal progression and bone age. Short-term results were better with ketoconazole.
Topics: Anastrozole; Androgen Antagonists; Anilides; Aromatase Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Genetic Predisposition to Disease; Humans; Infant; Ketoconazole; Male; Mutation; Nitriles; Puberty, Precocious; Receptors, LH; Sequence Analysis, DNA; Testosterone; Tosyl Compounds; Triazoles
PubMed: 26831561
DOI: 10.4274/jcrpe.2067 -
Journal of Clinical Research in... Jun 2021Familial male-limited precocious puberty (FMPP), also known as testotoxicosis, is a rare cause of precocious puberty in males. It is caused by a mutation in the...
Familial male-limited precocious puberty (FMPP), also known as testotoxicosis, is a rare cause of precocious puberty in males. It is caused by a mutation in the luteinizing hormone/chorionic gonadotropin receptor () gene, resulting in the receptor being constitutively activated. This causes excessive production of testosterone, leading to precocious puberty in males. Generally, boys present with signs of puberty, such as pubic hair growth, acne, and increased height velocity around the age of 2-4 years old. Like any other cause of precocious puberty, the goal of treatment is to prevent virilization and also delay closure of the epiphyseal plates to maintain adult height potential. Treatment, therefore, is aimed at decreasing the effects of testosterone, as well as stopping the conversion of testosterone to estrogen. Little is known about the long-term effects of treatment because the disorder is so rare. However, studies using bicalutamide and anastrozole have been promising. In this report, we present a boy with FMPP with a novel mutation in the gene, who has been responding well to therapy using both drugs.
Topics: Humans; Infant; Male; Mutation; Puberty, Precocious; Receptors, LH
PubMed: 32757547
DOI: 10.4274/jcrpe.galenos.2020.2020.0067 -
BMC Endocrine Disorders Oct 2023The pineal lesion affecting melatonin is a rare cause of central precocious puberty by decreasing the inhibition of hypothalamic-pituitary-gonadal axis. Germ cell tumor... (Review)
Review
BACKGROUND
The pineal lesion affecting melatonin is a rare cause of central precocious puberty by decreasing the inhibition of hypothalamic-pituitary-gonadal axis. Germ cell tumor secreting human chorionic gonadotropin is a rare cause of peripheral puberty.
CASE PRESENTATION
A 5.8-year-old male presented facial hair and phallic growth, deepened voice, and accelerated growth velocity for 6 months. The elevated human chorionic gonadotropin level with undetectable gonadotropin levels indicated peripheral precocious puberty. Brain imaging revealed a pineal mass and further pathology indicated the diagnosis of teratoma. During chemoradiotherapy with operation, the elevated human chorionic gonadotropin level reduced to normal range, while the levels of gonadotropins and testosterone increased. Subsequently, progressing precocious puberty was arrested with gonadotrophin-releasing hormone analog therapy. Previous cases of transition from peripheral precocious puberty to central precocious puberty were reviewed. The transitions were caused by the suddenly reduced feedback inhibition of sex steroid hormones on gonadotropin releasing hormone and gonadotropins.
CONCLUSIONS
For patients with human chorionic gonadotropin-secreting tumors, gonadotropin levels increase prior to sex steroid decrease, seems a sign of melatonin-related central PP related to melatonin.
Topics: Child, Preschool; Humans; Male; Chorionic Gonadotropin; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone; Melatonin; Neoplasms, Germ Cell and Embryonal; Puberty, Precocious
PubMed: 37884982
DOI: 10.1186/s12902-023-01494-0 -
The Journal of Pediatrics Nov 2017Antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone analog (GnRHa) treatment normalizes growth rate and bone maturation and increases predicted adult... (Clinical Trial)
Clinical Trial
OBJECTIVE
Antiandrogen, aromatase inhibitor, and gonadotropin-releasing hormone analog (GnRHa) treatment normalizes growth rate and bone maturation and increases predicted adult height (AH) in boys with familial male-limited precocious puberty (FMPP). To evaluate the effect of long-term antiandrogen, aromatase inhibitor, and GnRHa on AH, boys with FMPP who were treated were followed to AH.
STUDY DESIGN
Twenty-eight boys with FMPP, referred to the National Institutes of Health, were started on antiandrogen and aromatase inhibitor at 4.9 ± 1.5 years of age; GnRHa was added at 6.9 ± 1.5 years of age. Treatment was discontinued at 12.2 ± 0.5 years of age (bone age, 14.4 ± 1.3). AH was assessed at 16.4 ± 1.3 years of age (bone age, 18.5 ± 0.6).
RESULTS
AH (mean ± SD) for all treated subjects was 173.6 ± 6.8 cm (-0.4 ± 1.0 SD relative to adult US males). For 25 subjects with pretreatment predicted AH, AH significantly exceeded predicted AH at treatment onset (173.8 ± 6.9 vs 164.9 ± 10.7 cm; P < .001), but fell short of predicted AH at treatment discontinuation (177.3 ± 9.0 cm; P < .001). For 11 subjects with maternal or sporadic inheritance, the mean AH was 3.1 cm (0.4 SD score) below sex-adjusted midparental height (175.4 ± 5.8 vs 178.5 ± 3.1 cm [midparental height]; P = .10). For 16 subjects with affected and untreated fathers, AH was significantly greater than fathers' AH (172.8 ± 7.4 vs 168.8 ± 7.2 cm; P < .05).
CONCLUSIONS
Long-term treatment with antiandrogen, aromatase inhibitor, and GnRHa in boys with FMPP results in AH modestly below sex-adjusted midparental height and within the range for adult males in the general population.
Topics: Adult; Anastrozole; Androgen Antagonists; Aromatase Inhibitors; Body Height; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Male; Nitriles; Puberty, Precocious; Spironolactone; Testolactone; Treatment Outcome; Triazoles; Triptorelin Pamoate
PubMed: 29144249
DOI: 10.1016/j.jpeds.2017.07.047