Peripheral Precocious Puberty Research Articles

7291 From Vaginal Bleeding to Genetic Complexity: McCune Albright Syndrome in a Toddler; Emphasizing Atypical Manifestations, Diagnostic Challenges, and Comprehensive Management

Abstract Disclosure: A.G. Martinez Sanchez: None. N. Fernandez: None. C.L. Bustamante Escobar: None. Background: McCune Albright Syndrome (MAS) is a rare genetic disorder characterized by a triad of peripheral precocious puberty, irregular café-au-lait spots, and bone fibrous dysplasia. It is often caused by post-zygotic somatic mutations in the GNAS1 gene. We present a case of a patient initially presenting with precocious puberty, whose diagnostic journey revealed MAS with atypical manifestations. Presentation: A 23-month-old girl was brought to the emergency department after her mother noticed vaginal bleeding during a diaper change; denied any trauma, fever, rash, or dysuria. Patient developed accelerated growth about six months earlier, followed by pubic hair three months prior and bilateral thelarche two weeks before presentation. The patient had no exposure to endocrine disruptors. The physical examination revealed a well-developed child, in the 92nd percentile for weight and 97th for height. Additionally, breast buds, fine hair on the labia, and minimal blood at the vaginal introitus, with no apparent signs of trauma. Initial laboratory findings showed prepubertal LH and FSH levels, elevated estradiol 120 pg/ml (prepubertal range <10) and advanced bone age (4.2 years). Normal levels of testosterone, 17-hydroxyprogesterone, and DHEA sulfate. Pelvic ultrasound demonstrated an enlarged uterus (5.6 x 1.8 x 2.4 cm) and a large cystic lesion (4.4 cm) on the right ovary. During a follow-up at the endocrinology department one week later, a meticulous examination identified an irregular café-au-lait spot measuring about 2cm over the occipital right side of her scalp. Further tests, including GnRH stimulation test, tumor markers (LDH, b-HCG, CEA, and Ca19-9), brain MRI and bone scan, yielded normal findings. Given the presentation consistent with Peripheral precocious puberty, Letrozole was initiated at 1.25 mg daily. Three months later, her growth velocity remained accelerated. However, there was a decrease in both breast tissue and uterus size (4.2 x 1.2 x 1.7 cm), and the ovarian cyst was resolved. Genetic testing in blood indicated no mutations. To conduct a thorough assessment, the insulin-like growth factor (IGF-1) level was measured and found to be 200 ng/mL (normal range 56-144 ng/mL). Unfortunately, obtaining prolactin levels was challenging due to difficult intravenous (IV) access. Conclusion: This case reveals the complexity of MAS in precocious puberty, emphasizing atypical features that add complexity to the diagnosis. Identifying an irregular café-au-lait spot served as a diagnostic indicator, revealing the diverse clinical presentations. The challenges of relying solely on genetic testing for diagnosis are evident due to the mosaic nature and tissue-specific distribution of the mutation, as highlighted by the absence of mutations in this patient. Long-term management requires ongoing monitoring and a multidisciplinary approach for optimal patient outcomes. Presentation: 6/1/2024

Central precocious puberty should be taken seriously in children with Leydig cell tumors of the testis after surgical treatment: a tertiary center experience.

Central precocious puberty secondary to Leydig cell tumors is rare in children. We retrospectively analyzed the mid- to long-term follow-up data of patients with Leydig cell tumors. The clinical data of 12 consecutive patients who were treated at Beijing Children's Hospital, Capital Medical University (Beijing, China), between January 2016 and October 2023 were retrospectively reviewed. Clinical evaluations, including physical examination, hormone examination, serum tumor marker analysis, abdominal and scrotal ultrasound, chest X-ray, and bone age measurement, were conducted before surgery and at follow-up time points. Surgical approaches were selected according to the individual conditions. Patients with an abnormal hormonal status and suspected of having central precocious puberty were referred to endocrinologists to confirm the diagnosis. Subsequently, gonadotropin-releasing hormone analog therapy was proposed. The mean patient age was 81.3 (range: 40-140) months at the time of the operation. Ten patients had peripheral precocious puberty at admission. All patients had elevated preoperative testosterone levels, whereas tumor marker levels were normal. Testis-sparing surgery was performed in eleven patients, and radical orchiectomy was performed in one patient. The follow-up duration (mean ± standard deviation) was 36.2 ± 25.3 months. Five patients had central precocious puberty, with a mean duration of 3.4 (range: 1-6) months postoperatively. Three patients were receiving gonadotropin-releasing hormone analog therapy, and good suppression of puberty was observed. No risk factors were found for secondary central precocious puberty. There was a high prevalence of central precocious puberty secondary to Leydig cell tumors in our study. Gonadotropin-releasing hormone analog therapy has satisfactory treatment effects. Larger sample sizes and long-term follow-up are needed in future studies.

Analysis of clinical features of 193 Chinese patients with McCune-Albright syndrome through a literature review

To retrospectively analyze the clinical characteristics of 193 Chinese patients with McCune-Albright syndrome (MAS). By using keywords "McCune-Albright syndrome", "Albright syndrome", or " fibrous dysplasia " as the search terms, 193 cases of MAS reported in China from January 1990 to November 2022 from the Wanfang data, CNKI, VIP, PubMed, and Embase databases were obtained, and their clinical data was retrospectively analyzed. Intergroup comparisons were carried out by using t test, Mann-Whitney U test, and X2 test. The 193 MAS patients had included 42 males and 151 females, with the median first-visit age of females being younger than males. The typical triad group had accounted for 46.1% of patients, and the middle first-visit and diagnosis age was younger than the atypical group. The primary reason for first-visit in males of MAS was fibrous dysplasia (FD), whilst that in females of MAS was peripheral precocious puberty (PPP). FD has occurred in 84.5% of the patients, with an average age of onset age being 6.1 years old, and 90% was ≤ 16 years of age. Endocrine hyperfunction was found in 79.3% of the patients, with a higher proportion in females compared with males (P < 0.05). Pituitary involvement was seen in 21.8% of the patients, and the incidence of craniofacial FD and cranial nerve compression was significantly higher in those with elevated growth hormone (GH) than without (P < 0.05). Café-au-Lait Spots were noted in 86.5% of the patients, and 28.3% (28/99) had located on the different side of FD. Most MAS patients had atypical manifestations and multi-systemic involvement. It is more common and occurs earlier in females. The most common reasons for initial diagnosis in male and female patients were FD and PPP, respectively. Patients with elevated GH should be examined for cranial nerve compression.

Diagnostic Value of Stimulated Urine Luteinizing Hormone After Triptorelin Stimulation Test in Girls with Central Precocious Puberty.

To investigate the diagnostic value of urine luteinizing hormone (ULH) after the triptorelin stimulation test detected by immunochemiluminometric assay (ICMA) in girls with central precocious puberty (CPP). The girls with precocious puberty were included. The triptorelin stimulation test at 8:30 a.m. was performed. Two consecutive 12-hour urine samples were collected after the test, defined as the first 12-hour and second 12-hour urine, respectively. ICMA measured ULH. Urine creatinine (Cr) concentration was measured. CPP and peripheral precocious puberty (PPP) were diagnosed by the same pediatric endocrinologist based on clinical symptoms, signs, and progression of clinical development. A total of 97 cases (CPP n=69; PPP n=28) were included, with 12 cases not meeting the receiver operating characteristic analysis criteria. The first and second 12-hour ULH/Cr in the CPP group were higher than those in the PPP group. When the first 12-hour ULH/Cr was≥287.252 IU/mol, the sensitivity and specificity for diagnosing CPP were 87.3% and 90.9%, respectively. When the second 12-hour ULH/Cr was≥152.769 IU/mol, the sensitivity and specificity for diagnosing CPP were 92.1% and 90.9%, respectively. The area under the curve of the first and second 12-hour ULH/Cr were 0.933 and 0.954, respectively. The ULH detection method after the triptorelin stimulation test has clinical significance for diagnosing CPP in girls. When blood sampling compliance in girls with precocious puberty is poor, the first 12-hour ULH/Cr≥288 IU/mol (or second 12-hour≥153 IU/mol) after the triptorelin stimulation test can serve as a laboratory indicator for diagnosis of CPP.

Lipidomics reveals ceramide biomarkers for detecting central precocious puberty in girls

BackgroundPubertal timing is modulated by complex interactions between the pituitary and gonadal sex steroid hormones. Evidence indicates that sphingolipids are involved in the biosynthesis of steroid hormones at multiple levels. MethodThis study recruited adolescent female patients from pubertal and pediatric endocrine clinics in Northern and Southern Taiwan from the Taiwan Puberty Longitudinal Study. A total of 112 plasma samples (22 healthy control, 29 peripheral precocious puberty (PPP), and 61 CPP samples) were collected. We extracted lipids from the plasma samples using the modified Folch method. The un-targeted ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was employed for the lipid analysis. ResultsWe identified sphingolipid-linked metabolites, including Cer(18:0/15:0), Cer(18:1/16:0), and Cer(18:1/26:0) as candidate biomarkers for distinguishing girls with CPP from the control group by using an excellent discrimination model (AUC = 0.964). Moreover, Cer(18:0/22:0) and Cer(d18:0/18:1) were identified as potential biomarkers of PPP, with an AUC value of 0.938. Furthermore, CerP(18:1/18:0) was identified as the sole candidate biomarker capable of differentiating CPP from PPP. ConclusionsThe biomarkers identified in this study can facilitate the accurate detection of CPP in girls, provide insights into lipid-linked pathophysiology, and present a novel method of monitoring the progression of this disorder.

PRECOCIOUS PUBERTY: EPIDEMIOLOGY, CLINICAL PRESENTATION, DIAGNOSIS, AND ETIOLOGIES

Precocious puberty, defined as the onset of sexual characteristics before the age of 8 in girls and 9 in boys, can arise from various causes, including central and peripheral mechanisms. While central precocious puberty (CPP) originates from premature activation of the hypothalamic-pituitary axis, peripheral precocious puberty (PPP) results from gonadal or adrenal hormone secretion independent of hypothalamic control. We conducted a retrospective study spanning eight years, from 2015 to 2023, at the Mohamed 6 University Hospital in Marrakech, Morocco, to investigate the epidemiological, clinical findings, laboratory, and etiological aspects of precociuos puberty in 12 children. We found a predominance of CPP, particularly in girls, with breast development being the most common clinical sign. In boys, early puberty typically presented with pubic hair development and increased penile size. Diagnostic evaluation included hormonal assays and imaging studies, with elevated levels of gonadal hormones confirming the diagnosis. CPP was predominantly idiopathic in girls, while traumatic brain injury and CNS lesions were common causes in boys. Adrenal disorders, including congenital adrenal hyperplasia, accounted for PPP cases. Brain imaging was crucial for identifying central lesions, while adrenal imaging aided in diagnosing adrenal pathologies. Despite limitations such as retrospective design and incomplete data, our study emphasizes the importance of early recognition and appropriate diagnostic procedures for children showing signs of early puberty to optimize management and outcomes.

A zebra among horses - testotoxicosis as a rare cause of peripheral precocious puberty

A zebra among horses - testotoxicosis as a rare cause of peripheral precocious puberty

Irisin combined index to diagnose central precocious puberty in girls: a cross-sectional study

BackgroundTo investigate serum irisin levels in girls at different developmental status and explore the significance of irisin for the diagnosis of central precocious puberty (CPP) in girls.MethodsIn this cross-sectional study 111 girls were enrolled, including 43 cases of CPP, 44 cases of peripheral precocious puberty (PPP) and 24 cases of girls with normal sexual development as controls. The data on age, weight and height, measured blood levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, and irisin were collected. Pelvic Doppler ultrasound was performed to evaluate uterine length, transverse diameter, anteroposterior diameter. The girls were divided into non-CPP group and CPP group according to gonadotropin-releasing hormone (GnRH) stimulation test.ResultsSerum irisin levels were significantly higher in CPP group than in PPP group and normal control group. Serum irisin level was positively correlated with basal LH level, basal FSH level, peak LH level, peak LH /FSH ratio, uterine volume, bone age, and bone age index. The area under the curve, cut-off value, sensitivity and specificity of serum irisin were 0.958, 219.255 pg/ml, 100% and 80.6%. The combined diagnosis of CPP in girls by serum irisin and serum basal LH combined with uterine volume had an AUC, sensitivity, and specificity of 0.994, 97.6%, and 100%, superior to that of the single index.ConclusionsSerum irisin level in girls with CPP is significantly increased. An irisin combined index could help the diagnosis of CPP in girls.

Precocious Puberty: Etiology and Current Treatment

Precocious puberty also known as premature puberty is an abnormal pubertal development that can affect a child's growth and development. The clinical manifestations of precocious puberty are generally diverse and based on etiology are classified into central precocious puberty (GnRH dependent) and peripheral precocious puberty (GnRH independent). The main concern with precocious puberty is that precocious puberty can be a clinical symptom of an underlying serious disease such as a brain tumor, adrenal or gonadal tumor and others. Early identification of etiology plays an important role in prevention, diagnosis, and treatment of this disease. This literature review aims to determine the etiology and current management of precocious puberty. This literature review uses the keywords "Precocious Puberty AND etiology AND treatment" through the National Center for Biotechnology Information (NCBI) and Google Scholar databases. This article uses 11 articles that were used as references in its preparation. In conclusion, it is necessary to know the etiology of precocious puberty using imaging examinations for optimal management and excluding malignant abnormalities. The current treatment for central precocious puberty is GnRH agonists (gold-standard) and surgery in cases of intracranial lesions and peripheral precocious puberty using a combination of androgen antagonists (spironolactone) and aromatase inhibitors (anastrozole, testolactone) and surgery is indicated for gonadal and adrenal tumors. The role of parents is very important in early detection of precocious puberty, because the earlier the therapy, the better the prognosis.

Precocious Puberty in Hypothyroidism: Mini-Review of Van Wyk-Grumbach Syndrome.

Severe hypothyroidism can affect a variety of organs and can develop atypical manifestations. Peripheral precocious puberty may be secondary to other endocrinological diseases, which must be taken into account in the differential diagnosis in order to avoid unnecessary additional tests. Van Wyk-Grumbach syndrome is an infrequent manifestation characterized by severe hypothyroidism and incomplete precocious puberty. Diagnosis is made by clinical and complementary tests, and the main treatment goal is to achieve euthyroidism through hormone replacement. Prognosis is good once the treatment is established. The aim of this study is to review the available literature about Van Wyk-Grumbach syndrome following the PRISMA statement, and to present the first clinical case published in Spain. We have included the articles published during the period from 1905 to week 40 of 2022. A total of 68 articles have been selected for study and analysis, within which there are 99 published clinical cases. Girls accounted for 92.1% of cases (median age at the diagnosis 8.5 years). Metrorrhagia was the most prevalent symptom, present in 80.5% of the girls. Abdominal ultrasound was performed in 93.3% of the girls and 97.8% of them had at least one ovarian cyst. All cases were treated with levothyroxine, responding satisfactorily after the first doses of treatment. To conclude, Van Wyk-Grumbach syndrome is characterized by severe hypothyroidism and incomplete precocious puberty, which is important to keep in mind in order to avoid complementary exams and unnecessary surgical interventions.

Challenging clinical scenario: Germ cell tumor masquerading as peripheral precocious puberty in a one-year-old boy from Pakistan

Challenging clinical scenario: Germ cell tumor masquerading as peripheral precocious puberty in a one-year-old boy from Pakistan

Central precocious puberty secondary to peripheral precocious puberty due to a pineal germ cell tumor: a case and review of literature

BackgroundThe 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 presentationA 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.ConclusionsFor 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.

Precocious Puberty: Types, Pathogenesis and Updated Management.

Precocious puberty (PP) means the appearance of secondary sexual characters before the age of eight years in girls and nine years in boys. Puberty is indicated in girls by the enlargement of the breasts (thelarche) in girls and in boys by the enlargement of the testes in either volume or length (testicular volume = 4 mL, testicular length = 25 mm, or both). Two types of PP are recognized - namely central PP (CPP) and peripheral PP (PPP). This paper aims to describe the clinical findings and laboratory workup of PP and to illustrate the new trends in the management of precocious sexual maturation. Gonadotropin-releasing hormone (GnRH)-independent type (PPP) refers to the development of early pubertal maturation not related to the central activation of the hypothalamic-pituitary-gonadal (HPG) axis. It is classified into genetic or acquired disorders. The most common forms of congenital or genetic causes involve McCune-Albright syndrome (MAS), familial male-limited PP, and congenital adrenal hyperplasia. The acquired causes include exogenous exposure to androgens, functioning tumors or cysts, and the pseudo-PP of profound primary hypothyroidism. On the other hand, CPP is the most common and it is a gonadotropin-dependent form. It is due to premature maturation of the HPG axis. CPP may occur as genetic alterations, such asMKRN3, DLK1, or KISS1;as a part of mutations in theepigenetic factors that regulate the HPG axis, such as Lin28b and let-7; or as a part of syndromes, central lesions such as hypothalamic hamartoma, and others. A full, detailed history and physical examination should be taken. Furthermore, several investigations should be conducted for both types of PP, including the estimation of serum gonadotropins such as luteinizing and follicle-stimulating hormones and sex steroids, in addition to a radiographic workup and thyroid function tests. Treatment depends on the type of PP: Long-acting GnRHa, either intramuscularly or implanted, is the norm of care for CPP management, while in PPP, especially in congenital adrenal hyperplasia, the goal of management is to suppress adrenal androgen secretion by glucocorticoids. In addition, anastrozole and letrozole - third-generation aromatase inhibitors - are more potent for MAS.

A toddler with testosterone: where did it come from?

Precocious development of secondary sexual characters not involving pulsatile gonadotropin secretion is known as gonadotropin independent precocious puberty or peripheral precocious puberty (PPP). This form of sexual precocity in males can occur due to gonadal, adrenal, or other testosterone secreting tumors (teratomas, hepatomas, and choriocarcinomas), untreated congenital adrenal hyperplasia, testotoxicosis, and familial male limited precocious puberty. We report a case of a 2-year-old boy with PPP caused due to hepatoblastoma. Complete surgical resection of the tumor was done, and the child received cisplatin chemotherapy.

THU198 Peripheral Precocious Puberty In Girls Due To Ovarian Cyst

Abstract Disclosure: H. Lee: None. J. Hwang: None. Y. Shim: None. S. Heo: None. Objective: Peripheral precocious puberty (PPP) is precocious development of secondary sexual characteristics caused by mechanisms that do not involve activation of pulsatile GnRH secretion. PPP in girl is less frequent than central precocious puberty (CPP). it is caused by various disease such as gonadal and adrenal tumors, ovarian cysts, hypothyroidism and exposure to exogenous sex steroids. In particular, discordant pubertal development with vaginal bleeding within one year of breast development suggests hyperestrogenic state, and may be caused by autonomous ovarian cysts, McCune-Albright syndrome (MAS) and hypothyroidism. We aimed to investigate clinical characteristics and long-term clinical course of PPP in girls with ovarian cyst. Methods: This study was conducted through a retrospective medical record analysis. We studied 12 patients who were diagnosed with PPP due to ovarian cyst after pelvic sonography from January 2003 to May 2022. Patients were examined for pelvic sonography when there was vaginal bleeding and/or nipple pigmentation in PPP. pelvic sonography findings, clinical characteristics, management and prognosis of patients with ovarian cysts were investigated. Results: Ten out of 12 cases had vaginal bleeding and the 3 cases had nipple pigmentation. E2 was elevated to median value 36 pg/mL ([IQR], 19-61). There was a total of 18 episodes of ovarian cyst including recurrence. The median size of cyst was 28 mm ([IQR], 24- 34). Surgical management was performed in one patient with large cyst of 70 mm. Aromatase inhibitor was used in three cases. Follow-up pelvic sonography was performed to confirm regression of ovarian cyst. Median time to regression of ovarian cyst was 6 months ([IQR], 3-9). Five cases were diagnosed with MAS. Later, In 4 out of 12 cases were progressed to CPP and cyst was recurred more than 2 episodes in 3 cases. Median total follow-up duration of cases was 2.5 years ([IQR], 0.9-5.3). Conclusion: Most of ovarian cysts in PPP disappear spontaneously. However, It may appear as a one of findings with MAS or can progress to CPP in recurrent case. Therefore, careful follow-up is necessary in ovarian cysts of PPP. Presentation: Thursday, June 15, 2023

THU197 Peripheral Precocious Puberty In A 6-year-old Girl With Extreme Estradiol Elevation With Rapid Normalization: A Case Report

Abstract Disclosure: L. Meller: None. M. Marinkovic: None. M.E. Patterson: None. Background: Peripheral precocious puberty (PPP) in girls is typically associated with ovarian or adrenal tumors, ovarian cysts, McCune-Albright syndrome (MAS), or exogenous hormone exposure. We present an unusual case of PPP with extreme estradiol elevation and rapid normalization. Clinical Case: A 6.5-year-old previously healthy girl presented with two-month history of bilateral breast growth and tenderness, associated with daily cramping. Subsequently, she developed clear, odorless vaginal discharge. Two days prior to the visit she started light vaginal bleeding. Parents denied any medication intake or use of lavender or essential oils. She had no family history of early puberty. On the exam, she was tall for her age (95%) with a recent growth spurt. She had breast buds (Tanner 2) and vaginal bleeding without pubic hair (Tanner 1) or signs of hyperandrogenemia. There were no skin lesions or gross bone abnormalities. Bone age was equal to chronological age. She had an extreme elevation of estradiol of 156pg/mL and 170pg/mL (reference range&amp;lt;=16pg/mL) measured two weeks apart with prepubertal LH/FSH. Thyroid tests were normal. Pelvic ultrasound and abdomen/pelvis CT showed no abnormalities of ovaries and adrenal glands. Nine days after the onset, vaginal bleeding and cramping spontaneously resolved. Estradiol levels measured two days after cessation of vaginal bleeding normalized (7pg/mL) while LH/FSH remained prepubertal. Interestingly, two weeks after the bleeding stopped her pelvic ultrasound showed significantly enlarged ovaries (R 4.1mL, L 4.3mL), while her estradiol remained normal (5pg/mL). Conclusion: We describe an unusual presentation of PPP in a young girl with extreme estradiol elevation causing simultaneous premature breast development and vaginal bleeding. We suspect PPP was secondary to ruptured ovarian cyst that was not captured by imaging. Other differentials include MAS, exogenous hormone exposure, adrenal or ovarian tumors. These were unlikely due to lack of abnormal skin or bone findings, environmental hormone exposure and normal imaging. Her ovarian enlargement could be secondary to high endogenous estrogen exposure, and she may be at risk of developing central precocious puberty. This unique case emphasizes the importance of prompt assessment of children with precocious puberty and discusses the differential diagnosis process for PPP with markedly elevated estradiol with rapid normalization. Presentation: Thursday, June 15, 2023

THU235 Usefulness Of Digital Droplet Polymerase Chain Reaction (ddPCR) For Molecular Diagnosis Of McCune-Albright Syndrome In DNA From Peripheral Blood Leukocytes

Abstract Disclosure: A.G. de Faria: None. L.R. Montenegro: None. A.A. Jorge: None. R.S. Jallad: None. R.M. Martin: None. M.C. Fragoso: None. A.P. Canton: None. C.E. Seraphim: None. F.R. Tinano: None. N.C. Pinto: None. B.B. Mendonca: None. A. Latronico: None. V.N. Brito: None. Background: McCune-Albright Syndrome (MAS) is a rare congenital disorder caused by post-zygotic activating mutations in GNAS gene. Due to the mosaic pattern of this disease, mutation abundance is frequently low in several tissues, including blood cells. The emergence of digital droplet Polymerase Chain Reaction (ddPCR) is a breakthrough technology of quantitative PCR useful for a targeted detection and quantification of rare events. Objective: This study aims to identify the GNAS mutation in peripheral blood leukocytes of patients with MAS using ddPCR. Patients and Methods: Thirty-four patients (25 female and 9 male) with typical (classic triad) or atypical (one or two features) MAS were included. DNA was extracted from peripheral blood and was analyzed through ddPCR method. Two ddPCR mutation detection assays were used, each one targeting the p.R201C or p.R201H mutations. For each assay, the Taqman PCR system was used with two fluorescence probes: the first labeled with HEX, targeting de (WT allele), and the second labeled 6-FAM, targeting the (mutated allele). The mixture (reagents + DNA) was divided into 20,000 nanodrops, which was placed on a PCR plate and amplified by PCR. After amplification by PCR, the fluorescence of each droplet was read on the 200 Droplet Digital PCR system (Bio-Rad), being classified as positive (drop containing the target sequence) or negative. Results were analyzed using Quantasoft software (Bio-Rad) to determine the total amount of positive droplets in the original sample. The results were reported in fractional abundance (FA), corresponding to the percentage of mutated alleles within the total alleles. Results: Among all patients, the most common MAS feature was osteofibrous dysplasia (OFD) (73.5%), followed by peripheral precocious puberty (PPP) (64.7%), and café-au-lait skin spots (52.9%). Acromegaly or hyperthyroidism was diagnosed in 6 and 4 patients, respectively. Classical MAS triad, 2 clinical features, or 1 clinical feature (PPP or OFD) were present in 15, 9, and 10 patients, respectively. GNAS mutations were identified in 12/34 (35.3%) MAS patients: the p.R201C in 5 and the p.R201H in 7. Among them, 8 patients presented typical MAS and 4 patients with two MAS clinical features, respectively. Considering only typical MAS group, the positive molecular test rate was 53.3% (8/15). GNAS mutations were not identified in patients with only one MAS feature. There was a positive correlation between a positive molecular test and the number of MAS clinical features (p = 0.01). Median FA was 1.45%, ranged from 0.25% to 8.4%. There was no association between FA rate and the number of MAS clinical features (p=1.0). Conclusion: ddPCR representeds a more sensitive tool for identifying GNAS mutations in peripheral blood leukocytes, even with low abundance, in patients with classical and atypical MAS. Presentation: Thursday, June 15, 2023

THU202 Peripheral Precocious Puberty In A 7-year-old Female As A Result Of Exposure To Bath Bombs

Abstract Disclosure: C.C. Gordner: None. Introduction: Recent studies have demonstrated a progressive decrease in the age of onset of puberty in children. Endocrine disrupters are increasingly being identified as an important contributing factor to this shift in pubertal timing. We present here a case of peripheral precocious puberty in a 7-year-old female after a brief intense exposure to bath bombs. Clinical Case: A healthy pre-pubertal 7-year-old female used daily bath bombs for 7 days. She developed tender Tanner II breast buds the following week with no other pubertal or adrenarchal signs. Growth chart review revealed stable linear growth without growth acceleration. Bone age x-ray was consistent with chronologic age (CA 7y0m, BA 6y10m). LH, ECL, was 0.058 miU/mL (ref: 0.02-0.3), Estradiol, LCMS, was 2.0 pg/mL (ref &amp;lt; 15), DHEA-Sulfate, LCMS, was 45 mcg/dL (ref: 6-7y: &amp;lt; 72). The breast buds started to resolve after 2 months and were completely gone after 3 months from the initial exposure. Clinical Lessons: Endocrine-disrupting chemicals are found in pesticides, plasticizers, lavender, fennel, and tea tree oils and can lead to precocious puberty, delayed puberty, and/or impact sexual differentiation. Consumer products are often not well labeled to identify these chemicals and often use confusing terminology like “all-natural” and “organic” which can be misleading. Conclusions: Bath bombs should now be added to the growing list of consumer products associated with precocious puberty. Leaders should advocate for better labeling of consumer products to help identify potentially harmful products. Presentation: Thursday, June 15, 2023

THU227 Isosexual Peudo-precocious Puberty Due To Leydig Cell Tumor In A Prepubertal Child

Abstract Disclosure: M. Baby: None. A. Xu: None. N. Shacham: None. E. Shapiro: None. B.C. Shah: None. Background: Testicular tumors account for 2-4% of all childhood cancers. Leydig cell tumors are the most common form of sex cord stromal tumors and represent 1-3% of all testicular tumors. In the pediatric population, testicular Leydig cell tumors present with signs of precocious puberty. Workup reveals low gonadotropins with elevated testosterone and testicular mass on ultrasound. Treatment involves surgical enucleation (partial orchiectomy) in most cases. Clinical case: We present the case of a 4 year 10 month old male who presented to endocrine clinic for precocious puberty. He developed pubic hair three months prior with body odor. He did not have any CNS symptoms including headaches or visual changes. There was no use of exogenous androgens at home. He was born full term, small for gestational age with an uncomplicated postnatal course. There was no family history of precocious puberty. Height was at the 99th percentile (z-score 2.7), weight 98th percentile (z-score 2.07), and BMI 86th percentile (z-score 1.09). On exam, he was lean and appeared muscular. His testes were asymmetrical with the right testicle measuring 3 ml and the left testicle 2 ml. Scrotal hair was curly and sparse, Tanner III. Stretched penile length was 7 cm (90th percentile), width was 3.2 cm. Results: Bone age was advanced to 10 year 0 months with height age of 7 year 3 months. Serum gonadotropins were low, testosterone was pubertal at 115 ng/dl (Electrochemiluminescence Immunoassay). Serum 17-hydroxyprogesterone (221 ng/dl, ref range 0-90 ng/dl) androstenedione (163 ng/dl, ref range = &amp;lt; 51 ng/dl), and IGF-1 (368 ng/ml, ref range 108 – 293 ng/ml) were elevated. ACTH, cortisol, thyroid profile, and prolactin were normal. Beta-HCG and AFP were negative. ACTH stimulation test showed normal response. Testicular ultrasound with doppler was performed; right testicle measured 1.82 x 1.06 x 1.36 cm, volume of 1.4 ml, while left measured 1.27 x 0.72 x 0.87 cm, 0.4 ml. Within the right testicle, there was a mass that was hypoechoic, vascular (with a testicular artery feeding branch in the periphery), multinodular and measured 1.2 x 0.8 x 1.10 cm (0.53 ml). He was referred to urology and underwent enucleation of the right testicular mass through an inguinal approach. Grossly, the mass appeared tan and lobulated and surgical pathology confirmed a benign Leydig cell tumor. The patient recovered well and post-operative serum testosterone level at 2 weeks was &amp;lt;2.5 ng/dl. Conclusion: We present a case of a testicular Leydig cell tumor that presented as peripheral precocious puberty marked by low gonadotropins and elevated testosterone with ultrasound findings of a vascular mass with testicular artery feeding branch in the periphery. Early detection of a Leydig cell tumor is crucial as it can be treated by enucleation thus salvaging the testes. Presentation: Thursday, June 15, 2023

Metabolomic Studies in Girls With Central and Peripheral Precocious Puberty

Puberte prekoks (PP), kızlarda sekonder cinsel özelliklerin sekiz yaşından önce başlamasıdır. Hipotalamus hipofiz-gonad ekseninin erken aktivasyonu nedeniyle "merkezi puberte prekoks (CPP)" meydana gelir. "Periferik puberte prekoks (PPP)" hipotalamus-hipofiz-gonad (HPG) aksına bağlı olmayan daha nadir görülen farklı bir durumdur ve periferik nedenlere bağlıdır. Metabolomiks, küçük molekül metabolitlerinin (