Differential diagnosis of precocious puberty in girls during the COVID-19 pandemic: a pilot study.

BACKGROUND: To investigate the differential diagnosis of girls aged 6 to 8 years with idiopathic premature thelarche (IPT) and central precocious puberty (CPP) during the COVID-19 pandemic. We explored predicted adult height (PAH) discrepancy to guide appropriate diagnosis and treatment. METHODS: From January 2020 to December 2021, Chinese girls aged 6 to 8 years with precocious puberty were recruited. They were divided into IPT and CPP groups. Clinical characteristics, including height, weight, body mass index (BMI), basal luteinizing hormone (LH), oestradiol, uterine length and volume, follicle numbers (d > 4 mm) and bone age (BA) were recorded. We analysed differential diagnosis and PAH discrepancy in both groups. Binary logistic regression analysis was used to explore risk factors for CPP, and receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic value of related indexes. RESULTS: Sixty patients, including 40 girls with IPT and 20 girls with CPP, were recruited. The prevalence of overweight and obesity in the entire cohort was 25% (15/60) and was significantly higher in IPT than CPP, 32.5% (13/40) vs. 10% (2/20), respectively (P=0.045). There were significant differences in LH, uterine volume, follicle numbers and BA (P<0.05). The impaired PAH of IPT and CPP was 0.01 ± 1.19 SD and 0.62 ± 0.94 SD with significant differences (P=0.047). Logistic regression analysis showed that LH and follicle numbers were independent risk factors for CPP. The ROC curve showed that the area under the curve (AUC) of LH and follicle numbers were 0.823 and 0.697. The sensitivity and specificity of LH with a cut off of 0.285 IU/L were 78.9% and 77.8%. The sensitivity and specificity of follicle numbers with a cut off of 3.5 were 89.5% and 52.8%. CONCLUSION: The prevalence of overweight and obesity in 6- to 8-year-old girls with precocious puberty was high. Auxological data should not be used in the differential diagnosis of IPT and CPP. Basal LH above 0.285 IU/L and follicle numbers greater than 4 were important features suggestive of CPP. PAH was impaired in individuals with CPP, but it was not impaired in individuals with IPT.

The importance of vaginoscopy in premenarchal girls with vaginal bleeding- call for more PAG practioners

Introduction: Prepubertal vaginal bleeding outside the neonatal period is always abnormal and is very alarming to both parents and physicians. The variable etiologies of vulvovaginitis are the most common causes of vaginal bleeding during the prepubertal period. We report a series of three cases observed during covid" period of 2020-2022. Case report: two patients 8 and 9 year -old girls, were refered to pediatric secondary center due to of external vaginal bleeding. Hormonal levels were pre-pubertal and bone age was not advanced. Both girls were hospitalized and sellar X-ray and pelvic MRI were done during further course, not revealing the etiology of bleeding. Six months after the first bleeding, they were reffered to a pediatric gynecologist where foreign bodies (grass seed) were found during vaginoscopy. Third patient, a 3-year- old girl, was examined by her pediatrician because of heavy bleeding. Hormonal analysis and bone age were not suggestive of precocious puberty. Additional analyses revealed elevated alpha fetoprotein level (>5000 IJ,), which led to the diagnosis of yolk sac tumor in vagina wall, which was then confirmed by vagionoscopy and biopsy. It is important to perform vaginoscopy in premenarchal girls with repeated vaginal bleeding because in patients older than five years, a common reason for vaginal bleeding is foreign body but in younger patients, the primary goal is to exclude a malignant tumor.Copyright © 2023

Change in Incidence of Central Precocious Puberty Treated with GnRHa During COVID- 19 Pandemic: Single-center Retrospective Review

Objectives To study the incidence of new central precocious puberty (CPP) patients treated with GnRH agonist (GnRHa) in our Endocrinology clinic during Covid. Findings add to literature pertaining Covid pandemic effects on pediatric endocrine conditions, including CPP. Methods We performed a retrospective comparison of the incidence of newly diagnosed CPP with GnRHa treatment during the Covid pandemic (5/2020-4/2021) and pre-covid (5/2018-4/2019). CPP diagnosis was defined by a random LH >0.3 IU/L, a GnRH stimulated LH >5 IU/L, or a GnRH stimulated estradiol >40 pg/mL. Girls had onset of breast development at < 8 years-old, and boys had testicular size >4 ml at <9 years-old. We compared the number of new Endocrinology visits during the time periods. We evaluated time from diagnosis to GnRHa order, and time from GnRHa order to first day of treatment. We compared bone age (BA) and chronological age (CA), BA/CA and BA-CA between treatment windows. Results During pre-Covid year, 28 children (1 boy, 27 girls) were treated with GnRHa for CPP out of 2340 new Endocrinology visits (1.2% of patients seen). During Covid year, 64 children (7 boys, 57 girls) were treated out of 2261 new visits (2.8%). The incidence of new CPP cases on GnRHa during Covid has more than doubled compared to pre-Covid (p<0.01, Chi Square). There were no significant differences between the groups in age at diagnosis, time between diagnosis and treatment order, time between order and treatment, degree of BA advancement, or BMI (Tables 1-2). CPP incidence was consistent between 26-37 cases/year over the past 4 years prior to Covid. The number of cases per month did not correlate with the peaks of Covid cases (Figure). Conclusions CPP cases requiring GnRHa treatment significantly increased during the first year of Covid compared to pre-covid. There was no delay in presentation or treatment initiation during Covid based on bone age advancement. Preliminary data did not show a significant difference in rate of BA progression, time from diagnosis to onset of treatment, or changes in BMI during covid. Factors influencing a higher incidence of CPP during the pandemic are unclear, and likely multifactorial, including lifestyle changes and direct effects of the virus, potentially contributing to disruption of hormonal pathways. Controlled studies in larger cohorts are required to understand the pathogenic factors contributing to higher incidence of CPP during the pandemic.

Impact of Environmental and Psychosocial stressors on Precocious Puberty seen in Girls during the COVID-19 Pandemic

Objectives The COVID-19 pandemic caused stress, social isolation and physical inactivity in many. We proposed to review anthropometric/biochemical profiles in girls seen for precocious puberty (PP) (ages 5-8 years) during the pandemic (3/2020- 3/2021) compared to girls seen in the prior 2 years (2/2018-2/2020) and look at environmental and psychosocial impacts. Methods A retrospective chart review of the girls prepandemic (Pre-PD) were compared to those seen during the pandemic (PD). Criteria for PP: luteinizing hormone (LH range: 0.02-0.3 mIU/L, ECLIA, Esoterix) with >0.3 defined as pubertal;estradiol (range <36 pg/ml for age 7-9 years, LCMS, ARUP) with >=36.0 pg/ml defined as pubertal;follicle stimulating level (FSH 0.4- 6.5 IU/L ECLIA, ARUP). Girls with isolated adrenarche were excluded. Pelvic ultrasound with ovarian volumes (OVs>1cc considered pubertal) and MRI pituitary were done as indicated. Bone age/chronological age ratio (BA/CA) >1 was considered advanced. A Covid-19 impact survey was sent via a HIPAA compliant REDCap link to assess activity, sleep, and psychosocial stressors, distress on 0-10 scale (mild 0-4, moderate 5-7, severe 8-10) to families. T-tests and bivariate correlations were run (SPSS Ver 21). Results In total 56 subjects were included (pre-PD=23 vs. PD=33). A 30% increase in puberty referrals was noted during the pandemic. Weight (mean+ SD: Pre-PD vs. PD: 26.8+/-5 vs. 26.9+/-5.7 kg) and BMI (17.3+/-2.3 vs.16.8+/-2.3kg/m2). Estradiol (9.7+/-7.5 vs.21.9+/-16.6 pg/ml;p-value =0.006), random LH (1 vs. 15) were pubertal. OVs (1.75+/-1.1 vs. 2.75 cc) and BA/CA (1.1+/- 0.4 vs. 1.0+/-0.5) were seen in the two groups respectively. There was a correlation between estradiol levels and OVs in PD group (r= 0.5;p=.05). Survey results showed 61% of subjects used remote learning, 55% spent >4 hours on social media (Tik Tok, WhatsApp, etc.), 50% reported no exercise and 33% reported no social interaction. Stress was moderate with a parental report of 5.4/10, (50%essential workers, 18% lost jobs) & children reported stress level of 4.8/10. Conclusions We report an increased incidence of PP during the pandemic (perhaps due to a delay in evaluation) and a more advanced puberty (higher estradiol levels and greater OVs) compared to Pre-PD patients. Though weight gain, potentially due to inactivity, did not appear to contribute, we believe that stress, excessive social media use and/or isolation could be factors which contributed to the increased incidence of PP during the pandemic.

Increased basal levels of 17- Hydroxyprogesterone in the COVID era: Must we change the cut-off point to request acth test?

Background: 17-hydroxyprogesterone (17-OHP) basal levels greater than 2ng/ml has been related to the need to request an ACTH test to dismiss non-classic congenital adrenal hyperplasia. We have seen an increase in baseline levels in 2021 compared to 2020. Objective(s): To determine how many of the tests that were requested due to a high basal 17-OHP value, were positive. Assess the need to modify the cut-off points to request an ACTH test. To determine the possible relationship of the increase in basal levels of 17-OHP with the BMI SDS. Material(s) and Method(s): retrospective descriptive study of all patients who underwent an ACTH test between January 1, 2020 and December 31, 2021, in a region of northern Spain. We analyze: sex, age, Tanner stage, BMI SDS, baseline 17-OHP and ACTH test results and main reason for requesting. The test was considered: diagnostic with a peak of 17-OHP at 60 minutes higher than 15 ng/ ml, and suggestive if 10-15ng/ml. Laboratory method for the determination of 17-OHP: chemiluminescence immunoassay in Maglumi 2000 Analyzer (Snibe-Diagnostic). The trial meets the quality criteria certified by EQAS QCNet (BioRad-Laboratories, Inc, UK). Result(s): 149 ACTH tests were performed, 45 in 2020 and 104 in 2021. 116 women (77.9%). Mean age: 10.1 years (range 2.2-15.9 years). 114 had already started puberty. 21 BMI>2SDS. Main reason for requesting the ACTH test: elevated baseline 17-OHP 38%(20% in 2020, 45% in 2021), accelerated bone age (>2 years)48%, pubarche 9%. Mean baseline 17-OHP was 2.93ng/ ml(+/-3.6ng/ml), median 1.26ng/ml(range 0.1-26ng/ml) in 2020 and 2.67ng/ml(range 0.56-16.2ng/ml) in 2021, difference not statistically significant (p 0.67), but clinically relevant. ACTH test results: mean peak at 60 minutes was 4.98ng/ml(range 0.1-64). The determination of baseline 17-OHP was above 2ng/ml in 61 patients, and above 4ng/ml in 24. But only in 7 cases the test was positive (diagnostic or suggestive), all them with basal 17OHP>4ng/ml. This cut-off point shows a higher specificity with the same sensitivity. Comparing 2020 with 2021, we found no difference in BMI SDS (p 0.27). Relationship between BMI SDS and basal 17OHP was not confirmed (p 0.81). Conclusion(s): Our study confirms a significant increase in the number of ACTH tests performed, as well as in the basal level of 17-OHP in the last year. A baseline value of 17-OHP greater than 4ng/dl seems to be the most appropriate as the main indicator of the need to perform the test.

Precocious Puberty and Rapidly Progressive Puberty during the Covid-19 Pandemic

Introduction: During the COVID-19 pandemic, we have seen an increase in consultations for Precocious puberty (PP) and accelerated puberty. Aim(s): To assess the frequency of PP and its progression before and during the pandemic. Material(s) and Method(s): We retrospectively evaluated the patients's medical records referred to a Paediatric Endocrinolgy Unit between April 2018-March 2021. Patients who consulted for suspected PP during the pandemic were analyzed (Period 3: April 2020-March 2021) and compared with two years previous (Period 1: April 2018-March 2019 and Period 2: April 2019-March 2020). We collected clinical and complementary studies. The initial evaluation and evolution were recorded. Study according to the declaration of Helsinki II and approved by Ethics Committee. Stata software was used for the analysis. Qualitative variables were described using frequency and percentage and quantitative variables with mean and standard deviation. The association between qualitative variables was evaluated with Chi-square test and Fisher's exact test, and quantitative variables with Student's t-test. Result(s): 5151 consultations were recorded. An increase in the percentage of consultations due to suspected PP was observed during Period 3 (21% vs.10% and 11%.p<0.001). The number of patients who consulted for suspected PP in Period 3 increased 2.3 times (80 vs.29 and 31.p<0,001). 95% were girls, this population was analyzed. 132 patients were included. Age was similar in the 3 groups (8+/-1,1;8,2+/-0,6 and 8,2+/-0,9.p:0,912) as well as the risk factors for PP. The patients were similar in Weight (1,6+/-1,4 vs. 1,2+/-1,2 vs. 0,9+/-1,5;p:0,104), Height (1,5+/-1,2 vs. 1,5+/-1,2 vs. 1,2+/-1;p:0,925) and DELTA Height-target genetic height (0,9+/-1,3 vs. 0,9+/-1,4 vs. 0,8+/-0,9;p:0,925). Lower BMI was observed in Period 3 (0,7+/-1,2 vs1,3+/-1 and 1+/-0,9;p:0,033). A higher percentage of breast stage Tanner 3-4 (78% vs.64% vs.51%;p:0,02) and larger uterine size (36,2+/-9,9 vs.29,6+/-9,2 and 34,6+/-6,7mm;p:0,012) were found in Period 3. Bone age was similar in the 3 groups (8,9+/-2 vs. 9,5+/-1,6 vs. 9,3+/-1,7 years;p:0,506) as well as hormonal determinations. 106 patients completed the initial evaluation. Treatment was indicated in 26%. In the rest, evolution was controlled for an average of 13 months. 49% presented a rapidly progressive evolution, during Period 3 in 87%. Conclusion(s): It's the first study in our country to evaluate PP during the pandemic. An increase of 2.3 times in consultations for suspected PP and accelerated evolution were observed in girls.

Precocious puberty before and after the COVID-19 pandemic

Introduction: A novel coronavirus defined as coronavirus disease 2019 (COVID-19) was first detected in China at the end of 2019 and spread rapidly all over the world. As the covid 19 pandemic has led to changes in life all over the world, the prognosis of diseases have also been affected. This study presents how early puberty has been affected during the pandemic period. Method(s): A total of 210 subjects;113 individuals ( 94 girls;3 boys) after the covid19 (2020-2021) and 97 individuals (104 girls;9 boys) before covid19 (2018-2019) evaluated with suspicion of precocious puberty at the Pediatric Endocrinology department of Erciyes university. Age, sex, the time of pubertal signs, initial admission findings, exposure to endocrine disruptors, bone age, anthropometric measurements and tanner stages at the first examination, MRI results, peak FSH, peak LH and basal E2 levels, the time between bone age and chronological age, uterine long axis and ovarian measurements were collected from clinical records. Result(s): Before covid19, the median age of 97 patients was 7,58 (3.6-9.8) years while after covid19, the median age of 113 patients was 8,04 (5,1-10,6) years. The increase was observed in patients with precocious puberty during covid19 period. The mean of bone ages before covid19 were 8.5 years (+1.81) while after covid19 was 9.4 years (+1.51). The time between bone age and chronological age;pre-pandemic mean was 1.1 (+1.14);post-pandemic was 1.4 (+1.24). The body mass index (BMI) SD value was:0.81 (+1.1) at the first admission before the pandemic, it was 1.14 (+1.08) after the pandemic. Before and after the pandemic statistically bone ages (p<0.01), BMI (p:0.032) SD value, patient ages (p<0.01), FSH peaks (p:0.034) were evaluated and the results were significant. Girls presented with precocious puberty more frequently in both periods before and after the pandemic. The most common complaint was thelarche in both periods. Endocrine disruptor exposure was found to be increased in the post-pandemic group and it was statistically significant. Conclusion(s): The Covid 19 epidemic was effective in precocious puberty cases as well as in many diseases. During this period, a significant increase was observed in endocrine disrupting exposure and the increase in bone age and BMI SD value of the patients were notable.

Maturation-dependent vulnerability of emotion regulation as a response to COVID-19 related stress in adolescents.

BACKGROUND: The COVID-19 pandemic created unpredictable circumstances resulting in increased psychological strain. Here we investigate pandemic-related alterations in emotion regulation in adolescents assessed before and during the pandemic. We also take biological age into account in the response to the pandemic. METHODS: Mann-Whitney U tests were conducted to compare baseline data on the Difficulties in Emotion Regulation Scale (DERS) total scores of a pre-pandemic adolescent cohort (n = 241) with those obtained during the second wave of the pandemic (n = 266). We estimated biological age based on an ultrasonic boneage assessment procedure in a subgroup of males, including grammar school and vocational school students in the 9th and 10th grades, and analyzed their data independently. FINDINGS: There is a gender difference in the timing of vulnerability for pandemic-related stress in grammar school students: females are affected a year earlier than males. Vocational school male students mature faster than grammar school male students, and the timing of emotional vulnerability also precedes that of the grammar school students'. DISCUSSION: We interpret our findings within a developmental model suggesting that there might be a window of highest vulnerability in adolescent emotion regulation. The timing of the window is determined by both chronological and biological age, and it is different for females and males. APPLICATION TO PRACTICE: Defining the exact temporal windows of vulnerability for different adolescent cohorts allows for the timely integration of preventive actions into adolescent care to protect mental health during future chronic stressful situations.

Socio-economic Barriers to Care and Medical Complexity Leading to a 5-year Diagnostic Delay of Untreated Chronic Diabetes Insipidus and Rapidly Progressive Puberty in a 10-year-old Venezuelan Immigrant

Introduction: Germ cell tumors, including germinomas, account for 10% of pediatric chronic Diabetes Insipidus (DI) cases. Delays in diagnosis of germinomas are generally longer than six months, however, no reported cases of suprasellar germinomas causing chronic DI and precocious puberty have been known to exceed a 5-year delay in both treatment of DI symptoms and a definitive diagnosis. Case Description: A 10-year-old Hispanic male presented with a 5-year history of polydipsia and polyuria. He underwent evaluation in Venezuela, where DI was reportedly 'ruled out';however, no head MRI was performed. After two years in the US struggling to acquire insurance, he presented to his pediatrician with worsening symptoms. A head MRI, ordered to evaluate dilute high-volume urine output, revealed a suprasellar mass. He was admitted for diagnostic evaluation and met the criteria for DI. Notably, he had an elevated Beta-Human Chorionic Gonadotropin (B-HCG) level. Biopsy confirmed the diagnosis of a Central Nervous System (CNS) germinoma. He was treated with DDAVP and proton therapy with subsequent remission of his tumor. Discussion: Throughout the patient's disease course, there were multiple delays in seeking and receiving care. These include a 5-year delay in seeking care despite worsening symptoms, a one-month delay in completing a 24-hour urine collection, a one-month delay in consulting pediatric nephrology, and another month delay before completing a retroperitoneal ultrasound. Multiple medical and socio-economic factors led to these delays. The patient did not present with symptoms more typical of CNS Germinomas like headaches, nausea, and vomiting. He had no visual disturbances despite mass effect on his optic chiasm. His increased stretched penis length and Tanner staging, which were identified later in his disease course, were contradicted by his pre-pubertal testicular volume and bone age. The patient is from a Spanishspeaking/Limited English Proficiency (SSLEP) household. While Spanish interpreters were present at each appointment, the language barrier proved to be a consistent issue. Initially, the child's mother indicated that the diagnosis of DI was 'ruled out' in Venezuela. In reality, the recommended imaging was never performed. Mychart messages left by his father further highlighted communication difficulties. Without access to an interpreter, he was forced to use broken English to relay his concerns. These frantic messages indicated misunderstandings regarding scheduling with various services and completing vital labs. Care only proceeded after significant physician intervention. Poverty in Venezuela, lack of insurance, and anxiety regarding COVID-19 also contributed to these delays. Conclusion: To our knowledge, this is the first case report of a pediatric patient presenting with a 5-year history of untreated polyuria and polydipsia due to undiagnosed DI with a B-HCG secreting CNS germinoma, without spinal metastasis. This study also illustrates the importance of supporting SSLEP families as they grapple with the complicated process of navigating our healthcare system. Sagittal T1 post gadolinium contrast image (A) and axial T2 FLAIR image (B) show an enigmatic, homogeneous, briskly enhancing mass in the suprasellar cistern (red arrow) with mass effect on the optic chiasm which is displaced upward and anteriorly (green arrow).

Impact of COVID-19 lockdown on idiopathic central precocious puberty - experience from an Indian centre.

OBJECTIVES: Owing to increase in referrals for precocity observed during COVID-19 lockdown, this study was conducted to estimate the proportion of patients referred for precocity and within these, those with idiopathic central precocious puberty (iCPP) before vs. during the COVID lockdown, and to assess the differences in anthropometric and clinical characteristics among iCPP patients in the two groups. METHODS: Retrospective study conducted at a tertiary level paediatric endocrinology centre (Western India) evaluating proportion of referrals for precocity and comparing demographics, anthropometry, pubertal staging and bone age at presentation among children with iCPP divided into two groups (pre-lockdown-group 1, lockdown-group 2). RESULTS: During lockdown, 155 (5.1%; 146 girls) of 3,053 referrals for precocity as opposed to 59 (1.4%; 54 girls) of 4,208 before the lockdown (p<0.05) were seen; increase was higher in girls (p<0.05). Proportion of referrals for iCPP was significantly higher in the lockdown (4.4%; 136 children vs. 1%; 44 children in group 2) among both genders. Mean age at first visit was 7.8 ± 1.3 and 8.2 ± 1.2 years in groups 1 and 2, respectively. Mean height, weight, BMI and height minus mid-parental height Z scores were not significantly different between the groups. Children in group 2 had a significantly advanced mean bone age (10.7 ± 2 years) and difference in bone and chronological ages (2.5 ± 1.2 years) as compared to group-1 (9.7 ± 1.9; 1.9 ± 1.2) and a larger proportion presented in late puberty. CONCLUSIONS: We found an increase in the referrals for precocious puberty and an increase in number of children diagnosed with iCPP during COVID lockdown.