Congenital Adrenal Hyperplasia.

We describe congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, which is the most common primary adrenal insufficiency in children and adolescents. In this comprehensive review of CAH, we describe presentations at different life stages depending on disease severity. CAH is characterized by androgen excess secondary to impaired steroidogenesis in the adrenal glands. Diagnosis of CAH is most common during infancy with elevated 17-hydroxyprogesterone levels on the newborn screen in the United States. However, CAH can also present in childhood, with late-onset symptoms such as premature adrenarche, growth acceleration, hirsutism, and irregular menses. The growing child with CAH is treated with hydrocortisone for glucocorticoid replacement, along with increased stress doses for acute illness, trauma, and procedures. Mineralocorticoid and salt replacement may also be necessary. Although 21-hydroxylase deficiency is the most common type of CAH, there are other rare types, such as 11ß-hydroxylase and 3ß-hydroxysteroid dehydrogenase deficiency. In addition, classic CAH is associated with long-term comorbidities, including cardiometabolic risk factors, impaired cognitive function, adrenal rest tumors, and bone health effects. Overall, early identification and treatment of CAH is important for the pediatric patient.

Associations of central precocious puberty with blood pressure trajectories: prospective cohort study.

BACKGROUND: Sex differences in blood pressure (BP) appear during childhood and adolescence, but the role of central precocious puberty (CPP) remains unclear. In this study, we aimed to examine the association of CPP with the risk of early hypertension and BP trajectories in girls and boys. METHODS: We analyzed trajectories of BP before and after puberty in girls aged 6-13 years (n = 305) and boys aged 10-15 years (n = 153) in the Taiwan Pubertal Longitudinal Study. The timing of puberty onset was defined as the month at which the children reached Tanner stage 2. We examined the association of CPP with the risk of early hypertension and BP trajectories before and after puberty onset. RESULTS: Among boys, CPP was found to be associated with early hypertension (odds ratio, 7.45 [95% CI, 1.15-48.06]), whereas no such association was observed among girls. Boys with CPP had higher systolic BP than did those with normal puberty onset before puberty onset (mean difference, 6.51 [95% CI, 0.58-12.43]) and after puberty onset (mean difference, 8.92 [95% CI, 8.58-15.26]). CONCLUSION: A large proportion of the higher systolic BP observed in boys with CPP compared with in those with normal puberty onset is accrued after puberty. IMPACT: We examined the sex-specific association of central precocious puberty with blood pressure trajectories to better understand whether central precocious puberty was associated with early hypertension. Central precocious puberty was associated with differences in systolic blood pressure trajectories, especially after puberty onset in boys. For boys only, central precocious puberty was associated with early hypertension. A large proportion of the higher systolic blood pressure observed in boys with central precocious puberty compared with in those with normal puberty onset was accrued after puberty. Interventions targeting central precocious puberty are likely to influence systolic blood pressure in early adulthood.

Endocrine features of primary mitochondrial diseases.

PURPOSE OF REVIEW: Primary mitochondrial diseases are one of the most prevalent groups of multisystem genetic disorders. Endocrinopathies associated with mitochondrial diseases may have clinical features that are distinct from the more common forms. We provide an overview of mitochondrial disorder genetics and phenotypes, focusing on recent studies regarding identification and treatment of associated endocrinopathies. RECENT FINDINGS: Known endocrine phenotypes of mitochondrial disorders continue to expand, and now include growth hormone deficiency, hypogonadism, precocious puberty, hypoparathyroidism, hypo- and hyperthyroidism, diabetes, and adrenal insufficiency. Recent studies suggest several genotype-phenotype correlations, including those related to nuclear variants. Diagnosis is important, as special considerations should be made in the management of endocrinopathies in mitochondrial patients. Finally, new mitochondrial replacement strategies may soon be available for women interested in preventing mitochondrial disease transmission to offspring. SUMMARY: Patients with multiple endocrinopathies or atypical endocrinopathies should be evaluated for primary mitochondrial disease, as a diagnosis may impact management of these individuals.

An updated meta-analysis of the relationship between vitamin D levels and precocious puberty.

Background: Some studies have investigated the association between vitamin D levels and precocious puberty (PP) but with limited sample sizes and inconsistent conclusions across studies. Methods: Until July 2022, a comprehensive electronic search of works of literature was conducted in MEDLINE, Web of Science, and CNKI (Chinese National Knowledge Infrastructure). A systematic review and meta-analysis of 15 case-control studies with 2145 cases and 2063 controls was conducted to explore the relationship between vitamin D and PP. Stratified analyses by year of publication, country, diagnosis category of PP, child's sex, and methods of 25(OH)D test were conducted. Results: There was a negative correlation between 25(OH)D concentrations and PP in all study populations (SMD = -1.046, 95%CI = -1.366, -0.726). The pooled SMD remained significant in Chinese studies (SMD = -1.113, 95%CI = -0.486, -0.741), studies published before or after 2018 (SMD = -0.9832 and -1.185, 95%CI = -2.044, -1.133 and -1.755, -0.726), studies with female children (SMD = -1.114, 95%CI = -1.446, -0.781), and studies using electrochemiluminescence to detect 25(OH)D (SMD = -0.999, 95%CI = -1.467, -0.531). Vitamin D deficiency also increased the risk of PP (OR = 1.531, 95%CI = 1.098, 2.134). Unfortunately, heterogeneity was high in all analyses, and there was some publication bias. Conclusion: This systematic review and meta-analysis demonstrated an association between vitamin D and precocious puberty. We recommend more high-quality studies, especially prospective cohort studies with big sample sizes or some randomized controlled intervention trials, to validate the reliability of the results.

Association of size for gestational age and dehydroepiandrosterone sulfate with cardiometabolic risk in central precocious puberty girls.

Objective: The aim of this study was to assess whether size for gestational age and dehydroepiandrosterone sulfate (DHEAS) are associated with cardiometabolic risk in central precocious puberty (CPP) girls. Methods: The retrospective study included 443 patients with newly diagnosed CPP. Subjects were categorized by birth weight for gestational age (appropriate [AGA], small [SGA], and large [LGA] for gestational age) and serum DHEAS concentration (high [≥75th percentile] and normal [<75th percentile] DHEAS). Cardiometabolic parameters were examined. Composite cardiometabolic risk (CMR) score was calculated based on BMI, blood pressure, glucose, insulin, triglyceride, and HDL cholesterol. Non-obesity CMR score was computed, omitting the value from BMI. Logistic regression models, general linear models, and partial correlation analyses were used to evaluate associations. Propensity score matching was performed for sensitivity analyses. Results: Overall, 309 patients (69.8%) were born AGA, 80 (18.1%) were born SGA, and 54 (12.2%) were born LGA. Compared with AGA counterparts, CPP girls born SGA were more prone to have elevated HbA1c (adjusted OR = 4.54; 95% CI, 1.43-14.42) and low HDL cholesterol (adjusted OR = 2.33; 95% CI, 1.18-4.61). In contrast, being born LGA was not associated with increased risk for any glucose or lipid derangements. Despite the fact that elevated CMR score was more common among individuals born LGA than AGA (adjusted OR = 1.84; 95% CI, 1.07-4.35), no significant difference was found on non-obesity CMR score (adjusted OR = 0.75; 95% CI, 0.30-1.88). When controlling for age, birth weight SDS, and current BMI-SDS, individuals with high DHEAS exhibited higher HDL cholesterol and apolipoprotein A-1 concentrations and lower triglyceride level and non-obesity CMR score. Furthermore, DHEAS correlated positively with HDL cholesterol and apolipoprotein A-1 and negatively with triglyceride, prominently in girls born SGA, after adjustments for the three abovementioned confounders. Sensitivity analyses corroborated the findings. Conclusion: Among CPP girls, those born SGA were more likely to possess cardiometabolic risk factors compared to their AGA peers. The difference we observed in cardiometabolic risk between individuals born LGA and AGA was driven by BMI. High DHEAS was associated with favorable lipid profile in CPP girls, even in subjects born SGA.

Leptin/adiponectin ratio as a prognostic factor for increased weight gain in girls with central precocious puberty.

Objective: To determine if the leptin, adiponectin, and leptin/adiponectin ratio (LAR) can predict weight gain at the end of GnRH analogs (GnRHa) treatment in girls with central precocious puberty (CPP). Material and methods: Study design: prospective cohort. Serum levels of leptin and adiponectin were determined at diagnosis of CPP. Anthropometry was performed at diagnosis of CPP and every six-months, until treatment with GnRHa was discontinued and they presented menarche. Patients were divided according to BMI<94 and BMI>95 percentile at diagnosis of CPP. The outcome was the increased in weight gain (e.g., from normal weight to overweight) at the end of follow-up. Statistical analysis: repeated measures ANOVA test and Student's t-test were used to compare groups. Logistic regression analysis was used to evaluate the association of leptin and adiponectin levels, as well as LAR values with increased weight gain. Results: Fifty-six CPP patients were studied, 18 had BMI >95 percentile and 38 BMI <94 percentile. Of the 18 patients who initially had BMI >95th, two patients went from obesity to overweight, while among the 38 patients who started with BMI <94th, 21 (55.2%) increased their weight gain at the end of follow-up. This last group had higher leptin levels (8.99 ± 0.6 vs 6.14 ± 0.8, p=0.005) and higher LAR values compared to those who remained in the same weight (1.3 ± 0.5 vs 0.96 ± 0.56, p=0.01). In the logistic regression analysis, it was found that higher leptin levels and higher LAR values were associated with increased weight gain (RR 1.31, 95%CI 1.03-1.66, RR 4.86, 95%CI 1.10-21.51, respectively), regardless of birth weight, pubertal stage, age, and bone/chronological age ratio. Conclusions: In patients with CPP, leptin levels and higher LAR values appear to be associated with significantly greater weight gain during GhRHa treatment, particularly in girls starting with BMI < 94 percentile.

Vaginal bleeding in children: A retrospective audit at a tertiary paediatric gynaecology service.

AIM: The aim of this study was to describe the clinical features and investigations of vaginal bleeding in prepubertal children. METHODS: We performed a retrospective case series of children under the age of 10 who presented with vaginal bleeding to our institution between 2018 and 2019. RESULTS: There were 32 cases identified during the timeframe, with a mean age of 5.5 years (standard deviation 3.2 years, range 5.5 days to 9.6 years). Vulvovaginitis was the most common diagnosis (n = 12, 37.5%), followed by precocious puberty (n = 5, 15.6%). Uncommon but serious causes were vaginal rhabdomyosarcoma (n = 1), and sexual abuse (one patient presenting with gonorrhoea and one with a non-accidental injury). Vaginoscopy was performed in nine patients (28.1%) for various reasons, and a vaginal foreign body was identified in two patients (6.3%). All the patients who had a serious cause of bleeding (neoplasm or sexual assault) or who required specific treatment (precocious puberty, lichen sclerosus, urethral prolapse) presented with red flags on history and/or examination: recurrent episodes of vaginal bleeding, heavy bleeding, associated general symptoms (poor feeding and growth), presence of thelarche, abdominal mass, associated profuse vaginal discharge and abnormal genital examination (skin changes, urethral prolapse or protruding mass from the vagina). CONCLUSIONS: A thorough history-taking and clinical examination aiming at identifying red flags may help to discriminate between benign causes of vaginal bleeding, where no further investigations are indicated, and alternative diagnoses with a poor outcome and/or requiring specific treatment and additional investigations.

Endocrinopathy After Treatment for Medulloblastoma: Results From the SJMB03 Trial of Risk-Adapted Radiation Therapy.

PURPOSE: The objective of this study was to estimate the cumulative incidence of endocrinopathy in pediatric patients treated for medulloblastoma with surgery, risk-adapted photon craniospinal irradiation, and dose-intensive chemotherapy. METHODS AND MATERIALS: Children and adolescents (n = 156) treated between 2003 and 2013 were evaluated for evidence of endocrinopathy. Clinical information and mean radiation dose to hypothalamus and thyroid were calculated and used to estimate cumulative incidence of growth hormone deficiency, hypothyroidism, adrenal insufficiency, hypogonadism, and precocious puberty. RESULTS: The 5-year cumulative incidences were estimated for growth hormone deficiency, 68.9% (60.9%, 75.6%); hypothyroidism, 48.4% (95% confidence interval (CI), 40.2%-56.1%); adrenal insufficiency, 13.0% (95% CI, 8.3%-18.9%); hypogonadism, 33.9% (95% CI, 25.2%-42.7%); and precocious puberty, 2.0% (95% CI, 0.6%-5.4%). Growth hormone deficiency was associated with increased hypothalamus dose (hazard ratio [HR], 1.035; 95% CI, 1.010-1.061; P = .0055) in average-risk patients and cerebrospinal fluid shunt (HR, 2.532; 95% CI, 1.325-4.838; P = .0049) in high-risk patients. In average-risk patients, hypothyroidism was associated with younger age (HR, 0.902; 95% CI, 0.842-0.973; P = .0070), hypothalamus dose (HR, 1.039; 95% CI, 1.004-1.075; P = .0273), and thyroid dose (HR, 1.070; 95% CI, 1.008-1.136; P = .0263). In high-risk patients, hypothyroidism was associated with increased hypothalamus dose (HR, 1.068; 95% CI, 0.995-1.147; P = .0671) and thyroid dose (HR, 1.050; 95% CI, 1.000-1.104; P = .0515). Adrenal insufficiency was associated with increased hypothalamus dose (HR, 1.112; 95% CI, 1.058-1.170; P < .0001). Growth hormone deficiency incidence was higher when comparing patients treated with cerebrospinal fluid shunt versus those not having a shunt/extraventricular drain placed during initial surgery (HR, 1.712; 95% CI, 1.109-2.643). CONCLUSIONS: Incidence and time to onset of clinically significant endocrinopathy after photon craniospinal irradiation for pediatric medulloblastoma is influenced by radiation dose to target organs and patient age at time of treatment. Advanced radiation therapy methods and dose-reduction strategies are needed to reduce the incidence of endocrinopathy.

Premature adrenarche in Prader-Willi syndrome is associated with accelerated pre-pubertal growth and advanced bone age.

OBJECTIVES: Prader-Willi syndrome (PWS) is characterized by obesity, growth hormone deficiency, hypogonadism, and a high prevalence of premature adrenarche despite reported hypothalamic-pituitary-adrenal axis dysfunction. While idiopathic premature adrenarche is associated with accelerated pre-pubertal growth and advanced bone age, the consequences of elevated adrenal androgens on growth and bone maturation in PWS remain unknown. This study therefore sought to describe age-related changes in dehydroepiandrosterone sulfate (DHEAS) and their effects on growth and bone maturation in PWS. METHODS: This retrospective observational study included 62 children with PWS. Simple and multiple regression models were constructed to relate age and BMI-SDS with DHEAS levels. Height velocity was compared to age and sex-based norms with t-tests and two-way ANOVA. Patterns in bone age Z-score were examined with two-way ANOVA, and the contributions of age, BMI-SDS, and DHEAS to bone age Z-score were analyzed with multiple regression. RESULTS: DHEAS levels rose earlier and were less strongly correlated with age in males and females with PWS (R2=0.12 and 0.30) compared to healthy controls (R2=0.89 and 0.88) in a pattern unrelated to BMI-SDS (adjusted R2=0.076, p=0.10 for age, and 0.29 for BMI-SDS). Mid-childhood height velocity was increased in males and preserved in females with PWS before declining at the age of expected puberty (p<0.0001). Peri-adrenarchal bone age was advanced in a manner associated with DHEAS but not BMI-SDS (p<0.0001; adjusted R2=0.48, p=0.0014 for DHEAS, and 0.78 for BMI-SDS). CONCLUSIONS: An obesity-independent increase in adrenal androgens is associated with accelerated mid-childhood growth and bone maturation in PWS.

Precocious and accelerated puberty in children with neurofibromatosis type 1: results from a close follow-up of a cohort of 45 patients.

PURPOSE: Central precocious puberty (CPP) in neurofibromatosis type 1 (NF1) occurs mainly in association with optic pathway glioma (OPG), but it can also develop in the absence of OPG. The aim of this study was to analyze the prevalence of puberty disorders in children with NF1 and its association with OPG and its location. METHODS: A retrospective study of 45 children with NF1 (68.9% boys) followed at our center between 2008 and 2020 was conducted. A cerebral MRI scan was performed in all children. We analyzed auxological, laboratory, and imaging data of children with CPP or accelerated puberty (AP). Treatments used for CPP/AP and their effect on height were also evaluated. RESULTS: The prevalence of puberty disorders in our cohort was 17.8% (male to female ratio of 7:1). CPP and AP were diagnosed in 8/45 (17.8%) NF1 children. Among children with puberty disorders, 5/8 (62.5%) had an OPG with chiasm involvement, 1/8 (12.5%) had an isolated optic nerve tumor, and 2/8 (25%) did not have any evidence of OPG on MRI. Fisher's exact test showed an association between CPP/AP and chiasm OPG (p = 0.025). Treatment with triptorrelin was initiated in 5/8 children, of whom four attained final predicted height. CONCLUSION: Our study confirms the higher prevalence of CPP/AP in NF1 patients, as well as an association between chiasm OPG and puberty disorders. However, CPP/AP also occurred in the absence of OPG with an incidence of 9.1%. Comprehensive evaluation of every child with NF1 regardless of the presence of OPG is therefore essential.

Case 308: Van Wyk-Grumbach Syndrome.

HISTORY: An 11-year-old girl presented to the pediatric gastroenterology outpatient department of our institution with gradually increasing painless abdominal distention. The distention started 2 years earlier and was not associated with any other constitutional symptoms, vomiting, diarrhea, jaundice, hematemesis, or melaena. She reported early satiety and heaviness in the lower abdomen. The abdominal swelling was predominantly in the infraumbilical region and was soft at palpation. She was the first child of nonconsanguineous parents and had an uneventful perinatal course after a normal vaginal delivery. Her developmental milestones were normal. She had an average scholastic performance at school. There was no history of visual problems, seizures, or inappropriate behaviors. She had an early menarche 2 years previously. Her menstrual cycles were regular, and there was no abnormal vaginal discharge. Her breast development was normal (Tanner stage III), while pubic and axillary hair were absent (Tanner stage I). She was short for her age (104 cm; normal range, 120-154 cm). There was no history of short stature among her siblings or parents. Laboratory investigations were performed to measure thyroid-stimulating hormone (1354.34 µIU/mL; normal range, 0.35-5.5 µIU/mL), triiodothyronine (<2.5 ng/dL [0.0385 pmol/L]; normal range, 100-200 ng/dL [1.54-3.08 pmol/L]), thyroxine (1.35 µg/dL [17.37 nmol/L]; normal range, 5-12 µg/dL [64.35-154.44 nmol/L]), ß-human chorionic gonadotropin (<1.2 mIU/mL; normal, <5 mIU/mL), luteinizing hormone (0.08 mIU/mL; normal range, 0.1-6.0 mIU/mL), and follicle-stimulating hormone (6.93 mIU/mL; normal range, 0.3-2.0 mIU/mL) levels. Complete blood count was normal. An abdominal mass was suspected, and abdominopelvic CT was performed and followed by US; these examinations revealed multiple large cysts in both ovaries. The uterus was pubertal in shape, and endometrial thickness was 9 mm, representing normal follicular phase measurement. Serum CA-125 and inhibin levels were normal. To evaluate short stature, radiographs of the hand and pelvis were obtained as part of a limited skeletal survey, keeping in mind the possible skeletal changes associated with hypothyroidism. In view of the hypothyroidism, US of the neck was also performed. Treatment was started based on the clinical and radiologic parameters, and the child's condition improved with medical treatment.

[OPTIC DISC EDEMA IN McCUNE-ALBRIGHT SYNDROME].

INTRODUCTION: Craniofacial polyostotic fibrous dysplasia, as part of McCune-Albright syndrome, can have severe complications including vision loss. Also, patients with this syndrome are at greater risk of secondary intra-cranial pressure elevation due to medication side effects. BACKGROUND: : A 6-year-old girl with McCune-Albright syndrome and polyostotic craniofacial fibrous dysplasia and optic canal narrowing, developed signs of slowly progressive optic nerve compression on clinical examination including deteriorating visual acuity, positive relative afferent pupillary defect )RAPD) and bilateral optic disc swelling. Imaging using optical coherence tomography (OCT) revealed progressive retinal nerve fiber layer thickening. Prior to deterioration, the dose of triptorelin, a gonadotrophin-releasing hormone analogue, she was treated with for precocious puberty, was increased. Medication cessation was followed by improvement in clinical and imaging findings. CONCLUSIONS: : McCune-Albright syndrome patients with craniofacial involvement and/or gonadotrophin-releasing hormone analogue treatment should be monitored regularly for clinical signs of optic neuropathy together with routine OCT imaging.

Precocious puberty in narcolepsy type 1: Orexin loss and/or neuroinflammation, which is to blame?

Narcolepsy type 1 (NT1) is a rare neurological sleep disorder triggered by postnatal loss of the orexin/hypocretin neuropeptides. Overweight/obesity and precocious puberty are highly prevalent comorbidities of NT1, with a close temporal correlation with disease onset, suggesting a common origin. However, the underlying mechanisms remain unknown and merit further investigation. The main question we address in this review is whether the occurrence of precocious puberty in NT1 is due to the lack of orexin/hypocretin or rather to a wider hypothalamic dysfunction in the context of neuroinflammation, which is likely to accompany the disease given its autoimmune origins. Our analysis suggests that the suspected generalized neuroinflammation of the hypothalamus in NT1 would tend to delay puberty rather than hastening it. In contrast, that the brutal loss of orexin/hypocretin would favor an early reactivation of gonadotropin-releasing hormone (GnRH) secretion during the prepubertal period in vulnerable children, leading to early puberty onset. Orexin/hypocretin replacement could thus be envisaged as a potential treatment for precocious puberty in NT1. Additionally, we put forward an alternative hypothesis regarding the concomitant occurrence of sleepiness, weight gain and early puberty in NT1.

Ovarian cell tumor in a child with neurofibromatosis type 1.

Juvenile granulosa cell ovarian tumor is a rare cause ofpseudo-precociouspuberty. We report a case of a 6-year-old female with neurofibromatosis type 1 (NF1), associated with pseudo-precocious puberty (PPP). A thorough workup revealed a large multi-cystic right ovarian mass, which turned out to be a juvenile granulosa cell tumor (JGCT). This report documented a rare case of PPP caused by JGCT in a child with NF1. Verbal consent was taken from the family.

Résumé La tumeur ovarienne juvénile à cellules de la granulosa est une cause rare de puberté pseudo-précoce. Nous rapportons le cas d'une fillette de 6 ans atteinte de neurofibromatose de type 1 (NF1), associée à une puberté pseudo-précoce (PPP). Un bilan approfondi a révélé une grande masse ovarienne droite multikystique, qui s'est avérée être une tumeur juvénile des cellules de la granulosa (JGCT). Ce rapport a documenté un cas rare de PPP causé par JGCT chez un enfant atteint de NF1. Le consentement verbal a été recueilli auprès de la famille.. Mots-clés: Cellule de la granulosa, juvénile, neurofibromatose, tumeur ovarienne, puberté précoce.

Face-sparing Congenital Generalized Lipodystrophy Type 1 Associated With Nonclassical Congenital Adrenal Hyperplasia.

CONTEXT: Congenital generalized lipodystrophy, type 1 (CGL1), due to biallelic pathogenic variants in AGPAT2, is characterized by the near total loss of body fat from the face, trunk, and extremities. Patients develop premature diabetes, hypertriglyceridemia, hepatic steatosis, and polycystic ovary syndrome. However, sparing of the facial fat and precocious pubertal development has not been previously reported in CGL1. CASE DESCRIPTION: We report a 21-year-old woman of European descent with CGL1 who had sparing of the facial fat and premature thelarche at birth with premature pubarche and menstrual bleeding at age 3 years. Her serum 17-OH progesterone level rose to 1000 ng/dL (30.26 nmol/L) after cosyntropin stimulation test, suggestive of nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. Hydrocortisone replacement therapy from age 3.5 to 10 years resulted in cessation of menstruation and growth of pubic hair, and a reduction of breast size. Sanger and whole-exome sequencing revealed compound heterozygous variants c.493-1G>C; p.(Leu165_Gln196del), and c.del366_588+534; p.(Leu123Cysfs*55) in AGPAT2 plus c.806G>C; p.(Ser269Thr) and c.844G>T; p.(Val282Leu) in CYP21A2. She developed diabetes at age 13 requiring high-dose insulin and had 7 episodes of acute pancreatitis due to extreme hypertriglyceridemia in the next 5 years. Metreleptin therapy was initiated at age 18 and after 3 years, she had remission of diabetes and hypertriglyceridemia; however, menstrual irregularity and severe hirsutism did not improve. CONCLUSION: Concomitant NCAH in this CGL1 patient was associated with precocious pubertal development and sparing of facial fat. Metreleptin therapy drastically improved her hyperglycemia and hyperlipidemia but not menstrual irregularity and hirsutism.

Transition From Diencephalic Syndrome to Hypothalamic Obesity in Children With Suprasellar Low Grade Glioma: A Case Series.

Background: Children with suprasellar low grade glioma (LGG) frequently develop problems to maintain their body weight within the normal range, due to hypothalamic dysfunction. Hypothalamic damage may result in the diencephalic syndrome (DS), characterized by underweight or failure to thrive, but also in hypothalamic obesity (HO). Children with LGG presenting with DS at young age often develop HO later in life. The underlying pathophysiology for this change in body mass index (BMI) is not understood. Previous hypotheses have focused on the tumor or its treatment as the underlying cause. To better understand its etiology, we aimed to relate changes in BMI over time in children with suprasellar LGG presenting with DS to age, tumor progression, treatment, and endocrine function. We hypothesize that the development of HO in children with LGG presenting with DS is related to maturation status of the hypothalamus at time of injury and thus age. Methods: In this retrospective case series, all cases diagnosed in the Netherlands with suprasellar located LGG, currently treated or followed, with a history of DS developing into HO were included. Results: In total, 10 children were included. Median age at LGG diagnosis was 1.5 years (range 0.4-5.5), median BMI SDS was -2.64. The children developed overweight at a median age of 4.5 years (2.2-9.8). The median total difference in BMI SDS between underweight and obesity was +5.75 SDS (4.5-8.7). No association could be found between transition of DS to HO and onset of a pituitary disorder (present in 70.0%), surgery, chemotherapy, or tumor behavior. Two had developed central precocious puberty (CPP), both while having underweight or normal weight. Conclusion: The shift from DS to HO in children with hypothalamic LGG may be associated with age and not to tumor behavior, treatment characteristics or pituitary function. The development of CPP in these children seems not to be related to obesity. Our findings may indicate that the clinical picture of hypothalamic dysfunction reflects the maturation state of the hypothalamus at time of lesioning. Future prospective studies are needed to better understand underlying causative mechanisms of the morbid changes in body weight.

New insights into precocious puberty and ADHD: a nationwide cohort study.

BACKGROUND: Attention deficit-hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children; however, studies delineating the association between ADHD and central precocious puberty are limited. This study aimed to understand whether children with ADHD are at a higher risk of central precocious puberty. METHODS: This population-based retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan to investigate the association between ADHD and the incidence of central precocious puberty between 2000-2015. We identified ADHD individuals treated with methylphenidate, atomoxetine or not. The control cohort consisted of individuals without ADHD. The outcome measure was central precocious puberty diagnosis. RESULTS: Among 290,148 children (mean age: 5.83 years), central precocious puberty incidence was 4.24 and 1.95 per 105 person-years in the ADHD and control groups, respectively. Children with ADHD treated with medication had a higher risk than those without ADHD. However, medication use did not affect the incidence of central precocious puberty among children with ADHD. CONCLUSION: This study showed an association between ADHD and a higher risk of central precocious puberty. Early referral of children with ADHD to a pediatric endocrinologist for evaluation may facilitate correct diagnoses and early interventions. IMPACT: ADHD is associated with a higher risk of central precocious puberty. This study provides relevant findings, as it is the first nationwide, population-based cohort study to investigate the association between ADHD and the risk of central precocious puberty with a 15-year follow-up. Early referral of children with ADHD to a pediatric endocrinologist for the evaluation of suspected precocious puberty could facilitate correct diagnosis. Early intervention treatment with gonadotropin-releasing hormone agonist might improve final height in children with central precocious puberty.

Disorders of Puberty in Girls.

Puberty is the process through which reproductive competence is achieved and comprises gonadarche and adrenarche. Breast development is the initial physical finding of pubertal onset in girls and typically occurs between 8 and 13 years. Menarche normally occurs 2 to 3 years after the onset of breast development. Pubertal onset is controlled by the gonadotropin-releasing hormone pulse generator in the hypothalamus; however, environmental factors such as alterations in energy balance and exposure to endocrine-disrupting chemicals can alter the timing of pubertal onset. Improvement in nutritional and socioeconomic conditions over the past two centuries has been associated with a secular trend in earlier pubertal onset. Precocious puberty is defined as onset of breast development prior to 8 years and can be central or peripheral. Delayed puberty can be hypogonadotropic or hypergonadotropic and is defined as lack of breast development by 13 years or lack of menarche by 16 years. Both precocious and delayed puberty may have negative effects on self-esteem, potentially leading to psychosocial stress. Patients who present with pubertal differences require a comprehensive assessment to determine the underlying etiology and to devise an effective treatment plan.

Central Precocious Puberty in a Boy with Pseudohypoparathyroidism Type 1A due to a Novel GNAS Variant, with Congenital Hypothyroidism as the First Manifestation

Pseudohypoparathyroidism (PHP) type 1A (PHP1A) is a disorder of multiple hormone resistance, mainly parathyroid hormone. It is associated with Albright hereditary osteodystrophy phenotypes. Patients with PHP1A may initially present with hypothyroidism during infancy and later develop typical PHP1A characteristics during their childhood. Central precocious puberty (CPP) is extremely rare among PHP1A patients in whom gonadotropin resistance is more usual. This is a case report of a 9.5-year-old boy with congenital hypothyroidism who developed hypocalcemia secondary to PHP. He had relatively short stature with height standard deviation score of -0.9. Obesity had been noted since the age of two years. At the presentation of PHP, pubertal-sized testes of 10 mL were observed, and CPP was documented with serum testosterone concentration of 298 ng/dL (normal for Tanner stage III, 100-320), luteinizing hormone of 3.9 IU/L (normal, 0.2-5.0), and follicle stimulating hormone of 4.8 IU/L (normal, 1.2-5.8). Pituitary magnetic resonance imaging was unremarkable. Genetic analysis confirmed the diagnosis of PHP1A with a novel heterozygous missense variant of GNAS gene in exon 13, c.1103A>G (p.Asp368Gly). Awareness of PHP1A diagnosis in patients with congenital hypothyroidism and early childhood-onset obesity is important for early diagnosis. Apart from multiple hormone resistance, CPP may manifest in patients with PHP1A.

Extent of Extraskeletal Manifestations of Fibrous Dysplasia/McCune-Albright Syndrome in Patients with Mazabraud's Syndrome.

Mazabraud's syndrome (MZB) is a rare condition in which fibrous dysplasia of bone/the McCune-Albright syndrome (FD/MAS) co-exists with intramuscular myxomas. Both FD and the myxomas harbor the GNAS-mutation. Recent studies have shown that extraskeletal, GNAS-related features are associated with a more severe phenotype of FD/MAS. However, patients with MZB are often only seen by orthopedic surgeons. We therefore evaluated MZB patients seen in tertiary referral centers from the Netherlands (LUMC), USA (National Institutes of Health) and France (INSERM UMR 1033 (Lyos), Hôpital Edouard Herriot). All FD/MAS patients known in these centers with an additional diagnosis of a myxoma were included. Demographic information and data on disease extent and extraskeletal manifestations of FD/MAS such as precocious puberty (PP) or café-au-lait patches (CAL) were retrieved from patient's medical records. Thirty MZB patients were included: 20 women (67%) and 10 men (33%). Patients received a diagnosis of MZB (median 42 years, range 16-19) significantly later than the diagnosis of FD/MAS (median 30 years, range 0-60), p < 0.01. Twenty-six patients were diagnosed with polyostotic disease (87%). In 97% the myxoma was located near the skeletal FD lesion. The combination of MZB and MAS was made in 13 patients in whom PP (n = 7), CAL (n = 7), GH-excess (n = 3) and hyperthyroidism (n = 3) were present. Other extraskeletal features were (multinodular) goiter (n = 2) and thyroid cysts (n = 1). Furthermore, in this cohort of patients with MZB several (pre-)malignant tumors were observed; ductal carcinoma in situ of the breast in 3 patients (10%), breast cancer in 1 patient (3.3%), intra pancreatic mucinous neoplasms in 3 patients (10%) and liver adenomas in 2 patients (6.6%). A total of 47% of patients with MZB had an additional extraskeletal feature such as an endocrinopathy. In MZB, 87% of patients suffer from polyostotic FD, 43% of patients have extraskeletal GNAS-features such as an hyperfunctioning endocrinopathy and 30% (pre-)malignant tumors. We therefore advocate that MZB patients should undergo a complete screening and long-term follow-up for extent of bone disease, but also extraskeletal GNAS features of FD/MAS.