Cognitive performance in young adult women with a history of premature adrenarche.

BACKGROUND: Girls with premature adrenarche (PA) mature earlier than peers and have been found to have greater symptom accounts reflecting anxiety compared to peers. It is not known, however, whether PA effects cognitive development. This longitudinal case-control cohort study aimed: (1) To investigate whether a history of PA leads to measurable changes in adulthood cognitive performance, and (2) to assess whether findings characteristic of PA girls predict adulthood cognitive performance. METHODS: Twenty-seven girls with PA and 27 age-matched control girls were examined and followed from mid-childhood (mean age 7.2 years) until early adult age (18.5 years). Wechsler Adult Intelligence Scale, Fourth Edition scores were used as main outcome measure. RESULTS: Allostatic load (AL) scores, which compile multisystem variables to reflect the overall wear and tear of the body from increased and prolonged stress, were higher in the PA group in both prepuberty and adulthood, but there were no differences in WAIS-IV results between the groups (full-scale IQ 92.7 vs. 97.5, p 0.376; no differences in separate indexes). Childhood androgen levels, glucose metabolism biomarkers, and AL scores failed to predict adulthood cognitive performance outcomes. CONCLUSION: The study suggests that PA does not predispose to adverse adulthood outcomes of cognitive development. IMPACT: The study suggests that a history of premature adrenarche (PA) does not affect cognitive performance in adult age. Childhood androgen levels and biomarkers of glucose metabolism failed to predict adulthood cognitive outcomes in this study. Allostatic load scores were elevated in the PA group both in childhood and adulthood but did not predict adulthood cognitive outcomes.

Bisphosphonate treatment for skeletal complications in paediatric cancer-Experience from a single tertiary centre.

AIMS: The aim was to analyse the use and safety of bisphosphonate treatment for metabolic bone complications in paediatric cancer patients. METHODS: We retrospectively describe our experience with bisphosphonate treatment in 25 childhood cancer patients (aged <18 years) in a single tertiary hospital between 1999 and 2020. RESULTS: The most common primary diagnosis was acute lymphoblastic leukaemia (n = 16) and Hodgkin lymphoma (n = 3). Eleven patients (44%) had received allogeneic stem cell transplantation and two patients autologous stem cell transplantation. Sixteen patients (64%) had been treated with radiotherapy, either total-body (n = 11) or local (n = 5). The main indication for bisphosphonates was osteoporosis with vertebral compression fractures in 13/25, osteonecrosis in 6/25 and hypercalcaemia in 2/25. The bisphosphonate treatment was started on average 13 (range 0-76) months after the diagnosis of the bone complication. Bisphosphonate treatment lasted between weeks (hypercalcaemia) to 5 years (severe osteoporosis). Mild, non-symptomatic hypophosphatemia (n = 8), hypocalcaemia (n = 6) and moderate, transient pain (n = 6) were the most common adverse effects. No severe side effects were observed even when bisphosphonates were administered concomitantly with chemotherapy. Bone mineral density significantly improved with the bisphosphonate treatment (mean lumbar spine Z-score -1.17 vs. -0.07, p < 0.001). CONCLUSION: Bisphosphonate treatment was well tolerated in this paediatric patient cohort.

The human cathelicidin hCAP-18 in serum of children with haemato-oncological diseases.

The human cathelicidin hCAP-18 (pro-LL-37) is the pro-protein of the antimicrobial peptide LL-37. hCAP-18 can be produced by many different cell types; bone marrow neutrophil precursors are the main source of hCAP-18 in the circulation. Neutrophil count is used as a marker for myelopoiesis but does not always reflect neutrophil production in the bone marrow, and thus additional markers are needed. In this study, we established the reference interval of serum hCAP-18 level in healthy children and compared serum hCAP-18 levels between different diagnostic groups of children with haemato-oncological diseases, at diagnosis. We found that children with diseases that impair myelopoiesis, such as acute leukaemia, aplastic anaemia, or myelodysplastic syndrome, presented with low hCAP-18 levels, whereas patients with non-haematological malignancies displayed serum hCAP-18 levels in the same range as healthy children. Children with chronic myeloid leukaemia presented with high circulating levels of hCAP-18, probably reflecting the high number of all differentiation stages of myeloid cells. We suggest that analysis of serum hCAP-18 provides additional information regarding myelopoiesis in children with haemato-oncological diseases, which may have future implications in assessment of myelopoiesis in clinical management.

Bisphosphonate treatment in children with acute lymphoblastic leukemia and osteonecrosis - radiological and clinical findings in a national cohort.

Background: Osteonecrosis (ON) is a recognized complication of childhood ALL, but its optimal management remains unestablished. This study evaluated the effect of bisphosphonate (BP) treatment on the evolution of ON lesions in childhood ALL.Material and Methods: We included a national cohort of ALL patients diagnosed with symptomatic ON before 18 years of age and treated with BPs (N = 10; five males). Patients were followed both clinically and with serial MRIs. ON lesions were graded according to the Niinimäki classification.Results: The 10 patients had a total of 55 ON lesions. The median age was 13.3 years at ALL diagnosis and 14.8 years at ON diagnosis. Four patients had received HSCT before the ON diagnosis. BPs used were pamidronate (N = 7), alendronate (N = 2) and ibandronate (N = 1). The duration of BP treatment varied between 4 months and 4 years. In 4/10 patients, BP treatment was given during the chemotherapy. BPs were well-tolerated, with no severe complications or changes in kidney function. At the end of follow up 13/55 (24%) ON lesions were completely healed both clinically and radiographically; all these lesions were originally graded 3 or less. In contrast, ON lesions originally classified as grade 5 (joint destruction; N = 4) remained at grade 5. All grade 5 hip joint lesions needed surgical treatment. During BP treatment, the pain was relieved in 7/10 patients. At the end of follow-up, none of the patients reported severe or frequent pain.Conclusion: BP treatment was safe and seemed effective in relieving ON-induced pain in childhood ALL. After articular collapse (grade 5) lesions did not improve with BP treatment. Randomized controlled studies are needed to further elucidate the role of BPs in childhood ALL-associated ON.

Serum androgen bioactivity is low in children with premature adrenarche.

BACKGROUND: Clinical findings in children with premature adrenarche (PA) correlate only partly with circulating levels of adrenal androgens. It is not known whether the prepubertal low circulating concentrations of testosterone (T) and dihydrotestosterone, together with those of adrenal androgens, are capable of activating the androgen receptor. METHODS: This cross-sectional study was performed at a university hospital. Circulating androgen bioactivity was measured in 67 prepubertal children with clinical signs of PA and 94 control children using a novel androgen bioassay. RESULTS: Circulating androgen bioactivity was low in the PA and control children. In the subgroup of children (n = 28) with serum T concentration over the assay sensitivity (0.35 nmol/l) and a signal in the androgen bioassay, we found a positive correlation between androgen bioactivity and serum T (r = 0.50; P < 0.01) and the free androgen index (r = 0.61; P < 0.01) and a negative correlation with serum sex hormone-binding globulin concentration (r = -0.41; P < 0.05). CONCLUSION: Peripheral metabolism of adrenal androgen precursors may be required for any androgenic effects in PA. However, the limitations in the sensitivity of the bioassay developed herein may hide some differences between the PA and control children.

Demographic and disease-related factors impact bone turnover and vitamin D in children with hemato-oncological diseases.

Children with hemato-oncological diseases may have significant skeletal morbidity, not only during and after treatment but also at the time of diagnosis before cancer treatment. This study was designed to evaluate the vitamin D status and circulating bone metabolic markers and their determinants in children at the time of diagnostic evaluation for hemato-oncological disease. This cross-sectional study included 165 children (91 males, median age 6.9 yr range 0.2-17.7 yr). Of them, 76 patients were diagnosed with extracranial or intracranial solid tumors, 83 with leukemia, and 6 with bone marrow failure. Bone metabolism was assessed by measuring serum 25OHD, PTH, bone alkaline phosphatase, intact N-terminal propeptide of type I procollagen, and C-terminal cross-linked telopeptide of type I collagen. Vitamin D deficiency was found in 30.9% of children. Lower 25OHD levels were associated with older age, lack of vitamin D supplementation, season outside summer, and a country of parental origin located between latitudes -45° and 45°. Children diagnosed with leukemia had lower levels of markers of bone formation and bone resorption than those who had solid tumors or bone marrow failure. In conclusion, vitamin D deficiency was observed in one-third of children with newly diagnosed cancer. Bone turnover markers were decreased in children with leukemia, possibly because of the suppression of osteoblasts and osteoclasts by leukemic cells. The identification of patients with suboptimal vitamin D status and compromised bone remodeling at cancer diagnosis may aid in the development of supportive treatment to reduce the adverse effects of cancer and its treatment.

Cardiorespiratory Fitness in Young Adult Women With a History of Premature Adrenarche.

Context: Premature adrenarche (PA) may predispose to some adverse long-term health outcomes. Cardiorespiratory fitness (CRF) is one of the strongest factors known to predict overall health, but no data exist on the CRF of women with a history of PA. Objective: To study if hyperandrogenism in childhood resulting from PA leads to a measurable difference in CRF between young adult PA and control women. Methods: A total of 25 women with PA and 36 age-matched controls were followed from prepubertal age until adulthood. Anthropometric measurements, body composition, biochemical, and lifestyle factors were assessed. The main outcome measure was maximal cycle ergometer test result at the mean age of 18.5 years. We also assessed prepubertal predicting factors for CRF with different linear regression models. Results: Though prepubertal children with PA were taller and heavier than their non-PA peers, there were no significant differences in height, body mass index, body composition, or physical activity in young adulthood. We observed no significant differences in any of the parameters of the maximal cycle ergometer test, including maximal load (P = .194) or peak oxygen consumption (P = .340). Hemodynamic responses of the groups were similar. None of the examined models or prepubertal factors significantly predicted CRF at adult age. Conclusion: This study suggests that hyperandrogenism in childhood/adolescence resulting from PA does not have a significant impact on adulthood CRF.

Lymphomas in cartilage-hair hypoplasia - A case series of 16 patients reveals advanced stage DLBCL as the most common form.

Background: Patients with cartilage-hair hypoplasia (CHH) have an increased risk of malignancy, particularly non-Hodgkin lymphoma and basal cell carcinoma. The characteristics, clinical course, response to therapy and outcome of lymphomas in CHH remains unexplored. Methods: We assessed clinical features of lymphoma cases among Finnish patients with CHH. Data were collected from the Finnish Cancer Registry, hospital records, the National Medical Databases and Cause-of-Death Registry of Statistics Finland. Results: Among the 160 CHH patients, 16 (6 men, 10 women) were diagnosed with lymphoma during 1953-2016. Lymphoma was diagnosed in young adulthood (median age 26.4 years, range from 6.4 to 69.5 years), mostly in advanced stage. The most common lymphoma type was diffuse large cell B-cell lymphoma (DLBCL) (6/16, 38%). Eight patients received chemotherapy (8/16, 50%), and two of them survived. Standard lymphoma chemotherapy regimens were administered in the majority of cases. Altogether, eleven CHH patients died due to lymphomas (11/16, 69%). In almost all surviving lymphoma patients, the diagnosis was made either during routine follow-up or after evaluation for non-specific mild symptoms. Search for CHH-related clinical predictors demonstrated higher prevalence of recurrent respiratory infections, in particular otitis media, and Hirschsprung disease in patients with lymphoma. However, three patients had no clinical signs of immunodeficiency prior to lymphoma diagnosis. Conclusion: DLBCL is the most common type of lymphoma in CHH. The outcome is poor probably due to advanced stage of lymphoma at the time of diagnosis. Other CHH-related manifestations poorly predicted lymphoma development, implying that all CHH patients should be regularly screened for malignancy.

PCOS Features and Steroid Profiles Among Young Adult Women with a History of Premature Adrenarche.

CONTEXT: Premature adrenarche (PA) may increase the risk for polycystic ovary syndrome (PCOS). OBJECTIVE: To study features of PCOS in young adult women with a history of PA. METHODS: Thirty PA and 42 control females were followed from prepuberty to young adulthood (median age 18.1 years). The main outcome measures were ovarian function, the use of contraceptives, and clinical and biochemical indicators of hyperandrogenism. RESULTS: We found no differences in the use of hormonal contraceptives (50 vs 50%, PA vs controls, respectively; P > .999), indication for using contraceptives (P = .193), or in the history of oligo- (17 vs 26%, P = .392) and amenorrhea (0 vs 0%, P > .999). Among women not using hormonal contraceptives, those with a history of PA had a higher prevalence of hirsutism (27 vs 0%, P = .023) but not acne (87 vs 67%, P = .252). Steroid profiles were broadly comparable between the groups, but PA women had lower sex hormone-binding globulin (SHBG) concentrations (30.1 vs 62.4 nmol/L, P < .001) resulting in higher free androgen index (3.94 vs 2.14, P < .001). The difference in SHBG levels persisted through body mass index adjustment. SHBG correlated negatively with the homeostasis model assessment for insulin resistance (r -0.498, P = .003). Anti-Müllerian hormone concentrations were comparable between the groups (39.3 vs 32.1 pmol/L, P = .619). CONCLUSION: PA was not associated with evident ovarian dysfunction in young adult women. However, women with a history of PA had decreased SHBG levels and thus, increased bioavailability of circulating androgens.

Girls with premature adrenarche have accelerated early childhood growth.

OBJECTIVE: To evaluate the effect of premature adrenarche (PA) on prepubertal growth. STUDY DESIGN: The prepubertal growth of 54 girls with PA and 52 control girls was analyzed retrospectively. Birth measures were noted, and childhood length/height and weight were measured annually until age 5 years and at the current visit (at a median age of 7.6 years). The growth variables were correlated with serum insulin-like growth factor (IGF)-1, dehydroepiandrosterone sulfate, and insulin concentrations. RESULTS: There were no significant differences in birth length or weight standard deviation scores (SDSs) between the 2 study groups. The girls with PA demonstrated a significant length SDS increment during the first 2 years of life (median +1.0 SDS; P < .001). Compared with controls, they were taller (median current height 1.2 vs 0 SDS; P < .001) and gained more weight throughout childhood. The difference in weight-for-height became significant at a later age compared with the difference in height. Median serum IGF-1 concentration adjusted for both age and body mass index SDS was higher in the PA group (24 vs 19 nmol/L; P < .031). CONCLUSIONS: PA was not associated with small birth size in our population. Girls with PA had enhanced growth already in early childhood, which was not explained by weight gain. Enhanced IGF-1 production may contribute to the prepubertal growth acceleration in PA.

LRP5 in premature adrenarche and in metabolic characteristics of prepubertal children.

OBJECTIVE: Premature adrenarche (PA) is associated with unfavourable metabolic characteristics. We hypothesized that genetic variation in low density lipoprotein (LDL) receptor-related protein 5 (LRP5), which is involved in Wnt signalling in the adrenal cortex and in cholesterol metabolism, plays a role in the pathogenesis of PA. DESIGN AND PATIENTS: We performed a cross-sectional association study in 73 Finnish children with PA and 97 age- and gender-matched healthy controls. MEASUREMENTS: LRP5 genotypes were determined by direct sequencing. Single-marker associations with clinical-metabolic characteristics, including adrenocortical function, glucose tolerance and lipid profile, were examined with age and gender as covariates. RESULTS: Nineteen single nucleotide polymorphisms (SNPs) in LRP5 were found in the 170 children. No significant differences in the genotype distributions were observed between the PA and control groups. SNPs A1330V and N740N were associated with higher serum dehydroepiandrosterone sulphate (DHEAS) levels in the control subjects (A/A vs. A/a; mean 0.8 vs. 1.4 micromol/l, P = 0.01). They were also associated with higher plasma levels of total (4.2 vs. 4.7 mmol/l, P = 0.02) and LDL cholesterol (2.4 vs. 2.9 mmol/l, P = 0.02) in the control group, as was SNP V1119V (P = 0.04 and P = 0.03, respectively). SNPs F549F and V1119V were associated with higher systolic blood pressure (P = 0.04 and P = 0.02, respectively). There were no differences in the parameters of glucose metabolism between the genotype groups. CONCLUSIONS: Genetic variation in LRP5 did not predispose to PA but was associated with metabolic characteristics, especially lipid profile, in healthy prepubertal children.

Gonadal Failure Is Common in Long-Term Survivors of Childhood High-Risk Neuroblastoma Treated With High-Dose Chemotherapy and Autologous Stem Cell Rescue.

Background: Neuroblastoma is the most common extra-cranial solid tumor in children. Intensive therapy including autologous stem-cell transplantation (HSCT) has improved the poor prognosis of high-risk neuroblastoma (HR-NBL) but may impair gonadal function. Objectives: To investigate the gonadal function and fertility in long-term survivors of childhood HR-NBL. Design: A cohort including all Finnish (n = 20; 11 females) long-term (>10 years) survivors of HR-NBL and an age- and sex-matched control group (n = 20) was examined at a median age of 22 (16-30) years. Oncologic treatments, pubertal timing, hormonal therapies and the number of off-spring were recorded, and pituitary and gonadal hormones were measured. Results: Altogether 16/20 of the long-term survivors of HR-NBL entered puberty spontaneously; puberty was hormonally induced in four survivors (three females). Among the 8/11 female survivors with spontaneous puberty, seven had spontaneous menarche, but 5/8 developed ovarian failure soon after puberty. Nine females currently needed estrogen substitution. AMH, a marker of ovarian reserve, was lower in the female survivors than controls (median 0.02 vs. 1.7 µg/l, p < 0.001). As a group, male survivors had smaller testicular size (8.5 vs. 39 ml, p < 0.001) and lower inhibin B (<10 vs. 170 ng/l, p < 0.001) compared with control males, with altogether 6/9 survivor males fulfilling the criteria of gonadal failure (absent puberty, small testicle size or increased FSH with need of testosterone substitution). Gonadal failure was more common in female and male survivors treated with total-body irradiation. Three survivors (one male) had offspring, all treated without total-body irradiation and moderate dose of alkylating chemotherapy. Growth velocity was compromised in all survivors after HR-NBL diagnosis, with absent pubertal growth spurt in 7/17 survivors with complete growth data. Conclusion: Gonadal failure is common in long-term survivors of HR-NBL treated with HSCT. Fertility may be preserved in some survivors treated without total-body irradiation.

Cardiometabolic Risk Profile Among Young Adult Females With a History of Premature Adrenarche.

CONTEXT: Premature adrenarche (PA) is associated with childhood overweight and hyperinsulinemia; the long-term cardiometabolic outcome is unknown. OBJECTIVE: To study cardiometabolic profile in adult women with previous PA. DESIGN AND PARTICIPANTS: Thirty women with PA and 41 control subjects were followed from prepuberty to young adulthood. MAIN OUTCOME MEASURES: Prevalence of the metabolic syndrome (MetS) and clinical and biochemical cardiovascular risk factors. RESULTS: There were no differences in the prevalence of MetS or in any parameters indicating dyslipidemia, hypertension, hepatosteatosis, atherosclerosis, or low-grade inflammation between the study groups. However, prevalence of insulin resistance (IR; P = 0.014) and acanthosis nigricans (P = 0.010) was higher in the PA group. Neither fasting glucose nor insulin concentrations differed between the study groups, but HbA1c [adjusted for body mass index (BMI) P = 0.011] and Homeostatic Model Assessment of Insulin Resistance (P = 0.044; BMI-adjusted P = nonsignificant) were higher in the PA group. Although BMI and fat percentage were comparable between the study groups, the PA group had higher central fat mass than the control group. In the whole study population, MetS and IR were associated with greater adult fat mass, but no prepubertal factors predicting later IR were found. CONCLUSION: PA does not seem to be associated with MetS, dyslipidemia, hypertension, atherosclerosis, or low-grade inflammation in young adult women. However, some women with PA may be at an increased risk of unfavorable glucose metabolism, which is associated with increased central adiposity at adult age rather than determined by prepubertal factors.

Androgen receptor gene CAG repeat polymorphism and X-chromosome inactivation in children with premature adrenarche.

CONTEXT: There is variation in the adrenal androgen levels and clinical findings of children with premature adrenarche (PA). OBJECTIVES: We hypothesized that androgen sensitivity, indicated by the length of CAG repeat in the X-chromosomal androgen receptor (AR) gene has a role in the polygenic pathogenesis of PA. DESIGN AND PATIENTS: We performed a cross-sectional association study among 73 Finnish Caucasian children with PA (10 boys and 63 girls) and 97 age- and gender-matched healthy controls (18 boys and 79 girls). MAIN OUTCOME MEASURES: AR gene methylation-weighted CAG(n)(mwCAG(n)) via CAG(n) length and X-chromosome inactivation analysis and clinical phenotype were determined. SETTING: The study took place at a university hospital. RESULTS: PA subjects had significantly shorter mwCAG(n) than controls [mean difference (95% confidence interval); 0.76 (0.14-1.38); P = 0.017]. AR gene mwCAG(n) did not correlate with androgen or SHBG levels in either group. In children with PA, mwCAG(n) correlated positively with body mass index (BMI) (tau = 0.19; P = 0.02). The mean of mwCAG(n) was significantly shorter in PA children with lower BMI compared with PA children with higher BMI [BMI sd score < 0.79, n = 35, vs. BMI sd score > 0.79, n = 36; 1.13 (0.38-1.87), P = 0.004] and in PA children with lower BMI compared with healthy children with same BMI (P = 0.004). CONCLUSIONS: The AR gene CAG(n) polymorphism may have a significant role in the pathogenesis of PA, especially in lean children.

Trajectories of Growth and Serum DHEAS and IGF-1 Concentrations in Girls With a History of Premature Adrenarche: Attenuation of the Phenotype by Adulthood.

Background: It has been speculated that premature adrenarche (PA) could lead to unfavorable outcome, including shorter adult stature, but longitudinal follow-up data are insufficient. Methods: This prospective case-control study included 30 PA and 42 control females who were born mostly full-term and appropriate for gestational age. They were examined first at the median age of 7.6 years and now at 18.1 years. Main outcome measures were height, body mass index (BMI), age at menarche, and serum dehydroepiandrosterone sulfate (DHEAS) and insulin-like growth factor 1 (IGF-1) concentrations. Results: The PA and control females had comparable mean (standard deviation) adult height [167.2 (6.8) vs. 164.5 (5.1) cm, P = 0.059] and median (25th-75th percentiles) BMI [22.8 (21.1-28.9) vs. 21.6 (19.8-24.3) kg/m2, P = 0.068, respectively]. Adult heights were comparable with the mid-parental heights in both study groups. The PA females were taller than the controls until the age of 12 years and they lacked a distinct pubertal growth spurt. Serum DHEAS and IGF-1 concentrations did not differ between the PA and control groups at the age of 18 years. Median (range) age at menarche was significantly lower in the PA than control females [11.5 (9.5-15.0) vs. 13.0 (10.0-15.0), P = 0.001]. Conclusions: Although PA girls have advanced growth and earlier pubertal development together with a tendency to be more overweight, their height, BMI, and serum DHEAS and IGF-1 concentrations are comparable to those of their peers at the age of 18 years. Our findings indicate a benign outcome of PA in appropriate for gestational age -born females concerning adult height and adrenal androgen secretion.

Children with a History of Premature Adrenarche Have Good Health-Related Quality of Life at the Age of 12 Years.

BACKGROUND/AIM: Children with premature adrenarche (PA) are taller and more overweight than their healthy peers, and PA girls have a slightly accelerated pubertal development. There is some evidence that early exposure to androgens may have an influence on psychosocial development. The aim of this cross-sectional case-control study was to evaluate health-related quality of life (HRQoL) in PA children at the age of 12 years. METHODS: The HRQoL was assessed for 43 PA (36 girls) and 63 control children (52 girls) at the median age of 12.0 years using the standardized 16D instrument, and the scores of the PA children were compared to those of the control children and reference population. RESULTS: The mean overall HRQoL scores did not differ between PA and control girls, PA and control boys, or all PA and control children or the reference population. Independently of PA, overweight girls had a lower mean overall HRQoL score than lean girls, and both overweight girls and boys were on average worse off on the dimension of appearance than their lean peers. CONCLUSIONS: PA children have as good self-rated HRQoL as their peers at the age of 12 years. Overweight is associated with a worse HRQoL profile independently of PA.

Polyostotic Fibrous Dysplasia With and Without McCune-Albright Syndrome-Clinical Features in a Nordic Pediatric Cohort.

OBJECTIVE: Fibrous dysplasia (FD) presents as skeletal lesions in which normal bone is replaced by abnormal fibrous tissue due to mosaic GNAS mutation. McCune-Albright syndrome (MAS) refers to FD combined with skin (café-au-lait) and endocrine manifestations. This study describes the clinical childhood manifestations of polyostotic FD and MAS in a Nordic cohort. PATIENTS AND DESIGN: We retrospectively reviewed a cohort of pediatric patients (n = 16) with polyostotic FD with or without MAS diagnosed and followed in two Nordic Pediatric tertiary clinics between 1996 and 2017. RESULTS: Half of the 16 patients with polyostotic FD presented with MAS. All patients with MAS (n = 8) had café-au-lait spots, and either gonadotropin-independent precocious puberty (PP) (girls; n = 5) or abnormal testicle structure (boys, n = 3). None manifested hyperthyroidism or growth hormone excess. Mild hypophosphatemia was common (11/16), but none had signs of hypophosphatemic rickets. Craniofacial bone involvement was found in 12 patients (75%); in 5 of these, skeletal lesions were limited to craniofacial area. One child with craniofacial disease had lost vision due to optic nerve damage. Eleven (69%) patients had sustained a fracture at FD lesion, over half of them requiring surgical fixation of the fracture, most commonly in the proximal femur. The first symptoms leading to FD/MAS diagnosis included skull/facial asymmetry (n = 4), PP (n = 3), abnormal gait (n = 3), pathologic fracture (n = 3), wide-spread café-au-lait spots (n = 1), headache (n = 1), and vision loss (n = 1). CONCLUSION: Polyostotic FD and MAS remain diagnostic and therapeutic challenges because of the broad clinical spectrum. Recurrent fractures, pain, and even vision loss may impair the quality of life in children with FD.

Childhood metabolic syndrome and its components in premature adrenarche.

CONTEXT: Premature pubarche (PP), the main clinical manifestation of premature adrenarche (PA), has been associated with insulin resistance and dyslipidemia in selected populations. OBJECTIVES: Our aim was to determine the prevalence of childhood metabolic syndrome (cMBS) and to study its components in prepubertal Northern European girls with PA. DESIGN AND PATIENTS: We conducted a cross-sectional study on 63 prepubertal girls with PA (32 with PP = PP-PA, 31 without PP = nonPP-PA) and 80 healthy age-matched control girls. A standard 2-h oral glucose tolerance test with insulin sampling was performed. Plasma lipids and serum SHBG were analyzed, and blood pressure and weight-for-height were recorded. cMBS was defined by modified criteria of the U.S. National Cholesterol Education Project Adult Treatment Panel III and the World Health Organization. SETTING: The study was performed at University Hospital. RESULTS: The mean weight-for-height (P = 0.002) and the prevalence of cMBS by the modified Adult Treatment Panel III (24 vs. 10%) and World Health Organization definitions (16 vs. 5%) (P < 0.05 for both) were higher in the PA than control girls. The weight-for-height adjusted serum insulin concentrations during the oral glucose tolerance test were elevated in the whole PA group, whereas the fasting insulin concentrations were increased and SHBG was decreased only in the PP-PA subgroup. The weight-for-height adjusted blood pressure, lipid, or glucose levels did not differ between the study groups. CONCLUSIONS: Prepubertal Northern European PA girls have increased prevalence of cMBS mainly due to being overweight and their hyperinsulinism. Among the PA children, the nonPP-PA girls have milder metabolic changes than the PP-PA girls.

Girls with a History of Premature Adrenarche Have Advanced Growth and Pubertal Development at the Age of 12 Years.

BACKGROUND: Premature adrenarche (PA) has been linked to early thelarche and menarche, but longitudinal data on growth and pubertal development after PA are insufficient. METHODS: Growth and pubertal development of mostly full-term and appropriate for gestational age-born 43 PA (36 girls) and 63 control children (52 girls) were analyzed prospectively. Children examined first at the mean age of 7.6 years were reexamined at the mean age of 12.0 years. RESULTS: The PA girls but not the boys were taller and had higher body mass index (BMI) than the controls. A higher proportion of the PA than control girls had reached menarche, while the same percentage of the PA and control boys were at Tanner genital stage ≥2. The PA girls with premature pubarche (PP) were taller but not heavier and had more often reached menarche by the age of 12 years than the PA girls without PP. The PA girls with menarche had lower birth length (BL) and higher prepubertal insulin-like growth factor 1 (IGF-1) concentrations compared with non-menarcheal PA girls. In logistic regression analyses for all girls, lower BL standard deviation score, earlier maternal menarche, and higher prepubertal IGF-1 were independently associated with menarche. CONCLUSION: At 12 years of age, the PA girls had higher BMI, advanced linear growth, and accelerated pubertal development with earlier menarche than the control girls. The PA girls with PP were taller and had earlier menarche than the PA girls without PP. Lower BL and higher prepubertal IGF-1 concentration were predictive factors for menarche by the age of 12 years.

Inhibition of DNA methylation increases follistatin expression and secretion in the human adrenocortical cell line NCI-H295R.

Activin affects adrenocortical steroidogenesis and increases apoptosis, while follistatin (FS) acts as an activin antagonist by binding to activin, preventing attachment to its receptors. The regulation of FS expression in the adrenal cortex is poorly understood. Adrenocortical tumors often display aberrant methylation. In the present study, we investigated the effect of DNA methylation on FS mRNA expression and peptide secretion in adrenocortical cells. We treated human NCI-H295R adrenocortical cells with the methylation inhibitor 5-Aza-2'deoxycytidine (Azad; 0.1-100 microM for 1, 4 or 7 days) and measured FS mRNA expression by Northern blot and quantitative real time RT-PCR analyses as well as FS secretion by specific ELISA. Methylation-specific PCR showed decreased methylation in the FS promoter region after Azad treatment. A significant (P < 0.05) time- and dose-dependent increase in FS mRNA expression (up to 4.6-fold) and peptide secretion (up to 17.1-fold) was detected after Azad treatment. We conclude that FS gene expression and peptide secretion in NCI-H295R adrenocortical cells are regulated by DNA methylation. Thus, variable methylation in different adrenocortical tumors may influence activin bioactivity and its consequences in steroidogenesis and cell proliferation/apoptosis.