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 (cafe-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 cafe-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 cafe-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.Peer reviewe

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. Copyright (C) 2019 Endocrine SocietyPeer reviewe

Circulating TNF-Alpha and IL-6 Concentrations and TNF-Alpha -308 G > A Polymorphism in Children with Premature Adrenarche

Premature adrenarche (PA), the early rise in adrenal androgen production leading to prepubertal signs of androgen action, has been connected with adverse metabolic features. The metabolic syndrome is characterized by low-grade inflammation which in turn is associated with increases in circulating proinflammatory cytokines, like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). We tested the hypothesis that serum concentrations of TNF-α and IL-6 are increased in PA by studying 73 children with PA and 98 age- and gender-matched controls. Serum TNF-α and IL-6 concentrations were measured using a multiplex bead array. The subjects were genotyped for the TNF-α gene -308 G > A polymorphism (known to affect TNF-α gene transcription), and genotype–phenotype associations were studied. The mean serum TNF-α concentration was higher in the PA than control children (20.4 vs. 18.4 pg/ml, P = 0.048), whereas there was no significant difference in the mean serum IL-6 concentrations between the study groups. The difference in TNF-α was not explained by excess body weight in the PA subjects as the difference remained significant after BMI-adjustment (P = 0.038). In the PA group, TNF-α concentration was not associated with metabolic-endocrine features, but high IL-6 was associated with lower birth weight. There was no difference in the genotype distribution of the TNF-α gene -308 G > A polymorphism between the PA and control groups. In conclusion, PA was associated with increased serum TNF-α concentrations which, unexpectedly, were not connected with BMI or insulin resistance. The TNF-α gene -308 G > A polymorphism does not seem to be associated with the development of PA

Body composition and bone mineral density in children with premature adrenarche and the association of LRP5 gene polymorphisms with bone mineral density

Peer reviewe

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

BackgroundPatients 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. MethodsWe 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. ResultsAmong 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. ConclusionDLBCL 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.Peer reviewe

Ennenaikainen adrenarke : yleinen, moni-ilmeinen ja hyväennusteinen kehitysvariantti

Vertaisarvioitu. English summaryPeer reviewe

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 mu g/l, p <0.001). As a group, male survivors had smaller testicular size (8.5 vs. 39ml, p <0.001) and lower inhibin B ( 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.Peer reviewe

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

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 Niinimaki 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.Peer reviewe