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.

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.

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.

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.

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.

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.

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.

Premature adrenarche--a common condition with variable presentation.

Adrenarche refers to a maturational increase in the secretion of adrenal androgen precursors, mainly dehydroepiandrosterone (DHEA) and its sulfate (DHEAS). In premature adrenarche (PA), clinical signs of androgen action appear before the age of 8/9 years in girls/boys, concurrently with the circulating DHEA(S) concentrations above the usually low prepubertal level. The most pronounced sign of PA is the appearance of pubic/axillary hair, but also other signs of androgen effect (adult type body odor, acne/comedones, greasy hair, accelerated statural growth) are important to recognize. PA children are often overweight and taller than their peers, and the higher prevalence of PA in girls than in boys is probably explained by higher female adiposity and peripheral DHEA(S) conversion to active androgens. PA diagnosis requires exclusion of other causes of androgen excess: congenital adrenal hyperplasia, androgen-producing tumors, precocious puberty, and exogenous source of androgens. PA has been linked with unfavorable metabolic features including hyperinsulinism, dyslipidemia, and later-appearing ovarian hyperandrogenism. Although this common condition is usually benign, PA children with additional risk factors including obesity should be followed up, with the focus on weight and lifestyle. Long-term follow-up studies are warranted to clarify if the metabolic changes detected in PA children persist until adulthood.

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.

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.

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.

Continuum of phenotypes and sympathoadrenal function in premature adrenarche.

OBJECTIVES: Premature adrenarche (PA), the early rise in adrenal androgen (AA) production, can manifest with different clinical signs of androgen effect. Premature pubarche defined as appearance of pubic hair before the age of 8/9 years in girls/boys, is the most prominent clinical sign of PA and often erroneously described as a synonym of PA. Our aim was to determine the association of circulating AA concentrations with different prepubertal signs of androgen action (SAA). Secondly, we tested whether adrenomedullary function is altered in children with SAA, as it is in congenital adrenal hyperplasia (CAH) also causing adrenal hyperandrogenism. DESIGN AND METHODS: We examined 73 Finnish prepubertal children with any hyperandrogenic sign(s) having appeared before the age of 8/9 years (girls/boys) (35 with pubic and/or axillary hair=PAH; 38 without=nonPAH), and 98 age- and sex-matched controls. Circulating adrenal steroid and catecholamine concentrations were measured and correlated with clinical parameters. RESULTS: None of the children with SAA had CAH or virilizing tumor. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione concentrations overlapped between the SAA and control children, and they were lower in the nonPAH than PAH group (P<0.01). SAA children had similar plasma epinephrine but higher norepinephrine (NE) concentrations than their controls (mean (95% confidence interval) 1.61 (1.44, 1.77) versus 1.39 (1.30, 1.49) nmol/l, P=0.03). CONCLUSIONS: PA forms a continuum with more pronounced increase in circulating androgens in children with PAH than in those without. Some children show SAA with fairly low androgen concentrations. The clinical significance of elevated NE concentrations associated with SAA needs to be confirmed in further studies.

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.