Adrenal insufficiency management in the pediatric emergency setting and risk factors for adrenal crisis development.

BACKGROUND: In patients with adrenal insufficiency (AI), adrenal crisis (AC) represents a clinical emergency. Early recognition and prompt management of AC or AC-risk conditions in the Emergency Department (ED) can reduce critical episodes and AC-related outcomes. The aim of the study is to report the clinical and biochemical characteristics of AC presentation to improve their timely recognition and proper management in a ED setting. METHODS: Single-centre, retrospective, observational study on pediatric patients followed at the Department of Pediatric Endocrinology of Regina Margherita Children's Hospital of Turin for primary AI (PAI) and central AI (CAI). RESULTS: Among the 89 children followed for AI (44 PAI, 45 CAI), 35 patients (21 PAI, 14 CAI) referred to the PED, for a total of 77 accesses (44 in patients with PAI and 33 with CAI). The main causes of admission to the PED were gastroenteritis (59.7%), fever, hyporexia or asthenia (45.5%), neurological signs and respiratory disorders (33.8%). The mean sodium value at PED admission was 137.2 ± 1.23 mmol/l and 133.3 ± 1.46 mmol/l in PAI and CAI, respectively (p = 0.05). Steroids administration in PED was faster in patients with CAI than in those with PAI (2.75 ± 0.61 and 3.09 ± 1.47 h from PED access, p = 0.83). Significant factors related to the development of AC were signs of dehydration at admission (p = 0.027) and lack of intake or increase of usual steroid therapy at home (p = 0.059). Endocrinological consulting was requested in 69.2% of patients with AC and 48.4% of subjects without AC (p = 0.032). CONCLUSION: children with AI may refer to the PED with an acute life-threatening condition that needs prompt recognition and management. These preliminary data indicate how critical the education of children and families with AI is to improve the management at home, and how fundamental the collaboration of the pediatric endocrinologist with all PED personnel is in raising awareness of early symptoms and signs of AC to anticipate the proper treatment and prevent or reduce the correlated serious events.

Pediatric Myxedema Due to Autoimmune Hypothyroidism: A Rare Complication of a Common Disorder.

In children, hypothyroidism usually presents non-specific symptoms; symptoms can emerge gradually, compromising a timely diagnosis. We report the case of a 13-year-old male, who was admitted to the hospital due to swelling of the torso and neck. Besides these symptoms, the child was healthy, except for a significant growth delay. Ultrasound evaluation and blood tests led to the diagnosis of myxedema secondary to severe hypothyroidism, which was due to autoimmune thyroiditis. Further investigations revealed pericardial effusion and pituitary hyperplasia, with hyper-prolactinemia. Treatment with levothyroxine led to edema regression and clinical, hemato-chemical and radiological improvement. After 6 months, growth velocity increased, although the recovery of growth already lost was not guaranteed. Brain MRI showed regression of pituitary hyperplasia. The diagnostic delay in this case was probably due to the patient's apparent good health, and the underestimation of growth restriction. This report underlines the importance of growth monitoring in adolescence, a critical period for identifying endocrine conditions; if undiagnosed, these conditions can lead to serious complications, such as myxedema in hypothyroidism, with potential effects beyond growth on multiple organs.

Clinical features of thyroid cancer in paediatric age. Experience of a tertiary centre in the 2000-2020 period.

PURPOSE: To describe the clinical features of a paediatric cohort affected by differentiated thyroid cancer (DTC) followed in a tertiary Department of Paediatric Endocrinology. METHODS: Clinical data of 41 patients affected by DTC in the 2000-2020 period were reviewed. RESULTS: The main risk factor was autoimmune thyroiditis (39%). Cytological categories were TIR3b in 39%, TIR4 in 9.8%, TIR5 in 51.2%. After total thyroidectomy, radioiodine treatment was performed in 38 subjects (92.7%). ATA low-risk category was assigned in 11 (30.5%), intermediate-risk category in 15 (41.7%), and high-risk category in 10 patients (27.8%). Age at diagnosis was 15.1 ± 0.92 years in low-risk category, 14.7 ± 0.59 in intermediate-risk category, 11.7 ± 0.89 years in high-risk category (p = 0.01). TIR3b was manly observed in low-risk class (63.6%), while TIR5 was mainly reported in intermediate and high-risk class (60 and 80% respectively) (p = 0.04). Post-surgery stimulated thyroglobulin was increased in high-risk class (407.8 ± 307.1 ng/ml) [p = 0.04]. Tumour size was larger in high-risk category (42.6 ± 2.6 mm), than in low and intermediate-risk categories (19.4 ± 3.5 mm and 28.5 ± 3.9 mm, respectively) (p = 0.008). Patients in intermediate and high-risk categories displayed more tumour multifocality (60 and 90% respectively) (p < 0.005). Disease relapse was mainly observed in high risk category (40%, p = 0.04). CONCLUSION: DTC in childhood is more aggressive than in adults, but the overall survival rate is excellent. The therapeutic approach is still heterogeneous, especially in low-risk category. Further studies are needed to standardise management and reduce disease persistence in childhood.

Pediatric thyroid surgery: Retrospective analysis on the first 25 pediatric thyroidectomies performed in a reference center for adult thyroid diseases.

Introduction: Pediatric thyroid carcinoma represents about 4-5% of all pediatric carcinoma with an incidence of 0.5 cases/100,000, compared to 2-10/100000 cases in the adult population. The aim of this study is to present the experience of a reference adult endocrine surgery unit in charge of the treatment of pediatric thyroid diseases. Materials and methods: From January 2019 to September 2022, 25 patients, aged 5-17, underwent thyroid surgery. We analysed indications for surgery, use of intraoperative nerve monitoring (IONM), definitive histological examination, postoperative outcomes and risk factors related. Results: Surgical indication was performed for Graves' disease (27%) and for nodular pathology (73%): of these, four were malignant lesions (TIR4/TIR5), eight with indeterminate characteristics (TIR3A/TIR3B) and four characterized as benign (TIR1/TIR2). Total thyroidectomy (TT) was performed in 76% of cases, three of which were prophylactic for the activation of the RET gene mutation in MEN 2A. IONM was used in eight cases (32%), all patients aged 11 years or less. FNA's accuracy was 100% for lesions typified as benign and malignant (TIR1/TIR2 and TIR4/TIR5). The overall malignancy rate achieved was 40% and in the final histological examination 75% of the TIR 3B lesions were malignant. Six patients (24%) developed hypoparathyroidism in the first postoperative day, with normalization of calcium values within thirty days in 5 patients. Conclusions: Pediatric thyroid nodules are rare and distinguished from adult thyroid disease by a worse prognosis and higher malignancy rates. Our work reports a much higher malignancy rate among indeterminate TIR 3B lesions than observed in the adult population and the three patients who underwent prophylactic total thyroidectomy for activating RET gene mutation had all a definitive histological diagnosis of medullary carcinoma. Post-surgical hypoparathyroidism is a common finding in these patients: in most cases the condition is transient and it benefits from supportive therapy. Intraoperative finding of a thinner recurrent laryngeal nerve in younger patients makes nerve isolation more difficult than in adult surgery: IONM is recommended in patients under 12. Pediatric thyroid surgery is challenging, we sustain it requires referral thyroid Centers for thyroid disease with highly skilled general endocrine surgeons.

Growth hormone deficiency in a case of septo-optic-dysplasia due to SOX2 mutation: should we re-test patients during the transition period?

Gene mutations encoding transcription factors, including SOX2, have been associated with growth hormone deficiency (GHD) and abnormal pituitary development. Guidelines on GHD management in the transition period state that patients with genetic-based childhood-onset GHD can skip retesting due to a high likelihood of permanent GHD. We describe a case of septo-optic-dysplasia due to SOX2 mutation characterised by childhood-onset GHD, which showed a normal somatotropic function at the transition period. This case raises the opportunity to retest for GHD during the transition period, even in patients with a known genetic cause, in order to avoid inappropriate GH treatment.

Genetic Testing for a Patient with Suspected 3 Beta-Hydroxysteroid Dehydrogenase Deficiency: A Case of Unreported Genetic Variants.

3beta-hydroxysteroid dehydrogenase type II deficiency (HSD3B2 deficiency), a rare form of congenital adrenal hyperplasia (CAH), is characterized by varying degrees of salt loss and incomplete masculinization in males and mild virilization or normal external genitalia in females. We report the case of a patient (46XY) showing salt loss and incomplete masculinization, markedly elevated levels of 17OHP (17 hydroxyprogesterone), ACTH (Adreno Cortico Tropic Hormone), testosterone and delta4androstenedione (delta4A), low levels of cortisol and absence of bone skeletal alterations that frequently characterize POR (Cytochrome P450 oxidoreductase) deficiency. Mutation analysis by Sanger sequencing of the HSD3B2 gene showed that the patient presented with a compound heterozygote for two novel variants c.370A>G p.Ser124Gly and c.308-6 G>A. The two HSD3B2 gene variants were also present in the patient's older brother showing only incomplete masculinization. The in silico analysis revealed a probable damaging effect of c.370A>G p.Ser124Gly: residue p.Ser124 is highly conserved among species and seems to be located in the catalytic site of the enzyme, playing a pivotal role in NAD(H) binding to its substrate. Intronic c.308-6G>A variant is predicted to be likely pathogenic; the substitution seems to cause a change in the splice acceptor site located 6bp downstream of the variant. The two siblings seem to be affected by 3ß-HSD2 deficiency; nevertheless, the two novel variants are likely to cause variable expressivity of the disease.

Expert Opinion on the Management of Growth Hormone Deficiency in Brain Tumor Survivors: Results From an Italian Survey.

Background: Growth hormone deficiency (GHD) is the first and most common endocrine complication in pediatric brain tumor survivors (BTS). GHD can occur due to the presence of the tumor itself, surgery, or cranial radiotherapy (CRT). Aims: This study aimed to evaluate management and adherence to current guidelines of the Italian centers engaged in the diagnosis and follow-up of GHD patients with BTS. Methods: A multidisciplinary scientific board of pediatric endocrinologists, oncologists and radiologists with neuroimaging expertise discussed and reviewed the main issues relating to the management of GHD in pediatric BTS and developed a survey. The survey included questions relating to organizational aspects, risk factors, diagnosis, definition of stable disease, and treatment. The online survey was sent to an expanded panel of specialists dedicated to the care of pediatric BTS, distributed among the three specialty areas and throughout the country (23 Italian cities and 37 Centers). Results: The online questionnaire was completed by 86.5% (32 out of 37) of the Centers involved. Most had experience in treating these patients, reporting that they follow more than 50 BTS patients per year. Responses were analyzed descriptively and aggregated by physician specialty. Overall, the results of the survey showed some important controversies in real life adherence to the current guidelines, with discrepancies between endocrinologists and oncologists in the definition of risk factors, diagnostic work-up, decision-making processes and safety. Furthermore, there was no agreement on the neuroimaging definition of stable oncological disease and how to manage growth hormone therapy in patients with residual tumor and GHD. Conclusions: The results of the first Italian national survey on the management of GHD in BTS highlighted the difference in management on some important issues. The time to start and stop rhGH treatment represent areas of major uncertainty. The definition of stable disease remains critical and represents a gap in knowledge that must be addressed within the international guidelines in order to increase height and to improve metabolic and quality of life outcomes in cancer survivors with GHD.

"Lymphocyte population in peripheral blood in children and adolescents with graves disease. Potential predictive tool for severity of the disease".

PURPOSE: To date, few data are available on the prognostic role of lymphocyte subsets in pediatric Graves' Disease (GD). The aim of this retrospective study is to analyze the role of lymphocyte subtypes in predicting the severity of GD. METHODS: Data of 10 pediatric subjects aged <18 years with GD onset in the period November 2017-April 2021 were collected. The lymphocyte population was assessed at the onset of GD as well as hormonal and clinical data. The follow-up period was 2.4 ± 0.8 years. RESULTS: Pearson correlation coefficient between CD4+ /CD8+ ratio and fT3 levels and thyroid volume at diagnosis was 0.72 (p = 0.04) and 0.81 (p = 0.004) respectively; that between CD4+ /CD8+ ratio and the TRAb titer at diagnosis and after 6, 12 and 24 months was 0.89, 0.89, 0.73 and 0.77 respectively (p = 0.02, p = 0.01, p = 0.03 and 0.04). The correlation coefficient of anti-thyroid drug (ATD) dose after 6 and 12 months with CD4+ /CD8 ratio was 0.88 and 0.78 (p = 0.001 and p = 0.02 respectively). Patients with a higher CD4+ /CD8+ ratio at diagnosis displayed higher fT3 levels (28.73 ± 2.18 vs 13.48 ± 2.19 pmol/L, p = 0.03) and higher TRAb titers (28.9 ± 11.2 vs 4.88 ± 0.97, p = 0.01). CONCLUSION: CD4+/CD8+ ratio appears as a promising predictive tool to be considered together with other prognostic factors to better manage pediatric GD. These preliminary data need to be confirmed over a longer follow-up period and in larger cohorts.

Management of Childhood-onset Craniopharyngioma in Italy: A Multicenter, 7-Year Follow-up Study of 145 Patients.

CONTEXT: Nationwide data on children diagnosed with craniopharyngioma (CP) are not available in Italy. OBJECTIVE: This work aimed to identify patients' characteristics, type of surgical approach, complications and recurrences, number of pituitary deficits, and number of patients starting growth hormone (GH) treatment. METHODS: A retrospective multicenter collection took place of 145 patients aged 0 to 18 years who underwent surgery for CP between 2000 and 2018, and followed up in 17 Italian centers of pediatric endocrinology. RESULTS: Age at diagnosis was 8.4 ± 4.1 years. Duration of symptoms was 10.8 ± 12.5 months and headache was most frequent (54%), followed by impaired growth (48%) and visual disturbances (44%). Most lesions were suprasellar (85%), and histology was adamantinomatous in all cases but two. Surgical approach was transcranial (TC) in 67.5% of cases and transsphenoidal (TS) in 31.%. The TC approach was prevalent in all age groups. Postsurgery complications occurred in 53% of cases, with water-electrolyte disturbances most frequent. Radiotherapy was used in 39% of cases. All patients but one presented with at least one hormone pituitary deficiency, with thyrotropin deficiency most frequent (98.3%), followed by adrenocorticotropin (96.8%), arginine vasopressin (91.1%), and GH (77.4%). Body mass index (BMI) significantly increased over time. A hypothalamic disturbance was present in 55% of cases. GH therapy was started during follow-up in 112 patients at a mean age of 10.6 years, and 54 developed a recurrence or regrowth of the residual lesion. CONCLUSION: CP is often diagnosed late in Italy, with TC more frequent than the TS surgical approach. Postsurgery complications were not rare, and hypopituitarism developed almost in all cases. BMI shows a tendency to increase overtime.

Multidisciplinary Approach for Hypothalamic Obesity in Children and Adolescents: A Preliminary Study.

Hypothalamic obesity (HO) is delineated by an inexorable weight gain in subjects with hypothalamic disorder (congenital or acquired). The aim of the present study was to evaluate the effect of a multidisciplinary approach on weight trend and metabolic outcome in children and adolescents with hypothalamic disease who were overweight or obese. Thirteen patients (aged 8.1-16.1 years) received a personalized diet, accelerometer-based activity monitoring, and psychological assessment. Height, weight, body mass index (BMI), and serum metabolic parameters were assessed at baseline (T0) and after six months (T1). Metformin was introduced at T1 in four subjects who were then re-evaluated after six months (T2). At T1, weight gain was significantly reduced compared with T0 (0.29 ± 0.79 kg/month vs. 0.84 ± 0.55 kg/month, p = 0.03), and weight standard deviation score (SDS) and BMI SDS did not change significantly, as serum metabolic parameters. The four subjects treated with metformin showed a reduction of weight SDS and BMI SDS at T2. In conclusion, patients treated with our multidisciplinary approach showed, after 6 months, favorable results characterized by decreased weight gain and stabilization of weight SDS and BMI SDS in a condition usually characterized by inexorable weight gain. However, further analysis, larger cohorts, and longer follow-up are needed to confirm these preliminary data.

Predictive factors of malignancy in pediatric patients with thyroid nodules and performance of the Italian classification (SIAPEC 2014) in the outcome of the cytological FNA categories.

PURPOSE: The rate of malignancy (ROM) among pediatric studies using the Bethesda System is 39.5% and 41.5% for atypia of undetermined significance/follicular lesion of undetermined significance and for suspected follicular neoplasm, respectively. Data reported on the basis of Bethesda System showed lower ROM in adults with indeterminate nodules (30.5 and 28.9% respectively). Studies on adults based on the Italian Society of Anatomic Pathology and Cytology (SIAPEC) classification, report ROM of 14.2% for TIR3a and 44.6% for TIR3b category, showing greater sensitivity in detecting malignancy. To date, no performance data are available about SIAPEC classification in pediatric age. METHODS: Retrospective data were collected from 200 pediatric subjects with thyroid nodules in the period 2000-2020. RESULTS: The distribution of cytological categories after fine needle aspiration biopsy (FNAB) was 7 TIR1, 4 TIR1c, 22 TIR2, 14 TIR3a, 9 TIR3b, 3 TIR4, and 16 TIR5. The surgical approach was performed in 40/200 subjects, with total ROM of 65% (0% for TIR1-TIR3a, 77.8% for TIR3b, and 100% for TIR4-TIR5). Total FNAB accuracy was 95%, while the sensibility and specificity were 92.3 and 92.6%, respectively. CONCLUSIONS: The reported data seem to confirm a greater sensitivity of SIAPEC classification to identify malignancy within the indeterminate category also in pediatric age and not only in adulthood. This finding may orient clinicians toward clinical follow-up for the indeterminate TIR3a group and toward surgical approach with total thyroidectomy in the indeterminate TIR3b group, although this indication should be confirmed in further national multicenter studies including larger cohorts.

"Primary Hyperparathyroidism (PHPT) in Children: Two Case Reports and Review of the Literature".

Primary hyperparathyroidism (PHPT) is a rare disorder in children and adolescents. Typical biochemical features are hypercalcemia and hypophosphatemia, but the clinical features can be heterogeneous, and in some cases, symptoms are vague and nonspecific, leading to misdiagnosis or late diagnosis. Herein, we report two cases of PHPT in pediatric age with different presenting symptoms, pain in the foot, and progressive alteration of the gait in the first case and recurrent abdominal pain with emotional lability in the second. Biochemical and radiological assessment confirmed PHPT. Both cases were treated surgically as definitive treatment, but in the second case, previous medical treatment with cinacalcet, a calcimimetic agent, was required to reduce serum PTH and calcium levels. After surgery, despite conventional treatment with calcium and calcitriol, case 1 developed a hungry bone syndrome. The analysis of the MEN-1 (Multiple Endocrine Neoplasia) gene was negative in both cases. A diagnosis of PHPT should be considered when children or adolescents present bone pain with radiological imaging of osteolytic lesion and biochemical feature of hypercalcemia associated with hypophosphatemia. In PHPT, the gold standard treatment is represented by surgery followed by strict postoperative endocrine monitoring to maintain adequate homeostasis of calcium and bone metabolism.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy in Two Siblings: Same Mutations but Very Different Phenotypes.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by mutations in the AIRE gene, is mainly characterized by the triad of hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis, but can include many other manifestations, with no currently clear genotype-phenotype correlation. We present the clinical features of two siblings, a male and a female, with the same mutations in the AIRE gene associated with two very different phenotypes. Interestingly, the brother recently experienced COVID-19 infection with pneumonia, complicated by hypertension, hypokalemia and hypercalcemia. Although APECED is a monogenic disease, its expressiveness can be extremely different. In addition to the genetic basis, epigenetic and environmental factors might influence the phenotypic expression, although their exact role remains to be elucidated.

Incidence of primary congenital hypothyroidism and relationship between diagnostic categories and associated malformations.

PURPOSE: The incidence of primary congenital hypothyroidism (CH) has grown progressively and literature data indicate an association between CH and congenital malformations. The purpose of this study is to establish the current incidence of CH in the Italian Region of Piedmont and verify the relationship between CH diagnostic categories and associated malformations. METHODS: The biochemical and clinical data of 105 newborns with CH diagnosed in the period January 2014 to December 2019 were analyzed. RESULTS: The incidence of CH in the Italian Piedmont region in the 2014-2019 period increased to 1:1090. Thyroid dysgenesis was responsible for 47.6% (50/105) of all cases, with agenesis in 14.3% (15/105), while ectopia and hypoplasia in 23.8% (25/105) and 9.5% (10/105) of the cases, respectively; dyshormonogenesis defects were found in 52.4% (55/105) of cases. Congenital extra-thyroid anomalies were identified in 33/105 (31.4%) of newborns with CH and mainly involve the cardiac system (17/85, 16.1%), urogenital tract (7/85, 6.7%), gastrointestinal tract (5/105, 4.8%), and the musculoskeletal system (5/105, 4.8%). The highest rate of malformations was observed in patients with thyroid agenesis and dyshormonogenesis, respectively, in 53.5% and 36.4% of cases, while in the presence of thyroid ectopia and hypoplasia, the rate was 12% and 20%, respectively, (p = 0.03). CONCLUSION: In the Italian region of Piedmont, the incidence of primary CH has been increased over time, with a variation in the percentage of the different forms of CH. Congenital malformations, especially affecting the cardiovascular, urogenital, gastrointestinal, and musculoskeletal systems, seem to be mainly associated with thyroid agenesis or defects in hormonogenesis.

Distribution of plasma copeptin levels and influence of obesity in children and adolescents.

In recent years, a more stable AVP surrogate, called copeptin, has been used as an adjuvant diagnostic tool for dysnatremia in adults and appears to be promising even in the pediatric age. The aim of this study is to present the distribution of plasma copeptin in a large pediatric cohort and to observe the influence of fluid consumption and obesity on its values. A cohort of 128 children and adolescents was divided into two groups on the basis of nocturnal deprivation (group A) or free access to oral fluids in the 6-8 h before blood collection (group B). At all distribution percentiles, copeptin levels were higher (p < 0.0001) in group A, as were plasma sodium levels and osmolality (p = 0.02 and p = 0.008, respectively). The influence of BMI on copeptin levels was investigated by dividing the cohort into nonobese (group C) and obese children and adolescents (group D). Copeptin levels were higher in group D (p = 0.04).Conclusion: The measurement of copeptin could represent a useful tool for the diagnostic pathway of dysnatremic conditions, but its interpretation should take into consideration the state of hydration. Furthermore, it could also be a promising marker for obesity and metabolic syndrome, although this hypothesis needs further studies to be confirmed. What is Known: • Copeptin use as a diagnostic tool in AVP-related disorders, such as diabetes insipidus or syndrome of inappropriate secretion of antidiuretic hormone, is well established in adults • In pediatric age, few studies are available, but the preliminary data, including our previous study, seems to be promising. What is New: • In this study, we represent the distribution of copeptin levels in a pediatric cohort and show the significant influence of fluid ingestion on its plasma levels. • Also BMI seems to be a significant variable on copeptin levels and may be used as an obesity marker in pediatric age.

Effects of treatments on gonadal function in long-term survivors of pediatric hematologic malignancies: A cohort study.

BACKGROUND: Potentially gonadotoxic protocols are currently used for the treatment of childhood hematologic malignancies. This study aims to evaluate the prevalence of gonadal dysfunction and the most important associated risk factors in a cohort of hematologic malignancy survivors. PROCEDURE: We considered all patients referred to our long-term follow-up clinic for childhood cancer survivors, between November 2001 and December 2017. Inclusion criteria were: (a) previous diagnosis of hematologic malignancy; (b) age at hematologic malignancy diagnosis < 18 years; (c) at least five years after the end of anticancer treatments; (d) at least one evaluation of gonadal function after the 18th birthday. Patients diagnosed before January 1, 1990, were excluded. RESULTS: Three hundred twenty-seven survivors (males = 196) were included. Isolated spermatogenesis damage was found in 58/196 (29.6%) of males, whereas 18/196 (9.2%) had Leydig cell failure. In females, 35/131 (26.7%) experienced premature ovarian insufficiency. In both sexes, abdominopelvic irradiation and hematopoietic stem cell transplantation were strongly associated with the risk of gonadal dysfunction. For every 1000 mg/m2 increase in cyclophosphamide-equivalent dose exposure, the risk of spermatogenesis damage increased 1.52-fold and that of Leydig cell failure increased 1.34-fold, whereas the risk of premature ovarian insufficiency increased 1.80-fold. About 30% of those males who developed Leydig cell failure did so more than five years after the end of treatments. CONCLUSIONS: Gonadal dysfunction is still a significant late effect of therapies for pediatric hematologic malignancies. In males, the reevaluation of Leydig cell function may be useful even several years after the exposure to gonadotoxic treatments.

Clinical Approach to Sodium Homeostasis Disorders in Children with Pituitary-Suprasellar Tumors.

Children with pituitary-suprasellar tumors are at high risk of developing sodium metabolism disorders since the tumoral mass itself or surgical and medical treatment can damage AVP release circuits. Additional risk factors are represented by the use of hypotonic fluids, the young age, total parenteral nutrition, and obstructive hydrocephalus secondary to tumor pathology. The most frequent hyponatremic disorders related to AVP in these patients are the syndrome of inappropriate ADH secretion and the cerebral/renal salt wasting syndrome, while hypernatremic conditions include central diabetes insipidus (CDI) and adipsic CDI. The main challenge in the management of these patients is to promptly distinguish the AVP release disorder at the base of the sodium imbalance and treat it correctly by avoiding rapid sodium fluctuations. These disorders can coexist or follow each other in a few hours or days; therefore, careful clinical and biochemical monitoring is necessary, especially during surgery, the use of chemotherapeutic agents, or radiotherapy. This monitoring should be performed by experienced healthcare professionals and should be multidisciplinary, including pediatric endocrinologists, neurosurgeons, and oncologists since maintaining sodium homeostasis also plays a prognostic role in terms of disease survival, therapeutic response, hospitalization rate, and mortality. In this review, we analyze the management of sodium homeostasis disorders in children with pituitary-suprasellar tumors and discuss the main challenges in the diagnosis and treatment of these conditions based on literature data and over 30 years of clinical experience at our Department of Pediatric Endocrinology.

Teriparatide (rhPTH 1-34) treatment in the pediatric age: long-term efficacy and safety data in a cohort with genetic hypoparathyroidism.

BACKGROUND: Hypoparathyroidism is characterized by the absence or inadequately low circulating concentrations of the parathyroid hormone, resulting in hypocalcemia, hyperphosphatemia, and elevated fractional excretion of calcium in the urine. The use of activated vitamin D analogs and calcium supplements represent conventional therapy. Subcutaneous recombinant human parathormone [rhPTH(1-34)] has been proposed as a substitutive treatment, even to avoid side effects of vitamin D and calcium. OBJECTIVE: To assess the long-term safety and efficacy of rhPTH(1-34) in a pediatric cohort of patients with genetic hypoparathyroidism. METHODS: The study is a 9.2-year self-controlled study of six pediatric patients (four males and two females, aged 9.4 ± 5.2) with DiGeorge, hypoparathyroidism-deafness-renal dysplasia (HDR) or autoimmune-candidiasis-polyendocrinopathy-ectodermal-dysplasia (APECED) syndrome, associated with autoimmune intestinal malabsorption in a patient. The presence of clinical signs of hypocalcemia and biochemical parameters, such as calcium, phosphate, alkaline phosphatase in the blood and calcium-creatinine ratio in urine, were compared during conventional treatment and rhPTH(1-34) (teriparatide, 12.5 µg twice daily). RESULTS: The rhPTH(1-34) treatment allowed a reduction, although not always a complete suspension, of calcium supplementation and a slight reduction of calcitriol therapy. The number of tetanic episodes was reduced in four patients during the rhPTH(1-34) treatment. Mean blood calcium, alkaline phosphatase, and phosphate did not significantly change, while a significant reduction of the urinary calcium-to-creatinine ratio (0.55 ± 0.32 vs 0.16 ± 0.09, p = 0.03) was obtained. Renal ultrasound examination showed a worsening in three patients, while it did not change in the remaining three subjects during the follow-up. CONCLUSIONS: In children with syndromic hypoparathyroidism presented here, replacement therapy with rhPTH(1-34) allowed to maintain adequate levels of the calcium and phosphate in the blood, normalize urinary calcium excretion, and reduce tetanic episodes. In patients with low compliance to conventional therapy or intestinal malabsorption, the use of rhPTH(1-34) could be considered, also to reduce the side effects of treatment with vitamin D and calcium.

Uniparental disomy and pretreatment IGF-1 may predict elevated IGF-1 levels in Prader-Willi patients on GH treatment.

Pediatric patients with Prader-Willi syndrome (PWS) can be treated with recombinant human GH (rhGH). These patients are highly sensitive to rhGH and the standard doses suggested by the international guidelines often result in IGF-1 above the normal range. We aimed to evaluate 1 the proper rhGH dose to optimize auxological outcomes and to avoid potential overtreatment, and 2 which patients are more sensitive to rhGH. In this multicenter real-life study, we recruited 215 patients with PWS older than 1 year, on rhGH at least for 6 months, from Italian Centers for PWS care. We collected auxological parameters, rhGH dose, IGF-1 at recruitment and (when available) at start of treatment. The rhGH dose was 4.3 (0.7/8.4) mg/m2/week. At recruitment, IGF-1 was normal in 72.1% and elevated in 27.9% of the patients. In the group of 115 patients with IGF-1 available at start of rhGH, normal pretreatment IGF-1 and uniparental disomy were associated with elevated IGF-1 during the therapy. No difference in height and growth velocity was found between patients treated with the highest and the lowest range dose. The rhGH dose prescribed in Italy seems lower than the recommended one. Normal pretreatment IGF-1 and uniparental disomy are risk factors for elevated IGF-1. The latter seems to be associated with higher sensitivity to GH. In case of these risk factors, we recommend a more accurate titration of the dose to avoid overtreatment and its potential side effects.

Growth hormone-Insulin-like growth factor 1 axis hyperactivity on bone fibrous dysplasia in McCune-Albright Syndrome.

CONTEXT: In fibrous dysplasia (BFD), normal bone and bone marrow are replaced by fibro-osseous tissue, leading to fracture, deformity and pain. BFD may be isolated, or in association with cutaneous hyperpigmentation and/or hyperfunctioning endocrinopathies, termed McCune-Albright syndrome (MAS). GH hypersecretion has been described in 10%-20% of MAS-BFD patients. Aim of the study was to determine the impact of GH-insulin like growth factor 1 (IGF1) axis hyperactivity on MAS-BFD morbidities and the efficacy of GH excess therapy. DESIGN AND PATIENTS: A multicentric cross-sectional analysis was conducted on three different MAS cohorts. From 195 MAS patients, 37 subjects (19%) with GH excess were identified and compared with 34 MAS controls without GH hypersecretion. RESULTS: Mean head circumference SDS was significantly higher in GH excess: 4.025 SDS vs 0.683 SDS (P < .0001). The risk of optic neuropathy (Odds ratio 4.231; P = .039), hearing deficit (Odds ratio 2.961; P = .0481), facial asymmetry (Odds ratio 6.563; P = .0192), malignancies (Odds ratio 15.24; P = .0173) were higher in GH excess group. Overall, pharmacotherapy (octreotide alone 10-30 mg/mo or with pegvisomant 10-20 mg/d) was effective in IGF1 normalization (IGF1 Z-score between -2 and +2 SDS) in 21/29 patients (72.4%) with good compliance to the regimen. Late diagnosis and GH excess treatment after 16 years old of age was associated with an increased risk of optic neuropathy (Odds ratio 4.500; P = .0491) and growth of pituitary adenomas (Odds ratio 7.846; P = .050). CONCLUSIONS: GH-IGF1 hyperactivity increases risk of morbidities in MAS. Medical therapy is effective in normalizing IGF1 in most patients, and early treatment during paediatric age is associated with a decreased risk of optic neuropathy and GH-secreting adenomas growth.