Prevalence of Polycystic Ovarian Syndrome in Girls with a History of Idiopathic Central Precocious Puberty.

INTRODUCTION: The prevalence of polycystic ovarian syndrome (PCOS) in adolescent girls is between 1 and 4.3%. It remains controversial whether women with a history of idiopathic central precocious puberty (ICPP) are at increased risk for PCOS. Our objective was to assess the prevalence of PCOS in adolescents with a history of ICPP compared with healthy adolescents and the prevalence of PCOS among ICPP girls who have received or not gonadotropin-releasing hormone analogue (GnRHa) treatment. METHODS: We assessed post-menarcheal girls with a history of ICPP. Girls were evaluated at gynecological age ≥2.5 years. Data collected were age at menarche, menstrual cycle characteristics, BMI, clinical hyperandrogenism (HA), total and free testosterone levels. PCOS diagnosis was defined by criteria for adolescents. Subjects were also analyzed regarding whether or not they had received GnRHa treatment. RESULTS: Ninety-four subjects were assessed, and 63 had been treated with GnRHa. Menstrual disorders were found in 29%, clinical HA in 36%, and biochemical HA in 23%. Twelve percent met the diagnostic criteria for PCOS. There was no difference in BMI or in the incidence of menstrual dysfunction or hyperandrogenemia between treated and untreated patients. A higher proportion of clinical HA was found in untreated patients when compared to treated girls. The relative risk (RR) of developing PCOS in ICPP girls was 2.5 compared to a population of healthy adolescents. This RR was not higher in patients who received treatment with GnRHa than in those who did not. CONCLUSION: Adolescent girls with a history of ICPP have an increased risk of PCOS. This risk seems not to be related to GnRHa treatment.

Diagnosing and treating anterior pituitary hormone deficiency in pediatric patients.

Hypopituitarism, or the failure to secrete hormones produced by the anterior pituitary (adenohypophysis) and/or to release hormones from the posterior pituitary (neurohypophysis), can be congenital or acquired. When more than one pituitary hormone axis is impaired, the condition is known as combined pituitary hormone deficiency (CPHD). The deficiency may be primarily due to a hypothalamic or to a pituitary disorder, or concomitantly both, and has a negative impact on target organ function. This review focuses on the pathophysiology, diagnosis and management of anterior pituitary hormone deficiency in the pediatric age. Congenital hypopituitarism is generally due to genetic disorders and requires early medical attention. Exposure to toxicants or intrauterine infections should also be considered as potential etiologies. The molecular mechanisms underlying the fetal development of the hypothalamus and the pituitary are well characterized, and variants in the genes involved therein may explain the pathophysiology of congenital hypopituitarism: mutations in the genes expressed in the earliest stages are usually associated with syndromic forms whereas variants in genes involved in later stages of pituitary development result in non-syndromic forms with more specific hormone deficiencies. Tumors or lesions of the (peri)sellar region, cranial radiation therapy, traumatic brain injury and, more rarely, other inflammatory or infectious lesions represent the etiologies of acquired hypopituitarism. Hormone replacement is the general strategy, with critical periods of postnatal life requiring specific attention.

Uso de ibuprofeno en el tratamiento de pacientes pediátricos con poliuria y disnatremia. Reporte de una serie de casos / Ibuprofen use for the treatment of pediatric patients with polyuria and dysnatremia. A case series report

Los niños con lesiones selares y/o supraselares pueden presentar diabetes insípida central con posterior secreción inadecuada de hormona antidiurética. Nosotros observamos, en algunos casos, aumento de la incidencia de poliuria, natriuresis e hiponatremia, tríada diagnóstica del síndrome cerebral perdedor de sal. Aquí comunicamos la evolución de 7 pacientes con antecedentes de daño agudo del sistema nervioso central y diabetes insípida central seguida por síndrome cerebral perdedor de sal. Como tratamiento aportamos secuencialmente fluidos salinos parenterales, cloruro de sodio oral, desmopresina, mineralocorticoides e incluso tiazidas. Ante la persistencia de poliuria con hiponatremia, agregamos ibuprofeno. Como resultado de este esquema terapéutico secuencial, este grupo redujo significativamente los valores de diuresis diaria de 10 ml/kg/h a 2 ml/kg/h en un tiempo promedio de 5 días, normalizando también las natremias (de 161 mEq/L a 143 mEq/L) en un tiempo promedio de 9 días. En ningún caso observamos efectos adversos asociados al tratamiento.

Children with sellar and/or suprasellar lesions may develop central diabetes insipidus with subsequent inappropriate antidiuretic hormone secretion. An increased incidence of polyuria, natriuresis, and hyponatremia has been reported in some cases, which make up the diagnostic triad of cerebral salt wasting syndrome. Here we report the clinical course of 7 patients with a history of acute central nervous system injury and central diabetes insipidus followed by cerebral salt wasting syndrome. Treatment included the sequential use of parenteral saline solution, oral sodium chloride, desmopressin, mineralocorticoids, and even thiazides. Due to persistent polyuria and hyponatremia, ibuprofen was added. As a result of this sequential therapeutic regimen, daily urine output reduced significantly from 10 mL/ kg/h to 2 mL/kg/h over an average period of 5 days, together with a normalization of natremia (from 161 mEq/L to 143 mEq/L) over an average period of 9 days. No treatment-related adverse effects were observed in any case.

Testicular dysfunction at diagnosis in children and teenagers with haematopoietic malignancies improves after initial chemotherapy.

Introduction: Hematopoietic malignancies are the most frequent type of cancer in childhood. Recent advances in cancer treatment have significantly improved survival until adulthood. There is an extensive literature on the effects of cancer treatment on the gonadal axis in adult survivors of childhood cancer mainly focused on sperm production, but scarce information exists on the immediate impact of cancer and its treatment in boys. Objectives: In this work, we determined the status of the hypothalamic-pituitary-testicular (HPT) axis function at diagnosis and the immediate impact of chemotherapy at the start of treatment in children and adolescents with hematopoietic malignancies. Subjects and methods: In a prospective study of 94 boys and adolescents with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or non-Hodgkin lymphoma (NHL), we determined serum AMH, inhibin B and FSH to assess the gonadotrophin-Sertoli cell component of the HPT axis, and testosterone and LH to evaluate the gonadotrophin-Leydig cell component, at diagnosis and after 3 months of chemotherapy. Secondarily, the general health state was evaluated. Results: In prepubertal boys, at diagnosis, AMH, inhibin B and FSH were lower compared to the reference population, reflecting an FSH-Sertoli cell axis dysfunction. After 3 months of chemotherapy, all hormone concentrations increased. At pubertal age, at diagnosis, AMH and inhibin B were lower compared to the reference population for Tanner stage, with inappropriately normal FSH, suggesting a primary Sertoli cell dysfunction with insufficient gonadotrophin compensation. The LH-Leydig cell axis was mildly disrupted. After 3 months of chemotherapy, inhibin B and AMH were unchanged while median FSH levels rose to values that exceeded the reference range, indicating a significant impairment of Sertoli cell function. Testosterone normalized concomitantly with an abnormal LH elevation reflecting a compensated Leydig cell impairment. General health biomarkers were impaired at diagnosis and improved after 3 months. Conclusion: The HPT axis function is impaired in boys with hematopoietic malignancies before the initiation of chemotherapy. There is a primary testicular dysfunction and a concomitant functional central hypogonadism that could be due to an impaired overall health. The HPT axis function improves during the initial 3 months of chemotherapy concomitantly with the general health state. However, in pubertal boys the dysfunction persists as shown by elevated gonadotropin levels after 3 months.

Novel Insulin-Like Growth Factor 1 Gene Mutation: Broadening of the Phenotype and Implications for Insulin Resistance.

CONTEXT: Insulin-like growth factor (IGF)1 gene mutations are extremely rare causes of pre- and postnatal growth retardation. Phenotype can be heterogenous with varying degrees of neurosensory deafness, cognitive defects, glucose metabolism impairment and short stature. OBJECTIVE: This study describes a 12.6-year-old girl presenting with severe short stature and insulin resistance, but with normal hearing and neurological development at the lower limit of normal. METHODS: DNA was obtained from the proband and both parents for whole exome sequencing (WES). In silico analysis was performed to predict the impact of the IGF1 variant on IGF1 and insulin receptors (IGF1R and IR) signaling. Phosphorylation of the IGF1R at activating Tyr residues and cell proliferation analyses were used to assess the ability of each subject's IGF1 to bind and activate IGF1R. RESULTS: The proband had low immunoreactive IGF1 in serum and WES revealed a novel homozygous IGF1 missense variant (c.247A>T), causing a change of serine 83 for cysteine (p.Ser83Cys; p.Ser35Cys in mature peptide). The proband's parents were heterozygous for this mutation. In silico analyses indicated the pathogenic potential of the variant with electrostatic variations with the potential of hampering the interaction with the IGF1R but strengthening the binding to IR. The mutant IGF1 protein had a significantly reduced activity on in vitro bioassays. CONCLUSION: We describe a novel IGF1 mutation leading to severe loss of circulating IGF1 immunoreactivity and bioactivity. In silico modeling predicts that the mutant IGF1 could interfere with IR signaling, providing a possible explanation for the severe insulin resistance observed in the patient. The absence of significant hearing and neurodevelopmental involvement in the present case is unusual and broadens the clinical spectrum of IGF1 mutations.

Type 1 Insulin-Like Growth Factor Receptor Nuclear Localization in High-Grade Glioma Cells Enhances Motility, Metabolism, and In Vivo Tumorigenesis.

Gliomas are the most frequent solid tumors in children. Among these, high-grade gliomas are less common in children than in adults, though they are similar in their aggressive clinical behavior. In adults, glioblastoma is the most lethal tumor of the central nervous system. Insulin-like growth factor 1 receptor (IGF1R) plays an important role in cancer biology, and its nuclear localization has been described as an adverse prognostic factor in different tumors. Previously, we have demonstrated that, in pediatric gliomas, IGF1R nuclear localization is significantly associated with high-grade tumors, worst clinical outcome, and increased risk of death. Herein we explore the role of IGF1R intracellular localization by comparing two glioblastoma cell lines that differ only in their IGF1R capacity to translocate to the nucleus. In vitro, IGF1R nuclear localization enhances glioblastoma cell motility and metabolism without affecting their proliferation. In vivo, IGF1R has the capacity to translocate to the nucleus and allows not only a higher proliferation rate and the earlier development of tumors but also renders the cells sensitive to OSI906 therapy. With this work, we provide evidence supporting the implications of the presence of IGF1R in the nucleus of glioma cells and a potential therapeutic opportunity for patients harboring gliomas with IGF1R nuclear localization.

Improving safety in paediatric thyroidectomy by PTH measurements.

OBJETIVE: We followed our previously reported algorithm based on intra and postoperative parathyroid hormone (PTH) levels to predict postthyroidectomy hypoparathyroid hypocalcemia. The objective of the study was to assess if this strategy is useful and safe to reduce hypocalcemia, hospitalisation length and postsurgery calcium sampling. DESIGN, PATIENTS, MEASSUREMENTS: We classified our series of 66 patients according to their risk of hypoparathyroidism based on PTH determinations. We treated high-risk patients with calcium and vitamin D1-25 supplementation and obtained routine daily calcium samples to control low-risk patients until 48 h postsurgery. We compared the outcomes and overall results of this new approach with those of a historical control group of patients with equivalent PTH measurements who were treated only if they presented hypocalcemia. RESULTS: In the high-risk subgroup (n = 30), five patients had hypocalcemia within the first 24 h. Compared with the high-risk control subgroup, the incidence of hypocalcemia fell from 100% to 17% (p < .001), and the median hospitalisation length from 6 to 3 days (p < .001). In the low-risk subgroup (n = 36), 28 patients remained normocalcemic with significantly less calcium sampling (p < .001). Eight patients had hypocalcemia; seven of them required neck dissection, which was the only risk factor related to postsurgical hypoparathyroidism (RR: 2.1 [confidence interval 95%: 1.4-3.1]; p < .001). The overall incidence of hypocalcemia decreased by 58% in our patients compared to the control group. CONCLUSIONS: Assessing PTH levels to classify the risk of hypoparathyroidism and to initiate preventive therapy was an effective approach that improved the safety of our paediatric patients by reducing the incidence of hypocalcemia and the length of hospitalisation after thyroidectomy in paediatric patients.

High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency.

Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.

Comprehensive Identification of Pathogenic Gene Variants in Patients With Neuroendocrine Disorders.

PURPOSE: Congenital hypopituitarism (CH) can present in isolation or with other birth defects. Mutations in multiple genes can cause CH, and the use of a genetic screening panel could establish the prevalence of mutations in known and candidate genes for this disorder. It could also increase the proportion of patients that receive a genetic diagnosis. METHODS: We conducted target panel genetic screening using single-molecule molecular inversion probes sequencing to assess the frequency of mutations in known hypopituitarism genes and new candidates in Argentina. We captured genomic deoxyribonucleic acid from 170 pediatric patients with CH, either alone or with other abnormalities. We performed promoter activation assays to test the functional effects of patient variants in LHX3 and LHX4. RESULTS: We found variants classified as pathogenic, likely pathogenic, or with uncertain significance in 15.3% of cases. These variants were identified in known CH causative genes (LHX3, LHX4, GLI2, OTX2, HESX1), in less frequently reported genes (FOXA2, BMP4, FGFR1, PROKR2, PNPLA6) and in new candidate genes (BMP2, HMGA2, HNF1A, NKX2-1). CONCLUSION: In this work, we report the prevalence of mutations in known CH genes in Argentina and provide evidence for new candidate genes. We show that CH is a genetically heterogeneous disease with high phenotypic variation and incomplete penetrance, and our results support the need for further gene discovery for CH. Identifying population-specific pathogenic variants will improve the capacity of genetic data to predict eventual clinical outcomes.

Raquitismo vinculado al uso de fórmulas elementales: Reporte de caso / Rickets associated to the use of elemental formula: A case report

El raquitismo afecta la diferenciación y mineralización del cartílago de crecimiento como consecuencia, en última instancia, de una alteración en los niveles de fósforo y/o calcio. El secundario a la deficiencia de vitamina D es la forma más frecuente (raquitismo carencial). Las manifestaciones clínicas durante los primeros años de vida suelen comprometer en forma más marcada las epífisis de los huesos.Se describe el caso de un lactante de 8 meses con diagnóstico de alergia a la proteína de la leche de vaca que presentó múltiples fracturas patológicas mientras se encontraba bajo tratamiento con fórmulas lácteas a base de aminoácidos. Se efectuó el diagnóstico de raquitismo hipofosfatémico por deficiencia de fósforo y, tras 3 meses de tratamiento con sales de fosfato, calcio, calcitriol, el abandono paulatino de la leche elemental y el descenso gradual de la medicación antiácida, el paciente evolucionó con curación clínico-radiológica del cuadro

The rickets is a disease that affects the differentiation and mineralization of the growth cartilage, as an ultimate consequence of a balance loss in calcium and phosphate levels. Vitamin D deficiency is the most common cause of the rickets (nutritional rickets). Its clinical manifestation during the first years of life involves long bones epiphysis in a more severe way.We report an 8-month-old infant who was diagnosed with cow ́s milk protein allergy and suffered from multiple fractures while receiving elemental formula as part of his treatment. The final etiology was hypophosphatemic rickets secondary to phosphate deficiency, and after 3 months of phosphate, calcium and calcitriol supplementation, in addition to the gradually reduction of the proportion of elemental formula intake and the decline of the antacid doses, clinical and radiological heal was achieved.

Clinical lessons learned in constitutional hypopituitarism from two decades of experience in a large international cohort.

CONTEXT: The international GENHYPOPIT network collects phenotypical data and screens genetic causes of non-acquired hypopituitarism. AIMS: To describe main phenotype patterns and their evolution through life. DESIGN: Patients were screened according to their phenotype for coding sequence variations in 8 genes: HESX1, LHX3, LHX4, PROP1, POU1F1, TBX19, OTX2 and PROKR2. RESULTS: Among 1213 patients (1143 index cases), the age of diagnosis of hypopituitarism was congenital (24%), in childhood (28%), at puberty (32%), in adulthood (7.2%) or not available (8.8%). Noteworthy, pituitary hormonal deficiencies kept on evolving during adulthood in 49 of patients. Growth Hormone deficiency (GHD) affected 85.8% of patients and was often the first diagnosed deficiency. AdrenoCorticoTropic Hormone deficiency rarely preceded GHD, but usually followed it by over 10 years. Pituitary Magnetic Resonance Imaging (MRI) abnormalities were common (79.7%), with 39.4% pituitary stalk interruption syndrome (PSIS). The most frequently associated extrapituitary malformations were ophthalmological abnormalities (16.1%). Prevalence of identified mutations was 7.3% of index cases (84/1143) and 29.5% in familial cases (n = 146). Genetic analysis in 449 patients without extrapituitary phenotype revealed 36 PROP1, 2 POU1F1 and 17 TBX19 mutations. CONCLUSION: This large international cohort highlights atypical phenotypic presentation of constitutional hypopituitarism, such as post pubertal presentation or adult progression of hormonal deficiencies. These results justify long-term follow-up, and the need for systematic evaluation of associated abnormalities. Genetic defects were rarely identified, mainly PROP1 mutations in pure endocrine phenotypes.

Síndrome de Cushing exógeno por interacción medicamentosa de ritonavir y fluticasona inhalada. Reporte de tres casos pediátricos / Exogenous Cushing syndrome due to drug interaction of ritonavir and inhaled fluticasone. Report of three pediatric cases

El incremento de la expectativa de vida con el advenimiento de la terapia antirretroviral de alta eficacia plantea desafíos en cuanto a la toxicidad e interacciones medicamentosas. El síndrome de Cushing exógeno por interacción entre ritonavir y fluticasona inhalada en niños con diagnóstico de infección por virus de la inmunodeficiencia humana y patología pulmonar crónica es infrecuente. Hasta el momento, hay 20 casos reportados. Se describen 3 casos pediátricos con diagnóstico de infección por virus de la inmunodeficiencia humana y patología pulmonar crónica que presentaron síndrome de Cushing exógeno con fluticasona inhalada en dosis habituales por la interacción medicamentosa entre esta y ritonavir. Los pacientes resolvieron el cuadro clínico luego de 2-4 meses de suspensión de la fluticasona y permanecieron asintomáticos en el seguimiento

The increase in life expectancy with the advent of highly effective antiretroviral therapy poses challenges in terms of toxicity and drug interactions. Exogenous Cushing syndrome by interaction between ritonavir and inhaled fluticasone in children diagnosed with human immunodeficiency virus infection and chronic pulmonary pathology is rare. So far, there are 20 cases reported. Three pediatric cases are reported, with a diagnosis of human immunodeficiency virus infection and chronic pulmonary pathology who presented exogenous Cushing syndrome with inhaled fluticasone at usual doses due to drug interaction between it and ritonavir. The patients resolved the clinical Síndrome de Cushing exógeno por interacción medicamentosa de ritonavir y fluticasona inhalada. Reporte de tres casos pediátricos Exogenous Cushing syndrome due to drug interaction of ritonavir and inhaled fluticasone. Report of three pediatric cases picture after 2-4 months of fluticasone suspension and remain asymptomatic in the follow-up.

Síndrome de osteoporosis-pseudoglioma: a propósito de un caso pediátrico de osteoporosis primaria / Osteoporosis-pseudoglioma Syndrome: a pediatric case of primary osteoporosis

La osteoporosis es un trastorno para tener en cuenta en niños con patologías crónicas graves o con algunas enfermedades genéticas que predisponen al incremento de la fragilidad ósea. La osteoporosis primaria es una entidad con etiologías emergentes y puede ocurrir en forma sindrómica. La asociación con pliegues retinianos congénitos debe orientar al diagnóstico de osteoporosis-pseudoglioma (OMIM 259770), síndrome poco frecuente (prevalencia de 1/2000000), que se origina por la pérdida de función de la proteína LRP5 (low-density lipoprotein receptor-related protein 5) y compromete la vía de señalización de Wnt/ß-catenina. Se presenta el caso de un niño con pliegues retinianos congénitos, ceguera progresiva y múltiples fracturas cuyo estudio clínico, bioquímico y genético confirmó el diagnóstico de osteoporosis primaria debido a una nueva variante inactivante en el gen LRP5 en homocigosis

Osteoporosis should be considered in children with severe chronic diseases or in association with some genetic diseases that bear an increased risk of bone fragility. Primary osteoporosis is an entity in which emerging aetiologies are being recognized. Its association with congenital retinal folds should guide the diagnosis to the Osteoporosis-Pseudoglioma syndrome (OMIM 259770), a rare disease (prevalence of 1/2000000), caused by the loss of function of the protein LRP5 (low-density lipoprotein receptor-related protein 5) resulting in the alteration of the Wnt/ß-catenin signalling pathway. We report the case of a child with congenital retinal folds, progressive loss of vision and multiple fractures whose clinical, biochemical and genetic studies confirmed the diagnosis of primary osteoporosis due to a novel homozygous inactivating variant in LRP5

Development and Validation of a Prediction Rule for Growth Hormone Deficiency Without Need for Pharmacological Stimulation Tests in Children With Risk Factors.

Introduction: Practice guidelines cannot recommend establishing a diagnosis of growth hormone deficiency (GHD) without performing growth hormone stimulation tests (GHST) in children with risk factors, due to the lack of sufficient evidence. Objective: Our goal was to generate an evidence-based prediction rule to diagnose GHD in children with growth failure and clinically identifiable risk factors. Methods: We studied a cohort of children with growth failure to build the prediction model, and a second, independent cohort to validate the prediction rule. To this end, we assessed the existence of: pituitary dysgenesis, midline abnormalities, (supra)sellar tumor/surgery, CNS infection, traumatic brain injury, cranial radiotherapy, chemotherapy, genetic GHD, pituitary hormone deficiencies, and neonatal hypoglycemia, cholestasis, or hypogenitalism. Selection of variables for model building was performed using artificial intelligence protocols. Specificity of the prediction rule was the main outcome measure in the validation set. Results: In the first cohort (n=770), the resulting prediction rule stated that a patient would have GHD if (s)he had: pituitary dysgenesis, or two or more anterior pituitary deficiencies, or one anterior pituitary deficiency plus: neonatal hypoglycemia or hypogenitalism, or diabetes insipidus, or midline abnormalities, or (supra)sellar tumor/surgery, or cranial radiotherapy ≥18 Gy. In the validation cohort (n=161), the specificity of the prediction rule was 99.2% (95% CI: 95.6-100%). Conclusions: This clinical rule predicts the existence of GHD with high specificity in children with growth disorders and clinically identifiable risk factors, thus providing compelling evidence to recommend that GHD can be safely diagnosed without recurring to GHST in neonates and children with growth failure and specific comorbidities.

Safety of standardised treatments for haematologic malignancies as regards to testicular endocrine function in children and teenagers.

STUDY QUESTION: Does standardised treatments used in children and adolescents with haematologic malignancies, including acute lymphoblastic (ALL) or myeloid leukaemia (AML) and non-Hodgkin lymphoma (NHL), affect endocrine function of the developing testes? SUMMARY ANSWER: Therapy of haematologic malignancies do not provoke an overt damage of Sertoli and Leydig cell populations, as revealed by normal levels of anti-Müllerian hormone (AMH) and testosterone, but a mild primary testicular dysfunction may be observed, compensated by moderate gonadotropin elevation, during pubertal development. WHAT IS KNOWN ALREADY: Evidence exists on the deleterious effect that chemotherapy and radiotherapy have on germ cells, and some attention has been given to the effects on Leydig and Sertoli cells of the adult gonads, but information is virtually non-existent on the effects of oncologic treatment on testicular somatic cell components during childhood and adolescence. STUDY DESIGN, SIZE, DURATION: A retrospective, analytical, observational study included 97 boys with haematological malignancies followed at two tertiary paediatric public hospitals in Buenos Aires, Argentina, between 2002 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical records of males aged 1-18 years, referred with the diagnoses of ALL, AML or NHL for the assessment of gonadal function, were eligible. We assessed serum levels of AMH and FSH as biomarkers of Sertoli cell endocrine function and testosterone and LH as biomarkers of Leydig cell function. MAIN RESULTS AND THE ROLE OF CHANCE: All hormone levels were normal in the large majority of patients until early pubertal development. From Tanner stage G3 onwards, while serum AMH and testosterone kept within the normal ranges, gonadotropins reached mildly to moderately elevated values in up to 35.9% of the cases, indicating a compensated Sertoli and/or Leydig cell dysfunction, which generally did not require hormone replacement therapy. LIMITATIONS, REASONS FOR CAUTION: Serum inhibin B determination and semen analysis were not available for most patients; therefore, we could not conclude on potential fertility impairment or identify whether primary Sertoli cell dysfunction resulted in secondary depleted spermatogenesis or whether primary germ cell damage impacted Sertoli cell function. WIDER IMPLICATIONS OF THE FINDINGS: The regimens used in the treatment of boys and adolescents with ALL, AML or NHL in the past two decades seem relatively safe for endocrine testicular function; nonetheless, a mild primary testicular endocrine dysfunction may be observed, usually compensated by slightly elevated gonadotropin secretion by the pituitary in adolescents, and not requiring hormone replacement therapy. No clinically relevant risk factor, such as severity of the disease or treatment protocol, could be identified in association with the compensated endocrine dysfunction. STUDY FUNDING/COMPETING INTEREST(S): This work was partially funded by grants PIP 11220130100687 of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and PICT 2016-0993 of Fondo para la Investigación Científica y Tecnológica (FONCYT), Argentina. R.A.R., R.P.G. and P.B. have received honoraria from CONICET (Argentina) for technology services using the AMH ELISA. L.A.A. is part-time employee of CSL Behring Argentina. The other authors have no conflicts of interest to disclose.

Aplicación de Hibridación In Situ Fluorescente (FISH) en pacientes con sospecha clínica de Síndrome de Deleción 22q11. 2 (SD22q11. 2) / Applying Fluorescent in situ hy-bridiza on (FISH) in patients with suspected clinical signs of 22q11. 2 dele on syndrome (DS22q11. 2)

El SD22q11.2 está asociado a síndromes de DiGeorge, velocardiofacial, facioconotruncal y Cayler, reconocidos con la misma etiología: microdeleción 22q11.2. El fenotipo es variable y presenta cardiopatía conotruncal (CC), dismorfias faciales, anomalías palatinas, inmunodeficiencias y trastornos del neurodesarrollo. Las manifestaciones endocrinológicas que predominan son talla baja, hipocalcemia neonatal asociada a hipoparatiroidismo y disfunción tiroidea. El 90% de los afectados presenta una deleción típica de 3-Mb, mientras que el resto tiene deleciones de menor tamaño o deleción localizada más distal a la región crítica . El objetivo del trabajo es identificar en una cohorte de 63 pacientes con sospecha clínica de SD22q11.2, la presencia de la microdeleción 22q11.2 empleando como método diagnóstico la técnica de FISH y describir brevemente las características clínicas más prevalentes que presentan los pacientes con resultado de FISH positivo y negativo. La microdeleción 22q11.2 se identificó en el 38% (24/63) de los pacientes estudiados. Las características clínicas más prevalentes en este grupo fueron las cardiopatías congénitas conotruncales (95,6%), microcefalia (50%), inmunodeficiencias (50%), hipocalcemia (48,8%), anomalías del paladar (45,8%), retraso del desarrollo y déficit cognitivo (41,5%). En nuestro hospital, el algoritmo diagnóstico para la detección de la microdeleción 22q11.2 es el cariotipo de alta resolución y el estudio por la técnica de FISH.

DS22q11.2 is associated with a wide spectrum of clinical disorders (DiGeorge, velocardiofacial, facioconotrunal and Cayler syndromes) known to arise from the same etiology 22q11.2 microdeletion The phenotype is variable and includes conotruncal cardiac defect (CCD), facial phenotype, palate anomalies, inmunodeficiency and developmental disorders. The endocrine manifestations are short stature (ST), neonatal hypocalcemia due to hypoparathyroidism, and thyroid dysfunction. In 90% of patients with 22q11.1 deletion a common 3-Mb deletion has been found, whereas the rest of cases share a smaller deletion or more distal atypical deletions. The aim of the present study was to identify the 22q11.2 microdeletion by FISH in 63 patients from the Genetic and Endocrinology Division between 2002 and 2017 who had more than one clinical feature of DS22q11. 2. High resolution karyotype and fluorescent in situ hybridization (FISH) were performed with different commercial probes. The 22q11.2 microdeletion was demonstrated in 24/63 patients (38%). The more relevant clinical features in this group were: conotruncal cardiac defect (95.6%), microcephaly (50%), immunodeficiency (50%), hypocalcaemia (48.8%) palate anomalies (45.8%), development delay and cognitive deficit (41.5%). In our hospital, the diagnostic algorithm for the detection of the 22q11.2 microdeletion is the high resolution karyotype and the study by the FISH technique.

One-year treatment with gonadotropin-releasing hormone analogues does not affect body mass index, insulin sensitivity or lipid profile in girls with central precocious puberty.

Background Puberty is associated with a physiological decline in insulin sensitivity (IS). Overweight (OW) and obesity (OB) are common among girls with central precocious puberty (CPP). CPP is considered a risk factor for metabolic diseases. The aim of this study was to assess surrogate measures of IS, body mass index (BMI) and other metabolic parameters in CPP girls at diagnosis and during treatment with gonadotropin-releasing hormone analogues (GnRHa). Methods We present a prospective longitudinal study of CPP girls. The standard oral glucose tolerance test, homeostatic model assessment of insulin resistance (HOMA-IR), whole-body IS index (ISI) and fasting lipid profiles were evaluated at diagnosis, and at 6 and 12 months of treatment. Results Nineteen CPP girls were included; 17 were evaluable. At baseline, seven patients had normal weight (NW), five were OW and five were OB. During GnRHa treatment no significant changes were observed in BMI, HOMA-IR or ISI when considering the whole group. Whereas, when we analyzed patients according to BMI status, in NW patients, BMI increased significantly with no changes in HOMA-IR or ISI along treatment. In the OW/OB group, no significant differences were observed in BMI, HOMA-IR or ISI. Conclusions Girls with CPP showed a high frequency of OW/OB and a high prevalence of IR. GnRHa did not affect BMI, IS or the lipid profile when considering the whole cohort of patients. However, there was an increase in BMI in NW girls but not in OW/OB patients.

Heterozygous LHX3 mutations may lead to a mild phenotype of combined pituitary hormone deficiency.

LHX3 is an LIM domain transcription factor involved in the early steps of pituitary ontogenesis. We report here functional studies of three allelic variants, including the first heterozygous variant of LHX3 NM_178138.5(LHX3):c.587T>C (p.(Leu196Pro)) that may be responsible for a milder phenotype of hypopituitarism. Our functional studies showed that NM_178138.5(LHX3):c.587T>C (p.(Leu196Pro)) was not able to activate target promoters in vitro, as it did not bind DNA, and likely affected LHX3 function via a mechanism of haplo-insufficiency. Our study demonstrates the possibility that patients with a heterozygous variant of LHX3 may have pituitary deficiencies, with a milder phenotype than patients with homozygous variants. It is thus of vital to propose an optimal follow-up of such patients, who, until now, were considered as not being at risk of presenting pituitary deficiency. The second variant NM_178138.5(LHX3):c.622C>G (p.(Arg208Gly)), present in a homozygous state, displayed decreased transactivating ability without loss of binding capacity in vitro, concordant with in silico analysis; it should thus be considered to affect LHX3 function. In contrast, the NM_178138.5(LHX3):c.929G>C (p.(Arg310Pro)) variant, in a heterozygous state, also predicted as deleterious in silico, proved functionally active in vitro, and should thus still be classified as a variant of unknown significance. Our study emphasizes the need for functional studies due to the limits of software-based predictions of new variants, and the possible association of a pituitary phenotype to heterozygous LHX3 variants.

Niveles bajos de fosfatasa alcalina en niños, revisión retrospectiva / Low levels of alkaline phosphatase in children, retrospective review

Introducción: Los niveles elevados de fosfatasa alcalina (FAL) son utilizados en la evaluación de enfermedades hepatobiliares y óseas, pero los niveles disminuidos en general, no son tenidos en cuenta a pesar de ser indicadores de enfermedad como la Hipofosfatasia. Es importante contar con valores de referencia ajustados para edad y sexo. Objetivo: Determinar en los niños que consultan al endocrinólogo pediatra, la proporción de pacientes que presentan una FAL disminuida. Material y Métodos: Se realizó una revisión de corte transversal, retrospectiva, de todas las FAL que se determinaron a pacientes en consulta en la División de Endocrinología Infantil. Resultados: se obtuvieron 5.110 determinaciones de FAL, 938 (18%) presentaban una FAL menor a 100 U/L, los cuales correspondían a 634 pacientes. Los pacientes menores de 18 años fueron categorizados de acuerdo con los valores de referencia de D'Isa y col. y de Colantonio y col. La distribución etaria fue dispersa, con un rango de 2,94 años a 16,13 años, una mediana de 11,88 años; 93% pertenecía al sexo femenino y se describieron los datos clínicos relevantes de los pacientes. Si bien en sus historias clínicas se encontraba registrado, dicho valor no fue jerarquizado. Conclusión: La proporción de pacientes con niveles de FAL menores a 100 U/L es de un 18% que disminuye notablemente si se consideran algunos métodos de referencia propuestos. Es indispensable contar con valores de referencia de FAL ajustados a sexo y edad adecuados para alertar al médico de valores bajos y altos de FAL

Introduction: High levels of Alkaline Phosphatase (ALP) are used in the evaluation of hepatobiliary and bone diseases, but generally decreased levels are not considered despite being indicators of disease such as hypophosphatasia. It is important to have reference values adjusted for age and sex. Objective: to determine in the children who consult the pediatric endocrinologist, the proportion of patients who have a decreased ALP. Material and Methods: A cross-sectional, retrospective review was made of all the ALP´s that were determined to patients in consultation at the Division of Pediatric Endocrinology. Results: 5110 ALP determinations were obtained, 938 (18%) had an ALP less than 100 U/L, which corresponded to 634 patients. Patients younger than 18 years were categorized according to the reference values of D'Isa et al., and Colantonio et al. The age of distribution was scattered, with a range of 2.94 years to 16.13 years, a median of 11.88 years and 93% belonged to the female sex, and the relevant clinical data of the patients were described. Although it was registered in medical records, this value was not considered relevant. Conclusion: The proportion of patients with FAL levels lower than 100 U / L is 18%, which decreases considerably if some proposed reference methods are considered. It is essencial to have FAL reference values adjusted to sex and age to alert the physician of low and high FAL values