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Background: Persistent müllerian duct syndrome (PMDS) is characterized by the persistence of müllerian duct derivatives in otherwise normally virilized 46,XY males. Biallelic mutations of the anti-müllerian hormone (AMH) and AMH receptor type 2 (AMHR2) genes lead to PMDS type 1 and 2, respectively. Aim: The aims of the study were to report the clinical, hormonal, and genetic findings in a patient with PMDS and discuss surgical strategies to achieve successful orchidopexy. Results: A 4-year-old boy was evaluated after the incidental finding of müllerian derivates during laparoscopy for nonpalpable gonads. Karyotype was 46,XY and laboratory tests revealed normal serum gonadotropin and androgen levels but undetectable serum AMH levels. PMDS was suspected. Molecular analysis revealed a novel variant c.902_929del in exon 5 and a previously reported mutation (c.367C>T) in exon 1 of the AMH gene. Successful orchidopexy was performed in two sequential surgeries in which the müllerian duct structure was preserved and divided to protect the vascular supply to the gonads. Histological evaluation of the testicular biopsy showed mild signs of dysgenesis. Doppler ultrasound showed blood flow in both testes positioned in the scrotum 1.5 years after surgery. Conclusion: PMDS is a rare entity that requires a high index of suspicion (from surgeons) when evaluating a patient with bilateral cryptorchidism. Surgical treatment is challenging and long-term follow-up is essential. Histological evaluation of the testis deserves further investigation.

Recent reports indicate an increase in Leydig cell tumor (LCT) incidence. Radical orchiectomy is the standard therapy in children and adults, although it entails physical and psychosocial side effects. Testis-sparing surgery can be a consideration for benign LCT of 2.5 cm or less in size. Malignant LCTs respond poorly to conventional chemotherapy, so new treatment modalities are needed. In this study, we observed increased histidine decarboxylase expression and pro-angiogenic potential in LCT surgically resected from pediatric patients (fetal to pubertal) vs control samples from patients without endocrine or metabolic disorders which were collected at necropsy. We, therefore, evaluated for the first time the antitumor efficacy of two histidine decarboxylase inhibitors (α-methyl-dl-histidine dihydrochloride (α-MHD) and epigallocatechin gallate (EGCG)), alone and combined with carboplatin, in two preclinical models of LCT. MA-10 and R2C Leydig tumor cells, representing two different LCT subtypes, were used to generate syngeneic and xenograft mouse LCT models, respectively. In the syngeneic model, monotherapy with α-MHD effectively reduced tumor growth and angiogenesis. In the xenografts, which showed co-expression of histidine decarboxylase and CYP19, the combination of EGCG plus carboplatin was the most effective therapy, leading to LCT growth arrest and undetectable levels of plasmatic estradiol. Testicular and body weights remained unaltered. On the basis of this study, histidine decarboxylase may emerge as a novel pharmacological target for LCT treatment.

Pediatric adrenocortical tumors are rare and heterogeneous endocrine malignancies. Objectives To report clinical, biochemical, and histological features, staging, and therapeutic interventions in a cohort of 28 patients treated at a single tertiary center. Methods A retrospective review of medical records of children with PACT (diagnosed before Results Mean age at diagnosis was 4.6 years (range, 0.3–17.3 years) and median follow-up was 4.17 years (range, 0–12 years). Female to male ratio was 2.5:1. Signs and symptoms that prompted medical intervention were hormonal overproduction (57%), abdominal complaints (36%), and hypertensive encephalopathy (7%). In patients with clinically virilizing tumors (n=16) mean height standard deviation score (SDS) and bone age advance were significantly higher while body mass index (BMI) SDS was significantly lower than in those with clinical Cushing’s (n=10) (p Conclusions Height SDS and BMI SDS seem to mirror hormonal secretion in pediatric adrenocortical tumors. Higher DHEAS levels were found in patients with more advanced disease. Further large-scale studies are needed to validate a possible role for DHEAS as a biochemical marker of tumor stage and to draw robust conclusions on the use of adjuvant chemotherapy.

Background: Aromatase deficiency is a rare autosomal recessive disorder. 46,XY-affected patients often remain undiagnosed until late puberty. Only 2 pediatric cases have been reported. Data on pubertal development in affected males are scarce. Aim: To report the clinical phenotype and hormonal studies of an aromatase-deficient boy during the prepubertal and early pubertal period. Results: The patient was the older brother of a 46,XX girl with aromatase deficiency. Molecular analysis revealed a previously reported homozygous mutation (Arg192Cys) in the CYP19A1 gene. Pubertal onset was at 9.8 years. At 11.3 years of age, signs of rapidly progressive puberty were seen. Laboratory tests revealed normal pubertal basal and GnRH-stimulated gonadotropin levels, normal Sertoli cell markers, and increased testosterone. The prepubertal lumbar spine bone mineral density (BMD) was normal but pubertal bone mineral accrual was incomplete, leading to osteopenia. Conclusion: Estrogen restraint on gonadotropin secretion has been demonstrated in animal and human models. Interestingly, our patient presented with accelerated puberty and apparently normal pituitary gonadal function. These findings suggest that aromatase activity may be required to define pubertal progression in boys. Estrogen deficiency due to aromatase deficiency is responsible for insufficient bone mineral accrual during puberty.

Context: The low-dose (1 μg) ACTH test (LDT) is widely used to assess central adrenal insufficiency (CAI); however, the serum cortisol cutoff value is controversial. Salivary cortisol (SC) may be a more accurate measurement for CAI. Objective: To assess a new maximum cutoff value of serum cortisol after LDT in pediatric patients, taking into account serum and SC measurements. Design and Setting: Prospective study in a pediatric tertiary referral center. Working Hypothesis: The combined analysis of serum and SC response to LDT might improve LDT for CAI diagnosis. Participant and Outcome Measurement: A total of 145 pediatric patients underwent LDT. Serum and SC levels were measured. A central adrenal sufficient (CAS) response was established according to the reference serum cortisol cutoff value of ≥497 nmol/L. Results: The LDT study showed central adrenal sufficiency in 72 patients and CAI in 73 patients. Considering the lower quartile of maximum SC value (21 nmol/L) in the CAS group, an intermediate CAI (InCAI) group and a real CAI (RCAI) group were defined. Regarding the median maximum value of serum cortisol levels in the InCAI group, a new serum cortisol cutoff value of 450 nmol/L was established. Furthermore, 91% of the patients in the RCAI group were below this cutoff value. Conclusion: The combined evaluation of maximum serum and SC levels to LDT might be useful to define an InCAI group and to avoid unnecessary hormone replacement therapy. However, rigorous patient follow-up is required © 2019 Fil: Vaiani, Elisa. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Lazzati, Juan Manuel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Ramirez, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Costanzo, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Gil, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Dratler, Gustavo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Zaidman, Verónica. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Chaler, Eduardo Adrian. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Hypothyroidism caused by Hashimoto's thyroiditis is the most common reason for thyroid dysfunction in children. Our objective was to analyze its impact on final stature in relation to height and pubertal stage at the time of diagnosis in children younger than 18 years with severe autoimmune hypothyroidism. Out of 79 patients, 78.5 % were girls. Those with goiter (56 %) had a better height at diagnosis than those without goiter (mean standard deviation score for height: 0.2 versus -2.42; p0.0001). Five girls (6.3 %) had precocious puberty. When considering the final stature of patients (n: 33), among those with short stature at the time of diagnosis, pubertal children had a significantly shorter final stature than prepubertal children (mean standard deviation score for height: -2.82 versus -1.52; p = 0.0311). The late diagnosis of severe hypothyroidism in pediatrics has a negative impact on final stature, especially in those who were pubertal patients at the time of diagnosis.El hipotiroidismo por tiroiditis de Hashimoto es la causa más frecuente de disfunción tiroidea en niños. Nuestro objetivo fue analizar el impacto en la talla final según la talla y el estadio puberal al momento del diagnóstico en menores de 18 años con hipotiroidismo grave de origen autoinmune. De los 79 pacientes, el 78,5 % fueron mujeres. Los que presentaron bocio (el 56 %) mostraron mejor talla en el diagnóstico que los que no lo tenían (puntaje de desvío estándar de media de talla: 0,2 vs. -2,42; p0,0001). Cinco niñas (el 6,3 %) presentaron pubertad precoz. De los pacientes con talla final (n: 33), dentro de los que presentaron talla baja al momento del diagnóstico, los púberes tuvieron una talla final significativamente menor que los prepúberes (puntaje de desvío estándar media: -2,82 vs. -1,52; p = 0,0311). El diagnóstico tardío de hipotiroidismo grave en pediatría tiene un impacto negativo en la talla final, especialmente, en los pacientes puberales al momento del diagnóstico.

Healthcare budgets worldwide are facing increasing pressureto reduce costs and improve efficiency, while maintainingquality. Laboratory testing has not escaped thispressure.The clinical laboratory control of demand is oftenconfused with demand management. Control of demandrefers to the reduction of costs, while demand managementfocusses on ensuring appropriate requesting. Hence,the latter has an inbuilt quality aspect and may result inincreased as well as decreased testing (i.e. to reduce overordering,underordering and misordering of tests) [1, 2].It has been widely accepted that the major changes inthyroid function in adult subjects may initially be studiedby assessing of thyroid-stimulating hormone (TSH) [3].Free thyroxine (fT4) should be measured in the setting ofan abnormal TSH, and free triiodothyronine (fT3) only inspecific circumstances, such as cases of suspected hyperthyroidismwith a normal fT4 and suppressed TSH [4].The recommendations by Wisely et al. [5] from theAmerican Society for Clinical Pathology (ASCP) adviseagainst ordering multiple tests in the initial investigationof patients with suspected non-neoplastic thyroid disease.In the paediatric population the impact of thyroidhormone deficiency on neuro development and growth,warrant evaluation of an aetiology of central origin. Herewe propose the use of serum TSH and fT4 to evaluateprimary and central thyroid dysfunction in this population[6, 7]. However, to our knowledge, currently noevidence exists on whether serum TSH and fT4 providesufficient information for the screening of thyroid functionin children.The aim of the study was to retrospectively assessserum full thyroid profile (TSH, fT4, T4 and T3) vs. TSHand fT4 only for the primary evaluation of thyroid diseasein children describing the results obtained and subsequentmedical management.We retrospectively analysed consecutive patients(n = 5999) in whom thyroid function was studied with afull thyroid test seen between November 2014 and September2015. Tests were performed on the day of sampling. Weexcluded those subjects who were previously diagnosedwith thyroid disease, those that were not seen by anyphysician after the studies, those who had been treatedwith levothyroxine (LT), methimazole, or antiepilepticdrugs, and severely ill patients. The remaining 5738 subjectsincluded were categorised into 12 groups accordingto age from 1 week to 12 years. TSH, T3 and fT4 weremeasured with Architect i4000 (Abbott) and we used ourown reference interval (RI) [8] for total T4 IMMULITE 2000(Siemens) and was used the RI by Elmlinger et al. [9]. Allwith percentiles between 2.5 and 97.5.Subjects with serum TSH and fT4 within the (RI)according to age were selected (n = 4007, 69.8%).From this group, children who had T3 and/or T4outside the RI were selected (n = 390, 6.79%) (Figure 1)(Supplementary Material 1 and 2). In the clinical records (CR) of 381 patients (6.63%) nocomment was made on thyroid function or the thyroidprofile was reported to be normal, in spite of T3 and/or T4outside the RI.In nine patients (0.15%) a comment was made inthe CR; five patients were sent home without further interventions, in one patient with high T3 and T4, highserum levels of thyroxine-binding globulin were found,and the three remaining were finally treated with LT(0.05% from de selected subjects). All of them had fT4below the 10th percentile of the RI and one additionallyhad TSH above the 90th percentile of the RI.Of the study population n = 5738, 69.8% presentedwith normal serum TSH and fT4 levels. Overall patients,6.79% had T3 and/or T4 outside the RI, which is statisticallyacceptable for a reference population. Accordingto the definition of RI using the central 95% values fromreference population in both analytes, 5% of healthy subjectsis statistically expected to be found outside the RI, ifwe used two analytes is possible to found almost 9.75% ofhealthy subjects outside the RI ([1?(0.95)2] *100 = 9.75%).In the CR of 381 patients (6.63%) no comment wasmade, this may have happened because in all cases T3and/or T4 were within the reference change value (RCV)on the limits of the RI (Supplementary Material 2).As to the nine patients that had some medicalcomment in their CR regarding thyroid test results, onlythree were put on treatment, and all had fT4 below the10th percentile and one had TSH above the 90th percentileas well. Moreover, the three patients who duringfollow-up showed a drop in serum thyroid hormones,and showed clinical signs of hypothyroidism and werestarted on supplementary treatment with LT had medulloblastoma,neurofibromatosis and Prader-Willi syndrome,diseases that may be associated with centralhypothyroidism. In adults the use of only serum TSH by primary careproviders, may be sufficient for screening of thyroiddisease. However, in children functional disorders of thethyroid, such as hypothyroidism and hyperthyroidism dueto chronic lymphocytic thyroiditis and Graves? Basedowdisease, are frequent. The combination of TSH and fT4allows detection of these two disorders as well as the centralabnormalities of the hypothalamus pituitary thyroid axis;the findings in our series support this concept.When considering cost-effectiveness, costs could bereduced by 46% in each patient studied, with a positiveimpact on the management of demand without effectingclinical outcome.In conclusion, we found that the use of TSH and fT4is useful for primary evaluation of thyroid disease in paediatrics.However, TSH and fT4 should be assessed with astricter RI between the 10th and 90th percentile. In caseof persistent clinical signs suggestive of a disorder of thethyroid gland in a child, assessment of a complete thyroidprofile, including antithyroid antibodies, total or free T3,and total T4, is recommended.This study suggests that questionable testing patternscontribute to inappropriate thyroid test utilisation. A prospectivestudy in a paediatric population would be necessaryto clinically confirm these results and subsequentlydefine medical management. Fil: Zaidman, Verónica. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Lazzati, Juan Manuel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Maceiras, Mercedes Carmen. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Herzovich, Viviana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Pelanda, Melina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Ribas, Alejandra. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina Fil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Chaler, Eduardo Adrian. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina

The responsibility of clinical laboratories includes adequate assay methods, measurement procedures, and the definition of the appropriate quality specifications for each mensurand as well as the identification of criteria required for obtaining the optimal interpretation and utilization of results, with reference intervals and adequate decision limits. Fil: Lazzati, Juan Manuel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Zaidman, Verónica. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Maceiras, Mercedes. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Chaler, Eduardo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina

Vitamin D (Vit D) is well recognized as an immunomodulator [...] Fil: Zaidman, Verónica E.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Maceiras, Mercedes. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Lazzati, Juan Manuel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Kutasz, Ezequiel P.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: D’ Isa, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Chilleli, Carla. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Tau, Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Viterbo, Gisela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Rivarola, Marco Aurelio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Chaler, Eduardo A.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina

Hospital de Pediatr i a Prof. Dr. Juan P. Garrahan, Combate de los Pozos 1881, Ciudad Autonoma de Buenos Aires, CP 1245, Argentina, Phone: +54 11 43084300, Fax: +54 11 43086700, mE- ail: echaler@yahoo.com Juan M. Lazzati, Mercedes Maceiras, Marco A. Rivarola and Alicia Belgorosky: Hospital de Pediatr i a Prof. Dr. Juan P. Garrahan , Buenos Aires , Argentina Gabriela Ballerini, Mauro Frusti, Ignacio Bergada and Gabriela Ropelato: Hospital de Ni n os Ricardo Gutierrez , Buenos Aires , Argentina

Establishment of reliable reference intervals remains valuable for confirming validity and advancing standardization across methods and populations. Moreover, knowledge of the measurement uncertainty (U) and of the reference change value (RCV) has important applications in clinical chemistry.Starting from the information available in the laboratory data base (29,901 subjects) an initial selection was carried out by eliminating all subjects with a clinical or laboratory pathological report; data from 7581 0- to 20-year-old subjects (53.87% girls) remained in the study. These subjects, divided into nine age groups, were used to define reference distribution percentiles (2.5th, 50th and 97.5th) of serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4), and free T4 (fT4), as well as U and RCV of these assays.In early infancy, T4 and fT4 values were higher than in the older age groups. Serum T4 95th percentile reference value, useful for the diagnosis of hyperthyroidism, was 142.9 in 20-year-old boys and 230.4 nmol/L in early infants and serum T3 95th percentile was 2.6 and 3.5 nmol/L, respectively, while fT4 2.5th percentile reference value, useful for the diagnosis of hypothyroidism, was 9.6 and 13.0 pmol/L, respectively. Serum TSH 97.5th percentile showed less age variation, 4.38–4.88 mIU/L. Performance of the four assays resulted in approximately 20% Us, reflecting simple and complex imprecision, trueness, analytical and functional sensitivity. RCV of serum TSH (58.6%) was larger than for thyroid hormones (28.3%–34.7%), probably due to the high biological variation of this hormone.We have established reference interval for TSH and thyroid hormones, as well as Us for assessing reliability of measurements, and RCVs to alert users on the presence of clinical significant changes.

The specific thyroid hormone transporter, MCT8, located on the X chromosome, has led to the identification a novel syndrome. The objective is to relate phenotype with several tissue-specific thyroid functions. A 1-year-old boy, who had severe psychological damage and low serum T4, had received l-T4 for 3 months. At admission, body length was normal but weight was low. Off therapy, serum TSH was mildly elevated, serum T4 and free T4 were low, and serum T3 and free T3 were high. Direct sequencing of the MCT8 gene revealed a single nucleotide change that resulted in a novel nonsense mutation at codon 261 (Q261X) in exon 3. Since serum T3 was high, peripheral markers of hyperthyroidism were looked for. Bone age was advanced, despite the presence of malnutrition and low T4. Serum SHBG, a marker of thyroid hormone action in liver, was markedly elevated. Markers of skeletal muscle catabolism, ammonemia and lactic acid, were found to be elevated. The phenotype of MCT 8 mutation might be explained by differences in the entry of thyroid hormones into different cells. In the presence of an inactive MCT8 transporter, the high blood T3 levels might not be enough to prevent brain damage early in life, while they seem to be able to induce a postnatal state of peripheral hyperthyroidism in other tissues, such as liver, bone and skeletal muscle.