NCoA3 upregulation in breast cancer­associated adipocytes elicits an inflammatory profile.

Nuclear receptor coactivator 3 (NCoA3) is a transcriptional coactivator of NF­κB and other factors, which is expressed at relatively low levels in normal cells and is amplified or overexpressed in several types of cancer, including breast tumors. NCoA3 levels have been shown to be decreased during adipogenesis; however, its role in tumor­surrounding adipose tissue (AT) remains unknown. Therefore, the present study assessed the modulation of NCoA3 in breast cancer­associated adipocytes and evaluated its association with the expression of inflammatory markers. 3T3­L1 adipocytes were stimulated with conditioned medium from human breast cancer cell lines and the expression levels of NCoA3 were evaluated by reverse transcription­quantitative (q)PCR. NF­κB activation was measured by immunofluorescence, and tumor necrosis factor and monocyte chemoattractant protein 1 levels were analyzed by qPCR and dot blot assays. The results obtained from the in vitro model were supported using mammary AT (MAT) from female mice, MAT adjacent to tumors from patients with breast cancer and bioinformatics analysis. The results revealed that adipocytes expressing high levels of NCoA3 were mainly associated with a pro­inflammatory profile. In 3T3­L1 adipocytes, NCoA3 downregulation or NF­κB inhibition reversed the expression of inflammatory molecules. In addition, MAT from patients with a worse prognosis exhibited high levels of this coactivator. Notably, adipocyte NCoA3 levels could be modulated by inflammatory signals from tumors. The modulation of NCoA3 levels in synergy with NF­κB activity in MAT in a tumor context could be factors required to establish breast cancer­associated inflammation. As adipocytes are involved in the development and progression of breast cancer, this signaling network deserves to be further investigated to improve future tumor treatments.

Endocrine Sequelae in 157 Pediatric Survivors of Hematopoietic Stem Cell Transplantation (HSCT).

Context: Successful rates of hematopoietic stem cell transplantation (HSCT) face paralleled escalation of late endocrine and metabolic effects. Objective: This work aimed to characterize these sequelae distinguishing between the underlying pathologies and treatments received. Methods: A retrospective descriptive study was conducted in 157 children post-HSCT (hematopoietic pathology [N = 106], solid tumors [N = 40], and rare entities [N = 11]) followed at a single endocrine department between 2009 and 2019. Regression analysis was used to ascertain association. Results: Of all patients, 58.7% presented with at least one endocrine abnormality. Endocrinopathies post HSCT were most frequently developed in lymphoblastic leukemia (60.5% of them), whereas myeloid leukemias had the fewest. A total of 64% of patients presented with primary hypogonadism, 52% short stature, and 20% obesity. Endocrinopathy was associated with older age at HSCT (9.78 years [6.25-12.25] vs 6.78 years [4.06-9.75]) (P < .005), pubertal Tanner stage V (P < .001), chronic graft-vs-host disease (GVHD) (P = .022), and direct gonadal therapy (P = .026). The incidence of endocrinopathies was higher in girls (15% more common; P < .02) and in patients who received radiotherapy (18% higher), steroids (17.4% increase), allogenic HSCT (7% higher), thymoglobulin, or cyclophosphamide. Those on busulfan presented with a 27.5% higher rate of primary hypogonadism (P = .003). Conclusion: More than half of children surviving HSCT will develop endocrinopathies. Strikingly, obesity has risen to the third most frequent endocrine disruption, mainly due to steroids, and partly adhering to the general population tendency. Lymphoblastic leukemia was the condition with a higher rate of endocrine abnormalities. Female sex, older age at HSCT, pubertal stage, allogenic transplant, radiotherapy, alkylating drugs, and GVHD pose risk factors for endocrine disturbances.

When is it best to discontinue diazoxide in children with persistent hyperinsulinaemic hypoglycaemia and negative genetics for KATP channel gene variants?

Diazoxide is the first-line treatment in children with hyperinsulinaemic hypoglycaemia (HH); however, limited information is available on the duration of diazoxide treatment in children who require over 2 years of it. Hence, we retrospectively reviewed the clinical and biochemical aspects, as well as the duration of therapy and neurodevelopmental assessment, in genetically uncharacterised diazoxide-responsive HH patients admitted to a tertiary hospital over the last 16 years, who had successfully discontinued diazoxide and remained euglycaemic. To exclude transient HH forms, only patients that required diazoxide for over 2 years were studied. We identified a total of 17 patients (70% males), in whom HH was diagnosed between 1 day and 18 months of age, and 88% were born at term with a median birth weight of 3.79 kg. All children responded to diazoxide at a median dose of 11.5 mg/kg/day, and it was stopped at a median age of 8.5 years, with a median duration of therapy of 7.25 years. The cases that required diazoxide the longest manifested no specific biochemical or clinical characteristics. Fasting tests performed after diazoxide discontinuation showed no longer requirement of diazoxide in all the cases. A total of 64.7% of the children showed mild to moderate developmental delay. Therefore, it seems that long-term resolution of HH in children with negative genetics for KATP channel genes who required diazoxide for over 2 years will ensue, and thus regular evaluation is crucial. The possible molecular mechanisms involved are unclear.

Syndromic Forms of Hyperinsulinaemic Hypoglycaemia-A 15-year follow-up Study.

OBJECTIVE: Hyperinsulinaemic hypoglycaemia (HH) is one of the commonest causes of hypoglycaemia in children. The molecular basis includes defects in pathways that regulate insulin release. Syndromic conditions like Beckwith-Wiedemann (BWS), Kabuki (KS) and Turner (TS) are known to be associated with a higher risk for HH. This systematic review of children with HH referred to a tertiary centre aims at estimating the frequency of a syndromic/multisystem condition to help address stratification of genetic analysis in infants with HH. METHODS: We performed a retrospective study of 69 patients with syndromic features and hypoglycaemia in a specialist centre from 2004 to 2018. RESULTS: Biochemical investigations confirmed HH in all the cases and several genetic diagnoses were established. Responsiveness to medications and the final outcome following medical treatment or surgery were studied. CONCLUSIONS: This study highlights the association of HH with a wide spectrum of syndromic diagnoses and that children with features suggestive of HH-associated syndromes should be monitored for hypoglycaemia. If hypoglycaemia is documented, they should also be screened for possible HH. Our data indicate that most syndromic forms of HH are diazoxide-responsive and that HH resolves over time; however, a significant percentage continues to require medications years after the onset of the disease. Early diagnosis of hyperinsulinism and initiation of treatment is important for preventing hypoglycaemic brain injury and intellectual disability.

Octreotide-related exocrine pancreatic insufficiency (EPI) in congenital hyperinsulinism.

Background Congenital hyperinsulinism (CH) is the most frequent cause of persistent hypoglycemia in the newborn. Octreotide, a long-acting somatostatin receptor analog (SSRA), is a second line treatment for diazoxide unresponsive CH patients. Although it has been found to be a safe and effective treatment, long-term benefits and side effects, have not been thoroughly evaluated. Case presentation Some authors have indicated that exocrine pancreatic insufficiency (EPI) is a common but under-recognized adverse reaction in adults treated with octreotide. However, no pediatric patient with SSRA-induced EPI has been reported to date. Here we report a case of an infant with diazoxide unresponsive, diffuse CH, caused by a heterozygous pathogenic paternally inherited mutation in the ABCC8 gene (NM_000352.4:c.357del), that developed exocrine pancreatic insufficiency and secondary vitamin K deficiency associated to chronic octreotide therapy. Conclusions We point out the atypical clinical onset with a cutaneous hemorrhagic syndrome, emphasizing the clinical relevance of this potential side effect.

Modelo demostrativo de identificación precoz y atención continua de pacientes con cáncer y necesidad paliativas / Demonstrative model for early identification and continuous care of cancer patients with palliative needs

Los cuidados paliativos (CP) se incorporaron en la salud pública de muchos países con gran variabilidad e inequidad. Argentina posee una incidencia de cáncer media-alta y el Programa Nacional de Cuidados Paliativos no identifica la población diana. El instrumento NECPAL CCOMS-ICO© identifica enfermos con necesidades paliativas. Combina una pregunta (¿Le sorprendería que su paciente falleciera en el próximo año?) con indicadores específicos. El objetivo fue identificar precozmente y mejorar la asistencia integral de pacientes con cáncer y necesidades paliativas. Se reporta la implementación de una intervención sanitaria (Programa Modelo de Atención Paliativa). MÉTODOS: Se incluyó a todos los pacientes oncológicos del hospital universitario (julio de 2014- julio de 2016). Se entrevistó a sus 10 médicos en 69 sesiones individuales con el NECPAL. Se diseñó un programa demostrativo en 4 etapas. RESULTADOS: Hubo 317 pacientes, 57% con necesidades paliativas (NECPAL+). Como resultado de la implementación, el 94% (n=172) de 183 pacientes NECPAL+ fueron derivados a CP (frente a 28% antes del programa); media de seguimiento de 7,4 meses y 183 fallecieron (28 en domicilio). Se superaron estándares de calidad de estructura, proceso y resultado. DISCUSIÓN: Por primera vez en Argentina, esta intervención sanitaria incluyó a casi la totalidad de pacientes con cáncer y necesidades paliativas tempranas en un programa de asistencia continua hasta su fallecimiento en el hospital o domicilio.

Post-Prandial Hyperinsulinaemic Hypoglycaemia after Oesophageal Surgery in Children.

INTRODUCTION: Post-prandial hyperinsulinaemic hypoglycaemia (PPHH) is a recognized complication of various gastric surgeries in children, but rarely reported after oesophageal atresia repair. We report 2 children diagnosed with PPHH after oesophageal surgery and the challenges of their management. Case 1: A 2-year-old boy diagnosed with oesophageal atresia at birth was surgically repaired requiring 6 oesophageal dilatations in the first year of life. At 11 months of age, he manifested hypoglycaemic seizures and investigations confirmed PPHH. Acarbose and diazoxide trials failed. He was managed with 17-h continuous gastrostomy feeds. Currently, he is 28 months old with euglycaemia on daytime bolus gastrostomy feeds and overnight 12-h continuous gastrostomy feeds. Case 2: A 6-month-old girl diagnosed with Wolf-Hirschhorn syndrome and tracheo-oesophageal fistula was surgically repaired, requiring monthly oesophageal dilatations. At 5 months of age, she was reported to have hypoglycaemia and PPHH was confirmed. She responded to diazoxide and continuous nasogastric tube feeds, but developed pulmonary hypertension pos-sibly diazoxide-induced. Subsequently, diazoxide was stopped and normoglycaemia was secured via 20-h continuous gastrostomy feeds. CONCLUSION: PPHH may be an underdiagnosed complication in children undergoing surgery for oesophageal atresia. These children must be monitored closely for symptoms of hypoglycaemia and if there are concerns must be screened for possible PPHH. Our cases demonstrate that continuous feeding regimens might be the only therapeutic option, until PPHH gradually lessens in intensity over time.

The Use of a Long-Acting Somatostatin Analogue (Lanreotide) in Three Children with Focal Forms of Congenital Hyperinsulinaemic Hypoglycaemia.

BACKGROUND: A long-acting somatostatin analogue (lanreotide) is used in the management of a diazoxide-unresponsive diffuse form of congenital hyperinsulinism (CHI). However, no reports of its use in patients with the focal form of CHI exist. Case 1: A 1-month-old boy diagnosed with diazoxide-unresponsive CHI due to a paternal heterozygous ABCC8 gene mutation showed partial response to octreotide. 18F-DOPA-PET/CT scan revealed a focal lesion in the pancreatic head. Surgical removal of the lesion was unsuccessful. He was switched to monthly lanreotide treatment at the age of 11 months, which stabilised his blood glucose over a 12-month period. Case 2: A 1-month-old boy with diazoxide-unresponsive CHI due to a paternal heterozygous KCNJ11 gene mutation was partially responsive to octreotide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. Over 6 months, he underwent 3 lesionectomies and afterwards responded to octreotide. At the age of 9 months, treatment was switched to monthly lanreotide. Currently, he is aged 3, with stable glycaemia, and improved fasting tolerance. Case 3: A 3-week-old girl with a paternal heterozygous ABCC8 gene mutation was unresponsive to diazoxide. 18F-DOPA-PET/CT scan confirmed a focal pancreatic head lesion. She responded to octreotide, and her parents preferred to avoid pancreatic surgery. At the age of 20 months, treatment was switched to monthly lanreotide, resulting in euglycaemia over the last 7 months. CONCLUSION: CHI patients with focal pancreatic head lesions are challenging, especially if not surgically amenable. Conservative treatment is preferable, and lanreotide might be an option. The therapeutic impact of lanreotide treatment in patients with the focal forms of CHI should be confirmed in prospective studies with close monitoring of the side effects.

A novel GLI2 mutation responsible for congenital hypopituitarism and polymalformation syndrome.

OBJECTIVE: We report a novel GLI2 frameshift mutation and describe the phenotypic spectrum of mutations within this gene. PATIENTS AND METHODS: A male with congenital hypopituitarism and polymalformation syndrome was clinically, biochemically and neuroradiologically characterized. Genetic analysis for congenital hypopituitarism was performed using a targeted NGS custom gene panel. RESULTS: A heterozygous frameshift mutation, NM_005270.4:c.2125del, p.(Leu709Trpfs*15), was identified in GLI2 exon 12. This mutation has not been previously reported and confirms the diagnosis of Culler-Jones syndrome (MIM #615849). CONCLUSION: GLI2 mutations should be suspected in the presence of congenital hypopitutarism, characteristic facial abnormalities and polydactyly.

RAC3 influences the chemoresistance of colon cancer cells through autophagy and apoptosis inhibition.

BACKGROUND: RAC3 coactivator overexpression has been implicated in tumorigenesis, contributing to inhibition of apoptosis and autophagy. Both mechanisms are involved in resistance to treatment with chemotherapeutic agents. The aim of this study was to investigate its role in chemoresistance of colorectal cancer. METHODS: The sensitivity to 5-fluorouracil and oxaliplatin in colon cancer cells HT-29, HCT 116 and Lovo cell lines, expressing high or low natural levels of RAC3, was investigated using viability assays. RESULTS: In HCT 116 cells, we found that although 5-fluorouracil was a poor inducer of apoptosis, autophagy was strongly induced, while oxaliplatin has shown a similar ability to induce both of them. However, in HCT 116 cells expressing a short hairpin RNA for RAC3, we found an increased sensitivity to both drugs if it is compared with control cells. 5-Fluorouracil and oxaliplatin treatment lead to an enhanced caspase 3-dependent apoptosis and produce an increase of autophagy. In addition, both process have shown to be trigged faster than in control cells, starting earlier after stimulation. CONCLUSIONS: Our results suggest that RAC3 expression levels influence the sensitivity to chemotherapeutic drugs. Therefore, the knowledge of RAC3 expression levels in tumoral samples could be an important contribution to design new improved therapeutic strategies in the future.

Sirolimus precipitating diabetes mellitus in a patient with congenital hyperinsulinaemic hypoglycaemia due to autosomal dominant ABCC8 mutation.

BACKGROUND: Sirolimus (mTOR inhibitor) is proven to be effective in children with congenital hyperinsulinism (CHI). Studies in animals suggest that sirolimus may have diabetogenic actions. However, its role in precipitating diabetes mellitus (DM) in children with CHI has not been reported. CASE PRESENTATION: A 16-year-old female with CHI due to a dominant ABCC8 gene mutation was switched from diazoxide therapy to sirolimus, due to the hypertrichosis side effect of diazoxide. She developed facial cellulitis that was treated with clarithromycin and a month later, once the infection was resolved, she was found to have persistent hyperglycaemia, and was diagnosed with DM. She was unresponsive to oral sulfonylurea therapy and is currently managed with metformin. Her mother, who had the same ABCC8 mutation, developed DM at her 30s. CONCLUSIONS: Patients with dominant ABCC8 gene mutations are prone to DM in adulthood, but Sirolimus therapy might increase the risk of developing diabetes at an early age, as this case illustrates.

Hyperinsulinaemic hypoglycaemia in children and adults.

Pancreatic ß cells are functionally programmed to release insulin in response to changes in plasma glucose concentration. Insulin secretion is precisely regulated so that, under normal physiological conditions, fasting plasma glucose concentrations are kept within a narrow range of 3·5-5·5 mmol/L. In hyperinsulinaemic hypoglycaemia, insulin secretion becomes dysregulated (ie, uncoupled from glucose metabolism) so that insulin secretion persists in the presence of low plasma glucose concentrations. Hyperinsulinaemic hypoglycaemia is the most common cause of severe and persistent hypoglycaemia in neonates and children. At a molecular level, mutations in nine different genes can lead to the dysregulation of insulin secretion and cause this disorder. In adults, hyperinsulinaemic hypoglycaemia accounts for 0·5-5·0% of cases of hypoglycaemia and can be due either to ß-cell tumours (insulinomas) or ß-cell hyperplasia. Rapid diagnosis and prompt management of hyperinsulinaemic hypoglycaemia is essential to avoid hypoglycaemic brain injury, especially in the vulnerable neonatal and childhood periods. Advances in the field of hyperinsulinaemic hypoglycaemia include use of rapid molecular genetic testing for the disease, application of novel imaging techniques (6-[fluoride-18]fluoro-levodopa [18F-DOPA] PET-CT and glucagon-like peptide 1 (GLP-1) receptor imaging), and development of novel medical treatments (eg, long-acting octreotide formulations, mTOR inhibitors, and GLP-1 receptor antagonists) and surgical therapies (eg, laparoscopic surgery).

Assessment of Nifedipine Therapy in Hyperinsulinemic Hypoglycemia due to Mutations in the ABCC8 Gene.

CONTEXT: Previous case reports have documented the effectiveness of l-type calcium channel blockers (such as nifedipine and verapamil) for treating different forms of hyperinsulinemic hypoglycemia (HH). OBJECTIVE: To systematically assess the glycemic response to nifedipine therapy in 11 patients with HH due to mutations in the ABCC8 gene. DESIGN: Dose escalation of nifedipine therapy. SETTINGS AND PATIENTS: Eleven children who were inpatients at a tertiary hospital and had diazoxide unresponsive HH due to mutations in the ABCC8 gene. INTERVENTION(S): Nifedipine was administered orally at an escalating dose up to a maximum of 2.5 mg/kg/d. MAIN OUTCOME MEASURES: Improvement in glycemic control, avoidance of hypoglycemic episodes, reduction of intravenous glucose infusion, and reduction in the requirements of other medical therapies. RESULTS: The median age of the patients was 0.44 years (range 0.14 to 3.77). The ABCC8 gene mutations were homozygous in 3 cases, paternally inherited heterozygous in 4, and compound heterozygous in 4. 18F-DOPA PET/CT scan demonstrated a focal lesion in 2 cases and the rest were diffuse HH disease. One subject had nifedipine as monotherapy, whereas the rest had it in combination with octreotide/glucagon/diazoxide or cornstarch. After a median of 6.5 (3 to 23) days of maximal (2.5 mg/kg/d) dose of nifedipine therapy, none of the patients showed any improvement in glycemic control and patients continued to have hypoglycemic episodes. CONCLUSIONS: HH due to mutations in the ABCC8 gene does not respond to nifedipine therapy. Mutations in the KATP channel genes might render the l-type calcium channel ineffective to therapy with nifedipine.

El papel de estructura argumental en el procesamiento de los compuestos verbo-nombre del español: Evidencias experimentales / The role of semantic argument structure in spanish verb-noun compound words: Experimental evidence

Los compuestos verbo-nombre del español presentan la particularidad de carecer de un núcleo que aporte los rasgos morfológicos, de categoría o semántico-referenciales. El acceso al significado depende entonces de la relación que mantienen los constituyentes entre sí y no a partir de la identificación de un elemento nuclear, como ocurre en compuestos que poseen un lexema referencial (telaraña, bocacalle). Dentro del compuesto verbo-nombre, la relación semántica que se establece entre los constituyentes no es única. Si bien la estructura semántica prototípica responde al patrón agente-paciente (cortacésped), existen otras posibilidades argumentales, como las relaciones locativas (pasacalle). El estudio realizado tuvo como objetivo determinar hasta qué punto la estructura argumental proyectada por el verbo tiene una influencia en el procesamiento cognitivo de estas unidades. Primeramente, se llevó a cabo un juicio de aceptabilidad para asegurar que los estímulos se correspondieran con la realidad lingüística de los participantes del estudio experimental. A continuación, se administró una prueba de decisión léxica con compuestos que poseían distintos tipos de estructura argumental: (1) agente / paciente (algo que V a N, abrelatas), (2) agente / paciente menos prototípica (procesos metafóricos, chupasangre) y (3) locativos (lugar donde x hace V a N, guardamuebles). Los resultados muestran que los tiempos de decisión (respuesta) ante compuestos locativos fueron significativamente mayores que ante los prototípicos. Este resultado no puede ser explicado por diferencias en longitud o frecuencia de los compuestos o sus constituyentes, por lo que parecen apoyar la hipótesis de que la estructura argumental juega un rol central en el procesamiento de estas palabras.

Research on the processing of compound words offers important insights on how the mental lexicon is organized. It is a current topic in psycholinguistics if compound words are represented and processed as unitary lexical units (full-listing models) or only as individual constituents analyzed via acombinatorial mechanism (full-parsing models). There is enough experimental evidence that both mechanisms are involved (dual-route models). Several characteristics of the stimuli, like length, morphological family size, frequency of compounds and their constituents are important factors to determine how they are processed. Compound words are meaningful units that contain smaller meaningful units. Therefore, in the domain of compounds' studies, several hypotheses have been proposed to explain how only one interpretation is achieved from two independent meanings. Models that describe the construction of lexical semantic features in compound words, like APPLE - Automatic Progressive Parsing and Lexical Excitation (Libben 1994,1998) or CARIN - Competition Among Relations in Nominals (Gagné, 2000), are based on the notion of a morphological head. According to these theories the recognition of the head would trigger an interpretation of the whole word. In noun-noun compounds (pez espada, 'swordfish', telaraña 'spiderweb'), in which the head has the referential features, the identification of this head and the posterior clarification of the relationship with the non-head lexeme is the way to interpret the whole compound (pez 'fish' and tela 'web', respectively). However, not every compound has a head with the referential attributes inside. Verb-noun compounding is an extremely productive word-formation process in Romance languages. Spanish verb-noun compounds have the particularity of being exocentric: these constructions do not present a categorical, morphological or semantic head. Therefore, access to the meaning depends on the relationship between both of their constituent lexemes. For these units, the traditional distinction between semantically transparent and semantically opaque compounds is not suitable, because it doesn't take under consideration the projection of the argument structure by the verbal constituent. The semantic relationship established between the lexemes within a compound is not unique. While the prototypical semantic structure responds to the agent-patient pattern (cortacésped), there are other semantic possibilities, such as locative relationships (pasacalle). The present study addresses the issue of the comprehension of Spanish verb-noun compounds in order to provide evidence about the role of the argument structure projected by the first lexeme in the whole-word meaning. It is proposed that the argument structure of the verbal constituent has a cognitive influence on the processing and comprehension of these units. Firstly, an acceptability judgment test was administrated in order to identify a group of verb-noun compounds that were adequate for the Argentinean Spanish lexicon. Secondly, a lexical decision task was conducted with the stimuli selected as acceptable. Thirty native speakers (20 females), ranged in age from 19 to 34 years old, with at least 12 years of schooling, participated in the experiment. The lexical decision task included three types of compounds according to their argument structure: (1) Agent / patient (abrelatas), (2) Agent / patient with less prototypical features or metaphorical processes (chupasangre), and (3) locatives (guardamuebles). Stimuli were matched according to the whole-word and constituent frequency and length. For the statistical analysis, ANOVAs were calculated for error rates and response times (RTs) for each condition. Results show that reaction times (answers) to locative compounds were significantly higher than to agent-patient compounds. This contrast cannot be explained by differences in frequency or length, of the compounds or their constituents. Consequently, the present results seem to support the hypothesis that argument structure plays a central role in the processing of these words.

Hepatocyte Nuclear Factor-4 Alfa Mutation Associated with Hyperinsulinaemic Hypoglycaemia and Atypical Renal Fanconi Syndrome: Expanding the Clinical Phenotype.

BACKGROUND: The p.R63W mutation in the hepatocyte nuclear factor-4 alpha (HNF4A) results in macrosomia and atypical Fanconi syndrome, in addition to hyperinsulinaemic hypoglycaemia (HI). We describe 2 infants carrying this mutation, presenting with additional features. Cases Series: Patient 1, a male born with a birth weight of 1.7 SDS, was diagnosed with HI on day 2 of life. He responded to 3-10 mg/kg/day of diazoxide. Raised serum creatinine led to the investigation of renal tubular function, showing leaking of electrolytes and protein. The patient also had conjugated hyperbilirubinaemia with liver steatosis. Patient 2 was a male born with a weight of 0.36 SDS. His mother had renal Fanconi syndrome. He received parenteral nutrition and presented with HI at 1 month of age, while establishing enteral feeds. Biochemistry workup showed renal tubular leaking of calcium, sodium, and phosphate. A hypoglycaemia screen documented HI, and the patient was commenced on 2 mg/kg/day of diazoxide. Continuous glucose monitoring was performed in his mother, revealing overnight hypoglycaemia. CONCLUSION: Renal Fanconi syndrome represents the only HNF4A feature showing complete penetrance. Our cases suggest that the p.R63W HNF4A mutation must be considered in subjects with a normal birth weight and postulate the possibility of liver involvement as a part of this condition.

Idiopathic postprandial hyperinsulinaemic hypoglycaemia.

BACKGROUND: Idiopathic postprandial hyperinsulinaemic hypoglycaemia (PPHH) has rarely been reported in the paediatric age. The objective of this study was to describe the clinical characteristics, diagnosis and management in a group of children with PPHH. METHODS: Six children (three females) with a mean follow-up of 3.5±3.0 years at a single tertiary paediatric hospital. All had 24-h blood glucose monitoring, diagnostic fast and prolonged oral glucose tolerance test (OGTT). Follow-up included: 24-h blood glucose monitoring or continuous glucose monitoring system, prolonged OGTT and/or mixed meal (MM) test. RESULTS: Age at diagnosis ranged from 5.4 to 15.7 years and auxology parameters were within normal range in all subjects. All the children had a normal fasting tolerance for age. Prolonged OGTT demonstrated symptomatic hypoglycaemia after 120 min in all the patients with simultaneous detectable serum insulin concentration. Acarbose was tried in three patients, having a positive effect on glycaemic and symptom control, but due to side effects, only two patients continued acarbose in the long run. Diazoxide proved to be beneficial in one patient. The rest of the patients were managed with frequent feeds but despite this, prolonged OGTT/MM demonstrated on-going PPHH. CONCLUSIONS: Prolonged OGTT is necessary to diagnose PPHH in children. Acarbose is beneficial in children with PPHH, although not well tolerated. Patients managed exclusively on frequent feeds demonstrated persistent hypoglycaemia on OGTT. The underlying cause of the PPHH in these patients remains unknown.

Management of Cushing syndrome in children and adolescents: experience of a single tertiary centre.

UNLABELLED: The diagnosis and management of paediatric Cushing syndrome (CS) is highly challenging. This study aims to characterise its presentation, diagnosis, management and outcome by a retrospective case review of 30 patients (14 females) followed at a single tertiary paediatric endocrinology centre over a 30-year period. At presentation, median age was 8.9 years (0.2-15.5) and the commonest manifestations were weight gain (23/30), hirsutism (17/30), acne (15/30) and hypertension (15/30). Growth retardation was present in 11/30. Median body mass index (BMI) was +2.1 standard deviation score (SDS) (-6.5 to +4.6). Urinary free cortisol (UFC) was abnormal in 17/18 (94 %), midnight cortisol in 27/27 (100 %) and low-dose dexamethasone suppression (LDDS) test in 20/20 (100 %). High-dose dexamethasone suppression (HDDS) test was abnormal in 6/6 (100 %) of adrenal tumours, 1/10 (10 %) of Cushing disease (CD) and 1/2 (50 %) of ectopic tumours. Bilateral inferior petrosal sinus sampling (IPSS) identified five CD cases and one ectopic tumour. All patients underwent surgery and subsequently required cortisol replacement. Final diagnoses were 16 CD, 11 adrenal disease, 2 ectopic ACTH-secreting lesions and 1 case of unidentified aetiology. One year post-diagnosis, median BMI was 0.5 SDS (-2.5 to +3.7), hypertension was present in 4/14 (28 %), and 43 % (12/30) of individuals were off hydrocortisone. CONCLUSION: The prevalence of the clinical manifestations differs from that reported in other series. Screening tests were highly sensitive, with UFC, midnight cortisol and LDDS performing well. One year post-treatment, BMI and BP normalised in the majority of patients and almost half of them were able to discontinue replacement hydrocortisone. WHAT IS KNOWN: •Cushing syndrome is an extremely rare entity in the paediatric and adolescent age groups, so not many cohort studies have been published in this population. •Several tests can be employed to firstly diagnose hypercortisolaemia and secondly identify the source of origin of it. The efficacy and safety of these tests in children is still uncertain. What is New: •This study includes cases due to the different aetiologies of endogenous hypercortisolaemia (pituitary, adrenal and ectopic hypercortisolaemia) allowing us to compare the differences in presentation, diagnosis, management and long-term outcome between the groups. •There is a difference in the prevalence of Cushing syndrome symptoms and in the performance of the tests in our cohort compared to previously published studies in the literature.

Severe Hyperinsulinaemic Hypoglycaemia in Beckwith-Wiedemann Syndrome due to Paternal Uniparental Disomy of 11p15.5 Managed with Sirolimus Therapy.

BACKGROUND: Almost half of the children with Beckwith-Wiedemann syndrome (BWS) will develop hyperinsulinaemic hypoglycaemia (HH). In the majority of BWS cases, HH will be transient; however, approximately in 5% of them, HH will be severe and often medically-unresponsive. Children with BWS due to paternal uniparental disomy (UPD) of chromosome 11p15 belong to this severe category and have traditionally required near-total pancreatectomy. The use of mTOR inhibitors had not been reported yet in this type of patients. CASE: A 1-month-old female with genetically confirmed BWS due to UPD of chromosome 11p15 was admitted for management of severe HH. Blood glucose concentrations were stabilised with high intravenous dextrose concentration, glucagon and octreotide infusions as she was proven to be diazoxide unresponsive. To avoid a subtotal pancreatectomy, an mTOR inhibitor - sirolimus - was introduced. The dose of sirolimus was optimised progressively and she was able to come off intravenous fluids and glucagon therapy. She has not presented any side effects and her growth is normal after 19 months of therapy. CONCLUSION: This is the first case reported of BWS due to UPD of chromosome 11p15 where sirolimus treatment has been effective in stabilising the blood glucose concentrations and avoiding a near-total pancreatectomy without major side effects detected.

The Diagnosis and Management of Hyperinsulinaemic Hypoglycaemia.

Insulin secretion from pancreatic ß-cells is tightly regulated to keep fasting blood glucose concentrations within the normal range (3.5-5.5 mmol/L). Hyperinsulinaemic hypoglycaemia (HH) is a heterozygous condition in which insulin secretion becomes unregulated and its production persists despite low blood glucose levels. It is the most common cause of severe and persistent hypoglycaemia in neonates and children. The most severe and permanent forms are due to congenital hyperinsulinism (CHI). Recent advances in genetics have linked CHI to mutations in 9 genes that play a key role in regulating insulin secretion (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A and HNF1A). Histologically, CHI can be divided into 3 types; diffuse, focal and atypical. Given the biochemical nature of HH (non-ketotic), a delay in the diagnosis and management can result in irreversible brain damage. Therefore, it is essential to diagnose and treat HH promptly. Advances in molecular genetics, imaging methods (18F-DOPA PET-CT), medical therapy and surgical approach (laparoscopic surgery) have completely changed the management and improved the outcome of these children. This review provides an overview of the genetic and molecular mechanisms leading to development of HH in children. The article summarizes the current diagnostic methods and management strategies for the different types of CHI.

Hyperinsulinemic Hypoglycemia.

In hyperinsulinemic hypoglycemia (HH) there is dysregulation of insulin secretion from pancreatic ß-cells. Insulin secretion becomes inappropriate for the level of blood glucose leading to severe hypoglycemia. HH is associated with a high risk of brain injury because insulin inhibits lipolysis and ketogenesis thus preventing the generation of alternative brain substrates (such as ketone bodies). Hence HH must be diagnosed as soon as possible and the management instituted appropriately to prevent brain damage. This article reviews the mechanisms of glucose physiology in the newborn, the mechanisms of insulin secretion, the etiologic types of HH, and its management.