Gene expression signatures predict response to therapy with growth hormone.

Recombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response are inexact. GHD (n = 71) and TS patients (n = 43) were recruited to study response to r-hGH over 5 years. Analysis was performed using 1219 genetic markers and baseline (pre-treatment) blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria for prediction. However, we identified an identical set of genes in both GHD and TS whose expression could be used to classify therapeutic response to r-hGH with a high accuracy (AUC > 0.9). Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management. Trial registration numbers: NCT00256126 and NCT00699855.

Prolyl Endopeptidase-like Deficiency Associated with Growth Hormone Deficiency

Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and whole gene deletion in the other) with early growth impairment in infancy. GH deficiency was confirmed at 20 months of life. Recombinant GH treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

Contribution of Dynamic and Genetic Tests for Short Stature Diagnosing: A Case Report.

Genetic tests have led to the discovery of many novel genetic variants related to growth failure, but the clinical significance of some results is not always easy to establish. The aim of this report is to describe both clinical phenotype and genetic characteristics in an adult patient with short stature associated with a homozygous variant in disintegrin and metalloproteinase with thrombospondin motifs type 17 gene (ADAMTS17) combined with a homozygous variant in the GH secretagogue receptor (GHS-R). The index case had severe short stature (SS) (-3.0 SD), small hands and feet, associated with eye disturbances. Genetic tests revealed homozygous compounds for ADAMTS17 responsible for Weill-Marchesani-like syndrome but a homozygous variant in GHS-R was also detected. Dynamic stimulation with an insulin tolerance test showed a normal elevation of GH, while the GH response to macimorelin stimulus was totally flattened. We show the implication of the GHS-R variant and review the molecular mechanisms of both entities. These results allowed us to better interpret the phenotypic spectrum, associated co-morbidities, its implications in dynamic tests, genetic counselling and treatment options not only to the index case but also for her relatives.

Pituitary macroadenomas in childhood and adolescence: a clinical analysis of 7 patients.

BACKGROUND: Pituitary adenomas (PPAs) are uncommon in childhood and adolescence, accounting for 2-6% of all intracranial neoplasms. Delayed puberty, growth retardation, galactorrhea and weight gain are common features at presentation in pediatric patients. Functional tumors constitute a vast majority (90%) of PPAs, with the most frequent being prolactinomas. CASE PRESENTATION: A retrospective review of the clinical features and outcomes of 7 pediatric patients with pituitary macroadenomas was conducted. We included PPAs in patients under 18 years at diagnosis with diameters larger than 10 mm by magnetic resonance (MRI). Six patients were males (85%), with age at diagnosis ranging from 8 to 15 (median 14 ± 2.8SDS). The primary symptoms that led to medical attention were growth retardation, gigantism and secondary amenorrhea. The visual field was reduced in three cases (42%). Suprasellar extension was present in 3 subjects, and one had a giant adenoma. Adenomas were clinically functioning in 6 patients (85%) (three prolactinomas, two somatropinomas, one secreting FSH and one no-producer). The prolactinomas responded to treatment with cabergoline. For the rest, one required transsphenoidal surgery and the other three both surgery and radiotherapy. All patients undergoing radiotherapy had secondary panhypopituitarism. In relation to the genetic studies, two patients presented a pathogenic mutation of the AIP gene and one of the MEN1. DISCUSION AND CONCLUSION: Pediatric pituitary macroadenomas are a distinct entity, mostly found in males and with a predominance of functional tumors leading to detrimental effects on growth and puberty in addition to neuro-ophthalmological manifestations. It is important to perform genetic studies in patients with macroadenomas appearing under the age of 18 years as genetic and syndromic associations are more frequent in this age group.

Myocardial tissue characterization by cardiovascular magnetic resonance T1 mapping and pericardial fat quantification in adolescents with morbid obesity. Cardiac dimorphism by gender.

PURPOSE: Changes in the myocardial extracellular matrix (ECM) identified using T1 mapping cardiovascular magnetic resonance (CMR) have been only reported in obese adults, but with opposite conclusions. The objectives are to assess the composition of the myocardial ECM in an obese pediatric population without type 2 diabetes by quantifying native T1 time, and to quantify the pericardial fat index (PFI) and their relationship with cardiovascular risk factors. METHODS: Observational case-control research of 25 morbidly obese adolescents and 13 normal-weight adolescents. Native T1 and T2 times (ms), left ventricular (LV) geometry and function, PFI (g/ht3) and hepatic fat fraction (HFF, %) were calculated by 1.5-T CMR. RESULTS: No differences were noticed in native T1 between obese and non-obese adolescents (1000.0 vs. 990.5 ms, p0.73), despite showing higher LV mass values (28.3 vs. 22.9 g/ht3, p0.01). However, the T1 mapping values were significantly higher in females (1012.7 vs. 980.7 ms, p < 0.01) while in males, native T1 was better correlated with obesity parameters, particularly with triponderal mass index (TMI) (r = 0.51), and inflammatory cells. Similarly, the PFI was correlated with insulin resistance (r = 0.56), highly sensitive C-reactive protein (r = 0.54) and TMI (r = 0.77). CONCLUSION: Female adolescents possess myocardium peculiarities associated with higher mapping values. In males, who are commonly more exposed to future non-communicable diseases, TMI may serve as a useful predictor of native T1 and pericardial fat increases. Furthermore, HFF and PFI appear to be markers of adipose tissue infiltration closely related with hypertension, insulin resistance and inflammation.

Genetics and Natural History of Non-pancreatectomized Patients With Congenital Hyperinsulinism Due to Variants in ABCC8.

CONTEXT: Patients with congenital hyperinsulinism due to ABCC8 variants generally present severe hypoglycemia and those who do not respond to medical treatment typically undergo pancreatectomy. Few data exist on the natural history of non-pancreatectomized patients. OBJECTIVE: This work aims to describe the genetic characteristics and natural history in a cohort of non-pancreatectomized patients with congenital hyperinsulinism due to variants in the ABCC8 gene. METHODS: Ambispective study of patients with congenital hyperinsulinism with pathogenic or likely pathogenic variants in ABCC8 treated in the last 48 years and who were not pancreatectomized. Continuous glucose monitoring (CGM) has been periodically performed in all patients since 2003. An oral glucose tolerance test was performed if hyperglycemia was detected in the CGM. RESULTS: Eighteen non-pancreatectomized patients with ABCC8 variants were included. Seven (38.9%) patients were heterozygous, 8 (44.4%) compound heterozygous, 2 (11.1%) homozygous, and 1 patient carried 2 variants with incomplete familial segregation studies. Seventeen patients were followed up and 12 (70.6%) of them evolved to spontaneous resolution (median age 6.0 ± 4 years; range, 1-14). Five of these 12 patients (41.7%) subsequently progressed to diabetes with insufficient insulin secretion. Evolution to diabetes was more frequent in patients with biallelic variants in the ABCC8 gene. CONCLUSION: The high remission rate observed in our cohort makes conservative medical treatment a reliable strategy for the management of patients with congenital hyperinsulinism due to ABCC8 variants. In addition, a periodic follow-up of glucose metabolism after remission is recommended, as a significant proportion of patients evolved to impaired glucose tolerance or diabetes (biphasic phenotype).

Contribution of human growth hormone-releasing hormone receptor (GHRHR) gene sequence variation to isolated severe growth hormone deficiency (ISGHD) and normal adult height.

OBJECTIVE: Molecular causes of isolated severe growth hormone deficiency (ISGHD) in several genes have been established. The aim of this study was to analyse the contribution of growth hormone-releasing hormone receptor (GHRHR) gene sequence variation to GH deficiency in a series of prepubertal ISGHD patients and to normal adult height. DESIGN, SUBJECTS AND MEASUREMENTS: A systematic GHRHR gene sequence analysis was performed in 69 ISGHD patients and 60 normal adult height controls (NAHC). Four GHRHR single-nucleotide polymorphisms (SNPs) were genotyped in 248 additional NAHC. An analysis was performed on individual SNPs and combined genotype associations with diagnosis in ISGHD patients and with height-SDS in NAHC. RESULTS: Twenty-one SNPs were found. P3, P13, P15 and P20 had not been previously described. Patients and controls shared 12 SNPs (P1, P2, P4-P11, P16 and P21). Significantly different frequencies of the heterozygous genotype and alternate allele were detected in P9 (exon 4, rs4988498) and P12 (intron 6, rs35609199); P9 heterozygous genotype frequencies were similar in patients and the shortest control group (heights between -2 and -1 SDS) and significantly different in controls (heights between -1 and +2 SDS). GHRHR P9 together with 4 GH1 SNP genotypes contributed to 6·2% of height-SDS variation in the entire 308 NAHC. CONCLUSIONS: This study established the GHRHR gene sequence variation map in ISGHD patients and NAHC. No evidence of GHRHR mutation contribution to ISGHD was found in this population, although P9 and P12 SNP frequencies were significantly different between ISGHD and NAHC. Thus, the gene sequence may contribute to normal adult height, as demonstrated in NAHC.

[Bariatric surgery in adolescents]. / Cirugía bariátrica en adolescentes.

The increased prevalence of obesity in children and adolescents is becoming a public health problem. As in adults, obesity is associated with other comorbidities and their risks. This systematic review aims to summarize the implications of morbid obesity in adolescents, and identify the currently accepted treatments for its management. Various treatments such as lifestyle changes, drug therapy, and surgery are the classical therapeutic triad. This review attempts to clarify the role of each of the major treatments in terms of safety and efficacy. Although obesity surgery in adolescents remains controversial for some aspects, there is evidence that the lack of effective treatment can lead to serious medical consequences in the future. Gastric bypass and gastric banding techniques remain of choice, but the role of other currently more popular techniques, such as sleeve gastrectomy should be clarified.

A New MAMLD1 Variant in an Infant With Microphallus and Hypospadias With Hormonal Pattern Suggesting Partial Hypogonadotropic Hypogonadism-Case Report.

MAMLD1 (X chromosome) is one of the recognized genes related to different sex development. It is expressed in testis and ovaries and seems to be involved in fetal sex development and in adult reproductive function, including testosterone biosynthesis. However, its exact role remains unclear. Over 40 genetic variants have been described, mainly in male individuals and mostly associated with hypospadias. Although MAMLD1 has been shown to regulate the expression of the steroidogenic pathway, patients with MAMLD1 variants mostly show normal gonadal function and normal testosterone levels. Here we describe a patient (46,XY) with hypospadias and microphallus, with low testosterone and dihydrotestosterone (DHT) levels, and with inappropriately low values of luteinizing hormone (LH) during minipuberty. This hormonal pattern was suggestive of partial hypogonadotropic hypogonadism. A stimulation test with hCG (4 months) showed no significant increase in both testosterone and dihydrotestosterone concentrations. At 5 months of age, he was treated with intramuscular testosterone, and the penis length increased to 3.5 cm. The treatment was stopped at 6 months of age. Our gonadal function massive-sequencing panel detected a previously unreported nonsense variant in the MAMLD1 gene (c.1738C>T:p.Gln580Ter), which was classified as pathogenic. This MAMLD1 variant, predicting a truncated protein, could explain his genital phenotype. His hormonal profile (low testosterone, dihydrotestosterone, and LH concentrations) together with no significant increase of testosterone and DHT plasma concentrations (hCG test) highlight the potential role of this gene in the biosynthesis of testosterone during the fetal stage and minipuberty of the infant. Besides this, the LH values may suggest an involvement of MAMLD1 in the LH axis or a possible oligogenesis. It is the first time that a decrease in DHT has been described in a patient with an abnormal MAMLD1.

Novel variant in HHAT as a cause of different sex development with partial gonadal dysgenesis associated with microcephaly, eye defects, and distal phalangeal hypoplasia of both thumbs: Case report.

The palmitoylation of the Hedgehog (Hh) family of morphogens, named sonic hedgehog (SHH), desert hedgehog (DHH), and Indian hedgehog (IHH), is crucial for effective short- and long-range signaling. The hedgehog acyltransferase (HHAT) attaches the palmitate molecule to the Hh; therefore, variants in HHAT cause a broad spectrum of phenotypes. A missense HHAT novel variant c.1001T>A/p.(Met334Lys) was described in a patient first referred for a 46,XY different sexual development with partial gonadal dysgenesis but with microcephaly, eye defects, and distal phalangeal hypoplasia of both thumbs. The in silico analysis of the variant predicted an affectation of the nearest splicing site. Thus, in vitro minigene studies were carried out, which demonstrated that the variant does not affect the splicing. Subsequent protein in silico studies supported the pathogenicity of the variant, and, in conclusion, this was considered the cause of the patient's phenotype.

Different profiles of lipoprotein particles associate various degrees of cardiac involvement in adolescents with morbid obesity.

Introduction: Dyslipidemia secondary to obesity is a risk factor related to cardiovascular disease events, however a pathological conventional lipid profile (CLP) is infrequently found in obese children. The objective is to evaluate the advanced lipoprotein testing (ALT) and its relationship with cardiac changes, metabolic syndrome (MS) and inflammatory markers in a population of morbidly obese adolescents with normal CLP and without type 2 diabetes mellitus, the most common scenario in obese adolescents. Methods: Prospective case-control research of 42 morbidly obese adolescents and 25 normal-weight adolescents, whose left ventricle (LV) morphology and function had been assessed. The ALT was obtained by proton nuclear magnetic resonance spectroscopy, and the results were compared according to the degree of cardiac involvement - normal heart, mild LV changes, and severe LV changes (specifically LV remodeling and systolic dysfunction) - and related to inflammation markers [highly-sensitive C-reactive protein and glycoprotein A (GlycA)] and insulin-resistance [homeostatic model assessment for insulin-resistance (HOMA-IR)]. A second analysis was performed to compare our results with the predominant ALT when only body mass index and metabolic syndrome criteria were considered. Results: The three cardiac involvement groups showed significant increases in HOMA-IR, inflammatory markers and ALT ratio LDL-P/HDL-P (40.0 vs. 43.9 vs. 47.1, p 0.012). When only cardiac change groups were considered, differences in small LDL-P (565.0 vs. 625.1 nmol/L, p 0.070), VLDL size and GlycA demonstrated better utility than just traditional risk factors to predict which subjects could present severe LV changes [AUC: 0.79 (95% CI: 0.54-1)]. In the second analysis, an atherosclerotic ALT was detected in morbidly obese subjects, characterized by a significant increase in large VLDL-P, small LDL-P, ratio LDL-P/HDL-P and ratio HDL-TG/HDL-C. Subjects with criteria for MS presented overall worse ALT (specially in triglyceride-enriched particles) and remnant cholesterol values. Conclusions: ALT parameters and GlycA appear to be more reliable indicators of cardiac change severity than traditional CV risk factors. Particularly, the overage of LDL-P compared to HDL-P and the increase in small LDL-P with cholesterol-depleted LDL particles appear to be the key ALT's parameters involved in LV changes. Morbidly obese adolescents show an atherosclerotic ALT and those with MS present worse ALT values.

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe.

Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Design and methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN. Results: Pdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4-5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France. Conclusions: This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.

[Diagnostic accuracy of the tri-ponderal mass index in identifying the unhealthy metabolic obese phenotype in obese patients]. / Precisión diagnóstica del índice de masa triponderal (kg/m3) para identificar el fenotipo de riesgo metabólico en pacientes obesos.

INTRODUCTION: The metabolically healthy obese (MHO) phenotype defines obese patients who have preserved insulin sensitivity and absence of metabolic complications. This phenotype is associated with a lower risk of cardiovascular disease and type2 diabetes in adulthood. OBJECTIVES: To determine the prevalence of MHO and the metabolically unhealthy obesity (MUO) phenotype in a cohort of obese children and adolescents and to establish the predictive capacity of the tri-ponderal mass index (TMI) and other anthropometric parameters in order to identify these patients. PATIENTS AND METHODS: A cross-sectional study was conducted on 239 obese patients (125males) from 8 to 18years of age. Grade3 obesity was present in 45.9% of the patients. ROC curves were used to find the best cut-off point for: TMI, body mass index (BMI), BMI z-score (BMIzs), and waist/height index (WHI). MHO components: plasma blood glucose, plasma triglycerides, HDL-cholesterol, and blood pressure. RESULTS: The prevalence of MUO in the study cohort was 62.4%. No differences between genders were observed, and it was increasing with the age and obesity degree. The TMI has a sensitivity of 75.8 and a specificity of 42.2 to identify the MUO patients. The best cut-off point for TMI is 18.7kg/m3, for BMI it was 30.4kg/m2, for BMIzs +3.5SD, and 0.62 for WHI. CONCLUSIONS: The diagnostic accuracy of TMI in identifying obese adolescents with metabolic risk was similar to BMI and WHI. However, the TMI is much simpler to use and simplifies the categorization of the obesity in both genders.

Growth Hormone Treatment and Papilledema: A Prospective Pilot Study

Objective: To investigate the incidence of pseudotumor cerebri syndrome (PTCS) in children treated with growth hormone (GH) in a paediatric hospital and to identify risk factors for this complication. Methods: Prospective pilot study of paediatric patients treated with recombinant human GH, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later. Results: Two hundred and eighty-nine patients were included, of whom 244 (84.4%) had GH deficiency, 36 (12.5%) had short stature associated with small for gestational age, six (2.1%) had a mutation in the SHOX gene and three (1.0%) had Prader-Willi syndrome. Five (1.7%) developed papilledema, all were asymptomatic and had GH deficiency due to craniopharyngioma (n=1), polymalformative syndrome associated with hypothalamic-pituitary axis anomalies (n=2), a non-specified genetic disease with hippocampal inversion (n=1) and one with normal magnetic resonance imaging who had developed a primary PTCS years before. Conclusion: GH treatment is a cause of PTCS. In our series, at risk patients had GH deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosomal diseases. Fundus examination should be systematically screened in all patients in this at-risk group, irrespective of the presence or not of symptoms.

Myocardial Geometry and Dysfunction in Morbidly Obese Adolescents (BMI 35-40 kg/m2).

This study evaluated the preclinical effect of obesity on the ventricular remodeling in adolescents with morbid obesity, and determined if subjects labelled as metabolically healthy obesity (MHO) presented better heart index than those with metabolically unhealthy obesity (MUO). Prospective case-control research of 45 adolescents (14-year-old) with morbid obesity and 25 normal weight adolescents' gender- and age-matched with Tanner stage 4-5. Left ventricle (LV) was evaluated by conventional Doppler echocardiography, tissue Doppler imaging and two-dimensional speckle tracking echocardiography. Compared to normal-weight subjects, adolescents with morbid obesity presented a high percentage of pathological LV geometry (87%; p<0.01), and systolic and diastolic dysfunctions only detected by E/A ratio (2.0 vs 1.7, p<0.01), global longitudinal strain (-21.0% vs -16.5%, p<0.01), and early diastolic strain rate (3.2 vs 2.2, p<0.01). A correlation was found between impaired cardiac index and body mass index (BMI), high blood pressure, hyperglycemia, low HDL-cholesterol and hypertriglyceridemia. BMI and HDL-cholesterol were the most significant independent variables. No significant differences were found in structural and functional cardiac index when MHO and MUO subjects were compared (global longitudinal strain: -17.0% vs -16.4%, p0.79). Morbidly obese adolescents have an abnormal LV geometry, closely related to BMI, and systolic and diastolic LV dysfunctions. Adolescents labelled as MHO, despite exhibiting better BMI and insulin-resistance values, present the same pathological heart changes as MUO.

Phenotypic Variability of Patients With PAX8 Variants Presenting With Congenital Hypothyroidism and Eutopic Thyroid.

PURPOSE: Thyroid dyshormonogenesis is a heterogeneous group of hereditary diseases produced by a total/partial blockage of the biochemical processes of thyroid-hormone synthesis and secretion. Paired box 8 (PAX8) is essential for thyroid morphogenesis and thyroid hormone synthesis. We aimed to identify PAX8 variants in patients with thyroid dyshormonogenesis and to analyze them with in vitro functional studies. PATIENTS AND METHODS: Nine pediatric patients with a eutopic thyroid gland were analyzed by the Catalan screening program for congenital hypothyroidism. Scintigraphies showed absent, low, or normal uptake. Only one patient had a hypoplastic gland. On reevaluation, perchlorate discharge test was negative or compatible with partial iodine-organization deficit. After evaluation, 8 patients showed permanent mild or severe hypothyroidism. Massive-sequencing techniques were used to detect variants in congenital hypothyroidism-related genes. In vitro functional studies were based on transactivating activity of mutant PAX8 on a TG-gene promoter and analyzed by a dual-luciferase assays. RESULTS: We identified 7 heterozygous PAX8 exonic variants and 1 homozygous PAX8 splicing variant in 9 patients with variable phenotypes of thyroid dyshormonogenesis. Five were novel and 5 variants showed a statistically significant impaired transcriptional activity of TG promoter: 51% to 78% vs the wild type. CONCLUSIONS: Nine patients presented with PAX8 candidate variants. All presented with a eutopic thyroid gland and 7 had deleterious variants. The phenotype of affected patients varies considerably, even within the same family; but, all except the homozygous patient presented with a normal eutopic thyroid gland and thyroid dyshormonogenesis. PAX8 functional studies have shown that 6 PAX8 variants are deleterious. Our studies have proven effective in evaluating these variants.

Glycogen storage disease type III with hypoketosis.

A rare case of glycogen storage disease type III with unusually absent ketone body production during hypoglycemia is presented. A 10-month-old boy presented with asymptomatic hepatomegaly. GOT/GPT 2555/1160 IU/L, CK 302 IU/L, triglycerides 1223 mg/dL, cholesterol 702 mg/dL and uric acid 7.9 mg/dL. After a 9-hour fast, glucose was 27 mg/dL and adequate lipolysis without ketogenesis was observed (total/free carnitine 34.5/20 micromol/L, free fatty acids 1620 micromol/L and beta-hydroxybutyrate 172 micromol/L). Result of MCT (medium-chain triglycerides) load test: basal hydroxybutyrate 29 micromol/L rose to 5748 micromol/L. Treatment with a fat-restricted diet supplemented with formula containing MCT was initiated and the patient presented a satisfactory initial evolution. Three months later, CK were 3000 IU/L. Muscle biopsy was diagnostic of glycogenosis. Enzymatic activity in skin fibroblasts was 0% for amylo-1,6-glucosidase. The diagnosis of glycogenosis type III was established. Echocardiography performed at that time showed non-obstructive ventricular hypertrophy. Until now hypoketosis during hypoglycemia has only been described in glycogenosis type I.

Hypophosphatasia: A Novel Mutation Associated with an Atypical Newborn Presentation

Hypophosphatasia, a rare genetic disease affecting bone metabolism, is characterized by decreased activity of tissue non-specific alkaline phosphatase (TNAP). The gene encoding TNAP (ALPL) has considerable allelic heterogeneity, which could explain different degrees of enzyme activity resulting in a wide clinical variability. We report the case of a preterm newborn in whom a corneal opacity was detected at birth. Blood tests performed to investigate this finding showed low alkaline phosphatase concentrations. The corneal opacity disappeared within a week but alkaline phosphatase remained persistently low. With persistently decreased levels of alkaline phosphatase, upon suspicion of hypophosphatasia, plain radiography detected changes suggestive of rickets. Sequencing of the ALPL gene revealed a heterozygous variant that has not been described in the literature to date. Our patient's condition may be an atypical neonatal form of the syndrome, with a mild phenotype, very different from the classic neonatal form, which can lead to severe skeletal disease and respiratory failure. However, it could also be an early diagnosis of the childhood form, which is associated with a better prognosis.

ACTH-dependent precocious pseudopuberty in an infant with DAX1 gene mutation.

DAX1 gene (Xp21) expression is involved in the development of the hypothalamo-pituitary-gonadal and adrenal axes, and acts as a negative regulator of steroidogenesis. Mutations of this gene determine adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism. We report the case of a 9-month-old boy referred for the study of macrogenitosomia and pubic hair development. He had presented acute adrenal crises in the neonatal period and, later, a clinical picture of peripheral precocious puberty. A mutation in the DAX1 gene was found (Trp291Arg) and a diagnosis of AHC was made. Replacement doses of hydrocortisone (HC) (10 mg/m2/day) failed to produce a feedback inhibition of adrenocorticotropic hormone (ACTH), and testosterone levels remained high. Testosterone and ACTH values normalized after HC was progressively increased to 18 mg/m2/day. In conclusion, peripheral precocious puberty in patients with DAX1 gene mutations appears to be secondary to the stimulus exerted by ACTH on melanocortin receptors in Leydig cells and to the overexpression of testicular steroidogenesis activators by the loss of transcriptional repression.

Ezetimibe as monotherapy in the treatment of hypercholesterolemia in children and adolescents.

BACKGROUND: A prospective study was conducted to evaluate low-density lipoprotein-cholesterol (LDL-C) lowering efficacy and tolerability of ezetimibe as monotherapy in children and adolescents with polygenic hypercholesterolemia (PH) or familial hypercholesterolemia (FH). METHODS AND RESULTS: Children with PH (n=6) or FH (n=11) aged 5-15 years were consecutively enrolled to receive ezetimibe as monotherapy at 10 mg/day for 11.3 +/- 7.3 and 15.9 +/- 10.1 months, respectively. Plasma biochemical and lipid profiles were assessed before and after treatment. Ezetimibe significantly lowered total cholesterol (TC) and LDL-C in patients with PH and FH: TC from 260.5 +/- 12.4 to 180.0 +/- 21.6 mg/dl (p = 0.02) and from 315.3 +/- 41.8 to 233.3 +/- 36.8 mg/dl (p = 0.003), respectively, and LDL-C from 177.1 +/- 17.7 to 102.6 +/- 16.7 mg/dl (p = 0.02) and from 243.0 +/- 41.8 to 170.0 +/- 29.8 mg/dl (p = 0.003), respectively. However, high-density lipoprotein-cholesterol (HDL-C) only decreased significantly (from 58.1 +/- 10.0 to 49.3 +/- 9.1 mg/dl) (p < 0.01) in patients with FH and remained unaltered in patients with PH. Triglyceride levels remained unchanged in both groups. Biochemical profile (hemogram, transaminases, creatinine, calcium, phosphorus and liposoluble vitamins A and E) remained unchanged; no adverse effects were observed. CONCLUSIONS: Our data show that ezetimibe as monotherapy significantly lowered TC and LDL-C in children with PH and FH.