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

MAMLD1 gene; Hypospadias; MinipubertyGen MAMLD1; Hipospàdies; MinipubertatGen MAMLD1; Hipospadias; MinipubertadMAMLD1 (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

Adherence and long-term outcomes of growth hormone therapy with easypod™ in pediatric subjects: Spanish ECOS study

E-health; Easypod; Electronic deviceE-salut; Easypod; Dispositiu electrònicE-salud; Easypod; Dispositivo electrónicoBackground: Non-adherence to r-hGH treatments occurs in a variable percentage of subjects. One problem found when evaluating adherence is the great variability in methods of detection and definitions utilized in studies. This study assessed the level of adherence in subjects receiving r-hGH with the easypod™ electronic device. Methods: National, multicenter, prospective and observational study involving 238 subjects (144 with GH deficiency (GHD), and 86 with small for gestational age (SGA), 8 with Turner Syndrome), who received r-hGH with easypod™ for at least 3 months before inclusion. The follow-up period was 4 years. Results: Overall adherence was 94.5%; 97.5% after 6 months, 95.3% after 1 year, 93.7% after 2, 94.4% after 3 and 95.5% after 4 years of treatment. No differences in adherence were observed between prepubertal and pubertal groups and GHD and SGA groups. Change in height after 1 and 2 years, change in height SDS after 1 and 2 years, HV after 1 year, HV SDS after at 1 and 4 years, change in BMI after 1 year and change in BMI SDS at 1 and 2 years showed significant correlation with adherence. No significant differences in adherence according to IGF-I levels were found in follow-up visits or between groups. Conclusions: The easypod™ electronic device, apart from being a precise and objective measure of adherence to r-hGH treatment, allows high compliance rates to be achieved over long periods of time. Adherence significantly impacts growth outcomes associated with r-hGH treatmentThis study was funded by Merck, S.L., Madrid, Spain

Hyperinsulinaemic hypoglycaemia, renal Fanconi syndrome and liver disease due to a mutation in the HNF4A gene

HNF4A gene mutations have been reported in cases of transient and persistent hyperinsulinaemic hypoglycaemia of infancy (HHI), particularly in families with adulthood diabetes. The case of a patient with HHI, liver impairment and renal tubulopathy due to a mutation in HNF4A is reported

Guía clínica de atención a menores transexuales, transgéneros y de género diverso

Transgénero; Terapia hormonal cruzada; Identidad de géneroTransgender; Hormone cross therapy; Gender identityTransgènere; Teràpia hormonal creuada; Identitat de gènereSome people, including minors, have a gender identity that does not correspond to the sex assigned at birth. They are known as trans* people, which is an umbrella term that encompasses transgender, transsexual, and other identities not conforming to the assigned gender. Healthcare units for trans* minors require multidisciplinary working, undertaken by personnel expert in gender identity, enabling, when requested, interventions for the minor and their social–familial environment, in an individualized and flexible way during the gender affirmation path. This service model also includes hormonal treatments tailored as much as possible to the individual's needs, beyond the dichotomic goals of a traditional binary model. This guide addresses the general aspects of professional care of trans* minors and presents the current evidence-based protocol of hormonal treatments for trans* and non-binary adolescents. In addition, it details key aspects related to expected body changes and their possible side effects, as well as prior counselling about fertility preservation.Algunas personas, también las menores de edad, tienen una identidad de género que no se corresponde con el sexo asignado al nacer. Se les conoce como personas trans*, que es el término paraguas que engloba transgénero, transexual y otras identidades no conformes con el género asignado. Las unidades de asistencia sanitaria a menores trans* requieren un trabajo multidisciplinario, realizado por personal experto en identidad de género, que permita, cuando así lo soliciten, intervenciones para el menor y su entorno sociofamiliar, de forma individualizada y flexible durante el camino de afirmación de género. Este modelo de servicio también incluye tratamientos hormonales adaptados en la medida de lo posible a las necesidades del individuo, más allá de los objetivos dicotómicos de un modelo binario tradicional. Esta guía aborda los aspectos generales de la atención profesional de menores trans* y presenta el protocolo actual basado en evidencia de tratamientos hormonales para adolescentes trans* y no binarios. Además, detalla aspectos clave relacionados con los cambios corporales esperados y sus posibles efectos secundarios, así como el asesoramiento previo sobre preservación de la fertilidad

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

Different sexual development; Minigene studiesDesarrollo sexual diferente; Estudios de minigenesDesenvolupament sexual diferent; Estudis minigènicsThe 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.This study was partly supported by a grant from the Fondo de Investigación Sanitaria (PI15/01647 [to MF-C and SB-S])

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

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. 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. 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. 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

Human growth hormone (GH1) gene polymorphism map in a normal-statured adult population

OBJECTIVE: GH1 gene presents a complex map of single nucleotide polymorphisms (SNPs) in the entire promoter, coding and noncoding regions. The aim of the study was to establish the complete map of GH1 gene SNPs in our control normal population and to analyse its association with adult height. DESIGN, SUBJECTS AND MEASUREMENTS: A systematic GH1 gene analysis was designed in a control population of 307 adults of both sexes with height normally distributed within normal range for the same population: −2 standard deviation scores (SDS) to +2 SDS. An analysis was performed on individual and combined genotype associations with adult height. RESULTS: Twenty-five SNPs presented a frequency over 1%: 11 in the promoter (P1 to P11), three in the 5′UTR region (P12 to P14), one in exon 1 (P15), three in intron 1 (P16 to P18), two in intron 2 (P19 and P20), two in exon 4 (P21 and P22) and three in intron 4 (P23 to P25). Twenty-nine additional changes with frequencies under 1% were found in 29 subjects. P8, P19, P20 and P25 had not been previously described. P6, P12, P17 and P25 accounted for 6·2% of the variation in adult height (P = 0·0007) in this population with genotypes A/G at P6, G/G at P6 and A/G at P12 decreasing height SDS (−0·063 ± 0·031, −0·693 ± 0·350 and −0·489 ± 0·265, Mean ± SE) and genotypes A/T at P17 and T/G at P25 increasing height SDS (+1·094 ± 0·456 and +1·184 ± 0·432). CONCLUSIONS: This study established the GH1 gene sequence variation map in a normal adult height control population confirming the high density of SNPs in a relatively small gene. Our study shows that the more frequent SNPs did not significantly contribute to height determination, while only one promoter and two intronic SNPs contributed significantly to it. Studies in larger populations will have to confirm the associations and in vitro functional studies will elucidate the mechanisms involved. Systematic GH1 gene analysis in patients with growth delay and suspected GH deficiency/insufficiency will clarify whether different SNP frequencies and/or the presence of different sequence changes may be associated with phenotypes in them

Thyroid Function in 509 Premature Newborns Below 31 Weeks of Gestational Age : Evaluation and Follow-up

Preterm and low birth weight (LBW) neonates may present with thyroid dysfunction during a critical period for neurodevelopment. These alterations can be missed on routine congenital hypothyroidism (CH) screening which only measures thyroid stimulating hormone (TSH). The objective of this study was to evaluate a protocol for thyroid function screening (TFS) six years after national implementation. Serum TSH and free thyroxine (fT4) were measured during the second week of life in neonates below 31 weeks. Patients with abnormal TFS (fT4 5 mU/L) were followed up with repeated tests until normal levels were reported. Patients who were still on levothyroxine (LT4) at three years of age were re-evaluated. Five-hundred and nine neonates were included. Thyroid dysfunction was detected in 170 neonates (33%); CH n=20 (3.9%) including typical CH n=1; delayed TSH elevation CH n=19; hypothyroxinemia of prematurity (HOP) n=15 (2.9%); and transient hyperthyrotropinemia n=135 (26.5%). Twenty-one neonates (4.1%) were treated (20 for CH and 1 for HOP). At 3-year follow-up only three patients were diagnosed with permanent CH and still need treatment. LBW infants tended to have TSH levels higher than those with adequate weight. This protocol was able to detect thyroid dysfunction in preterm neonates who were not identified by the current program based on TSH determination in whole-blood. This thyroid dysfunction seems to resolve spontaneously in a few months in the great majority of neonates, but in some cases LT4 could be needed. There is a critical need for specific guidelines regarding the follow-up and re-evaluation of transient CH in preterm neonates

Successful use of cinacalcet to treat parathyroid-related hypercalcemia in two pediatric patients

Summary Two pediatric patients with different causes of hyperparathyroidism are reported. First patient is a 13-year-old male with severe hypercalcemia due to left upper parathyroid gland adenoma. After successful surgery, calcium and phosphate levels normalized, but parathormone levels remained elevated. Further studies revealed a second adenoma in the right gland. The second patient is a 13-year-old female with uncommon hypercalcemia symptoms. Presence of pathogenic calcium-sensing receptor gene (CASR) mutation was found, resulting in diagnosis of symptomatic familial hypocalciuric hypercalcemia. Cinacalcet, a calcium-sensing agent that increases the sensitivity of the CASR, was used in both patients with successful results. Learning points: Hyperparathyroidism is a rare condition in pediatric patients. If not treated, it can cause serious morbidity. Genetic tests searching for CASR or MEN1 gene mutations in pediatric patients with primary hyperparathyroidism should be performed. Cinacalcet has been effective for treating different causes of hyperparathyroidism in our two pediatric patients. Treatment has been well tolerated and no side effects have been detected. </jats:sec

Safety Outcomes During Pediatric GH Therapy : Final Results From the Prospective GeNeSIS Observational Program

Altres ajuts: Financial Support: GeNeSIS was sponsored by Eli Lilly and Company (Indianapolis, IN). In compliance with the Uniform Requirements for Manuscripts, established by the International Committee of Medical Journal Editors, the sponsor of this study did not impose any impediment, directly or indirectly, on the publication of the study's results. Disclosure Summary: C.J.C. and N.J. are employees and stockholders ofEliLilly and Company (Indianapolis, IN).W.F.B. and A.G.Z. are former employees and are stockholders of Lilly. C.L.D., T.H., M.M., and R.G.R. are former members of the GeNeSIS International Advisory Board; S.L., J.P.S., A.R.-U., and M.P. have served as regional advisors. B.P. has consulted for Eli Lilly Italia SpA, and E.C. has received grant support from Lilly. W.F.B. also reports heis aconsultant forAmmonett Pharma,Lilly Germany, and Merck KGaA Darmstadt. C.L.D. also reports receipt of grants, consultancy honoraria, and speaker fees from Lilly,EMD Serono, and Sandoz; grants fromOpko Prolor, Pfizer, and Versatis; honoraria and speaker fees from Roche; honoraria from Pfizer; and speaker fees from Novo Nordisk. The remaining authors have nothing to disclose.Safety concerns have been raised regarding premature mortality, diabetes, neoplasia, and cerebrovascular disease in association with GH therapy. To assess incidence of key safety outcomes. Prospective, multinational, observational study (1999 to 2015). A total of 22,311 GH-treated children from 827 investigative sites in 30 countries. Children with growth disorders. GH treatment. Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) with 95% CIs for mortality, diabetes, and primary cancer using general population registries. Predominant short stature diagnoses were GH deficiency (63%), idiopathic short stature (13%), and Turner syndrome (8%), with mean ± SD follow-up of 4.2 ± 3.2 years (∼92,000 person-years [PY]). Forty-two deaths occurred in patients with follow-up, with an SMR (95% CI) of 0.61 (0.44, 0.82); the SMR was elevated for patients with cancer-related organic GH deficiency [5.87 (3.21, 9.85)]. Based on 18 cases, type 2 diabetes mellitus (T2DM) risk was elevated [SIR: 3.77 (2.24, 5.96)], but 72% had risk factors. In patients without cancer history, 14 primary cancers were observed [SIR: 0.71 (0.39, 1.20)]. Second neoplasms occurred in 31 of 622 cancer survivors [5.0%; 10.7 (7.5, 15.2) cases/1000 PY] and intracranial tumor recurrences in 67 of 823 tumor survivors [8.1%; 16.9 (13.3, 21.5) cases/1000 PY]. All three hemorrhagic stroke cases had risk factors. GeNeSIS (Genetics and Neuroendocrinology of Short Stature International Study) data support the favorable safety profile of pediatric GH treatment. Overall risk of death or primary cancer was not elevated in GH-treated children, and no hemorrhagic strokes occurred in patients without risk factors. T2DM incidence was elevated compared with the general population, but most cases had diabetes risk factors. Safety of GH therapy was assessed in a pediatric observational study. Death and primary cancer rates were not higher than in the general population; T2DM rate was higher owing to risk factors