Evaluation of pancreas with strain elastography in children with type 1 diabetes mellitus

Background: To investigate changes in pancreatic elasticity in children with type 1 diabetes mellitus (T1DM). Material/Methods: The study group consisted of 60 children with T1DM, and the control group was comprised of 60 healthy children. Strain ratios were obtained for the pancreas using ultrasound strain elastography (Toshiba Applio 500 device). Baseline descriptive data, hemoglobin A1c (%) level, time since diagnosis of T1DM (months), and strain ratio values were noted and compared between the 2 groups. Furthermore, correlation between strain ratio values and other variables was investigated. Results: ROC analysis yielded an optimal cut-off value of 2.245 (AUC=0.999, p<0.001, sensitivity=0.983, specificity=1.00) for the strain ratio. Strain ratio values greater than 2.245 were likely to be pathological, which could be attributed to increased tissue stiffness in T1DM. The strain ratio was significantly higher in T1DM patients than in the control group (3.38±0.66 vs. 1.32±0.35; p<0.001). The strain ratio correlated positively with age and duration of T1DM (p<0.001 for both), and there was a correlation between the strain ratio and age in the control group (p=0.011). Conclusions: Strain elastography is a promising, safe, non-invasive, and practical method for early detection, long-term screening, and follow-up in children with T1DM

A Novel Mutation of AMHR2 in Two Siblings with Persistent Mullerian Duct Syndrome

WOS: 000451667000014PubMed ID: 29687786Persistent Mullerian Duct syndrome (PMDS) develops due to deficiency of anti-Mullerian hormone (AMI I) or insensitivity of target organs to AMH in individuals with 46,XY karyotype. PMDS is characterized by normal male phenotype of external genitals, associated with persistence of Mullerian structures. This report includes the presentation of a 2.5 year old male patient due to bilateral undescended testis. His karyotype was 46,XY. The increase in testosterone following human chorionic gonadotropin stimulation test was normal. The patient was referred to our clinic after uterine, fallopian tube and vaginal remnants were recognized during the orchiopexy surgery. The family reported that the eight year old elder brother of the patient was operated on for right inguinal hernia and left undescended testis at the age of one year. A right transverse testicular ectopia was found in the elder brother. Both cases had normal AMH levels. AMHR2 gene was analyzed and a homozygous NM_020547.3:c.233-I G> A mutation was found that was not identified previously. In conclusion, we determined a novel mutation in the AMHR2 gene that was identified for the first time. This presented with different phenotypes in two siblings

Aromatase Deficiency due to a Novel Mutation in CYP19A1 Gene

WOS: 000451667000012PubMed ID: 29553041Aromatase deficiency is a rare autosomal recessive genetic disorder with an unknown incidence. Aromatase converts androgens into estrogen in the gonadal and extra-gonadal tissues. Aromatase deficiency causes ambiguous genitalia in the Female fetus and maternal virilization (hirsutism, acne, cliteromegaly, deep voice) during pregnancy due to increased concentration of androgens. A 19 months old girl patient was assessed due to presence of ambiguous genitalia. There were findings of maternal virilization during pregnancy. The karyotype was 46,XX. Congenital adrenal hyperplasia was not considered since adrenocorticotropic hormone, cortisol, and 17-hydroxyprogesterone levels were within normal ranges. At age two months, follicle-stimulating hormone and total testosterone levels were elevated and estradiol level was low. Based on these findings, aromatase deficiency was suspected. A novel homozygous mutation IVS7-2A > G (c.744-2A >G) was identified in the CYP19A1 gene. Pelvic ultrasound showed hypoplasic ovaries rather than large and cystic ovaries. We identified a novel mutation in the CYP19A1 gene in a patient who presented with ambiguous genitalia and maternal virilization during pregnancy. Presence of large and cystic ovaries is not essential in aromatase deficiency

BMP4 mutations as a novel cause of normosmic hypogonadotropic hypogonadism

WOS: 000485922401062

La inactivación de GLI1 causa alteraciones del desarrollo solapantes con el Síndrome de Ellis-vanCreveld

Resumen del trabajo presentado a la XI Reunión Anual CIBERER, celebrada en Castelldefels, Barcelona del 12 al 14 de marzo de 2018.Los factores transcripcionales GLI1, GLI2 y GLI3 actúan en el desarrollo embrionario como mediadores de los morfógenos Hedgehog (Hh). En consecuencia, variantes deletéreas en GLI2 y GLI3 han sido reportadas como responsables de defectos congénitos. Sin embargo, hasta la fecha no se habían descrito mutaciones en GLI1, por lo que el papel de este gen en el desarrollo humano permanecía desconocido. Aquí presentamos 8 pacientes de tres familias distintas con mutaciones en GLI1 y características clínicas similares a las del Síndrome de Ellis-van Creveld (EvC), una enfermedad causada por la disminución de la actividad de la vía de Hh. Dos familias portaban mutaciones de fin de mensaje en el último exón del gen y la tercera un codón de parada en la región N-terminal. El análisis de fibroblastos de uno de los pacientes con mutaciones en el último exón demostró que las células de este paciente sintetizan la proteína truncada correspondiente e inducen su expresión en respuesta a un agonista químico de Hh. Sin embargo, ensayos “in vivo” y en cultivo celular revelaron que la actividad transcripcional de la proteína mutante se encontraba drásticamente disminuida. Consistentemente, las células del paciente presentaron menor expresión de la diana de Hh, PTCH1. Este trabajo muestra que la inactivación de GLI1 da lugar a alteraciones del desarrollo que varían desde polidactilia postaxial aislada hasta fenotipos solapantes con EvC, a la vez que pone de manifiesto que todos los miembros de la triada GLI son necesarios en el desarrollo humano.Peer reviewe

The molecular basis and genotype-phenotype correlations of congenital adrenal hyperplasia (CAH) in Anatolian population

Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder due to presence of mutations in the genes involved in the metabolism of steroid hormones in adrenal gland. There are two main forms of CAH, classic form and non-classic form. While classic form stands for the severe form, the non-classic form stands for the moderate and more frequent form of CAH. The enzyme deficiencies such as 21-hydroxylase, 11-beta-hydroxylase, 3-beta-hydroxysteroid dehydrogenase, 17-alpha-hydroxylase deficiencies are associated with CAH. In this study, we aimed to investigate CYP21A2, CYP11B1, HSD3B2 genes which are associated with 21-hydroxylase, 11-beta-hydroxylase and 3-beta-hydroxysteroid dehydrogenase enzyme deficiencies, respectively, in 365 individuals by using Sanger sequencing method. We emphasized the classification of variants according their disease causing potential, and evaluated variants' frequencies including newly discovered novel variants. As a result, 32 variants of CYP21A2 including 10 novel variants, 9 variants of CYP11B1 including 3 novel variants and 6 variants of HSD3B2 including 4 novel variants were identified. The conclusions of our study showed that in Anatolia, discovery of novel variants is quite common on account of tremendous ratios of consanguineous marriages which increases the frequency of CAH. These results will contribute to the understanding of molecular pathology of the disease

YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress

Neonatal diabetes is caused by single gene mutations reducing pancreatic pcell number or impairing beta cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in beta cells. We identified 6 patients from 5 families with homozygous mutations in the MPS gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human beta cell models (YIPF5 silencing in EndoC-beta H1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects beta cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and beta cell failure. Partial YIPF5 silencing in EndoC-beta H1 cells and a patient mutation in stem cells increased the beta cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in beta cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.Peer reviewe