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Hypoparathyroidism in pediatric patients
Published in Pallavi Iyer, Herbert Chen, Thyroid and Parathyroid Disorders in Children, 2020
Andrew C. Calabria, Michael A. Levine
Isolated hypoparathyroidism can be caused by genetic defects that impair embryologic development of only the parathyroid glands. The most common form of isolated parathyroid aplasia is due to loss-of-function mutations in the glial cells missing 2 (GCM2) gene located at 6p23-24. This gene is considered to be the “master regulator” of parathyroid gland development. In most patients, hypoparathyroidism is due to biallelic mutations that inactivate GCM2, and are transmitted in an autosomal recessive manner. On the other hand, some cases show a dominant pattern of inheritance in which GCM2 mutations produce an abnormal GCM2 protein with dominant-negative effects. GCM2 is a member of a small family of homologous proteins that regulate gene transcription by interacting with DNA at a unique GCM binding motif. GCM2 is expressed principally if not exclusively in parathyroid cells, and is first detected during early development in the second and third pharyngeal pouches, where it participates as part of a network of transcription factors (e.g., GATA3 and TBX1) that are required for the normal development of the parathyroid gland. Isolated hypoparathyroidism can also be inherited in an X-linked recessive pattern, with affected patients presenting with hypocalcemic seizures during infancy. These patients carry mutations at Xq26-27, in which there is a deletion-insertion involving chromosomes 2p25.2 and Xq27.1, near Sry-box 3 (SOX3), which is also thought to impact parathyroid gland development.
Primary Pituitary Disease
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Christopher M. Jones, John Ayuk
Combined pituitary hormone deficiency may also arise as part of a syndrome, as is the case in septo-optic dysplasia, Rieger’s syndrome and holoprosencephaly.6 Septo-optic dysplasia carries an incidence of approximately 1:10 000 and both sporadic and familial cases have been described with HESX1, SOX2 and SOX3 implicated in the pathogenesis of this disorder.7 Hypoplasia of both the pituitary and optic nerve is seen as a consequence, in addition to defects of the midline forebrain. This commonly results in neurological defects. Visual impairment and variable endocrine deficiencies – the most common of which are isolated GH deficiency and combined TSH and ACTH deficiency – are also seen.
Short Stature
Published in Michael B O’Neill, Michelle Mary Mcevoy, Alf J Nicholson, Terence Stephenson, Stephanie Ryan, Diagnosing and Treating Common Problems in Paediatrics, 2017
Michael B O’Neill, Michelle Mary Mcevoy, Alf J Nicholson, Terence Stephenson, Stephanie Ryan
Isolated growth hormone deficiency is a clinical diagnosis, supported by auxological, biochemical and radiological findings. Growth hormone deficiency can be divided into three categories; congenital, acquired and idiopathic. Congenital causes can be the result of genetic mutations or structural defects. Known genes include those that code for growth hormone (GH1), growth-hormone-releasing hormone receptor (GHRHR) and transcription factor SOX3. Acquired causes of growth hormone deficiency include space occupying lesions, head trauma, infection, radiation therapy, infiltrative disease such as histiocytocis and autoimmune conditions such as lymphocytic hypophysitis. Idiopathic growth hormone deficiency is where no known cause is found. The phenotype of children with growth hormone deficiency is highly variable. However, they have a characteristically immature facies with a prominent forehead and depressed midline development. When other pituitary hormone deficiencies are present, there may be a history of neonatal jaundice, hypoglycaemia, micropenis with undescended testes and hypothyroidism.
Septo-optic dysplasia presenting with nystagmus, pseudo-disc edema, and fovea hypoplasia
Published in Ophthalmic Genetics, 2022
Richard Sather ΙΙΙ, Dorothy Thompson, Jacqueline Ihinger, Sandra R. Montezuma
The incidence of SOD is 1 in 10,000 live births, with boys and girls affected equally (3). The etiology is unclear, though SOD has been associated with a younger maternal age and environmental factors may play a role (4). Some of these environmental risk factors that may contribute to malformations typical of SOD include drug consumption, viral infections, and maternal diabetes (4). The underlying genetic mechanisms are still being worked out, and common genetic abnormalities include common pathogenic gene variants in two genes: HESX1 and SOX2 (5). The HESX1 homeobox gene functions as a transcriptional repressor and is responsible for pituitary organogenesis (6). The SOX2 gene has been linked as a critical component in the proper development of the pituitary gland, forebrain, and eye during human embryogenesis (7). Other genes including SOX3 and OTX2 have also been identified in some cases of SOD (8).
Radiation effects on early phase of NT2/D1 neural differentiation in vitro
Published in International Journal of Radiation Biology, 2019
Danijela Stanisavljevic, Jelena Popovic, Isidora Petrovic, Slobodan Davidovic, Michael J. Atkinson, Nataša Anastasov, Milena Stevanovic
For quantitative PCR analysis, cDNAs were subjected to real time PCR using Power SYBR Green PCR Master Mix (Applied Biosystems®) in 7500 Real Time PCR Systems (Applied Biosystems®) as previously described (Popovic et al. 2014). BAX was amplified using primers 5′-TGGCAGCTGACATGTTTTCTGAC-3′ (forward) and 5′-TCACCCAACCACCCTGGTCTT-3′ (reverse), while for Bcl2 amplification we used 5′-TCGCCCTGTGGATGACTGA-3′ (forward) and 5′- CAGAGACAGCCAGGAGAAATC-3′ (reverse) primers. SOX3 was amplified using following primer sets 5′ - GACCTGTTCGAGAGAACTCATCA-3′ (forward), 5′-CGGGAAGGGTAGGCTTATCAA-3′ (reverse). PAX6 was amplified using following primer sets 5′-CATATTCGAGCCCCGTGGAA-3′ (forward) and 5′-CCGTTGGACACCTGCAGAAT-3′ (reverse). SOX2 was amplified using following primer sets 5′-CCCCTGGCATGGCTCTTGGC-3′ (forward) and 5′-TCGGCGCCGGGGAGATACAT-3′ (reverse). OCT4 was amplified using following primer sets 5′-TCTCCAGGTTGCCTCTCACT-3′ (forward) and 5′-GCTTTGAGGCTCTGCAGCTT-3′ (reverse). GAPDH was amplified with 5′-GGACCTGACCTGCCGTCTAG-3′ (forward) and 5′-CCACCACCCTGTTGCTGTAG-3′ (reverse) to control for equivalent amounts of cDNA per reaction. All samples were measured in triplicate and the mean value was considered. The relative level of BAX, Bcl2, SOX3, PAX6, SOX2 and OCT4 expression was determined using a comparative quantification algorithm where the resulting ΔΔCt value was incorporated to determine the fold difference in expression (2−ΔΔCt). Relative BAX, Bcl-2, SOX3, PAX6, SOX2 and OCT4 mRNA levels were presented as a percentage of mRNA expression in differentiated NT2/D1 cells sham irradiated.
Targeting SOX2 in anticancer therapy
Published in Expert Opinion on Therapeutic Targets, 2018
Laura Hüser, Daniel Novak, Viktor Umansky, Peter Altevogt, Jochen Utikal
SOX2, together with SOX1 and SOX3, belongs to the SOXB1 group within the SOX family [5]. The SOX2 gene is located on chromosome 3q26.3-q27 and encodes for a protein consisting of 317 amino acids [6]. SOX2 is composed of 3 major domains: an N-terminal domain, an HMG domain which is highly preserved between different species, and a C-terminal transactivation domain, which interacts with the promoter of target genes and thereby activates or represses transcription [3].