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Prader–Willi syndrome (PWS) is a multisystemic complex genetic disorder related to the lack of a functional paternal copy of chromosome 15q11-q13. Several clinical manifestations are reported, such as short stature, cognitive and behavioral disability, temperature instability, hypotonia, hypersomnia, hyperphagia, and multiple endocrine abnormalitie...
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Prader–Willi Syndrome (PWS, OMIM #176270) is a rare complex genetic disorder due to the loss of expression of paternally derived genes in the PWS critical region on chromosome 15q11-q13. It affects multiple neuroendocrine systems and may present failure to thrive in infancy, but then, hyperphagia and morbid obesity starting in early childhood becam...
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... There are several genes involved in PWS, located at chromosomal position 15q11.2. These genes include MKRN3 (makorin ring finger protein 3), MAGEL2 (MAGE family member L2), NDN (necdin), NPAP1 (nuclear pore associated protein 1), SNURF-SNRPN (SNRPN upstream reading frame-small nuclear ribosomal protein 1), and SNORD 116 (small nucleolar RNA, C/D box 116 cluster) [49][50][51]. The latter gene plays a crucial role in the regulation of food intake, and its microdeletion is associated with the development of the PWS phenotype [52]. ...
Obesity is a multifactorial chronic disease with a high, increasing worldwide prevalence. Genetic causes account for 7% of the cases in children with extreme obesity.
This narrative review was conducted by searching for papers published in the PubMed/MEDLINE, Embase and SciELO databases and included 161 articles. The search used the following search terms: “obesity”, “obesity and genetics”, “leptin”, “Prader-Willi syndrome”, and “melanocortins”. The types of studies included were systematic reviews, clinical trials, prospective cohort studies, cross-sectional and prospective studies, narrative reviews, and case reports.
The leptin-melanocortin pathway is primarily responsible for the regulation of appetite and body weight. However, several important aspects of the pathophysiology of obesity remain unknown. Genetic causes of obesity can be grouped into syndromic, monogenic, and polygenic causes and should be assessed in children with extreme obesity before the age of 5 years, hyperphagia, or a family history of extreme obesity. A microarray study, an analysis of the melanocortin type 4 receptor gene mutations and leptin levels should be performed for this purpose. There are three therapeutic levels: lifestyle modifications, pharmacological treatment, and bariatric surgery.
Genetic study technologies are in constant development; however, we are still far from having a personalized approach to genetic causes of obesity. A significant proportion of the affected individuals are associated with genetic causes; however, there are still barriers to its approach, as it continues to be underdiagnosed.
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... NDN is highly expressed in certain regions of the brain, such as the locus coeruleus and hypothalamus and placenta ( Figure 2) [17,[46][47][48]. In particular, NDN is highly expressed in GnRH neurons in the mature hypothalamus [49]. Necdin plays an integral role in neuronal differentiation [47], so Necdin deficiency leads to widespread nervous system abnormalities [50]. ...
... Furthermore, the profound hyperphagia and morbid obesity that are hallmark features of PWS are not usually associated with SYS [122]; however, weight gain and food-seeking behavior are present in adult SYS patients [5]. Hypogonadism may be less frequent in SYS, as it is only reported in 15-25% of females and 55-65% of males with SYS compared to 70-100% of PWS patients [49,122]. Other PWS features that are not commonly observed in SYS patients include hypopigmentation, PWS characteristic facial features, small hands and feet, thick saliva, and behavioral problems [21]. ...
... The molecular functions of several PWS genes impinge on the regulation of GnRH and the GnRH-gonadotropin-sex hormones endocrine axis (Table 1). NDN is highly expressed in GnRH neurons [49], and its deletion in mice significantly reduces the quantity of hypothalamic GnRH neurons and recapitulates PWS-associated hypogonadism [24,48,[50][51][52]. Necdin is also proposed to activate GnRH transcription by preventing MSX-mediated repression of GnRH [48]. ...
The hypothalamus regulates fundamental aspects of physiological homeostasis and behavior, including stress response, reproduction, growth, sleep, and feeding, several of which are affected in patients with Prader–Willi (PWS) and Schaaf–Yang syndrome (SYS). PWS is caused by paternal deletion, maternal uniparental disomy, or imprinting defects that lead to loss of expression of a maternally imprinted region of chromosome 15 encompassing non-coding RNAs and five protein-coding genes; SYS patients have a mutation in one of them, MAGEL2. Throughout life, PWS and SYS patients suffer from musculoskeletal deficiencies, intellectual disabilities, and hormonal abnormalities, which lead to compulsive behaviors like hyperphagia and temper outbursts. Management of PWS and SYS is mostly symptomatic and cures for these debilitating disorders do not exist, highlighting a clear, unmet medical need. Research over several decades into the molecular and cellular roles of PWS genes has uncovered that several impinge on the neuroendocrine system. In this review, we will discuss the expression and molecular functions of PWS genes, connecting them with hormonal imbalances in patients and animal models. Besides the observed hormonal imbalances, we will describe the recent findings about how the loss of individual genes, particularly MAGEL2, affects the molecular mechanisms of hormone secretion. These results suggest that MAGEL2 evolved as a mammalian-specific regulator of hypothalamic neuroendocrine function.
... Patients with this condition experience constant hunger, developing obesity and eventually type 2 diabetes. People suffering from the disease manifest certain intellectual disability and mental health disorders; infertility is also common, due to hypogonadism (Napolitano et al., 2021), while other characteristics include short stature and small hands and feet (Butler and Palmer, 1983;Butler, 1990). Prader-Willi syndrome is associated, in 75% of the cases, to a deletion in the paternal chromosome 15 (or an abnormality in the imprinting process in the 15q11.2-q13 ...
Obesity can be considered a multifactorial disease, with a variety of
origins and a multitude of genes involved, affecting 300-400 million
people worldwide. In extreme cases, obesity is a life-threatening condition,
requiring drastic treatments, such as bariatric surgery. This disease can be
triggered by genetic syndromes, but is often the result of enteric dysbiosis,
caused by either an inadequate diet or simply gluttony. This review
focuses on particular biochemical and genetic markers that, together with
enteric microorganisms, are believed to generate the current global obesity
epidemic.
... Besides hyperphagia, other abnormalities are observed in patients with PWS due to hypothalamic dysfunction-such as short stature, hypersomnia, temperature instability, endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, and hypogonadism. Developmental delay and behavioral problems also occur in Prader-Willi syndrome [4,5]. ...
Oxidative stress is implicated in the pathophysiology of Prader–Willi syndrome (PWS), but there are no data on these disorders in non-obese children with PWS. Therefore, the presented study examined total oxidant capacity (TOC), total antioxidant capacity (TAC), the oxidative stress index (OSI), and adipokine levels in 22 non-obese children with PWS during dietary intervention and growth hormone treatment compared with 25 non-obese healthy children. Serum concentrations of TOC, TAC, nesfatin-1, leptin, hepcidin, ferroportin, and ferritin were determined using immunoenzymatic methods. We found that TOC concentrations were higher by 50% (p = 0.006) in patients with PWS than in healthy children, but no significant differences in TAC concentrations were observed between these groups. The OSI was higher in children with PWS than in the controls (p = 0.002). We found positive associations between TOC values and the percentage of the Estimated Energy Requirement, body mass index (BMI) Z-score, percentage of fat mass, and leptin, nesfatin-1, and hepcidin concentrations in patients with PWS. A positive association was also found between the OSI and nesfatin-1 levels. These observations suggest that higher daily energy intake and weight gain may be accompanied by an increasing prooxidant state in these patients. Adipokines such as leptin, nesfatin-1, or hepcidin may also play a role in the prooxidant state in non-obese children with PWS.
... The exact causes of testicular cancer are not well understood, but several risk factors have been identified, including age, cryptorchidism, abnormal testicle development, personal and familiar history of testicular cancer, ethnicity, and a weakened immune system [6]. Additionally, certain medical conditions, such as Klinefelter syndrome and Down syndrome, may also increase the risk of developing testicular cancer [7][8][9]. Considering the rarity of the condition, the relative ease of diagnosis due to the accessibility of the testis to imaging and clinical exploration, and the potential impairment to fertility related to the treatment, the role and the identification of risk factors in the development of testicular cancer still represent a topic of high clinical interest. The aim of this research paper is, ...
The incidence of testicular cancer is steadily increasing over the past several decades in different developed countries. If on one side better diagnosis and treatment have shone a light on this disease, on the other side, differently from other malignant diseases, few risk factors have been identified. The reasons for the increase in testicular cancer are however unknown while risk factors are still poorly understood. Several studies have suggested that exposure to various factors in adolescence as well as in adulthood could be linked to the development of testicular cancer. Nevertheless, the role of environment, infections, and occupational exposure are undoubtedly associated with an increase or a decrease in this risk. The aim of this narrative review is to summarize the most recent evidence regarding the risk factors associated with testicular cancer, starting from the most commonly evaluated (cryptorchidism, family history, infections) to the newer identified and hypothesized risk factors.
... The positive effects of sex steroids are widely described in the literature, for example, increasing bone mineral density and muscle mass and favoring an adequate development of secondary sexual characteristics [26,31,40]. No data on weight evolution during HRT have been reported. ...
Severe obesity remains one of the most important symptoms of Prader–Willi Syndrome (PWS), and controlling weight represents a crucial point in the therapeutical approach to the syndrome. We present an overview of different progressive patterns of growth that involve controlling weight in PWS. Mechanisms involved in the development of obesity and in preventive and therapeutic strategies to control weight gain are discussed. Early diagnosis, a controlled diet regimen, regular physical activity, follow-up by multidisciplinary teams, and hormonal treatment improved the management of excessive weight gain. In selected cases, a surgical approach can be also considered. Controlling weight in PWS remains a challenge for pediatricians. The importance of consulting different healthcare specialists, starting from the neonatal and pediatric age, is also considered as a crucial approach to controlling weight, as well as to limiting and preventing the onset of obesity and its complications.
... This rare obesity-related genetic disorder has severe infantile hypotonia accompanied by poor suck with swallowing problems, sticky saliva and failure to thrive along with hypogonadism, hypogenitalism and development delay; many of these features compose the consensus diagnostic criteria triggering genetic testing for PWS [1,[6][7][8]. Unique facial features are noted in PWS including bifrontal narrowing, almond-shaped eyes and a small chin with a high palate; additionally, small hands and feet with short stature due to growth and other hormone deficiencies involving the endocrine system and sex organs, pancreas, adrenal and thyroid glands occur [1,4,[6][7][8][9][10][11][12][13][14][15][16][17]. Obesity, growth anomalies and hypogonadism are due to central and peripheral mechanisms involving the hypothalamus-pituitary-gonadal axis. ...
... There are 165 recognized human and 197 mouse genes currently known to be imprinted or active depending on the parent of origin. Several genes in the 15q11-q13 region have been implicated in neurodevelopment and function with a role in behavior and learning, ataxia, hyperphagia and obesity, magnesium transportation, hypogonadism and precocious puberty, circadian rhythm, autism and skin pigment production with albinism [1,2,7,17,[24][25][26][27][28]. ...
... The MKRN3 gene plays a role in puberty and is expressed in the hypothalamus. It blocks transcription of KISS (KiSS-1 metastasis suppressor) and TAC3 (tachykinin precursor 3), which are important for release of GnRH (gonadotrophin-releasing hormone) which initiates puberty [7,17]. SNURF-SNRPN (SNRPN upstream reading frame (SNURF)small nuclear ribonucleoprotein polypeptide N (SNRPN)), a complex gene locus belonging to the SNRPN SmB/SmN family. ...
Prader–Willi syndrome (PWS) is a complex genetic disorder with three PWS molecular genetic classes and presents as severe hypotonia, failure to thrive, hypogonadism/hypogenitalism and developmental delay during infancy. Hyperphagia, obesity, learning and behavioral problems, short stature with growth and other hormone deficiencies are identified during childhood. Those with the larger 15q11-q13 Type I deletion with the absence of four non-imprinted genes (NIPA1, NIPA2, CYFIP1, TUBGCP5) from the 15q11.2 BP1-BP2 region are more severely affected compared with those with PWS having a smaller Type II deletion. NIPA1 and NIPA2 genes encode magnesium and cation transporters, supporting brain and muscle development and function, glucose and insulin metabolism and neurobehavioral outcomes. Lower magnesium levels are reported in those with Type I deletions. The CYFIP1 gene encodes a protein associated with fragile X syndrome. The TUBGCP5 gene is associated with attention-deficit hyperactivity disorder (ADHD) and compulsions, more commonly seen in PWS with the Type I deletion. When the 15q11.2 BP1-BP2 region alone is deleted, neurodevelopment, motor, learning and behavioral problems including seizures, ADHD, obsessive-compulsive disorder (OCD) and autism may occur with other clinical findings recognized as Burnside–Butler syndrome. The genes in the 15q11.2 BP1-BP2 region may contribute to more clinical involvement and comorbidities in those with PWS and Type I deletions.
... От момента рождения до 9-месячного возраста (фаза 1а) наиболее тяжелыми симптомами являются мышечная гипотония и нарушение нейрорефлекторной деятельности, ввиду угнетения сосательного рефлекса возникают проблемы с кормлением и недостаточная прибавка массы тела [12,13]. Часто встречаются следующие стигмы дизэмбриогенеза: высокий и узкий лоб, долихоцефалия, миндалевидный разрез глаз с тонкими опущенными веками, опущенные углы рта, микродонтия, узкая верхняя губа, гипопигментация кожных покровов и радужной оболочки глаз, акромикрия, гипогонадизм и гипоплазия гениталий [4,6,14,15]. Гипотония при СПВ имеет центральное происхождение. ...
... Среди фенотипических особенностей самыми распространенными были высокий узкий лоб, миндалевидный разрез глаз с тонкими, опущенными веками, долихоцефалия, узкая височная часть черепа, тонкая верхняя губа, опущенные углы рта, наблю-давшиеся у всех пациентов (5/5), а также гипертелоризм глаз (3/5), акромикрия (4/5), гипогонадизм (4/5), микрогнатия (2/5), гипопигментация радужки, кожи и волос (1/5). Все перечисленные сведения подтверждаются литературными данными [4,6,14,15]. Ввиду угнетения сосательного рефлекса у 4 пациентов их кормление осуществлялось адаптированной молочной смесью для доношенных (у 1 ребенкадля недоношенных) с использованием назогастрального зонда, до 5-6 нед. ...
Objective. To demonstrate the clinical features of Prader–Willi syndrome (PWS) in the neonatal period, to assess the impact of perinatal factors on the development and severity of PWS, and to compare the data obtained with literary sources. Patients and methods. This cross-sectional open-label retrospective study was conducted between 2022 and 2023. It included 5 neonates with severe hypotonia and subsequently confirmed PWS. Anamnestic, anthropometric, age- and sex-related characteristics of children with PWS and anamnestic data of their mothers, as well as clinical manifestations of PWS were investigated. Results. Most of the children with PWS were born prematurely, with a mean birth weight of 2512.0 ± 549.5 g, height of 48.2 ± 5.1 cm, and head circumference of 32.9 ± 2.5 cm, which is below the standard values for preterm infants. The mean Apgar score was 5.8 ± 2.8/7.2 ± 1.9. Three out of five children were not appropriate for gestational age, having low values according to the INTERGROWTH-21st standards. Children were born to mothers aged 35 ± 5 years, and 3 (60%) out of 5 women had an aggravated somatic and/or obstetric and gynecological history. Evaluation of clinical manifestations of PWS revealed post-hypoxic injury of the central nervous system (CNS) (100%), respiratory disorders (100%), infectious toxicosis and intrauterine pneumonia (80%). Objective examination revealed hypotonia, hyporeflexia, reduced motor function in all patients, and 80% of children had poor sucking reflex. The most common phenotypic features were high forehead, almondshaped eyes, dolichocephaly, narrow temporal bones, thin upper lip, down-turned corners of the mouth; orbital hypertelorism, acromicria, and hypogonadism were observed less frequently. Conclusion. Early diagnosis of PWS is possible with a comprehensive differential diagnosis in children with the “floppy baby syndrome”. Special attention should be paid to children with intrauterine growth restriction, typical stigmas of dysembryogenesis, respiratory disorders, and hypoxic CNS injury. Genetic counseling and karyotyping should be performed as early as possible in all newborns with suspected PWS to prevent the development of complications. Key words: Prader–Willi syndrome, floppy baby syndrome, stigmas of dysembryogenesis, hypotonia, hyporeflexia, poor sucking reflex, feeding disorders, developmental delay, hypogonadism
... HERC2 encodes the E3 ubiquitin ligase HERC2. This gene is located on the 15 th chromosome and is associated with PWS, Angelman Syndrome, and Oculocutaneous Albinism, three syndromes which have been noted to be comorbid with pubertal disorders (41). In addition to ubiquitination, HERC2 contains an intronic regulatory element known to inhibit the promoter of OCA2. ...
Gonadotrophin dependent sexual precocity, commonly referred to as central precocious puberty (CPP), results from a premature reactivation of the hypothalamic-pituitary-gonadal (HPG) axis before the normal age of pubertal onset. CPP is historically described as girls who enter puberty before the age of eight, and boys before the age of nine. Females are more likely to be diagnosed with idiopathic CPP; males diagnosed with CPP have a greater likelihood of a defined etiology. These etiologies may include underlying CNS congenital defects, tumors, trauma, or infections as well as environmental, genetic, and epigenetic factors. Recently, genetic variants and mutations which may cause CPP have been identified at both the level of the hypothalamus and the pituitary. Single nucleotide polymorphisms (SNPs), monogenetic mutations, and modifications of the epigenome have been evaluated in relationship to the onset of puberty; these variants are thought to affect the development, structure and function of GnRH neurons which may lead to either precocious, delayed, or absent pubertal reactivation. This review will describe recent advances in the field of the genetic basis of puberty and provide a clinically relevant approach to better understand these varying etiologies of CPP.
... (Table 1). A significant proportion of patients with SYS experience hypogonadism, although it is not as common as that in PWS 2,12,13) . ...
Schaaf-Yang syndrome (SYS) is a rare genomic imprinting disorder caused by truncating mutations in the paternally derived MAGE family member L2 ( MAGEL2 ) allele. It is also responsible for Prader-Willi syndrome, characterized by neonatal hypotonia, developmental delay, intellectual disability, respiratory distress in early infancy, and arthrogryposis. More than 250 individuals with approximately 57 different molecular variants have been reported since 2013, but the phenotype-genotype association in SYS is not yet fully understood. Here, we describe the case of a Korean patient diagnosed with SYS harboring a mutation in the paternal allele of MAGEL2 : c.2895G>A, resulting in a protein change of p.Trp965*. The patient’s phenotype included respiratory distress, arthrogryposis, hypotonia, and feeding difficulty in the early neonatal period. Mild renal dysfunction and hearing impairment were observed during infancy.
