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1.
Exp Suppl ; 111: 419-441, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588542

RESUMO

Obesity is caused by an imbalance between energy intake and output, influenced by numerous environmental, biological, and genetic factors. Only a minority of people with obesity have a genetic defect that is the main cause of their obesity. A key symptom for most of these disorders is early-onset obesity and hyperphagia. For some genetic obesity disorders, the hyperphagia is the main characteristic, often caused by disruptions of the leptin-melanocortin pathway, the central pathway that regulates the body's satiety and energy balance. For other disorders, obesity is part of a distinct combination of other clinical features such as intellectual disability, dysmorphic facial features, or organ abnormalities. This chapter focuses on genetic obesity disorders and also summarizes the present knowledge on the genetics of the more common polygenic/multifactorial obesity.


Assuntos
Hiperfagia/genética , Obesidade/genética , Ingestão de Energia , Metabolismo Energético , Humanos , Leptina , Melanocortinas , Saciação
2.
Reprod Toxicol ; 87: 125-139, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31181251

RESUMO

Methotrexate is a folic acid antagonist known to be teratogenic in humans. Several cases of congenital malformations after fetal exposure to methotrexate have been published, resulting in the establishment of the 'fetal methotrexate syndrome'. However, it is unclear which congenital anomalies can truly be attributed to methotrexate exposure. The objective of this review is to delineate a consistent phenotype of the fetal methotrexate syndrome. We performed a systematic review that yielded 29 cases of (congenital) anomalies after in utero exposure to methotrexate and compared their malformation pattern to that of children and fetuses with congenital anomalies in general. Statistically significant higher proportions of microcephaly, craniosynostosis, tetralogy of Fallot, pulmonary valve atresia, limb reduction defects and syndactyly were found in the methotrexate group, indicating that these congenital anomalies are truly part of the fetal methotrexate syndrome. These results aid clinicians with diagnosing fetal methotrexate syndrome.

3.
Obes Facts ; 12(4): 369-384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31216558

RESUMO

BACKGROUND: Obesity has been associated with miscellaneous weight-inducing determinants. A comprehensive assessment of known obesity-related factors other than diet and physical activity within one cohort is currently lacking. OBJECTIVES: To assess the prevalence of potential contributors to obesity and self-reported triggers for marked weight gain in an adult population with obesity and between obesity classes. METHODS: In this observational cohort study, we assessed 408 persons with obesity (aged 41.3 ± 14.2 years, BMI 40.5 ± 6.2) visiting our obesity clinic. They were evaluated for use of weight-inducing drugs, hormonal abnormalities, menarcheal age, (high) birth weight, sleep deprivation, and obstructive sleep apnea syndrome (OSAS). We additionally assessed self-reported triggers for marked weight gain and performed genetic testing in patients suspected of genetic obesity. RESULTS: Nearly half of the patients were using a potentially weight-inducing drug, which was also the most reported trigger for marked weight gain. For the assessed hormonal conditions, a relatively high prevalence was found for hypothyroidism (14.1%), polycystic ovary syndrome (12.0%), and male hypogonadism (41.7%). A relatively low average menarcheal age (12.6 ± 1.8 years) was reported, whereas there was a high prevalence of a high birth weight (19.5%). Sleep deprivation and OSAS were reported in, respectively, 14.5 and 13.7% of the examined patients. Obesity class appeared to have no influence on the majority of the assessed factors. Of the genetically analyzed patients, a definitive genetic diagnosis was made in 3 patients (1.9%). CONCLUSIONS: A thorough evaluation of patients with obesity yields a relatively high prevalence of various potentially weight-inducing factors. Diagnostic screening of patients with obesity could therefore benefit these patients by potentially reducing the social stigma and improving the outcomes of obesity treatment programs by tackling, where possible, the weight-inducing factors in advance.

4.
Mol Genet Genomic Med ; 7(6): e00632, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31055886

RESUMO

BACKGROUND: Pathogenic PTEN gene mutations are known to cause PTEN tumor hamartoma syndrome. Recent studies also suggest a role for PTEN mutations in the pathogenesis of obesity. No PTEN mutations have been reported among bariatric surgery patients and obesity treatment results are unknown. Since preventive screening for associated tumors is offered to patients with molecular proven PTEN hamartoma tumor syndrome, recognition of this condition in the bariatric surgery clinic is important. METHOD: We present a patient with morbid obesity who carries a known pathogenic PTEN mutation, identified at the bariatric surgery clinic using an obesity gene panel consisting of 52 obesity-associated genes. We analyzed the weight loss response during the first 3 years after Sleeve Gastrectomy. RESULTS: At 1, 2 and 3 years after surgery, the patient achieved a Total Body Weight Loss of 39.4%, 48.8% and 44.9%, respectively. This corresponds to the results of a control group of 18 female patients with normal genetic test results. CONCLUSION: Our patient illustrates the importance of recognizing this serious genetic condition for which preventive cancer screening options are available. The positive weight loss results after Sleeve Gastrectomy suggest that this could be a successful treatment option for obesity patients with PTEN mutations.

5.
Ned Tijdschr Geneeskd ; 1632019 Mar 21.
Artigo em Holandês | MEDLINE | ID: mdl-30945833

RESUMO

16p11.2 deletion syndrome is one of the most prevalent microdeletion syndromes in the world. Nevertheless, many doctors are not (yet) familiar with this syndrome. Prevalence has been estimated at approximately 3 in 10,000. The deletion can be identified in around 1 out of 100 people with autism. The syndrome is characterized by a wide range of phenotypic features including developmental delay, autism, obesity, increased head circumference, and epilepsy. Here we describe an 8-year-old female patient with developmental delay, autistic features and hyperphagia. After diagnosis of 16p11.2 deletion syndrome, her parents struggled due to limited information and support provision by healthcare staff. Since then, multidisciplinary healthcare has been introduced for this condition. In parallel, the patient's parents started an online support group for Dutch patients and parents. Given the diverse phenotype of 16p11.2 deletion syndrome, multidisciplinary collaboration is important. Establishing the diagnosis contributes to better treatment and understanding for parents and healthcare providers.

6.
Obes Rev ; 20(6): 795-804, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30821060

RESUMO

Obesity is a worldwide growing problem. When confronted with obesity, many health care providers focus on direct treatment of the consequences of adiposity. We plead for adequate diagnostics first, followed by an individualized treatment. We provide experience-based and evidence-based practical recommendations (illustrated by clinical examples), to detect potential underlying diseases and contributing factors. Adult patients consulting a doctor for weight gain or obesity should first be clinically assessed for underlying diseases, such as monogenetic or syndromic obesity, hypothyroidism, (cyclic) Cushing syndrome, polycystic ovarian syndrome (PCOS), hypogonadism, growth hormone deficiency, and hypothalamic obesity. The most important alarm symptoms for genetic obesity are early onset obesity, dysmorphic features/congenital malformations with or without intellectual deficit, behavioral problems, hyperphagia, and/or striking family history. Importantly, also common contributing factors to weight gain should be investigated, including medication (mainly psychiatric drugs, (local) corticosteroids, insulin, and specific ß-adrenergic receptor blockers), sleeping habits and quality, crash diets and yoyo-effect, smoking cessation, and alcoholism. Other associated conditions include mental factors such as chronic stress or binge-eating disorder and depression.Identifying and optimizing the underlying diseases, contributing factors, and other associated conditions may not only result in more effective and personalized treatment but could also reduce the social stigma for patients with obesity.

7.
Eur J Hum Genet ; 27(5): 738-746, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30679813

RESUMO

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

8.
Metabolism ; 92: 26-36, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30639246

RESUMO

Body fat mass increases when energy intake exceeds energy expenditure. In the long term, a positive energy balance will result in obesity. The worldwide prevalence of obesity has increased dramatically, posing a serious threat to human health. Therefore, insight in the pathogenesis of obesity is important to identify novel prevention and treatment strategies. This review describes the physiology of energy expenditure and energy intake in the context of body weight gain in humans. We focus on the components of energy expenditure and the regulation of energy intake. Finally, we describe rare monogenetic causes leading to an impairment in central regulation of food intake and obesity.

9.
Dis Model Mech ; 11(10)2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30355756

RESUMO

The zebrafish (Danio rerio) has become a popular vertebrate model organism to study organ formation and function due to its optical clarity and rapid embryonic development. The use of genetically modified zebrafish has also allowed identification of new putative therapeutic drugs. So far, most studies have relied on broad overexpression of transgenes harboring patient-derived mutations or loss-of-function mutants, which incompletely model the human disease allele in terms of expression levels or cell-type specificity of the endogenous gene of interest. Most human genetically inherited conditions are caused by alleles carrying single nucleotide changes resulting in altered gene function. Introduction of such point mutations in the zebrafish genome would be a prerequisite to recapitulate human disease but remains challenging to this day. We present an effective approach to introduce small nucleotide changes in the zebrafish genome. We generated four different knock-in lines carrying distinct human cardiovascular-disorder-causing missense mutations in their zebrafish orthologous genes by combining CRISPR/Cas9 with a short template oligonucleotide. Three of these lines carry gain-of-function mutations in genes encoding the pore-forming (Kir6.1, KCNJ8) and regulatory (SUR2, ABCC9) subunits of an ATP-sensitive potassium channel (KATP) linked to Cantú syndrome (CS). Our heterozygous zebrafish knock-in lines display significantly enlarged ventricles with enhanced cardiac output and contractile function, and distinct cerebral vasodilation, demonstrating the causality of the introduced mutations for CS. These results demonstrate that introducing patient alleles in their zebrafish orthologs promises a broad application for modeling human genetic diseases, paving the way for new therapeutic strategies using this model organism.

10.
Am J Med Genet A ; 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30238631

RESUMO

Schaaf-Yang syndrome (SYS) was recently identified as a genetic condition resembling Prader-Willi syndrome. It is caused by mutations on the paternal allele of the MAGEL2 gene, a gene that has been mapped in the Prader-Willi critical region. Here, we present an infant with SYS who sadly died because of the combination of hypotonia, sleep apnea, and obesity. A heterozygous premature stop mutation in MAGEL2 was identified in the patient. The main factors reported in the mortality of SYS are lethal arthrogryposis multiplex congenita, fetal akinesia, and pulmonary problems. Our clinical report indicates that obesity and its complications are an important additional factor in the mortality associated with SYS. Therefore, we advise to strictly monitor weight and intensively treat overweight and obesity in SYS.

11.
Hypertens Res ; 41(11): 981-988, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30209282

RESUMO

Autosomal-dominant hypertension and brachydactyly syndrome (HTNB; Bilginturan syndrome) is known to cause stroke before age 50 when untreated. We report a novel PDE3A gene mutation in a mother and daughter affected with dominant brachydactyly of the hands and feet, a short stature, and hypertension. The hypertension was medically responsive to anti-hypertensive treatment. The 3-bp deletion in the PDE3A gene presented de novo in the mother. Here, we expand the list of PDE3A mutations identified in Bilginturan syndrome and emphasize the importance of standardized genetic testing of HTNB patients to improve diagnostics at an early age. We recommend extended phenotyping in patients with brachydactyly, a short stature or hypertension in clinical practice.

12.
Pediatr Nephrol ; 33(10): 1701-1712, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29974258

RESUMO

BACKGROUND: Nephronophthisis is an autosomal recessive ciliopathy and important cause of end-stage renal disease (ESRD) in children and young adults. Diagnostic delay is frequent. This study investigates clinical characteristics, initial symptoms, and genetic defects in a cohort with nephronophthisis-related ciliopathy, to improve early detection and genetic counseling. METHODS: Forty patients from 36 families with nephronophthisis-related ciliopathy were recruited at university medical centers and online. Comprehensive clinical and genotypic data were recorded. Patients without molecular diagnosis were offered genetic analysis. RESULTS: Of 40 patients, 45% had isolated nephronophthisis, 48% syndromic diagnosis, and 7% nephronophthisis with extrarenal features not constituting a recognizable syndrome. Patients developed ESRD at median 13 years (range 5-47). Median age of symptom onset was 9 years in both isolated and syndromic forms (range 5-26 vs. 5-33). Common presenting symptoms were fatigue (42%), polydipsia/polyuria (33%), and hypertension (21%). Renal ultrasound showed small-to-normal-sized kidneys, increased echogenicity (65%), cysts (43%), and abnormal corticomedullary differentiation (32%). Renal biopsies in eight patients showed nonspecific signs of chronic kidney disease (CKD). Twenty-three patients (58%) had genetic diagnosis upon inclusion. Thirteen of those without a genetic diagnosis gave consent for genetic testing, and a cause was identified in five (38%). CONCLUSIONS: Nephronophthisis is genetically and phenotypically heterogeneous and should be considered in children and young adults presenting with persistent fatigue and polyuria, and in all patients with unexplained CKD. As symptom onset can occur into adulthood, presymptomatic monitoring of kidney function in syndromic ciliopathy patients should continue until at least age 30.

13.
J Med Genet ; 55(9): 578-586, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29970488

RESUMO

BACKGROUND: Obesity is a global and severe health problem. Due to genetic heterogeneity, the identification of genetic defects in patients with obesity can be time consuming and costly. Therefore, we developed a custom diagnostic targeted next-generation sequencing (NGS)-based analysis to simultaneously identify mutations in 52 obesity-related genes. The aim of this study was to assess the diagnostic yield of this approach in patients with suspected genetic obesity. METHODS: DNA of 1230 patients with obesity (median BMI adults 43.6 kg/m2; median body mass index-SD children +3.4 SD) was analysed in the genome diagnostics section of the Department of Genetics of the UMC Utrecht (The Netherlands) by targeted analysis of 52 obesity-related genes. RESULTS: In 48 patients pathogenic mutations confirming the clinical diagnosis were detected. The majority of these were observed in the MC4R gene (18/48). In an additional 67 patients a probable pathogenic mutation was identified, necessitating further analysis to confirm the clinical relevance. CONCLUSIONS: NGS-based gene panel analysis in patients with obesity led to a definitive diagnosis of a genetic obesity disorder in 3.9% of obese probands, and a possible diagnosis in an additional 5.4% of obese probands. The highest yield was achieved in a selected paediatric subgroup, establishing a definitive diagnosis in 12 out of 164 children with severe early onset obesity (7.3%). These findings give a realistic insight in the diagnostic yield of genetic testing for patients with obesity and could help these patients to receive (future) personalised treatment.

15.
BMJ Case Rep ; 20172017 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-28951511

RESUMO

This case report of an infant with severe early-onset obesity illustrates the societal condemnation of persons with obesity. In addition, it underlines the importance of diagnosing rare forms of monogenic obesity, even if no drug treatment is available. Here, we describe a 2-year-old girl with severe progressive obesity from birth onwards due to insatiable hunger. Genetic studies eventually reveal that the girl has a monogenic form of obesity caused by two mutations in the LEPR gene. No drug treatment is available (as yet) for this disease. Parents describe the stigmatic remarks they have to deal with every day. Diagnosing this rare genetic disorder was very important for understanding that satiety regulation is a complex system, of which willpower is only a small portion. In these patients, reduction of obesity can be achieved, but a different approach to lifestyle intervention is needed.


Assuntos
Hiperfagia/genética , Mutação de Sentido Incorreto/genética , Obesidade Mórbida/genética , Receptores para Leptina/genética , Resposta de Saciedade , Idade de Início , Pré-Escolar , Feminino , Humanos , Hiperfagia/diagnóstico , Hiperfagia/psicologia , Obesidade Mórbida/diagnóstico , Obesidade Mórbida/psicologia , Pais/educação , Pais/psicologia , Educação de Pacientes como Assunto , Estigma Social , Apoio Social
16.
J Med Genet ; 54(7): 460-470, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28377535

RESUMO

BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.


Assuntos
Encefalopatias/genética , Mutação/genética , Receptores de N-Metil-D-Aspartato/genética , Encefalopatias/tratamento farmacológico , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Memantina/uso terapêutico , Terapia de Alvo Molecular , Neuroimagem , Fenótipo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo
17.
J Biol Chem ; 292(19): 7904-7920, 2017 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-28302725

RESUMO

Infantile-onset inflammatory bowel disease (IO IBD) is an invalidating illness with an onset before 2 years of age and has a complex pathophysiology in which genetic factors are important. Homozygosity mapping and whole-exome sequencing in an IO IBD patient and subsequent sequencing of the candidate gene in 12 additional IO IBD patients revealed two patients with two mutated ankyrin repeat and zinc-finger domain-containing 1 (ANKZF1) alleles (homozygous ANKZF1 R585Q mutation and compound heterozygous ANKZF1 E152K and V32_Q87del mutations, respectively) and two patients with one mutated ANKZF1 allele. Although the function of ANKZF1 in mammals had not been previously evaluated, we show that ANKZF1 has an indispensable role in the mitochondrial response to cellular stress. ANKZF1 is located diffusely in the cytoplasm and translocates to the mitochondria upon cellular stress. ANKZF1 depletion reduces mitochondrial integrity and mitochondrial respiration under conditions of cellular stress. The ANKZF1 mutations identified in IO IBD patients with two mutated ANKZF1 alleles result in dysfunctional ANKZF1, as shown by an increased level of apoptosis in patients' lymphocytes, a decrease in mitochondrial respiration in patient fibroblasts with a homozygous ANKZF1 R585Q mutation, and an inability of ANKZF1 R585Q and E152K to rescue the phenotype of yeast deficient in Vms1, the yeast homologue of ANKZF1. These data indicate that loss-of-function mutations in ANKZF1 result in deregulation of mitochondrial integrity, and this may play a pathogenic role in the development of IO IBD.


Assuntos
Repetição de Anquirina/genética , Proteínas de Transporte/genética , Doenças Inflamatórias Intestinais/genética , Dedos de Zinco , Idade de Início , Alelos , Apoptose , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Pré-Escolar , Exoma , Feminino , Fibroblastos/metabolismo , Genoma Humano , Células HEK293 , Homozigoto , Humanos , Lactente , Inflamação , Doenças Inflamatórias Intestinais/metabolismo , Linfócitos/citologia , Masculino , Mitocôndrias/metabolismo , Mutação , Fenótipo , RNA Interferente Pequeno/metabolismo , Análise de Sequência de DNA , Zinco/química
18.
J Clin Invest ; 127(3): 1005-1018, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28192369

RESUMO

Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1). Electrophysiological studies in murine neuronal cultures and functional analyses in Caenorhabditis elegans revealed that the UNC13A variant causes a distinct dominant gain of function that is characterized by increased fusion propensity of synaptic vesicles, which leads to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity. Our study underscores the critical importance of fine-tuned presynaptic control in normal brain function. Further, it adds the neuronal Munc13 proteins and the synaptic vesicle priming process that they control to the known etiological mechanisms of psychiatric and neurological synaptopathies.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Transtornos Motores/metabolismo , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/metabolismo , Transmissão Sináptica , Vesículas Sinápticas/metabolismo , Substituição de Aminoácidos , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Linhagem Celular , Feminino , Humanos , Lactente , Masculino , Transtornos Motores/genética , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal , Neurônios/metabolismo , Vesículas Sinápticas/genética
20.
Am J Med Genet A ; 170(9): 2431-5, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27338644

RESUMO

Pseudohypoparathyroidism (PHP) is a genetic disorder with resistance to parathyroid hormone (PTH) as most important feature. Main subtypes of the disease are pseudohypoparathyroidism 1b (PHP1b) and pseudohypoparathyroidism 1a (PHP1a). PHP1b is characterized by PTH resistance of the renal cortex due to reduced activity of the stimulatory G protein α subunit (Gsα) of the PTH receptor. In addition to resistance to PTH, PHP1a patients also lack sensitivity for other hormones that signal their actions through G protein-coupled receptors and display physical features of Albright hereditary osteodystrophy (AHO), which is not classically seen in PHP1b patients. PHP1a is caused by heterozygous loss-of-function mutations in maternally inherited GNAS exons 1-13, which encode Gsα. PHP1b is often caused by deletion of the STX16 gene, which is thought to have an important role in controlling the methylation and thus imprinting at part of the GNAS locus. Here we present a patient with PHP1b caused by the previously described recurrent 3-kb STX16 deletion. The patient's first symptoms were macrosomia, early onset obesity, and macrocephaly. Since this is an atypical but previously described rare presentation of PHP1b, we reemphasize STX16 deletions and PHP1b as a rare cause for early onset obesity and macrosomia. © 2016 Wiley Periodicals, Inc.


Assuntos
Macrossomia Fetal/genética , Deleção de Genes , Megalencefalia/genética , Obesidade/genética , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/genética , Sintaxina 16/genética , Análise Mutacional de DNA , Éxons , Facies , Feminino , Macrossomia Fetal/diagnóstico , Estudos de Associação Genética , Gráficos de Crescimento , Humanos , Recém-Nascido , Megalencefalia/diagnóstico , Obesidade/diagnóstico , Linhagem , Fenótipo
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