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Endocrine Reviews Mar 2023The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or...
The etiology of central precocious puberty (CPP) is multiple and heterogeneous, including congenital and acquired causes that can be associated with structural or functional brain alterations. All causes of CPP culminate in the premature pulsatile secretion of hypothalamic GnRH and, consequently, in the premature reactivation of hypothalamic-pituitary-gonadal axis. The activation of excitatory factors or suppression of inhibitory factors during childhood represent the 2 major mechanisms of CPP, revealing a delicate balance of these opposing neuronal pathways. Hypothalamic hamartoma (HH) is the most well-known congenital cause of CPP with central nervous system abnormalities. Several mechanisms by which hamartoma causes CPP have been proposed, including an anatomical connection to the anterior hypothalamus, autonomous neuroendocrine activity in GnRH neurons, trophic factors secreted by HH, and mechanical pressure applied to the hypothalamus. The importance of genetic and/or epigenetic factors in the underlying mechanisms of CPP has grown significantly in the last decade, as demonstrated by the evidence of genetic abnormalities in hypothalamic structural lesions (eg, hamartomas, gliomas), syndromic disorders associated with CPP (Temple, Prader-Willi, Silver-Russell, and Rett syndromes), and isolated CPP from monogenic defects (MKRN3 and DLK1 loss-of-function mutations). Genetic and epigenetic discoveries involving the etiology of CPP have had influence on the diagnosis and familial counseling providing bases for potential prevention of premature sexual development and new treatment targets in the future. Global preventive actions inducing healthy lifestyle habits and less exposure to endocrine-disrupting chemicals during the lifespan are desirable because they are potentially associated with CPP.
Topics: Humans; Puberty, Precocious; Gonadotropin-Releasing Hormone; Hypothalamic Diseases; Hypothalamus; Puberty; Ubiquitin-Protein Ligases
PubMed: 35930274
DOI: 10.1210/endrev/bnac020 -
Neurology Nov 2021Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging... (Review)
Review
Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in and other patterning genes are involved in HH pathogenesis. About 50%-80% of children with HH have severe rage and aggression and a majority of patients exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep, and endocrine disorders are typical. The purpose of this article is to provide a summary of the current understanding of HH and to highlight opportunities for future research.
Topics: Child; Comorbidity; Epilepsy; Hamartoma; Humans; Hypothalamic Diseases
PubMed: 34607926
DOI: 10.1212/WNL.0000000000012773 -
American Journal of Human Genetics Feb 2022Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent...
Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.
Topics: Adolescent; Alleles; Brain Stem; Cell Line, Tumor; Central Nervous System Cysts; Cerebellar Vermis; Child; Child, Preschool; Congenital Disorders of Glycosylation; Female; Fetus; Glycosylation; Hamartoma; Humans; Hypothalamus; Intellectual Disability; Leukocytes; Male; Mannose; Oligosaccharides; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; Polymicrogyria; Tongue; alpha-Mannosidase
PubMed: 35045343
DOI: 10.1016/j.ajhg.2021.12.010 -
Epileptic Disorders : International... Oct 2022We aimed to determine the prevalence of epilepsy and neurodevelopmental disorders, including autism spectrum disorder, in children and adolescents with hypothalamic...
OBJECTIVE
We aimed to determine the prevalence of epilepsy and neurodevelopmental disorders, including autism spectrum disorder, in children and adolescents with hypothalamic hamartoma (HH). We also sought to explore the relationship between these neurodevelopmental comorbidities and epilepsy and to establish the predictive value of structural characteristics of the hamartoma itself.
METHODS
We retrospectively studied a cohort of 62 children with HH, with neuroimaging reviewed at Great Ormond Street Hospital (GOSH) between 2008 and 2018. Clinical records were reviewed, cognitive and language data analysed, and MRI scans studied.
RESULTS
We confirmed a high burden of epilepsy (56%), autism (19%) and other neurodevelopmental disorders. Although rates of some neurodevelopmental disorders were significantly higher in those with epilepsy, autistic features and/or early developmental concerns often predated the onset of seizures, in particular generalized seizures, or occurred independently of seizures. We found a significant correlation between certain structural characteristics of the hamartoma itself and both epilepsy and certain neurodevelopmental comorbidities.
SIGNIFICANCE
These findings suggest that although seizure burden clearly contributes to the cognitive and behavioural phenotypes seen, the hamartoma itself, and particular characteristics of it, are likely to be primary determinants of both the epilepsy and neurodevelopmental profiles. It is also probable that the underlying aetiology, likely genetic, directly contributes to the clinical profile, with epilepsy, neurodevelopmental impairment and the hamartoma itself representing markers of this aetiology. We propose that atypical neurodevelopmental profiles in HH could best be conceptualized as a developmental and epileptic encephalopathy. These findings have implications for counselling, monitoring and treatment.
Topics: Autism Spectrum Disorder; Epilepsy; Hamartoma; Humans; Hypothalamic Diseases; Magnetic Resonance Imaging; Retrospective Studies; Seizures
PubMed: 35860877
DOI: 10.1684/epd.2022.1458 -
Journal of Neurosciences in Rural... Oct 2020
PubMed: 33144817
DOI: 10.1055/s-0040-1715080 -
Neurologia Medico-chirurgica May 2005The incidence of hypothalamic hamartomas (HHs) has increased since the introduction of magnetic resonance (MR) imaging. The etiology of this anomaly and the pathogenesis... (Review)
Review
The incidence of hypothalamic hamartomas (HHs) has increased since the introduction of magnetic resonance (MR) imaging. The etiology of this anomaly and the pathogenesis of its peculiar symptoms remain unclear, but recent electrophysiological, neuroimaging, and clinical studies have yielded important data. Categorizing HHs by the degree of hypothalamic involvement has contributed to the accurate prediction of their prognosis and to improved treatment strategies. Rather than undergoing corticectomy, HH patients with medically intractable seizures are now treated with surgery that targets the HH per se, e.g. HH removal, disconnection from the hypothalamus, stereotactic irradiation, and radiofrequency lesioning. Although surgical intervention carries risks, total eradication or disconnection of the lesion leads to cessation or reduction of seizures and improves the cognitive and behavioral status of these patients. Precocious puberty in HH patients is safely controlled by long-acting gonadotropin-releasing hormone agonists. The accumulation of knowledge regarding the pathogenesis of symptoms and the development of safe, effective treatment modalities may lead to earlier intervention in young HH patients and prevent the decline in their cognitive abilities and quality of life. This review of hypothalamic hamartomas presents current classifications, pathophysiologies, and treatment modalities.
Topics: Hamartoma; Humans; Hypothalamic Diseases
PubMed: 15914961
DOI: 10.2176/nmc.45.221