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Clinical Epigenetics May 2024Temple syndrome (TS14) is a rare imprinting disorder caused by maternal UPD14, imprinting defects or paternal microdeletions which lead to an increase in the maternal...
BACKGROUND
Temple syndrome (TS14) is a rare imprinting disorder caused by maternal UPD14, imprinting defects or paternal microdeletions which lead to an increase in the maternal expressed genes and a silencing the paternally expressed genes in the 14q32 imprinted domain. Classical TS14 phenotypic features include pre- and postnatal short stature, small hands and feet, muscular hypotonia, motor delay, feeding difficulties, weight gain, premature puberty along and precocious puberty.
METHODS
An exon array comparative genomic hybridization was performed on a patient affected by psychomotor and language delay, muscular hypotonia, relative macrocephaly, and small hand and feet at two years old. At 6 years of age, the proband presented with precocious thelarche. Genes dosage and methylation within the 14q32 region were analyzed by MS-MLPA. Bisulfite PCR and pyrosequencing were employed to quantification methylation at the four known imprinted differentially methylated regions (DMR) within the 14q32 domain: DLK1 DMR, IG-DMR, MEG3 DMR and MEG8 DMR.
RESULTS
The patient had inherited a 69 Kb deletion, encompassing the entire DLK1 gene, on the paternal allele. Relative hypermethylation of the two maternally methylated intervals, DLK1 and MEG8 DMRs, was observed along with normal methylation level at IG-DMR and MEG3 DMR, resulting in a phenotype consistent with TS14. Additional family members with the deletion showed modest methylation changes at both the DLK1 and MEG8 DMRs consistent with parental transmission.
CONCLUSION
We describe a girl with clinical presentation suggestive of Temple syndrome resulting from a small paternal 14q32 deletion that led to DLK1 whole-gene deletion, as well as hypermethylation of the maternally methylated DLK1-DMR.
Topics: Humans; Calcium-Binding Proteins; DNA Methylation; Chromosomes, Human, Pair 14; Intercellular Signaling Peptides and Proteins; Genomic Imprinting; Membrane Proteins; Child; Male; Comparative Genomic Hybridization; Female; Chromosome Deletion; Child, Preschool; Phenotype; Abnormalities, Multiple; Imprinting Disorders; Muscle Hypotonia; Facies
PubMed: 38715103
DOI: 10.1186/s13148-024-01652-8 -
Cell Reports. Medicine May 2024The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association...
The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.
Topics: Humans; Genome-Wide Association Study; Head; Neoplasms; Female; Male; Polymorphism, Single Nucleotide; Genetic Variation; Organ Size; Signal Transduction; Adult; Genetic Predisposition to Disease
PubMed: 38703765
DOI: 10.1016/j.xcrm.2024.101529 -
International Dental Journal May 2024Patients with PTEN hamartoma tumour syndrome (PHTS) have an increased risk of developing cancer due to a pathogenic germline variant in the PTEN tumour suppressor gene....
AIMS
Patients with PTEN hamartoma tumour syndrome (PHTS) have an increased risk of developing cancer due to a pathogenic germline variant in the PTEN tumour suppressor gene. Early recognition of PHTS facilitates initiation of cancer surveillance which is highly effective in preventing the development of advanced malignancies. PHTS is rare and due to its varied phenotype, even within families, oral abnormalities may be a valuable tool in the identification of these patients at an early stage before cancer development.
MATERIALS AND METHODS
Between 1997 and 2020, phenotypic characteristics were evaluated in 81 paediatric (median age: 9 years) and 86 adult (median age: 40 years) PHTS patients by one of 2 medical experts during yearly surveillance visits at a Dutch PHTS expertise centre. Oral features evaluated included gingival hypertrophy, oral papillomas, and high palate (in adults).
RESULTS
Within adults, gingival hypertrophy was present in 94%, oral papillomas in 88%, and a high palate in 89%. All adult patients had at least one of these oral features, and 99% showed at least 2 oral features. Oral features were less common in paediatric patients, especially under 11 years of age. Gingival hypertrophy was observed in 44% and oral papillomas in 54% of paediatric patients.
CONCLUSIONS
The presence of 2 or 3 oral features may indicate PHTS in adults or adolescents, especially if macrocephaly is present. Dental professionals are well-positioned to recognise these oral manifestations could be related to PHTS. They can initiate an overall clinical assessment of the patient by alerting the patient's medical practitioner of the findings and the possible need for genetic testing. This could significantly improve outcomes, including life expectancy, for patients and possibly for their relatives.
CLINICAL RELEVANCE
Dental professionals are ideally placed to recognise oral features and initiate early assessment of PHTS which could significantly improve patient outcomes.
PubMed: 38697906
DOI: 10.1016/j.identj.2024.04.014 -
Genes Mar 2024O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant disorder caused by mutations in the gene. The clinical phonotype of the affected individuals is...
O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant disorder caused by mutations in the gene. The clinical phonotype of the affected individuals is typically characterized by global developmental delay, autism, epilepsy, hypotonia, macrocephaly, and very mild dysmorphic facial features. In this report, we describe the case of a 6-year-old boy with ODLURO syndrome who is a carrier of the synonymous mutation c.186G>A (p.Ala62=) in the gene, predicted to alter splicing by in silico tools. Given the lack of functional studies on the c.186G>A variant, in order to assess its potential functional effect, we sequenced the patient's cDNA demonstrating its impact on the mechanism of splicing. To the best of our knowledge, our patient is the second to date reported carrying this synonymous mutation, but he is the first whose functional investigation has confirmed the deleterious consequence of the variant, resulting in exon 4 skipping. Additionally, we suggest a potential etiological mechanism that could be responsible for the aberrant splicing mechanism in .
Topics: Child; Humans; Male; Autistic Disorder; Developmental Disabilities; DNA-Binding Proteins; Intellectual Disability; Megalencephaly; Phenotype; RNA Splicing; Silent Mutation
PubMed: 38674365
DOI: 10.3390/genes15040430 -
Journal of Clinical Medicine Apr 2024Sotos syndrome is a genetic disorder caused by gene (nuclear receptor binding SET domain containing protein 1) variants and characterized by overgrowth, macrocephaly,... (Review)
Review
Sotos syndrome is a genetic disorder caused by gene (nuclear receptor binding SET domain containing protein 1) variants and characterized by overgrowth, macrocephaly, learning disabilities, and co-occurring neuropsychiatric symptoms. Literature sources published in 2002-2023 were selected and analyzed from PubMed and Google Scholar databases. Neuropsychiatric symptoms are observed among children and adolescents with Sotos syndrome. The majority have intellectual disabilities or borderline intellect. Verbal IQ is higher than performance IQ. Individuals display difficulties in expressing language. Aggression is reported by parents. Children express autistic behavior, ADHD, anxiety based on phobias, and early bedtime-wake times. Sotos syndrome is associated with neuropsychiatric disorders in children. Slow intellectual and language development, aggressive outbursts, anxiety, autism spectrum disorder, and hyperactivity are present in the newest studies. Comprehensive assistance is needed for Sotos syndrome patients in responding to areas of difficulty. There is still a lack of research on the developmental characteristics of these children and the possibilities of improving psychosocial adaptation by providing multidisciplinary long-term medical, educational, and social care.
PubMed: 38673476
DOI: 10.3390/jcm13082204 -
Frontiers in Pediatrics 2024A diagnosis of Silver-Russell syndrome (SRS), a rare imprinting disorder responsible for foetal growth restriction, is considered for patients presenting at least four...
BACKGROUND
A diagnosis of Silver-Russell syndrome (SRS), a rare imprinting disorder responsible for foetal growth restriction, is considered for patients presenting at least four criteria of the Netchine-Harbison clinical scoring system (NH-CSS). Certain items of the NH-CSS are not assessable until the age of 2 years. The objective was to determine perinatal characteristics of children with SRS to allow an early diagnosis.
METHODS
We retrospectively compared the perinatal characteristics of children with SRS ( = 17) with those of newborns small for gestational age (SGA) due to placental insufficiency (PI) ( = 21).
RESULTS
Children with SRS showed earlier and more severely altered foetal biometry than SGA newborns due to PI. Twenty-three percent of patients with SRS showed uterine artery Doppler anomalies. SRS children were significantly smaller at birth (birth length <-3 SDS in 77% of cases in the SRS group vs. 15% in the PI group, = 0.0001).
CONCLUSION
The diagnosis of SRS must be evoked in the neonatal period for SGA newborns with a growth delay present from the second trimester of pregnancy, a birth length <-3 SDS and a relative macrocephaly. Doppler anomalies, classically used to orient the cause of SGA towards PI, did not rule out the diagnosis of SRS.
PubMed: 38638586
DOI: 10.3389/fped.2024.1367433 -
Iranian Journal of Child Neurology 2024Gangliosidosis is one of the hereditary metabolic diseases caused by the accumulation of Gangliosid in the central nervous system, leading to severe and progressive...
ABSTRACT
Gangliosidosis is one of the hereditary metabolic diseases caused by the accumulation of Gangliosid in the central nervous system, leading to severe and progressive neurological deficits. Regarding phenotype, GM1 and GM2-Gangliosidosis are divided into Infantile, Juvenile, and Adult.
MATERIALS & METHODS
In this study, thirty-seven patients with GM1 and GM2-Gangliosidosis were referred to the neurology department of Mofid Children's Hospital in Tehran, Iran, whose disease was confirmed from September 2019 to December 2021. This study assessed age, sex, and developmental status before the onset of the disease, clinical manifestations, brain imaging, and electroencephalography.
RESULTS
97.20% of patients were the result of family marriage. Approximately 80% of juvenile patients were developmentally normal before the onset of the disease. Developmental delay was more common among infantile GM1-Gangliosidosis than infantile GM2-Gangliosidosis, but in total, more than 50% of GM1&GM2-Gangliosidosis patients had reached their developmental milestone before the onset of the disease. With the onset of disease symptoms, 100% of patients regressed in terms of movement, 97.20% of them mentally, and 75% of them had seizures during the disease. The most common clinical findings were cherry-red spot, Mongolian spot, macrocephaly, organomegaly, hyperacusis, and scoliosis. The most common brain imaging findings included bilateral thalamus involvement, brain atrophy, PVL, and delayed myelination. The most common finding in electroencephalography was background low voltage with abnormal sharp waves.
CONCLUSION
This study concluded that most of the patients are the result of family marriage, and most of the juvenile patients are developmentally normal before the onset of the disease. In addition, more than 50% of infantile patients reach their developmental milestones before the onset of the disease. The most common clinical findings of these patients are seizures, cherry-red spot, macrocephaly, hyperacusis, Mongolian spot, and bilateral involvement of the thalamus.
PubMed: 38617391
DOI: 10.22037/ijcn.v18i2.40751 -
Frontiers in Endocrinology 2024Silver-Russell syndrome (SRS, OMIM, 180860) is a rare genetic disorder with a wide spectrum of symptoms. The most common features are intrauterine growth retardation...
Silver-Russell syndrome (SRS, OMIM, 180860) is a rare genetic disorder with a wide spectrum of symptoms. The most common features are intrauterine growth retardation (IUGR), poor postnatal development, macrocephaly, triangular face, prominent forehead, body asymmetry, and feeding problems. The diagnosis of SRS is based on a combination of clinical features. Up to 60% of SRS patients have chromosome 7 or 11 abnormalities, and <1% show abnormalities in IGF2 signaling pathway genes (, , and ). The underlying genetic cause remains unknown in about 40% of cases (idiopathic SRS). We report a novel variant c.[-6-2A>G] (NM_000612) in a child with severe IUGR and clinical features of SRS and confirm the utility of targeted exome sequencing in patients with negative results to common genetic analyses. In addition, we report that long-term growth hormone treatment improves height SDS in this patient.
Topics: Child; Female; Humans; Silver-Russell Syndrome; Growth Hormone; Paternal Inheritance; Phenotype; Human Growth Hormone; Fetal Growth Retardation; Insulin-Like Growth Factor II
PubMed: 38596219
DOI: 10.3389/fendo.2024.1364234