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SAGE Open Medical Case Reports 2024Germline pathogenic variants found in the phosphatase and tensin homolog gene are associated with a range of rare syndromes that collectively fall under the umbrella of...
Germline pathogenic variants found in the phosphatase and tensin homolog gene are associated with a range of rare syndromes that collectively fall under the umbrella of phosphatase and tensin homolog hamartoma tumor syndromes. Due to the wide array of possible clinical presentations and the varying degrees of symptom severity, many individuals with phosphatase and tensin homolog hamartoma tumor syndromes might remain undiagnosed for an extended period. We describe a case of a male child who received the diagnosis at the age of 12. His clinical features included macrocephaly, hypertrophy in the left arm, thyroid nodules, penile freckles, developmental delay, and an autism spectrum disorder. Whole exome sequencing revealed a de novo heterozygous variant in the phosphatase and tensin homolog. The case highlights the diverse and complex nature of phosphatase and tensin homolog hamartoma tumor syndromes, emphasizing the necessity for early diagnosis, multidisciplinary care, and surveillance protocols, offering the potential for improved prognostic outcomes and enhanced quality of life for affected individuals.
PubMed: 38585419
DOI: 10.1177/2050313X241245317 -
World Journal of Clinical Cases Mar 2024A rare autosomal recessive genetic disorder, 3M syndrome, is characterized by severe intrauterine and postnatal growth retardation. Children with 3M syndrome typically...
BACKGROUND
A rare autosomal recessive genetic disorder, 3M syndrome, is characterized by severe intrauterine and postnatal growth retardation. Children with 3M syndrome typically exhibit short stature, facial deformities, long tubular bones, and high vertebral bodies but generally lack mental abnormalities or other organ damage. Pathogenic genes associated with 3M syndrome include , and . The clinical and molecular characteristics of patient with 3M syndrome are unique and serve as important diagnostic indicators.
CASE SUMMARY
In this case, the patient displayed square shoulders, scoliosis, long slender tubular bones, and normal neurological development. Notably, the patient did not exhibit the typical dysmorphic facial features, relative macrocephaly, or growth retardation commonly observed in individuals with 3M syndrome. Whole exon sequencing revealed a novel heterozygous c.56681+1G>C (Splice-3) variant and a previously reported nonsense heterozygous c.3341G>A (p.Trp1114Ter) variant of . Therefore, it is important to note that the clinical features of 3M syndrome may not always be observable, and genetic confirmation is often required. Additionally, the identification of the c.5683+1G>C variant in is noteworthy because it has not been previously reported in public databases.
CONCLUSION
Our study identified a new variant (c.5683+1G>C) of that contributes to expanding the molecular profile of 3M syndrome.
PubMed: 38576808
DOI: 10.12998/wjcc.v12.i8.1454 -
Heliyon Apr 2024We report here the clinical and genetic features of -related neurodevelopmental disorder caused by a novel heterozygous frameshift variant in in a Chinese family.
BACKGROUND
We report here the clinical and genetic features of -related neurodevelopmental disorder caused by a novel heterozygous frameshift variant in in a Chinese family.
CASE PRESENTATION
A 7-year-old Chinese boy with mild-to-moderate intellectual disability, significant language impairment, motor disability, and coordination difficulties presented to our hospital because he "could not speak and did not look at others." He was diagnosed with autism spectrum disorder previously owing to developmental delays in cognition, language expression, and understanding. The child also had variable nonspecific features including macrocephaly, wide button-hole space and nasal bridge, low ear, social behavior disorder, and foot deformities. Exome sequencing (ES) revealed that both the proband and his younger brother had inherited a novel heterozygous frameshift variant c.438_439ins[ASD; KT192064.1:1_310] of the gene from their father. Bioinformatics analysis showed that the novel mutation affected the structure of the KMT5B pre-SET domain, mainly in the α-helix region. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this type of variant was eventually determined to be likely pathogenic (PVS1+PM2_P).
CONCLUSIONS
Our investigation expands the mutation spectrum of to help us to better understand -related neurodevelopmental disorder.
PubMed: 38571636
DOI: 10.1016/j.heliyon.2024.e28686 -
Molecular Autism Apr 2024Clinicians diagnosing autism rely on diagnostic criteria and instruments in combination with an implicit knowledge based on clinical expertise of the specific signs and...
BACKGROUND
Clinicians diagnosing autism rely on diagnostic criteria and instruments in combination with an implicit knowledge based on clinical expertise of the specific signs and presentations associated with the condition. This implicit knowledge influences how diagnostic criteria are interpreted, but it cannot be directly observed. Instead, insight into clinicians' understanding of autism can be gained by investigating their diagnostic certainty. Modest correlations between the certainty of an autism diagnosis and symptom load have been previously reported. Here, we investigated the associations of diagnostic certainty with specific items of the ADOS as well as other clinical features including head circumference.
METHODS
Phenotypic data from the Simons Simplex Collection was used to investigate clinical correlates of diagnostic certainty in individuals diagnosed with Autistic Disorder (n = 1511, age 4 to 18 years). Participants were stratified by the ADOS module used to evaluate them. We investigated how diagnostic certainty was associated with total ADOS scores, age, and ADOS module. We calculated the odds-ratios of being diagnosed with the highest possible certainty given the presence or absence of different signs during the ADOS evaluation. Associations between diagnostic certainty and other cognitive and clinical variables were also assessed.
RESULTS
In each ADOS module, some items showed a larger association with diagnostic certainty than others. Head circumference was significantly higher for individuals with the highest certainty rating across all three ADOS modules. In turn, head circumference was positively correlated with some of the ADOS items that were associated with diagnostic certainty, and was negatively correlated with verbal/nonverbal IQ ratio among those assessed with ADOS module 2.
LIMITATIONS
The investigated cohort was heterogeneous, e.g. in terms of age, IQ, language level, and total ADOS score, which could impede the identification of associations that only exist in a subgroup of the population. The variability of the certainty ratings in the sample was low, limiting the power to identify potential associations with other variables. Additionally, the scoring of diagnostic certainty may vary between clinicians.
CONCLUSION
Some ADOS items may better capture the signs that are most associated with clinicians' implicit knowledge of Autistic Disorder. If replicated in future studies, new diagnostic instruments with differentiated weighting of signs may be needed to better reflect this, possibly resulting in better specificity in standardized assessments.
Topics: Child; Humans; Adolescent; Child, Preschool; Autistic Disorder; Language; Autism Spectrum Disorder
PubMed: 38570867
DOI: 10.1186/s13229-024-00592-7 -
Genes, Brain, and Behavior Apr 2024Mutations in CHD8 are one of the highest genetic risk factors for autism spectrum disorder. Studies in mice that investigate underlying mechanisms have shown Chd8...
Mutations in CHD8 are one of the highest genetic risk factors for autism spectrum disorder. Studies in mice that investigate underlying mechanisms have shown Chd8 haploinsufficient mice display some trait disruptions that mimic clinical phenotypes, although inconsistencies have been reported in some traits across different models on the same strain background. One source of variation across studies may be the impact of Chd8 haploinsufficiency on maternal-offspring interactions. While differences in maternal care as a function of Chd8 genotype have not been studied directly, a previous study showed that pup survival was reduced when reared by Chd8 heterozygous dams compared with wild-type (WT) dams, suggesting altered maternal care as a function of Chd8 genotype. Through systematic observation of the C57BL/6 strain, we first determined the impact of Chd8 haploinsufficiency in the offspring on WT maternal care frequencies across preweaning development. We next determined the impact of maternal Chd8 haploinsufficiency on pup care. Compared with litters with all WT offspring, WT dams exhibited less frequent maternal behaviors toward litters consisting of offspring with mixed Chd8 genotypes, particularly during postnatal week 1. Dam Chd8 haploinsufficiency decreased litter survival and increased active maternal care also during postnatal week 1. Determining the impact of Chd8 haploinsufficiency on early life experiences provides an important foundation for interpreting offspring outcomes and determining mechanisms that underlie heterogeneous phenotypes.
Topics: Animals; Female; Mice; Autism Spectrum Disorder; Genotype; Haploinsufficiency; Mice, Inbred C57BL; Phenotype
PubMed: 38560770
DOI: 10.1111/gbb.12892 -
Cureus Feb 2024Macrocephaly is defined as an abnormal increase in head circumference greater than two standard deviations above the mean for a given age and sex. We present the case of...
Macrocephaly is defined as an abnormal increase in head circumference greater than two standard deviations above the mean for a given age and sex. We present the case of a 16-month-old boy with congenital progressive macrocephaly, who was referred to our hospital for a ventriculoperitoneal shunt placement for external hydrocephalus diagnosed at 13 months of age. The patient had a febrile seizure 12 hours after the shunt was placed and the emergency CT exam revealed collapsed ventricles and a right frontal subdural collection, suggestive of an over-drainage and intracranial hypotension. A subsequent electroencephalogram (EEG) revealed some anomalies, but the patient was discharged two days later due to having no neurological symptoms after being placed on anticonvulsants. The patient returned to the hospital one week later due to recurrent seizures. Further clinical examination revealed prominent and tortuous veins of the skull, palpated in the left occipital region. A thrill and a left carotid murmur were heard during auscultation. A subsequent brain MRI with MR arteriography and venography was performed in search of an explanation for hydrocephaly. The sequences were suggestive of a dural arteriovenous fistula, which was confirmed and then treated using coils during an interventional angiography. A second procedure was performed two months later to complete the embolization, with subsequent imaging follow-ups showing the procedure to have been successful. The measurement of the cranial circumference, its regular evaluation, and its evolution allow a hierarchical diagnosis strategy by distinguishing primary and secondary macrocephaly, progressive or not. Dural arteriovenous fistulas (DAVF) are an under-appreciated cause of macrocephaly, with which they are associated in 35% of cases. Intracranial DAVFs are pathologic shunts between dural arteries and dural venous sinuses, meningeal veins, or cortical veins. Patients with DAVFs may be completely asymptomatic. Symptoms, when present, may range from neurological deficits, seizures, and hydrocephaly to fatal hemorrhage. The symptoms depend on the location and venous and drainage patterns of the DAVF. They can be difficult to identify on routine MRIs unless specifically searched for, especially in cases of technically suboptimal examinations. We aim to give a practical approach to identify the clinical clues that warrant further investigation. Several specific protocols exist regarding the management of macrocephaly and should be followed carefully once a diagnosis has been reached, but further studies are needed to integrate more clinical and neuroimaging findings to permit an early diagnosis.
PubMed: 38558721
DOI: 10.7759/cureus.55288 -
Genes Mar 2024Alexander disease (AxD) is a rare neurodegenerative condition that represents the group of leukodystrophies. The disease is caused by mutation. Symptoms usually occur...
INTRODUCTION
Alexander disease (AxD) is a rare neurodegenerative condition that represents the group of leukodystrophies. The disease is caused by mutation. Symptoms usually occur in the infantile age with macrocephaly, developmental deterioration, progressive quadriparesis, and seizures as the most characteristic features. In this case report, we provide a detailed clinical description of the neonatal type of AxD.
METHOD
Next-Generation Sequencing (NGS), including a panel of 49 genes related to Early Infantile Epileptic Encephalopathy (EIEE), was carried out, and then Whole Exome Sequencing (WES) was performed on the proband's DNA extracted from blood.
CASE DESCRIPTION
In the first weeks of life, the child presented with signs of increased intracranial pressure, which led to ventriculoperitoneal shunt implementation. Recurrent focal-onset motor seizures with secondary generalization occurred despite phenobarbital treatment. Therapy was modified with multiple anti-seizure medications. In MRI contrast-enhanced lesions in basal ganglia, midbrain and cortico-spinal tracts were observed. During the diagnostic process, GLUT-1 deficiency, lysosomal storage disorders, organic acidurias, and fatty acid oxidation defects were excluded. The NGS panel of EIEE revealed no abnormalities. In WES analysis, missense heterozygous variant NM_002055.5: c.1187C>T, p.(Thr396Ile) was detected, confirming the diagnosis of AxD.
CONCLUSION
AxD should be considered in the differential diagnosis in all neonates with progressive, intractable seizures accompanied by macrocephaly.
Topics: Child; Infant, Newborn; Humans; Alexander Disease; Glial Fibrillary Acidic Protein; Drug Resistant Epilepsy; Hyponatremia; Spasms, Infantile; Bone Diseases; Demyelinating Diseases; Lysosomal Storage Diseases; Megalencephaly
PubMed: 38540409
DOI: 10.3390/genes15030350 -
Clinical Neurophysiology Practice 2024Pathogenic variants of the MTOR gene result in the Smith-Kingsmore syndrome, whose phenotypical spectrum includes facial dysmorphisms and neurological features....
INTRODUCTION
Pathogenic variants of the MTOR gene result in the Smith-Kingsmore syndrome, whose phenotypical spectrum includes facial dysmorphisms and neurological features. Expressivity is variable, patients exhibit a combination of intellectual disability, macrocephaly and epilepsy. The diagnosis can be missed, failing to detect the causative pathogenic mutation in patients with somatic mosaicism or even skipping to analyze when the phenotype is not completely expressed.
CASE STUDY
Herein, we report two children harboring the same MTOR recurring mutation (c.5395G>A/p.Glu1799Lys) whose EEG displayed a peculiar combination of midline rhythmic waveforms and asynchronous spike-and-wave discharges with anterior fast activity in sleep and wake. : We suggest these features might be considered as possible hallmarks of the syndrome and could aid to expedite the diagnosis when the phenotype is incomplete.
PubMed: 38495955
DOI: 10.1016/j.cnp.2024.02.001 -
Frontiers in Genetics 2024The leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by infantile-onset macrocephaly and chronic edema of the brain white...
The leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC) is characterized by infantile-onset macrocephaly and chronic edema of the brain white matter. With delayed onset, patients typically experience motor problems, epilepsy and slow cognitive decline. No treatment is available. Classic MLC is caused by bi-allelic recessive pathogenic variants in or (also called ). Heterozygous dominant pathogenic variants in lead to remitting MLC, where patients show a similar phenotype in early life, followed by normalization of white matter edema and no clinical regression. Rare patients with heterozygous dominant variants in and classic MLC were recently described. In addition, two siblings with bi-allelic recessive variants in and remitting MLC have been identified. The last systematic overview of variants linked to MLC dates back to 2006. We provide an updated overview of published and novel variants. We report on genetic variants from 508 patients with MLC as confirmed by MRI diagnosis (258 from our database and 250 extracted from 64 published reports). We describe 151 unique variants, 29 variants, 2 variants and 1 variant observed in these MLC patients. We include experiments confirming pathogenicity for some variants, discuss particularly notable variants, and provide an overview of recent scientific and clinical insight in the pathophysiology of MLC.
PubMed: 38487253
DOI: 10.3389/fgene.2024.1352947