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Molecular Cytogenetics Mar 2024Silver-Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and...
BACKGROUND
Silver-Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and characteristic (facial) dysmorphisms. The majority of patients shows a hypomethylation of the imprinting center region 1 (IC1) in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat), but in addition a broad spectrum of copy number variations (CNVs) and monogenetic variants (SNVs) has been reported in this cohort. These heterogeneous findings reflect the clinical overlap of SRS with other congenital disorders, but some of the CNVs are recurrent and have therefore been suggested as SRS-associated loci. However, this molecular heterogeneity makes the decision on the diagnostic workup of patients with SRS features challenging.
CASE PRESENTATION
A girl with clinical features of SRS but negatively tested for the IC1 hypomethylation and upd(7)mat was analyzed by whole genome sequencing in order to address both CNVs and SNVs in the same run. We identified a 11p13 microduplication affecting a region overlapping with a variant reported in a previously published patient with clinical features of Silver-Russel syndrome.
CONCLUSIONS
The identification of a 11p13 microduplication in a patient with SRS features confirms the considerable contribution of CNVs to SRS-related phenotypes, and it strengthens the evidence for a 11p13 microduplication syndrome as a differential diagnosis SRS. Furthermore, we could confirm that WGS is a valuable diagnostic tool in patients with SRS and related disorders, as it allows CNVs and SNV detection in the same run, thereby avoiding a time-consuming diagnostic testing process.
PubMed: 38486332
DOI: 10.1186/s13039-024-00672-6 -
BMC Medical Genomics Mar 2024Thousand and one amino-acid kinase 1 (TAOK1) encodes the MAP3K protein kinase TAO1, which has recently been displayed to be essential for neuronal maturation and... (Review)
Review
Heterozygous truncating variant of TAOK1 in a boy with periventricular nodular heterotopia: a case report and literature review of TAOK1-related neurodevelopmental disorders.
BACKGROUND
Thousand and one amino-acid kinase 1 (TAOK1) encodes the MAP3K protein kinase TAO1, which has recently been displayed to be essential for neuronal maturation and cortical differentiation during early brain development. Heterozygous variants in TAOK1 have been reported in children with neurodevelopmental disorders, with or without macrocephaly, hypotonia and mild dysmorphic traits. Literature reports lack evidence of neuronal migration disorders in TAOK1 patients, although studies in animal models suggest this possibility.
CASE PRESENTATION
We provide a clinical description of a child with a neurodevelopmental disorder due to a novel TAOK1 truncating variant, whose brain magnetic resonance imaging displays periventricular nodular heterotopia.
CONCLUSIONS
To our knowledge, this is the first report of a neuronal migration disorder in a patient with a TAOK1-related neurodevelopmental disorder, thus supporting the hypothesized pathogenic mechanisms of TAOK1 defects.
Topics: Animals; Male; Child; Humans; Periventricular Nodular Heterotopia; Amino Acids; Phosphorylation; Brain; Neurodevelopmental Disorders
PubMed: 38443934
DOI: 10.1186/s12920-024-01840-8 -
Journal of Neurology May 2024Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related...
BACKGROUND
Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related neurodevelopmental disorders. Several different clinical manifestations, affecting neurodevelopmental and systemic domains, have been described, presenting with highly variable expressivity. Some expressions are well established and comprise autism spectrum disorders, psychomotor delay with cognitive impairment, postnatal overgrowth with macrocephaly, structural brain abnormalities, gastrointestinal disturbances, and behavioral and sleep-pattern problems. However, the complete phenotypic spectrum of CHD8-related disorders is still undefined. In 2021, our group described two singular female patients with CHD8-related neurodevelopmental disorder and striking dystonic manifestations, prompting the suggestion that dystonia should be considered a possible component of this condition.
CASE SERIES PRESENTATION
We describe three additional unrelated female individuals, each carrying a different CHD8 frameshift variant and whose clinical presentations were primarily characterized by young-onset dystonia. Their dystonic manifestations were remarkably heterogeneous and ranged from focal, exercise-dependent, apparently isolated forms to generalized permanent phenotypes accompanied by spasticity and tremor. Neurocognitive impairment and autistic behaviors, typical of CHD8-related disorders, were virtually absent or at the mild end of the spectrum.
CONCLUSIONS
This work validates our previous observation that dystonia is part of the phenotypic spectrum of CHD8-related neurodevelopmental disorders with potential female preponderance, raising new challenges and opportunities in the diagnosis and management of this condition. It also highlights the importance of in-depth neurologic phenotyping of patients carrying variants associated with neurodevelopmental disorders, as the connection between neurodevelopmental and movement disorders is proving closer than previously appreciated.
Topics: Humans; Female; Phenotype; DNA-Binding Proteins; Dystonia; Transcription Factors; Child; Adolescent; Neurodevelopmental Disorders; Adult; Dystonic Disorders; Frameshift Mutation; Young Adult; Child, Preschool
PubMed: 38441608
DOI: 10.1007/s00415-024-12271-x -
European Journal of Medical Genetics Apr 2024Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis,...
Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis, brachydactyly, macrocephaly with frontal bossing and midface hypoplasia. Ligamentous laxity has been reported as a striking feature of ACH, but its prevalence and characteristics have not been systematically evaluated yet. There is growing evidence that ligamentous laxity can be associated with chronic musculoskeletal problems and may affect motor development leading to abnormal developmental trajectories. This study aimed to assess the prevalence of ligamentous laxity in children with ACH through standardized tools, the Beighton scale and its modified version for preschool-age children. A total of 33 children (mean age 6.4 ± 3.2 years; age range 1-12.5 years) diagnosed with ACH by the demonstration of a pathogenic variant in the FGFR3 gene and 33 age- and sex-matched healthy controls were included in the study. Both ligamentous laxity assessment and neurological examinations were performed; medical history was also collected from caregivers. Children with ACH showed a 2 times higher risk of ligamentous laxity than the group without skeletal dysplasia (OR = 2.2; 95% CI = 1.0 to 4.7), with 55% of children meeting the diagnostic criteria for hypermobility. No significant difference in ligamentous laxity was observed between males and females. Joint involvement analysis revealed characteristic patterns, with knee hypermobility observed in 67% of patients, while rare was elbow hypermobility. Longitudinal assessments indicated a decreasing trend in ligamentous laxity scores over time, suggesting a potential decrease in hypermobility issues during adulthood. The findings of this study provide valuable insights into the prevalence and characteristics of ligamentous laxity in ACH. Implementation of standardized ligamentous laxity assessments might guide patients' follow-up and facilitate early interventions, helping to prevent pain and improve outcomes and quality of life for such patients. Further prospective studies are needed to explore the natural history of ligamentous laxity in ACH and investigate the potential impact of emerging pharmacological treatments upon hypermobility.
Topics: Male; Child; Child, Preschool; Female; Humans; Adult; Infant; Prevalence; Quality of Life; Joint Instability; Achondroplasia; Prospective Studies; Osteochondrodysplasias
PubMed: 38428804
DOI: 10.1016/j.ejmg.2024.104930 -
Child's Nervous System : ChNS :... Jun 2024The aim of this study was to provide a full characterization of a cohort of 11 pediatric patients diagnosed with PTEN hamartoma tumor syndrome (PHTS).
OBJECTIVE
The aim of this study was to provide a full characterization of a cohort of 11 pediatric patients diagnosed with PTEN hamartoma tumor syndrome (PHTS).
PATIENTS AND METHODS
Eleven patients with genetic diagnostic of PHTS were recruited between February 2019 and April 2023. Clinical, imaging, demographic, and genetic data were retrospectively collected from their hospital medical history.
RESULTS
Regarding clinical manifestations, macrocephaly was the leading sign, present in all patients. Frontal bossing was the most frequent dysmorphism. Neurological issues were present in most patients. Dental malformations were described for the first time, being present in 27% of the patients. Brain MRI showed anomalies in 57% of the patients. No tumoral lesions were present at the time of the study. Regarding genetics, 72% of the alterations were in the tensin-type C2 domain of PTEN protein. We identified four PTEN genetic alterations for the first time.
CONCLUSIONS
PTEN mutations appear with a wide variety of clinical signs and symptoms, sometimes associated with phenotypes which do not fit classical clinical diagnostic criteria for PHTS. We recommend carrying out a genetic study to establish an early diagnosis in children with significant macrocephaly. This facilitates personalized monitoring and enables anticipation of potential PHTS-related complications.
Topics: Humans; Female; Male; PTEN Phosphohydrolase; Child; Hamartoma Syndrome, Multiple; Child, Preschool; Adolescent; Retrospective Studies; Infant; Mutation; Megalencephaly
PubMed: 38407606
DOI: 10.1007/s00381-024-06301-2 -
Frontiers in Oncology 2024Cowden syndrome (CS) is a rare genetic disorder associated with gene mutations. It is characterized by macrocephaly, specific mucocutaneous features, and a...
BACKGROUND
Cowden syndrome (CS) is a rare genetic disorder associated with gene mutations. It is characterized by macrocephaly, specific mucocutaneous features, and a predisposition to benign and malignant tumors. Cases of CS primarily presenting with oral clinical manifestations are relatively uncommon.
METHODS/RESULTS
We report the case of a 41-year-old male proband who presented with bilateral commissural and lingual externally projecting symmetric lesions for over two years. The proband also exhibited other features, including macrocephaly, communication difficulties, and obesity. Similar oral clinical manifestations were observed in family members. Whole exome sequencing analysis revealed gene mutations associated with CS in both the proband and his younger brother. This case serves as a reminder to be aware of the diverse presentations of CS in oral clinical practice and highlights the importance of genetic testing for guiding diagnosis and treatment.
CONCLUSION
There are few reported cases of CS primarily presenting with oral lesions. This finding contributes to further understanding of certain aspects of the pathogenesis of CS and enhances awareness of CS cases primarily exhibiting oral clinical manifestations.
PubMed: 38406815
DOI: 10.3389/fonc.2024.1323225 -
Journal of Vascular Surgery Cases and... Apr 2024Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a congenital, autosomal-dominant disorder characterized by a triad of macrocephaly, lipomatosis, and pigmentation of the...
Bannayan-Riley-Ruvalcaba syndrome (BRRS) is a congenital, autosomal-dominant disorder characterized by a triad of macrocephaly, lipomatosis, and pigmentation of the glans penis. The symptoms of this rare syndrome vary greatly and include multiple hamartomatous polyps, macrocephaly, increased birth weight, developmental delay, and intellectual disability. Vascular abnormalities, including arteriovenous malformations (AVMs), have rarely been reported as part of the vascular manifestations associated with BRRS. Congenital AVMs can rarely progress, resulting in limb- or life-threatening complications. We present the case of a young man with BRRS diagnosed in childhood and presenting with three AVMs involving the right upper extremity and chest. We also provide a brief literature summary of reported cases of BRRS with AVMs. Our paper highlights the importance of recognizing and understanding the vascular manifestations in patients with BRRS. Knowledge of the association between BRRS and AVMs is crucial for guiding patient diagnosis and management, optimizing treatment strategies, and improving overall patient outcomes.
PubMed: 38379611
DOI: 10.1016/j.jvscit.2024.101428 -
Cureus Jan 2024Long-standing overt ventriculomegaly in adults (LOVA) is a type of chronic hydrocephalus with presumable infant onset characterized by macrocephaly and massive...
Long-standing overt ventriculomegaly in adults (LOVA) is a type of chronic hydrocephalus with presumable infant onset characterized by macrocephaly and massive ventriculomegaly that causes clinical presentations in later adult life. We report a case of a 20-year-old man who was referred from the ophthalmology department for further investigation of his visual disturbances. MRI of the head revealed massive ventriculomegaly with an Evan's index of 0.44. A careful investigation revealed coexisting aqueductal stenosis, absent septum pellucidum, ventricular rupture, and spontaneous ventriculostomy. The clinical presentations were relatively mild compared to his MRI findings. He was referred to a neurosurgeon for potential surgical interventions after the administration of conservative hyperosmolar drugs and neuroprotective agents.
PubMed: 38357077
DOI: 10.7759/cureus.52292