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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 -
Molecular Genetics & Genomic Medicine Feb 2024Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, inherited disorder that causes epilepsy, intellectual disorders, and early onset...
BACKGROUND
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare, inherited disorder that causes epilepsy, intellectual disorders, and early onset macrocephaly. MLC1 has been identified as a main pathogenic gene.
METHODS
Clinical data such as magnetic resonance imaging (MRI), routine blood tests, and physical examinations were collected from proband. Trio whole-exome sequencing (WES) of the family was performed, and all variants with a minor allele frequency (<0.01) in the exon and canonical splicing sites were selected for further pathogenic evaluation. Candidate variants were validated using Sanger sequencing.
RESULTS
Here, we report a new homozygous variant identified in two children from the same family in the MLC1 gene [NM_015166.4: c.838_843delinsATTTTA, (p.Ser280_Phe281delinsIleLeu)]. This variant is classified as variant of uncertain significance (VUS) according to the ACMG guidelines. Further experiments demonstrate that the newly identified variant causes a decrease of MLC1 protein levels when expressed in a heterologous expression system.
CONCLUSION
Our case expands on this genetic variation and provides new evidence for the clinical diagnosis of MLC1-related MLC.
Topics: Child; Humans; Membrane Proteins; Mutation; Hereditary Central Nervous System Demyelinating Diseases; Megalencephaly; Cysts
PubMed: 38337154
DOI: 10.1002/mgg3.2394 -
Medicine Feb 2024To determine whether health status during pregnancy is associated with autism spectrum disorder (ASD) and abnormal head circumference (HC) in the offspring. This study...
To determine whether health status during pregnancy is associated with autism spectrum disorder (ASD) and abnormal head circumference (HC) in the offspring. This study included 41 Han children with ASD who visited the Children's Health Clinic of the Second Hospital of Shandong University between March 2018 and February 2019, and 264 Han children with typical development (TD) who visited the clinic during the same period. Physical measurements were performed on the children. The questionnaire obtained information on maternal risk factors that may be related to the increased risk of ASD and folic acid (FA) supplementation. We designed an observational case-control study using propensity score matching and multivariate logistic regression analysis. The incidence of macrocephaly in the ASD group was 22.0%, significantly higher than that in the TD group (1.8%). The incidence of microcephaly in the ASD group was 17.1% (n = 7), significantly higher than that in the TD group (1.8%). The differences between the comparisons were statistically significant. Maternal FA supplementation during pregnancy was significantly associated with ASD (P < .05), with an odds ratio (95% confidence interval of 3.69 (1.76, 7.76)). Also was associated with macrocephaly (P < .05), odds ratio (95% confidence interval) were 8.13 (1.63, 40.61) and 4.16 (1.18, 14.60), respectively. The incidence of abnormal HC was higher in the ASD group than that in the TD group. Maternal FA supplementation during pregnancy may be negatively associated with the occurrence of ASD and abnormal HC in the offspring. Further examination of the role of maternal health status in the etiology of ASD is recommended.
Topics: Child; Pregnancy; Female; Humans; Folic Acid; Autism Spectrum Disorder; Dietary Supplements; Case-Control Studies; Propensity Score; Mothers; Megalencephaly
PubMed: 38335372
DOI: 10.1097/MD.0000000000036104 -
American Journal of Medical Genetics.... Jun 2024Capillary malformations (CMs) are the most common type of vascular anomalies, affecting around 0.3% of newborns. They are usually caused by somatic pathogenic variants...
Capillary malformations (CMs) are the most common type of vascular anomalies, affecting around 0.3% of newborns. They are usually caused by somatic pathogenic variants in GNAQ or GNA11. PIK3CA and PIK3R1, part of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin pathway, are mutated in fainter CMs such as diffuse CM with overgrowth and megalencephaly CM. In this study, we present two young patients with a CM-like phenotype associated with cerebral anomalies and severe epilepsy. Pathogenic variants in PIK3CA and PIK3R1, as well as GNAQ and GNA11, were absent in affected cutaneous tissue biopsies. Instead, we identified two somatic pathogenic variants in the AKT3 gene. Subsequent analysis of the DNA obtained from surgically resected brain tissue of one of the two patients confirmed the presence of the AKT3 variant. Focal cortical dysplasia was also detected in this patient. Genetic analysis thus facilitated workup to reach a precise diagnosis for these patients, associating the vascular anomaly with the neurological symptoms. This study underscores the importance of searching for additional signs and symptoms to guide the diagnostic workup, especially in cases with atypical vascular malformations. In addition, it strongly emphasizes the significance of genotype-phenotype correlation studies in guiding clinicians' informed decision-making regarding patient care.
Topics: Female; Humans; Infant, Newborn; Male; Capillaries; Epilepsy; Genetic Association Studies; Genetic Predisposition to Disease; Mosaicism; Mutation; Phenotype; Proto-Oncogene Proteins c-akt; Telangiectasis; Vascular Malformations; Adolescent
PubMed: 38321651
DOI: 10.1002/ajmg.a.63551