-
American Journal of Medical Genetics.... Feb 2023We systematically delineated the prenatal phenotype, and obstetrical and neonatal outcomes of the RASopathy cardio-facio-cutaneous (CFC) syndrome. A comprehensive,...
We systematically delineated the prenatal phenotype, and obstetrical and neonatal outcomes of the RASopathy cardio-facio-cutaneous (CFC) syndrome. A comprehensive, retrospective medical history survey was distributed to parents of children with confirmed CFC in collaboration with CFC International, Inc. Data were collected on CFC gene variant, maternal characteristics, pregnancy course, delivery, and neonatal outcomes with the support of medical records. We identified 43 individuals with pathogenic variants in BRAF (81%), MEK1 (14%), or MEK2 (5%) genes. The median age was 8.5 years. Hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia occurred in 5/43 (12%), 4/43 (9%), 3/43 (7%), and 3/43 (7%) of pregnancies, respectively. Second and third trimester ultrasound abnormalities included polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Delivery occurred via spontaneous vaginal, operative vaginal, or cesarean delivery in 15/42 (36%), 7/42 (16%), and 20/42 (48%), respectively. Median gestational age at delivery was 37 weeks and median birth weight was 3501 grams. Germline pathogenic vaiants had mutiple congenital consequences including polyhydramnios, renal and cardiac abnormalities, macrosomia, and macrocephaly on second and third trimester ultrasound. Elevated rates of operative delivery and neonatal complications were also noted. Understanding and defining a prenatal phenotype may improve prenatal prognostic counseling and outcomes.
Topics: Humans; Pregnancy; Female; Retrospective Studies; Fetal Macrosomia; Polyhydramnios; Proto-Oncogene Proteins B-raf; Ectodermal Dysplasia; Facies; Heart Defects, Congenital; Megalencephaly
PubMed: 36308388
DOI: 10.1002/ajmg.a.63020 -
Frontiers in Pediatrics 2023Sotos Syndrome (SS, OMIM#117550) is a heterogeneous genetic condition, recognized by three main clinical features present in most cases: overgrowth with macrocephaly,...
INTRODUCTION
Sotos Syndrome (SS, OMIM#117550) is a heterogeneous genetic condition, recognized by three main clinical features present in most cases: overgrowth with macrocephaly, typical facial appearance and different degrees of intellectual disability. Three different types are described caused by variants or deletions/duplications in and genes. We aimed to describe a cohort of pediatric patients reporting the typical and unexpected findings in order to expand the phenotype of this syndrome and trying to find genotype-phenotype correlations.
METHODS
In our referral center, we collected and analyzed clinical and genetic data of 31-patients cohort diagnosed with SS.
RESULTS
All of them presented with overgrowth, typical dysmorphic features and different degree of developmental delay. Although structural cardiac defects have been reported in SS, non-structural diseases such as pericarditis were outstanding in our cohort. Moreover, we described here novel oncological malignancies not previously linked to SS such as splenic hamartoma, retinal melanocytoma and acute lymphocytic leukemia. Finally, five patients suffered from recurrent onychocryptosis that required surgical procedures, as an unreported prevalent medical condition.
DISCUSSION
This is the first study focusing on multiple atypical symptoms in SS at the time that revisits the spectrum of clinical and molecular basis of this heterogeneous entity trying to unravel a genotype-phenotype correlation.
PubMed: 37384309
DOI: 10.3389/fped.2023.1184529 -
Frontiers in Pediatrics 2022The role of lysine methyltransferases (KMTs) and demethylases (KDMs) in the regulation of chromatin modification is well-established. Recently, deleterious heterozygous...
The role of lysine methyltransferases (KMTs) and demethylases (KDMs) in the regulation of chromatin modification is well-established. Recently, deleterious heterozygous variants in were implicated in individuals with intellectual disability (ID) and/or autism spectrum disorder. We describe three unrelated patients with global developmental delay (GDD) or ID, macrocephaly and additional features. Using whole exome sequencing, each of the probands was found to harbor a distinct heterozygous disease-causing variant in : c.541C > G (p.His181Asp); c.833A > T (p.Asn278Ile); or c.391_394delAAAG (p.Lys131GlufsTer6). We discuss herein their clinical presentations, and compare them to those of previously reported patients. Furthermore, using a three-dimensional computational model of the protein, we demonstrate the predicted structural effects of the two missense variants. Our findings support the role of missense and nonsense variants in -associated GDD/ID, and suggest that this gene should be considered in the differential diagnosis of neurodevelopmental disorders accompanied by macrocephaly and/or overgrowth.
PubMed: 35433545
DOI: 10.3389/fped.2022.844845 -
European Journal of Medical Genetics Oct 2023Silver-Russell syndrome (SRS) is a rare genetic disorder that is mainly associated with prenatal and postnatal growth retardation. Loss of methylation on chromosome...
BACKGROUND
Silver-Russell syndrome (SRS) is a rare genetic disorder that is mainly associated with prenatal and postnatal growth retardation. Loss of methylation on chromosome 11p15 and maternal uniparental disomy on chromosome 7 (upd(7)mat) are two common causes, accounting for approximately 50% and 10% of all patients, respectively. Pathogenic variants of genes, such as HMGA2, IGF2, CDKN1C, and PLAG1, have also been detected in patients with SRS. So far, SRS caused by PLAG1 alterations have only been described in two sporadic cases and three families.
PATIENT PRESENTATION
The genetic and clinical manifestations of SRS in a patient carrying a novel variant of PLAG1 were reported and these results were compared with those of five previously reported cases. Trio-based whole-exome sequencing revealed a heterozygous variation in PLAG1 (NM_002655.3: c.131del; p.(Asn44Thrfs*6)) in an infant girl with clinical suspicion of SRS. Familial studies confirmed that the mutation was inherited from her father. As seen in previously reported cases, the patient presented with prenatal and postnatal growth retardation, relative macrocephaly at birth, prominent forehead during infancy, and triangular face. However, no clinical characteristics such as feeding difficulties, hypothyroidism, or psychomotor and speech delay.
CONCLUSIONS
This study identified the sixth documented case of PLAG1 variants leading to SRS and expanded our knowledge of the molecular spectrum of SRS phenotypes.
PubMed: 37673301
DOI: 10.1016/j.ejmg.2023.104837 -
Molecular Genetics & Genomic Medicine Aug 2021Phosphatase and tensin homolog (PTEN) germline mutations are associated with cancer syndromes (PTEN hamartoma tumor syndrome; PHTS) and in pediatric patients with autism...
BACKGROUND
Phosphatase and tensin homolog (PTEN) germline mutations are associated with cancer syndromes (PTEN hamartoma tumor syndrome; PHTS) and in pediatric patients with autism spectrum disorder (ASD) and macrocephaly. The exact prevalence of PTEN mutations in patients with ASD and macrocephaly is uncertain; with prevalence rates ranging from 1% to 17%. Most studies are retrospective and contain more adult than pediatric patients, there is a need for more prospective pediatric studies.
METHODS
We recruited 131 patients (108 males, 23 females) with ASD and macrocephaly between the ages of 3 and 18 from five child and adolescent psychiatry clinics in Turkey from July 2018 to December 2019. We defined macrocephaly as occipito-frontal HC size at or greater than 2 standard deviations (SD) above the mean for age and sex on standard growth charts. PTEN gene sequence analysis was performed using a MiSeq next generation sequencing (NGS) platform, (Illumina).
CONCLUSION
PTEN gene sequence analyses identified three pathogenic/likely pathogenic mutations [NM_000314.6; p.(Pro204Leu), (p.Arg233*) and novel (p.Tyr176Cys*8)] and two variants of uncertain significance (VUS) [NM_000314.6; p.(Ala79Thr) and c.*10del]. We also report that patient with (p.Tyr176Cys*8) mutation has Grade 1 hepatosteatosis, a phenotype not previously described. This is the first PTEN prevalence study of patients with ASD and macrocephaly in Turkey and South Eastern Europe region with a largest homogenous cohort. The prevalence of PTEN mutations was found 3.8% (VUS included) or 2.29% (VUS omitted). We recommend testing for PTEN mutations in all patients with ASD and macrocephaly.
Topics: Adolescent; Autism Spectrum Disorder; Child; Child, Preschool; Female; Gene Frequency; Humans; Male; Megalencephaly; Mutation; PTEN Phosphohydrolase; Turkey
PubMed: 34268892
DOI: 10.1002/mgg3.1739 -
Cureus May 2022Alexander disease is an uncommon autosomal dominant leukodystrophy that influences the white matter of the central nervous system (CNS), predominantly affecting the...
Alexander disease is an uncommon autosomal dominant leukodystrophy that influences the white matter of the central nervous system (CNS), predominantly affecting the frontal lobe bilaterally. The most obvious pathogenic hallmark is the extensive deposition of cytoplasmic inclusions known as "Rosenthal fibers" in perivascular, subpial, and subependymal astrocytes throughout the CNS. The hereditary cause is mutations in the glial fibrillary acidic protein (GFAP) gene. Infantile, adult, and juvenile onsets are the three subtypes. Psychomotor retardation, mile-stone regression, spastic paresis, brain stem symptoms (swallowing, speech, etc.), and seizures define the juvenile variety, which emerges between the ages of three and 10 years. Macrocephaly has a lower likelihood of being a juvenile type. It is generally diagnosed based on clinical and magnetic resonance imaging findings. A five-year-old girl is presented as a case of juvenile Alexander disease, with typical clinical and MRI features.
PubMed: 35698668
DOI: 10.7759/cureus.24870 -
Neurologia Jun 2022Neurofibromatosis type 1 (NF1) is a progressive multisystem disorder following an autosomal dominant inheritance pattern that presents with multiple neurological... (Review)
Review
INTRODUCTION
Neurofibromatosis type 1 (NF1) is a progressive multisystem disorder following an autosomal dominant inheritance pattern that presents with multiple neurological manifestations.
METHODS
We reviewed medical histories of patients with NF1 followed up at our hospital's paediatric neurology department from May 1990 to 31 December 2018. We collected data on neurological symptoms.
RESULTS
A total of 128 patients with NF1 were identified. Mean age (SD) at NF1 diagnosis was 4.43 (3.38) years (range, 0.5-14.5 years). There was a slight female predominance (53.1%). Macrocephaly (head circumference over 2 SDs above average for age) was present in 37.5% of cases. Attention-deficit/hyperactivity disorder was recorded in 28.9% of patients (37): combined type in 20 patients, predominantly inattentive in 15, and predominantly impulsive/hyperactive in 2. Other manifestations included headache (18.6%), cognitive impairment (7.8%), motor deficit (6.2%), and epilepsy (4.68%). Brain MRI was performed in 85 patients, revealing T2-weighted hyperintensities in the basal ganglia and/or cerebellum in 60 patients (70.5%), Chiari malformation type 1 in 4 cases, and arachnoid cysts in 3. Optic nerve gliomas were identified by MRI in 22 patients (25.8%). Other MRI findings included plexiform neurofibromas (9.3%) and central nervous system gliomas (3.1%).
CONCLUSIONS
The neurological manifestations identified in our sample are consistent with those reported in the literature. Effective transfer strategies from paediatric neurology departments and subsequent clinical follow-up by adult neurology departments are needed to prevent loss to follow-up in adulthood.
Topics: Adolescent; Adult; Attention Deficit Disorder with Hyperactivity; Child; Child, Preschool; Epilepsy; Female; Headache; Humans; Infant; Magnetic Resonance Imaging; Male; Neurofibromatosis 1
PubMed: 35672119
DOI: 10.1016/j.nrleng.2019.05.008 -
Brain : a Journal of Neurology Aug 2022Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies,...
Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations.
Topics: Cadherins; Cell Cycle Proteins; Epilepsy; Female; Hemimegalencephaly; Humans; Malformations of Cortical Development; Malformations of Cortical Development, Group I; Mutation; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Protocadherins; TOR Serine-Threonine Kinases
PubMed: 35441233
DOI: 10.1093/brain/awac117 -
Diagnostics (Basel, Switzerland) Apr 2021Brain tumors in infants including those diagnosed in fetal age, newborns and under a year old represent less than 10% of pediatric nervous system tumors and present... (Review)
Review
Brain tumors in infants including those diagnosed in fetal age, newborns and under a year old represent less than 10% of pediatric nervous system tumors and present differently when compared with older children in terms of clinical traits, location and histology. The most frequent clinical finding is a macrocephaly but non-specific symptoms can also be associated. The prognosis is usually poor and depends on several factors. Surgery continues to be the main option in terms of therapeutic strategies whereas the role of chemotherapy is not yet well defined and radiotherapy is exceptionally undertaken. In view of this situation, a molecular characterization could assist in providing therapeutic options for these tumors. This review highlights the recent advances in the diagnosis and treatment of brain tumors in infants with a particular focus on the molecular landscape and future clinical applications.
PubMed: 33917833
DOI: 10.3390/diagnostics11040670