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1.
Rev Neurol ; 78(11): 323-326, 2024 Jun 01.
Artigo em Espanhol | MEDLINE | ID: mdl-38813790

RESUMO

INTRODUCTION: Pathogenic variants in BRWD3 gene have been described as a rare cause of syndromic X-linked intellectual disability. Its phenotype shows neurodevelopmental delay with intellectual disability in all reported patients, facial dysmorphic features, macrocephaly, overgrowth and obesity. The great majority of cases yield point variants in the gene, only three large deletions including only the BRWD3 gene have been reported. The BRWD3 protein is an epigenetic reader that regulates chromatin remodeling. We report a boy with a compatible phenotype and a deletion including only this gene. CASE REPORT: Boy, without family and perinatal pathological background, with neurodevelopmental delay: psychomotor delay, speech delay and intellectual disability, macrocephaly (p > 99) and obesity. Phenotype with facial dysmorphic features: wide forehead, deep set eyes, bulbous nose, prominent ears and pointed chin. The array-CGH analysis showed a 586 kb deletion at Xq21.1 including only one gene with associated disorder, BRWD3. Afterwards, the deletion was also identified in his asymptomatic mother and sister. CONCLUSIONS: Our patient confirms that the haploinsufficiency due to BRWD3 deletion is a causal genetic mechanism of the BRWD3-related syndromic X-linked intellectual disability. It is important to recognize the phenotype for the diagnosis and follow up of the patients, and also to carry out the family genetic analysis in order to identify and give genetic counselling to the women who also have the genetic defect, because the majority of them are asymptomatic, as the mother and sister of our patient.


TITLE: Síndrome de discapacidad intelectual ligada a X con macrocefalia por deleción del gen BRWD3.Introducción. Variantes patógenas en el gen BRWD3 son la causa de un tipo poco frecuente de discapacidad intelectual sindrómica ligada a X. Su fenotipo se asocia a la alteración neuroconductual con discapacidad intelectual, dismorfia facial, macrocefalia, sobrecrecimiento y obesidad. La gran mayoría de los pacientes presenta variantes puntuales en el gen y sólo se han descrito tres casos con deleciones parciales que incluyen únicamente al gen BRWD3. Funcionalmente es un lector epigenético que regula la remodelación de la cromatina. Presentamos un varón con fenotipo compatible con una deleción que incluye sólo este gen asociado a patología. Caso clínico. Varón sin antecedentes familiares ni perinatales de interés con alteración en el neurodesarrollo: retraso psicomotor, retraso del lenguaje y discapacidad cognitiva, macrocefalia (p > 99) y obesidad. Fenotipo con dismorfia facial: frente amplia, ojos hundidos, nariz bulbosa, pabellones auriculares despegados y mentón afilado. Array de hibridación genómica comparada con deleción de 586 kb en Xq21.1, que incluye un único gen asociado a la patología, BRWD3. Posteriormente se realizó un estudio a la madre y a la hermana, asintomáticas, y ambas portan la deleción. Conclusiones. Nuestro caso confirma que la haploinsuficiencia debida a la deleción del gen BRWD3 es un mecanismo genético causal de la discapacidad intelectual sindrómica ligada a X asociada al gen BRWD3. Es importante reconocer el fenotipo para el diagnóstico y el seguimiento, así como la realización del estudio familiar para asesoramiento genético a las mujeres que porten la alteración, puesto que en la mayoría de los casos son asintomáticas, como la madre y la hermana de este paciente.


Assuntos
Deleção de Genes , Deficiência Intelectual , Megalencefalia , Humanos , Megalencefalia/genética , Masculino , Deficiência Intelectual/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Fenótipo , Criança , Proteínas que Contêm Bromodomínio , Fatores de Transcrição
2.
DNA Cell Biol ; 43(7): 325-330, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38700464

RESUMO

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH), a type of overgrowth syndrome, is characterized by progressive megalencephaly, cortical brain malformations, and distal limb anomalies. Previous studies have revealed that the overactivity of the phosphatidylinositol 3-kinase-Protein kinase B pathway and the increased cyclin D2 (CCND2) expression were the main factors contributing to this disease. Here, we present the case of a patient who exhibited megalencephaly, polymicrogyria, abnormal neuronal migration, and developmental delay. Serum tandem mass spectrometry and chromosome examination did not detect any metabolic abnormalities or copy number variants. However, whole-exome sequencing and Sanger sequencing revealed a de novo nonsense mutation (NM_001759.3: c.829C>T; p.Gln277X) in the CCND2 gene of the patient. Bioinformatics analysis predicted that this mutation may disrupt the structure and surface charge of the CCND2 protein. This disruption could potentially prevent polyubiquitination of CCND2, leading to its resistance against degradation. Consequently, this could drive cell division and growth by altering the activity of key cell cycle regulatory nodes, ultimately contributing to the development of MPPH. This study not only presents a new case of MPPH and expands the mutation spectrum of CCND2 but also enhances our understanding of the mechanisms connecting CCND2 with overgrowth syndromes.


Assuntos
Ciclina D2 , Megalencefalia , Polidactilia , Polimicrogiria , Feminino , Humanos , Masculino , Códon sem Sentido/genética , Ciclina D2/genética , Sequenciamento do Exoma , Hidrocefalia , Malformações do Desenvolvimento Cortical , Megalencefalia/genética , Megalencefalia/diagnóstico , Polidactilia/genética , Polidactilia/diagnóstico , Polimicrogiria/genética , Polimicrogiria/diagnóstico , Pré-Escolar
4.
Int J Mol Sci ; 25(10)2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38791606

RESUMO

Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.


Assuntos
Dedos , Megalencefalia , Humanos , Megalencefalia/genética , Dedos/anormalidades
5.
Genes (Basel) ; 15(4)2024 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-38674365

RESUMO

O'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant disorder caused by mutations in the KMT2E 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 KMT2E 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 KMT2E.


Assuntos
Proteínas de Ligação a DNA , Deficiências do Desenvolvimento , Criança , Humanos , Masculino , Transtorno Autístico/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Megalencefalia/genética , Fenótipo , Splicing de RNA/genética , Mutação Silenciosa
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(4): 480-485, 2024 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-38565516

RESUMO

OBJECTIVE: To explore the clinical characteristics of 1q21.1 microdeletion by using single nucleotide polymorphism microarrays (SNP array). METHODS: Eighteen cases of 1q21.1 microdeletion syndrome diagnosed at the Longgang District Maternal and Child Health Care Hospital of Shenzhen City from June 2017 to December 2022 were selected as the study subjects. Clinical data of the patients were collected. Results of chromosomal karyotyping and SNP assay were retrospectively analyzed. RESULTS: Among the 18 cases with 1q21.1 microdeletions, 13 had a deletion between BP3 and BP4, 4 had a deletion between BP1/BP2 and BP4, whilst 1 had a proximal 1q21.1 deletion (between BP2 and BP3) involving the Thrombocytopenia-absent radius (TAR) region. The deletions had spanned from 360 kb to 3.9 Mb, which encompassed the GJA5, GJA8, CHD1L, RBM8AB and other morbid genes. In three families, the proband child has inherited the same 1q21.1 microdeletion from their parents, whose clinical phenotype was normal or slightly abnormal. The clinical phenotypes of 1q21.1 microdeletion had included cognitive or behavioral deficits in 9 cases (9/18, 50.0%), growth retardation in 8 cases (8/18, 44.4%), craniofacial deformities in 7 cases (7/18, 38.8%), cardiovascular malformations in 5 cases (5/18, 27.8%), and microcephaly in 3 cases (3/18, 16.7%). CONCLUSION: 1q21.1 microdeletion syndrome has incomplete penetrance and varied expression such as intellectual impairment, growth and development delay, and microcephaly, with a wide range of non-specific phenotypes.


Assuntos
Anormalidades Múltiplas , Deficiência Intelectual , Megalencefalia , Microcefalia , Criança , Humanos , Microcefalia/genética , Estudos Retrospectivos , Deleção Cromossômica , Fenótipo , Biologia Molecular , Deficiência Intelectual/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Cromossomos Humanos Par 1
8.
Am J Med Genet A ; 194(7): e63585, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38459620

RESUMO

Germline gain of function variations in the AKT3 gene cause brain overgrowth syndrome with megalencephaly and diffuse bilateral cortical malformations. Here we report a child with megalencephaly, who is a carrier of a novel heterozygous missense variant in the AKT3 gene NM_005465.7:c.964G>T,p.Asp322Tyr. The phenotype of this patient is associated with pituitary deficiencies diagnosed at 2 years of age: growth hormone (GH) deficiency responsible for growth delay and central hypothyroidism. After 6 months of GH treatment, intracranial hypertension was noted, confirmed by the observation of papilledema and increased intracranial pressure, requiring the initiation of acetazolamide treatment and the discontinuation of GH treatment. This is the second reported patient described with megalencephaly and AKT3 gene variant associated with GH deficiency . Other endocrine disorders have also been reported in few cases with hypothyroidism and hypoglycemia. Pituitary deficiency may be a part of the of megalencephaly phenotype secondary to germline variant in the AKT3 gene. Special attention should be paid to growth in these patients and search for endocrine deficiency is necessary in case of growth retardation or hypoglycemia.


Assuntos
Mutação em Linhagem Germinativa , Megalencefalia , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-akt , Humanos , Megalencefalia/genética , Megalencefalia/patologia , Mutação de Sentido Incorreto/genética , Proteínas Proto-Oncogênicas c-akt/genética , Mutação em Linhagem Germinativa/genética , Masculino , Pré-Escolar , Fenótipo , Hipotireoidismo/genética , Hipotireoidismo/patologia , Hipotireoidismo/complicações , Feminino , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/genética
9.
Genes (Basel) ; 15(3)2024 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-38540409

RESUMO

INTRODUCTION: Alexander disease (AxD) is a rare neurodegenerative condition that represents the group of leukodystrophies. The disease is caused by GFAP 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, GFAP 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.


Assuntos
Doença de Alexander , Doenças Ósseas , Doenças Desmielinizantes , Epilepsia Resistente a Medicamentos , Hiponatremia , Doenças por Armazenamento dos Lisossomos , Megalencefalia , Espasmos Infantis , Criança , Recém-Nascido , Humanos , Doença de Alexander/genética , Doença de Alexander/patologia , Proteína Glial Fibrilar Ácida/genética , Megalencefalia/genética
10.
Medicine (Baltimore) ; 103(6): e36104, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38335372

RESUMO

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.


Assuntos
Transtorno do Espectro Autista , Megalencefalia , Criança , Gravidez , Feminino , Humanos , Ácido Fólico , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/etiologia , Suplementos Nutricionais , Estudos de Casos e Controles , Pontuação de Propensão , Mães , Megalencefalia/complicações
11.
Mol Genet Genomic Med ; 12(2): e2394, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38337154

RESUMO

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.


Assuntos
Cistos , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Megalencefalia , Criança , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Mutação , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 41(2): 230-233, 2024 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-38311565

RESUMO

OBJECTIVE: To explore the genetic etiology of a child with Cowden syndrome 1 (CS1). METHODS: A child who had visited the Ningbo Women and Children's Hospital on August 26, 2022 was selected as the study subject. Clinical information of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The child, a 13-year-old boy, had manifested with severe mental retardation, hyperactivity, autistic behavior, sparse and prominent teeth, macrocephaly, and skin freckles on the penis. His mother had presented with multiple papules, hamartomatous polyps, thyroid adenoma and macrocephaly. WES results revealed that the child has harbored a nonsense c.781C>T (p.Q261*) variant of the PTEN gene, which was inherited from his mother. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.781C>T variant was classified as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION: The c.781C>T variant of the PTEN gene probably underlay the pathogenesis in the child and his mother. Above finding has facilitated genetic counseling for this family.


Assuntos
Transtorno do Espectro Autista , Síndrome do Hamartoma Múltiplo , Megalencefalia , Adolescente , Humanos , Masculino , Síndrome do Hamartoma Múltiplo/genética , Mães , Mutação , Pele
13.
Childs Nerv Syst ; 40(6): 1689-1697, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38407606

RESUMO

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.


Assuntos
Síndrome do Hamartoma Múltiplo , PTEN Fosfo-Hidrolase , Humanos , Feminino , Masculino , PTEN Fosfo-Hidrolase/genética , Criança , Síndrome do Hamartoma Múltiplo/genética , Síndrome do Hamartoma Múltiplo/diagnóstico por imagem , Pré-Escolar , Adolescente , Estudos Retrospectivos , Lactente , Mutação/genética , Megalencefalia/genética , Megalencefalia/diagnóstico por imagem
14.
J Mech Behav Biomed Mater ; 152: 106423, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38290393

RESUMO

The modulation of cell behavior during culture is one of the most important aspects of bone tissue engineering because of the necessity for a complex mechanical and biochemical environment. This study aimed to improve the physicochemical properties of chitosan/multi-phase calcium phosphate (MCaP) scaffolds using an optimized mixture design experiment and evaluate the effect of biofunctionalization of the obtained scaffolds with the bone morphogenetic protein BMP-2 on stem cell behavior. The present study evaluated the compressive strength, elastic modulus, porosity, pore diameter, and degradation in simulated body fluids and integrated these responses using desirability. The properties of the scaffolds with the best desirability (18.4% of MCaP) were: compressive strength of 23 kPa, elastic modulus of 430 kPa, pore diameter of 163 µm, porosity of 92%, and degradation of 20% after 21 days. Proliferation and differentiation experiments were conducted using dental pulp stem cells after grafting BMP-2 onto scaffolds via the carbodiimide route. These experiments showed that MCaP promoted cell proliferation and increased alkaline phosphatase activity, whereas BMP-2 enhanced cell differentiation. This study demonstrates that optimizing the composition of a mixture of chitosan and MCaP improves the physicochemical and biological properties of scaffolds, indicating that this solution is viable for application in bone tissue engineering.


Assuntos
Anormalidades Múltiplas , Quitosana , Megalencefalia , Dermatopatias Vasculares , Telangiectasia/congênito , Biomimética , Engenharia Tecidual , Osso e Ossos , Fosfatos de Cálcio
15.
Orphanet J Rare Dis ; 19(1): 29, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38281003

RESUMO

AIM: Achondroplasia is the most common of the skeletal dysplasias that cause fatal and disabling growth and developmental disorders in children, and is caused by a mutation in the fibroblast growth factor receptor, type 3 gene(FGFR3). This study aims to analyse the clinical characteristics and gene mutations of ACH to accurately determine whether a patient has ACH and to raise public awareness of the disease. METHODS: The database of Pubmed, Cochrane Library, Wanfang and CNKI were searched with terms of "Achondroplasias" or "Skeleton-Skin-Brain Syndrome" or "Skeleton Skin Brain Syndrome" or "ACH" and "Receptor, Fibroblast Growth Factor, Type 3" or "FGFR3". RESULTS: Finally, four hundred and sixty-seven patients with different FGFR3 mutations were enrolled. Of the 138 patients with available gender information, 55(55/138, 40%) were female and 83(83/138, 60%) were male. Among the patients with available family history, 47(47/385, 12%) had a family history and 338(338/385, 88%) patients were sporadic. The age of the patients ranged from newborn babies to 36 years old. The mean age of their fathers was 37 ± 7 years (range 31-53 years). Patients came from 12 countries and 2 continents, with the majority being Asian (383/432, 89%), followed by European (49/432, 11%). Short stature with shortened arms and legs was found in 112(112/112) patients, the abnormalities of macrocephaly in 94(94/112) patients, frontal bossing in 89(89/112) patients, genu valgum in 64(64/112) patients and trident hand were found in 51(51/112) patients. The most common mutation was p.Gly380Arg of the FGFR3 gene, which contained two different base changes, c.1138G > A and c.1138G > C. Ten rare pathogenic mutations were found, including c.831A > C, c.1031C > G, c.1043C > G, c.375G > T, c.1133A > G, c.1130T > G, c.833A > G, c.649A > T, c.1180A > T and c.970_971insTCTCCT. CONCLUSION: ACH was caused by FGFR3 gene mutation, and c.1138G > A was the most common mutation type. This study demonstrates the feasibility of molecular genetic testing for the early detection of ACH in adolescents with short stature, trident hand, frontal bossing, macrocephaly and genu valgum.


Assuntos
Acondroplasia , Geno Valgo , Megalencefalia , Osteocondrodisplasias , Criança , Recém-Nascido , Adolescente , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Acondroplasia/genética , Acondroplasia/patologia , Mutação/genética
16.
Am J Med Genet A ; 194(5): e63516, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38168088

RESUMO

The NFIX gene encodes a DNA-binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of NFIX are associated with two autosomal dominant Mendelian disorders, Malan syndrome (MIM 614753) and Marshall-Smith syndrome (MIM 602535), which are clinically distinct due to different disease-causing mechanisms. NFIX variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N-terminal DNA binding and dimerization domain or are protein-truncating variants that trigger nonsense-mediated mRNA decay (NMD) resulting in NFIX haploinsufficiency. NFIX variants associated with Marshall-Smith syndrome are protein-truncating and are clustered between exons 6 and 10, including a recurrent Alu-mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall-Smith syndrome is likely due to a dominant-negative effect of these protein-truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo NFIX intragenic duplication. Using genome sequencing, exon-level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to NFIX haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic NFIX duplication.


Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Anormalidades Craniofaciais , Deficiência Intelectual , Megalencefalia , Displasia Septo-Óptica , Síndrome de Sotos , Criança , Humanos , Fatores de Transcrição NFI/genética , Síndrome de Sotos/genética , Éxons/genética , Megalencefalia/genética , Deficiência Intelectual/genética , Análise de Sequência de RNA
17.
Childs Nerv Syst ; 40(1): 219-225, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37688615

RESUMO

The syndrome of megalencephaly, mega corpus callosum (MEG-MegaCC) accompanied by complete lack of motor development is a rare condition with only few sporadic cases having been reported in the literature. In this paper, we describe a child from non-consanguineous parents presenting with MegaCC, psychomotor retardation, and language impairment linked to MEG-MegaCC syndrome. Genetic analysis, radiological findings, and detailed neurological phenotype of MEG-MegaCC syndrome with its overlapping syndromes would allow for a better classification of the disease spectrum.


Assuntos
Megalencefalia , Malformações do Sistema Nervoso , Criança , Humanos , Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/complicações , Agenesia do Corpo Caloso/diagnóstico por imagem , Megalencefalia/complicações , Megalencefalia/diagnóstico por imagem , Síndrome
18.
Clin Pediatr (Phila) ; 63(4): 506-511, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-37350029

RESUMO

Abusive head trauma (AHT) is a significant cause of morbidity and mortality for infants. Determining when to pursue a complete physical abuse evaluation can be difficult, especially for nonspecific findings or when a child appears clinically well. This retrospective study of 7 cases sought to describe the presentation, evaluation, and diagnoses for infants with abnormal subdural collections identified on cranial ultrasound for macrocephaly, and to determine how frequently AHT is diagnosed. The results of this study showed that while each patient presented due to asymptomatic macrocephaly, the extent of the workup varied greatly. In addition, no infants had suspicious injuries for abuse during the initial evaluation or the year following. In summary, among the 7 patients seen for asymptomatic macrocephaly with possible subdural hemorrhage, there were very inconsistent child abuse workups. There needs to be a standardized clinical guideline for this specific patient population involving a child abuse pediatric evaluation.


Assuntos
Maus-Tratos Infantis , Traumatismos Craniocerebrais , Megalencefalia , Lactente , Criança , Humanos , Estudos Retrospectivos , Hematoma Subdural/diagnóstico por imagem , Hematoma Subdural/etiologia , Traumatismos Craniocerebrais/diagnóstico por imagem , Maus-Tratos Infantis/diagnóstico , Megalencefalia/diagnóstico por imagem , Megalencefalia/complicações
19.
Neuropediatrics ; 55(1): 71-74, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36914163

RESUMO

Subdural hemorrhages (SDHs) in the pediatric population are associated with a high mortality and morbidity and may present in the context of abusive head trauma. Diagnostic investigations for such cases often include evaluation for rare genetic and metabolic disorders that can have associated SDH. Sotos syndrome is an overgrowth syndrome associated with macrocephaly and increased subarachnoid spaces and rarely with neurovascular complications. Here, we report two cases of Sotos syndrome, one with SDH during infancy who underwent repeated evaluation for suspected child abuse prior to the Sotos syndrome diagnosis and the other with enlarged extra-axial cerebrospinal fluid spaces, demonstrating a possible mechanism for SDH development in this setting. These cases suggest that some individuals with Sotos syndrome may be at elevated risk of developing SDH in infancy and that Sotos syndrome should be on the differential diagnosis during a medical genetics evaluation in cases of unexplained SDH, especially in the setting of macrocephaly.


Assuntos
Maus-Tratos Infantis , Traumatismos Craniocerebrais , Megalencefalia , Síndrome de Sotos , Humanos , Criança , Lactente , Síndrome de Sotos/complicações , Síndrome de Sotos/diagnóstico , Síndrome de Sotos/genética , Hematoma Subdural/diagnóstico , Traumatismos Craniocerebrais/complicações , Maus-Tratos Infantis/diagnóstico , Megalencefalia/etiologia , Megalencefalia/complicações
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