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1.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
2.
Am J Hum Genet ; 108(5): 857-873, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33961779

RESUMO

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Rim Fundido/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Proteínas Nucleares/genética , Osteocondrodisplasias/genética , Adolescente , Sequência de Aminoácidos , Animais , Encefalopatias/etiologia , Criança , Pré-Escolar , Epilepsia/complicações , Evolução Molecular , Feminino , Frequência do Gene , Humanos , Lactente , Masculino , Camundongos , Modelos Moleculares , Proteínas Nucleares/química , Proteínas Nucleares/deficiência , Fenótipo , Estabilidade Proteica , Síndrome , Fatores de Elongação da Transcrição/química , Fatores de Elongação da Transcrição/genética , Adulto Jovem , Peixe-Zebra/genética
3.
Hum Genet ; 140(4): 681-690, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33389145

RESUMO

PURPOSE: Nuclear receptor binding SET domain protein 1, NSD1, encodes a histone methyltransferase H3K36. NSD1 is responsible for the phenotype of the reciprocal 5q35.2q35.3 microdeletion-microduplication syndromes. We expand the phenotype and demonstrate the functional role of NSD1 in microduplication 5q35 syndrome. METHODS: Through an international collaboration, we report nine new patients, contributing to the emerging phenotype, highlighting psychiatric phenotypes in older affected individuals. Focusing specifically on the undergrowth phenotype, we have modeled the effects of Mes-4/NSD overexpression in Drosophila melanogaster. RESULTS: The individuals (including a family) from diverse backgrounds with duplications ranging in size from 0.6 to 4.5 Mb, have a consistent undergrowth phenotype. Mes-4 overexpression in the developing wing causes undergrowth, increased H3K36 methylation, and increased apoptosis. We demonstrate that altering the levels of insulin receptor (IR) rescues the apoptosis and the wing undergrowth phenotype, suggesting changes in mTOR pathway signaling. Leucine supplementation rescued Mes-4/NSD induced cell death, demonstrating decreased mTOR signaling caused by NSD1. CONCLUSION: Given that we show mTOR inhibition as a likely mechanism and amelioration of the phenotype by leucine supplementation in a fly model, we suggest further studies should evaluate the therapeutic potential of leucine or branched chain amino acids as an adjunct possible treatment to ameliorate human growth and psychiatric phenotypes and propose inclusion of 5q35-microduplication as part of the differential diagnosis for children and adults with delayed bone age, short stature, microcephaly, developmental delay, and psychiatric phenotypes.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 5 , Duplicação Gênica , Histona-Lisina N-Metiltransferase/genética , Serina-Treonina Quinases TOR/metabolismo , Adolescente , Adulto , Animais , Caspases/metabolismo , Morte Celular , Criança , Pré-Escolar , Regulação para Baixo , Drosophila melanogaster , Feminino , Humanos , Leucina/metabolismo , Leucina/farmacologia , Masculino , Linhagem , Fenótipo , Transdução de Sinais , Adulto Jovem
4.
Genet Med ; 22(5): 857-866, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31949312

RESUMO

PURPOSE: Four patients with Saul-Wilson syndrome were reported between 1982 and 1994, but no additional individuals were described until 2018, when the molecular etiology of the disease was elucidated. Hence, the clinical phenotype of the disease remains poorly defined. We address this shortcoming by providing a detailed characterization of its phenotype. METHODS: Retrospective chart reviews were performed and primary radiographs assessed for all 14 individuals. Four individuals underwent detailed ophthalmologic examination by the same physician. Two individuals underwent gynecologic evaluation. Z-scores for height, weight, head circumference and body mass index were calculated at different ages. RESULTS: All patients exhibited short stature, with sharp decline from the mean within the first months of life, and a final height Z-score between -4 and -8.5 standard deviations. The facial and radiographic features evolved over time. Intermittent neutropenia was frequently observed. Novel findings included elevation of liver transaminases, skeletal fragility, rod-cone dystrophy, and cystic macular changes. CONCLUSIONS: Saul-Wilson syndrome presents a remarkably uniform phenotype, and the comprehensive description of our cohort allows for improved understanding of the long-term morbidity of the condition, establishment of follow-up recommendations for affected individuals, and documentation of the natural history into adulthood for comparison with treated patients, when therapeutics become available.


Assuntos
Nanismo , Adulto , Feminino , Humanos , Fenótipo , Estudos Retrospectivos
5.
Am J Hum Genet ; 104(3): 422-438, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30773277

RESUMO

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.


Assuntos
Instabilidade Cromossômica , Dano ao DNA , Variação Genética , Anormalidades Musculoesqueléticas/patologia , NF-kappa B/genética , Osteocondrodisplasias/patologia , Adolescente , Adulto , Alelos , Animais , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Estudos de Associação Genética , Humanos , Camundongos , Camundongos Knockout , Anormalidades Musculoesqueléticas/genética , Osteocondrodisplasias/genética , Sequenciamento Completo do Exoma , Adulto Jovem , Peixe-Zebra
6.
Am J Hum Genet ; 103(5): 752-768, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388402

RESUMO

The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly.


Assuntos
Haploinsuficiência/genética , Deficiência Intelectual/genética , Megalencefalia/genética , Fatores de Transcrição NFI/genética , Adolescente , Adulto , Animais , Córtex Cerebral/patologia , Criança , Pré-Escolar , Códon sem Sentido/genética , Estudos de Coortes , Corpo Caloso/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
7.
Am J Hum Genet ; 103(4): 553-567, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30290151

RESUMO

The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.


Assuntos
Síndrome do Cromossomo X Frágil/genética , Transporte Proteico/genética , Proteoglicanas/genética , Proteínas de Transporte Vesicular/genética , Adulto , Substituição de Aminoácidos/genética , Animais , Animais Geneticamente Modificados/genética , Linhagem Celular , Criança , Pré-Escolar , Retículo Endoplasmático/genética , Matriz Extracelular/genética , Feminino , Fibroblastos/patologia , Glicosilação , Complexo de Golgi/genética , Heterozigoto , Humanos , Lactente , Masculino , Peixe-Zebra
8.
Nat Genet ; 49(1): 36-45, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27841880

RESUMO

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology.


Assuntos
Aberrações Cromossômicas , Anormalidades Congênitas/genética , Rearranjo Gênico , Marcadores Genéticos/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Feminino , Humanos , Masculino
10.
Hum Mutat ; 36(11): 1052-63, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26178382

RESUMO

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.


Assuntos
Substituição de Aminoácidos , Códon , Mutação de Sentido Incorreto , Neurofibromina 1/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Nanismo/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neurofibromina 1/química , Adulto Jovem
11.
Eur J Hum Genet ; 23(6): 761-5, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25271087

RESUMO

Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or translational repression of specific messenger RNA in a fundamental biological process called RNA interference (RNAi). The Argonaute proteins, which derive from a highly conserved family of genes found in almost all eukaryotes, are critical mediators of this process. Four AGO genes are present in humans, three of which (AGO 1, 3, and 4) reside in a cluster on chromosome 1p35p34. The effects of germline AGO variants or dosage alterations in humans are not known, however, prior studies have implicated dysregulation of the RNAi mechanism in the pathogenesis of several neurodevelopmental disorders. We describe five patients with hypotonia, poor feeding, and developmental delay who were found to have microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes. We postulate that haploinsufficiency of AGO1 and AGO3 leading to impaired RNAi may be responsible for the neurocognitive deficits present in these patients. However, additional studies with rigorous phenotypic characterization of larger cohorts of affected individuals and systematic investigation of the underlying molecular defects will be necessary to confirm this.


Assuntos
Proteínas Argonauta/genética , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Deficiências do Desenvolvimento/genética , Fatores de Iniciação em Eucariotos/genética , Hipotonia Muscular/genética , Adolescente , Criança , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Feminino , Haploinsuficiência , Humanos , Masculino , Hipotonia Muscular/diagnóstico , Síndrome
12.
Eur J Hum Genet ; 22(4): 464-70, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23963300

RESUMO

Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (<400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-of-function for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Cromossomos Humanos Par 4/genética , Histona-Lisina N-Metiltransferase/genética , Proteínas de Membrana/genética , Proteínas Repressoras/genética , Síndrome de Wolf-Hirschhorn/genética , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Fenótipo , Deleção de Sequência , Síndrome de Wolf-Hirschhorn/diagnóstico
13.
Am J Hum Genet ; 92(1): 137-43, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23273567

RESUMO

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60% of cases overall, including both of the families in our cohort with more than one affected child and 50% of the simplex cases.


Assuntos
Mutação , Osteocondrodisplasias/genética , Monoéster Fosfórico Hidrolases/genética , Criança , Pré-Escolar , Feminino , Genoma Humano , Humanos , Lactente , Recém-Nascido , Masculino , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases
14.
Am J Hum Genet ; 92(1): 150-6, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23261301

RESUMO

Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ~50% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ~70% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.


Assuntos
Artrogripose/genética , Metaloendopeptidases/genética , Consanguinidade , Feminino , Ligação Genética , Humanos , Masculino , Mutação , Análise de Sequência de DNA
15.
Am J Med Genet A ; 140(22): 2416-25, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17036343

RESUMO

Several brain malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain-imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the cortical malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain malformation. We also noted mild cerebellar hypoplasia or mega-cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain malformation associated with DEL22q11.


Assuntos
Córtex Cerebral/anormalidades , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Síndrome , Tomografia Computadorizada por Raios X , Insuficiência Velofaríngea/genética
16.
J Pediatr ; 146(2): 253-7, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15689919

RESUMO

OBJECTIVES: Medical dictionaries and anthropologic sources define brachycephaly as a cranial index (CI = width divided by length x 100%) greater than 81%. We examine the impact of supine sleeping on CI and compare orthotic treatment with repositioning. STUDY DESIGN: We compared the effect of repositioning versus helmet therapy on CI in 193 infants referred for abnormal head shape. RESULTS: Eighty percent of the infants had a pretreatment CI > 81%. Their initial mean CI at mean age 5.3 months was 89%, and after treatment, their mean CI was 87% (+/-2 SE = 0.9%) at mean age 9.0 months. For 92 infants with an initial CI at or above 90%, their initial mean CI of 96.1% was reduced to a mean of 91.9%. CONCLUSIONS: Post-treatment CI was 86% to 88%, CI in neonates delivered by cesarean section was 80%, and CI in supine-sleeping Asian children was 85% to 91%, versus 78% to 83% for prone-sleeping American children. Repositioning was less effective than cranial orthotic therapy in correcting severe brachycephaly. We recommend varying the head position when putting infants to sleep.


Assuntos
Plagiocefalia não Sinostótica/terapia , Crânio/anormalidades , Decúbito Dorsal/fisiologia , Feminino , Dispositivos de Proteção da Cabeça , Humanos , Lactente , Estudos Longitudinais , Masculino , Plagiocefalia não Sinostótica/fisiopatologia , Sono/fisiologia , Resultado do Tratamento
17.
J Pediatr ; 146(2): 258-62, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15689920

RESUMO

OBJECTIVES: We compare positioning with orthotic therapy in 298 consecutive infants referred for correction of head asymmetry. STUDY DESIGN: We evaluated 176 infants treated with repositioning, 159 treated with helmets, and 37 treated with initial repositioning followed by helmet therapy when treatment failed. We compared reductions in diagonal difference (RDD) between repositioning and cranial orthotic therapy. Helmets were routinely used for infants older than 6 months with DD >1 cm. RESULTS: For infants treated with repositioning at a mean age of 4.8 months, the mean RDD was 0.55 cm (from an initial mean DD of 1.05 cm). For infants treated with cranial orthotics at a mean age of 6.6 months, the mean RDD was 0.71 cm (from an initial mean DD of 1.13 cm). CONCLUSIONS: Infants treated with orthotics were older and required a longer length of treatment (4.2 vs 3.5 months). Infants treated with orthosis had a mean final DD closer to the DD in unaffected infants (0.3 +/- 0.1 cm), orthotic therapy was more effective than repositioning (61% decrease versus 52% decrease in DD), and early orthosis was significantly more effective than later orthosis (65% decrease versus 51% decrease in DD).


Assuntos
Plagiocefalia não Sinostótica/terapia , Decúbito Dorsal/fisiologia , Fatores Etários , Oftalmopatias/etiologia , Oftalmopatias/terapia , Feminino , Dispositivos de Proteção da Cabeça , Humanos , Lactente , Estudos Longitudinais , Masculino , Plagiocefalia não Sinostótica/complicações , Plagiocefalia não Sinostótica/fisiopatologia , Crânio/anormalidades , Resultado do Tratamento
18.
Am J Med Genet A ; 120A(3): 400-5, 2003 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-12838563

RESUMO

In 1983, Johnson et al. described 16 related individuals with alopecia, anosmia or hyposmia, conductive hearing loss, microtia and/or atresia of the external auditory canal, and hypogonadotrophic hypogonadism inherited in an autosomal dominant pattern. Other less constant manifestations included facial asymmetry, mental retardation, congenital heart defect, cleft palate, and choanal stenosis. An isolated case was reported later (Johnston et al. [1987: Am J Med Genet 26: 925-927]) and thereafter an affected mother and son (Hennekam and Holtus [1993: Am J Med Genet 47: 714-716]). We describe an additional unrelated female patient with features resembling those of the previously reported cases. She presented with intrauterine growth deficiency, microcephaly, alopecia, bilateral microtia with canal atresia, conductive hearing loss, partial left facial palsy, posterior cleft palate, left choanal stenosis, tetralogy of Fallot, developmental delay, and right thumb polydactyly. Because the phenotypic abnormalities in this syndrome affect the brain, facial structures, ectoderm and its derivatives, outflow tract of the heart, and Rathke's pouch derivatives, this has suggested to previous authors etiologic involvement of the ectoderm and neuroectoderm of the first and second branchial arches, Rathke's pouch, and the diencephalon. Microtia with conductive hearing loss differentiates the condition from other ectodermal dysplasias. In the initial report, females appeared somewhat less affected than males, and there was male-to-male transmission. The mother of our patient manifests subtle features, which suggest she may be a mildly affected female. Additionally, there is a family history of early-onset alopecia in the maternal grandfather's relatives.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Perda Auditiva Condutiva/fisiopatologia , Síndromes Neurocutâneas/fisiopatologia , Anormalidades Múltiplas/genética , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Perda Auditiva Condutiva/genética , Humanos , Lactente , Recém-Nascido , Síndromes Neurocutâneas/genética
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