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1.
Hum Genet ; 139(4): 531-543, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32030560

RESUMO

We present a comprehensive clinically oriented workflow for large-insert genome sequencing (liGS)-based nucleotide level resolution and interpretation of de novo (dn) apparently balanced chromosomal abnormalities (BCA) in prenatal diagnosis (PND). Retrospective or concomitant with conventional PND and liGS, molecular and newly developed clinically inspired bioinformatic tools (TAD-GConTool and CNV-ConTool) are applied to analyze and assess the functional and phenotypic outcome of dn structural variants (dnSVs). Retrospective analysis of four phenotype-associated dnSVs identified during conventional PND precisely reveal the genomic elements disrupted by the translocation breakpoints. Identification of autosomal dominant disease due to the disruption of ANKS1B and WDR26 by t(12;17)(q23.1;q21.33)dn and t(1;3)(q24.11;p25.3)dn breakpoints, respectively, substantiated the proposed workflow. We then applied this workflow to two ongoing prenatal cases with apparently balanced dnBCAs: 46,XX,t(16;17)(q24;q21.3)dn referred for increased risk on combined first trimester screening and 46,XY,t(2;19)(p13;q13.1)dn referred due to a previous trisomy 21 pregnancy. Translocation breakpoints in the t(16;17) involve ANKRD11 and WNT3 and disruption of ANKRD11 resulted in KBG syndrome confirmed in postnatal follow-up. Breakpoints in the t(2;19) are within ATP6V1B1 and the 3' UTR of CEP89, and are not interpreted to cause disease. Genotype-phenotype correlation confirms the causative role of WDR26 in the Skraban-Deardorff and 1q41q42 microdeletion phenocopy syndromes, and that disruption of ANKS1B causes ANKS1B haploinsufficiency syndrome. In sum, we show that an liGS-based approach can be realized in PND care providing additional information concerning clinical outcomes of dnBCAs in patients with such rearrangements.


Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Transtornos Cromossômicos , Cromossomos Humanos/genética , Facies , Genes Dominantes , Deficiência Intelectual , Diagnóstico Pré-Natal , Anormalidades Dentárias , Translocação Genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Gravidez , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Fluxo de Trabalho
3.
J Orthop Surg (Hong Kong) ; 28(1): 2309499019889902, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31898473
4.
Am J Obstet Gynecol ; 222(6): 615.e1-615.e9, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31930994

RESUMO

BACKGROUND: In 2014, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Imaging Workshop consensus recommended that sonograms be offered routinely to all pregnant women. In the absence of another indication, this examination is recommended at 18-22 weeks of gestation. Studies of anomaly detection often focus on pregnancies at risk for anomalies and on the yield of detailed sonography, topics less applicable to counseling low-risk pregnancies about the benefits and limitations of standard sonography. The clinical utility of follow-up sonogram in low-risk pregnancies for the purpose of fetal anomaly detection has not been established. OBJECTIVE: The objective of the study was to evaluate the utility of follow-up standard sonography for anomaly detection among low-risk pregnancies in a nonreferred population. STUDY DESIGN: We performed a retrospective cohort study of singleton pregnancies that underwent standard sonography at 18-21 6/7 weeks of gestation from October 2011 through March 2018 with subsequent delivery of a live-born infant at our hospital. Pregnancies with indications for detailed sonography in our system were excluded to evaluate fetal anomalies first identified with standard sonography. Anomalies were categorized according to the European Registration of Congenital Anomalies and Twins (EUROCAT) system, with confirmation based on neonatal evaluation. Among those with no anomaly detected initially, we evaluated the rate of subsequent detection according to number of follow-up sonograms, gestational age at sonography, organ system(s) affected, and anomaly severity. Statistical analyses were performed using χ2 and a Mantel-Haenszel test. RESULTS: Standard sonography was performed in 40,335 pregnancies at 18-21 6/7 weeks, and 11,770 (29%) had at least 1 follow-up sonogram, with a second follow-up sonogram in 3520 (9%). Major abnormalities were confirmed in 387 infants (1%), with 248 (64%) detected initially and 28 (7%) and 5 (1%) detected on the first and second follow-up sonograms. Detection of residual anomalies on follow-up sonograms was significantly lower than detection on the initial standard examination: 64% on initial examination, 45% for first follow-up, and 45% for second follow-up (P < .01). A larger number of follow-up examinations were required per anomalous fetus detected: 163 examinations per anomalous fetus detected initially, 420 per fetus detected at the first follow-up examination, and 705 per fetus detected at the second follow-up sonogram (P < .01). The number of follow-up examinations to detect each additional anomalous fetus was not affected by gestational age (P = .7). Survival to hospital discharge was significantly lower for fetuses with anomalies detected on initial (88%) than for fetuses with anomalies undetected until delivery (90 of 91, 99%; P < .002). CONCLUSION: In a low-risk, nonreferred cohort with fetal anomaly prevalence of 1%, follow-up sonography resulted in detection of 45% of fetal anomalies that had not been identified during the initial standard sonogram. Significantly more follow-up sonograms were required to detect each additional anomalous fetus.


Assuntos
Anormalidades Congênitas/diagnóstico por imagem , Idade Gestacional , Guias de Prática Clínica como Assunto , Ultrassonografia Pré-Natal/métodos , Anormalidades Múltiplas/diagnóstico por imagem , Adulto , Doenças do Desenvolvimento Ósseo/congênito , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Estudos de Coortes , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades do Sistema Digestório/diagnóstico por imagem , Feminino , Cardiopatias Congênitas/diagnóstico por imagem , Humanos , Recém-Nascido , Malformações do Sistema Nervoso/diagnóstico por imagem , Gravidez , Segundo Trimestre da Gravidez , Anormalidades do Sistema Respiratório/diagnóstico por imagem , Estudos Retrospectivos , Ultrassonografia Pré-Natal/normas , Anormalidades Urogenitais/diagnóstico por imagem
5.
BMC Med Genet ; 21(1): 7, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31910817

RESUMO

BACKGROUND: Osteocraniostenosis (OCS) is a rare genetic disorder characterised by premature closure of cranial sutures, gracile bones and perinatal lethality. Previously, diagnosis has only been possible postnatally on clinical and radiological features. This study describes the first prenatal diagnosis of OCS. CASE PRESENTATION: In this case prenatal ultrasound images were suggestive of a serious but non-lethal skeletal dysplasia. Due to the uncertain prognosis the parents were offered Whole Exome Sequencing (WES), which identified a specific gene mutation in the FAMIIIa gene. This mutation had previously been detected in two cases and was lethal in both perinatally. This established the diagnosis, a clear prognosis and allowed informed parental choice regarding ongoing pregnancy management. CONCLUSIONS: This case report supports the use of targeted WES prenatally to confirm the underlying cause and prognosis of sonographically suspected abnormalities.


Assuntos
Doenças do Desenvolvimento Ósseo/diagnóstico , Anormalidades Craniofaciais/diagnóstico , Citocinas/genética , Diagnóstico Pré-Natal , Sequenciamento Completo do Exoma , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/patologia , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Feminino , Humanos , Recém-Nascido , Pais , Gravidez
6.
Eur J Endocrinol ; 182(3): C9-C12, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31972544

RESUMO

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients.


Assuntos
Doença de Addison/genética , Hiperplasia Suprarrenal Congênita/genética , Doença de Addison/complicações , Doença de Addison/diagnóstico , Doença de Addison/fisiopatologia , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/fisiopatologia , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/fisiopatologia , Encefalopatias/etiologia , Encefalopatias/genética , Encefalopatias/fisiopatologia , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Transtornos do Desenvolvimento Sexual/etiologia , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/fisiopatologia , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/fisiopatologia , Humanos , Hipoadrenocorticismo Familiar/complicações , Hipoadrenocorticismo Familiar/diagnóstico , Hipoadrenocorticismo Familiar/genética , Hipoadrenocorticismo Familiar/fisiopatologia , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/fisiopatologia , Técnicas de Diagnóstico Molecular , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/genética , Síndrome Nefrótica/fisiopatologia , Dermatopatias/etiologia , Dermatopatias/genética , Dermatopatias/fisiopatologia
7.
J Pediatr Orthop ; 40(2): e138-e143, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31022017

RESUMO

BACKGROUND: Primary treatment for Blount disease has changed in the last decade from osteotomies or staples to tension band plate (TBP)-guided hemiepiphysiodesis. However, implant-related issues have been frequently reported with Blount cases. The purpose of our study is to evaluate the surgical failure rates of TBP in Blount disease and characterize predictors for failure. METHODS: We performed an Institutional Review Board-approved retrospective chart-review of pediatric patients with Blount disease to evaluate the results of TBP from 2008 to 2017 and a systematic literature review. Blount cases defined as pathologic tibia-vara with HKA (hip-knee-ankle) axis and MDA (metaphyseal-diaphyseal angle) deviations ≥11 degrees were included in the analysis. Surgical failure was categorized as mechanical and functional failure. We studied both patient and implant-related characteristics and compared our results with a systematic review. RESULTS: In 61 limbs of 40 patients with mean follow-up of 38 months, we found 41% (25/61) overall surgical failure rate and 11% (7/61) mechanical failure rate corresponding to 11% to 100% (range) and 0% to 50% (range) in 8 other studies. Statistical comparison between our surgical failure and nonfailure groups showed significant differences in deformity (P=0.001), plate material (P=0.042), and obesity (P=0.044) in univariate analysis. The odds of surgical failure increased by 1.2 times with severe deformity and 5.9 times with titanium TBP in the multivariate analysis after individual risk-factor adjustment. All 7 mechanical failures involved breakage of cannulated screws on the metaphyseal side. CONCLUSIONS: Most of the studies have reported high failure rates of TBP in Blount cases. Besides patient-related risk factors like obesity and deformity, titanium TBP seems to be an independent risk factor for failure. Solid screws were protective for mechanical failure, but not for functional failure. In conclusion, efficacy of TBP still needs to be proven in Blount disease and implant design may warrant reassessment. LEVEL OF EVIDENCE: Level III-retrospective comparative study with a systematic review.


Assuntos
Doenças do Desenvolvimento Ósseo/cirurgia , Placas Ósseas , Procedimentos Ortopédicos/métodos , Procedimentos Ortopédicos/estatística & dados numéricos , Osteocondrose/congênito , Adolescente , Placas Ósseas/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Obesidade/complicações , Procedimentos Ortopédicos/efeitos adversos , Procedimentos Ortopédicos/instrumentação , Osteocondrose/cirurgia , Estudos Retrospectivos , Índice de Gravidade de Doença , Titânio , Falha de Tratamento
9.
Toxicol Lett ; 321: 122-130, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31874197

RESUMO

Our previous studies confirmed that prenatal caffeine exposure (PCE) could induce susceptibility to osteoarthritis in adult offspring rats due to poor chondrocyte differentiation, but its mechanism remains to be further investigated. This study aimed to explore whether subchondral bone dysplasia mediates susceptibility to osteoarthritis in adult offspring rats induced by PCE. Pregnant Wistar rats were treated with caffeine (120 mg/kg.d) or saline from gestational day (GD) 9 to 20. The female offspring were euthanized to collect femurs at GD20, postnatal week (PW) 6, and PW28 (non-ovariectomy and ovariectomy groups) to detect osteoarthritis-like phenotype, subchondral bone mass, ossification center development, and other evidence. The results showed that PCE increased the Mankin score of pathological articular cartilage, but decreased articular cartilage thickness and subchondral bone mass, which were more obvious after ovariectomy. Meanwhile, the correlation analysis results demonstrated that the Mankin score of articular cartilage was significantly negatively correlated with subchondral bone mass, and the thickness of articular cartilage was significantly positively correlated with subchondral bone mass. Further, the length and area of the primary and secondary ossification centers, the number of osteoblasts, and the related genes' expression of osteogenic differentiation (e.g., Runx2, BSP, ALP, and OCN) were all significantly decreased in the PCE group before and after birth. Taken together, PCE induced susceptibility to osteoarthritis in adult female offspring, which was likely related to the subchondral bone dysplasia and reduction of subchondral bone mass production due to developmental disorder of primary and secondary ossification centers caused by osteoblast differentiation disability before and after birth.


Assuntos
Doenças do Desenvolvimento Ósseo/induzido quimicamente , Cafeína/toxicidade , Cartilagem Articular/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Osteoartrite/induzido quimicamente , Osteogênese/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Fatores Etários , Animais , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/metabolismo , Doenças do Desenvolvimento Ósseo/patologia , Cartilagem Articular/patologia , Diferenciação Celular/efeitos dos fármacos , Feminino , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Fêmur/patologia , Idade Gestacional , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteogênese/genética , Ovariectomia , Gravidez , Ratos Wistar , Fatores Sexuais , Tíbia/efeitos dos fármacos , Tíbia/metabolismo , Tíbia/patologia
10.
J Pediatr Orthop ; 40(1): 17-22, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31815857

RESUMO

BACKGROUND: In juvenile and adolescent tibia vara patients with sufficient growth remaining, implant-controlled hemiepiphyseodesis, or guided growth, can be used to correct deformity. Recent reports have described hardware failure of certain hemiepiphyseodesis implants in overweight patients with tibia vara. We describe our experience using transphyseal screws to correct deformity in this patient population. METHODS: A retrospective chart and radiograph review was conducted on all juvenile and adolescent tibia vara patients who underwent lateral proximal tibial hemiepiphyseodesis using a single transphyseal screw. Charts were queried for preoperative and postoperative mechanical axis deviation, medial proximal tibial angle, lateral distal femoral angle, and postoperative complications or need for further surgery. RESULTS: In total, 14 affected limbs in 9 patients (6 males) who underwent lateral proximal tibial transphyseal screw hemiepiphyseodesis were considered. Average chronologic age at implantation was 10.4 years and average body mass index was 31.7 kg/m. At average 23-month follow-up, the average mechanical axis deviation improved from 46 to 0 mm (P<0.001), and the average medial proximal tibial angle improved from 81 to 92 degrees (P<0.001). No limbs underwent further surgery to correct residual deformity. There were no complications or instances of implant failure associated with the transphyseal screws. CONCLUSIONS: Hemiepiphyseodesis using transphyseal screws is an effective technique to correct deformity in juvenile and adolescent tibia vara patients with sufficient growth remaining. This method can be used safely with few complications and with minimal risk of mechanical failure, even in overweight patients. LEVEL OF EVIDENCE: Level IV-therapeutic.


Assuntos
Doenças do Desenvolvimento Ósseo/cirurgia , Parafusos Ósseos , Procedimentos Ortopédicos/métodos , Osteocondrose/congênito , Fenômenos Biomecânicos , Índice de Massa Corporal , Doenças do Desenvolvimento Ósseo/complicações , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Criança , Feminino , Fêmur/cirurgia , Seguimentos , Humanos , Masculino , Procedimentos Ortopédicos/instrumentação , Osteocondrose/complicações , Osteocondrose/diagnóstico por imagem , Osteocondrose/cirurgia , Obesidade Pediátrica/complicações , Complicações Pós-Operatórias/etiologia , Falha de Prótese , Radiografia , Estudos Retrospectivos , Tíbia/cirurgia
11.
J Pediatr Orthop B ; 29(1): 65-72, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30741749

RESUMO

There is limited information regarding the use of temporary hemiepiphysiodesis for Blount disease. We performed a systematic review of patients treated for Blount disease using either extraperiosteal staples or plates to identify characteristics affecting clinical outcome, including the need for unplanned procedures. A total of 53 patients (63 bone segments) underwent temporary hemiepiphysiodesis at a mean age of 8.8 years (1.8-14.7 years). Overall, 32/63 (51%) segments achieved neutral mechanical axis and 31/63 (49%) underwent unplanned subsequent procedures, with or without a subsequent osteotomy. On the basis of the available heterogeneous data, neither age at index surgery nor the type of implant correlated with the need for unplanned additional surgeries.


Assuntos
Artrodese/efeitos adversos , Epífises/cirurgia , Articulação do Joelho/cirurgia , Complicações Pós-Operatórias , Doenças do Desenvolvimento Ósseo , Lâmina de Crescimento/cirurgia , Humanos , Osteocondrose/congênito , Fatores de Risco , Falha de Tratamento
12.
Bone Joint J ; 101-B(12): 1563-1569, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31787003

RESUMO

AIMS: The aim of this study was to compare the surgical and quality-of-life outcomes of children with skeletal dysplasia to those in children with idiopathic early-onset scoliosis (EOS) undergoing growth-friendly management. PATIENTS AND METHODS: A retrospective review of two prospective multicentre EOS databases identified 33 children with skeletal dysplasia and EOS (major curve ≥ 30°) who were treated with growth-friendly instrumentation at younger than ten years of age, had a minimum two years of postoperative follow-up, and had undergone three or more lengthening procedures. From the same registries, 33 matched controls with idiopathic EOS were identified. A total of 20 children in both groups were treated with growing rods and 13 children were treated with vertical expandable prosthetic titanium rib (VEPTR) instrumentation. RESULTS: Mean preoperative major curves were 76° (34° to 115°) in the skeletal dysplasia group and 75° (51° to 113°) in the idiopathic group (p = 0.55), which were corrected at final follow-up to 49° (13° to 113°) and 46° (12° to 112°; p = 0.68), respectively. T1-S1 height increased by a mean of 36 mm (0 to 105) in the skeletal dysplasia group and 38 mm (7 to 104) in the idiopathic group at the index surgery (p = 0.40), and by 21 mm (1 to 68) and 46 mm (7 to 157), respectively, during the distraction period (p = 0.0085). The skeletal dysplasia group had significantly worse scores in the physical function, daily living, financial impact, and parent satisfaction preoperatively, as well as on financial impact and child satisfaction at final follow-up, than the idiopathic group (all p < 0.05). The domains of the 24-Item Early-Onset Scoliosis Questionnaire (EOSQ24) remained at the same level from preoperative to final follow-up in the skeletal dysplasia group (all p > 0.10). CONCLUSION: Children with skeletal dysplasia gained significantly less spinal growth during growth-friendly management of their EOS and their health-related quality of life was significantly lower both preoperatively and at final follow-up than in children with idiopathic EOS. Cite this article: Bone Joint J 2019;101-B:1563-1569.


Assuntos
Doenças do Desenvolvimento Ósseo/complicações , Procedimentos Ortopédicos/métodos , Escoliose/cirurgia , Estudos de Casos e Controles , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Seguimentos , Humanos , Masculino , Procedimentos Ortopédicos/instrumentação , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Estudos Retrospectivos , Escoliose/etiologia , Coluna Vertebral/crescimento & desenvolvimento , Coluna Vertebral/cirurgia , Resultado do Tratamento
13.
Am J Obstet Gynecol ; 221(6): B10-B12, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31787157

Assuntos
Pé Torto Equinovaro/diagnóstico por imagem , Ultrassonografia Pré-Natal , Amniocentese , Síndrome de Bandas Amnióticas/complicações , Síndrome de Bandas Amnióticas/diagnóstico , Artrogripose/complicações , Artrogripose/diagnóstico , Doenças do Desenvolvimento Ósseo/complicações , Doenças do Desenvolvimento Ósseo/diagnóstico , Apresentação Pélvica/diagnóstico , Amostra da Vilosidade Coriônica , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Transtornos da Motilidade Ciliar/complicações , Transtornos da Motilidade Ciliar/diagnóstico , Transtornos da Motilidade Ciliar/genética , Pé Torto Equinovaro/complicações , Pé Torto Equinovaro/diagnóstico , Pé Torto Equinovaro/etiologia , Pé Torto Equinovaro/genética , Diagnóstico Diferencial , Encefalocele/complicações , Encefalocele/diagnóstico , Encefalocele/genética , Feminino , Testes Genéticos , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Humanos , Análise em Microsséries , Oligo-Hidrâmnio/diagnóstico , Síndrome de Pierre Robin/complicações , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/genética , Doenças Renais Policísticas/complicações , Doenças Renais Policísticas/diagnóstico , Doenças Renais Policísticas/genética , Gravidez , Segundo Trimestre da Gravidez , Retinite Pigmentosa/complicações , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/genética
14.
Medicine (Baltimore) ; 98(50): e18268, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852098

RESUMO

RATIONALE: Wolf-Hirschhorn Syndrome (WHS) is a rare disorder caused by the loss of the distal part of the short arm of chromosome 4, and has various phenotypes depending on the deletion size. Although many articles report on urinary tract malformations or ophthalmologic abnormalities, there are few descriptions of the skeletal anomalies. This is an extremely rare case of cervical dysplasia in WHS. PATIENT CONCERNS: A 24-year-old pregnant woman was transferred to our hospital at 21 gestational weeks for intrauterine growth retardation and oligohydramnios and decided to preserve the pregnancy after evaluation. A female was born at full term by normal vaginal delivery, weighing 1791 g. The patient was suspected to have congenital dysplasia of the cervical vertebrae on the routine newborn chest radiograph, and cervical spine magnetic resonance imaging revealed nonossification of the C3 and C4 vertebral bodies. DIAGNOSIS: The newborn had the "Greek warrior helmet" face typical of WHS. A deletion was detected in the distal portion of the short arm of chromosome 4 (p 16.3) by fluorescence in situ hybridization analysis. INTERVENTIONS: She was hospitalized for nutritional management and congenital anomaly evaluation for a month before being discharged with rehabilitation and antiepileptic drugs. OUTCOMES: The patient has been readmitted with seizure attacks 5 times to date. At one year of age, she still shows severe head lag and feeding problems. Her last weight was below the 3rd centile. LESSONS: Although cervical dysplasia is a rarely reported morphology in WHS, it may provide artefacts for diagnosing WHS as cervical anomalies, unlike facial anomalies or developmental delays, are seldom found in congenital disease.


Assuntos
Doenças do Desenvolvimento Ósseo/etiologia , Vértebras Cervicais/patologia , Cromossomos Humanos Par 4/genética , Síndrome de Wolf-Hirschhorn/complicações , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Deleção Cromossômica , Feminino , Humanos , Recém-Nascido , Cariotipagem , Imagem por Ressonância Magnética , Fenótipo , Gravidez , Síndrome de Wolf-Hirschhorn/diagnóstico , Síndrome de Wolf-Hirschhorn/genética , Adulto Jovem
15.
Am J Hum Genet ; 105(6): 1294-1301, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31761294

RESUMO

The development of hindlimbs in tetrapod species relies specifically on the transcription factor TBX4. In humans, heterozygous loss-of-function TBX4 mutations cause dominant small patella syndrome (SPS) due to haploinsufficiency. Here, we characterize a striking clinical entity in four fetuses with complete posterior amelia with pelvis and pulmonary hypoplasia (PAPPA). Through exome sequencing, we find that PAPPA syndrome is caused by homozygous TBX4 inactivating mutations during embryogenesis in humans. In two consanguineous couples, we uncover distinct germline TBX4 coding mutations, p.Tyr113∗ and p.Tyr127Asn, that segregated with SPS in heterozygous parents and with posterior amelia with pelvis and pulmonary hypoplasia syndrome (PAPPAS) in one available homozygous fetus. A complete absence of TBX4 transcripts in this proband with biallelic p.Tyr113∗ stop-gain mutations revealed nonsense-mediated decay of the endogenous mRNA. CRISPR/Cas9-mediated TBX4 deletion in Xenopus embryos confirmed its restricted role during leg development. We conclude that SPS and PAPPAS are allelic diseases of TBX4 deficiency and that TBX4 is an essential transcription factor for organogenesis of the lungs, pelvis, and hindlimbs in humans.


Assuntos
Anormalidades Múltiplas/etiologia , Doenças do Desenvolvimento Ósseo/etiologia , Ectromelia/etiologia , Quadril/anormalidades , Homozigoto , Ísquio/anormalidades , Mutação com Perda de Função , Pneumopatias/etiologia , Pulmão/anormalidades , Patela/anormalidades , Pelve/anormalidades , Proteínas com Domínio T/genética , Anormalidades Múltiplas/patologia , Adolescente , Doenças do Desenvolvimento Ósseo/patologia , Criança , Ectromelia/patologia , Feminino , Quadril/patologia , Humanos , Ísquio/patologia , Pulmão/patologia , Pneumopatias/patologia , Masculino , Patela/patologia , Linhagem , Pelve/patologia , Prognóstico
16.
Medicine (Baltimore) ; 98(45): e17887, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702664

RESUMO

RATIONALE: Dysplasia epiphysealis hemimelica (DEH), also known as Trevor disease, is a rare, developmental bone disorder of childhood. PATIENT CONCERNS: A 9-year-old girl was admitted due to pain in front of the medial malleolus of her right foot after a long walk or distance movement, in which the pain could be relieved after rest, while it was repeated and lasted for several months. DIAGNOSIS: Dysplasia epiphysealis hemimelica INTERVENTIONS:: The patient underwent an open resection surgery. After operation, the pain was totally relieved. Postoperative pathological diagnosis showed DEH. OUTCOMES: At the 6-month follow-up, pain and claudication symptoms fully disappeared, and range of motion of the right foot returned to normal level. CONCLUSIONS: Dysplasia epiphysealis hemimelica is an uncommon disease which can cause pain of foot in children. LESSONS: When the pediatric orthopedic surgeon treated the children suffered with foot pain should be aware of this rare disease, especially accessory scaphoid bone was found in another foot.


Assuntos
Doenças do Desenvolvimento Ósseo/diagnóstico , Fêmur/anormalidades , Osso Escafoide/anormalidades , Tíbia/anormalidades , Doenças do Desenvolvimento Ósseo/cirurgia , Criança , Feminino , Fêmur/cirurgia , Pé/patologia , Humanos , Osso Escafoide/diagnóstico por imagem , Osso Escafoide/cirurgia , Tíbia/cirurgia , Resultado do Tratamento
17.
Horm Metab Res ; 51(12): 798-804, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31745940

RESUMO

To assess total cortisol levels in children being evaluating for short stature with normal cortisol reserve and to correlate this response to clinical and laboratory data. Children assessed with glucagon test in our department were recruited in this study retrospectively. Inclusion criteria were: i) age>1 year, ii) absence of chronic illness or medication interfering with ACTH-cortisol axis, iii) GH stimulation levels>3ng/mL at least in one provocation test (glucagon or clonidine), iv) absence of multiple pituitary growth hormone deficiencies, v) normal short Synacthen test in cases of low cortisol response in glucagon test.Two hundred and thirty-seven subjects (160 males, 67.5%) with a mean age of 9.02±3.19 years, were finally included in the analysis. Cortisol peak levels but not cortisol AUC were significantly increased in females compared to males (26.83±7.31 µg/dl vs. 24.04±7.20 µg/dl). When linear correlations were studied, both cortisol peak levels and cortisol AUC were linearly but inversely correlated to age (r=-0.234, p<0.001 and r=-0.315, p<0.001, respectively). Finally, cortisol AUC was inversely correlated to weight Z-scores (r=-0.160, p=0.014). When our analysis was limited only to subjects with intact GH response (GH peak> 7 ng/mL), age was still inversely correlated to cortisol AUC (r=-0.312, p<0.001), and cortisol AUC was linearly correlated to GH AUC assessed with clonidine test (r=0.223, p=0.013). Girls, younger and thinner children exhibit higher cortisol response to glucagon test.


Assuntos
Doenças do Desenvolvimento Ósseo/tratamento farmacológico , Glucagon/administração & dosagem , Hidrocortisona/sangue , Hormônio Adrenocorticotrópico/sangue , Estatura/efeitos dos fármacos , Doenças do Desenvolvimento Ósseo/sangue , Criança , Pré-Escolar , Feminino , Hormônio do Crescimento Humano/sangue , Humanos , Masculino , Estudos Retrospectivos
18.
Am J Med Genet C Semin Med Genet ; 181(4): 611-626, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31730271

RESUMO

The nuclear factor one (NFI) site-specific DNA-binding proteins represent a family of transcription factors that are important for the development of multiple organ systems, including the brain. During brain development in mice, the expression patterns of Nfia, Nfib, and Nfix overlap, and knockout mice for each of these exhibit overlapping brain defects, including megalencephaly, dysgenesis of the corpus callosum, and enlarged ventricles, which implies a common but not redundant function in brain development. In line with these models, human phenotypes caused by haploinsufficiency of NFIA, NFIB, and NFIX display significant overlap, sharing neurodevelopmental deficits, macrocephaly, brain anomalies, and variable somatic overgrowth. Other anomalies may be present depending on the NFI gene involved. The possibility of variants in NFI genes should therefore be considered in individuals with intellectual disability and brain overgrowth, with individual NFI-related conditions being differentiated from one another by additional signs and symptoms. The exception is provided by specific NFIX variants that act in a dominant negative manner, as these cause a recognizable entity with more severe cognitive impairment and marked bone dysplasia, Marshall-Smith syndrome. NFIX duplications are associated with a phenotype opposite to that of haploinsufficiency, characterized by short stature, small head circumference, and delayed bone age. The spectrum of NFI-related disorders will likely be further expanded, as larger cohorts are assessed.


Assuntos
Crescimento/genética , Mutação , Fatores de Transcrição NFI/genética , Anormalidades Múltiplas/genética , Animais , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Duplicação Gênica , Transtornos do Crescimento/genética , Humanos , Camundongos , Displasia Septo-Óptica/genética , Síndrome
19.
Am J Hum Genet ; 105(5): 1040-1047, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31630789

RESUMO

Variants in genes encoding ribosomal proteins have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. Here, we report one de novo missense variant and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13 (also called eL13), in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. In contrast to observations from Diamond-Blackfan anemia, we detected no evidence of significant pre-rRNA processing disturbance in cells derived from two affected individuals. Consistently, we showed that the insertion-containing protein is stably expressed and incorporated into 60S subunits similar to the wild-type protein. Erythroid proliferation in culture and ribosome profile on sucrose gradient are modified, suggesting a change in translation dynamics. We also provide evidence that RPL13 is present at high levels in chondrocytes and osteoblasts in mouse growth plates. Taken together, we show that the identified RPL13 variants cause a human ribosomopathy defined by a rare skeletal dysplasia, and we highlight the role of this ribosomal protein in bone development.


Assuntos
Doenças do Desenvolvimento Ósseo/genética , Nanismo/genética , Mutação de Sentido Incorreto/genética , Proteínas de Neoplasias/genética , Proteínas Ribossômicas/genética , Anemia de Diamond-Blackfan/genética , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL
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