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1.
PLoS One ; 15(1): e0220348, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31935221

RESUMO

In a process linked to DNA replication, duplicated chromosomes are entrapped in large, circular cohesin complexes and functional sister chromatid cohesion (SCC) is established by acetylation of the SMC3 cohesin subunit. Roberts Syndrome (RBS) and Warsaw Breakage Syndrome (WABS) are rare human developmental syndromes that are characterized by defective SCC. RBS is caused by mutations in the SMC3 acetyltransferase ESCO2, whereas mutations in the DNA helicase DDX11 lead to WABS. We found that WABS-derived cells predominantly rely on ESCO2, not ESCO1, for residual SCC, growth and survival. Reciprocally, RBS-derived cells depend on DDX11 to maintain low levels of SCC. Synthetic lethality between DDX11 and ESCO2 correlated with a prolonged delay in mitosis, and was rescued by knockdown of the cohesin remover WAPL. Rescue experiments using human or mouse cDNAs revealed that DDX11, ESCO1 and ESCO2 act on different but related aspects of SCC establishment. Furthermore, a DNA binding DDX11 mutant failed to correct SCC in WABS cells and DDX11 deficiency reduced replication fork speed. We propose that DDX11, ESCO1 and ESCO2 control different fractions of cohesin that are spatially and mechanistically separated.


Assuntos
Acetiltransferases/genética , Proteínas de Ciclo Celular/genética , Cromátides/metabolismo , Proteínas Cromossômicas não Histona/genética , RNA Helicases DEAD-box/genética , DNA Helicases/genética , Células Epiteliais/enzimologia , Fibroblastos/enzimologia , Acetiltransferases/metabolismo , Animais , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Linhagem Celular Transformada , Proliferação de Células , Cromátides/ultraestrutura , Proteínas Cromossômicas não Histona/metabolismo , Quebra Cromossômica , Segregação de Cromossomos , Anormalidades Craniofaciais/enzimologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , RNA Helicases DEAD-box/metabolismo , DNA Helicases/metabolismo , Ectromelia/enzimologia , Ectromelia/genética , Ectromelia/patologia , Células Epiteliais/patologia , Fibroblastos/patologia , Expressão Gênica , Humanos , Hipertelorismo/enzimologia , Hipertelorismo/genética , Hipertelorismo/patologia , Camundongos , Mitose , Modelos Biológicos , Mutação , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
2.
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
3.
BMJ Case Rep ; 12(11)2019 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-31767602

RESUMO

Sirenomelia, also known as mermaid syndrome, is an extremely rare congenital disorder involving the lower spine and lower limbs. We present a case of a grand multiparous with poorly controlled gestational diabetes who delivered a live baby weighing 2.43 kg at 38 weeks' gestation. The baby was noted to have significant respiratory distress, and resuscitation was promptly commenced. Severe congenital abnormalities indicative of sirenomelia were obvious and after availability of antenatal records which indicated an extremely poor prognosis, resuscitative efforts were aborted. The baby was handed over to the mother for comfort care and died 18 min postdelivery.


Assuntos
Ectromelia/diagnóstico por imagem , Anormalidades Múltiplas/diagnóstico por imagem , Evolução Fatal , Humanos , Recém-Nascido , Masculino , Doenças Raras
4.
Indian J Pathol Microbiol ; 62(4): 611-613, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31611453

RESUMO

Sirenomelia is a rare congenital anomaly characterized by the presence of a median single lower appendage. The affected fetus is popularly referred to as a "Mermaid baby," due to the uncanny resemblance to the fictious fable character. The manifestation is a result of the merger of the lower limbs with variable fusion or complete absence of bones. Sirenomelia is universally fatal due to the associated lethal anomalies involving the internal organs, which are usually part of the VACTER or VACTERL complex. However, this sirenomelia-afflicted fetus is unique in being associated with VACTERL as well as congenital hydrocephalus.


Assuntos
Ectromelia/diagnóstico por imagem , Feto/patologia , Humanos , Hidrocefalia/etiologia , Ultrassonografia
5.
J Pediatr Orthop ; 39(9): 458-465, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31503231

RESUMO

BACKGROUND: Limb lengthening for congenital femoral deficiency (CFD) with or without fibular hemimelia can be performed with both external and internal devices. The purpose of this study is to compare clinical outcomes of femoral lengthening utilizing monolateral external fixation versus a magnetically motorized intramedullary nail in patients with CFD with or without fibular hemimelia. METHODS: This retrospective review included 62 patients with femoral lengthening, 32 patients had monolateral external fixation (group A), 30 patients had internal lengthening nail (group B). Mean age in years was 9.4±3.8 and 15.4±4.9 for groups A and B, respectively. Mean follow-up in years was 4.47±2.7 and 1.86±0.7 years for groups A and B, respectively. RESULTS: Mean lengthening achieved was 5.6±1.7 and 4.8±1.4 cm for group A and group B, respectively (P=0.052). Mean distraction index was 0.7±0.2 mm/d for group A and 0.7±0.2 mm/d for the group B (P=0.99). Mean consolidation index for group A was 29.3±12.7 and 34.8±11.2 d/cm for group B (P=0.08). Mean arc of motion before surgery and at final follow-up were similar between groups (P=0.35). Group A had significantly less range of motion at the end of distraction (P=0.0007) and at consolidation (P<0.0001). Both groups had similar rates of obstacles and complications. A significant difference between groups was found in the total problems (P<0.001) specifically with pin site/superficial infection (P<0.0001). CONCLUSIONS: The intramedullary nail had superior range of motion during the lengthening phase and at consolidation and an overall lower problem complication rate, while maintaining similar distraction and healing indices to monolateral external fixation. Internal lengthening nails represent a significant advance in technology for CFD lengthening. LEVEL OF EVIDENCE: Level IV-therapeutic.


Assuntos
Alongamento Ósseo/instrumentação , Pinos Ortopédicos , Fixadores Externos , Fêmur/anormalidades , Fêmur/cirurgia , Desigualdade de Membros Inferiores/cirurgia , Adolescente , Criança , Pré-Escolar , Ectromelia/complicações , Feminino , Fíbula/anormalidades , Seguimentos , Fixação de Fratura , Humanos , Masculino , Amplitude de Movimento Articular , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
6.
J Pediatr Orthop ; 39(9): e708-e717, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31503232

RESUMO

BACKGROUND: Fibular hemimelia is the most common deficiency involving the long bones. Paley classification is based on the ankle joint morphology, identifies the basic pathology, and helps in planning the surgical management. Reconstruction surgery encompasses foot deformity correction and limb length equalization. The SUPERankle procedure is a combination of bone and soft tissue procedures that stabilizes the foot and addresses all deformities. METHODS: We retrospectively reviewed 29 consecutive patients (29 limb segments), surgically treated between December 2000 and December 2014. Among the 29 patients, 27 were treated with reconstructive procedures. Type 1 (8 patients) cases were treated with only limb lengthening, and correction of tibial deformities. Type 2 (7 patients) cases were treated by distal tibial medial hemiepiphysiodesis or supramalleolar varus osteotomy. In type 3 (10 patients) cases, the foot deformity was corrected using the SUPERankle procedure. Type 4 (2 patients) cases were treated with supramalleolar osteotomy along with posteromedial release and lateral column shortening. In a second stage, limb lengthening was performed, using the Ilizarov technique. In the remaining 2 patients (type 3A and type 3C), amputation was performed using Syme technique as a first choice of treatment. RESULTS: The results were evaluated using Association for the Study and Application of Methods of Ilizarov scoring. Excellent results were obtained in 15 of 27 (55%) patients. Six (22%) patients had good results, 4 (14.8%) had fair results, and 2 (7%) had poor results. Mean limb length discrepancy at initial presentation was 3.55 cm (range: 2 to 5.5 cm) which significantly improved to 1.01 cm (range: 0 to 3 cm) after treatment (P=0.015). CONCLUSIONS: Our results and a review of the literature clearly suggest that limb reconstruction according to Paley classification, is an excellent option in the management of fibular hemimelia. Our 2-staged procedure (SUPERankle procedure followed by limb lengthening) helps in reducing the complications of limb lengthening and incidence of ankle stiffness. Performing the first surgery at an earlier age (below 5 y) plays a significant role in preventing recurrent foot deformities. LEVEL OF EVIDENCE: Level IV.


Assuntos
Articulação do Tornozelo/cirurgia , Ectromelia/classificação , Ectromelia/cirurgia , Fíbula/cirurgia , Desigualdade de Membros Inferiores/cirurgia , Procedimentos Cirúrgicos Reconstrutivos/métodos , Amputação , Alongamento Ósseo , Criança , Pré-Escolar , Ectromelia/complicações , Feminino , Humanos , Técnica de Ilizarov , Lactente , Desigualdade de Membros Inferiores/etiologia , Masculino , Osteotomia , Estudos Retrospectivos , Tíbia/cirurgia
7.
J Med Case Rep ; 13(1): 213, 2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31300067

RESUMO

BACKGROUND: Sirenomelia is a rare and fatal congenital defect. The rarity of this case and its association with abdominal total wall defect drove us to report this case. CASE PRESENTATION: We report a rare case of sirenomelia characterized by lower limb fusion, thoracolumbar spinal anomalies, sacrococcygeal agenesis with a rudimentary tail, and genitourinary and anorectal atresia. Coexistent anterior abdominal wall defect in this case highlights its fatalness because of complications associated with the malformation. CONCLUSIONS: Sirenomelia syndrome has seldom been reported. The present case highlights the rare atypical association of sirenomelia with anterior abdominal wall defect. Because the investigations were done in a low-resource setting, the etiology regarding this case remains unclear.


Assuntos
Anormalidades Múltiplas , Anormalidades do Sistema Digestório , Ectromelia/fisiopatologia , Parede Abdominal/anormalidades , Adulto , Ectromelia/diagnóstico , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/fisiopatologia , Humanos , Gravidez , Natimorto
8.
BMC Med Genet ; 20(1): 108, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200655

RESUMO

BACKGROUND: Split hand/foot malformation (SHFM) is a group of congenital skeletal disorders which may occur either as an isolated abnormality or in syndromic forms with extra-limb manifestations. Chromosomal micro-duplication or micro-triplication involving 17p13.3 region has been described as the most common cause of split hand/foot malformation with long bone deficiency (SHFLD) in several different Caucasian and Asian populations. Gene dosage effect of the extra copies of BHLHA9 gene at this locus has been implicated in the pathogenesis of SHFLD. CASE PRESENTATION: The proband was a female child born to non-consanguineous parents. She was referred for genetic evaluation of bilateral asymmetric ectrodactyly involving both hands and right foot along with right tibial hemimelia. The right foot had fixed clubfoot deformity with only 2 toes. The mother had bilateral ectrodactyly involving both hands, but the rest of the upper limbs and both lower limbs were normal. Neither of them had any other congenital malformations or neurodevelopmental abnormalities. Genetic testing for rearrangement of BHLHA9 gene by quantitative polymerase chain reaction confirmed the duplication of the BHLHA9 gene in both the proband and the mother. CONCLUSIONS: We report the first Sri Lankan family with genetic diagnosis of BHLHA9 duplication causing SHFLD. This report along with the previously reported cases corroborate the possible etiopathogenic role of BHLHA9 gene dosage imbalances in SHFM and SHFLD across different populations.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Duplicação Gênica , Deformidades Congênitas dos Membros/genética , Tíbia/anormalidades , Duplicação Cromossômica , Cromossomos Humanos Par 17/genética , Hibridização Genômica Comparativa , Ectromelia , Feminino , Deformidades Congênitas do Pé/genética , Dosagem de Genes , Rearranjo Gênico/genética , Estudos de Associação Genética , Loci Gênicos , Predisposição Genética para Doença , Deformidades Congênitas da Mão/genética , Humanos , Recém-Nascido , Deformidades Congênitas dos Membros/diagnóstico por imagem , Deformidades Congênitas dos Membros/fisiopatologia , Tíbia/diagnóstico por imagem , Tíbia/fisiopatologia
9.
Fetal Pediatr Pathol ; 38(6): 524-533, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31213098

RESUMO

Background: Sirenomelia is a lethal congenital anomaly, presenting with fusion of lower extremities and malformed perineum. The pathogenesis is unclear, and "defective blastogenesis" is the proposed mechanism. Chlamydia trachomatis (CT) is an obligate intracellular pathogen which reportedly invades placenta and may result in fetal demise. It has documented cytopathogenic effects, specifically, cellular disruption, tissue dysgenesis, and genomic instability.Case report: An infant with sirenomelia was born as a product of 30 weeks of pregnancy, which was normal except for a persistent maternal CT infection. The infant expired shortly after birth.Conclusion: Fetal invasion by CT, conceivably, may induce structural anomalies, such as sirenomelia by virtue of its cytopathic effects. We intend to draw attention to such a possibility by reporting this case. This association, however, is speculative and more cases of sirenomelia with CT positive mothers need to be described in order to make definite conclusions about such a relationship.


Assuntos
Infecções por Chlamydia/patologia , Chlamydia trachomatis , Ectromelia/patologia , Feto/patologia , Infecções por Chlamydia/microbiologia , Feminino , Morte Fetal/prevenção & controle , Feto/microbiologia , Humanos , Recém-Nascido , Placenta/microbiologia , Placenta/patologia , Gravidez
10.
Eur J Med Genet ; 62(7): 103666, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31078790

RESUMO

PURPOSE: Considering the paucity of reports on large series of patients with tibial hemimelia, we assessed the clinical spectrum of this rare congenital disorder in patients seen at a single Indian center over 10 years. METHODS: Retrospective review of medical records of patients seen at single center in 10 years. RESULTS: Thirty-five cases of TH, mostly Jones types Ia (18) and II (10), were diagnosed in 24 patients (13 had unilateral TH). Associated foot deformities included equinovarus (22), varus foot (10), absence of the medial row of toes (5) and polydactyly (3). Upper limbs anomalies included split-hand deformity (five patients) and radial club hand (two patients). Nine limbs of seven patients were surgically reconstructed. Modified orthosis was provided to seven patients, custom designed prosthesis fitment in six and amputation with prosthesis fitment in one. Patients presenting at adolescence or later were habituated to their deformity for indoor ambulation; families declined amputation. CONCLUSION: Reports of more TH cases will provide input to researchers to consider comprehensive rehabilitation for enhancing indoor and community ambulation.


Assuntos
Ectromelia/patologia , Tíbia/anormalidades , Adolescente , Criança , Pré-Escolar , Ectromelia/genética , Feminino , Humanos , Índia , Lactente , Masculino , Fenótipo , Tíbia/patologia , Adulto Jovem
11.
Obstet Gynecol ; 133(5): 971-974, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30969202

RESUMO

INTRODUCTION: Amelia, the complete absence of a limb, presents various management issues in pregnancy and delivery. CASE: A woman with amelia of both lower limbs and flipper-like upper limb buds (phocomelia) presented in her first pregnancy at 19 weeks of gestation. Challenging issues encountered in the care of the patient included venous access, reliable blood pressure measurement, recommendations regarding mode of delivery, and preparation for caring for the child. The patient had abnormalities of the pelvis but an adequate midpelvis, so she was able to deliver vaginally without complication. CONCLUSION: Careful planning to allow necessary modification of intrapartum management can allow for normal vaginal birth for a patient with severe limb reduction abnormalities such as amelia and phocomelia.


Assuntos
Ectromelia , Trabalho de Parto , Mães , Adulto , Feminino , Idade Gestacional , Humanos , Pelve/anormalidades , Gravidez
12.
Skeletal Radiol ; 48(7): 1137-1143, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30712123

RESUMO

Ulnar hemimelia is a very rare skeletal abnormality characterized by the total or partial absence of the ulna. It is reported to occur in approximately 1 per 150,000 live births. Some shortening of the forearm, radial bowing, and tendency of the hand to drift to the ulnar side of the wrist usually accompany ulnar hemimelia. Other skeletal anomalies such as humeroradial synostosis, radial head dislocation, carpal or metacarpal coalition, and digital abnormalities may also be seen in cases of ulnar hemimelia. The patients may be asymptomatic in the presence of an isolated mild ulnar deficiency. On the other hand, cases of prominent ulnar deficiency accompanied by complex upper limb abnormalities leading to severe disability may also be observed. We herein present four patients with varying degrees of ulnar hemimelia. Our first case had an isolated ulnar hemimelia, whereas the other three had additional upper limb abnormalities of different types.


Assuntos
Ectromelia/diagnóstico por imagem , Ulna/anormalidades , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Masculino
13.
Medicine (Baltimore) ; 98(3): e14031, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30653110

RESUMO

RATIONALE: Tibial hemimelia is known as a rare congenital lower limb deficiency. It has been classified into different types based on Jones classification, and the traditional treatment of tibial hemimelia is amputation. Here we present a variant and unclassified case of tibial hemimelia, which was caused by osteomyelitis. And the lower limb with tibial hemimelia was salvaged by asymmetric limb lengthening. PATIENT CONCERNS: 19-year-old girl had the shortened and curved left lower extremity with walking abnormalities. DIAGNOSIS: The patient's deformity was caused by osteomyelitis of tibia occurred when she was 18 month old. The tibial shaft was absent, while the proximal and distal tibia was present but was hypoplastic with radiographic analysis. The fibula was hypertrophied and curved like the capital letter C. The leg length discrepancy (LLD), mostly coming from the left lower leg, was 22 cm. INTERVENTIONS: We were able to salvage the limb successfully by 5 operations, including releasing soft tissue, fusing the proximal tibiofibular joint, fibular osteotomy, femur lengthening, and fibular lengthening. OUTCOMES: The whole treatment time for the patient was 3 years and 2 months, and she was followed up for 5 years afterward. The length of femur lengthening and fibula lengthening during the reconstruction were 7.8 cm and 11 cm, respectively. Most of the deformities were corrected, except that the left lower limb was still 2 cm shorter than the contralateral limb, and the 34 mm of mechanical axis deviation (MAD) of left lower limb remained. The reason why the patient's lower limbs were asymmetric was that the femur and fibular lengthening were performed within the affected limb only. Overall, the patient was very satisfied with her asymmetric limbs and its function after surgeries. LESSONS: The LLD in this case mainly came from tibial hemimelia. However, the fibula was unable to be lengthened to 22 cm during the lower leg distraction process because of blood flow disturbance. We could only lengthen the femur to salvage the limb in this situation. Even though the patient still had a few residual deformities and a pair of asymmetric lower limbs, she was satisfied with the function and appearance of the reconstructed limb. Therefore, the lower limb with tibial hemimelia can be salvaged by asymmetric limb lengthening in special cases.


Assuntos
Alongamento Ósseo/métodos , Ectromelia/cirurgia , Desigualdade de Membros Inferiores/cirurgia , Osteomielite/complicações , Tíbia/anormalidades , Tíbia/cirurgia , Ectromelia/etiologia , Feminino , Humanos , Desigualdade de Membros Inferiores/etiologia , Adulto Jovem
14.
Pediatr Radiol ; 49(1): 122-127, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30269159

RESUMO

BACKGROUND: Fibular hemimelia is the most common congenital long-bone deficiency. It is usually unilateral and results in a limb-length discrepancy. The literature generally subscribes to the concept of constant inhibition, a process by which limb-length ratios between the shorter and longer extremity remain constant throughout growth, but scientific data supporting this concept are sparse. Additionally, recent literature suggests that these children have abnormal skeletal maturation. OBJECTIVE: To elucidate the lower-extremity long-bone growth patterns and skeletal maturation of children with unilateral fibular hemimelia. MATERIALS AND METHODS: We reviewed medical records of children with unilateral fibular hemimelia seen at a large pediatric hospital over a 17-year period. Inclusion criteria were: at least two scanograms prior to any shortening/lengthening procedure, and no other congenital or acquired disorders. We collected the study cohort's femoral and tibial lengths (scanogram reports), plotted them against patient chronological ages and compared them to published growth standards. When these children's bone ages (Greulich and Pyle) were available, we plotted them against the children's chronological ages. RESULTS: Twenty-three children were included (total=115 scanograms). At least 1 bone-age assessment was performed in 19 children (total=84 bone ages). All bone growth curves were within normal growth standards for the femur and tibia. Length ratios between shorter and longer limbs remained constant. Skeletal maturation was within two standard deviations of normal in 90% of bone ages. CONCLUSION: Lower-extremity long bones of children with unilateral fibular hemimelia have relatively normal growth curves, supporting and confirming the concept of constant inhibition. Most children show normal skeletal maturation.


Assuntos
Ectromelia/diagnóstico por imagem , Fíbula/anormalidades , Adolescente , Determinação da Idade pelo Esqueleto , Desenvolvimento Ósseo , Criança , Pré-Escolar , Progressão da Doença , Feminino , Fíbula/diagnóstico por imagem , Humanos , Lactente , Masculino , Tíbia/anormalidades , Tíbia/diagnóstico por imagem
15.
J Pediatr Orthop B ; 28(2): 144-152, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30234726

RESUMO

We describe a technique for optimal use of fibula in reconstruction of type II tibial hemimelia. Six affected children with mean age of 1.4 years and treated over a 5-year period were reviewed. All underwent staged reconstruction by lowering the fibula to below knee level using Ilizarov soft tissue distraction, transfer of distal fibula under proximal tibia, and foot centralization. Mean follow-up period was 3.6 years (range: 1.6-6.05 years). Mean age at follow-up was 4.4 years, and increase in length was 4.08 cm. Tibiofibular union and foot centralization were universally achieved. Mild residual equinovarus deformity was present in three children and braced. Our technique allowed significant length gain and foot centralization in toddlers without distraction osteogenesis.


Assuntos
Ectromelia/cirurgia , Fíbula/cirurgia , Procedimentos Cirúrgicos Reconstrutivos/métodos , Tíbia/anormalidades , Criança , Pré-Escolar , Ectromelia/diagnóstico , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Tíbia/cirurgia , Resultado do Tratamento
16.
Congenit Anom (Kyoto) ; 59(2): 39-42, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29653020

RESUMO

To investigate the abnormalities that are specific to administration of flucytosine at one time point during embryonic organogenesis, flucytosine was administered orally to pregnant Sprague Dawley (SD) rats in a single dose on day 11 of pregnancy at 25 or 35 mg/kg. Fetuses on day 20 of pregnancy were externally, viscerally, and skeletally examined. Maternal body weight gain and food consumption were suppressed the day after administration of a 35 mg/kg. Fetal examinations revealed various alterations in both dose groups: externally preaxial polydactyly in the hind limb; skeletally fused lumbar centrum, absent sacral centrum, supernumerary sacral vertebra, and absent ribs. Our findings indicated that specific types of external and skeletal anomalies were induced following flucytosine administration on day 11 of pregnancy.


Assuntos
Anormalidades Induzidas por Medicamentos/patologia , Ectromelia/patologia , Desenvolvimento Fetal/efeitos dos fármacos , Flucitosina/toxicidade , Polidactilia/patologia , Teratogênios/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Administração Oral , Animais , Esquema de Medicação , Ingestão de Alimentos/efeitos dos fármacos , Ectromelia/induzido quimicamente , Feminino , Feto , Membro Posterior/anormalidades , Membro Posterior/efeitos dos fármacos , Região Lombossacral/anormalidades , Masculino , Exposição Materna/efeitos adversos , Organogênese/efeitos dos fármacos , Polidactilia/induzido quimicamente , Gravidez , Ratos , Ratos Sprague-Dawley , Costelas/anormalidades , Costelas/efeitos dos fármacos , Ganho de Peso/efeitos dos fármacos
17.
Congenit Anom (Kyoto) ; 59(2): 32-38, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29722137

RESUMO

The aims of this study were to test whether the Y-chromosome and the autosomal dominant hemimelia (Dh) mutation can affect mandible morphology in mice. I analyzed mandible size and shape using landmark-based geometric morphometrics in 16 DH-Chr Y@ -+/+ (@ represents one of the inbred strain names) strains and observed significant differences in mandible size. The largest mandible was identified in strain DH-Chr YC3H and the smallest in strain DH-Chr YKK . Canonical variate and discriminant function analyses suggested that the mandible shapes of strains DH-Chr YC3H and DH-Chr YKK differed from those of the other strains. Because seven of the DH-Chr Y@ -+/+ strains were maintained with dominant hemimelia, I also analyzed the potential influence of dominant hemimelia on mandible morphology because dominant hemimelia is known to cause various skeletal malformations. There were no significant differences in mandible size in seven sets of DH-Chr Y@ -+/+ and DH-Chr Y@ -Dh/+ strains. However, canonical variate analysis mapped strains DH-Chr YCAS -Dh/+ and DH-Chr YCBA -Dh/+ mapped distantly from the rest. Additionally, I observed similar patterns of shape change between DH-Chr YCAS -+/+ and DH-Chr YCAS -Dh/+, and between DH-Chr YCBA -+/+ and DH-Chr YCBA -Dh/+. These data indicate that the Y-chromosome affects the size and shape of the mouse mandible. Dominant hemimelia affects mandible shape but not size, and its effects emerge depending on the kinds of Y-chromosomes.


Assuntos
Ectromelia/genética , Morfogênese/genética , Mutação , Característica Quantitativa Herdável , Cromossomo Y/química , Animais , Animais Endogâmicos , Mapeamento Cromossômico , Ectromelia/patologia , Genes Dominantes , Masculino , Mandíbula/anormalidades , Mandíbula/anatomia & histologia , Mandíbula/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos CBA , Camundongos Knockout , Tamanho do Órgão/genética , Locos de Características Quantitativas
18.
Int J Radiat Oncol Biol Phys ; 103(5): 1194-1202, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30508616

RESUMO

PURPOSE: Roberts syndrome (RBS) is a rare, recessively transmitted developmental disorder characterized by growth retardation, craniofacial abnormalities, and truncation of limbs. All affected individuals to date have mutations in the ESCO2 (establishment of cohesion 2) gene, a key regulator of the cohesin complex, which is involved in sister chromatid cohesion and DNA double-strand break (DSB) repair. Here we characterize DNA damage responses (DDRs) for the first time in an RBS-affected family. METHODS AND MATERIALS: Lymphoblastoid cell lines were established from an RBS family, including the proband and parents carrying ESCO2 mutations. Various DDR assays were performed on these cells, including cell survival, chromosome break, and apoptosis assays; checkpoint activation indicators; and measures of DNA breakage and repair. RESULTS: Cells derived from the RBS-affected individual showed sensitivity to ionizing radiation (IR) and mitomycin C-induced DNA damage. In this ESCO2 compound heterozygote, other DDRs were also defective, including enhanced IR-induced clastogenicity and apoptosis; increased DNA DSB induction; and a reduced capacity for repairing IR-induced DNA DSBs, as measured by γ-H2AX foci and the comet assay. CONCLUSIONS: In addition to its developmental features, RBS can be, like ataxia telangiectasia, considered a DDR-defective syndrome, which contributes to its cellular, molecular, and clinical phenotype.


Assuntos
Acetiltransferases/genética , Cromátides/genética , Proteínas Cromossômicas não Histona/genética , Anormalidades Craniofaciais/genética , Quebras de DNA de Cadeia Dupla , Distúrbios no Reparo do DNA/genética , Ectromelia/genética , Hipertelorismo/genética , Tolerância a Radiação/genética , Linhagem Celular , Sobrevivência Celular , Cromátides/efeitos da radiação , Ensaio Cometa , Anormalidades Craniofaciais/patologia , DNA/efeitos da radiação , Ectromelia/patologia , Feminino , Histonas/análise , Humanos , Hipertelorismo/patologia , Imunoprecipitação/métodos , Recém-Nascido , Mitomicina/farmacologia , Mutação/genética , Inibidores da Síntese de Ácido Nucleico/farmacologia , Fenótipo
19.
Birth Defects Res ; 111(4): 222-228, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30589520

RESUMO

BACKGROUND: Despite the numerous reports on the limb body wall complex (LBWC), this association has never been adequately defined. Amniotic bands (AB) are frequently present but their role remains unclear. Since most reports were based on clinical and often subjective diagnoses, the aim of this work was to define LBWC and the role of AB, minimizing subjectivity. METHODS: Data were obtained from the ECLAMC maternity hospitals network database. A total of 450 live and stillborn infants, born during 1967-2013, with AB or the LBWC were selected. A hierarchical cluster analysis was used to classify cases into homogeneous groups (sharing similar associated defects); robustness of the classification was confirmed with a discriminant analysis. The frequency of associated defects was compared among groups; those whose frequency differed significantly were included in a logistic regression to establish their association within each group. RESULTS: The cluster analysis identified two groups: a body wall defect (BWD) predominating in one, AB in the other. These groups were further divided into: BWD (cases with only BWD), AB (with only AB), BWD + AB, and NONE (with neither). Association with caudal defects and lower limb amelia was observed for BWD, with cephalic defects and upper limb amputations for BWD + AB. CONCLUSIONS: The results, obtained with the least possible subjectivity, indicated that BWD and BWD + AB are different conditions. Since BWD specifically associates with amelia, we propose that this defect and not any limb deficiency should be considered as inclusion criterium and that it should be included in the BWD acronym as LBWC.


Assuntos
Anormalidades Múltiplas , Síndrome de Bandas Amnióticas , Bases de Dados Factuais , Ectromelia , Natimorto/epidemiologia , Anormalidades Múltiplas/epidemiologia , Anormalidades Múltiplas/patologia , Síndrome de Bandas Amnióticas/epidemiologia , Síndrome de Bandas Amnióticas/patologia , Ectromelia/epidemiologia , Ectromelia/patologia , Feminino , Humanos , Recém-Nascido , Masculino , Estudos Retrospectivos
20.
Eur J Med Genet ; 62(12): 103608, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30590172

RESUMO

Roberts/SC phocomelia syndrome (RBS/SC) is a rare autosomal recessive inherited condition characterized by prenatal-onset growth retardation, craniofacial anomalies, and symmetrical limb reduction defects. Here, we present two affected siblings with RBS/SC who have consanguineous parents. Both patients had intrauterine growth retardation; similar facial findings, including arched eyebrows, epicanthic folds, posteriorly angulated ears, and retrognathia; and hypopigmented patches on their skin. However, despite these common findings, the extremity involvement was different between the patients. The more severely affected boy had hypoplasia of the tibia and symmetrical agenesis of the radius, ulna, proximal carpal bones, and fibula. The slightly affected girl presented with mild symmetrical mesomelic shortening. The cytogenetic analysis showed aneuploidies at varying rates concerning different chromosomes in the analyses of different culture materials. As a remarkable finding in the cytogenetic studies, chromosome analysis of fibroblast cultures obtained from the hypopigmented skin region showed a much higher frequency of aneuploidy, especially trisomy 7, than normopigmented skin fibroblasts and lymphocyte cultures for both patients, which was also proven ex vivo by qPCR analyses from uncultured skin tissues. In the subsequent ESCO2 gene sequence analysis, both patients were found to be homozygous for the mutation c.1111dupA (p.Thr371Asnfs*32; NM_001017420.2), which is known to be pathogenic. In the literature search, only two RBS/SC patient reports with hypopigmented skin patches could be found. In addition, the presence of pigmentation defects in the embryo was reported in some different animal models for RBS/SC. When the literature review and study are evaluated together, hypopigmented patches can be considered as a rare finding for RBS/SC. It can be suggested that somatic aneuploidies seen in the natural course of the disease, especially aneuploidy of chromosome 7, which has many genes associated with pigmentation, may be responsible for the hypopigmentation patches.


Assuntos
Aneuploidia , Anormalidades Craniofaciais/genética , Ectromelia/genética , Hipertelorismo/genética , Pigmentação da Pele/genética , Acetiltransferases/genética , Adolescente , Criança , Proteínas Cromossômicas não Histona/genética , Anormalidades Craniofaciais/patologia , Ectromelia/patologia , Feminino , Humanos , Hipertelorismo/patologia , Masculino , Mutação , Pele/metabolismo , Pele/patologia
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