Clinical and genetic characteristics of 9 rare cases with coexistence of dual genetic diagnoses / 中华儿科杂志

Objective: To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses (DGD). Methods: Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively. Results: Among the 9 children, 6 were boys and 3 were girls. The age of last visit or follow-up was 5.0 (2.7,6.8) years. The main clinical manifestations included motor retardation, mental retardation, multiple malformations, and skeletal deformity. Cases 1-4 were all all boys, showed myopathic gait, poor running and jumping, and significantly increased level of serum creatine kinase. Disease-causing variations in Duchenne muscular dystrophy (DMD) gene were confirmed by genetic testing. The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, and cerebral cavernous malformations type 3, respectively. Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1, COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV, Turner syndrome (45, X0/46, XX chimera) with TH gene-related Segawa syndrome, Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1, and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy. DMD was the most common, and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations. Conclusions: Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes. When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease, a second rare genetic disease should be considered, and autosomal dominant diseases caused by de novo heterozygous pathogenic variation should be paid attention to. Trio-based whole-exome sequencing combining a variety of molecular genetic tests would be helpful for precise diagnosis.

Clinical and genetic analysis of three children with KBG syndrome due to novel variants of ANKRD11 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of three children with KBG syndrome.@*METHODS@#Clinical data of the three children from two families who have presented at the First Affiliated Hospital of Zhengzhou University between October 2019 and September 2020 and their family members were collected. Trio-whole exome sequencing (trio-WES) and Sanger sequencing were carried out.@*RESULTS@#All children had feeding difficulties, congenital heart defects and facial dysmorphism. The sib- pair from family 1 was found to harbor a novel de novo heterozygous c.6270delT (p.Q2091Rfs*84) variant of the ANKRD11 gene, whilst the child from family 2 was found to harbor a novel heterozygous c.6858delC (p.D2286Efs*51) variant of the ANKRD11 gene, which was inherited from his mother who had a mild clinical phenotype.@*CONCLUSION@#The heterozygous frameshift variants of the ANKRD11 gene probably underlay the disease in the three children. Above findings have enriched the spectrum of the ANKRD11 gene variants.

Tratamiento artroscópico del síndrome de fricción femoroacetabular en pacientes con displasia limítrofe. Estudio comparativo / Arthroscopic treatment of femoroacetabular friction syndrome in patients with borderline dysplasia. Comparative study

Introducción: El tratamiento artroscópico del síndrome de fricción femoroacetabular (SFFA) en displasia de cadera es controversial. Inicialmente, algunos estudios demostraron una tasa elevada de fallas, mientras que otros más recientes describieron una mejoría clínica comparable con pacientes sin falta de cobertura acetabular. El propósito de este estudio fue comparar los resultados clínicos y funcionales de la artroscopía de cadera en dos cohortes: pacientes con displasia borderline y pacientes con ángulo centro-borde normal. Materiales y métodos: evaluamos los resultados clínicos y funcionales utilizando el Harris Hip Score (HHS), Hip Outcome Score (HOS) y l Escala Visual Análoga del Dolor (EVA) del tratamiento artroscópico del SFFA para dos grupos de pacientes: el grupo 1 conformado por aquellos que presentaban displasia borderline (DB) y el grupo 2, compuesto por pacientes con un valor del ángulo centro-borde normal (ACBN). Resultados: los valores postoperatorios de las escalas de HHS y EVA no mostraron diferencias estadísticamente significativas entre los grupos (87.0 ± 5.3 versus 85.8 ± 3.6; p = 0.200 y 1.5 ± 0.6 versus 1.3 ± 0.5; p = 0.07, respectivamente).No se observaron diferencias significativas con respecto a las actividades de la vida diaria del score de HOS (91.8 ± 6.6 versus 93.2 ± 5.9; p = 0.28), ni de deportes, (85.1 ± 7.7 ± 8.3 versus 88.3 ± 11.9; p = 0.19). Conclusión: los pacientes sometidos a una artroscopía de cadera con displasia borderline, alcanzan resultados clínicos y funcionales similares que aquellos con ACBN con una media de seguimiento de tres años. Nivel de Evidencia: III

Introduction: Arthroscopic treatment of femoral-acetabular impingement syndrome in patients with hip dysplasia is controversial. There are some reports that observed an increased failure rate in this type of patients. More recent studies described good patients clinical and functional outcomes, comparable with patients with a normal acetabular coverage. The purpose of this study was to assess functional and clinical outcomes of arthroscopic treatment of FAI in two cohorts: patients with Borderline Dysplasia and patients with a normal lateral center-edge angle. Materials and methods: we assessed patients reported outcomes of two groups of patients: group 1 that consisted in patients with Borderline Dysplasia and group 2, with patients with a normal lateral center-edge angle. The minimum follow-up required was three years. Results: there were no statistically significant differences regarding Harris Hip Score and Visual Analogue Scale of Pain respectively (87.0 ± 5.3 versus 85.8 ± 3.6; p = 0.200 y 1.5 ± 0.6 versus 1.3 ± 0.5; p = 0.07) after surgery between both groups. We didn't observe differences regarding Daily Living Activities (91.8 ± 6,6 versus 93.2 ± 5.9; p = 0.28) or Sports of Hip Outcome Score (85.1 ± 7.7 ± 8.3 versus 88.3 ± 11.9; p = 0.19).Conclusion: arthroscopic treatment of FAI syndrome in patients with borderline dysplasia, achieves good clinical and functional outcomes, comparable with patients with a normal lateral center-edge angle. Level of Evidence: III

Madelung Deformity - Esthetic and Functional Outcomes from the Surgical Treatment with Distal Radial Dome Osteotomy and Vickers Ligament Section / Deformidade de Madelung - Resultado estético e funcional do tratamento cirúrgico com osteotomia em cúpula do rádio distal e secção do ligamento de Vickers

Abstract Objective The present study aimed to evaluate esthetic and functional outcomes from the surgical treatment of Madelung deformity in children. MethodThis is a retrospective study of pediatric patients with Madelung deformity who were surgically treated with dome osteotomy of the distal radius and Vickers ligament section from 2015 to 2018. Patients with a minimum postoperative follow-up period of 12 months were included. Demographic data, surgical technique, clinical and radiographic outcomes were analyzed. Pre and postoperative radiographic evaluation consisted of ulnar tilt, lunate subsidence lunate fossa angle, and palmar carpal displacement measurements. The postoperative clinical evaluation consisted of ranges of motion of the wrist, visual analog scale (VAS) and Disabilities of the Arm, Shoulder and Hand (DASH) score. Results Four patients were included, two with idiopathic Madelung deformity and two with bone dysplasia. All patients were females and presented bilateral disease. Six wrists were operated on. The median age at surgery was 15.5 years old, and the median postoperative follow-up time was of 37.5 months. The postoperative radiographic analysis revealed an average correction of 8.8 ± 7.5° for ulnar tilt, 3.0 ± 3.9 mm for lunate subsidence 8.2 ± 6.6° for lunate fossa angle, and 4.7 ± 2.6 mm for palmar carpal displacement. Average postoperative ranges of motion of the wrist joint were 75.8 ± 3.4° for flexion, 62.5 ± 14.1° for extension, 25.7 ± 2.9° for radial deviation, 40.0 ± 2.9° for ulnar deviation, 88.3 ± 2.4° for pronation, and 82.5 ± 2.5° for supination. The median VAS was 1 for residual pain, 0 for functional deficit, 0 for esthetic impairment, and 10 for recommending the surgical procedure. The median DASH score was 0. Conclusion Madelung deformity treatment using dome osteotomy of the distal radius and Vickers ligament section results in excellent esthetic and functional outcomes.

Resumo Objetivo Avaliar o resultado estético e funcional do tratamento cirúrgico da deformidade de Madelung em idade pediátrica. MétodoEstudo retrospectivo dos pacientes com deformidade de Madelung em idade pediátrica tratados cirurgicamente através de osteotomia em cúpula do rádio distal e secção do ligamento de Vickers entre 2015 e 2018. Foram incluídos doentes com tempo de seguimento pós-operatório mínimo de 12 meses. Foram analisados dados demográficos, técnica cirúrgica, resultados clínicos e radiográficos. A avaliação radiográfica pré e pós-operatória consistiu na medição da inclinação ulnar, do afundamento semilunar, do ângulo da fossa semilunar e do desvio palmar do carpo. A avaliação clínica pós-operatória consistiu na medição das amplitudes articulares do punho, escala visual analógica (EVA) e score Disabilities of the Arm, Shoulder and Hand (DASH). Resultados Foram incluídos quatro pacientes, dois com Madelung idiopática e dois com displasia óssea, todos do sexo feminino e com doença bilateral. Foram operados 6 punhos, a idade mediana à data de cirurgia foi 15,5 anos, e o tempo mediano de seguimento pós-operatório foi de 37,5 meses. Na análise radiográfica pós-operatória, verificou-se uma correção média de 8,8 ± 7,5° da inclinação ulnar, de 3 ± 3,9 mm do afundamento semilunar, de 8,2 ± 6,6° do ângulo da fossa semilunar e de 4,7 ± 2,6 mm do desvio palmar do carpo. Na avaliação da amplitude articular média pós-operatória, registrou-se uma flexão de 75,8 ± 3,4°; extensão de 62,5 ± 14,1°; desvio radial de 25,7 ± 2,9°; desvio cubital de 40,0 ± 2,9; pronação de 88,3 ± 2,4°; supinação de 82,5 ± 2,5°. Registou-se EVA mediana para dor residual = 1, défice funcional = 0, prejuízo estético = 0, e recomendação de procedimento cirúrgico = 10. A mediana do score DASH foi 0. Conclusão O tratamento da deformidade de Madelung através da osteotomia em cúpula do rádio distal e secção do ligamento de Vickers permite obter um excelente resultado estético e funcional.

Displasia ósea esclerosante en paciente adulto sin diagnóstico previo: presentación de un caso / Bone sclerosing dysplasia in an adult patient without previous diagnosis: a case report

La displasia ósea esclerosante es una afectación en el desarrollo intrínseco del esqueleto, por alteración en la formación y modelado del hueso, que lleva a una excesiva acumulación ósea con un aumento de la densidad (esclero-sis). Existen varios tipos y todos ellos son de origen genético. Presentamos el caso de una paciente de 37 años que llega a la consulta sin diagnóstico previo, por dolor en miembros inferiores de larga evolución con reagudizaciones, asociado a deformidad e impotencia funcional, que cedía parcialmente con analgésicos comunes. (AU)

Bone sclerosing dysplasia is an affectation of the intrinsic development of the skeleton by an alteration in bone formation and modeling. It causes excessive bone accumulation with an increase in density (sclerosis). There are several types of bone sclerosing dysplasia. They are of genetic origin. We report here a 37 year-old patient without a previous diagnosis of sclerosing bone dysplasia who was seen in the clinic for pain in the lower limbs associated with bone deformity with only partial response to analgesics. (AU)

Analysis of three patients with KBG syndrome and epileptic seizures due to variants of ANKRD11 gene / 中华医学遗传学杂志

OBJECTIVE@#To summarize the clinical phenotype and genotypic characteristics of 3 patients with KBG syndrome and epileptic seizure.@*METHODS@#Clinical data of the patients were collected. Family-trio whole exon sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing.@*RESULTS@#Patients 1 and 2 were boys, and patient 3 was an adult woman. All patients had epileptic seizures and mental deficiency. Their facial features included triangular face, low hair line, hypertelorism, large forward leaning auricles, broad nasal bridge, upturned nostrils, long philtrum, arched upper lip, and macrodontia. The two boys also had bilateral Simian creases. WES revealed that the three patients all harbored heterozygous de novo frameshift variants in exon 9 of the ANKRD11 gene including c.2948delG (p.Ser983Metfs*335), c.5397_c.5398insC (p.Glu1800Argfs*150) and c.1180_c.1184delAATAA (p.Asn394Hisfs*42). So far 291 patients with ANKRD11 gene variants or 16q24.3 microdeletions were reported, with over 75% being de novo mutations.@*CONCLUSION@#Above findings have enriched the spectrum of ANKRD11 gene mutations underlying KBG syndrome. WES is helpful for the early diagnosis of KBG, and provided reference for genetic counseling of this disease.

A importância da Odontologia na assistência a indivíduos com defeitos congênitos / The importance of Dentistry in assisting individuals with birth defects

Introdução: Defeitos congênitos são alterações estruturais ou funcionais que acontecem durante a vida intrauterina. O cirurgião-dentista deve reconhecer os defeitos craniofaciais para complementar a caracterização fenotípica e manejá-los junto a uma equipe multiprofissional. A presente revisão tem como objetivo auxiliar o cirurgião-dentista para o diagnóstico desses achados e apresentar quadros sindrômicos tipicamente associados a malformações craniofaciais. Revisão de Literatura: Manifestações craniofaciais de defeitos congênitos são condições que devem ser reconhecidas pelos cirurgiões--dentistas, pois frequentemente estão presentes em sua prática diária, podendo ser este profissional o primeiro a identificar tais achados. Os principais quadros sindrômicos tipicamente associados a micrognatia, fendas orais e displasias esqueléticas com manifestação craniofacial são apresentados, assinalando suas características clínicas e genéticas. Discussão: O cirurgião-dentista deve realizar uma anamnese detalhada incluindo a história familiar, bem como reconhecer as dismorfias tanto clínica quanto radiograficamente, observando o paciente de forma sistêmica. Conclusão: Os profissionais da odontologia devem receber treinamento teórico-prático para o diagnóstico, tratamento e vigilância de indivíduos com defeitos congênitos, seja na avaliação individual ou como parte de uma equipe multiprofissional.

Introduction: Birth defects are structural or functional changes that occur during intrauterine life. The dentist must recognize the craniofacial defects, complement the phenotypic characterization and manage them within a multidisciplinary team. The present review aims to assist the dentist to diagnose these findings and present syndromic conditions typically associated with cranio-facial malformations. Literature Review: Craniofacial manifestations of birth defects are conditions that must be recognized by dentists, as they are frequently present in their daily practices, and this professional may be the first to identify such findings. The main syndromic clinical pictures typically associated with micrognathia, oral clefts and skeletal dysplasias with craniofacial man-ifestation are presented, pointing out their clinical and genetic features. Discussion: The dentist must perform a detailed anamnesis including family history, as well as should recognize both clinical and radiographically the dysmorphisms, observing the patient systemically. Conclusion: Dentistry professionals should receive the-oretical-practical training for the diagnosis, treatment and surveillance of individuals with congenital defects, either in individual assessment or as part of a multipro-fessional team.

Gender difference in clinical manifestations of KBG syndrome due to variants of ANKRD11 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore gender difference in the clinical manifestations of two children with Keishi-Bukuryo-Gan syndrome (KBGS).@*METHODS@#Clinical manifestations of the two children were reviewed. Genetic testing was carried out through next generation sequencing (NGS). Treatment was summarized, and the prognosis was followed up.@*RESULTS@#Both children showed particular appearance including megatooth, abnormal hair distribution, hands' abnormality and language development delay. NGS revealed that both children have carried pathogenic variants of the ANKRD11 gene (c.1903_1907del and c.4911delT), which resulted in shifting of amino acid sequences starting from the Lysine and Proline at positions 635 and 1638, respectively. The female patient exhibited central precocious puberty. Her height has increased by 13 cm, and sex characteristics has retracted after treatment with leuprorelin for 23 months and recombinant human growth hormone for 1 month.@*CONCLUSION@#Comparison of the two cases with different genders and summary of previously reported cases found that male KBGS patients have more obvious dysmorphisms such as triangular face, synophrys, ocular hypertelorism and vertebral body abnormality, with higher morbidity of epilepsy, mental retardation, autism, congenital heart disease, immune thrombocytopenia and other complications. KBGS is an autosomal dominant disease featuring more evident peculiar appearance and global development delay. Male patients often have multi-system involvement, and multidisciplinary cooperation is required for early recognition of particular features in order to improve the prognosis.

Manejo cirúrgico de sequestro ósseo pósexodontia em paciente portador de displasia cemento-óssea florida: relato de caso / Surgical management of post-exodontia bone sequestral in patients with displasia bone cement-florida: case report

A displasia cemento-óssea florida (DCOF) é uma condição não neoplásica, esclerosante limitada aos ossos maxilares, relacionada ao osso do processo alveolar e, na maioria dos casos envolvendo bilateralmente a mandíbula. É uma condição rara que se apresenta nos maxilares, de forma autolimitante, evoluindo de um estágio osteolítico para osteoblástico, com prevalência pelo gênero feminino, de meia idade a idosas, melanoderma. Dessa forma, o objetivo do trabalho é relatar o caso clínico de uma paciente portadora de displasia cemento-óssea florida apresentando osteomielite local após exodontia.Paciente de 57 anos de idade, melanoderma, compareceu ao ambulatório do Hospital Manoel Victorino (Salvador, BA) do serviço de Cirurgia e Traumatologia Bucomaxilofacial, referindo histórico de exodontia do dente 47 há aproximadamente 02 anos, sem cicatrização local e presença de supuração e odor fétido. Ao exame intrabucal notou- se a presença fístula na região do dente 47 com secreção purulenta espontânea e presença de tecido necrótico. Ao exame de imagem (radiografia panorâmica), foi observado presença de lesões radiopacas multifocais das áreas posteriores mandibulares. Foi submetida a cirurgia, sob anestesia geral, para curetagem de sequestro ósseo e fechamento primário do defeito por primeira intenção e acompanhamento. O objetivo do trabalho foi relatar um caso clínico de um sequestro ósseo mandibular em uma paciente com displasia cemento- óssea florida(AU)

Flowery cementum-bone dysplasia (DCOF) is a non-neoplastic, sclerosing condition limited to maxillary bones, related to the alveolar process bone and, in most cases, bilaterally involving the mandible. When infected can lead to suppuration and kidnapping, resulting in a picture of osteomyelitis. It is a rare condition that occurs in the jaws, in a selflimiting way, evolving from an osteolytic stage to osteoblastic, with prevalence by the female gender, from middle age to the elderly, melanoderma. Therefore, the aim of this paper is to report a diagnosed case of florid cemento-ousseous dysplasia, presenting local osteomyelitis after a extraction. Patient 57 years old, melanoderma, attended the outpatient clinic of the Hospital Manoel Victorino (Salvador, BA) of the Bucomaxillofacial surgery and traumatology department, referring to a history of the right mandible exodontia for approximately 2 years, without local scarring and presence of odor and suppuration fetid The intraoral examination revealed the presence of a fistula in the region distal to the tooth 47 with spontaneous purulent secretion and necrotic tissue. At the imaging examination (panoramic radiography), the presence of multifocal radiopaque lesions of the mandibular posterior areas was observed. She underwent surgery under general anesthesia for curettage of bone sequestration and primary closure of the defect by first intention and follow-up. The objective of this study was to report a clinical case of a mandibular bone sequestration in a patient with florid cementoosseous dysplasia(AU)

Prenatal diagnosis and genetic analysis of 17 fetuses with skeletal dysplasia / 中华医学遗传学杂志

OBJECTIVE@#To explore strategies of prenatal genetic testing for fetuses featuring abnormal skeletal development.@*METHODS@#Clinical data of 17 fetuses with skeletal dysplasia was collected. The results of genetic testing and outcome of pregnancy were analyzed.@*RESULTS@#For 12 fetuses, the femur-to-foot length ratio was less than 0.9. Thirteen fetuses had a positive finding by genetic testing. One fetus was diagnosed with chromosomal aneuploidy, three were diagnosed with microdeletion/microduplications, and nine were diagnosed with hereditary bone diseases due to pathological variants of FGFR3, COL1A2, GPX4 or ALPL genes.@*CONCLUSION@#For fetuses with skeletal dysplasia characterized by short femur, in addition to chromosomal karyotyping and microarray analysis, sequencing of FGFR3 and other bone disease-related genes can improve the diagnostic rate.

Neurofibromatosis tipos 1 y 2 / Neurofibromatosis type 1 and 2

La neurofibromatosis (NF) comprende un grupo de enfermedades genéticas de herencia autosómica dominante, que se clasifican de la siguiente manera: neurofibromatosis tipo 1 (NF1), neurofibromatosis tipo 2 (NF2) y schwannomatosis (también conocida como neurofibromatosis tipo 3). Esta última es una enfermedad muy infrecuente, con una prevalencia aproximada de 1/126 000 personas, por lo que solo profundizaremos las dos primeras. La NF1, también conocida como la enfermedad de Von Recklinghausen, es la más frecuente de las tres y afecta principalmente la piel y el sistema nervioso periférico. Se caracteriza por la presencia de máculas "café con leche", pecas axilares o inguinales, nódulos de Lisch (hamartomas en el iris) y neurofibromas (tumores de la vaina de nervios periféricos). Otras manifestaciones menos frecuentes, aunque de mayor gravedad, incluyen gliomas del nervio óptico, meningiomas, neurofibromas malignos, escoliosis y displasia de la tibia. Su diagnóstico se suele realizar al nacimiento o durante los primeros años de vida, y se estima que un 50% de quienes la padecen presenta dificultades cognitivas. No hay datos concluyentes sobre la mortalidad en los pacientes con NF1, aunque se sabe que la expectativa de vida es menor que en la población general. La NF2 tiene una prevalencia considerablemente menor que la NF1 y su inicio es más tardío, afectando principalmente a adultos jóvenes. La presentación clínica típica se caracteriza por acúfenos, hipoacusia y ataxia en contexto de la presencia de schwannomas vestibulares bilaterales. Otros hallazgos menos frecuentes incluyen schwannomas de nervios periféricos, meningiomas, ependimomas o astrocitomas. La esperanza de vida es de unos 36 años, con una supervivencia media desde el momento del diagnóstico de 15 años. (AU)

Neurofibromatosis (NF) includes a group of genetic diseases with an autosomal-dominant inheritance pattern, and they are classified as follows: Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and Schwannomatosis (also known as neurofibromatosis type 3). This last one is a very rare disease, with an approximate prevalence of 1/126000, so we will only deepen in the first two. NF1, also known as von Recklinghausen disease, is the most frequent, and mainly affects the skin and peripheral nervous system. Its typical manifestations are the presence of café-au-lait macules, axillary or inguinal freckles, Lisch nodules (hamartomas in the iris) and neurofibromas (peripheral nerve sheath tumors). Less frequent manifestations, although more serious, include optic nerve gliomas, meningiomas, malignant neurofibromas, scoliosis and tibial dysplasia. The diagnosis is usually made at birth or during the first years of life, and approximately 50% of patients present cognitive difficulties. There is no conclusive data on mortality in patients with NF1, although it is known that life expectancy is lower than in general population. NF2 has a considerably lower prevalence than NF1, and its onset is later in life, mainly affecting young adults. Its typical clinical presentation is characterized by tinnitus, hearing loss and ataxia in the context in the presence of bilateral vestibular schwannomas. Less frequent findings include peripheral nerve schwannomas, meningiomas, ependymomas or astrocytomas. Life expectancy is about 36 years old, with a median survival from the moment of diagnosis of 15 years. (AU)

Defining a critical period in calvarial development for Hedgehog pathway antagonist-induced frontal bone dysplasia in mice / 国际口腔科学杂志·英文版

The Hedgehog (Hh) signalling pathway is essential for cellular proliferation and differentiation during embryonic development. Gain and loss of function of Hh signalling are known to result in an array of craniofacial malformations. To determine the critical period for Hh pathway antagonist-induced frontal bone hypoplasia, we examined patterns of dysmorphology caused by Hh signalling inhibition. Pregnant mice received a single oral administration of Hh signalling inhibitor GDC-0449 at 100 mg•kg or 150 mg•kg body weight at preselected time points between embryonic days (E)8.5 and 12.5. The optimal teratogenic concentration of GDC-0449 was determined to be 150 mg•kg. Exposure between E9.5 and E10.5 induced frontal bone dysplasia, micrognathia and limb defects, with administration at E10.5 producing the most pronounced effects. This model showed decreased ossification of the frontal bone with downregulation of Hh signalling. The osteoid thickness of the frontal bone was significantly reduced. The amount of neural crest-derived frontal bone primordium was reduced after GDC-0449 exposure owing to a decreased rate of cell proliferation and increased cell death.

Análisis de la displasia epifisaria hemimélica (enfermedad de Trevor) de tobillo / Analysis of dysplasia epiphysealis hemimelica (Trevor's disease) of the ankle

La displasia epifisaria hemimélica o enfermedad de Trevor es una deformidad osteocartilaginosa en la región epifisaria. Es poco frecuente y predomina en el sexo masculino. Se desarrolla en la infancia cuando los cartílagos de crecimiento están abiertos, y afecta principalmente el tobillo y la rodilla. Su origen es desconocido. Se presentan tres casos con distinto grado de compromiso y las alternativas terapéuticas. Un solo caso quirúrgico por equino irreductible. Se detallan la técnica quirúrgica, el manejo posoperatorio y el resultado de anatomía patológica. Se recomienda operar sólo a pacientes con alguna limitación funcional o severa deformidades por el alto índice de recidiva. Nivel de Evidencia: IV

Dysplasia epiphysealis hemimelica or Trevor's disease is an osteocartilaginous deformity in the epiphyseal region. It is an uncommon entity, and predominates in the male sex. It develops during childhood, when growth cartilages are open, and mainly affects the ankle and knee. Its origin is unknown. Three cases with different degree of involvement and therapeutic alternatives are presented. Only one surgical case due to irreductible equinovarus. Surgical technique, postoperative management and result of pathological anatomy are explained. We recommend surgery only for patients with some functional limitation or severe deformities due to its high rate of relapse. Level of Evidence: IV

Imperfect osteogenese: child case report / Osteogênese imperfeita: relato de caso infantil

Osteogenesis Imperfecta leads to alterations in type 1 collagen fiber, apart from causing bone fracture, blue sclera and other related deformities. As few medical records are available in the field of dentistry regarding these alterations, having a better understanding of this medical disorder and its dental management has become a matter of extreme relevance if one is to provide adequate treatment for patients suffering from this medical condition. This paper reports the case of a 2-year old patient with Osteogenesis Imperfecta who received treatment as part of the Acolher Project ­ PNE run by the Federal Fluminense University in Rio de Janeiro, Brazil. (AU)

Osteogênese Imperfeita leva a alteração na fibra colágena tipo I, ocasiona fraturas ósseas, escleras azuladas e outras deformidades. Essa alteração apresenta poucos registros científicos no ramo da odontologia sendo extremamente importante para as áreas de Pacientes Especiais, Odontopediatria e Odontologia Hospitalar no entendimento dessa desordem e o manejo odontológico. Este estudo relata o caso de uma paciente de 2 anos de idade com Osteogênese Imperfeita atendida no Projeto AcolherPNEUFF.(AU)

Parámetros diagnósticos de la displasia cleidocraneal: una enfermedad poco frecuente / Diagnostic parameters of cleidocranial dysplasia: a low frequent disease

Introducción: la displasia cleidocraneal (DCC) es una afección esquelética poco frecuente, con un rasgo genético autosómico dominante, originada por mutaciones en el gen CBFA1/RUNX2, se caracteriza por retraso en el cierre de las suturas craneales, hipoplasia o aplasia clavicular, tórax estrecho y anomalías dentales. Caso Clínico: paciente masculino de 16 años, con estatura baja, hombros caídos,tórax estrecho, fosas claviculares poco desarrolladas, gran movilidad de los hombros al aproximarlos hacia la línea media anterior del tórax, afecciones bucales como retraso en la erupción de la dentición secundaria y apiñamiento dental, radiográficamente hipoplasia clavicular, tórax en forma de campana y presencia de múltiples dientes supernumerarios, características compatibles con la displasia cleidocraneal, se relata el caso. Conclusión: la DCC presenta unas características clínicas y radiográficas que sirven como parámetros significativos para realizar un acertado diagnóstico, el estudio de la familia es importante ya que la patología es de herencia autosómica dominante..(AU)

Introduction: cleidocranial dysplasia is a rare skeletal condition with an autosomal dominant genetic trait, caused by mutations in the CBFA1 / RUNX2 gene, characterized by delayed cranial suture closure, clavicular hypoplasia or aplasia, narrow thorax and abnormalities Dental procedures. Clinical case: 16-year-old male patient, with short stature, sagging shoulders, narrow chest, poorly developed clavicular pits, great mobility of the shoulders when approaching the anterior midline of the thorax, oral conditions such as delayed eruption of the secondary dentition And dental crowding, radiographically clavicular hypoplasia, bell-shaped thorax and presence of multiple supernumerary teeth, characteristics compatible with cleidocranial dysplasia, the case is reported. Conclusion: the CDD presents clinical and radiographic characteristics that serve as significant parameters to make a correct diagnosis, the study of the family is important since the pathology is of autosomal dominant inheritance..(AU)

Displasia Torácica Asfixiante o Síndrome de Jeune / Asphyxiating Thoracic Dysplasia or Jeune Syndrome

El Síndrome de Jeune es una distrofia esquelética rara, caracterizada por costillas cortas y alteraciones en extremidades y pelvis. La dificultad respiratoria viene determinada por el grado de estrechez torácica, más tar-díamente pueden aparecer insuficiencia pancreática o renal. Se presenta el caso de un lactante de 7 meses que acudió al Hospital Vicente Corral Moscoso por neumonía sin respuesta al tratamiento en hospital cantonal;a su ingreso presenta insuficiencia respiratoria y llama la atención un tóraxcilíndrico, marcadamente estrecho y alargado además de micromelia y polidactilia. Se administró soporte ventilatorio y antibióticos teniendo una evolución favorable durante hospitalización.

Jeune Syndrome is a rare skeletal dystrophy, characterized by short ribsand alterations in limbs and pelvis. The respiratory distress is determinedby the degree of thoracic stricture, and later, pancreatic or renal insufficiencymay occur. A case of a 7-months-old infant who came to the Vicente Corral Moscoso Hospital for pneumonia without treatment response in the cantonal hospital was presented. When the patient arrives he presentsa respiratory insufficiency and it calls the attention a cylindrical thorax,markedly narrow and elongated in addition of micromelia and polydactyly.A respiratory support and antibiotics were given during hospitalization having a favorable evolution.

Growth hormone deficiency with advanced bone age: phenotypic interaction between GHRH receptor and CYP21A2 mutations diagnosed by sanger and whole exome sequencing

SUMMARY Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and, clinically, patients have delayed bone age. High sequence similarity between CYP21A2 gene and CYP21A1P pseudogene poses difficulties for exome sequencing interpretation. A 7.5 year-old boy born to second-degree cousins presented with severe short stature (height SDS −3.7) and bone age of 6 years. Clonidine and combined pituitary stimulation tests revealed GH deficiency. Pituitary MRI was normal. The patient was successfully treated with rGH. Surprisingly, at 10.8 years, his bone age had advanced to 13 years, but physical exam, LH and testosterone levels remained prepubertal. An ACTH stimulation test disclosed a non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency explaining the bone age advancement and, therefore, treatment with cortisone acetate was added. The genetic diagnosis of a homozygous mutation in GHRHR (p.Leu144His), a homozygous CYP21A2 mutation (p.Val282Leu) and CYP21A1P pseudogene duplication was established by Sanger sequencing, MLPA and whole-exome sequencing. We report the unusual clinical presentation of a patient born to consanguineous parents with two recessive endocrine diseases: non-classic congenital adrenal hyperplasia modifying the classical GH deficiency phenotype. We used a method of paired read mapping aided by neighbouring mis-matches to overcome the challenges of exome-sequencing in the presence of a pseudogene.

Caso Clínico: Uso de Biomodelos Tridimensionales para la Planificación Preoperatoria de Tumores Craneales Fronto - orbitarios / Case Report: Use of Tridimensional Biomodels for Surgical Planning in Fronto-orbital Bone Tumors

INTRODUCCIÓN: La impresión tridimensional de biomodelos ha demostrado en los últimos años ser de gran utilidad para el diagnóstico, tratamiento y planificación preoperatoria en prácticamente todas las especialidades quirúrgicas. En este reporte se presenta la experiencia inicial con el empleo de biomodelos tridimensionales, para la planificación pre quirúrgica de un paciente con displasia fibrosa fronto-orbitaria operado en Cuenca, Ecuador. CASO CLÍNICO: Paciente de sexo masculino de 11 años de edad que desde hace 4 años presentó una¿ masa frontal derecha dura, inmóvil, no dolorosa, de crecimiento progresivo, que produjo deformidad orbitaria con exoftalmia e hipotropia. La tomografía craneal demostró una lesión ósea de núcleo hipodenso, de 5 cm de diámetro mayor, con compromiso del techo de la órbita, porción lateral del seno paranasal frontal y extensión intracraneal extradural. EVOLUCIÓN: Para planificar la cirugía se elaboró un modelo óseo tridimensional que se usó para explicar al paciente y sus padres el objetivo del procedimiento y como se realizaría. El día de la intervención, se dibujaron las osteotomías y craneotomía en el modelo anatómico, plan que se aplicó exactamente en el paciente. El postoperatorio transcurrió sin novedades, la tomografía computarizada de control evidenció una resección completa de la lesión y una adecuada reconstrucción orbitaria. El paciente y sus familiares se mostraron muy satisfechos con las explicaciones dadas. CONCLUSIONES: La impresión 3D es una herramienta que cada vez gana más espacio en la docencia y también en la planificación quirúrgica pues permite disponer de modelos anatómicos muy precisos y simular el procedimiento operatorio, antes de realizar el procedimiento en el paciente real. (AU)

BACKGROUND: 3Dprinting of biomodels has shown in recent years to be very useful for diagnosis,treatmentandpreoperativeplanninginpracticallyall surgical specialties. Inthis reportispresentedthe initial experiencewiththeuseoftridimensionalbiomodels,forpre-surgicalplanninginapatientwithfronto-orbital fibrous dysplasia operated in Cuenca, Ecuador. CASE REPORT: An 11 years old boy presented with a 4-year history of a slow-growing, hard, non-mobile, painless rightfrontalmass which caused orbital deformity, proptosis, and hypotropia. Cranial Computer Tomography showed a 5 cm bone tumor with hypodense center compromising the orbital roof and the lateral aspect ofthe frontal paranasal sinus with intracranial extradural expansion. EVOLUTION: To design the surgery, a tridimensional bone model was elaborated and used to explain the patient and his parents the aim of the procedure and how it will be performed. The day of the intervention, the osteotomies and craniotomy were drawn on the anatomical model, plan that was exactly applied to the patient. The postoperative period was uneventful, control CT scan showed a complete resection of the lesion and an adequate orbital reconstruction. The patient and his relatives were very satisfied with the explanations given. CONCLUSIONS: 3D printing is a very useful surgical tool with wide applications in planning and education that allows simulate in very accurate biomodels an operative procedure before it was done in the actual patient(AU)

Preliminary study on the biocompatibility and osteoconductive properties of a new bovine bone graft / Estudio preliminar sobre las propiedades de biocompatibilidad y osteoconductividad de un nuevo injerto de hueso bovino

To prevent post-extraction resorption and preserve the integrity of the alveolar ridges, the placement of bone grafts at the time of extraction is recommended. Bovine bone grafts are biocompatibile and osteoconductive, allowing new bone apposition by osteoprogenitor cells. Although there are trademarks recognized internationally regarding bovine bone grafts, they are expensive and even difficult to acquire. Therefore, domestic industry development of high quality biomaterials will reduce the public health high costs in the dental field. Here, we evaluated and compared the effects of an Argentinean manufactured bovine bone graft (Synergy Bone Matrix) with a bovine bone graft recognized for its osteoconductive effects (Bio-Oss), on bone healing in an experimental model in rats. We created critical sized bone defects in rat tibiae and filled them with either one of the bovine bone grafts or control. Clinical responses, X-ray findings, bone mineral density, and histological parameters were evaluated. No abscess, encapsulation, suppuration or inflammation of lymphatic nodes were observed. Radiographically, all implants were amalgamated to the surrounding bony margins, suggesting proper healing. On the other hand, control tibiae exhibited no signs of recovery and remained either unfilled or showed fibrous tissue formation. No statistical differences were observed in BMC and BMD between tibiae filled with Synergy Bone Matrix or Bio-Oss. Histological analysis revealed particles of both bone grafts surrounded by laminar bone tissue indicating osteoconductivity, without any inflammatory sign. This preliminary study suggests that Synergy Bone Matrix, as well as Bio-Oss, present similar properties of biocompatibility and osteoconductivity. (AU)

Para prevenir la resorción post-exodoncia y preservar la integridad de los rebordes alveolares, se recomienda la colocación de injertos óseos en el momento de la extracción. Los injertos de hueso bovino son biocompatibles y osteoconductivos, permitiendo nueva aposición ósea por células osteoprogenitoras. Existen marcas internacionales de injertos de hueso bovino, pero resultan caros e incluso difíciles de adquirir. Por ello, la elaboración de biomateriales de alta calidad, nacionales, reduciría los altos costos de salud pública en odontología. En este estudio, se evaluaron y compararon los efectos de un injerto de hueso bovino fabricado en Argentina (Synergy Bone Matrix) versus un injerto de hueso bovino reconocido por sus efectos osteoconductivos (Bio-Oss), en el proceso de cicatrización ósea en un modelo experimental en ratas. Para ello, creamos un defecto óseo crítico en tibia de rata el cual se rellenó con uno de los injertos de hueso bovino o control. Se evaluó: respuesta clínica y radiográfica, densidad mineral ósea e histología. No se observaron abscesos, encapsulación, supuración o inflamación de los ganglios linfáticos. Radiográficamente, todos los implantes se integraron a los márgenes óseos circundantes, sugiriendo una cicatrización adecuada. Por el contrario, las tibias control no mostraron signos de recuperación con formación de tejido fibroso. No se observaron diferencias estadísticas en las BMC y BMD entre las tibias Synergy Bone Matrix o Bio-Oss. La histología reveló partículas de ambos injertos óseos rodeadas por tejido óseo laminar indicando osteoconductividad sin signos inflamatorios. Este estudio preliminar sugiere que Synergy Bone Matrix presenta propiedades similares de biocompatibilidad y osteoconductividad que Bio-Oss. (AU)

Deformidad de Madelung: presentación de un caso / Madelung deformity: case report

La deformidad de Madelung es una alteración poco común de la articulación de las muñecas, con una prevalencia desconocida por los pocos casos reportados hasta la actualidad. Se vincula a mutaciones del gen SHOX. Se caracteriza por presentar alteraciones en el radio, el carpo y el cúbito, con predominio bilateral. Afecta principalmente a pacientes de sexo femenino; los signos y síntomas se revelan al inicio de la adolescencia. Presentamos el caso clínico de una paciente de sexo femenino de 17 años que registra las manifestaciones clínicas y radiográficas características. (AU)

Madelung deformity is a rare alteration of the wrist joint of unknown prevalence due to the few cases reported. It has been linked to SHOX gene mutations. Madelung deformity is characterized by alterations of the radius, carpus and ulna, predominantly bilateral and mainly seen in female patients at the beginning of the adolescence. We report the clinical case of a 17-yearold female patient presenting the characteristic clinical and radiographic deformities. (AU)