Co-occurrence of heterozygous mutations in COL1A1 and SERPINF1 in a high-risk pregnancy complicated by osteogenesis imperfecta

Mutations in several genes, including SERPRINF1 and COL1A1, have been associated with the development of osteogenesis imperfecta (OI). Here, we reported the co-occurrence of a rare heterozygous variant (c.167C>G p.Ala56Gly) in SERPRINF1 and a novel heterozygous mutation (c.1634G>A p.Gly545Asp) in COL1A1 in a foetus with a severe form of OI. Bioinformatics modelling revealed that the effect of the mutation on SPERINF1 is neutral. In contrast, the mutation in COL1A1 is deleterious. It is predicted to cause distortion of the α (1) chain of the type I collagen and results in structural instability of the protein. Therefore, a novel dominant variant of COL1A1 likely underlies the severe foetal pathology observed, although we do not exclude the possibility that the heterozygous mutations in SERPINF and COL1A1 may interact and co-ordinately cause pathogenesis. This novel COL1A1 mutation is recommended to be included in the diagnostic panels for OI.

Pedigree analysis of a osteogenesis imperfect and prolactinoma family caused by a newly found gene mutation in COL1A1 / 中华内分泌代谢杂志

Objective To explore the collagen, typeⅠ, α 1 chain ( COL1A1) gene mutation in a family with type 1 osteogenesis imperfect. Methods The medical records and DNA samples of an osteogenesis imperfect patient and her family members were collected, and their DNA sequencing were performed and compared with 50 non-relative healthy control from the same area. Results The proband and her three family members ( father, younger brother, and younger nephew) with clinical features of osteogenesis imperfect as well as prolactinoma were confirmed of COL1A1 gene mutation at the 24th intron with a shear mutation of c. 1669-1 G＞A which was not reported previously. Other family members were genetically normal compared with the normal. Conclusions We found a new COL1A1 gene mutation family and mutation site, but the relationship between osteogenesis imperfect and prolactinoma was unknown.

A novel de novo COL1A1 mutation in a Thai boy with osteogenesis imperfecta born to consanguineous parents

Abstract Osteogenesis imperfecta (OI) is genetically heterogeneous. Mutations in COL1A1 and COL1A2 are responsible for at least 90% of the cases, which are transmitted in an autosomal dominant manner or are de novo events. We identified a Thai boy with OI whose parents were first cousins. Because the proband was the product of a consanguineous marriage, we hypothesized that he might be homozygous for a mutation in a known gene causing a recessive form of OI. Using whole exome sequencing (WES), we did not find any pathogenic mutations in any known gene responsible for an autosomal recessive form of OI. Instead, we identified a COL1A1 frameshift mutation, c.1290delG (p.Gly431Valfs*110) in heterozygosis. By Sanger sequencing, the mutation was confirmed in the proband, and not detected in his parents, indicating that it was a de novo mutation. These findings had implication for genetic counseling. In conclusion, we expanded the mutational spectrum of COL1A1 and provided another example of a de novo pathogenic mutation in heterozygosis in a patient born to consanguineous parents.

Alternative option for osteogenesis imperfecta and trigeminal neuralgia / Opção alternativa em tratamento da neuralgia do trigêmeo com osteogênese imperfeita

Summary Osteogenesis imperfecta (OI) is a bone disorder that can lead to skull base deformities such as basilar invagination, which can cause compression of cranial nerves, including the trigeminal nerve. Trigeminal neuralgia in such cases remains a challenge, given distorted anatomy and deformities. We present an alternative option, consisting in cannulation of the foramen ovale and classical percutaneous treatment. Percutaneous balloon microcompression was performed in a 28 year-old woman with OI and severe trigeminal neuralgia using computed tomography (CT) and radiographic-guided cannulation of the Gasserian ganglion without neuronavigation or stereotactic devices. The patient developed hypoesthesia on the left V1, V2 and V3 segments with good pain control. This alternative technique with a CT-guided puncture, using angiosuite without the need of any Mayfield clamp, neuronavigation systems, frame or frameless stereotactic devices can be a useful, safe and efficient alternative for patients with trigeminal neuralgia with other bone deforming diseases that severely affect the skull base.

Resumo Osteogênese imperfeita (OI) é uma doença óssea que pode levar a deformidades de base de crânio, como invaginação basilar que pode provocar compressão de nervo craniano, incluindo o nervo trigêmeo. Nestes casos, a neuralgia do trigêmeo permanece como um desafio, pela anatomia distorcida e pelas deformidades. Apresentamos uma alternativa que consiste na canulação do forame oval e no tratamento percutâneo clássico. A microcompressão percutânea por balão foi realizada em uma paciente de 28 anos apresentando OI e grave neuralgia do trigêmeo, sendo realizadas tomografia computadorizada (CT) e canulação guiadas do gânglio gasseriano sem neuronavegação ou dispositivos estereotáxicos. A paciente apresentou hipoestesia à esquerda dos segmentos V1, V2 e V3, com bom controle da dor. Essa técnica alternativa com punção orientada por CT utilizando o angiosuite sem a necessidade de qualquer grampo de Mayfield, sistemas de neuronavegação, ou dispositivos com ou sem arcos estereotáxicos, pode ser uma opção útil, segura e eficiente para pacientes com neuralgia do trigêmeo cursando com outras doenças deformativas que afetem a base craniana de modo grave.

New drugs for the treatment of osteogenesis imperfecta: Research advances / 国际药学研究杂志

Osteogenesis imperfecta(OI)is a genetic bone disease characterized by increased bone fragility and recurrent bone fractures. It belongs to orphan diseases of which the diagnosis and treatment are facing challenges. The effective treatments targeting at the underlying causes are still unavailable. Recently, many agents have been demonstrated to increase bone mineral density, improve bone microstructures, and reduce the incidence of fractures. Herein, we review the progress in new drugs for the treatment of OI.

Dentinogénesis imperfecta: reporte de un caso clínico y revisión literaria

La dentinogénesis imperfecta (DI), es una enfermedad poco frecuente que puede afectar ambas denticiones, y las implicaciones de un mal manejo podría traer consecuencias tanto estéticas como funcionales al paciente, por lo que es importante poder identificar las principales características de esta patología para brindar un adecuado diagnóstico y manejo en la práctica odontológica.

Dentinogenesis imperfect is a rare disease that can affect both dentitions, and implications of an inadequate management could bring aesthetic and functional consequences to the patient, so there is important to identify the main features of the disease to provide adequate diagnosis and management in the dental practice.

Caso de fractura de cúbito en niño con osteogénesis imperfecta, implicaciones anestésicas / A case of ulna fracture in a child with osteogenesis imperfecta, anesthetic implications

Introducción: la Osteogénesis Imperfecta (OI) es una rara enfermedad congénita autosómica dominante del tejido conectivo con una incidencia aproximada de 1:21 000 a 1:60 000 nacimientos, con mayor incidencia en mujeres.1 Aunque también se han descrito casos de herencia recesiva o mutación espontánea.2 La Osteogénesis Imperfecta puede ser causada por la mutación en los cromosomas 7 o 17, en uno de los dos genes que codifcan el colágeno tipo 1A1 o 1A2. 3 Sus manifestaciones clínicas incluyen la susceptibilidad a las fracturas óseas y retraso del crecimiento, así como compromiso del tejido conectivo de otros órganos. Bajo este contexto existen múltiples implicaciones anestésicas que determinan un buen desenlace en el posoperatorio. Caso: es una revisión de caso clínico y revisión bibliográfca. Resultados: el presente caso muestra el manejo anestésico en un niño de 12 años con Osteogénesis Imperfecta, sometido a osteosíntesis por fractura de miembro superior. Patología poco frecuente en nuestro medio. Conclusiones: se puede concluir que el manejo anestésico de un paciente con Osteogénesis Imperfecta implica varios ámbitos desde su fragilidad ósea, vía aérea difícil, control de temperatura entre otros. Además que se requiere un abordaje multidisciplinario en el perioperatorio.

Introduction: Osteogenesis Imperfecta (OI) is a rare autosomal dominant congenital connective tissue disorder with an incidence of 1:21 000 to 1:60 000 births, with higher incidence in women. 1 Also we can fnd cases of recessive heritage or spontaneous 1 mutation. 2 Osteogenesis Imperfecta (OI), can be caused by mutations in chromosomes 7 or 17, in one of two genes encoding collagen type 1A1 or 1A2. 3 Its clinical manifestations include susceptibility to bone fractures and delayed growth and commitment of the connective tissue of other organs. In this context there are multiple anesthetic implications that determine a good postoperative outcome. Case: this is a clinical case review and a literature review. Results: this case shows de anesthetic management in a 12 years old boy with Osteogénesis Imperfecta, who underwent an osteosinthesis of an upper limb fracture. A rare pathology in our environment. Conclusions: we can conclude that the anesthetic management of a patient with Osteogénesis Imperfecta, involves several scopes from bone fragility, diffcult airway, core temperature control, etc. Besides that a multidisciplinary approach is required in the perioperative.

Associação entre artrite idiopática juvenil e osteogenesis imperfecta: relato de caso / Association between Juvenile idiopathic arthritis and osteogenesis imperfecta: case report

Os autores relatam o caso de uma paciente de 53 anos que apresenta uma rara associação entre artrite idiopática juvenil (AIJ) e osteogenesis imperfecta (OI), com acometimento poliarticular, incluindo a articulação temporomandibular. Apresentam uma revisão da literatura e uma discussão dos aspectos radiológicos do acometimento da referida articulação. Não foram encontrados relatos de casos com semelhante associação de doenças na literatura especializada.

The authors report a rare association case of juvenile idiopathic arthritis (JIA) and osteogenesis imperfecta (OI) in a 53 years-old female patient, present a literature review and discuss the radiological aspects of the temporo-mandibular joint involvement. To our knowledge, this is the first case report of JIA an OI association.

Conduta anestésica em criança com osteogênese imperfeita e hemorragia epidural / Anesthesia management in a child with osteogenesis imperfecta and epidural / Hemorrhage conducta anestésica en niño con osteogénesis imperfecta y hemorragia epidural

Osteogênese imperfeita (OI) é o resultado de uma mutação genética que causa a formação defeituosa ou insuficiente de colágeno. OI pode causar várias complicações anestésicas por causa do manejo difícil das vias aéreas, da presença de deformidade da coluna vertebral, de doenças respiratórias, anomalias cardíacas, distúrbio da função plaquetária, risco de hipertermia, invaginação bacilar, deformidades ósseas e distúrbios metabólicos. A abordagem anestésica de pacientes com OI deve ser feita com cautela, por causa do risco de certas complicações respiratórias. Esses riscos são causados por deformidade do tórax, fraturas ósseas durante o movimento ou mudança de posição, fraturas mandibulares e cervicais relacionadas à intubação, intubação difícil e hipertermia maligna. As técnicas anestésicas com o uso de anestesia venosa total (AVT) e máscara laríngea são adequadas para o manejo de paciente pediátrico com OI. No entanto, essas técnicas ainda não foram mencionadas como úteis em relatos de casos neurocirúrgicos. Neste estudo, apresentamos o uso de AVT e máscara laríngea ProSeal (MLP) em uma criança com OI e hemorragia epidural. Concluímos que a MLP e a AVT podem ser usadas com segurança no manejo anestésico de pacientes com OI e problemas anestésicos graves.

Osteogenesis Imperfecta (OI) results from gene mutation that causes defective or insuffi cient collagen formation. It may cause various anesthetic complications due to the diffi culty in airway management, existence of spinal deformity, respiratory disorders, cardiac anomalies, thrombocyte function disorder, risk of hyperthermia, bacillary invagination, bone deformities and metabolic disorders. The anesthesia management of OI patients should be exercised with caution given certain risks of respiratory disorders. These risks are due to thorax deformity, bone fractures during moving or changing position, mandibular and cervical fractures related with intubation, diffi cult intubation and malignant hyperthermia. The anesthetic technique using Total Intravenous Anesthesia (TIVA) and laryngeal mask airway is suitable for pediatric patient care with OI. However, these techniques have not yet been reported as useful in neurosurgery case reports. In this study, we present the use of TIVA and ProSeal Laringeal Mask in a child with OI and epidural hemorrhage. We came to the conclusion that LMA and TIVA can safely be used in the anesthetic management of OI patients with severe anesthetic problems.

La osteogénesis imperfecta (OI) es el resultado de una mutación genética que causa la formación defectuosa o insufi ciente de colágeno. La OI puede causar varias complicaciones anestésicas a causa del manejo difícil de las vías aéreas, de la presencia de deformidad de la columna vertebral, de enfermedades respiratorias, anomalías cardíacas, trastorno de la función plaquetaria, riesgo de hipertermia, invaginación bacilar, deformidades óseas y trastornos metabólicos. El abordaje anestésico de pacientes con OI debe ser hecho con cautela, ya que existe un riesgo de ciertas complicaciones respiratorias. Esos riesgos son causados por deformidad del tórax, fracturas óseas durante el movimiento o el cambio de posición, fracturas mandibulares y cervicales relacionadas con la intubación, intubación difícil e hipertermia maligna. Las técnicas anestésicas con el uso de anestesia venosa total (AVT) y mascarilla laríngea, son adecuadas para el manejo de paciente pediátrico con OI. Sin embargo, esas técnicas todavía no han sido mencionadas como útiles en relatos de casos neuroquirúrgicos. En este estudio, presentamos el uso de AVT y mascarilla laríngea ProSeal (MLP) en un niño con OI y hemorragia epidural. Concluimos que la MLP y la AVT pueden ser usadas con seguridad en el manejo anestésico de pacientes con OI y problemas anestésicos graves.

Brittle bone disease: a case report / Doenca dos ossos frageis: relato de caso

We report a case of a female patient, 27 years old, with several episodes of fractures after low energy trauma and the first documented episode only to 18 years of age. Extensive research has not found the exact etiology of the disease. The orthopedic monitoring has targeted prevention and treatment of fractures.

Relata-se caso de paciente feminina, de 27 anos, com diversos episódios de fraturas após traumas de baixa energia, o primeiro documentado aos 18 anos. A extensiva investigação até o momento não concluiu a exata etiologia da doença. O acompanhamento ortopédico tem visado à prevenção e ao tratamento das fraturas.

Osteogenesis Imperfecta Type VI with Severe Bony Deformities Caused by Novel Compound Heterozygous Mutations in SERPINF1

Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders characterized by bone fragility, frequent fractures, and low bone mass. Dominantly inherited COL1A1 or COL1A2 mutations appear to be causative in the majority of OI types, but rare recessively inherited genes have also been reported. Recently, SERPINF1 has been reported as another causative gene in OI type VI. To date, only eight SERPINF1 mutations have been reported and all are homozygous. Our patient showed no abnormalities at birth, frequent fractures, osteopenia, and poor response on pamidronate therapy. At the time of her most recent evaluation, she was 8 yr old, and could not walk independently due to frequent lower-extremity fractures, resulting in severe deformity. No clinical signs were seen of hearing impairment, blue sclera, or dentinogenesis imperfecta. In this study, we describe the clinical and radiological findings of one Korean patient with novel compound heterozygous mutations (c.77dupC and c.421dupC) of SERPINF1.

Metabolic Characterization and Follow up of Adult Patients Affected by Osteogenesis Imperfecta in Long-term Treatment with Neridronic Acid.

Aims: Osteogenesis imperfecta (OI) is a rare inherited disorder causing low bone density and increased fragility. Bisphosphonates (BP) are a treatment of choice for OI. Few studies have investigated the long-term effects of BP in OI patients. Thus, aim of our study was to follow up adults affected by OI to evaluate changes in metabolic, clinical situation and safety of long-term neridronic acid therapy, BP authorized for OI treatment. Study design: Longitudinal observational study. Place and duration of the Study: Department of Experimental Medicine, Section of Medical Pathophysiology, Endocrinology and Nutrition. Year: 2004 - October 2010. Methodology: 68 patients underwent clinical examination, laboratory endocrine/ metabolic, pro-inflammatory cytokines screening, ECG at baseline and every 3 months and bone mineral density evaluation, by DEXA, once a year. Results: Skeletal evaluation showed a significant increase of BMD through follow up. Patients were evaluated for metabolic and cardiovascular risk factors, which were unmodified by long-term therapy. Conclusion: Long-term neridronic acid treatment increases bone density, does not alter metabolic parameters indicating that this therapy can be considered safe and a valid therapeutic option for OI patients.

Microarquitetura óssea de uma família portadora de osteogênese imperfeita, tipo I: análise comparativa entre as ferramentas oferecidas pela osteossonografia e osteossonometria -terceira geração falangeal e a densitometria óssea convencional / Bone microarchitecture of a family with osteogenesis imperfecta type I:comparative analysis of the parameters offered by osteosonography - third generation phalangeal and standard bone densitometry

Em cinco membros de uma família portadora de osteogênese imperfeita (OI), tipo I, com idades entre 8 e 58 anos foi realizada a análise da topologia óssea (microarquitetura e composição óssea) por meio da osteossonografia e osteossonometria – terceira geração falangeal, sendo comparada com os resultados da “densitometria óssea” convencional (Dexa-Lombar). Por meio da captação do registro elétrico do perfi l biofísico ósseo (PB) dos ossos endostal, trabecular e cortical na metáfise das falanges foram analisadas seis ferramentas, a saber: elasticidade, homogeneidade, estrutura óssea global, curvas de regressão específicas para a qualidade óssea e quantidade óssea e os cortes sonotomográficos. Os parâmetros que avaliam as propriedades mecânicas ósseas adicionaram importantes informações que facilitaram o entendimento da clínica dos portadores de OI. O estudo comparativo permitiu detectar graus variados de deterioração da matriz mesenquimal proteica óssea, colágeno ósseo, refinando, desde tenra idade e o diagnóstico da antiga doença denominada “doença dos ossos frágeis”. As ferramentas aplicadas adicionaram novas informações que facilitam a compreensão sobre os eventos de fratura. A fratura variou de 1 a 25 vezes, por paciente, ocorreu em todos os membros desde a infância e não guardou relação com a idade. O parâmetro UBPI que analisa a qualidade óssea registrou ampla dispersão em seus valores, oscilando de 0,34 a 0,83. O padrão do PB dos ossos endostal, trabecular e cortical é compatível com o padrão dos portadores de graves deteriorações na matriz mesenquimal proteica como deve ser observado na OI, condição impossível de ser definida quando avaliamos apenas a “densidade óssea” convencional. (...)

Five members of a family with osteogenesis imperfecta (OI) type I aged 8 to 58 years were submitted to complete analysis of bone topology(microarchitecture and bone composition) by third-generation phalangeal osteosonography and the results were compared to those obtained by standard bone densitometry. The following features were analyzed by the electrical recording of bone profile (BP) of endosteal, trabecular and cortical bone of the phalangeal metaphysis: elasticity, homogeneity, global bone structure, specific regression curves for ultrasound bone bone profi le index quality, bone quantity and sonotomographic sections. The parameters that evaluate the mechanical properties of bone added important information and facilitated the clinical understanding of subjects affected by OI. The comparative study permitted the detection of varying degrees of deterioration of the bone protein mesenchymal matrix and of bone collagen, with a refinement of the diagnosis of the disease long termed “brittle bone disease” from a tender age. The methods applied added new information that facilitated the understanding of fracture events. The fracture event ranged from 1 to 25 times per patient, occurred in all family members since childhood, and was not related to age. The UBPI parameter, which analyzes bone quality, showed a wide dispersal of values, ranging from 0.34 to 0.83. The BP pattern of endosteal, trabecular and cortical bone was compatible with the pattern of subjects with severe deterioration of the mesenchymal protein matrix, as observed in OI, a condition that is impossible to define when only bone “density” is evaluated. The six parameters offered by third-generation phalangeal osteosonography provided more encompassing information and satisfi ed the concepts of the New Bone Biology, as well as the more recent guidelines of the National Osteoporosis Foundation; 1999.