RESUMO
Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome.
Assuntos
Fenótipo , Proteínas Repressoras , Humanos , Proteínas Repressoras/genética , Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Anormalidades Dentárias/genética , Anormalidades Dentárias/patologia , Craniossinostoses/genética , Craniossinostoses/patologia , Deleção Cromossômica , Doenças do Desenvolvimento Ósseo , FáciesRESUMO
Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have been associated with syndromic craniosynostosis involving various cranial sutures and Chitayat syndrome, an ultrarare condition with respiratory distress, skeletal anomalies, and facial dysmorphism. Recently, a single patient with craniosynostosis and a phenotype resembling Noonan syndrome (NS), the most common disorder among the RASopathies, was reported to carry a de novo loss-of-function variant in ERF. Here, we clinically profile 26 individuals from 15 unrelated families carrying different germline heterozygous variants in ERF and showing a phenotype reminiscent of NS. The majority of subjects presented with a variable degree of global developmental and/or language delay. Their shared facial features included absolute/relative macrocephaly, high forehead, hypertelorism, palpebral ptosis, wide nasal bridge, and low-set/posteriorly angulated ears. Stature was below the 3rd centile in two-third of the individuals, while no subject showed typical NS cardiac involvement. Notably, craniosynostosis was documented only in three unrelated individuals, while a dolichocephalic aspect of the skull in absence of any other evidence supporting a premature closing of sutures was observed in other 10 subjects. Unilateral Wilms tumor was diagnosed in one individual. Most cases were familial, indicating an overall low impact on fitness. Variants were nonsense and frameshift changes, supporting ERF haploinsufficiency. These findings provide evidence that heterozygous loss-of-function variants in ERF cause a "RASopathy" resembling NS with or without craniosynostosis, and allow a first dissection of the molecular circuits contributing to MAPK signaling pleiotropy.
Assuntos
Craniossinostoses , Síndrome de Noonan , Fenótipo , Humanos , Craniossinostoses/genética , Craniossinostoses/patologia , Feminino , Masculino , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Criança , Pré-Escolar , Lactente , Mutação com Perda de Função , Adolescente , Proteínas Repressoras/genética , AdultoRESUMO
Sagittal suture synostosis is one of the most common craniosynostoses and is often diagnosed by characteristic narrow and long skull shape, scaphocephaly. However, some patients with sagittal suture synostosis do not present with typical scaphocephaly, making early diagnosis difficult. In this study, five cases of characteristic skull deformity showing a narrowing of the cranium posterior to the coronal suture on computed tomography (CT) are presented. The three older children presented with papilledema and intellectual disability and a closed sagittal suture on CT. The two infant cases were diagnosed with the characteristic cranial deformities with aggravation of the deformity over time, but sagittal suture closure was not evident on CT. All patients underwent cranial remodeling surgery. In the two infant cases, the histopathological findings showed that the anterior part of the sagittal suture was firmly fused with fibrous tissue without bony fusion. These findings suggested that narrowing of the cranium posterior to the coronal suture might be due to functional fusion of the anterior portion of the sagittal suture prior to bony fusion. In an infant presenting with such a deformity that shows aggravation of the deformity over time, surgical treatment should be considered.
Assuntos
Craniossinostoses , Procedimentos de Cirurgia Plástica , Lactente , Criança , Humanos , Adolescente , Craniossinostoses/diagnóstico por imagem , Craniossinostoses/cirurgia , Craniossinostoses/patologia , Suturas Cranianas/diagnóstico por imagem , Suturas Cranianas/cirurgia , Crânio/cirurgia , SuturasRESUMO
We present the first data-driven pediatric model that explains cranial sutural growth in the pediatric population. We segmented the cranial bones in the neurocranium from the cross-sectional CT images of 2068 normative subjects (age 0-10 years), and we used a 2D manifold-based cranial representation to establish local anatomical correspondences between subjects guided by the location of the cranial sutures. We designed a diffeomorphic spatiotemporal model of cranial bone development as a function of local sutural growth rates, and we inferred its parameters statistically from our cross-sectional dataset. We used the constructed model to predict growth for 51 independent normative patients who had longitudinal images. Moreover, we used our model to simulate the phenotypes of single suture craniosynostosis, which we compared to the observations from 212 patients. We also evaluated the accuracy predicting personalized cranial growth for 10 patients with craniosynostosis who had pre-surgical longitudinal images. Unlike existing statistical and simulation methods, our model was inferred from real image observations, explains cranial bone expansion and displacement as a consequence of sutural growth and it can simulate craniosynostosis. This pediatric cranial suture growth model constitutes a necessary tool to study abnormal development in the presence of cranial suture pathology.
Assuntos
Suturas Cranianas , Craniossinostoses , Humanos , Criança , Recém-Nascido , Lactente , Pré-Escolar , Craniossinostoses/patologia , Crânio/patologia , Cuidados PaliativosRESUMO
Very few clinical entities have undergone so many different treatment approaches over such a short period of time as craniosynostosis. Surgical treatments for this condition have ranged from simple linear craniectomies, accounting for the specific role of cranial sutures in assuring the normal growth of the skull, to more complex cranial vault reconstructions, based on the perceived role of the skull base in affecting the growth of the skull. While a great deal of evolution has occurred, there remains controversy regarding the ideal treatment including the best surgical technique, the optimal age for surgery, and the long-term morphological and neurodevelopmental outcomes. The evolution of the surgical management of craniosynostosis in the last 50 years has been affected by several factors. This includes the awareness of needing to operate on affected children during infancy to achieve the best results, the use of multistage operations, the availability of more sophisticated surgical tools, and improved perioperative care. In some forms of craniosynostosis, the operations can be carried out at a very young age with low morbidity, and with the postoperative use of a molding helmet, springs, or distractors, these operations prove to be as effective as traditional larger cranial reconstructions performed in older children. As a consequence, complex surgical operations have become progressively less utilized. A second relevant advance was the more recent advent of a molecular diagnosis, which allowed us to understand the pathogenesis of some associated malformations and neurodevelopmental issues that were observed in some children despite appropriate surgical treatment. Future research should focus on improving the analysis of longer-term outcomes and understanding the natural history of craniofacial conditions, including what issues persist despite optimal surgical correction. Progress in molecular investigations concerning the normal and pathological development of cranial sutures could be a further significant step in the management of craniosynostosis, possibly favoring a "medical" treatment in the near future. Artificial intelligence will likely have a role in establishing the diagnosis with less reliance on radiographic studies and in assisting with surgical planning. Overall, much progress has been made, but there remains much to do.
Assuntos
Craniossinostoses , Neurocirurgia , Humanos , Criança , Lactente , Inteligência Artificial , Craniossinostoses/diagnóstico por imagem , Craniossinostoses/cirurgia , Craniossinostoses/patologia , Crânio/cirurgia , Suturas Cranianas/diagnóstico por imagem , Suturas Cranianas/cirurgia , Base do Crânio/patologiaRESUMO
Autosomal recessive CYP26B1 disorder is characterised by syndromic craniosynostosis of variable severity, and survival ranging from prenatal lethality to survival into adulthood. Here we report on two related individuals of Asian-Indian origin with syndromic craniosynostosis characterised by craniosynostosis, and dysplastic radial heads, caused by monoallelic CYP26B1 likely pathogenic variant NM_019885.4:c.86C > A:p. (Ser29Ter). We propose the possibility of autosomal dominant phenotype of CYP26B1 variant.
Assuntos
Craniossinostoses , Haploinsuficiência , Feminino , Humanos , Gravidez , Craniossinostoses/genética , Craniossinostoses/patologia , Fenótipo , Ácido Retinoico 4 Hidroxilase/genética , Tomografia Computadorizada por Raios XRESUMO
SUMMARY: CRISPR-Cas genome editing tools are among the most substantial advances in the life sciences in modern history. Single-dose gene therapies to correct pathogenic mutations have moved quickly from bench to bedside, with several therapeutics designed by CRISPR pioneers entering various stages of clinical investigation. Applications of these genetic technologies are poised to reshape the practice of both medicine and surgery. Many of the most morbid conditions treated by craniofacial surgeons are syndromic craniosynostoses caused by mutations in fibroblast growth factor receptor genes, including Apert, Pfeiffer, Crouzon, and Muenke syndromes. The fact that pathogenic mutations in these genes are recurrent in the majority of affected families presents a unique opportunity to develop "off-the-shelf" gene editing therapies to correct these mutations in affected children. The therapeutic potential of these interventions could reshape pediatric craniofacial surgery, potentially first eliminating the need for midface advancement procedures in affected children.
Assuntos
Acrocefalossindactilia , Disostose Craniofacial , Craniossinostoses , Especialidades Cirúrgicas , Criança , Humanos , Craniossinostoses/genética , Craniossinostoses/cirurgia , Craniossinostoses/patologia , Mutação , Face/patologia , Disostose Craniofacial/genética , Disostose Craniofacial/cirurgia , Acrocefalossindactilia/genéticaRESUMO
Although neurocognitive impairment has been considered as the main argument for the surgical treatment of craniosynostosis (CS), recent studies reported subtle deficits in neurological function even in operated patients. However, the cause of these deficits remains poorly understood. This systematic review sought to examine the impact of CS on the brain microstructure, mainly on functional connectivity, and comprehensively summarize the clinical and experimental research available on this topic. A systematic review was performed considering the publications of the last 20 years in PubMed and Web of Science, including relevant human and animal studies of the types of brain-microstructure disturbances in CS. Among the 560 papers identified, 11 were selected for analysis. Seven of those were conducted in humans and 4 in animal models. Resting-state functional magnetic resonance imaging, task-based magnetic resonance imaging, and diffusion tensor imaging were the main instruments used to investigate brain connectivity in humans. The main findings were increased connectivity of the posterior segment of cingulum gyri, reduced interconnectivity of the frontal lobes, and reduced diffusivity on diffusion tensor imaging, which were associated with hyperactivity behaviors and poorer performance on neurocognitive tests. Conversely, despite the lack of evidence of brain dysfunction in animal studies, they reported a tendency toward the development of hyperactive behaviors and impairment of neurocognitive function. Skull restriction caused by CS apparently chronically increases the intracranial pressure and produces white matter injuries. The current evidence supports the contention that an early surgical approach could minimize brain-connectivity impairment in this context.
Assuntos
Craniossinostoses , Imagem de Tensor de Difusão , Humanos , Imagem de Tensor de Difusão/métodos , Encéfalo , Imageamento por Ressonância Magnética/métodos , Imagem de Difusão por Ressonância Magnética , Craniossinostoses/diagnóstico por imagem , Craniossinostoses/cirurgia , Craniossinostoses/patologiaRESUMO
Brachycephalic obstructive airway syndrome (BOAS) is a chronic, lifelong, debilitating, primarily obstructive airway disease which adversely affects the quality of life of many popular dog breeds. Respiratory restriction in bulldog breeds, pugs and Boston terriers frequently co-exist with pathologies of the gastrointestinal tract. In addition, many brachycephalic dogs that appear clinically normal are, in fact suffering from chronic hypoxia and its systemic consequences. Concurrent gastroesophageal reflux-associated conditions, sleep disorders and systemic hypertension further impact the welfare of affected dogs. Acceptance of BOAS and associated clinical signs as being 'normal for the breed' is common amongst owners. While surgical correction of the upper airway is the mainstay of treatment, the provision of subsequent, frequently lifelong medical management is equally important for the maintenance of an acceptable quality of life, at least for some affected patients. Here we review the current knowledge concerning brachycephaly, combine it with shared clinical experience in the management of this debilitating condition, and discuss ethical considerations and the responsibility of veterinarians to contribute public education and to support appropriate breed standards for animals under our care.
Assuntos
Obstrução das Vias Respiratórias , Craniossinostoses , Doenças do Cão , Cães , Animais , Qualidade de Vida , Doenças do Cão/patologia , Craniossinostoses/cirurgia , Craniossinostoses/veterinária , Craniossinostoses/patologia , Obstrução das Vias Respiratórias/cirurgia , Obstrução das Vias Respiratórias/veterinária , Obstrução das Vias Respiratórias/patologiaRESUMO
OBJECTIVE: The aim of the study was to investigate the awareness for the breed-related brachycephalic obstructive airway syndrome (BOAS) and the occurrence of other breed-typical diseases within the framework of an online survey for pug owners. MATERIAL AND METHODS: A digital questionnaire for owners was created, distributed via social media and subsequently evaluated. RESULTS: The questionnaire was completed by 1220 pug owners. According to the owners, 32â % (344/1073) of the animals that did not undergo airway dilatation surgery show slight and 3â % (34/1073) show distinct breathing sounds when at rest. 86â % (326/378) of the owners perceive these breathing sounds as "normal, breed-specific" and 14â % (51/378) consider them as sign of "disease". 20â % (210/1073) of the animals are considered "somewhat" and 5â % (57/1073) "frequently tired and quickly short of breath" after a small amount of time. 24â % (245/1220) of all animals suffer from ocular diseases, 10â % (122/1220) from skin diseases and 11â % (134/1220) from spinal diseases, among others. CONCLUSION: The survey shows that with 67â % (814/1220) more than half of the pug owners perceive clinical signs of BOAS and/or other breed-specific diseases in their animals, however, a large proportion consider these as being non-problematic. CLINICAL RELEVANCE: The present study reveals that the animals' clinical limitations associated with brachycephaly are oftentimes not perceived as being pathologic and are hence underestimated by the owners.
Assuntos
Obstrução das Vias Respiratórias , Craniossinostoses , Doenças do Cão , Obstrução das Vias Respiratórias/diagnóstico , Obstrução das Vias Respiratórias/patologia , Obstrução das Vias Respiratórias/veterinária , Animais , Craniossinostoses/diagnóstico , Craniossinostoses/patologia , Craniossinostoses/veterinária , Doenças do Cão/diagnóstico , Doenças do Cão/epidemiologia , Doenças do Cão/genética , Cães , Humanos , Sons Respiratórios/veterinária , Inquéritos e Questionários , SíndromeRESUMO
BACKGROUND: There is a paucity of data on normal intracranial volumes for healthy children during the first few years of life, when cranial growth velocity is greatest. The aim of this study was to generate a normative predictive model of intracranial volumes based on brain magnetic resonance imaging from a large sample of healthy children to serve as a reference tool for future studies on craniosynostosis. METHODS: Structural magnetic resonance imaging data for healthy children up to 3 years of age was acquired from the National Institutes of Health Pediatric MRI Data Repository. Intracranial volumes were calculated using T1-weighted scans with FreeSurfer (version 6.0.0). Mean intracranial volumes were calculated and best-fit logarithmic curves were generated. Results were compared to previously published intracranial volume curves. RESULTS: Two-hundred seventy magnetic resonance imaging scans were available: 118 were collected in the first year of life, 97 were collected between years 1 and 2, and 55 were collected between years 2 and 3. A best-fit logarithmic growth curve was generated for male and female patients. The authors' regression models showed that male patients had significantly greater intracranial volumes than female patients after 1 month of age. Predicted intracranial volumes were also greater in male and female patients in the first 6 months of life as compared to previously published intracranial volume curves. CONCLUSIONS: To the authors' knowledge, this is the largest series of demographically representative magnetic resonance imaging-based intracranial volumes for children aged 3 years and younger. The model generated in this study can be used by investigators as a reference for evaluating craniosynostosis patients.
Assuntos
Craniossinostoses , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Criança , Craniossinostoses/diagnóstico por imagem , Craniossinostoses/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Crânio/patologiaRESUMO
BACKGROUND: Nonsyndromic craniosynostosis is one of the most common anomalies treated by craniofacial surgeons. Despite optimal surgical management, nearly half of affected children have subtle neurocognitive deficits. Whereas timing and type of surgical intervention have been studied, the possibility of genetic influence on neurodevelopment in nonsyndromic craniosynostosis patients remains unexplored. METHODS: The authors performed whole-exome sequencing for 404 case-parent trios with sporadic nonsyndromic craniosynostosis. Statistical analyses were performed to assess the burden of de novo mutations in cases compared to both expectation and 1789 healthy control trios. Individuals with and without each mutation class were analyzed, and the presence or absence of various types of neurodevelopmental delay were recorded alongside demographic information. RESULTS: The authors identified a highly significant burden of damaging de novo mutations in mutation-intolerant [probability of loss of function intolerance (pLI) >0.9] genes in nonsyndromic craniosynostosis probands (p = 5.9 × 10-6). Children with these mutations had a two-fold higher incidence of neurodevelopmental delay (p = 0.001) and a more than 20-fold greater incidence of intellectual disability (p = 7.2 × 10-7), and were 3.6-fold more likely to have delays that persisted past 5 years of age (p = 4.4 × 10-4) in comparison with children with nonsyndromic craniosynostosis without these mutations. Transmitted loss of function mutations in high-pLI genes also conferred a 1.9-fold greater risk of neurodevelopmental delay (p = 4.5 ×10-4). CONCLUSIONS: These findings implicate genetic lesions concurrently impacting neurodevelopment and cranial morphogenesis in the pathoetiology of nonsyndromic craniosynostosis and identify a strong genetic influence on neurodevelopmental outcomes in affected children. These findings may eventually prove useful in determining which children with nonsyndromic craniosynostosis are most likely to benefit from surgical intervention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.
Assuntos
Craniossinostoses , Criança , Craniossinostoses/complicações , Craniossinostoses/genética , Craniossinostoses/patologia , Humanos , Incidência , Mutação , Crânio/patologia , Sequenciamento do ExomaRESUMO
Skeletal ciliopathies (e.g., Jeune syndrome, short rib polydactyly syndrome, and Sensenbrenner syndrome) are frequently associated with nephronophthisis-like cystic kidney disease and other organ manifestations. Despite recent progress in genetic mapping of causative loci, a common molecular mechanism of cartilage defects and cystic kidneys has remained elusive. Targeting two ciliary chondrodysplasia loci (ift80 and ift172) by CRISPR/Cas9 mutagenesis, we established models for skeletal ciliopathies in Xenopus tropicalis Froglets exhibited severe limb deformities, polydactyly, and cystic kidneys, closely matching the phenotype of affected patients. A data mining-based in silico screen found ttc30a to be related to known skeletal ciliopathy genes. CRISPR/Cas9 targeting replicated limb malformations and renal cysts identical to the models of established disease genes. Loss of Ttc30a impaired embryonic renal excretion and ciliogenesis because of altered posttranslational tubulin acetylation, glycylation, and defective axoneme compartmentalization. Ttc30a/b transcripts are enriched in chondrocytes and osteocytes of single-cell RNA-sequenced embryonic mouse limbs. We identify TTC30A/B as an essential node in the network of ciliary chondrodysplasia and nephronophthisis-like disease proteins and suggest that tubulin modifications and cilia segmentation contribute to skeletal and renal ciliopathy manifestations of ciliopathies in a cell type-specific manner. These findings have implications for potential therapeutic strategies.
Assuntos
Osso e Ossos/anormalidades , Ciliopatias/patologia , Craniossinostoses/patologia , Proteínas do Citoesqueleto/metabolismo , Displasia Ectodérmica/patologia , Embrião não Mamífero/patologia , Anormalidades Musculoesqueléticas/patologia , Doenças Renais Policísticas/patologia , Tubulina (Proteína)/química , Animais , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Ciliopatias/genética , Ciliopatias/metabolismo , Craniossinostoses/genética , Craniossinostoses/metabolismo , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Displasia Ectodérmica/genética , Displasia Ectodérmica/metabolismo , Embrião não Mamífero/metabolismo , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/metabolismo , Fenótipo , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/metabolismo , Tubulina (Proteína)/metabolismo , Xenopus laevisRESUMO
The cranial bones constitute the protective structures of the skull, which surround and protect the brain. Due to the limited repair capacity, the reconstruction and regeneration of skull defects are considered as an unmet clinical need and challenge. Previously, it has been proposed that the periosteum and dura mater provide reparative progenitors for cranial bones homeostasis and injury repair. In addition, it has also been speculated that the cranial mesenchymal stem cells reside in the perivascular niche of the diploe, namely, the soft spongy cancellous bone between the interior and exterior layers of cortical bone of the skull, which resembles the skeletal stem cells' distribution pattern of the long bone within the bone marrow. Not until recent years have several studies unraveled and validated that the major mesenchymal stem cell population of the cranial region is primarily located within the suture mesenchyme of the skull, and hence, they are termed suture mesenchymal stem cells (SuSCs). Here, we summarized the characteristics of SuSCs, this newly discovered stem cell population of cranial bones, including the temporospatial distribution pattern, self-renewal, and multipotent properties, contribution to injury repair, as well as the signaling pathways and molecular mechanisms associated with the regulation of SuSCs.
Assuntos
Regeneração Óssea/genética , Suturas Cranianas/citologia , Células-Tronco Mesenquimais/citologia , Osteócitos/citologia , Fraturas Cranianas/genética , Animais , Proteína Axina/genética , Proteína Axina/metabolismo , Catepsina K/genética , Catepsina K/metabolismo , Diferenciação Celular , Proliferação de Células , Suturas Cranianas/crescimento & desenvolvimento , Suturas Cranianas/lesões , Suturas Cranianas/metabolismo , Craniossinostoses/genética , Craniossinostoses/metabolismo , Craniossinostoses/patologia , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Osteócitos/metabolismo , Transdução de Sinais , Fraturas Cranianas/metabolismo , Fraturas Cranianas/patologia , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismoRESUMO
BACKGROUND: Craniosynostosis is an underdiagnosed complication associated with hypophosphatemic rickets. The study aims to describe the clinical and auxological characteristic of children with hypophosphatemic rickets and craniosynostosis, describe the usual treatment, and compare the characteristics with those of children without craniosynostosis. METHODS AND PATIENTS: An observational and retrospective cohort study was conducted. Clinical notes and cranial images were reviewed. Out of 96 children, only the 50 patients who had skull images were included. RESULTS: Out of 50 patients, 26 (15 males) had craniosynostosis (52%). No differences were observed in birth size, age, height, body proportions, alkaline phosphatase, serum phosphate, or percent tubular reabsorption of phosphate at first appointment among children with or without craniosynostosis. Among patients with craniosynostosis, dolichocephaly was prevalent. The sagittal suture was affected in all patients with craniosynostosis, with 19 of 26 children (73%) affected with isolated scaphocephaly. Pan-sutural craniosynostosis was present in 7 children (27%). None of the children had microcephaly, 7 of them presented macrocephaly and, in the remaining subjects, head circumference was normal. Five patients had undergone at least 1 cranial remodeling surgery. One patient with craniosynostosis was diagnosed with a Chiari I malformation. Molecular characterization of PHEX gene was performed in 14 cases. CONCLUSIONS: Craniosynostosis is an underdiagnosed complication of hypophosphatemic rickets. Many patients with normal head size and growth may go undiagnosed, thus it is important to consider this association for early diagnosis and possible surgical treatment. A multidisciplinary approach is necessary for a correct long-term follow-up.
Assuntos
Craniossinostoses/patologia , Raquitismo Hipofosfatêmico Familiar/complicações , Predisposição Genética para Doença , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Criança , Pré-Escolar , Craniossinostoses/etiologia , Craniossinostoses/metabolismo , Craniossinostoses/cirurgia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
Out of all the synostotic corrective surgeries, fronto-orbital advancement and cranial vault remodeling for patients with unilateral coronal synostosis is one of the hardest to maintain symmetric and proportional correction without some amount of relapse. Over the course of 20 years operating on these patients, the senior author has made multiple adjustments to compensate for relapse asymmetry, including overcorrection on the affected side, increased points of fixation, periosteal release, and scalp expansion with galeal scoring to minimize tension of the closure. As a result of these interventions, we have seen improved immediate results following surgery. However, we have continued to note clinically significant relapse postoperatively. As such, we have started to implement postoperative helmet therapy (PHT) to help maintain the surgical correction, improve secondary brachycephaly, and increase overall symmetry. PHT is a reasonable low-risk complement to fronto-orbital advancement and cranial vault remolding. Clinically, PHT appears to help minimize relapse and improve overall head symmetry. Further investigation and increased patient enrollment are required to determine the true benefits of PHT in this patient population.
Assuntos
Suturas Cranianas/cirurgia , Craniossinostoses/cirurgia , Dispositivos de Proteção da Cabeça/estatística & dados numéricos , Procedimentos Cirúrgicos Oftalmológicos/métodos , Crânio/cirurgia , Craniossinostoses/patologia , Feminino , Humanos , Lactente , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
We report the clinical, biochemical and genetic findings from a Spanish boy of Caucasian origin who presented with fever-dependent RALF (recurrent acute liver failure) and osteogenesis imperfecta (OI). Whole-exome sequencing (WES) uncovered two compound heterozygous variants in NBAS (c.[1265 T > C];[1549C > T]:p.[(Leu422Pro)];[(Arg517Cys)]), and a heterozygous variant in P4HB (c.[194A > G];[194=]:p.[(Lys65Arg)];[(Lys65=)]) that was transmitted from the clinically unaffected mother who was mosaic carrier of the variant. Variants in NBAS protein have been associated with ILFS2 (infantile liver failure syndrome-2), SOPH syndrome (short stature, optic nerve atrophy, and Pelger-Huët anomaly syndrome), and multisystem diseases. Several patients showed clinical manifestations affecting the skeletal system, such as osteoporosis, pathologic fractures and OI. Experiments in the patient's fibroblasts demonstrated that mutated NBAS protein is overexpressed and thermally unstable, and reduces the expression of MGP, a regulator of bone homeostasis. Variant in PDI (protein encoded by P4HB) has been associated with CLCRP1 (Cole-Carpenter syndrome-1), a type of severe OI. An increase of COL1A2 protein retention was observed in the patient's fibroblasts. In order to study if the variant in P4HB was involved in the alteration in collagen trafficking, overexpression experiments of PDI were carried out. These experiments showed that overexpression of mutated PDI protein produces an increase in COL1A2 retention. In conclusion, these results corroborate that the variants in NBAS are responsible for the liver phenotype, and demonstrate that the variant in P4HB is involved in the bone phenotype, probably in synergy with NBAS variants.
Assuntos
Colágeno Tipo I/genética , Falência Hepática Aguda/genética , Proteínas de Neoplasias/genética , Osteogênese Imperfeita/genética , Pró-Colágeno-Prolina Dioxigenase/genética , Isomerases de Dissulfetos de Proteínas/genética , Criança , Pré-Escolar , Craniossinostoses/complicações , Craniossinostoses/genética , Craniossinostoses/patologia , Nanismo/diagnóstico por imagem , Nanismo/genética , Nanismo/patologia , Anormalidades do Olho/complicações , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Febre/complicações , Febre/genética , Heterozigoto , Humanos , Hidrocefalia/complicações , Hidrocefalia/genética , Hidrocefalia/patologia , Lactente , Recém-Nascido , Fígado/diagnóstico por imagem , Fígado/patologia , Falência Hepática Aguda/complicações , Falência Hepática Aguda/diagnóstico por imagem , Falência Hepática Aguda/patologia , Masculino , Mutação/genética , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/patologia , Fenótipo , Sequenciamento do ExomaRESUMO
Achondroplasia is the most common disproportionate short statured skeletal dysplasia with a prevalence of approximately 1:20,000-30,000. We created the largest database to date of a historical cohort of 1374 patients with achondroplasia (CLARITY-aChondropLasia nAtuRal hIsTory studY). This cohort was queried for the presence of unrecognized or under-recognized features associated with achondroplasia. Craniosynostosis was found to co-occur with achondroplasia in 9 (0.65%) patients in this cohort, which is much higher than the general population prevalence of 3.1-7.2 per 10,000. In addition, 27 patients had seizures (2.0%), an apparent excess as compared to the general population. Only two people had diabetes despite a high rate of adult obesity. This report documents for the first time an increased prevalence of craniosynostosis in persons with achondroplasia, and adds support to previous observations of an apparently higher than expected prevalence of seizures and lower prevalence of diabetes mellitus.
Assuntos
Acondroplasia/epidemiologia , Craniossinostoses/epidemiologia , Osteocondrodisplasias/epidemiologia , Convulsões/epidemiologia , Acondroplasia/diagnóstico , Acondroplasia/patologia , Adulto , Craniossinostoses/diagnóstico , Craniossinostoses/patologia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Feminino , Humanos , Masculino , Mutação/genética , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/patologia , Fenótipo , Convulsões/diagnóstico , Convulsões/patologia , Adulto JovemRESUMO
Cranioectodermal dysplasia (CED) is a rare autosomal recessive disorder primarily characterized by craniofacial, skeletal, and ectodermal abnormalities. CED is a chondrodysplasia, which is part of a spectrum of clinically and genetically heterogeneous diseases that result from disruptions in cilia. Pathogenic variants in genes encoding components of the ciliary transport machinery are known to cause CED. Intra- and interfamilial clinical variability has been reported in a few CED studies and the findings of this study align with these observations. Here, we report on five CED patients from four Polish families with identical compound heterozygous variants [c.1922T>G p.(Leu641Ter) and c.2522A>T; p.(Asp841Val)] in WDR35. The frequent occurrence of both identified changes in Polish CED families suggests that these variants may be founder mutations. Clinical evaluation of the CED patients revealed interfamilial clinical variability among the patients. This includes differences in skeletal and ectodermal features as well as variability in development, progression, and severity of renal and liver insufficiency. This is the first report showing significant interfamilial clinical variability in a series of CED patients from unrelated families with identical compound heterozygous variants in WDR35. Our findings strongly indicate that other genetic and non-genetic factors may modulate the progression and expression of the patients' phenotypes.
Assuntos
Osso e Ossos/anormalidades , Craniossinostoses/genética , Proteínas do Citoesqueleto/genética , Displasia Ectodérmica/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Osso e Ossos/patologia , Criança , Pré-Escolar , Cílios/genética , Cílios/patologia , Craniossinostoses/epidemiologia , Craniossinostoses/patologia , Displasia Ectodérmica/epidemiologia , Displasia Ectodérmica/patologia , Feminino , Humanos , Lactente , Masculino , Mutação/genética , Linhagem , Fenótipo , Polônia/epidemiologiaRESUMO
OBJECTIVE: To determine whether an anatomical difference in esophageal hiatus (EH) size exists between brachycephalic and nonbrachycephalic dogs. STUDY DESIGN: Retrospective clinical study. ANIMALS: Client-owned dogs (n = 87). METHODS: Clinical records and images of dogs that underwent computed tomography between June 2015 and September 2018 were reviewed. For the first part of the study, EH and aortic (Ao) cross-sectional surface areas were measured in brachycephalic (group 1) and nonbrachycephalic dogs of similar body size (<15 kg) without respiratory or gastroesophageal (GE) signs (group 2) by using multiplanar reconstruction. Esophageal hiatus:aortic ratio was calculated. In the second part of the study, absolute EH measurements were also compared in weight-matched (WM) dogs (8-10 kg) from groups 1 and 2. RESULTS: Mean (±SD) of EH:Ao values for group 1 (8.1 ± 2.8) were higher (P < .0001) than those for group 2 (3.7 ± 1.1). In addition, EH measurements of 20 WM dogs in group 1 were higher than those of 20 dogs in group 2 (P < .05). CONCLUSION: Esophageal hiatus cross-sectional surface area (directly and indirectly measured) in brachycephalic dogs was considerably larger than that in nonbrachycephalic dogs of generally similar body size. CLINICAL SIGNIFICANCE: Results of this study provide evidence to support the existence of a specific anatomical factor that could likely correlate to functional GE alterations (eg, regurgitation, gastroesophageal reflux, and sliding hiatal hernia) commonly seen in brachycephalic dogs.