RESUMEN
Diaphanospondylodysostosis is an extremely rare, recessively inherited, perinatal lethal skeletal disorder associated with BMPER gene mutations. Clinically it is characterized by defects in costovertebral ossification, absent ribs, hypertelorism, short nose with depressed nasal bridge, low-set ears, and short neck. At the extraosseous level, the most frequent pathologic finding is nephroblastomatosis with multicystic kidneys. We present the case of a child of non-consanguineous parents who died at 2 months of age in our center. Autopsy showed a marked costovertebral ossification defect, perilobar nephrogenic rests and loss of white matter with periventricular leukomalacia. After genetic study, the diagnosis of diaphanospondylodysostosis was confirmed. A previously undescribed germinal mutation in the BMPER gene (c.576 + 2dupT) was found.
Asunto(s)
Proteínas Portadoras , Disostosis , Proteínas Portadoras/genética , Niño , Anomalías Craneofaciales , Disostosis/diagnóstico , Disostosis/genética , Disostosis/patología , Femenino , Humanos , Mutación , Embarazo , Costillas/anomalías , Costillas/patología , Columna Vertebral/anomalíasRESUMEN
Familial mutations of the protein kinase A (PKA) R1α regulatory subunit lead to a generalized predisposition for a wide range of tumors, from pituitary adenomas to pancreatic and liver cancers, commonly referred to as Carney complex (CNC). CNC mutations are known to cause overactivation of PKA, but the molecular mechanisms underlying such kinase overactivity are not fully understood in the context of the canonical cAMP-dependent activation of PKA. Here, we show that oligomerization-induced sequestration of R1α from the catalytic subunit of PKA (C) is a viable mechanism of PKA activation that can explain the CNC phenotype. Our investigations focus on comparative analyses at the level of structure, unfolding, aggregation, and kinase inhibition profiles of wild-type (wt) PKA R1α, the A211D and G287W CNC mutants, as well as the cognate acrodysostosis type 1 (ACRDYS1) mutations A211T and G287E. The latter exhibit a phenotype opposite to CNC with suboptimal PKA activation compared with wt. Overall, our results show that CNC mutations not only perturb the classical cAMP-dependent allosteric activation pathway of PKA, but also amplify significantly more than the cognate ACRDYS1 mutations nonclassical and previously unappreciated activation pathways, such as oligomerization-induced losses of the PKA R1α inhibitory function.
Asunto(s)
Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/química , AMP Cíclico/química , Mutación , Subunidades de Proteína/química , Regulación Alostérica , Animales , Sitios de Unión , Complejo de Carney/enzimología , Complejo de Carney/genética , Complejo de Carney/patología , Bovinos , Cristalografía por Rayos X , AMP Cíclico/metabolismo , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/metabolismo , Disostosis/enzimología , Disostosis/genética , Disostosis/patología , Activación Enzimática , Expresión Génica , Humanos , Discapacidad Intelectual/enzimología , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Cinética , Modelos Moleculares , Osteocondrodisplasias/enzimología , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Especificidad por SustratoRESUMEN
Sleep-disordered breathing (SDB) is common in patients with skeletal dysplasias. The aim of our study was to analyze SDB and respiratory management in children with rare skeletal dysplasias. We performed a retrospective analysis of patients with spondyloepiphyseal dysplasia congenita (SEDC), metatropic dysplasia (MD), spondyloepimetaphyseal dysplasia (SEMD), acrodysostosis (ADO), geleophysic dysplasia (GD), acromicric dysplasia (AD), and spondylocostal dysplasia (SCD) between April 2014 and October 2020. Polygraphic data, clinical management, and patients' outcome were analyzed. Thirty-one patients were included (8 SEDC, 3 MD, 4 SEMD, 1 ADO, 4 GD, 3 AD, and 8 SCD). Sixteen patients had obstructive sleep apnea (OSA): 11 patients (2 with SEDC, 1 with SEMD, 1 with ADO, 1 with GD, 2 with AD, and 4 with SCD) had mild OSA, 2 (1 SEMD and 1 GD) had moderate OSA, and 3 (1 SEDC, 1 MD, 1 SEMD) had severe OSA. Adenotonsillectomy was performed in one patient with SCD and mild OSA, and at a later age in two other patients with ADO and AD. The two patients with moderate OSA were treated with noninvasive ventilation (NIV) because of nocturnal hypoxemia. The three patients with severe OSA were treated with adenotonsillectomy (1 SEDC), adeno-turbinectomy and continuous positive airway pressure (CPAP; 1 MD), and with NIV (1 SEMD) because of nocturnal hypoventilation. OSA and/or alveolar hypoventilation is common in patients with skeletal dysplasias, underlining the importance of systematic screening for SDB. CPAP and NIV are effective treatments for OSA and nocturnal hypoventilation/hypoxemia.
Asunto(s)
Disostosis/congénito , Discapacidad Intelectual/terapia , Osteocondrodisplasias/congénito , Costillas/anomalías , Síndromes de la Apnea del Sueño/terapia , Apnea Obstructiva del Sueño/terapia , Columna Vertebral/anomalías , Adenoidectomía , Adolescente , Adulto , Niño , Preescolar , Presión de las Vías Aéreas Positiva Contínua/métodos , Disostosis/diagnóstico por imagen , Disostosis/patología , Disostosis/terapia , Femenino , Humanos , Lactante , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/patología , Masculino , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/patología , Osteocondrodisplasias/terapia , Polisomnografía , Costillas/diagnóstico por imagen , Costillas/patología , Síndromes de la Apnea del Sueño/diagnóstico por imagen , Síndromes de la Apnea del Sueño/patología , Apnea Obstructiva del Sueño/diagnóstico por imagen , Apnea Obstructiva del Sueño/patología , Columna Vertebral/diagnóstico por imagen , Columna Vertebral/patología , Tonsilectomía , Resultado del Tratamiento , Adulto JovenRESUMEN
RIPPLY2 is an essential part of the formation of somite patterning during embryogenesis and in establishment of rostro-caudal polarity. Here, we describe three individuals from two families with compound-heterozygous variants in RIPPLY2 (NM_001009994.2): c.238A > T, p.(Arg80*) and c.240-4 T > G, p.(?), in two 15 and 20-year-old sisters, and a homozygous nonsense variant, c.238A > T, p.(Arg80*), in an 8 year old boy. All patients had multiple vertebral body malformations in the cervical and thoracic region, small or absent rib involvement, myelopathies, and common clinical features of SCDO6 including scoliosis, mild facial asymmetry, spinal spasticity and hemivertebrae. The nonsense variant can be classified as likely pathogenic based on the ACMG criteria while the splice variants must be classified as a variant of unknown significance. With this report on two further families, we confirm RIPPLY2 as the gene for SCDO6 and broaden the phenotype by adding myelopathy with or without spinal canal stenosis and spinal spasticity to the symptom spectrum.
Asunto(s)
Vértebras Cervicales/anomalías , Disostosis/congénito , Proteínas Represoras/genética , Alelos , Niño , Codón sin Sentido , Disostosis/genética , Disostosis/patología , Cara/anomalías , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Mutación Missense , Sitios de Empalme de ARN , Costillas/anomalías , Escoliosis/genética , Somitos/patología , Médula Espinal/anomalías , Estenosis Espinal/genética , Secuenciación del ExomaRESUMEN
Acrodysostosis refers to a rare heterogeneous group of bone dysplasias that share skeletal features, hormone resistance, and intellectual disability. Two genes have been associated with acrodysostosis with or without hormone resistance (PRKAR1A and PDE4D). Severe intellectual disability has been reported with acrodysostosis but brain malformations and ichthyosis have not been reported in these syndromes. Here we describe a female patient with acrodysostosis, intellectual disability, cerebellar hypoplasia, and lamellar ichthyosis. The patient has an evolving distinctive facial phenotype and childhood onset ataxia. X-rays showed generalized osteopenia, shortening of middle and distal phalanges, and abnormal distal epiphysis of the ulna and radius. Brain magnetic resonance imaging showed cerebellar atrophy without other brainstem abnormalities. Genetic workup included nondiagnostic chromosomal microarray and skeletal dysplasia molecular panels. These clinical findings are different from any recognized form of acrodysostosis syndrome. Whole exome sequencing did not identify rare or predicted pathogenic variants in genes associated with known acrodysostosis, lamellar ichthyosis, and other overlapping disorders. A broader search for rare alleles absent in healthy population databases and controls identified two heterozygous truncating alleles in FBNL7 and PPM1M genes, and one missense allele in the NPEPPS gene. Identification of additional patients is required to delineate the mechanism of this unique disorder.
Asunto(s)
Proteínas de Unión al Calcio/genética , Cerebelo/anomalías , Disostosis/genética , Ictiosis/genética , Discapacidad Intelectual/genética , Malformaciones del Sistema Nervioso/genética , Osteocondrodisplasias/genética , Fosfoproteínas Fosfatasas/genética , Adolescente , Adulto , Atrofia/complicaciones , Atrofia/diagnóstico , Atrofia/genética , Atrofia/patología , Cerebelo/patología , Niño , Preescolar , Discapacidades del Desarrollo/complicaciones , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Disostosis/complicaciones , Disostosis/diagnóstico , Disostosis/patología , Epífisis/fisiopatología , Femenino , Heterocigoto , Humanos , Ictiosis/complicaciones , Ictiosis/diagnóstico , Ictiosis/patología , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Persona de Mediana Edad , Anomalías Musculoesqueléticas/genética , Anomalías Musculoesqueléticas/fisiopatología , Mutación Missense/genética , Malformaciones del Sistema Nervioso/complicaciones , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/patología , Osteocondrodisplasias/complicaciones , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/patología , Secuenciación del Exoma , Adulto JovenRESUMEN
Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.
Asunto(s)
Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Disostosis/genética , Epífisis/anomalías , Exostosis Múltiple Hereditaria/genética , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Rodilla/anomalías , Osteocondrodisplasias/genética , Fenotipo , Adolescente , Adulto , Niño , Disostosis/patología , Epífisis/patología , Exostosis Múltiple Hereditaria/patología , Femenino , Deformidades Congénitas de la Mano/patología , Heterocigoto , Humanos , Discapacidad Intelectual/patología , Rodilla/patología , Masculino , Mutación , Osteocondrodisplasias/patología , SíndromeRESUMEN
Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Mucopolisacaridosis I/metabolismo , Mucopolisacaridosis I/patología , Animales , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Modelos Animales de Enfermedad , Disostosis/diagnóstico por imagen , Disostosis/etiología , Disostosis/patología , Disostosis/terapia , Femenino , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Ratones , Mucopolisacaridosis I/terapia , Embarazo , Resultado del Tratamiento , Microtomografía por Rayos XRESUMEN
Diaphanospondylodysostosis (DSD) and ischiospinal dysostosis (ISD) are both rare skeletal dysplasias consisting of abnormal axial skeletal development but normal appendicular skeletal development. Both disorders recently have been found to result from mutations in the BMPER gene. We report a patient with one deletion and one mutation of the BMPER gene who has features most consistent with DSD but who has survived to age 9 years. Survival suggests that DSD and ISD reflect a spectrum of severity of one disease process.
Asunto(s)
Proteínas Portadoras/genética , Anomalías Craneofaciales/genética , Disostosis/genética , Isquion/patología , Mutación , Costillas/anomalías , Columna Vertebral/anomalías , Niño , Anomalías Craneofaciales/patología , Disostosis/patología , Humanos , Masculino , Pronóstico , Costillas/patología , Columna Vertebral/patologíaRESUMEN
Most disease-related mutations that impair cAMP protein kinase A (PKA) signaling are present within the regulatory (R) PKA RI alpha-subunit (RIα). Although mutations in the PRKAR1A gene are linked to Carney complex (CNC) disease and, more recently, to acrodysostosis-1 (ACRDYS1), the two diseases show contrasting phenotypes. While CNC mutations cause increased PKA activity, ACRDYS1 mutations result in decreased PKA activity and cAMP resistant holoenzymes. Mapping the ACRDYS1 disease mutations reveals their localization to the second of two tandem cAMP-binding (CNB) domains (CNB-B), and here, we characterize a recurrent deletion mutant where the last 14 residues are missing. The crystal structure of a monomeric form of this mutant (RIα92-365) bound to the catalytic (C)-subunit reveals the dysfunctional regions of the RIα subunit. Beyond the missing residues, the entire capping motif is disordered (residues 357-379) and explains the disrupted cAMP binding. Moreover, the effects of the mutation extend far beyond the CNB-B domain and include the active site and N-lobe of the C-subunit, which is in a partially open conformation with the C-tail disordered. A key residue that contributes to this crosstalk, D267, is altered in our structure, and we confirmed its functional importance by mutagenesis. In particular, the D267 interaction with Arg241, a residue shown earlier to be important for allosteric regulation, is disrupted, thereby strengthening the interaction of D267 with the C-subunit residue Arg194 at the R:C interface. We see here how the switch between active (cAMP-bound) and inactive (holoenzyme) conformations is perturbed and how the dynamically controlled crosstalk between the helical domains of the two CNB domains is necessary for the functional regulation of PKA activity.
Asunto(s)
Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/química , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , AMP Cíclico/metabolismo , Disostosis/genética , Disostosis/patología , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Proteínas Mutantes/química , Proteínas Mutantes/genética , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Cristalografía por Rayos X , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/metabolismo , Humanos , Modelos Moleculares , Proteínas Mutantes/metabolismo , Unión Proteica , Conformación Proteica , Eliminación de SecuenciaRESUMEN
Most congenital conditions have low prevalence, but collectively they occur in a few percent of all live births. Congenital conditions are rarely encountered in anthropological studies, not least because many of them have no obvious effect on the skeleton. Here, we discuss two groups of congenital conditions that specifically affect the skeleton, either qualitatively or quantitatively. Skeletal dysplasias (osteochondrodysplasias) interfere with the histological formation, growth and maturation of skeletal tissues leading to diminished postural length, but the building plan of the body is unaffected. Well- known skeletal dysplasias represented in the archeological record include osteogenesis imperfecta and achondroplasia. Dysostoses, in contrast, interfere with the building plan of the body, leading to e.g. missing or extraskeletal elements, but the histology of the skeletal tissues is unaffected. Dysostoses can concern the extremities (e.g., oligodactyly and polydactyly), the vertebral column (e.g., homeotic and meristic anomalies), or the craniofacial region. Conditions pertaining to the cranial sutures, i.e., craniosynostoses, can be either skeletal dysplasias or dysostoses. Congenital conditions that are not harmful to the individual are known as anatomical variations, several of which have a high and population-specific prevalence that could potentially make them useful for determining ethnic origins. In individual cases, specific congenital conditions could be determinative in establishing identity, provided that ante-mortem registration of those conditions was ensured. Clin. Anat. 29:878-891, 2016. © 2016 The Authors Clinical Anatomy published by Wiley Periodicals, Inc. on behalf of American Association of Clinical Anatomists.
Asunto(s)
Disostosis/diagnóstico , Osteocondrodisplasias/diagnóstico , Paleopatología , Suturas Craneales/patología , Disostosis/congénito , Disostosis/patología , Humanos , Osteocondrodisplasias/congénito , Osteocondrodisplasias/patologíaRESUMEN
Diaphanospondylodysostosis (DSD), caused by loss of bone morphogenetic protein-binding endothelial regulator (BMPER), has been considered a lethal skeletal dysplasia characterized by severe deficiency of vertebral body and sacral ossification, reduced rib number and cystic kidneys. In this study, however, we have demonstrated that variants in BMPER may cause a milder disorder, without renal anomalies, that is compatible with long-term survival. Four siblings, three males and one female, presented with severe congenital scoliosis associated with rib and vertebral malformations as well as strikingly delayed ossification of the pedicles. The female was stillborn from an unrelated cause. Stabilization of the scoliosis with expandable titanium rods was successful in the three boys, all of whom have short stature. An autosomal recessive mode of inheritance was hypothesized. Single nucleotide polymorphism microarray analysis was performed for three of the siblings to identify autosomal genes with shared allele patterns, suggesting possible linkage. Exome sequencing of one sibling was then performed. Rare variants were identified in 347 genes with shared alleles. Only one of these genes had bi-allelic variants in a gene strongly expressed in paraxial mesenchyme: BMPER, which is the cause of DSD, an autosomal recessive disorder. The disorder described herein could represent an attenuated form of DSD or could be designated a separate entity such as spondylopedicular dysplasia.
Asunto(s)
Alelos , Proteínas Portadoras/genética , Anomalías Craneofaciales/genética , Disostosis/genética , Enfermedades Genéticas Congénitas/genética , Ligamiento Genético , Polimorfismo de Nucleótido Simple , Costillas/anomalías , Columna Vertebral/anomalías , Anomalías Craneofaciales/patología , Disostosis/patología , Femenino , Enfermedades Genéticas Congénitas/patología , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Costillas/patología , Columna Vertebral/patologíaAsunto(s)
Disostosis/patología , Discapacidad Intelectual/patología , Osteocondrodisplasias/patología , Seudohipoparatiroidismo/patología , Huesos/anomalías , Disostosis/diagnóstico , Disostosis/genética , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Seudohipoparatiroidismo/diagnóstico , Seudohipoparatiroidismo/genéticaRESUMEN
Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of Praw = 4.759e-36 (genome-wide significant). Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.
Asunto(s)
Secuencia de Bases , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Enfermedades de los Perros/genética , Disostosis/congénito , Exones , Eliminación de Secuencia , Animales , Australia , Enfermedades de los Perros/patología , Perros , Disostosis/genética , Disostosis/patología , Disostosis/veterinaria , Femenino , Humanos , MasculinoRESUMEN
Spondylospinal thoracic dysostosis can be considered a type of spondylocostal dysostosis because of the occurrence of vertebral defects (hemivertebrae and vertebral body fusion) and thoracic anomalies (short thorax and pulmonary hypoplasia). This syndrome was described by Johnson et al. (1997) in two siblings with dwarfism, short thorax, curved spine, fusion of the vertebrae and spinal process, multiple pterygium, and arthrogryposis. We describe the case of a 16-year-old Mexican girl with the longest survival recorded (the previous oldest patient was 7 years old) and analyze the natural history and describe some new features of this rare entity.
Asunto(s)
Contractura/patología , Disostosis/patología , Osteocondrodisplasias/patología , Costillas/anomalías , Columna Vertebral/anomalías , Adolescente , Contractura/diagnóstico por imagen , Disostosis/diagnóstico por imagen , Familia , Femenino , Humanos , Osteocondrodisplasias/diagnóstico por imagen , Fenotipo , Radiografía , Costillas/diagnóstico por imagen , Costillas/patología , Columna Vertebral/diagnóstico por imagen , Columna Vertebral/patologíaRESUMEN
Acrodysostosis is a rare skeletal dysplasia, which has not been reported previously in patients of Chinese origin. The PRKAR1A gene and PDE4D gene have been found to be causative genes of acrodysostosis. A Chinese girl with acrodysostosis and concomitant multiple hormone resistance was recruited for our study. Clinical and biochemical characters were analyzed. DNA was extracted from leukocytes and was sequenced for GNAS, PDE4D and PRKAR1A gene mutations. A de novo heterozygous missense mutation (c.866G>A/p.G289E) was identified in the PRKAR1A gene. This mutation coincided with a mutation that had been found in a patient from another ethnic group. Our findings further suggest that the c.866G>A/p.G289E mutation in the PRKAR1A gene may be the cause of acrodysostosis with concomitant multiple hormone resistance. Moreover, it is the first report of acrodysostosis genetic analysis of Chinese origin.
Asunto(s)
Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Disostosis/genética , Discapacidad Intelectual/genética , Osteocondrodisplasias/genética , Adolescente , Secuencia de Bases , China , Disostosis/patología , Femenino , Heterocigoto , Humanos , Discapacidad Intelectual/patología , Osteocondrodisplasias/patología , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Transducción de SeñalRESUMEN
Acrodysostosis refers to a group of rare skeletal dysplasias that share in common characteristic clinical and radiological features including brachydactyly, facial dysostosis, and nasal hypoplasia. In the past, the term acrodysostosis has been used to describe patients with heterogeneous phenotypes, including, in some cases, patients that today would be given alternative diagnoses. The recent finding that mutations impairing the cAMP binding to PRKAR1A are associated with "typical" acrodysostosis and hormonal resistance initiates the era where this group of disorders can be categorized on a genetic basis. In this review, we will first discuss the clinical, radiologic, and metabolic features of acrodysostosis, emphasizing evidence that several forms of the disease are likely to exist. Second, we will describe recent results explaining the pathogenesis of acrodysostosis with hormonal resistance (ADOHR). Finally, we will discuss the similarities and differences observed comparing patients with ADOHR and other diseases resulting from defects in the PTHR1 signaling pathway, in particular, pseudohypoparathyroidism type 1a and pseudopseudohypoparathyroidism.
Asunto(s)
Disostosis/genética , Disostosis/patología , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Animales , Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Disostosis/diagnóstico por imagen , Disostosis/etiología , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/etiología , Mutación/genética , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/etiología , Fenotipo , Radiografía , Transducción de Señal/genéticaRESUMEN
Pycnodysostosis is a rare hereditary disease, characterized by systemic bone sclerosis, which is often brought to the orthopedic surgeon's attention because of repeated fractures. The operative treatment of the patient with a fracture is a real challenge for the orthopedic surgeon because of the unusual problems imposed by the hard but-brittle bone characteristics of the disease. We report a 27-year follow-up of a patient treated for fractures of both femurs and tibia with intramedullary nailing. According to our experience and literature review, we recommend the use of an internal fixation, preferably intramedullary nailing as the treatment of choice for these rare cases. Once the fractures are healed, the removal of the hardware is not recommended, as these keep the bones from further fractures.
Asunto(s)
Clavos Ortopédicos , Disostosis/cirugía , Fracturas del Fémur/cirugía , Fijación Intramedular de Fracturas/métodos , Fracturas de la Tibia/cirugía , Disostosis/complicaciones , Disostosis/patología , Femenino , Fracturas del Fémur/etiología , Fracturas del Fémur/patología , Curación de Fractura , Humanos , Fijadores Internos , Recuperación de la Función , Fracturas de la Tibia/etiología , Fracturas de la Tibia/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
Mandibuloacral dysplasia (MAD) is a rare recessively inherited premature aging disease characterized by skeletal and metabolic anomalies. It is part of the spectrum of diseases called laminopathies and results from mutations in genes regulating the synthesis of the nuclear laminar protein, lamin A. Homozygous or compound heterozygous mutations in the LMNA gene, which encodes both the precursor protein prelamin A and lamin C, are the commonest cause of MAD type A. In a few cases of MAD type B, mutations have been identified in the ZMPSTE24 gene encoding a zinc metalloproteinase important in the post-translational modification of lamin A. Here we describe a new case of MAD resulting from compound heterozygote mutations in ZMPSTE24 (p.N256S/p.Y70fs). The patient had typical skeletal changes of MAD, but in addition a number of unusual skeletal features including neonatal tooth eruption, amorphous calcific deposits, submetaphyseal erosions, vertebral beaking, severe cortical osteoporosis and delayed fracture healing. Treatment with conventional doses of pamidronate improved estimated volumetric bone density in the spine but did not arrest cortical bone loss. We reviewed the literature on cases of MAD associated with proven LMNA and ZMPSTE24 mutations and found that the unusual features described above were all substantially more prevalent in patients with mutations in ZMPSTE24 than in those with LMNA mutations. We conclude that MAD associated with ZMPSTE24 mutations has a more severe phenotype than that associated with LMNA mutations--probably reflecting the greater retention of unprocessed farnesylated prelamin A in the nucleus, which is toxic to cells.
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Huesos , Disostosis , Proteínas de la Membrana/genética , Metaloendopeptidasas/genética , Mutación , Fenotipo , Esqueleto , Adolescente , Animales , Huesos/patología , Huesos/fisiología , Análisis Mutacional de ADN , Disostosis/genética , Disostosis/patología , Humanos , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Masculino , LinajeRESUMEN
CONTEXT: Mutations in the cathepsin K gene (CTSK) cause a very rare form of short-limb dwarfism called pyknodysostosis (online inheritance in man 265800) that reduces adult height to 130-150 cm. OBJECTIVE: To study the effects of GH in children with pyknodysostosis. DESIGN AND METHODS: This was a pilot open study of three children with pyknodysostosis (P1, P2, P3) and 16 age-matched children with idiopathic short stature (ISS) treated with a similar IGF-I-based dosing of GH therapy. P1, P2, and P3 received a mean GH dose of 29, 67, and 120 microg/kg x d, respectively, during 12, 6.5, and 5 yr, whereas the ISS group received a mean dose of 62 +/- 21 microg/kg x d during 5.4 +/- 2 yr. RESULTS: P1, P2, and P3 had the typical clinical and radiological features of pyknodysostosis. They were shown to carry three different homozygous missense mutations of the CTSK gene. After onset of GH at 4.5, 5.4, and 10.9 yr of age, respectively, height increased from -2, -4.2, and -3 SD score to -1, -0.5, and -1 SD score after a 12, 6.5, and 5 yr GH treatment. Remarkably, body disproportion was largely corrected by GH treatment. IGF-I levels in P1, P2, and P3 were within the range of the ISS group. CONCLUSIONS: Pyknodysostotic patients can reach near-normal stature and skeletal proportions with a personalized GH treatment targeted at appropriate IGF-I levels. Given the severity of this rare dwarfism, we propose that GH should be offered to affected children.
Asunto(s)
Estatura/efectos de los fármacos , Disostosis/tratamiento farmacológico , Crecimiento/fisiología , Hormona de Crecimiento Humana/uso terapéutico , Adolescente , Desarrollo Óseo/efectos de los fármacos , Desarrollo Óseo/fisiología , Catepsina K/genética , Niño , Preescolar , ADN/genética , Disostosis/genética , Disostosis/patología , Femenino , Crecimiento/efectos de los fármacos , Humanos , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Mutación Missense , Proteínas Recombinantes/uso terapéutico , Resultado del TratamientoRESUMEN
Mucopolysaccharidosis type II (MPS-II) is a rare lysosomal storage disorder caused by deficiency in the activity of the enzyme iduronate-2-sulphatase. This enzyme is responsible for the catabolism of two different glycosaminoglycans (GAGs), dermatan sulfate and heparan sulfate. Lysosomal accumulation of these GAG molecules results in cell, tissue, and organ dysfunction. The skeletal-muscle system involvement is because of essential accumulated GAGs in joints and connective tissue. MPS-II has many clinical features and includes two recognized clinical entities, mild and severe, that represent two ends of a wide spectrum of clinical severity. The aim of this study is to review the involvement of the skeletal-muscle system in MPS-II.