Molecular diagnosis in a cohort of 114 patients with rare skeletal dysplasias.

Molecular diagnosis is important to provide accurate genetic counseling of skeletal dysplasias (SD). Although next-generation sequencing (NGS) techniques are currently the preferred methods for analyzing these conditions, some of the published results have not shown a detection rate as high as it would be expected. The present study aimed to assess the diagnostic yield of targeted NGS combined with Sanger sequencing (SS) for low-coverage exons of genes of interest and exome sequencing (ES) in a series of patients with rare SD and use two patients as an example of our strategy. This study used two different in-house panels. Of 93 variants found in 88/114 (77%) patients, 57 are novel. The pathogenic variants found in the following genes: B3GALT6, PCYT1A, INPPL1, LIFR, of four patients were only detected by SS. In conclusion, the high diagnostic yield reached in the present study can be attributed to both a good selection of patients and the utilization of the SS for the insufficiently covered regions. Additionally, the two case reports-a patient with acrodysostosis related to PRKAR1A and another with ciliopathy associated with KIAA0753, add new and relevant clinical information to the current knowledge.

Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara / Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology

La acrodisostosis es una displasia esquelética rara, de herencia autosómica dominante, que se caracteriza por la presencia de disostosis facial y periférica, talla baja y diferentes grados de obesidad. La acrodisostosis de tipo 1, secundaria a la mutación heterocigota en el gen PRKAR1A (17q24.2), se caracteriza por la asociación de resistencia hormonal múltiple con anomalías esqueléticas. Su incidencia está infradiagnosticada debido a que comparte rasgos clínicos y de laboratorio con otras entidades como el seudohipoparatiroidismo. Presentamos el caso de una niña de 8 años, con acrodisostosis tipo 1, confirmada mediante estudio genético. Además del fenotipo característico descrito, la talla baja y la resistencia hormonal, la paciente presentó una afectación progresiva de la función pulmonar: un patrón pulmonar obstructivo no reversible. En la literatura revisada, no se han encontrado otros casos que describan esta asociación entre acrodisostosis y afectación respiratoria.

Acrodysostosis is a rare skeletal displasia, of autosomal dominant inheritance, characterized by the presence of facial and peripheral dysostosis, short stature and obesity. Type 1 acrodysostosis is secondary to a mutation in the PRKAR1A (17q24.2) gene, which results in multi hormonal resistance and skeletal anomalities. This syndrome is under-diagnosed as it shares analytical and clinical characteristics with other entities, such as pseudohypoparathyroidism. We report the case of an eight-year-old girl with genetically confirmed type 1 acrodysostosis. In addition to the characteristic phenotype described, the short stature and the hormonal resistance, the patient suffered a progressive lung function deterioration: an irreversible pulmonary obstructive pattern. We have not found in previous literature cases reporting an association between acrodysostosis and lung function impairement.

[Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology]. / Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara.

Acrodysostosis is a rare skeletal displasia, of autosomal dominant inheritance, characterized by the presence of facial and peripheral dysostosis, short stature and obesity. Type 1 acrodysostosis is secondary to a mutation in the PRKAR1A (17q24.2) gene, which results in multi hormonal resistance and skeletal anomalities. This syndrome is under-diagnosed as it shares analytical and clinical characteristics with other entities, such as pseudohypoparathyroidism. We report the case of an eight-year-old girl with genetically confirmed type 1 acrodysostosis. In addition to the characteristic phenotype described, the short stature and the hormonal resistance, the Afectación respiratoria en paciente con acrodisostosis: una asociación infrecuente de una enfermedad rara Respiratory impairment in a patient with acrodysostosis: A rare association of an uncommon pathology patient suffered a progressive lung function deterioration: an irreversible pulmonary obstructive pattern. We have not found in previous literature cases reporting an association between acrodysostosis and lung function impairement.

La acrodisostosis es una displasia esquelética rara, de herencia autosómica dominante, que se caracteriza por la presencia de disostosis facial y periférica, talla baja y diferentes grados de obesidad. La acrodisostosis de tipo 1, secundaria a la mutación heterocigota en el gen PRKAR1A (17q24.2), se caracteriza por la asociación de resistencia hormonal múltiple con anomalías esqueléticas. Su incidencia está infradiagnosticada debido a que comparte rasgos clínicos y de laboratorio con otras entidades como el seudohipoparatiroidismo. Presentamos el caso de una niña de 8 años, con acrodisostosis tipo 1, confirmada mediante estudio genético. Además del fenotipo característico descrito, la talla baja y la resistencia hormonal, la paciente presentó una afectación progresiva de la función pulmonar: un patrón pulmonar obstructivo no reversible. En la literatura revisada, no se han encontrado otros casos que describan esta asociación entre acrodisostosis y afectación respiratoria.

Shortening Scarf Osteotomy for Macrodactyly and Valgus of the Hallux in Acrodysostosis Lesser Toes Brachydactyly.

LEVELS OF EVIDENCE: Level V: Case report.

Novel progressive acrodysostosis-like skeletal dysplasia, cerebellar atrophy, and ichthyosis.

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.

Diagnóstico prenatal del síndrome de Jarcho-Levin / Prenatal diagnosis of Jarcho-Levin syndrome

El síndrome de Jarcho-Levin es una rara entidad heterogénea caracterizada por dismorfia facial, extremidades de tamaño normal con cuello y tronco corto, múltiples anomalías vertebrales en todos los niveles de la columna vertebral y defectos costales. El síndrome se ha clasificado en 2 fenotipos clínicos principales, según la extensión y distribución de las anomalías esqueléticas, el patrón de herencia y el pronóstico. El diagnóstico ecográfica prenatal se caracteriza por la presencia de costillas desplegadas a partir de cuerpos vertebrales torácicos fusionados. Debido a la rareza de esta condición, existe un número limitado de informes en la literatura científica y muy pocos se diagnostican prenatalmente. Es un caso de síndrome de Jarcho-Levin en una mujer de 16 años con embarazo de 31 semanas y sin antecedentes patológicos prominentes. La ecografía reveló feto único con datos biométricos compatibles con 27 semanas. Se observó columna vertebral acortada con deformidad extrema y escoliosis moderada, canal medular ancho, segmentación de cuerpos vertebrales en las áreas torácicas y lumbares inferiores, aumento de la distancia intervertebral con tórax corto y estrecho, cuello corto hiperflexionado y occipucio que parecía fusionarse con las vértebras cervicales. Se realizó cesárea debido a sufrimiento fetal agudo, obteniendo recién nacido masculino. El examen físico mostró circunferencia cefálica normal, tórax corto, cuello corto y rígido, cifoescoliosis torácica con restricción del patrón respiratorio y abdomen abultado. No se observaron alteraciones faciales o craneales. Después de 4 días, el recién nacido muere debido a falla respiratoria aguda.

The Jarcho-Levin syndrome is a rare heterogeneous entity characterized by facial dysmorphism, short-neck, short-trunk, normal sizes limbs, with multiple vertebral anomalies at all levels of the vertebral column and ribs defects. The syndrome has been classified into 2 major clinical phenotypes, based on the extent and distribution of skeletal anomalies, the pattern of inheritance and the prognosis. The prenatal sonographic appearance is characterized by the presence of fanned-out ribs from fused thoracic vertebral bodies. Due to the rarity of this condition, there are a limited number of reports in the scientific literature and very few are diagnosed prenatally. We report a case of Jarcho-Levin syndrome in a 16-year-old pregnant woman with a 31 weeks pregnancy and no prominent pathological history. Ultrasound revealed a single fetus with biometrics compatible with 27 weeks. We found shortened vertebral column with extreme deformity and moderate scoliosis, wide medullary canal, segmentation of vertebral bodies in the lower thoracic and lumbar areas, increased intervertebral distance with the short and narrow thorax, hyper flexed short neck and occiput appeared to merge with the cervical vertebrae. Cesarean section was performed at term due to acute fetal distress, resulting in a newborn male birth. Physical examination showed normal cephalic circumference, short thorax, short and rigid neck, thoracic kyphoscoliosis with restriction of the respiratory pattern, bulging abdomen. No facial or cranial alterations were observed. After 4 days the newborn dies due to acute respiratory failure.

Expanding the phenotype of spondylospinal thoracic dysostosis (the Turkel-Chen-Johnson syndrome).

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.

Acro-spondylo-pubic dysostosis associated with cataracts, microcephaly, and normal intelligence.

We report on an adult male with normal intelligence who exhibited an unusual combination of microcephaly, dysostoses of limbs, vertebrae, patellae, and pubic bone, camptodactyly of all fingers, and syndactyly of toes, absent nails on thumbs and some fingers, bilateral cataract, cryptorchidism, polythelia, and nipple-like skin pigmentations of shoulders and upper back. We have been unable to find a description of a similar combination of manifestations in literature. The cause of the anomalies remains unknown.

Fryns syndrome with vertebral defects: a novel association in a Mexican infant.

We report a Mexican mestizo 2 months old male with Fryns syndrome and vertebral defects. The patient's phenotype included typical craniofacial dysmorphism, short neck, agenesis of the corpus callosum, congenital left diaphragmatic hernia, complex heart disease, C1 to C6 vertebral agenesis with increased interpedicular space, thoracic rotoscoliosis, broad medial ends of the clavicles, brachytelephalangy of hands and feet with fingers axially deviated, and nail hypoplasia. Renal and chromosomal evaluations were normal. Since this is the first description of cervical vertebrae agenesis and thoracic rotoscoliosis in Fryns syndrome, we propose that these clinical and radiological features should be incorporated to the Fryns syndrome phenotype and specifically looked for in other children.

Agenesia bilateral de rádio em felino (Felis catus domesticus) - relato de caso / Bilateral radial agenesis in a cat (Felis catus domesticus) case report / Agenesia bilateral de radio en gato (Felis catus domesticus) relato de caso

Disostoses são um conjunto de alterações morfológicas congênitas, caracterizadas por desenvolvimento anormal de um osso ou parte dele. Agenesia de rádio em cães e gatos é classificada como hemimelia longitudinal preaxial intercalar e embora seja um defeito congênito raro, é a hemimelia mais comum em cães e gatos, sendo mais frequente na forma unilateral, podendo também ser bilateral. Um gato, macho, sem raça definida foi atendido apresentando deformidade nos membros torácicos que, ao exame radiográfico, foi diagnosticada como agenesia bilateral de rádio com desvio varo. Ao completar dez meses, o animal foi reavaliado e apresentava boa qualidade de vida com apoio frequente dos membros torácicos, optando-se dessa forma por continuar com o tratamento conservativo. A agenesia bilateral de rádio observada no felino deste relato respondeu bem ao tratamento conservativo, com o animal apresentando boa qualidade de vida.(AU)

Dysostoses are a set of congenial morphological alterations characterized by the abnormal development of a bone or its section. Radial agenesis in dogs and cats is classified as intercalary preaxial longitudinal hemimelia. Although a rare congenial defect, it is the most common hemimelia in dogs and cats, mostly frequently occurring unilaterally, even though it can also be found bilaterally. A male cat was admitted with a deformity in its thoracic limbs. Radiographic examination revealed bilateral radial agenesis with varus deformity. The animal was re-evaluated at 10 months of age. On that occasion, the continuation of the conservative treatment was chosen because the cat enjoyed good quality of life with the frequent support of its thoracic limbs. Thus, this case of bilateral radial agenesis responded well to the conservative treatment, providing thereby good quality of life to the animal.(AU)

Las disostosis son un conjunto de alteraciones morfológicas congénitas, que se caracterizan por el desarrollo anormal de un hueso, o parte del mismo. La agenesia de radio en perros y gatos está clasificada como una hemimelia longitudinal preaxial intercalar y, a pesar de ser un defecto congénito raro, es la hemimelia mas común en estos animales, presentándose con mayor frecuencia en su forma unilateral, aunque también puede hacerlo en ambos miembros. Se presentó a consulta un gato macho mestizo con deformación de ambos miembros torácicos, en el que través del examen radiográfico se pudo diagnosticar una agenesia bilateral de radio con desviación en varo. Al completar diez meses de edad, el paciente fue re evaluado y se notó una buena condición de vida, con apoyo frecuente de los miembros torácicos, decidiéndose entonces dar continuidad al tratamiento conservador. La agenesia bilateral de radio que se diagnosticó en el citado animal, pudo solucionarse a través de un tratamiento no invasivo, consiguiendo que el paciente tuviera una buena condición de vida.(AU)

Agenesia bilateral de rádio em felino (Felis catus domesticus) - relato de caso / Bilateral radial agenesis in a cat (Felis catus domesticus) – case report / Agenesia bilateral de radio en gato (Felis catus domesticus) – relato de caso

Disostoses são um conjunto de alterações morfológicas congênitas, caracterizadas por desenvolvimento anormal de um osso ou parte dele. Agenesia de rádio em cães e gatos é classificada como hemimelia longitudinal preaxial intercalar e embora seja um defeito congênito raro, é a hemimelia mais comum em cães e gatos, sendo mais frequente na forma unilateral, podendo também ser bilateral. Um gato, macho, sem raça definida foi atendido apresentando deformidade nos membros torácicos que, ao exame radiográfico, foi diagnosticada como agenesia bilateral de rádio com desvio varo. Ao completar dez meses, o animal foi reavaliado e apresentava boa qualidade de vida com apoio frequente dos membros torácicos, optando-se dessa forma por continuar com o tratamento conservativo. A agenesia bilateral de rádio observada no felino deste relato respondeu bem ao tratamento conservativo, com o animal apresentando boa qualidade de vida.

Dysostoses are a set of congenial morphological alterations characterized by the abnormal development of a bone or its section. Radial agenesis in dogs and cats is classified as intercalary preaxial longitudinal hemimelia. Although a rare congenial defect, it is the most common hemimelia in dogs and cats, mostly frequently occurring unilaterally, even though it can also be found bilaterally. A male cat was admitted with a deformity in its thoracic limbs. Radiographic examination revealed bilateral radial agenesis with varus deformity. The animal was re-evaluated at 10 months of age. On that occasion, the continuation of the conservative treatment was chosen because the cat enjoyed good quality of life with the frequent support of its thoracic limbs. Thus, this case of bilateral radial agenesis responded well to the conservative treatment, providing thereby good quality of life to the animal.

Las disostosis son un conjunto de alteraciones morfológicas congénitas, que se caracterizan por el desarrollo anormal de un hueso, o parte del mismo. La agenesia de radio en perros y gatos está clasificada como una hemimelia longitudinal preaxial intercalar y, a pesar de ser un defecto congénito raro, es la hemimelia mas común en estos animales, presentándose con mayor frecuencia en su forma unilateral, aunque también puede hacerlo en ambos miembros. Se presentó a consulta un gato macho mestizo con deformación de ambos miembros torácicos, en el que través del examen radiográfico se pudo diagnosticar una agenesia bilateral de radio con desviación en varo. Al completar diez meses de edad, el paciente fue re evaluado y se notó una buena condición de vida, con apoyo frecuente de los miembros torácicos, decidiéndose entonces dar continuidad al tratamiento conservador. La agenesia bilateral de radio que se diagnosticó en el citado animal, pudo solucionarse a través de un tratamiento no invasivo, consiguiendo que el paciente tuviera una buena condición de vida.

Tomographic assessment of the spine in children with spondylocostal dysotosis syndrome.

OBJECTIVE: The aim of this study was to perform a detailed tomographic analysis of the skull base, craniocervical junction, and the entire spine in seven patients with spondylocostal dysostosis syndrome. METHOD: Detailed scanning images have been organized in accordance with the most prominent clinical pathology. The reasons behind plagiocephaly, torticollis, short immobile neck, scoliosis and rigid back have been detected. Radiographic documentation was insufficient modality. RESULTS: Detailed computed tomography scans provided excellent delineation of the osseous abnormality pattern in our patients. CONCLUSION: This article throws light on the most serious osseous manifestations of spondylocostal dysostosissyndrome.

Mandibular osteomyelitis and fracture in a patient with pyknodysostosis.

Pyknodysostosis is a rare, recessive, hereditary, autosomal disease belonging to the group of bone dysplasias. Complications such as osteomyelitis and fractures of the mandible are not uncommon and appear in the most varied forms. We report a case of chronic osteomyelitis with subsequent mandible fracture, which was successfully treated with the use of a reconstruction plate and antibiotic therapy. This article outlines the clinical and radiographic characteristics of this condition based on the clinical case described and proposes an approach regarding the best form of treatment. Considering the risks of fracture subsequent to removal of the graft from long bones as well as the presence of chronic infection, difficult-to-defeat infection, and bone contact on the compression band, the best choice is a more conservative treatment.

Mucopolysaccharidosis type II: skeletal-muscle system involvement.

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.

Tomographic assessment of the spine in children with spondylocostal dysotosis syndrome

OBJECTIVE: The aim of this study was to perform a detailed tomographic analysis of the skull base, craniocervical junction, and the entire spine in seven patients with spondylocostal dysostosis syndrome. METHOD: Detailed scanning images have been organized in accordance with the most prominent clinical pathology. The reasons behind plagiocephaly, torticollis, short immobile neck, scoliosis and rigid back have been detected. Radiographic documentation was insufficient modality. RESULTS: Detailed computed tomography scans provided excellent delineation of the osseous abnormality pattern in our patients. CONCLUSION: This article throws light on the most serious osseous manifestations of spondylocostal dysostosissyndrome.