Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 397
Filtrar
1.
Am J Med Genet C Semin Med Genet ; 187(3): 396-408, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34529350

RESUMO

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.


Assuntos
Disostoses , Osteocondrodisplasias , Colina-Fosfato Citidililtransferase , Galactosiltransferases , Aconselhamento Genético , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Sequenciamento Completo do Exoma
2.
Arch. argent. pediatr ; 119(4): e340-e344, agosto 2021. tab, ilus
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1281780

RESUMO

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.


Assuntos
Humanos , Feminino , Criança , Osteocondrodisplasias/complicações , Disostoses/complicações , Pneumopatias Obstrutivas/complicações , Osteocondrodisplasias/genética , Osteocondrodisplasias/diagnóstico por imagem , Espirometria , Diagnóstico Diferencial , Disostoses/genética , Disostoses/diagnóstico por imagem , Dispneia/complicações , Mutação/genética
3.
Arch Argent Pediatr ; 119(4): e340-e344, 2021 08.
Artigo em Espanhol | MEDLINE | ID: mdl-34309314

RESUMO

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.


Assuntos
Disostoses , Osteocondrodisplasias , Criança , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Disostoses/complicações , Disostoses/genética , Feminino , Humanos , Deficiência Intelectual , Osteocondrodisplasias/complicações , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética
4.
BMC Endocr Disord ; 21(1): 71, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858404

RESUMO

BACKGROUND: Acrodysostosis is a rare hereditary disorder described as a primary bone dysplasia with or without hormonal resistance. Pathogenic variants in the PRKAR1A and PDE4D genes are known genetic causes of this condition. The latter gene variants are more frequently identified in patients with midfacial and nasal hypoplasia and neurological involvement. The aim of our study was to analyse and confirm a genetic cause of acrodysostosis in a male patient. CASE PRESENTATION: We report on a 29-year-old Lithuanian man diagnosed with acrodysostosis type 2. The characteristic phenotype includes specific skeletal abnormalities, facial dysostosis, mild intellectual disability and metabolic syndrome. Using patient's DNA extracted from peripheral blood sample, the novel, likely pathogenic, heterozygous de novo variant NM_001104631.2:c.581G > C was identified in the gene PDE4D via Sanger sequencing. This variant causes amino acid change (NP_001098101.1:p.(Arg194Pro)) in the functionally relevant upstream conserved region 1 domain of PDE4D. CONCLUSIONS: This report further expands the knowledge of the consequences of missense variants in PDE4D that affect the upstream conserved region 1 regulatory domain and indicates that pathogenic variants of the gene PDE4D play an important role in the pathogenesis mechanism of acrodysostosis type 2 without significant hormonal resistance.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Disostoses/diagnóstico por imagem , Disostoses/genética , Variação Genética/genética , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/genética , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Adulto , Sequência de Bases , Humanos , Lituânia , Masculino , Mutação de Sentido Incorreto/genética
5.
Endocrine ; 72(3): 611-618, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33179219

RESUMO

Pseudohypoparathyroidism (PHP), the first known post-receptorial hormone resistance, derives from a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key component of the PTH/PTHrP signaling pathway. Since its first description, different studies unveiled, beside the molecular basis for PHP, the existence of different subtypes and of diseases in differential diagnosis associated with genetic alterations in other genes of the PTH/PTHrP pathway. The clinical and molecular overlap among PHP subtypes and with different but related disorders make both differential diagnosis and genetic counseling challenging. Recently, a proposal to group all these conditions under the novel term "inactivating PTH/PTHrP signaling disorders (iPPSD)" was promoted and, soon afterwards, the first international consensus statement on the diagnosis and management of these disorders has been published. This review will focus on the major and minor features characterizing PHP/iPPSDs as a group and on the specificities as well as the overlap associated with the most frequent subtypes.


Assuntos
Disostoses , Pseudo-Hipoparatireoidismo , Doenças Ósseas Metabólicas , Disostoses/diagnóstico , Disostoses/genética , Humanos , Deficiência Intelectual , Ossificação Heterotópica , Osteocondrodisplasias , Hormônio Paratireóideo , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/genética , Dermatopatias Genéticas
7.
Eur J Endocrinol ; 184(2): 311-320, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33270042

RESUMO

Objective: Pseudohypoparathyroidism and related disorders belong to a group of heterogeneous rare diseases that share an impaired signaling downstream of Gsα-protein-coupled receptors. Affected patients may present with various combination of symptoms including resistance to PTH and/or to other hormones, ectopic ossifications, brachydactyly type E, early onset obesity, short stature and cognitive difficulties. Several years ago we proposed a novel nomenclature under the term of inactivating PTH/PTHrP signaling disorders (iPPSD). It is now of utmost importance to validate these criteria and/or improve the basis of this new classification. Design: Retrospective study of a large international series of 459 probands and 85 relatives molecularly characterized. Methods: Information on major and minor criteria associated with iPPSD and genetic results were retrieved from patient files. We compared the presence of each criteria according to the iPPSD subtype, age and gender of the patients. Results: More than 98% of the probands met the proposed criteria for iPPSD classification. Noteworthy, most patients (85%) presented a combination of symptoms rather than a single sign suggestive of iPPSD and the overlap among the different genetic forms of iPPSD was confirmed. The clinical and molecular characterization of relatives identified familial history as an additional important criterion predictive of the disease. Conclusions: The phenotypic analysis of this large cohort confirmed the utility of the major and minor criteria and their combination to diagnose iPPSD. This report shows the importance of having simple and easily recognizable signs to diagnose with confidence these rare disorders and supports a better management of patients.


Assuntos
Proteína Relacionada ao Hormônio Paratireóideo/fisiologia , Hormônio Paratireóideo/fisiologia , Pseudo-Hipoparatireoidismo/classificação , Pseudo-Hipoparatireoidismo/diagnóstico , Terminologia como Assunto , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Disostoses/classificação , Disostoses/genética , Feminino , França/epidemiologia , Inativação Gênica , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/classificação , Deficiência Intelectual/genética , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Mutação , Ossificação Heterotópica/classificação , Ossificação Heterotópica/genética , Osteocondrodisplasias/classificação , Osteocondrodisplasias/genética , Hormônio Paratireóideo/genética , Proteína Relacionada ao Hormônio Paratireóideo/genética , Pseudo-Hipoparatireoidismo/epidemiologia , Pseudo-Hipoparatireoidismo/genética , Doenças Raras , Estudos Retrospectivos , Transdução de Sinais/genética , Espanha/epidemiologia , Adulto Jovem
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(10): 1128-1131, 2020 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-32924117

RESUMO

OBJECTIVE: To analyze the clinical characteristics and genetic variation in a child with acrodysostosis type 2. METHODS: The child has undergone history taking and physical examination. Genome DNA was extracted from peripheral blood samples from him and his parents. High-throughput sequencing was carried out. The result was verified by Sanger sequencing. RESULTS: The 8-year-old boy presented with midface hypoplasia, hypertelorism, prominent nasal bridge, small and upturned nostrils, broad thumb and great toes, and brachydactyly of remaining fingers and toes. Genetic testing revealed that the child has carried a heterozygous c.1813T>C (p.Tyr605His) missense mutation of the PDE4D gene. The same mutation was not found in either parent and was unreported previously. CONCLUSION: The child was diagnosed with acrodysostosis type 2 due to the novel mutation of the PDE4D gene.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Disostoses/genética , Deficiência Intelectual/genética , Osteocondrodisplasias/genética , Criança , Testes Genéticos , Humanos , Masculino , Mutação de Sentido Incorreto
10.
BMC Med Genet ; 21(1): 189, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993552

RESUMO

BACKGROUND: Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes. CASE PRESENTATION: The patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability. DISCUSSION AND CONCLUSIONS: Key challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.


Assuntos
Disostoses/terapia , Deficiência Intelectual/terapia , Comunicação Interdisciplinar , Osteocondrodisplasias/terapia , Equipe de Assistência ao Paciente , Pseudo-Hipoparatireoidismo/terapia , Osso e Ossos/anormalidades , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/metabolismo , Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Disostoses/diagnóstico , Disostoses/genética , Seguimentos , Predisposição Genética para Doença/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/genética , Radiografia/métodos , Fatores de Tempo
11.
Pediatr Endocrinol Rev ; 17(4): 317-326, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32780955

RESUMO

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder, caused by deficiency of α-L-iduronidase, and consequent accumulation of dermatan and heparan sulfates. Severity of the disease ranges from mild (Scheie) to moderate (Hurler-Scheie) to severe (Hurler or MPS-IH). A prominent clinical manifestation of MPS-IH is dysostosis multiplex, a constellation of skeletal abnormalities. We performed a retrospective review comparing manifestations of dysostosis multiplex in patients presenting with MPSIH and relevant animal models. Dog, cat and mouse models of MPS-IH are extensively studied to better understand the pathology of the disease. While all animal models display certain characteristics of human MPSIH, species-specific manifestations must be considered when evaluating skeletal abnormalities. Moreover, some skeletal abnormalities emerge at species-specific developmental stages, e.g. thoracolumbar kyphosis is an early manifestation in humans, while it appears late in the mouse model. The choice of the appropriate diagnostic test is of importance to avoid misleading conclusions.


Assuntos
Disostoses , Mucopolissacaridose I , Animais , Modelos Animais de Doenças , Cães , Humanos , Iduronidase , Estudos Retrospectivos
12.
Am J Med Genet A ; 182(10): 2214-2221, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32783359

RESUMO

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.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Cerebelo/anormalidades , Disostoses/genética , Ictiose/genética , Deficiência Intelectual/genética , Malformações do Sistema Nervoso/genética , Osteocondrodisplasias/genética , Fosfoproteínas Fosfatases/genética , Adolescente , Adulto , Atrofia/complicações , Atrofia/diagnóstico , Atrofia/genética , Atrofia/patologia , Cerebelo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Disostoses/complicações , Disostoses/diagnóstico , Disostoses/patologia , Epífises/fisiopatologia , Feminino , Heterozigoto , Humanos , Ictiose/complicações , Ictiose/diagnóstico , Ictiose/patologia , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Pessoa de Meia-Idade , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/fisiopatologia , Mutação de Sentido Incorreto/genética , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/patologia , Osteocondrodisplasias/complicações , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
14.
Pediatr Neurosurg ; 54(6): 367-374, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31597143

RESUMO

Spondylocostal dysostosis is a very rare combination of complex vertebra and rib malformations, accompanied occasionally by other disorders. A 3-year-old girl presented kyphoscoliosis, foot deformities, gate disturbance, and urinary incontinence. The CT and MRI examination revealed kyphosis and scoliosis with a double curve, some absent, broadened, bifurcating and fused ribs, hemivertebrae, butterfly and cleft vertebrae in thoracic and lumbar region, sporadic cleft or absent vertebral arches or pedicles, and hypoplastic sacrum with a cleft of the S2 vertebra. Spina bifida occulta extended from T10 to T11, and from L3 to the end of the sacrum. Two hemicords, separated by a bony septum and surrounded by their own dural tubes (type I), were present from the level of T9 to the conus medullaris. Filum terminale was thick and duplicated. Syringomyelia was present in the thoracic cord from T5 to T8. Finally, a small meningocele was seen at the T10-T11 level, and a subcutaneous lipoma in the thoracolumbar region. To our knowledge, such a combination of vertebra, rib, and cord malformations, including the mentioned additional disorders, has never been reported.


Assuntos
Disostoses/diagnóstico por imagem , Costelas/anormalidades , Costelas/diagnóstico por imagem , Medula Espinal/anormalidades , Pré-Escolar , Feminino , Deformidades Congênitas do Pé/etiologia , Transtornos Neurológicos da Marcha/etiologia , Humanos , Cifose/diagnóstico por imagem , Lipoma/diagnóstico por imagem , Vértebras Lombares/anormalidades , Vértebras Lombares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Meningocele/diagnóstico por imagem , Sacro/anormalidades , Sacro/diagnóstico por imagem , Escoliose/diagnóstico por imagem , Espinha Bífida Oculta/diagnóstico por imagem , Medula Espinal/diagnóstico por imagem , Tela Subcutânea/diagnóstico por imagem , Siringomielia/diagnóstico por imagem , Vértebras Torácicas/anormalidades , Vértebras Torácicas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Incontinência Urinária/etiologia
15.
Genesis ; 57(11-12): e23336, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31520578

RESUMO

Acrodysostosis is an extremely rare disorder at birth, that is, characterized by skeletal dysplasia with short stature and midfacial hypoplasia, which has been reported to be caused by PDE4D and PRKAR1A gene mutations. Here, a Chinese boy with acrodysostosis, ventricular septal defect, and pulmonary hypertension was recruited for our study, and his clinical and biochemical characteristics were analyzed. A novel de novo heterozygous missense mutation (NM_001104631: c.2030A>C, p.Tyr677Ser) of the PDE4D gene was detected by whole exome sequencing and confirmed by Sanger sequencing. The c.2030A>C (p.Tyr677Ser) variant was located in exon 15 of the PDE4D gene, predicted to be damaging by a functional prediction program and shown to be highly conserved among many species. Further functional analysis showed that the p.Tyr677Ser substitution changes the function of the PDE4D protein, affects its subcellular localization in transfected cells, increases PDE4 activity in the regulation of cAMP signaling and affects cell proliferation. Our study identified a novel de novo PDE4D mutation in acrodysostosis of Chinese origin that not only contributes a deeper appreciation of the phenotypic characteristics of patients with PDE4D mutations but also expands the spectrum of PDE4D mutations.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Disostoses/genética , Deficiência Intelectual/genética , Osteocondrodisplasias/genética , Grupo com Ancestrais do Continente Asiático/genética , Pré-Escolar , China , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Disostoses/metabolismo , Células HEK293 , Células HeLa , Heterozigoto , Humanos , Deficiência Intelectual/metabolismo , Masculino , Mutação , Mutação de Sentido Incorreto/genética , Osteocondrodisplasias/metabolismo , Sequenciamento Completo do Exoma
16.
Am J Med Genet A ; 179(7): 1330-1337, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31041856

RESUMO

Albright hereditary osteodystrophy (AHO) is a complex disorder defined by the presence of a short adult stature relative to the height of an unaffected parent and brachydactyly type E, as well as a stocky build, round face, and ectopic calcifications. AHO and pseudohypoparathyroidism (PHP) have been used interchangeably in the past. The term PHP describes end-organ resistance to parathyroid hormone (PTH), occurring with or without the physical features of AHO. Conversely, pseudopseudohypoparathyroidism (PPHP) describes individuals with AHO features in the absence of PTH resistance. PHP and PPHP are etiologically linked and caused by genetic and/or epigenetic alterations in the guanine nucleotide-binding protein alpha-stimulating (Gs α) locus (GNAS) in chromosome 20q13. Another less-recognized group of skeletal dysplasias, termed acrodysostosis, partially overlap with skeletal, endocrine, and neurodevelopmental features of AHO/PHP and can be overlooked in clinical practice, causing confusion in the literature. Acrodysostosis is caused by defects in two genes, PRKAR1A and PDE4D, both encoding important components of the Gs α-cyclic adenosine monophosphate-protein kinase A signaling pathway. We describe the clinical course and genotype of two adult patients with overlapping AHO features who harbored novel pathogenic variants in GNAS (c.2273C > G, p.Pro758Arg, NM_080425.2) and PRKAR1A (c.803C > T, p.Ala268Val, NM_002734.4), respectively. We highlight the value of expert radiological opinion and molecular testing in establishing correct diagnoses and discuss phenotypic features of our patients, including the first description of subcutaneous ossification and spina bifida occulta in PRKAR1A-related acrodysostosis, in the context of the novel inactivating PTH/PTH related peptide signaling disorder classification system.


Assuntos
Disostoses/genética , Deficiência Intelectual/genética , Osteocondrodisplasias/genética , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Hormônio Paratireóideo/metabolismo , Pseudo-Hipoparatireoidismo/genética , Transdução de Sinais , Disostoses/metabolismo , Humanos , Deficiência Intelectual/metabolismo , Masculino , Pessoa de Meia-Idade , Osteocondrodisplasias/metabolismo , Pseudo-Hipoparatireoidismo/metabolismo
17.
Front Horm Res ; 51: 147-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30641531

RESUMO

Pseudohypoparathyroidism (PHP), pseudo-PHP, acrodysostosis, and progressive osseous heteroplasia are heterogeneous disorders characterized by physical findings, differently associated in each subtype, including short bones, short stature, a stocky build, ectopic ossifications (features associated with Albright's hereditary osteodystrophy), as well as laboratory abnormalities consistent with hormone resistance, such as hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone (PTH) and thyroid-stimulating hormone levels. All these disorders are caused by impairments in the cAMP-mediated signal transduction pathway and, in particular, in the PTH/PTHrP signaling pathway: the main subtypes of PHP and related disorders are caused by de novo or autosomal dominantly inherited inactivating genetic mutations, and/or epigenetic, sporadic, or genetic-based alterations within or upstream of GNAS, PRKAR1A, PDE4D, and PDE3A. Here we will review the impressive progress that has been made over the past 30 years on the pathophysiology of these diseases and will describe the recently proposed novel nomenclature and classification. The new term "inactivating PTH/PTHrP signaling disorder," iPPSD: (1) defines the common mechanism responsible for all diseases, (2) does not require a confirmed genetic defect, (3) avoids ambiguous terms like "pseudo," and (4) eliminates the clinical or molecular overlap between diseases.


Assuntos
Doenças Ósseas Metabólicas , Disostoses , Deficiência Intelectual , Ossificação Heterotópica , Osteocondrodisplasias , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Hormônio Paratireóideo/metabolismo , Pseudo-Hipoparatireoidismo , Transdução de Sinais/fisiologia , Dermatopatias Genéticas , Doenças Ósseas Metabólicas/classificação , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/terapia , Disostoses/classificação , Disostoses/diagnóstico , Disostoses/metabolismo , Disostoses/terapia , Humanos , Deficiência Intelectual/classificação , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/metabolismo , Deficiência Intelectual/terapia , Ossificação Heterotópica/classificação , Ossificação Heterotópica/diagnóstico , Ossificação Heterotópica/metabolismo , Ossificação Heterotópica/terapia , Osteocondrodisplasias/classificação , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/terapia , Pseudo-Hipoparatireoidismo/classificação , Pseudo-Hipoparatireoidismo/diagnóstico , Pseudo-Hipoparatireoidismo/metabolismo , Pseudo-Hipoparatireoidismo/terapia , Dermatopatias Genéticas/classificação , Dermatopatias Genéticas/diagnóstico , Dermatopatias Genéticas/metabolismo , Dermatopatias Genéticas/terapia
19.
Eur J Med Genet ; 62(3): 167-171, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30006055

RESUMO

Diaphanospondylodysostosis (DSD) is a rare autosomal recessive skeletal disorder, characterized mainly by ossification defects in vertebrae, thorax malformations, renal cystic dysplasia and usually death in the perinatal period. DSD is caused by mutations in the bone morphogenetic protein-binding endothelial regulator (BMPER) gene. We describe the prenatal findings of a non-consanguineous Jewish couple (shared Balkan origin), with three affected fetuses that presented with malformations in the spine and chest, reduced ossification of the skull and spine, horseshoe kidney and increased nuchal translucency. The unique combination of these ultrasound (US) features raised the possibility of DSD, which was confirmed by whole exome sequencing (WES) performed on a single fetal DNA and familial segregation. In the three fetuses, a novel homozygous mutation in BMPER (c.410T > A; p.Val137Asp) was found. This mutation, which segregated in the family, was not found in 65 controls of Jewish Balkan origin, and in several large databases. Taken together, the combination of a detailed prenatal US examination and WES may be highly effective in confirming the diagnosis of a rare genetic disease, in this case DSD.


Assuntos
Proteínas de Transporte/genética , Anormalidades Craniofaciais/genética , Disostoses/genética , Costelas/anormalidades , Coluna Vertebral/anormalidades , Anormalidades Craniofaciais/diagnóstico por imagem , Disostoses/diagnóstico por imagem , Homozigoto , Mutação de Sentido Incorreto , Costelas/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagem , Ultrassonografia Pré-Natal
20.
Eur J Hum Genet ; 26(11): 1611-1622, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30006632

RESUMO

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.


Assuntos
Subunidade RIalfa da Proteína Quinase Dependente de AMP Cíclico/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Disostoses/genética , Epífises/anormalidades , Exostose Múltipla Hereditária/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Joelho/anormalidades , Osteocondrodisplasias/genética , Fenótipo , Adolescente , Adulto , Criança , Disostoses/patologia , Epífises/patologia , Exostose Múltipla Hereditária/patologia , Feminino , Deformidades Congênitas da Mão/patologia , Heterozigoto , Humanos , Deficiência Intelectual/patologia , Joelho/patologia , Masculino , Mutação , Osteocondrodisplasias/patologia , Síndrome
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...