RESUMEN
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.
Asunto(s)
Proteína Relacionada con la Hormona Paratiroidea/fisiología , Hormona Paratiroidea/fisiología , Seudohipoparatiroidismo/clasificación , Seudohipoparatiroidismo/diagnóstico , Terminología como Asunto , Adolescente , Adulto , Anciano , Niño , Preescolar , Disostosis/clasificación , Disostosis/genética , Femenino , Francia/epidemiología , Silenciador del Gen , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/clasificación , Discapacidad Intelectual/genética , Italia/epidemiología , Masculino , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Mutación , Osificación Heterotópica/clasificación , Osificación Heterotópica/genética , Osteocondrodisplasias/clasificación , Osteocondrodisplasias/genética , Hormona Paratiroidea/genética , Proteína Relacionada con la Hormona Paratiroidea/genética , Seudohipoparatiroidismo/epidemiología , Seudohipoparatiroidismo/genética , Enfermedades Raras , Estudios Retrospectivos , Transducción de Señal/genética , España/epidemiología , Adulto JovenRESUMEN
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.
Asunto(s)
Enfermedades Óseas Metabólicas , Disostosis , Discapacidad Intelectual , Osificación Heterotópica , Osteocondrodisplasias , Proteína Relacionada con la Hormona Paratiroidea/metabolismo , Hormona Paratiroidea/metabolismo , Seudohipoparatiroidismo , Transducción de Señal/fisiología , Enfermedades Cutáneas Genéticas , Enfermedades Óseas Metabólicas/clasificación , Enfermedades Óseas Metabólicas/diagnóstico , Enfermedades Óseas Metabólicas/metabolismo , Enfermedades Óseas Metabólicas/terapia , Disostosis/clasificación , Disostosis/diagnóstico , Disostosis/metabolismo , Disostosis/terapia , Humanos , Discapacidad Intelectual/clasificación , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/terapia , Osificación Heterotópica/clasificación , Osificación Heterotópica/diagnóstico , Osificación Heterotópica/metabolismo , Osificación Heterotópica/terapia , Osteocondrodisplasias/clasificación , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/terapia , Seudohipoparatiroidismo/clasificación , Seudohipoparatiroidismo/diagnóstico , Seudohipoparatiroidismo/metabolismo , Seudohipoparatiroidismo/terapia , Enfermedades Cutáneas Genéticas/clasificación , Enfermedades Cutáneas Genéticas/diagnóstico , Enfermedades Cutáneas Genéticas/metabolismo , Enfermedades Cutáneas Genéticas/terapiaRESUMEN
OBJECTIVE: Disorders caused by impairments in the parathyroid hormone (PTH) signalling pathway are historically classified under the term pseudohypoparathyroidism (PHP), which encompasses rare, related and highly heterogeneous diseases with demonstrated (epi)genetic causes. The actual classification is based on the presence or absence of specific clinical and biochemical signs together with an in vivo response to exogenous PTH and the results of an in vitro assay to measure Gsa protein activity. However, this classification disregards other related diseases such as acrodysostosis (ACRDYS) or progressive osseous heteroplasia (POH), as well as recent findings of clinical and genetic/epigenetic background of the different subtypes. Therefore, the EuroPHP network decided to develop a new classification that encompasses all disorders with impairments in PTH and/or PTHrP cAMP-mediated pathway. DESIGN AND METHODS: Extensive review of the literature was performed. Several meetings were organised to discuss about a new, more effective and accurate way to describe disorders caused by abnormalities of the PTH/PTHrP signalling pathway. RESULTS AND CONCLUSIONS: After determining the major and minor criteria to be considered for the diagnosis of these disorders, we proposed to group them under the term 'inactivating PTH/PTHrP signalling disorder' (iPPSD). This terminology: (i) defines the common mechanism responsible for all diseases; (ii) does not require a confirmed genetic defect; (iii) avoids ambiguous terms like 'pseudo' and (iv) eliminates the clinical or molecular overlap between diseases. We believe that the use of this nomenclature and classification will facilitate the development of rationale and comprehensive international guidelines for the diagnosis and treatment of iPPSDs.
Asunto(s)
Proteína Relacionada con la Hormona Paratiroidea , Hormona Paratiroidea , Seudohipoparatiroidismo/clasificación , Seudohipoparatiroidismo/diagnóstico , Enfermedades Óseas Metabólicas/sangre , Enfermedades Óseas Metabólicas/clasificación , Enfermedades Óseas Metabólicas/diagnóstico , Disostosis/sangre , Disostosis/clasificación , Disostosis/diagnóstico , Europa (Continente) , Humanos , Discapacidad Intelectual/sangre , Discapacidad Intelectual/clasificación , Discapacidad Intelectual/diagnóstico , Osificación Heterotópica/sangre , Osificación Heterotópica/clasificación , Osificación Heterotópica/diagnóstico , Osteocondrodisplasias/sangre , Osteocondrodisplasias/clasificación , Osteocondrodisplasias/diagnóstico , Hormona Paratiroidea/sangre , Proteína Relacionada con la Hormona Paratiroidea/sangre , Seudohipoparatiroidismo/sangre , Enfermedades Cutáneas Genéticas/sangre , Enfermedades Cutáneas Genéticas/clasificación , Enfermedades Cutáneas Genéticas/diagnósticoRESUMEN
Abnormal vertebral segmentation (AVS) in man is a relatively common congenital malformation but cannot be subjected to the scientific analysis that is applied in animal models. Nevertheless, some spectacular advances in the cell biology and molecular genetics of somitogenesis in animal models have proved to be directly relevant to human disease. Some advances in our understanding have come through DNA linkage analysis in families demonstrating a clustering of AVS cases, as well as adopting a candidate gene approach. Only rarely do AVS phenotypes follow clear Mendelian inheritance, but three genes-DLL3, MESP2, and LNFG-have now been identified for spondylocostal dysostosis (SCD). SCD is characterized by extensive hemivertebrae, trunkal shortening, and abnormally aligned ribs with points of fusion. In familial cases clearly following a Mendelian pattern, autosomal recessive inheritance is more common than autosomal dominant and the genes identified are functional within the Notch signaling pathway. Other genes within the pathway cause diverse phenotypes such as Alagille syndrome (AGS) and CADASIL, conditions that may have their origin in defective vasculogenesis. Here, we deal mainly with SCD and AGS, and present a new classification system for AVS phenotypes, for which, hitherto, the terminology has been inconsistent and confusing.
Asunto(s)
Disostosis/embriología , Disostosis/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Columna Vertebral/anomalías , Columna Vertebral/embriología , Animales , Susceptibilidad a Enfermedades , Disostosis/clasificación , Disostosis/patología , Humanos , Fenotipo , Columna Vertebral/crecimiento & desarrollo , Columna Vertebral/metabolismoRESUMEN
Although many constitutional disorders of bone are individually rare, collectively they make up a large group of disorders. They are broadly classified into osteochondrodysplasias and dysostoses. Because of the rarity of some of these conditions, they can be difficult to diagnose. Members of the International Dysplasia Group meet regularly to update and clarify the nomenclature. The last meeting was in Oxford in 2001. This article attempts to highlight the differences between the osteochondrodysplasias and the dysostoses, and provides a systematic approach to their radiological diagnosis.
Asunto(s)
Enfermedades del Desarrollo Óseo/clasificación , Enfermedades del Desarrollo Óseo/diagnóstico por imagen , Terminología como Asunto , Huesos/diagnóstico por imagen , Preescolar , Disostosis/clasificación , Disostosis/diagnóstico por imagen , Femenino , Humanos , Lactante , Masculino , Osteocondrodisplasias/clasificación , Osteocondrodisplasias/diagnóstico por imagen , Radiografía , Sensibilidad y Especificidad , Sociedades MédicasAsunto(s)
Anomalías Múltiples/clasificación , Disostosis/clasificación , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/embriología , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Diagnóstico Diferencial , Disostosis/diagnóstico , Disostosis/embriología , Disostosis/genética , Disostosis/patología , Genes Dominantes , Genes Recesivos , Humanos , Recién Nacido , Morfogénesis , Síndromes Orofaciodigitales/clasificación , Síndromes Orofaciodigitales/diagnóstico , Síndromes Orofaciodigitales/embriología , Síndromes Orofaciodigitales/genética , Síndromes Orofaciodigitales/patología , Fenotipo , SíndromeAsunto(s)
Oído Externo/anomalías , Adolescente , Adulto , Pruebas Calóricas , Niño , Preescolar , Disostosis/clasificación , Disostosis/genética , Disostosis/fisiopatología , Oído Externo/cirugía , Oído Medio/anomalías , Oído Medio/cirugía , Femenino , Trastornos de la Audición/diagnóstico , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
The Jarcho-Levin syndrome is a condition manifested by vertebral body and related rib malformations. We report on four new cases and review 57 cases from the literature. Analysis of the 61 cases suggests that there are two major subtypes (spondylocostal dysostosis and spondylothoracic dysostosis) with different survival rates, associated malformations, and inheritance patterns. Individuals with spondylothoracic dysostosis have vertebral body malformations and ribs which flare in a fanlike pattern but which are not significantly malformed. This is an autosomal recessive trait, and the patients have a higher mortality rate and greater incidence of neural tube defects. Individuals with spondylocostal dysostosis have vertebral malformations, frequent dramatic rib malformations, and short stature, but do not have a fanlike thoracic configuration. Most cases of spondylocostal dysostosis are inherited in an autosomal recessive fashion, although in a few families it is a dominant trait which is correlated with better survival. Respiratory compromise previously accounted for the high mortality in these conditions, but improvements in respiratory technology have increased survival. Appropriate classification of these similar phenotypes will improve counseling concerning recurrence risk, management, and prognosis.
Asunto(s)
Costillas/anomalías , Columna Vertebral/anomalías , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/diagnóstico por imagen , Disostosis/clasificación , Disostosis/congénito , Disostosis/diagnóstico por imagen , Femenino , Humanos , Recién Nacido , Masculino , Diagnóstico Prenatal , Radiografía , Costillas/diagnóstico por imagen , Columna Vertebral/diagnóstico por imagen , SíndromeRESUMEN
The author makes a few diagnostic comments regarding the so-called constitutional bone diseases, quoting the international nomenclature and a classification which is thought to be useful for diagnosis, based on clinical and radiological criteria rather than purely structural and metabolic findings.
Asunto(s)
Enfermedades del Desarrollo Óseo/diagnóstico , Enfermedades del Desarrollo Óseo/clasificación , Enfermedades Óseas Metabólicas/clasificación , Enfermedades Óseas Metabólicas/diagnóstico , Niño , Aberraciones Cromosómicas/clasificación , Aberraciones Cromosómicas/diagnóstico , Trastornos de los Cromosomas , Disostosis/clasificación , Disostosis/diagnóstico , Humanos , Osteocondrodisplasias/clasificación , Osteocondrodisplasias/diagnóstico , Osteólisis/clasificación , Osteólisis/diagnóstico , Terminología como AsuntoRESUMEN
Polydactyly is a common pedal deformity with great variation in clinical presentation. There is a tendency toward a higher incidence in previously affected families, but the actual occurrence rate of the different forms of polydactyly has not been agreed upon in the literature to date. Most authors agree that the isolated deformity is an expression of an autosomal dominant gene with varied penetrance. Syndromatically associated polydactyly is inherited as an autosomal recessive trait. Surgical intervention should be attempted as early as possible. Correction should be undertaken only after a thorough clinical and radiographic evaluation has been performed. The patient's postoperative goals should always be considered. It is not necessary to remove the supernumerary digit if it does not interfere with the foot's function and comfort. Cosmesis should not be the chief consideration. The surgeon should strive to return the foot to a more normal contour while maintaining or improving foot function.