Displasias esqueléticas: Reporte de un caso y revisión de la literatura / Skeletal dysplasias: Report of a case and review of the literature

RESUMEN Las displasias esqueléticas son un grupo heterogéneo de condiciones que afectan primariamente la formación y crecimiento de huesos y cartílagos, se caracterizan por un acortamiento generalizado de huesos largos. Son patologías de baja prevalencia, que se pueden diagnosticar con precisión mediante ultrasonografía del primer y segundo trimestre. La importancia de esta patología radica en que posee una letalidad cercana al 50%. La displasia esqueletica letal más frecuente es la displasia tanatofórica, la cual se caracteriza por macrocefalia con base de cráneo estrecha, tórax estrecho, cuerpos vertebrales planos, micromelia generalizada, ausencia de fracturas, ventriculomegalia, polihidroamnios y mineralización ósea normal. Debido a que la presentación de la displasia tanatoforica se debe a una mutación autosómica dominante de novo no germinal, el riesgo de recurrencia no es mayor que el de la población general. Dado su elevada letalidad no pasa a generaciones futuras.

SUMMARY Skeletal dysplasias are a heterogeneous group of conditions that primarily affect the formation and growth of bones and cartilage, characterized by a generalized shortening of long bones. These are pathologies of low prevalence, which can be accurately diagnosed by first and second trimester ultrasonography. The importance of this pathology lies in that it has a lethality close to 50%. The most common lethal skeletal dysplasia is tanophilic dysplasia, which is characterized by macrocephaly with a narrow cranial base, narrow chest, flat vertebral bodies, generalized micromelia, absence of fractures, ventriculomegaly, polyhydroamnios and normal bone mineralization. Because the presentation of the tanophoretic dysplasia is due to an autosomal dominant mutation of novo non-germinal, the risk of recurrence is not greater than that of the general population. Given its high lethality does not happen to future generations.

Diagnóstico ecográfico prenatal de displasia tanatofórica: a propósito de un caso / Prenatal diagnosis ultrasonographic thanatophoric dysplasia: report of a case

La Displasia tanatofórica es probablemente la displasia letal más común. Ocurre en aproximadamente en 0,69 por cada 10.000 nacimientos. Su etiología es posiblemente autosómica dominante y resulta de mutaciones nuevas del factor de crecimiento del receptor de los fibroblastos. La patogenia es debida a desorganización del cartílago de crecimiento con persistencia de tejido símil parenquimatoso. Es una condrodisplasia congénita letal caracterizada por el acortamiento de los miembros, hipoplasia torácica, cráneo en hoja de trébol, pliegue simiesco, fémur acortado, estrechamiento torácico, frente prominente, polo cefálico con dimensiones aumentadas aún sin ventriculomegalia y redundancia de las partes blandas.Ademásestá asociado a polihidramnios en un 70 %. Las anomalías asociadas son hidrocefalia, anomalías renales, defecto del tabique auricular, válvula tricúspide anómala, ano imperforado y sinóstosis radio cubital. Se presenta la experiencia de un caso de displasia tanatofórica que se ha podido diagnosticar con la ecografía prenatal.

Thanatophoric dysplasia is probably the most common lethal dysplasia. It occurs in about 0.69 of 10,000 births. Its etiologyis dominantand autosomal probabilly dueto new mutations from growth factor receptor fibroblasts. The pathogenesis is dueto disorganization of the growth cartilage with persistente of parenchymal like tissue. It´s a lethal congenital chondrodysplasia characterized by short limbs, thoracichypoplasia, skull cloverleaf, simiancrease, shortened femur, thoracic narrowing, prominent forehead, cephalic pole with increased dimension seven without ventriculomegaly, redundancy of the soft tissues. Also polyhydramniosis associated with in 70% of cases. The associated anomalies are hydrocephalus, kidney abnormalities, atrial septal defect, abnormal tricuspidvalve, imperforateanus which radioulnarsynostosis. The present a case with thanatophoric dysplasia which has been diagnosed with prenatal ultrasound.

Achondrogenesis: A Lethal Chondrodystrophy.

Achondrogenesis is a type of skeletal dysplasia. Skeletal dysplasias are the heterogeneous class of bone growth disorders resulting in abnormal shape and size of the skeleton. Here, we present a rare case of achondrogenesis which was delivered by induced abortion at 6½ months of gestation. The physical, radiological, and ultrasonographic examinations done raised the possibility of this very rare anomaly. Achondrogensis is characterized by extreme micromelia and marked discrepancy between the relatively large head and the decreased trunk length. This rare condition has got genetic mutations associated with it. Achondrogenesis resembles other chondrodystrophies, therefore, its diagnosis needs to be made promptly and accurately.

Displasia tanatofórica: una reflexión bioética a partir de un caso clínico / Thanatophoric dysplasia: case-based bioethical analysis

El presente artículo muestra un caso de displasia tanatofórica, diagnosticado en el período prenatal bajo criterios ultrasonográficos. Se describe la evolución del embarazo hasta el nacimiento, así como la evolución postnatal del producto. Este reporte busca invitar a la reflexión bioética y retomar sus principios apelando a la otredad y a la dignidad humana, en particular del binomio madre e hijo y su entorno familiar. En este sentido, un diagnóstico precoz permite acompañar a los padres para afrontar el proceso evolutivo de esta patología, e incluso un desenlace fatal.

This paper presents a case report of thanatophoric displasia diagnosed in the prenatal period using ultrasound standards. The course of the case pregnancy, birth process, and postnatal period is described. This report invites bioethical analysis using its principles, appealing to human dignity, diversity and otherness, particularly in the mother-child dyad and their family. An early diagnosis allows parental support as they face the course of this condition and its potentially fatal outcome.

Thanatophoric dysplasia in a dichorionic twin confirmed by genetic analysis at the early second trimester: A case report and literature review

Thanatophoric dysplasia (TD) is caused by mutation of the gene that encodes fibroblast growth factor 3 (FGFR3). Owing to the poor prognosis for TD, prenatal diagnosis is critical to optimal perinatal management. We report here a case of TD in twin pregnancy, which was prenatally diagnosed by DNA analysis following amniocentesis at 15 weeks, and was managed by selective fetal termination. Prenatal ultrasonography and molecular analysis to detect TD-specific mutations enable accurate diagnosis of FGFR3-related TD in utero and appropriate obstetrical management at early gestation during twin pregnancy.

Molecular analysis of a case of thanatophoric dysplasia reveals two de novo FGFR3 missense mutations located in cis

Thanatophoric dysplasia [TD] is the most common form of lethal skeletal dysplasia. It is primarily an autosomal dominant disorder and is characterised by macrocephaly, a narrow thorax, short ribs, brachydactyly, and hypotonia. In addition to these core phenotypic features, TD type I involves micromelia with bowed femurs, while TD type II is characterised by micromelia with straight femurs and a moderate to severe clover-leaf deformity of the skull. Mutations in the FGFR3 gene are responsible for all cases of TD reported to date. The objective of the study here was to delineate further the mutational spectrum responsible for TD. Conventional polymerase chain reaction [PCR], allele-specific PCR, and sequence analysis were used to identify FGFR3 gene mutations in a fetus with a lethal skeletal dysplasia consistent with TD, which was detected during a routine antenatal ultrasound examination. In this report we describe the identification of two de novo missense mutations in cis in the FGFR3 gene [p.Asn540Lys and p.Val555Met] in a fetus displaying phenotypic features consistent with TD. This is the second description of a case of TD occurring as a result of double missense FGFR3 gene mutations, suggesting that the spectrum of mutations involved in the pathogenesis of TD may be broader than previously recognised

Diagnóstico pré-natal de displasia tanatofórica: papel do ultrassom fetal / Prenatal diagnosis of thanatophoric dysplasia: role of the fetal ultrasound

OBJETIVO: Relatar o caso de um paciente com displasia tanatofórica, uma forma autossômica dominante e letal de nanismo, diagnosticado ainda no período pré-natal, e revisar a literatura, discutindo os principais diagnósticos diferenciais e ressaltando a importância do ultrassom fetal na identificação de fetos portadores dessa displasia. DESCRIÇÃO DO CASO: O paciente é o segundo filho de pais jovens sem história familiar de doenças genéticas. O ultrassom fetal realizado com 35 semanas de gestação mostrou polidrâmnio, proeminência frontal e desproporção entre crânio e tronco, com hipoplasia torácica e encurtamento dos ossos longos, compatível com o diagnóstico de displasia tanatofórica. Ao nascimento, a criança era pequena e possuía hipotonia, macrocefalia, fontanelas amplas, hipoplasia de face média, olhos protrusos, hemangioma plano no nariz e pálpebras, nariz em sela, micrognatia, pescoço e tórax curtos e encurtamento importante de braços, antebraços, coxas e pernas. A avaliação radiográfica mostrou crânio com grande diâmetro transverso, tórax com costelas curtas e corpos vertebrais reduzidos, importante encurtamento e deformidade dos ossos longos dos membros superiores e inferiores (os fêmures eram curvos) e hipoplasia da bacia. Esses achados confirmaram o diagnóstico pré-natal de displasia tanatofórica. O paciente evoluiu para o óbito poucos dias após o nascimento devido à insuficiência respiratória. COMENTÁRIOS: A ultrassonografia fetal é um método não invasivo capaz de diagnosticar inúmeras displasias ósseas, incluindo a tanatofórica. A importância do diagnóstico intra-útero reside no fato de que auxilia no diagnóstico diferencial, e permite o aconselhamento genético à família.

OBJECTIVE: To report a patient with thanatophoric dysplasia, an autosomal dominant and lethal form of nanism diagnosed in the prenatal period and to review the literature, discussing the main differential diagnosis and highlighting the importance of the fetal ultrasound in the identification of fetus with this dysplasia. CASE DESCRIPTION: The patient is the second son of young parents without family history of genetic diseases. The fetal ultrasound performed with 35 weeks of gestation showed polyhydramnios, prominent forehead and disproportion between skull and trunk, with thoracic hypoplasia and shortening of long bones, suggestive of thanatophoric dysplasia. At birth, the child was small and presented: hypotonia, macrocephaly, large fontanel, middle face hypoplasia, bulging eyes, nevus flammeus in the nose and eyelids, low nasal bridge, micrognathia, short neck and thorax, and an important shortening of arms, forearms, thighs and legs. Radiographic evaluation showed a great transverse diameter of the skull, thorax with short ribs and diminished vertebral bodies, shortening and deformity of the long bones of upper and lower limbs (with curved femora) and hypoplasia of the pelvis. These features confirmed the prenatal diagnosis of thanatophoric dysplasia. The patient died few days after birth due to respiratory insufficiency. COMMENTS: Fetal ultrasound is a non-invasive method capable of diagnosing several bone dysplasias, including the thanatophoric one. The intrauterine diagnosis allows the differential diagnosis of the condition as well as the genetic counseling for the family.

Acondrogénesis tipo IA: reporte de caso / Type IA achondrogenesis: case report

La acondrogénesis tipo IA (#MIM 200600) es una rara y letal displasia esquelética, caracterizada por un grave retardo de la osificación, con modo de herencia autosómico recesivo. Hasta el momento se desconocen sus bases moleculares. En este artículo se reporta el caso de un feto de sexo femenino, de 23 semanas de edad de gestación, de padres no consanguíneos, con diagnóstico ecográfico de hipoplasia torácica, hipoplasia pulmonar, costillas cortas con múltiples fracturas, micromelia grave, hipocalcificación y fractura de huesos largos, pies en varo y manos en garra. En el estudio microscópico se evidencia untrastorno de osificación endocondral. La acondrogénesis pertenece a la forma más crónica de condrodisplasias humanas invariablemente letales. Las bases bioquímicas y molecularesno son claras en la acondrogénesis tipo IA, ya que el diagnóstico se basa en la integración de estudios radiológicos e histológicos en cada caso específico, por lo cual se considera que el caso presentado corresponde a acondrogénesis tipo IA.

Thanatophoric dysplasia: a rare entity

Thanatophoric dysplasia is the lethal skeletal dysplasia characterized by marked underdevelopment of the skeleton and short-limb dwarfism. The child will be having a short neck, narrow thoracic cage and protuberant abdomen. Other anatomical features include a relatively enlarged head with frontal bossing, prominent eyes, hypertelorism and the depressed nasal bridge. The diagnosis is usually made with the ultrasonography in the second trimester. In this study we report a case of this rare entity with emphasis on its anatomical features, abnormalities and clinical profile with relevant review of literature

A case of thanatophoric dysplasia type I with an R248C mutation in the FGFR3 gene / 소아과

Thanatophoric dysplasia (TD) is a short-limb neonatal dwarfism syndrome that is usually lethal in the perinatal period. It is characterized by shortening of the limbs, severely small thorax, large head with a prominent forehead, macrocephaly, curved femur, and flattened vertebral bodies. These malformations result from the mutation in fibroblast growth factor receptor 3 (FGFR-3) gene which is located on the short arm of chromosome 4. A definite diagnosis should be established by molecular genetic analysis to find out the abnormal mutations in the FGFR3 gene. We confirmed by detection of a R248C mutation in the FGFR3 gene in DNA analysis.

Displasia tanatofórica. Reporte de un caso y revisión / Thanatophoric Dysplasia. A case report and review

Objetivo: presentar los hallazgos ecográficos de la displasia tanatofórica (DT) y su diagnóstico diferencial, desde el punto de vista del ultrasonido con la acondroplasia. Se presenta un caso clínico de una paciente gestante a quien se remitió con diagnóstico de feto con acondroplasia, y posterior a una ecografía de detalle fetal 2D-3D, se hizo el diagnóstico antenatal de displasia tanatofórica (DT), el cual se confirmó postmortem.Conclusión: se resalta la necesidad de afinar los criterios diagnósticos de la restricción del crecimiento, partiendo de reportar los hallazgos ecográficos en función del percentil de crecimiento fetal y no de la reasignación de una nueva edad gestacional con cada nueva ecografía, además se hacen algunas recomendaciones respecto al informe ecográfico.

Two case of thanatophoric dysplasia type I / 대한주산의학회잡지

Thanatophoric dysplasia (TD) is a lethal inherited skeletal disorder characterized by extremely short limbs, narrow chest, skull deformity and underdeveloped lungs. TD is divided into two types, depending primarily upon whether the bone in the upper leg (the femur) is curved or straight. We experienced two case of TD type I that were confirmed by clinical and radiological features after birth. Unlike previously reported cases of TD in our country, the multiple anomalies of CNS, kidney and cardiovascular system were identified in one of these cases.

Thanatophoric dysplasia: a case report and review of literature.

Autopsy was performed on a fetus of 6 months gestation with sonologic features of skeletal dysplasia to arrive at a pathological diagnosis. Radiograph of fetus was taken which showed short limb bones, curved femora, flattened vertebral bodies with wide intervertebral spaces, bell-shaped chest, short ribs with flared ends which are features described in Thanatophoric dysplasia. This was confirmed by histopathological findings in the epiphyseal growth plate. In this paper, we attempt to describe the radiological and pathological findings of our case with a discussion on comparative literature.

A case of prenatally diagnosed thanatophoric dysplasia type I using 3D multislice view / 대한산부인과학회지

Lethal skeletal dysplasia can be suspected at relatively early pregnancy by ultrasonography, but the final diagnosis is difficult to make. Genetic, histopathologic and radiologic examinations are needed for the diagnosis. The most common lethal skeletal dysplasia is thanatophoric dysplasia (TD) and which can be subdivided into two types according to its clinical features. Advances in prenatal ultrasound techniques, especially 3D multislice scan technique enable to get adequate plans to diagnose TD. We report one case of thanatophoric dysplasia type I diagnosed by new 3D multislice view technique and confirmed by histopathologic, genetic, radiologic examination after termination at 20 weeks of gestation.

Displasia tanatoforica: reporte de un caso / Thanatophoric dysplasia: a case report

Este caso concierne a paciente de 15 años quien fue referida del medio rural por presentar en su control pre-natal hallazgo ecográfico de malformación congénita: Polihidramnios severo, edema fetal generalizado (anasarca) hidrops no inmune con antecedente de hermano con malformación esuquelética congénita acondroplasia. Fue estudiada en el Servicio de ARO, observándose durante su hospitalización ausencia de frecuencia cardiaca fetal razón por la cual, se realiza inducción de trabajo de parto con obtención de producto con signos de maceración además de malformaciones esqueléticas en miembros superiores e inferiores, edema generalizado, desprendimiento de placenta 20 por ciento. Posteriormente se realiza curetaje uterino para verificar presencia o no de restos placentarios, después de 2 días de hospitalización la paciente se egresa debido a buena evolución clínica.

Thanatophoric dysplasia: roentgenographic findings and detection of a de novo mutation of FGFR3 gene in a Thai patient.

Thanatophoric dysplasia is the most common neonatal lethal skeletal dysplasia with an estimated incidence of 1 in 20,000 live births. This condition shares some similarity of radiological findings with other types of lethal skeletal dysplasias. Definite diagnosis is necessary for accurate medical and genetic counseling. The authors describe a male neonate who had characteristic features of thanatophoric dysplasia type I including severe shortening of limbs with redundant skin folds, large head, frontal bossing, depressed nasal bridge, and narrow thoracic cage with severe respiratory insufficiency. Postmortem radiographs revealed short ribs, flat vertebral bodies (platyspondyly), hypoplastic iliac bones, marked shortening of long bones including short and mild bowing of both femora, oval radiolucent area of proximal femur. Molecular analysis of Fibroblast Growth Factor Receptor 3 (FGFR3) gene identified a de novo mutation, p.R248C, in exon 7.

A Case of Thanatophoric Dysplasia Type II Prenatally Diagnosed at 20 Gestational Weeks / 대한산부인과학회지

Thanatophoric dysplasia is a lethal skeletal dysplasia due to the dysfunction of endochondral ossification characterized by short limbs, narrow chest, micromelia, cranial dysplasia. Tavormina described in 1995 that the dysfunction of endochondral ossification is due to the missence mutation of the gene presenting the Fibrblast Growth Factor Receptor 3. Thanatophoric dysplasia is classified as two types. The type I is characterized by the curved short limbs and severe platyspondyly, and the type II by the kleeblattschadel (cloverleaf deformity) and straight short limbs. Both are destined to the death a few days after the delivery due to the pulmonary hypoplasia from the hypoplastic thorax. We experienced a case of thanatophoric dysplasia on antenatal ultrasound examination and then pregnancy was terminated by vaginal delivery. Now, with the review of literature, we report the case of thanatophoric dysplasia confirmed by clinical features and radiological finding.

A Case of the Type I Thanatophoric Dysplasia Diagnosed in the 2nd Trimester / 대한산부인과학회지

Skeletal dysplasias, a heterogenous group of bone growth disorders including thanatophoric dysplasia can be detected by routine prenatal ultrasound examination. As it is difficult to make a specific diagnosis, prediction of prognosis is of importance for obstetric management. In order to specify diagnosis, radiological, pathological and molecular genetic examination are often required. Our report describes a case of the type I thanatophoric dysplasia diagnosed specifically and terminated in the 2nd trimester.

Displasia tantofórica / Thanatophoric dysplasia

Objetico: chamar atenção para a displasia tanatofórica, uma causa rara de insuficiência respiratória e a mais frequente condrodisplasia letal no recém-nascido. Descrição: o recém-nascido apresentava sinais de distúrbio respiratório. O fêmur em forma de telefone, um achado radiológico clássico, estava presente. /Objective: to focus attention on thanatophoric dwarfism, a rare cause of respiratory insufficiency and chondrodysplasia. The femur resembling a 'telephone receiver', a classical radiological finfing, was present...

Displasia tanatofórica: Relato de dois casos com estudo neuropatológico / Thanatophoric dysplasia: report of 2 cases with neuropathological study

O relato tem como objetivo apresentar dois casos de displasia tanatofórica (DT), um caso do tipo I e outro do tipo II, com especial atençäo ao sistema nervoso central. No caso compatível com DT tipo I foram observados macrocefalia, tórax estreito, hipoplasia pulmonar acentuada, abdome protuberante. Exames radiológicos revelaram platispondilia e ossos curtos encurvados com achatamento e fusäo metafisária. No caso compatível com DT tipo II foram observados megaencefalia, fenda palatina, membros curtos e crânio em "folha de trevo". Os achados radiológicos ósseos foram platispondilia, alargamento dos espaços intervertebrais, ossos do esqueleto apendicular mais retilíneos que o primeiro caso e macrocefalia. Ao exame microscópico de ambos os casos foram encontrados polimicrogiria, principalmente temporal; agenesia hipocampal e heterotopia neuroglial no espaço subaracnoideo. As alteraçöes eram mais intensas no segundo caso