Displasia tanatofórica tipo II, una entidad congénita inusual. Reporte de caso / Thanatophoric dysplasia type 2, an unusual congenital disease - Case Report

Resumen La displasia tanatofórica es un defecto congènito inusual y esporádico cuyo desenlace es la muerte intrauterina o pocos días después del nacimiento. Su aparición se ha descrito en 0,2-0,5 casos de cada 10.000 nacidos vivos, y depende de la mutación del receptor del factor de crecimiento fibroblasto-3. Cuenta con dos presentaciones clínicas: tipo I y tipo II; esta última es menos frecuente y se caracteriza por el hallazgo de cráneo en hoja de trébol y micromelia con fémures rectos. A continuación, se presenta el caso de una joven multípara con hallazgo en la primera ecografía del embarazo de feto con acortamiento general de las extremidades y disminución de la osificación general, sugestiva de displasia tanatofórica tipo II, que resultó en la interrupción voluntaria del embarazo. El diagnóstico temprano en la gestación es importante para orientar la práctica médica con base en el mal pronóstico del padecimiento de esta patología.

Abstract Thanatophoric dysplasia is an unusual and sporadic congenital defect whose outcome is intrauterine death or a few days after birth. Its appearance has been described in 0.2-0.5 cases of every 10,000 live births and depends on the mutation of the fibroblast growth factor receptor-3. It exhibits two clinical presentations, of these, the so-called type II is less frequent and is characterized by the finding of a cloverleaf skull and micromelia with straight femurs. The following is the case of a young multiparous pregnant woman with a finding in her first ultrasound of fetus pregnancy with general shortening of the limbs and decreased general ossification, suggestive of thanatophoric dysplasia type II, which resulted in the voluntary termination of pregnancy. Early diagnosis in pregnancy is important in order to guide medical practice based on the poor prognosis of suffering from this pathology.

Thanatophoric dysplasia: a case report

Thanatophoric Dysplasia (TD) is a congenital, sporadic and most lethal skeletal dysplasia caused by new mutation in FGFR3 gene. Authors report such a rare case of a term alive baby with dysmorphic features, born to an unbooked, 40 years old G4P3+0 with non-consanguineous marriage; admitted at 9 months of gestation to present hospital with complain of pain abdomen for 2 days. Patient delivered a term female baby of vaginally which had delayed cry after birth, Admitted in NICU immediately with respiratory distress. The baby looked dysmorphic and suggested TD as most likely diagnosis. The case is being reported for its rarity and for high importance of early booking and anomaly scan. Early diagnosis is important since it provides alternative options of termination of pregnancy when an affected foetus is detected.

Valoración ecográfica fetal en displasia esquelética: a propósito de un caso de displasia tanatofórica / Fetal ultrasound evaluation of skeletal dysplasia: apropos of a case of thanatophoric dysplasia

Se presenta el caso de una gestante de 30 semanas con feto afectado por displasia tanatofórica (TD) tipo I, quien fue remitida a la Unidad de Medicina Materno Fetal, Hospital Nacional Daniel Alcides Carrión, Callao, Perú, por sospecha de displasia esquelética. En la ultrasonografía se encontraron signos característicos de TD, con marcadores asociados con alto riesgo de letalidad. A propósito del caso sugerimos algunas recomendaciones para la evaluación ultrasonográfica ante la sospecha de casos de displasia esquelética, como una estrategia de acercamiento al diagnóstico.

The case of a 30 weeks pregnant woman and her fetus affected by thanatophoric dysplasia (TD) type I, referred to our Maternal Fetal Medicine Unit, Hospital Nacional Daniel Alcides Carrión, Callao, Perú, due to suspicion of skeletal dysplasia is reported. On the ultrasound, characteristic signs of TD and markers related to high risk of lethality were found. Recommendations are suggested for ultrasound evaluation of suspected cases of skeletal dysplasia, as a differentiated approach to diagnosis.

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.

Antenatal diagnosis of Thanatophoric dysplasia: a case report and review of literature.

Thanatophoric dysplasia is the lethal skeletal dysplasia characterized by marked underdevelopment of the skeleton and short-limb dwarfism. Foetus has short neck, narrow thoracic cage and protruberant abdomen. Other anatomical features include a relatively enlarged head with frontal bossing, platyspondyly, telephone handle femurs. Thanatophoric dysplasia is usually diagnosed using second trimester ultrasonography. We report this rare entity from rural India with emphasis on its anatomical features along with review of relevant literature.

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.

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.

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.

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.

Three–dimensional prenatal ultrasonography of thanatophoric dysplasia: Initial experience at Siriraj Hospital.

Objective: To initially report the prenatal diagnosis of thanatophoric dysplasia (TD) by using both 2 dimensional (2D-US) and 3 dimensional (3D-US) ultrasonography. Methods: During January 2004 to December 2006, 10 pregnant women who were referred to our Maternal Fetal Medicine Unit due to abnormal skeletal sonographic findings have been extensively investigated by 2D-US and 3D-US. Results: 3 cases of TD (30%) have been identified with an average gestational age of 26 weeks. Sonographic findings demonstrated short limbs, severe micromelia, telephone receiver like femoral bone, bell shaped small thorax, platyspondyly of vertebrae and normal shaped skull in all cases. Prenatal diagnosis was made earlier by 2D-US analysis and then was confirmed by 3D-US. Conclusion: 3D-US provides additional findings and increases interpreter confidence, It provides additional information in the evaluation of fetal skeletal dysplasia, including thanatophoric dysphasia, compared with 2D-US.

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.

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.

Thanatophoric dysplasia in a dizygotic twins conceived by intrauterine insemination / 대한산부인과학회잡지

Twin gestations complicated by a single anomalus fetus present difficulties in obstetric management. It is unclear how the presence of a congenital anomaly in one twin affects its normal sibling. Parents may elect for obstetric management option such as expectant management or selective termination of the anomalous fetus in the hope maximizing the outcome for the normal co-twin. Thanatophoric dysplasia (TD) is the most common type of lethal skeletal dysplasia. Features of the disease are micromelic shortening of the limbs, relative macrocephaly with frontal bossing, flattened vertebrae, disorganized chondrocytes and trabeculae in the growth plates of the long bones, and shortened ribs resulting in a reduced thorax and a bell-shaped abdomen. We experienced a case of TD type I diagnosed in a dizygotic twins by ultrasound at 23 weeks' gestation and reported with concerned literatures.

Mutation at exon 10 of the fibroblast growth factor receptor 3 (FGFR3) in a fetus with thanatophoric dysplasia type I (TDI) / 대한산부인과학회잡지

Thanatophoric dysplasia (TD) is a sporadic lethal type of skeletal dysplasia featuring micromelia, decreased thoracic dimension and macrocephaly. To date, several kinds of mutation in fibroblast growth factor receptor 3 (FGFR3) has been identified in TD. We experienced a case of TD type I and underwent sequencing of the exon 7, 10 and the stop codon of FGFR3 to identify the type of mutation. TDI was diagnosed by the prenatal ultrasound at 25 weeks of gestation. The pregnancy was terminated and the diagnosis was confirmed by radiological and histologic examinations. The genomic DNA was extracted and the sequences of the exon 7, 10 and the stop codon of FGFR3 were amplified by PCR. The sequencing was performed for the each PCR products by dideoxyterminator method. The nucleotide transition from G to T was found in the nucleotide 1108, which is a part of the transmembrane domain, exon 10. To date, only one type of mutation (nucleotide 742) in the FGFR3 was identified in TD1 among Asian. This case firstly reveals the mutation of FGFR3 other than mutation at nucleotide 742 in TD1.