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Thanatophoric Dysplasia

TD

Thanatophoric dysplasia is a lethal form of skeletal dysplasia that develops due to fibroblast growth factor receptor 3 (FGFR3) gene mutations. A generalized underdevelopment of virtually all bones in the body and marked changes of the brain parenchyma are the hallmarks of thanatophoric dysplasia. Imaging studies and genetic testing can be used to make a postnatal, but also a prenatal diagnosis.


Presentation

Derived from the word thanatophorus (meaning "death-bearing"), thanatophoric dysplasia is a lethal genetic disease [1] [2] [3]. Appearing in approximately 1 per 20,000 births, it arises as a result of mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, located on the short arm of chromosome 4 [2] [4]. The prognosis is quite poor, as the majority of neonates die during the first few hours of life, the most common cause being hypoplasia of the lungs and subsequent respiratory distress [1] [4] [5]. Rare reports have documented patients who managed to survive through infancy and reach adulthood [4]. The clinical presentation is distinguished by the appearance of skeletal and central nervous system malformations, and two subtypes have been described in the literature [1] [3]. Disproportionately short extremities that are bowed in type 1, but often straight in type 2, as well as a narrow thoracic cage (and consequent underdevelopment of the lungs) with very short ribs, platyspondyly (flat and immature vertebrae, more severely encountered in type 1 patients), and a very large head are main skeletal features [1] [2] [3] [4]. The pelvic girdle is particularly smaller, whereas a depressed nasal bridge and a prominent forehead are also reported [1] [2]. On the other hand, premature fusion of sutures in the brain (termed cloverleaf skull deformity) is one of the main central nervous system (CNS) manifestations of thanatophoric dysplasia, principally affecting the temporal lobes [2] [3] [6]. In addition, dysplasia of hippocampus, megalencephaly, ventriculomegaly, and abnormal enlargement of the temporal lobes are common [3] [6].

Dysmorphic Face
  • Physical examination revealed a large head with a prominent forehead in a cloverleaf shape, a dysmorphic face with a flat nose and very small extremities ( Figure 2 ). Figure 1: Ultrasound at 23 weeks showing Polyhydramnios and fetal morphology.[omicsonline.org]
Skin Edema
  • The prenatal ultrasound showed short straight femurs, prominent forehead, narrow chest, skin edema, short limbs, and cloverleaf skull consistent with the diagnosis of TD2. Amniocentesis revealed a karyotype of 46,XX.[ncbi.nlm.nih.gov]
Skeletal Dysplasia
  • […] acanthosis nigricans), and platyspondylic lethal skeletal dysplasia, San Diego type.[ncbi.nlm.nih.gov]
  • Currently, there are no effective treatments for these skeletal dysplasia diseases.[ncbi.nlm.nih.gov]
  • Thanatophoric dysplasia (TD) is the most frequent form of lethal skeletal dysplasia.[ncbi.nlm.nih.gov]
  • Our purpose was to remind the differential prenatal diagnosis with other skeletal dysplasias and new prenatal diagnostic modalities.[ncbi.nlm.nih.gov]
  • Based on these findings, a lethal form of skeletal dysplasia was suspected and a helical CT imaging with 3-D reconstruction depicted skeletal abnormalities which suggested TD.[ncbi.nlm.nih.gov]

Workup

Despite the disorder being life threatening, early recognition is vital. A detailed patient history, a comprehensive physical examination, and the use of imaging studies are the necessary steps in identifying this skeletal disorder. However, the role of prenatal ultrasonography, is perhaps pivotal, due to its ability to identify skeletal and CNS manifestations prenatally. One of the signs associated with an increased risk of developing thanotophoric dysplasia by several authors is the presence of polyhydramnios [1] [3]. The detection of a cloverleaf-shaped deformity of the skull, hypoplasia of the rib cage, limb length abnormalities, as well as flattening of the vertebrae and other associated skeletal or CNS changes can be visualized on standard ultrasonography during the second trimester [2] [5]. Postnatal assessment, if possible, mandates the use of plain X-rays, that will show very short (bowed or straight, depending on the subtype) long bones and shrunken vertebrae with wide intervertebral spaces [3]. As the exact type of dysplasia cannot be determined solely on clinical and imaging criteria, genetic studies should be implemented in order to make a definite diagnosis.

Gliosis
  • In this infant, malformations of the vertebral laminae, most prominent in the basiocciput and atlas vertebra, led to compression of the rostral cervical spinal cord, causing gliosis and focal necrosis.[ncbi.nlm.nih.gov]

Treatment

  • Currently, there are no effective treatments for these skeletal dysplasia diseases.[ncbi.nlm.nih.gov]
  • Normal processing was rescued by tyrosine kinase inhibitor treatment.[ncbi.nlm.nih.gov]
  • If aggressive treatment is deferred, palliative treatment is something that consists of keeping the newborn comfortable, warm, and nourished.[disabled-world.com]
  • Physical findings: • Growth deficiency of limbs of less than 5%; • Platyspondyly of the vertebrae; • Large anterior fontanel; ICD-9: 756.4 TREATMENT Treatment measures of the few survivors may include: antiepileptic drugs to control seizures, shunt placement[secure.ssa.gov]
  • These resources address the diagnosis or management of thanatophoric dysplasia and may include treatment providers.[buttonsandbutterflies.com]

Prognosis

  • 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.[ncbi.nlm.nih.gov]
  • The prognosis is quite poor, as the majority of neonates die during the first few hours of life, the most common cause being hypoplasia of the lungs and subsequent respiratory distress.[symptoma.com]
  • Prognosis: The condition is lethal due to severe pulmonary hypoplasia. Recurrence: No increased risk.[fetalmedicine.org]
  • […] ribs small scapulae Skull and face relative macrocephaly frontal bossing proptosis nasal bridge flattening kleeblattschaedel (cloverleaf) skull (with type II) 2-4 Spine platyspondyly : flattening of vertebral bodies normal trunk length Treatment and prognosis[radiopaedia.org]
  • Prognosis: Uniformly lethal. Management: Termination of pregnancy.[web.archive.org]

Etiology

  • While the etiology is unknown, either autosomal recessive or polygenic transmission with 0.2% recurrence risk had been suggested. It is a lethal disorder characterized by extremely short ribs, tubular bones and macrocephaly.[ncbi.nlm.nih.gov]
  • Any etiology proposed for TD must not only account for disordered endochondral and endomembranous bone formation but also explain the origins of early temporal-lobe dysplasia.[ncbi.nlm.nih.gov]
  • Etiology Only gold members can continue reading. Log In or Register to continue Dec 21, 2015 Posted by in PEDIATRIC IMAGING Comments Off on 113 Thanatophoric Dysplasia[radiologykey.com]
  • Etiology The etiology of thanatophoric dysplasia is unknown. Most cases have been sporadic, with a 2:1 ratio of affected males to females 19.[web.archive.org]
  • […] concerning dermatopathology and pathology Atlas of fetal pathology Congenital malformations Physiological developement of an embryo and fetus, growth and changes of the external shape Congenital malformations and congenital anomalies Basic terminology Etiology[atlases.muni.cz]

Epidemiology

  • We review the clinical, epidemiological, radiological, molecular aspects, and signaling pathways involved in these conditions. It is known that FGFR3 signaling is essential to regulate bone growth.[ncbi.nlm.nih.gov]
  • Epidemiology of osteochondrodysplasisa: changing trends due to advances in prenatal diagnosis. Am J Med Genet. 1996;61:49-58. Spranger J. International nomenclature of constitutional bone diseases (the Paris nomenclature).[msjonline.org]
  • Epidemiology Frequency United States Thanatophoric dysplasia (TD) has an incidence of 1 per 20,000 to 1 per 50,000 births. International Incidence in Spain is reported as 1 per 37,000 births.[emedicine.com]
Sex distribution
Age distribution

Pathophysiology

  • Germline mosaicism has not been clearly documented but remains a theoretical possibility. [1, 2] Pathophysiology FGFR3 is part of the tyrosine kinase receptor family. Normally, FGFR3 is a negative regulator of bone growth.[emedicine.com]
  • The pathophysiology of thanatophoric dysplasia is notable. FGFR3 is a part of the tyrosine kinase receptor family. Usually, FGFR3 is a negative regulator of bone growth.[disabled-world.com]
  • Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders Alessandra Mozzi, Diego Forni, Rachele Cagliani, Uberto Pozzoli, Mario Clerici & Manuela Sironi Scientific Reports (2017) Pathophysiological[nature.com]

Prevention

  • The first twin was breech and was "locked" with the second vertex twin preventing the delivery of the first twin. After surgical "unlocking", the vaginal delivery was essentially routine."[web.archive.org]
  • Low Birth Weight Infants 421 25 Cerebral Metabolism in the Very Low Birth Weight Infant 435 Part III Preterm Infants 449 26 The Relationship Between Growth and Perinatal Factors in Preterm Infants 451 A Focus on WHO Growth Curves After Discharge 465 Preventing[books.google.com]
  • This can cause a child to have: very brisk reflexes numbness weakness difficulty walking loss of bowel and bladder control sleep apnea – periods during sleep when the child stops breathing. 2-Hydrocephalus When the narrowing near the base of the spine prevents[beyondachondroplasia.org]

References

Article

  1. Dighe M, Fligner C, Cheng E, Warren B, Dubinsky T. Fetal skeletal dysplasia: an approach to diagnosis with illustrative cases. Radiographics. 2008;28(4):1061-1077.
  2. Sahinoglu Z, Uludogan M, Gurbuz A, Karateke A. Prenatal diagnosis of thanatophoric dysplasia in the second trimester: ultrasonography and other diagnostic modalities. Arch Gynecol Obstet. 2003;269:57–61.
  3. Miller E, Blaser S, Shannon P, Widjaja E. Brain and bone abnormalities of thanatophoric dwarfism. AJR Am J Roentgenol. 2009;192(1):48-51.
  4. Nikkel SM, Major N, King WJ. Growth and development in thanatophoric dysplasia – an update 25 years later. Clin Case Rep. 2013;1(2):75-78.
  5. Machado LE, Bonilla-Musoles F, Osborne NG. Thanatophoric dysplasia. Ultrasound Obstet Gynecol. 2001;18:85-86.
  6. Hevner RF. The cerebral cortex malformation in thanatophoric dysplasia: neuropathology and pathogenesis. Acta Neuropathol. 2005; 110:208-221.

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Last updated: 2019-07-11 20:44