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.
Derived from the word thanatophorus (meaning "death-bearing"), thanatophoric dysplasia is a lethal genetic disease   . 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  . 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   . Rare reports have documented patients who managed to survive through infancy and reach adulthood . The clinical presentation is distinguished by the appearance of skeletal and central nervous system malformations, and two subtypes have been described in the literature  . 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    . The pelvic girdle is particularly smaller, whereas a depressed nasal bridge and a prominent forehead are also reported  . 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   . In addition, dysplasia of hippocampus, megalencephaly, ventriculomegaly, and abnormal enlargement of the temporal lobes are common  .
Entire Body System
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]
The baby had a dysmorphic face, frontal bossing, low nasal bridge, low-set ears and short neck. The thorax was narrow and abdomen was protuberant. The upper and lower proximal limbs appeared short. [degruyter.com]
Disproportionate Short Stature
The proposita has disproportionate short stature, radial head dislocation, coxa vara, and bowing of some of the long bones, associated with an S-shaped deformity of the humerus, accompanied by widespread acanthosis nigricans in the integument. [ncbi.nlm.nih.gov]
Furthermore, they did not show any evidence of vertebral collapse. The thanatophoric dysplasia presented less bowed long bones, and never true angulation. The spine was steadily characterized by flattened anterior vertebral bodies. [ncbi.nlm.nih.gov]
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  . 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  . 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 . 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.
Currently, there are no effective treatments for these skeletal dysplasia diseases. [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]
Management and treatment Prenatally, treatment aims to avoid potential pregnancy and delivery complications. Postnatally, management should focus on the parents' wishes for provision of comfort-care for the newborn versus aggressive management. [orpha.net]
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]
Prognosis Prognosis is poor with death occurring in utero or shortly after birth in almost all cases. Death is likely due to respiratory insufficiency and/or spinal cord/brain stem compression. [orpha.net]
Prognosis: The condition is lethal due to severe pulmonary hypoplasia. Recurrence: No increased risk. [fetalmedicine.org]
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]
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]
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]
However, 20–30% of hydrops is of unknown etiology. Here, we report a case of TD type I with fetal hydrops diagnosed in the first trimester and thereafter shortening of the long bones and macrocephaly. [hindawi.com]
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]
Summary Epidemiology Thanatophoric dysplasia (TD) estimated incidence is about 1/20,000 to 1/50,000 births. Clinical description Characteristic morphological features are seen on prenatal ultrasounds. [orpha.net]
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]
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]
How can Thanatophoric Dysplasia be Prevented? Currently, Thanatophoric Dysplasia may not be preventable, since it is a genetic disorder. [dovemed.com]
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]
Transplantation Substance Use and Addiction Surgery Surgical Innovation Surgical Pearls Teachable Moment Technology and Finance The Rational Clinical Examination Tobacco and e-Cigarettes Toxicology Trauma and Injury Treatment Adherence United States Preventive [jamanetwork.com]
[…] dysplasia. 61 Chen CP...Wang W 29458880 2018 16 HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia. 61 Ota S...Hurlin PJ 27506979 2016 17 Mutant activated FGFR3 impairs endochondral bone growth by preventing [malacards.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]
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