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
- 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]
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]
Karyotype analysis failed in a further nine (23.1%), though three had trisomy 13, 18 and 21 ruled out by FISH (fluorescent in situ hybridization). Thus, a total of 29 (74.3%) had a karyotype result requested (tables II and III). [ncbi.nlm.nih.gov]
- Severe Short Stature
The signs and symptoms of Thanatophoric Dysplasia may include: Bowing of the long bones Decreased fetal movement Flared metaphysis Hypoplastic ilia Metaphyseal irregularity Severe platyspondyly Severe short stature Short long bone Short ribs Short sacroiliac [dovemed.com]
[…] by a long trunk and short limbs in infancy followed by severe and progressive kyphoscoliosis causing a reversal in proportions during childhood (short trunk and long limbs) and a final short stature in adulthood. [mendelian.co]
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]
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]
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 of the condition is very poor; most born with it die due to respiratory insufficiency shortly after birth, though some survive longer with medical assistance. [verywellhealth.com]
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]
[…] 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]
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]
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]
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]
Chalazion and Hordeolum ( Stye) - Etiology, pathophysiology, symptoms, signs, diagnosis & prognosis from the MSD Manuals - Medical Professional Version. [azuwavynyj.tk]
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]
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]
[…] 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]
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]
Coping There’s no doubt that the burden of this disease is very heavy, and, despite some solid progress, prevention or reversal of the condition is not possible. [verywellhealth.com]
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