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].

• Short Finger

  Commonly reported sonographic features were very short and sometimes bowed femora, frontal bossing, cloverleaf skull, short fingers, a small chest and polyhydramnios. [ncbi.nlm.nih.gov]

  Anywhere from 30 to 79 percent of the time, doctors observe: Short Fingers: Unusually short fingers and toes—a condition called “brachydactyly”—often occurs in those with the condition. [verywellhealth.com]

  People with this condition have very short arms and legs, underdeveloped pelvic bones, and unusually short fingers and toes (brachydactyly). [ghr.nlm.nih.gov]

  […] thorax Shorter than typical length between neck and abdomen 0010306 Skeletal dysplasia 0002652 30%-79% of people have these symptoms Brachydactyly Short fingers or toes 0001156 Frontal bossing 0002007 Gray matter heterotopia 0002282 Hearing impairment [rarediseases.info.nih.gov]

• Epilepsy

  Valerio Conti and Renzo Guerrini, Human Mutations Associated With Brain Malformations Resulting in Hyperexcitability in Rodents, Models of Seizures and Epilepsy, 10.1016/B978-0-12-804066-9.00056-0, (827-844), (2017). Chen Yang and Louis P. [doi.org]

  Rib-Polydactyly Syndrome [C05.116.099.708.857] MGI_4.01: Human Disease and Mouse Model Detail Cretinism [C05.116.099.343.314] CD Osteogenesis Imperfecta [C05.116.099.708.685] [CrossRef] OMIM entry 187600 GM01422 Enchondromatosis [C05.116.099.708.338] Epilepsy [drdiag.hu]

  mental retardation, and speech dyspraxia SRY 46,XX disorder of sex development, 46,XY disorder of sex development STAT5B Growth hormone insensitivity with immunodeficiency STIL Microcephaly SYN1 Epilepsy, with variable learning disabilities and behavior [genda.com.ar]

• 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]

• Respiratory Distress

  Two cases of prolonged survival of thanatophoric dysplasia are presented, in which ventilatory support was initiated in the neonatal period because of respiratory distress. [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]

  He had respiratory distress shortly after birth and had persistent severe respiratory distress despite adequate mechanical ventilation. On the third day, he had cardiac arrest; resuscitation was not done due to family request. [degruyter.com]

  Newborns have severe respiratory distress because of their small thorax. Although this distress can be treated by intense respiratory care, the long-term prognosis is poor. Figure 694-1 Stillborn infant with thanatophoric dysplasia. [ldysinger.com]

• Hearing Impairment

  The developmental mechanisms of hearing impairment in this disease were also discussed on the basis of the pertinent literature. [ncbi.nlm.nih.gov]

  METATROPIC DYSPLASIA Is also known as metatropic dwarfism;metatropic dwarfism Related symptoms: Autosomal dominant inheritance Hearing impairment Scoliosis Cleft palate Cataract SOURCES: SCTID ORPHANET MONDO MESH OMIM UMLS GARD More info about METATROPIC [mendelian.co]

  impairment Heterotopia Intrauterine growth retardation Midface retrusion Proptosis Ventriculomegaly Occasionally present symptoms in 5-29% of the cases: Abnormality of the kidney Abnormality of the sacroiliac joint Acanthosis nigricans Atrial septal [dovemed.com]

  impairment Deafness Hearing defect [ more ] 0000365 Intrauterine growth retardation Prenatal growth deficiency Prenatal growth retardation [ more ] 0001511 Midface retrusion Decreased size of midface Midface deficiency Underdevelopment of midface [ more [rarediseases.info.nih.gov]

• Hirsutism

  Anterior hypopituitarism Short columella Aplasia of the pectoralis major muscle Broad neck Stenosis of the external auditory canal Square pelvis bone Intestinal fistula Tetralogy of Fallot Abnormality of the pinna Renal hypoplasia Eczema Astigmatism Hirsutism [mendelian.co]

• Hypertrichosis

  SCTID OMIM NCIT GARD DOID ORPHANET More info about PETERS-PLUS SYNDROME Medium match COFFIN-SIRIS SYNDROME 1; CSS1 Coffin-Siris syndrome is a multiple malformation syndrome characterized by mental retardation associated with coarse facial features, hypertrichosis [mendelian.co]

• Platyspondyly

  Platyspondyly (low vertebral height / vertebral interspace ratio) (4) Narrow chest with protuberant abdomen ("champagne cork" phenomenon). Short ribs. Macrocrania with frontal bossing ± hydrocephalus. HC/AC ratio increases (5). Cloverleaf skull. [fetalultrasound.com]

  DIAGNOSTIC TESTING, PHYSICAL FINDINGS, AND ICD-9-CM CODING Diagnostic testing: • Prenatal ultrasound with findings of growth deficiency, ventriculomegaly, macrocephaly, well-ossified skull and spine, platyspondyly of the vertebrae, micromelia, bowed femurs [secure.ssa.gov]

  At birth, it is characterized by shortening of the limbs (micromelia), small conical thorax, platyspondyly (flat vertebral bodies), and macrocephaly. [atharvapub.net]

  The patient's main clinical and radiographic findings included severe limb shortening, narrow thorax shape; short ribs, marked platyspondyly, curved short femurs, and a cloverleaf skull. [ncbi.nlm.nih.gov]

• Macrocephaly

  The third fetus with TD1 was, however, not associated with macrocephaly, polyhydramnios, chest narrowing and severe femoral bowing on prenatal ultrasound at 18 weeks' gestation. [ncbi.nlm.nih.gov]

  With the evidence of short limbs, a hypoplastic thorax, and macrocephaly, we strongly suspected a skeletal disease as TD. [hindawi.com]

  Clinically this is characterized by shortening of the limbs (micromelia), small conical thorax, flat vertebral bodies and macrocephaly at birth. [oatext.com]

  At birth, it is characterized by shortening of the limbs (micromelia), small conical thorax, platyspondyly (flat vertebral bodies), and macrocephaly. [atharvapub.net]

• Narrow Thorax

  They have markedly short-limbs and narrow thoraxes. Histologically, generalized disruption of endochondral ossification with normal resting cartilage was seen at the epiphyseal region of femur. [ncbi.nlm.nih.gov]

  In the absence of cloverleaf skull, the disease should be suspected when severe rhizomelic dwarfism and a narrow thorax are detected. [web.archive.org]

  The ultrasound also reported anterior narrowing of the skull, short ribs, narrow thorax, increased nuchal translucency, frontal bossing, short fetal limbs and protuberant abdomen. [omjournal.org]

• Brachydactyly

  […] subsequently terminated, and a 480-g malformed fetus was delivered with macrocephaly, depressed nasal bridge, short upturned nasal tip, hypoplastic midface, frontal bossing, short digits, trident-shaped hands, short limbs, cloverleaf skull, narrow chest, brachydactyly [ncbi.nlm.nih.gov]

  C/Symphalangism-like pheno, Brachydactyly type A2 ESCO2 Roberts syndrome, SC phocomelia syndrome GDF5 Acromesomelic dysplasia, Hunter-Thompson, Brachydactyly type A2, Brachydactyly type C, Chondrodysplasia, Fibular hypoplasia and complex brachydactyly [genda.com.ar]

  The stillborn neonate in Figs. 113B and 113C shows dramatic platyspondyly with markedly shortened ribs, severe micromelia with straight long bones, marked brachydactyly and brachymetacarpalia, and “cloverleaf” or kleebattschädel skull, indicative of universal [radiologykey.com]

  Other features common to type I and type II include short ribs, narrow thorax, macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. [genome.jp]

  Brachydactyly with absence of the carpal and tarsal bones were noted on the X-rays (Table/Fig 1). Discussion Thanatophoric Dysplasia is a condition of unknown etiology with the majority of case reports being sporadic. [jcdr.net]

• Bowing of The Long Bones

  Prenatal diagnosis and postmortem examination showed severe rhizomelic shortness of limbs, bowing of the long bones with "telephone-receiver" femora in both twins, and cloverleaf skull and hydrocephalus in one of them. [ncbi.nlm.nih.gov]

  SHOWING 1-10 OF 38 REFERENCES Congenital bowing of the long bones B. HallJ. [semanticscholar.org]

  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]

  At 16 weeks of gestation, amniotic fluid examination showed a normal karyotype (46XX); however, a routine and a four-dimensional ultrasound revealed shortening and bowing of the long bones (femur length (FL) 11.6 mm) (Figures 1(c) and 1(d)) with no subsequent [hindawi.com]

• Frontal Bossing

  The ultrasound also reported anterior narrowing of the skull, short ribs, narrow thorax, increased nuchal translucency, frontal bossing, short fetal limbs and protuberant abdomen. [omjournal.org]

  Macrocrania with frontal bossing ± hydrocephalus. HC/AC ratio increases (5). Cloverleaf skull. Polyhydramnios (71%). Redundant, thickened soft tissues (deep skin folds along the neck, extremities and trunk). [fetalultrasound.com]

  Sonographically-detectable features may include: relatively narrow thoracic cavity 4 short, thick, bowed tubular bones, especially lower extremity 4 thickened soft tissues of extremities 4 comparatively large head with frontal bossing a cloverleaf skull [radiopaedia.org]

  On ultrasound examination, there was frontal bossing, increased nuchal translucency and short limbs at 12 weeks' gestation and a small thorax and short and bowed long bones on 3D at 16 weeks. [ncbi.nlm.nih.gov]

• Large Anterior Fontanels

  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]

  Neonates are macrocephalic with a large anterior fontanelle, frontal bossing, severe midface hypoplasia and proptosis. The thorax is narrow and bell-shaped. [orpha.net]

  anterior fontanel Cloverleaf-shaped skull due to premature closure of the cranial sutures Flat facies with low nasal bridge and proptotic eyes Narrow, bell-shaped thorax with short ribs Normal trunk length Protuberant abdomen Micromelia (marked bilateral [emedicine.medscape.com]

• Small Face

  […] abnormally formed scapulae Small face Small foramen magnum Wide-cupped costochondral junctions Very frequently present symptoms in 80-99% of the cases: Abnormality of the metaphysis Disproportionate short-limb short stature Flat face Increased nuchal [dovemed.com]

  The plain skiagrams of the baby revealed a large sized skull with short base, small face and a H shaped configuration of the vertebral bodies. [jcdr.net]

  […] kidney Polymicrogyria Abnormality of the skeletal system Flat face Short ribs Acanthosis nigricans Confusion Hypoplastic ilia Wide-cupped costochondral junctions Lethal skeletal dysplasia Tics Proptosis Lethal short-limbed short stature Small abnormally [mendelian.co]

• Large Fontanel

  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 [scielo.br]

• Aggressive Behavior

  […] nasal bridge Vomiting Posteriorly rotated ears Abnormal cardiac septum morphology Thick vermilion border Short toe Abnormality of digit Short 5th finger Downslanted palpebral fissures Long philtrum Oxycephaly Gastroesophageal reflux Nephrotic syndrome Aggressive [mendelian.co]

• Seizure

  However, for those rare individuals who do survive, there is the development of seizures, progression of craniocervical stenosis, ventilator dependence, and limitations in motor and cognitive abilities. [doi.org]

  Long-term survivors need neurologic, orthopedic, and audiologic evaluations, CT to monitor for craniocervical constriction, and EEG to monitor for seizure activity. [secure.ssa.gov]

  Rarely, cardiac and renal abnormalities have been reported as well as seizures. [orpha.net]

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.

• Shortened Long Bone

  Cloverleaf skull and relatively straight, shortened long bones distinguish this condition from the more common type 1 thanatophoric dysplasia. [ncbi.nlm.nih.gov]

  The diagnosis was made on ultrasound examination at 21 weeks of gestation, when shortened long bones, cloverleaf skull, and narrow thorax were observed. Due to the lethality of this type of dwarfism, the pregnancy was terminated. [journals.sagepub.com]

  Which Long Bones Are Affected? Proximal long bone shortening (rhizomelia) is present in achondroplasia. With osteogenesis imperfecta type II and achondrogenesis there is a generalized shortening (micromelia) of all of the long bones. [iame.com]

Currently, there are no effective treatments for these skeletal dysplasia diseases. [ncbi.nlm.nih.gov]

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]

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]

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 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: 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 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]

Discussion Thanatophoric Dysplasia is a condition of unknown etiology with the majority of case reports being sporadic. Some authors have reported a dominant gene mutation to be associated with this condition. [jcdr.net]

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]

The discussion covers the phenotype spectrum, epidemiology, mode of inheritance, pathogenesis, and clinical profile of each condition, all of which is accompanied by a wealth of illustrations. [books.google.com]

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 The estimated incidence is around 1:25,000-50,000. Pathology Genetics It results from a mutation coding for the fibroblast growth receptor 3 (FGFR3) located on chromosome 4p16.3. [pacs.de]

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]

Wilkie, A Genetic-Pathophysiological Framework for Craniosynostosis, The American Journal of Human Genetics, 10.1016/j.ajhg.2015.07.006, 97, 3, (359-377), (2015). Ellen M. Haugsten, Andreas Brech, Knut Liestøl, Jim C. [doi.org]

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]

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]

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]

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.