Thanatophoric dysplasia

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Thanatophoric dysplasia
Synonyms	Thanatophoric dwarfism
Pronounce	N/A
Specialty	N/A
Symptoms	Severe short stature, macrocephaly, narrow thorax, short ribs, curved femurs
Complications	Respiratory failure, hydrocephalus
Onset	Prenatal
Duration	Lifelong
Types	N/A
Causes	Genetic mutation in the FGFR3 gene
Risks	Advanced paternal age
Diagnosis	Prenatal ultrasound, genetic testing
Differential diagnosis	Achondroplasia, hypochondroplasia, osteogenesis imperfecta
Prevention	N/A
Treatment	Supportive care, ventilation support
Medication	N/A
Prognosis	Poor, often lethal in the neonatal period
Frequency	1 in 20,000 to 50,000 births
Deaths	N/A

Alternate names

Dwarfism thanatophoric; Thanatophoric Dwarfism; TD

Definition

Thanatophoric dysplasia is a severe skeletal disorder characterized by extremely short limbs and folds of extra (redundant) skin on the arms and legs.

Summary

The term thanatophoric is Greek for "death bearing." Infants with thanatophoric dysplasia are usually stillborn or die shortly after birth from respiratory failure; however, a few affected individuals have survived into childhood with extensive medical help.

Types

• Researchers have described two major forms of thanatophoric dysplasia, type I and type II.
• Type I thanatophoric dysplasia is distinguished by the presence of curved thigh bones and flattened bones of the spine (platyspondyly).
• Type II thanatophoric dysplasia is characterized by straight thigh bones and a moderate to severe skull abnormality called a cloverleaf skull

Epidemiology

This condition occurs in 1 in 20,000 to 50,000 newborns. Type I thanatophoric dysplasia is more common than type II.

Cause

• Mutations in the FGFR3 gene cause thanatophoric dysplasia.
• Both types of this condition result from mutations in the FGFR3 gene.
• This gene provides instructions for making a protein that is involved in the development and maintenance of bone and brain tissue.

Gene mutations

• Mutations in this gene cause the FGFR3 protein to be overly active, which leads to the severe disturbances in bone growth that are characteristic of thanatophoric dysplasia.
• It is not known how FGFR3 mutations cause the brain and skin abnormalities associated with this disorder.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

• Thanatophoric dysplasia is considered an autosomal dominant disorder because one mutated copy of the FGFR3 gene in each cell is sufficient to cause the condition.
• Virtually all cases of thanatophoric dysplasia are caused by new mutations in the FGFR3 gene and occur in people with no history of the disorder in their family.
• No affected individuals are known to have had children; therefore, the disorder has not been passed to the next generation.

Signs and symptoms

• This condition is characterized by extremely short limbs and folds of extra skin on the arms and legs.
• Other features of this condition include a narrow chest, short ribs, underdeveloped lungs, and an enlarged head with a large forehead and prominent, wide-spaced eyes.
• Most infants with thanatophoric dysplasia are stillborn or die shortly after birth from respiratory failure.
• A few affected individuals have survived into childhood with extensive medical help.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of the metaphysis(Abnormality of the wide portion of a long bone)
• Depressed nasal bridge(Depressed bridge of nose)
• Disproportionate short-limb short stature(Short limb dwarfism, disproportionate)
• Flat face(Flat facial shape)
• Increased nuchal translucency
• Intellectual disability, profound(IQ less than 20)
• Macrocephaly(Increased size of skull)
• Micromelia(Smaller or shorter than typical limbs)
• Muscular hypotonia(Low or weak muscle tone)
• Narrow chest(Low chest circumference)
• Platyspondyly(Flattened vertebrae)
• Pulmonary hypoplasia(Small lung)
• Redundant skin(Loose redundant skin)
• Short thorax(Shorter than typical length between neck and abdomen)
• Skeletal dysplasia

30%-79% of people have these symptoms

• [[Brachydactyly](Short fingers or toes)
• Frontal bossing
• Gray matter heterotopia
• Hearing impairment(Deafness)
• Intrauterine growth retardation(Prenatal growth deficiency)
• Midface retrusion(Decreased size of midface)
• Proptosis(Bulging eye)
• Ventriculomegaly

5%-29% of people have these symptoms

• Abnormality of the kidney(Abnormal kidney)
• Abnormality of the sacroiliac joint
• Acanthosis nigricans(Darkened and thickened skin)
• Atrial septal defect(An opening in the wall separating the top two chambers of the heart)
• Cloverleaf skull
• Downslanted palpebral fissures(Downward slanting of the opening between the eyelids)
• Hip dysplasia
• Hydrocephalus(Too much cerebrospinal fluid in the brain)
• Joint hyperflexibility(Joints move beyond expected range of motion)
• Joint stiffness(Stiff joint)
• Kyphosis(Hunched back)
• Low-set ears(Low set ears)
• Patent ductus arteriosus
• Polyhydramnios(High levels of amniotic fluid)
• Respiratory insufficiency(Respiratory impairment)
• Seizure

Diagnosis

The diagnosis of this condition with characteristic clinical ,radiologic features ,a heterozygous pathogenic variant in FGFR3 identified on molecular genetic testing.<ref>French T, Savarirayan R. Thanatophoric Dysplasia. 2004 May 21 [Updated 2020 Jun 18]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1366/</ref>[1].

Treatment

• Most infants with thanatophoric dysplasia are stillborn or die shortly after birth from respiratory failure. <ref>French T, Savarirayan R. Thanatophoric Dysplasia. 2004 May 21 [Updated 2020 Jun 18]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews¬Æ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1366/</ref>[2].
• A few affected individuals have survived into childhood with extensive medical help.
• Newborns require long-term respiratory support (typically with tracheostomy and ventilation) to survive.
• Anesthetic management is done for skeletal dysplasias to individuals with TD.
• Shunt placement for hydrocephalus
• suboccipital decompression for relief of craniocervical junction constriction
• Antiepileptic drugs to control seizures and hearing aids.

References

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NIH genetic and rare disease info

• NIH info on Thanatophoric dysplasia

Thanatophoric dysplasia is a rare disease.

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