Updated 2006-01-18 by Juliana Leite, MD

Original text 1999-05-24 Philippe Jeanty, MD, PhD & Sandra R Silva, MD

Definition:  Thanatophoric dysplasia is a lethal congenital form of short-limbed chondrodysplasia, divided into two subtypes:

• Type I is characterized by extreme rhizo­melia, bowed long bones, narrow thorax, a relatively large head, normal trunk length and absent cloverleaf skull. The spine shows platyspondyly, the cranium has a short base, and, frequently, the fora­men magnum is decreased in size. The forehead is prominent, and hypertelorism and a saddle nose may be present. Hands and feet are normal, but fingers are short.

• Type II is characterized by short, straight long bones and cloverleaf skull[2].

Synonyms: Thanatophoric dwarfism.

Incidence: 0.69:10,000; M2:F1.

Etiology: Possibly autosomal dominant but the majority of cases results from new mutations of the fibroblast growth factor receptor 3 (FGFR3)[4].

Recurrence risk: A general empiric risk was estimated in 2%[5].

Diagnosis: The sonographic diagnosis can be made in the presence of short-limbed dwarfism (fig. 1),  hypoplastic thorax (fig. 2), cloverleaf skull, frontal bossing (fig. 3) and simian crease. Femur bowing, narrow thorax, large head size even without ventriculomegaly, and redundant soft tissues are features that become more pronounced with advancing gestation but may not be present in midtrimester. In 70% of cases, thanatophoric dysplasia is associated with polyhydramnios, which may be massive and lead to premature labor. Fetal movements do not seem to be affected by the disease, but a decrease in motion during the third trimester has been reported. Decreased hand flexure is probably responsible for the presence of simian crease. In the absence of cloverleaf skull, the disease should be suspected when severe rhizomelic dwarfism and a narrow thorax are detected1. Sonographic measurement of fetal femur length, especially when correlated with biparietal diameter, is a reliable method in the identification of certain forms of short-limbed skeletal dysplasias, as well as Thanatophoric dysplasia[6].

Figure 1: Very short arm with redundant soft tissue. Note that the hand (on the left side of the image) is about as wide as the forearm.

Figure 2: Small chest compared to the abdomen with a diameter about ½ as large as that of the abdomen. This results from the short ribs and is the cause of pulmonary hypoplasia.

Figure 3: Frontal bossing.

Pathogenesis: Characteristic generalized disruption of growth plate with persistent mesenchymal-like tissue.

Associated anomalies: "Clover-leaf skull†(just in type II), horseshoe kidney, hydronephosis, atrial septal defect, defective tricuspid valve, imperforate anus, and radioulnar synostosis.

Differential diagnosis: Chondroectodermal dysplasia (Ellis-van Creveld syndrome), asphyxiating thoracic dysplasia, short rib-polydactyly syndrome and homozygous achondroplasia3. All short-limbed dwarfism should be considered. If type II is suspected, conditions that have association with craniosynostosis and cloverleaf skull should be excluded (Apert, Crouzon, Pfeiffer, Carpenter and Kleeblattschadel syndromes).

Prognosis: This is a uniformly lethal condition and in general affected die shortly after birtp 7. The cause of death is respiratory failure due to hypoplastic lungs.

Management: The option of pregnancy termination should be offered before viability. Sonographic evaluation of hydrocephalus is recommended, considering that it may cause mal-presentation and difficult delivery. If massive hydrocephalus is developed, cephalocentesis and/or elective cesarean section should be considered to avoid maternal trauma1.

References:

[1] Norris CD, Tiller G, Jeanty P, Malini S. Thanatophoric dysplasia in monozygotic twins. The Fetus, 1994, 4(6): 27-32.

[2] Fleischer AC, Romero R, Manning FA, et al. The principles and practice of ultrasonography in obstetrics and gynecology, 5th edition. Connecticut, Appleton and Lange 1995;295-297.

[3] Romero R, Pilu GL, Jeanty P. Prenatal diagnosis of congenital anomalies. Norwalk, Connecticut, 1988;335-339.

[4] Tavormina PL, Shiang R, Thompson LM, et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nature Genet 1995, 9:321-328.

[5] Chemke J, Graff G, Lancet M. Familial thanatophoric dwarfism. Lancet 1971;1:1358.

[6] Burrows PE, Stannard MW, Pearrow J, et al. Early antenatal sonographic recognition of thanatophoric dysplasia with cloverleaf skull deformity. AJR 1984;143:841-843.

[7] Buyse ML. Birth defects encyclopedia. Cambridge, Blackwell Scientific Medical Publications 1990;1661-1662.