AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Thanatophoric dysplasia (TD) is the most common form of skeletal dysplasia that is lethal in the neonatal period. The term thanatophoric derives from the Greek word thanatophorus, which means "death bringing". Characteristics of TD include severe shortening of the limbs, a narrow thorax, macrocephaly, and a normal trunk length. TD is divided into 2 clinically defined subtypes. TD type 1 (TD1), the most common subtype, is characterized by a normal-shaped skull and curved long bones (shaped like a telephone receiver); the femurs are most affected. TD type 2 (TD2) is associated with a cloverleaf-shaped skull and straight femurs. Some clinical overlap exists between the 2 subtypes. Autosomal dominant mutations in the fibroblast growth factor receptor 3 gene (FGFR3), which has been mapped to chromosome band 4p16.3, results in both subtypes. The vast majority of cases are due to de novo mutations. Gonadal mosaicism has not been definitively documented.

Pathophysiology

The FGFR3 gene is a member of the tyrosine kinase receptor family. Ligand binding induces receptor homodimerization, as well as heterodimerization, that results in activation of tyrosine kinase function and potentiates many effects on cell growth and differentiation. Some authors suggest that mutations in FGFR3 lead to the formation of cysteine residues that create disulfide bonds between the extracellular domains of mutant monomers. Activation of the homodimer receptor complex increases its stability and promotes translocation of the complex into the nucleus, where it may interfere with terminal chondrocyte differentiation.

Frequency

United States

TD has an prevalence of 1 per 10,000-35,000 live births.

International

Frequency in Spain is 2.7 per 100,000.

Mortality/Morbidity

Although the literature documents several reports of survival into childhood, TD is virtually always lethal in the neonatal period. Respiratory insufficiency secondary to reduced thoracic capacity or compression of the brainstem leads to death.

Sex

Males and females are equally affected.

Age

TD is lethal in neonates; however, long-term survival has been reported.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Most cases of thanatophoric dysplasia (TD) are diagnosed using ultrasonography during the second or third trimester of pregnancy.

• Typical ultrasonography findings include curved or straight short femurs, symmetric micromelia, a narrow chest with short ribs, and a protuberant abdomen.
• Polyhydramnios is often observed.

Physical

• Severe growth deficiency with an average length of 40 cm at term 
• A macrocephalic head with a frontal bossing, a flattened nasal bridge, and proptotic eyes
• In TD2, a cloverleaf-shaped skull due to premature closure of the cranial sutures
• Narrow thorax with small ribs
• Micromelic limbs with brachydactyly
• Protuberant abdomen
• Hydrocephalus and other cerebral parenchymal abnormalities

Causes

TD is an autosomal dominant disorder that results from sporadic de novo mutations in the FGFR3 gene. Gonadal mosaicism has been suggested as a possibility but has not been convincingly documented.

The following mutations that affect distinct domains of FGFR3 cause the TD subtypes:

• TD1: Amino acid substitutions in the extracellular domain of FGFR3 have resulted in TD1. The most common mutation in TD1 is arg248cys, which is present in approximately 50% of patients.
• TD2: In patients with TD2, lys650blu is the only reported gene mutation.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Achondroplasia (homozygous form)
Congenital hypophosphatasia
Lethal short-rib polydactyly syndromes

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Chromosomal analysis
• Molecular testing for FGFR3 mutations

Imaging Studies

• Prenatal
• • Two-dimensional (2D) ultrasonography reveals polyhydramnios, shortened limbs, a narrow thorax, flattened vertebrae, and frontal bossing. Brachydactyly may also be revealed.
  • Three-dimensional (3D) ultrasonography may reveal the fetal face, scapular anomalies, and chest hypoplasia better than 2D ultrasonography.
• Postnatal: Full-body radiography reveals the short limb bones, telephone receiver–shaped femurs, flattened vertebral bodies with wide intervertebral spacing, short ribs with flared ends, and an enlarged skull.
• If long-term survival is possible, perform neuroimaging to assess for ventriculomegaly, craniosynostosis, and stenosis of the foramen magnum.

Histologic Findings

Histologic analysis of the growth zones of the femora have shown 2 different patterns of ossification. The central osseous tongue is formed by enchondral ossification, and the peripheral lateral and medial osseous spurs are formed by perichondral ossification. In epiphyseal cartilage tissue, a reduced lobulation of the cell surfaces is observed. The transformation of osteoblasts to osteocytes is marked by a significant reduction of cell diameter and incomplete calcification of osteocytes.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Inpatient care is necessary. Intubation may be performed as aggressive treatment for respiratory distress.
• If aggressive treatment is deferred, palliative treatment consists of keeping the infant warm, comfortable, and nourished.

Consultations

• Geneticist
• Neurologist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Currently, drug therapy is not a component of care. Drugs may be indicated to treat the various coexisting conditions associated with thanatophoric dysplasia.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit patients to the neonatal ICU if extended survival appears possible.

Further Outpatient Care

• Outpatient care is indicated only in cases of long-term survival.

Transfer

• Transfer to a long-term care facility or hospice may be required for infants in whom survival is prolonged.

Complications

• Severe growth and developmental delay
• Hydronephrosis
• Hydrocephalus
• Ventilator dependency

Prognosis

• Thanatophoric dysplasia (TD) is usually lethal in the first few days of life. Death is caused by respiratory insufficiency.

Patient Education

• If a fetus has TD and if the pregnancy has proceeded past the period during which a therapeutic abortion can take place, discuss aggressive and nonaggressive management frankly with the parents.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider other skeletal dysplasias that can alter prognosis and recurrence risk in the differential diagnosis

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Baker KM, Olson DS, Harding CO, Pauli RM. Long-term survival in typical thanatophoric dysplasia type 1. Am J Med Genet. Jun 27 1997;70(4):427-36. [Medline].
• Chen CP, Chern SR, Wang W, Wang TY. Second-trimester molecular diagnosis of a heterozygous 742 --> T (R248C) mutation in the FGFR3 gene in a thanatophoric dysplasia variant following suspicious ultrasound findings. Ultrasound Obstet Gynecol. Mar 2001;17(3):272-3. [Medline].
• Delezoide AL, Lasselin-Benoist C, Legeai-Mallet L, et al. Abnormal FGFR 3 expression in cartilage of thanatophoric dysplasia fetuses. Hum Mol Genet. Oct 1997;6(11):1899-906. [Medline].
• Garjian KV, Pretorius DH, Budorick NE, et al. Fetal skeletal dysplasia: three-dimensional US--initial experience. Radiology. Mar 2000;214(3):717-23. [Medline].
• Ho KL, Chang CH, Yang SS, Chason JL. Neuropathologic findings in thanatophoric dysplasia. Acta Neuropathol (Berl). 1984;63(3):218-28. [Medline].
• Kolble N, Sobetzko D, Ersch J. Diagnosis of skeletal dysplasia by multidisciplinary assessment: a report of two cases of thanatophoric dysplasia. Ultrasound Obstet Gynecol. Jan 2002;19(1):92-8. [Medline].
• Lemyre E, Azouz EM, Teebi AS, et al. Bone dysplasia series. Achondroplasia, hypochondroplasia and thanatophoric dysplasia: review and update. Can Assoc Radiol J. Jun 1999;50(3):185-97. [Medline].
• Li D, Liao C, Ma X. Prenatal diagnosis and molecular analysis of type 1 thanatophoric dysplasia. Int J Gynaecol Obstet. Dec 2005;91(3):268-70. [Medline].
• Machado LE, Bonilla-Musoles F, Osborne NG. Thanatophoric dysplasia. Ultrasound Obstet Gynecol. Jul 2001;18(1):85-6. [Medline].
• Rousseau F, el Ghouzzi V, Delezoide AL, et al. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1). Hum Mol Genet. Apr 1996;5(4):509-12. [Medline].
• Sahinoglu Z, Uludogan M, Gurbuz A. Prenatal diagnosis of thanatophoric dysplasia in the second trimester: ultrasonography and other diagnostic modalities. Arch Gynecol Obstet. Nov 2003;269(1):57-61. [Medline].
• Schild RL, Hunt GH, Moore J, et al. Antenatal sonographic diagnosis of thanatophoric dysplasia: a report of three cases and a review of the literature with special emphasis on the differential diagnosis. Ultrasound Obstet Gynecol. Jul 1996;8(1):62-7. [Medline].
• Simsek M, Al-Gazali L, Al-Mjeni R. Improved diagnosis of a common mutation (R248C) in the human growth factor receptor 3 (FGFR3) gene that causes type I Thanatophoric dysplasia. Clin Biochem. Mar 2003;36(2):151-3. [Medline].
• Tavormina PL, Shiang R, Thompson LM, et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet. Mar 1995;9(3):321-8. [Medline].
• Tretter AE, Saunders RC, Meyers CM, et al. Antenatal diagnosis of lethal skeletal dysplasias. Am J Med Genet. Feb 17 1998;75(5):518-22. [Medline].
• Vidaeff AC, Lucas MJ, Strassberg MB, Spooner KI, Ramin SM. Dichorionic twins discordant for thanatophoric dysplasia managed with selective reduction at 20 weeks' gestation: a case report. J Reprod Med. Aug 2005;50(8):638-42. [Medline].
• Weber M, Johannisson T, Thomsen M, et al. Thanatophoric dysplasia type I: new radiologic, morphologic, and histologic aspects toward the exact definition of the disorder. J Pediatr Orthop B. Jan 1998;7(1):1-9. [Medline].
• Wilcox WR, Tavormina PL, Krakow D, et al. Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasia. Am J Med Genet. Jul 7 1998;78(3):274-81. [Medline].
• Yuce MA, Yardim T, Kurtul M, et al. Prenatal diagnosis of thanatophoric dwarfism in second trimester. A case report. Clin Exp Obstet Gynecol. 1998;25(4):149-50. [Medline].

Article Last Updated: Sep 21, 2007