eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Thanatophoric Dysplasia

Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Updated: Nov 6, 2009

Introduction

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" or "death bearing." Some salient phenotypic features of thanatophoric dysplasia include macrocephaly, narrow bell-shaped thorax, normal trunk length, and severe shortening of the limbs.

Infant with thanatophoric dysplasia. Note short-limbed dysplasia, large head, short neck, narrow thorax, short and small fingers, and bowed extremities. Radiographs demonstrate thin flattened vertebrae, short ribs, small sacrosciatic notch, extremely short long tubular bones, and markedly short and curved femora (telephone receiver–like appearance).

Pathophysiology

FGFR3 is part of the tyrosine kinase receptor family. Normally, FGFR3 is a negative regulator of bone growth. The mutations in thanatophoric dysplasia that code for FGFR3 cause a gain in function, sending negative signals to the cartilage cells (chondrocytes). This occurs when ligand binding within the chondrocytes induces receptor homodimerization and heterodimerization. This, in turn, activates tyrosine kinase function, which potentiates many effects on cell growth and differentiation.

Researchers suggest that mutations in FGFR3 lead to the formation of cysteine residues that create disulfide bonds between 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. Hence, generalized disorganization of endochondral ossification at the bone growth plate occurs.

TDI is caused by several different mutations that affect either the extracellular or intracellular domains of FGFR3. The two missense mutations, R248C and Y373C, account for as much as 80% of TDI cases. The more common of these two TDI mutations, R248C (known as p.Arg248Cys), is a C-to-T nucleotide transition and impacts the extracellular domain of FGFR3.

To date, all patients with TDII have a single point mutation, p.Lys650Glu, with an A → G nucleotide transition in the tyrosine kinase domain of FGFR3, also known as K650E.

Frequency

United States

Thanatophoric dysplasia has an incidence of 1 per 20,000-50,000 births.

International

Incidence in Spain is reported as 1 per 37,000 births.

Mortality/Morbidity

Newborns with thanatophoric dysplasia are stillborn or die shortly after birth. Death in the neonatal period is due to severe respiratory insufficiency from reduced thoracic capacity and hypoplastic lungs or respiratory failure due to brainstem compression. Very rare reports of survival into early childhood have been cited.

Sex

Males and females are equally affected.

Age

Thanatophoric dysplasia is lethal in neonates; however, survival beyond the neonatal period has been rarely reported.

Clinical

History

Most cases of a severe fetal skeletal dysplasia can be diagnosed by prenatal ultrasonography during the second or third trimester of pregnancy. However, making the diagnosis of thanatophoric dysplasia (TD) using only this imaging tool can be difficult. Key ultrasonography findings are the following:

• Growth deficiency with limb length of less than 5% (by 20 weeks' gestation)
• Ventriculomegaly
• Macrocephaly
• Cloverleaf-shaped skull or kleeblattschãdel (indicates thanatophoric dysplasia type II [TDII], also seen in thanatophoric dysplasia type I [TDI])¹
• Well-ossified skull and spine
• Platyspondyly of the vertebrae
• Micromelia
• Bowed femurs (usually indicates TDI)
• Narrow chest cavity with shortened ribs
• Polyhydramnios

Physical

Salient phenotypic features in an affected newborn are cited below:

• Severe growth deficiency with an average length of 40 cm (about 16 in) at term
• Generalized hypotonia
• Macrocephalic head with frontal bossing and large anterior fontanel
• Flat facies with low nasal bridge and proptotic eyes
• Cloverleaf-shaped skull due to premature closure of the cranial sutures
• Narrow, bell-shaped thorax with short ribs
• Normal trunk length
• Protuberant abdomen
• Marked bilateral shortening of the limbs (micromelia) with redundant skin folds
• Brachydactyly with a trident hand configuration

Causes

• Thanatophoric dysplasia is an autosomal dominant disorder that results from sporadic de novo mutations in the FGFR3 gene. Sequence and targeted mutation analysis of FGFR3 is available to assist with diagnosis when clinical concerns are present. Germline mosaicism has been suggested as a possibility but has not been clearly documented.
• The following mutations that affect distinct domains of FGFR3 cause the thanatophoric dysplasia subtypes:
  • TDI: Amino acid substitutions in the extracellular domain of FGFR3 have resulted in TDI. The most common mutation in TDI is p.Arg248Cys (R248C), which is present in approximately 50% of patients.
  • TDII: p.Lys650Glu (K650E) is the only reported gene mutation and is present in more than 99% of patients with TDII.
• TDI occurs more often than TDII. TDI and TDII do not share common FGFR3 mutations within the gene.

Differential Diagnoses

Achondrogenesis
Achondroplasia
Asphyxiating Thoracic Dystrophy (Jeune Syndrome)
Hypophosphatasia
Osteogenesis Imperfecta

Other Problems to Be Considered

Achondroplasia (homozygous form)
Camptomelic dysplasia (CD)
Congenital hypophosphatasia
Dyssegmental dysplasia, Silverman-Handmaker type (DDSH)
Osteogenesis Imperfecta (OI), type II 
Platyspondylic lethal skeletal dysplasia (PLSD)
Rhizomelic chondrodysplasia punctata (RCDP)
Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)
Short rib-polydactyly syndromes

Workup

Laboratory Studies

The following studies are indicated in suspected cases of thanatophoric dysplasia (TD):

• Chromosome analysis
• Molecular testing for FGFR3 with targeted and sequence mutation analyses available

Imaging Studies

• Prenatal ultrasonography²
  • Two-dimensional (2D) ultrasonography reveals polyhydramnios, growth deficiency, ventriculomegaly, micromelia, a narrow thorax, and flattened vertebrae.
  • Three-dimensional (3D) ultrasonography may reveal the fetal face, scapular anomalies, and chest hypoplasia better than 2D ultrasonography.
• Postnatal radiographs and other imaging studies (CT, MRI) reveal the following:
  • Rhizomelic shortening and irregular metaphyses of the long bones and "telephone receiver–shaped" bowed femurs
  • Flattened vertebral bodies (platyspondyly) with wide intervertebral spacing
  • Enlarged skull and a small foramen magnum with potential evidence of brain stem compression
  • CNS abnormalities such as hydrocephalus, brainstem hypoplasia, temporal lobe malformations, neuronal migration abnormalities

Histologic Findings

• Histologic evaluation of long bone structure in thanatophoric dysplasia shows disruption of endochondral ossification but not of periosteal ossification.

Treatment

Medical Care

Inpatient care is necessary for thanatophoric dysplasia (TD).

• If intubation is performed as aggressive treatment for respiratory distress, admission to a neonatal intensive unit is required.
• If aggressive treatment is deferred, palliative treatment consists of keeping the infant warm, comfortable, and nourished.

Consultations

• Geneticist and genetic counselor
• Neurologist

Medication

• Currently, drug therapy is not a component of care.
• Medications may be indicated to treat concurrent medical conditions associated with thanatophoric dysplasia (TD).

Follow-up

Further Inpatient Care

• Admit patients with thanatophoric dysplasia (TD) to the neonatal ICU if survival beyond the immediate newborn period seems 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
• Hydrocephalus
• Seizures
• Ventilator dependency
• Auditory impairment
• Joint contractures/Joint hypermobility 

Prognosis

• Thanatophoric dysplasia is usually lethal within the first few days of life.
• Death is due to respiratory failure.
• Rare survival into early childhood has been reported in a 3.7-year-old female and a 4.7-year-old male.

Patient Education

• If a fetus has thanatophoric dysplasia and if the pregnancy has proceeded past the period during which a therapeutic abortion can take place, discuss aggressive and nonaggressive management options frankly with the parents.
• Resources for patients and caregivers include the following:
  • International Skeletal Dysplasia Registry
    Web site: http://www.csmc.edu/3805.html
    Phone: 1-800-233-2771
  • Little People of America Inc
    Web site: http://www.lpaonline.org
    Phone: 1-888-LPA-2001, 1-714-368-3689
  • The Magic Foundation
    Web site: http://www.magicfoundation.org
    Phone: 1-708-383-0808, 1-800-3-MAGIC-3
  • R esource list from the University of Kansas Medical Center 

Miscellaneous

Medicolegal Pitfalls

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

Multimedia

Media file 1: Infant with thanatophoric dysplasia. Note short-limbed dysplasia, large head, short neck, narrow thorax, short and small fingers, and bowed extremities. Radiographs demonstrate thin flattened vertebrae, short ribs, small sacrosciatic notch, extremely short long tubular bones, and markedly short and curved femora (telephone receiver–like appearance).

References

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4. 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].

5. 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].

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Keywords

thanatophoric dysplasia, TD, skeletal dysplasia, thanatophoric dwarfism, fatal skeletal dysplasia, short limb dwarfism, TD type I, TD type 1, TDI, TD1, TD type II, TD type 2, TDII, TD2

Contributor Information and Disclosures

Author

Germaine L Defendi, MD, MS, FAAP, Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center
Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: Ambulatory Pediatric Association and American Academy of Pediatrics
Disclosure: Nothing to disclose.

Medical Editor

Ian Krantz, MD, Department of Pediatrics, Assistant Professor, University of Pennsylvania and Children's Hospital of Philadelphia
Ian Krantz, MD is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous authors M Carter, MS, and Susan J Gross, MD, FRCS(C), FACOG, FACMG, to the original writing and development of this article.

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