Clinical Description
The clinical and radiographic features of thanatophoric dysplasia (TD) types 1 and 2 are evident prenatally or in the immediate newborn period. Respiratory insufficiency typically results in early neonatal death, and is due to a small chest cavity and/or foramen magnum narrowing with brain stem compression. However, long-term survivors have been reported, including rare reports of survival to adulthood with aggressive ventilatory support and surgical management of neurologic complications.
To date, more than 200 individuals with TD have been identified with a pathogenic variant in FGFR3 [Xue et al 2014]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Select Features of Thanatophoric Dysplasia
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Feature | % of Persons w/Feature | Comment |
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Respiratory insufficiency
| 100% | Long-term survivors have all required mechanical ventilation. |
Foramen magnum narrowing
| ~100% 1 | |
Temporal lobe dysplasia
| ~100% 1, 2 | |
Hydrocephalus
| 56% 2 | |
Cloverleaf skull (multiple craniosynostosis)
| 100% in persons w/TD type 2; rarely in persons w/TD type 1 | |
Dysmorphic facial features
| 100% | Frontal bossing, flat facies, depressed nasal bridge, ocular proptosis |
Relative macrocephaly
| 100% | |
Growth deficiency
| 100% |
Birth length well < 3rd centile Birth weight & head circumference may be normal, but growth restriction of these parameters occurs in infancy & childhood.
|
Bowed femurs
| 100% in persons w/TD type 1; absent in persons w/TD type 2 | |
Survival past age 1 yr
| 5 persons 3 | Reports exist of long-term survivors into adulthood, all of whom have required long-term mechanical ventilation. |
Respiratory insufficiency. Most affected infants die of respiratory insufficiency in the first hours or days of life. Respiratory insufficiency may be secondary to a small chest with lung hypoplasia and/or compression of the brain stem due to a small foramen magnum. Some affected children have survived into childhood, universally requiring tracheostomy and aggressive ventilatory support. Nikkel et al [2013] described a long-term survivor with TD at age 28 years. Her course was exceptional, as she did not require invasive ventilatory support until age four months and required full-time ventilatory support from age 15 years.
Neurologic complications include small foramen magnum with brain stem compression, brain malformations (predominantly involving the temporal lobe), hydrocephalus, seizures, and profound developmental impairment in rare long-term survivors.
One infant reported at age 11 months required suboccipital decompression due to clonus and decreased limb movements secondary to a narrow foramen magnum [Thompson et al 2011]. One individual reported at age 28 years underwent surgical decompression of a small foramen magnum and insertion of a ventriculoperitoneal shunt [Nikkel et al 2013]. Despite this intervention, the individual developed cervical spinal cord compression and quadriplegia.
Temporal lobe malformations and megalencephaly are likely universal [Hevner 2005, Itoh et al 2013]. Temporal lobe abnormalities include enlargement, abnormal gyration and sulcation, polymicrogyria, and hippocampal abnormalities. Hydrocephalus is also common [Hevner 2005].
Brain malformations are the most likely etiology of seizures in individuals with TD; however, additional complications such as hypoxia related to respiratory insufficiency may also play a role.
Severe developmental delay is reported, with a stall in developmental progress at a developmental age of 12-20 months (see Table 3). Motor skills may be more significantly impaired due to the skeletal features and micromelia. Later deterioration in abilities following complications such as cord compression is described [Nikkel et al 2013].
Less common neurologic findings include hypoplasia or agenesis of the corpus callosum. Encephalocele has been reported, likely as a secondary consequence of raised intracranial pressure and abnormal skull formation [Martínez-Frías et al 2011].
Craniofacial. Relative macrocephaly is present at birth. Craniosynostosis with cloverleaf skull in individuals with TD type 2 contributes to hydrocephalus and neurologic complications. Dysmorphic facial features including frontal bossing, flat facies, depressed nasal bridge, and ocular proptosis are present.
Musculoskeletal complications in long-term survivors include kyphosis, osteopenia, and both joint hypermobility and joint contractures.
Growth deficiency. Prenatal short-limb short stature is present in all individuals. Growth deficiency persists with micromelia and redundant skin folds. Global growth deficiency is present in long-term survivors (see Table 3).
Integument. Extensive acanthosis nigricans has been reported with development of seborrheic keratoses in adult survivors [Nakai et al 2010, Nikkel et al 2013].
Hearing impairment is reported in several long-term survivors (see Table 3), but the etiology is not clear. The presence of midface hypoplasia in individuals with TD type 1, and recognition that FGFR3 may be implicated in inner ear development [Colvin et al 1996], suggest that hearing loss in individuals with TD type 1 may be multifactorial.
Vision. Intermittent exotropia has been reported in a long-term survivor [Nikkel et al 2013].
Other rarely
reported findings that do not have a proven association with TD include:
Table 3.
Thanatophoric Dysplasia: Clinical Features of Long-Term Survivors
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| Long-Term Survivor: Sex, Age at Report |
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Male, age 4.75 yrs 1 | Female, age 28 yrs 2 | Male, age 9 yrs 3 | Female, age 23 yrs 4 | Male, age 8 yrs 5 |
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Method of diagnosis
| Clinical / radiographic | Molecular (p.Arg248Cys) | Molecular (p.Arg248Cys) | Molecular (p.Arg248Cys) | Molecular (p.Gly370Cys) |
Ventilated from age
| Neonate | 2 mos | 9 yrs | ND | 2 days |
Estimated developmental age
| 2 mos | 8-18 mos as a teenager 6 | 18 mos | ND | 10-12 mos |
Neurologic
|
|
|
| ND | ND |
Skin
| ND | Acanthosis nigricans & seborrheic keratoses | Acanthosis nigricans | Acanthosis nigricans & seborrheic keratoses | Acanthosis nigricans |
Hearing
| Hearing impairment |
|
Mixed hearing impairment Bilateral hearing aids
| ND | ND |
Growth parameters at birth
| ND |
Weight: 2.1 kg Length: 37 cm OFC: 35 cm
|
Weight: 3.26 kg Length: 41 cm OFC: 39.5 cm
| ND |
Weight: 2.6 kg Length: 37 cm OFC: 37 cm
|
Growth parameters at specified age
| At age 4.75 yrs:
Weight: 8.82 kg Length: 65 cm OFC: 47.5 cm
| At age 3.75 yrs: 7
Weight: 6.5 kg Length: 55 cm OFC: 49 cm
| See footnote 8. | ND | At age 9 yrs:
Weight: 4.7 kg Length: 49 cm OFC: 46.1 cm
|
Other
| | Intermittent exotropia |
| | Renal calculi |
ND = not documented; OFC = occipitofrontal head circumference
- 1.
- 2.
- 3.
Unpublished data are referenced describing a boy age 9 years with TD [Baker et al 1997]. No information regarding diagnostic features is reported, but the individual is reported to have been ventilated from birth, with severe developmental delay, hydrocephalus, hearing impairment, and acanthosis nigricans.
- 4.
- 5.
- 6.
Further deterioration by third decade of life and no longer able to use limbs or lift head
- 7.
Growth parameter estimates based on growth charts
- 8.
Slow linear growth, -6 to -6.5 SD below the mean on the achondroplasia growth charts; OFC at +1 SD in infancy and at -1.7 SD at age 8.7 years
Mosaicism. A female age 47 years who was mosaic for the common TD type 1-causing pathogenic variant p.Arg248Cys had asymmetric limb length, bilateral congenital hip dislocation, focal areas of bone bowing, an S-shaped humerus, extensive acanthosis nigricans, redundant skin folds along the length of the limbs, and flexion deformities of the knees and elbows [Hyland et al 2003]. She had delayed developmental milestones as a child. Academic achievements were below those of healthy sibs, but she is able to read and write and is employed as a factory worker. Her only pregnancy ended with the stillbirth at 30 weeks' gestation of a male with a short-limb skeletal dysplasia and pulmonary hypoplasia.
Takagi et al [2012] described an individual with somatic mosaicism for the p.Arg248Cys substitution in FGFR3 (a pathogenic variant which typically results in TD type 1) who presented with features labeled as atypical achondroplasia.
Nomenclature
Thanatophoric dysplasia was originally described as thanatophoric dwarfism, a term no longer in use. The descriptor "thanatophoric" is derived from the Greek for "death bearing," and refers to the very high incidence of perinatal death due to the multisystem complications of this condition. However, aggressive management has resulted in rare reports of long-term survivors, contradicting this initial description.
The lethal platyspondylic dysplasia (San Diego type) was previously considered a separate clinical entity, but is now recognized as the same condition as TD [Brodie et al 1999, Hall 2002].
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], TD type 1 is referred to as FGFR3-related thanatophoric dysplasia (type 1), and TD type 2 is referred to as FGFR3-related thanatophoric dysplasia (type 2); both are included in the FGFR3 chondrodysplasias group.