Thanatophoric Dysplasia

Clinical characteristics.

Thanatophoric dysplasia (TD) is a short-limb skeletal dysplasia that is usually lethal in the perinatal period. TD is divided into subtypes:

• TD type I is characterized by micromelia with bowed femurs and, uncommonly, the presence of craniosynostosis of varying severity.
• TD type II is characterized by micromelia with straight femurs and uniform presence of moderate-to-severe craniosynostosis with cloverleaf skull deformity.

Other features common to type I and type II include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. Most affected infants die of respiratory insufficiency shortly after birth. Rare long-term survivors have been reported.

Diagnosis/testing.

The diagnosis of TD is established in a proband with characteristic clinical and/or radiologic features and/or a heterozygous pathogenic variant in FGFR3 identified on molecular genetic testing.

Management.

Treatment of manifestations: Most individuals with TD die in the perinatal period because of the multisystem complications of the disorder. Management goals should be established with the family, and may focus on provision of comfort care. Newborns require long-term respiratory support (typically with tracheostomy and ventilation) to survive. Anesthetic management guidelines for skeletal dysplasias are applicable to individuals with TD. Other treatment measures may include shunt placement for hydrocephalus, suboccipital decompression for relief of craniocervical junction constriction, antiepileptic drugs to control seizures, and hearing aids.

Surveillance: Long-term survivors need neuroimaging to monitor for craniocervical constriction, assessment of neurologic status, and EEG to monitor for seizure activity, as well as developmental, orthopedic, and audiology evaluations.

Pregnancy management: When TD is diagnosed prenatally, treatment goals are to avoid potential pregnancy complications including prematurity, polyhydramnios, malpresentation, and delivery complications from macrocephaly and/or a flexed and rigid neck; cephalocentesis and cesarean section may be considered to avoid maternal complications.

Genetic counseling.

TD is inherited in an autosomal dominant manner; the majority of probands have a de novo FGFR3 pathogenic variant. Risk of sib recurrence for parents who have had one affected child is not significantly increased over that of the general population. Germline mosaicism in healthy parents, although not reported to date, remains a theoretic possibility. Prenatal diagnosis is possible by ultrasound examination and molecular genetic testing.

Suggestive Findings

TD should be suspected in a fetus with the following prenatal imaging findings, or a neonate with the following clinical and radiographic features.

Prenatal ultrasound examination [Tonni et al 2010, Khalil et al 2011, Martínez-Frías et al 2011, Bondioni et al 2017] findings by trimester:

• First trimester
  • Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation
  • Increased nuchal translucency
• Second/third trimester
  • Growth deficiency with limb length below fifth centile recognizable by 20 weeks' gestation
  • Well-ossified spine and skull
  • Platyspondyly
  • Ventriculomegaly
  • Narrow chest cavity with short ribs
  • Polyhydramnios
  • Bowed femurs (TD type I)
  • Brain anomalies
  • Cloverleaf skull. Craniosynostosis involving coronal, lambdoid, and sagittal sutures, resulting in a trilobed skull shape (previously referred to as Kleeblattschädel (often in TD type II; occasionally in TD type I)
  • Relative macrocephaly

Postnatal physical examination

• Relative macrocephaly
• Cloverleaf skull (always in TD type II; sometimes in TD type I)
• Large anterior fontanelle
• Frontal bossing, flat facies with a depressed nasal bridge, ocular proptosis
• Marked shortening of the limbs (micromelia)
• Redundant skin folds
• Narrow bell-shaped thorax with short ribs and protuberant abdomen
• Relatively normal trunk length
• Brachydactyly with trident hand
• Bowed femurs (TD type I)
• Generalized hypotonia

Radiographs / other imaging studies [Wilcox et al 1998, Lemyre et al 1999, Bondioni et al 2017]

• Rhizomelic shortening of the long bones
• Irregular metaphyses of the long bones
• Platyspondyly
• Small foramen magnum with brain stem compression
• Bowed femurs (TD type I)
• Cloverleaf skull (always in TD type II; sometimes in TD type I)
• CNS abnormalities including temporal lobe malformations, hydrocephalus, brain stem hypoplasia, neuronal migration abnormalities [Wang et al 2014]

Other rarely reported findings that are not part of the core phenotype include cardiac defects, renal abnormalities, and abnormalities of lymphatic development (see Clinical Characteristics).

Establishing the Diagnosis

The diagnosis of thanatophoric dysplasia is established in a proband with the above clinical and radiographic features and/or a heterozygous pathogenic variant in FGFR3 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (targeted analysis, single-gene testing, and multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of thanatophoric dysplasia is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other lethal skeletal dysplasias are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The clinical and radiographic features of thanatophoric dysplasia (TD) types I and II 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.

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 II 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 I, and recognition that FGFR3 may be implicated in inner ear development [Colvin et al 1996], suggest that hearing loss in individuals with TD type I 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:

• Cardiac defects. Truncus arteriosus, ventricular septal defect, and patent foramen ovale have been reported [McBrien et al 2008]. Bradycardia has been reported in two individuals [Baker et al 1997, Nikkel et al 2013].
• Renal abnormalities [Prontera et al 2006]. In two long-term survivors, renal calculi were reported [Baker et al 1997, Kuno et al 2000].
• Protein losing enteropathy with intestinal lymphangestasia, reported in one individual [Yang & Dehner 2016]. An infant with TD was reported to have chylous ascites [Soo-Kyeong et al 2018].

Mosaicism. A female age 47 years who was mosaic for the common TD type I-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 I) who presented with features labeled as atypical achondroplasia.

Genotype-Phenotype Correlations

TD type I. FGFR3 pathogenic variants reported as causing the TD type I phenotype can be divided into three categories:

• Missense variants [Passos-Bueno et al 1999]. The two common variants p.Arg248Cys and p.Tyr373Cys probably account for 90% of TD type I [Xue et al 2014].
• No-stop codon variants represent fewer than 10% of TD type I-causing variants (see Table 9).
• An insertion variant has been reported in one individual [Lindy et al 2016] (see Table 9).

TD type II. A single FGFR3 pathogenic variant (p.Lys650Glu) has been identified in all individuals with TD type II [Bellus et al 2000]. Other pathogenic variants at this position give rise to different phenotypes: p.Lys650Met has been identified in TD type I, and p.Lys650Gln is seen in SADDAN (see Table 9).

Penetrance

The penetrance is 100%.

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].

Prevalence

The incidence of TD is reported to be 1:20,000 [Barbosa-Buck et al 2012] or higher (1:12,000 in Northern Ireland) in a population with optimized ascertainment [Donnelly et al 2010].