Thanatophoric dysplasia type I: A lethal neonatal skeletal dysplasia confirmed by FGFR3 mutation analysis

INTRODUCTION

Thanatophoric dysplasia (TD) is a rare, severe skeletal disorder and the most common form of lethal skeletal dysplasia, with an estimated incidence of 1 in 20,000–50,000 live births.^[1] It is caused by activating mutations in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene, located on chromosome 4p16.3, which plays a key role in bone growth and development. FGFR3 acts as a negative regulator of endochondral ossification. Pathogenic gain-of-function mutations – particularly those resulting in aberrant cysteine residues – lead to constitutive receptor activation, impaired chondrocyte proliferation and severe skeletal dysplasia.^[2,3] Early prenatal detection and genetic confirmation are essential for prognostication, counselling and planning future pregnancies.^[4,5]

TD is classified into two types:^[6,7]

• Type I: Characterised by curved femurs (‘telephone receiver’ appearance), micromelia, normal skull, narrow thorax and platyspondyly

• Type II: Presents with cloverleaf skull (Kleeblattschädel deformity), straight femurs and similar thoracic narrowing.

Antenatal diagnosis is feasible through ultrasonography, with confirmation through molecular genetic testing.^[4]The variant c.746C>G (p.Ser249Cys) is the most common pathogenic mutation associated with TD type I.^[6]

This case is clinically significant in our regional context, as genetically confirmed cases of TD are rarely reported from South India. To the best of our knowledge, this is among the few cases from the region with definitive FGFR3 variant confirmation, highlighting the value of integrating antenatal imaging with postnatal molecular diagnostics.

CASE REPORT

Physical examination

The newborn exhibited [Figure 1]:

• Macrocephaly with frontal bossing

• Potter-like facies

• Micromelia involving all four limbs

• Bell-shaped thorax

• Protuberant abdomen

• No spontaneous respiratory effort.

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Figure 1:

Clinical photograph of the neonate - clinical phenotype of a neonate with thanatophoric dysplasia type I, exhibiting macrocephaly, depressed nasal bridge, short limbs, redundant skin folds, and a protuberant abdomen, consistent with the characteristic dysmorphic features of the condition.

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Radiological findings

Radiographs revealed [Figure 2a and b]:

• Platyspondyly

• Telephone receiver-shaped femora (severely curved long bones)

• Rhizomelic limb shortening

• Flaring and squaring of the iliac wings

• Hypoplastic scapulae

• Narrow thoracic cage with short ribs.

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Figure 2:

Baby’s radiograph (a) frontal and (b) lateral view -radiographic features of thanatophoric dysplasia type I showing narrow thorax, short and curved long bones (telephone receiver-shaped femurs), flattened vertebral bodies and macrocephaly with frontal bossing.that the patient’s names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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DISCUSSION

TD is a uniformly fatal skeletal dysplasia due to its association with pulmonary hypoplasia and thoracic insufficiency.^[2] The narrow, bell-shaped thoracic cavity impedes lung development, leading to respiratory failure shortly after birth.^[2]

The c.746C>G (p.Ser249Cys) mutation is a recurrent and well-established pathogenic variant found in the majority of TD Type I cases.^[6] This mutation results in constitutive activation of FGFR3 signalling, negatively impacting endochondral ossification. The p.Ser249Cys substitution introduces an abnormal cysteine residue, promoting ligand-independent receptor dimerisation and overactivation, which underlies the severe skeletal phenotype observed in TD type I.^[3]

Differential diagnoses for severe antenatal limb shortening include achondroplasia, hypochondroplasia and TD type II.^[2,8] Achondroplasia typically presents with less severe micromelia, normal thoracic dimensions and characteristic frontal bossing, while TD type II is distinguished by a cloverleaf skull and straight femora. The pronounced femoral curvature, narrow thorax and classic radiographic features in our case strongly supported TD type I. Antenatal detection of severe micromelia, polyhydramnios and a narrow thorax should prompt evaluation for TD. Genetic confirmation is crucial for:

• Establishing a definitive diagnosis

• Providing accurate recurrence risk information (though most cases are de novo)

• Enabling early diagnosis in future pregnancies through targeted testing or preimplantation genetic diagnosis.^[4,5]

While traditionally considered lethal, a few long-term survivors of TD with significant medical support have been reported.^[9] This brings forth discussions regarding the appropriateness of using ‘lethal’ terminology and the role of palliative versus aggressive care. These cases also reinforce the importance of early, compassionate counselling regarding prognosis, options for pregnancy continuation and postnatal palliative approaches. Ethical considerations include balancing aggressive resuscitation efforts with quality-of-life expectations, parental preferences and cultural context.

CONCLUSION

TD type I remains a devastating diagnosis for families and clinicians. This case emphasises the importance of prenatal suspicion, prompt postnatal evaluation and the role of molecular diagnostics in confirming the condition and guiding genetic counselling. Given the high lethality and recurrence implications, multidisciplinary counselling and planning are essential.