P0881 - Chronic Respiratory Failure, Restrictive Lung Disease, and Skeletal Abnormalities in a Preterm Infant: A Case of Thanatophoric Dysplasia

Case presentation:
Our patient, now 7 months of age, was born at 34 weeks gestational age by Cesarean section. Maternal pregnancy was uneventful apart from suspected fetal skeletal abnormalities on prenatal ultrasound and preterm labor. Her birth history was significant for respiratory distress in the delivery room requiring initiation of continuous positive airway pressure. Examination showed tachypnea, chest retractions, macrocephaly with frontal bossing, hypertelorism, bell-shaped chest, micromelia, and loose skin folds. Due to persistent hypoxemia and respiratory distress despite surfactant, she required intubation and mechanical ventilation. Chest radiograph showed coarse pulmonary interstitial markings, mild cardiomegaly, narrow thorax with short ribs, and short upper extremities (Figure 1). Capillary blood gas showed acute respiratory acidosis with pH of 7.26 and PCO2 of 68 mmHg. Echocardiogram showed patent ductus arteriosus (PDA) and pulmonary hypertension. Cranial ultrasound was suspicious for temporal lobe dysplasia. Subsequently, MRI brain was performed and showed critical stenosis at the foramen magnum extending to the C2 level without any cerebrospinal fluid flow across the foramen magnum (Figure 2). Genetic tests showed a pathogenic mutation in the fibroblast growth factor receptor 3 (FGFR3) gene diagnostic of thanatophoric dysplasia (TD). At 6 weeks of age, she continued to require relatively high ventilator settings with persistent hypercapnia attributed to restrictive lung disease and pulmonary hypoplasia. Following multidisciplinary conferences, she underwent tracheostomy, gastrostomy tube placement, and C1 laminectomy for spinal cord decompression. At 3 months of age, echocardiogram showed resolved PDA and pulmonary hypertension. She was discharged home at 5 months of age on mechanical ventilation via tracheostomy.


Discussion:
TD is a rare and lethal skeletal dysplasia with an incidence of 1 in 20,000 - 50,000 births. Clinical features include characteristic dysmorphisms as seen in our patient. TD is caused by a mutation in the FGFR3 gene. Although most cases are due to de novo mutations, an autosomal dominant inheritance pattern has been described. TD can be diagnosed during prenatal ultrasound and confirmed with genetic studies. Mortality occurs either in-utero or shortly after birth due to respiratory failure. Respiratory failure is likely multifactorial and related to pulmonary hypoplasia, narrow thorax resulting in restrictive lung disease, hypotonia, and brain stem compression. Postnatal management is based on parental decision directed towards either comfort care or invasive ventilation and surgical interventions. There are rare reports of survival beyond the neonatal period with mechanical ventilation.
The early diagnosis of TD, possibly prenatally, has important implications for patient management. Our case highlights the importance of multidisciplinary care and the prompt initiation of invasive ventilation in neonates with TD to improve survival and transition to home-based care.