Jansen metaphyseal chondrodysplasia: analysis of craniofacial manifestations

Jansen metaphyseal chondrodysplasia (JMC) is an ultra-rare disorder caused by constitutive activation of parathyroid hormone type 1 receptor (PTH1R). We sought to characterize the craniofacial phenotype of patients with the disease. Six patients with genetically confirmed JMC underwent comprehensive craniofacial phenotyping revealing a distinct facial appearance that prompted a cephalometric analysis demonstrating a pattern of mandibular retrognathia. Oral examination was notable for flat and shallow palate, delayed eruption pattern, and impacted maxillary teeth. Subclinical and/or mild hearing loss was noted in 4 of 5 patients studied. The most common etiology was conductive, likely due to overcrowding of epitympanum which impedes the normal vibration of ossicles to sound. Paranasal sinus obliteration was noted in 5 of 6 patients. Computed tomography (CT) scan evaluation of craniofacial bones revealed bilaterally symmetric expansile lesions with predominant involvement of neural crest cell (NCC)-derived bones. Bilateral narrowing of facial nerve canals, particularly at the labyrinthine segment, was seen in 5 of 6 patients when compared to age-matched controls; 1 patient presented with progressive facial nerve palsy. Sagittal suture craniosynostosis was present in 5 of 6 patients-one of whom had a history of cranial reconstruction for pansynostosis in infancy. All patients demonstrated a significant degree of upper airway stenosis, as well as a more anterior hyoid bone displacement. Two patients had a diagnosis of obstructive sleep apnea. 18F-NaF Positron-emission tomography (PET)-CT revealed increased uptake associated with the skull base and gnathic bones in all patients. In conclusion, this first detailed systematic evaluation of the craniofacial phenotype of patients with JMC demonstrates a distinct and pronounced phenotype that predominantly affects the NCC-derived cranial bones indicating a critical role of PTH1R signaling in their development. These affects can result in significant disease-related morbidity, include hearing loss, nerve compression, craniosynostosis, dentoskeletal malocclusion, and airway compromise; all of which require close monitoring. Patients with Jansen metaphyseal chondrodysplasia (JMC) have severely shortened long bones. However, the effect on craniofacial bones has not been studied. We evaluated 6 individuals with JMC and noted a distinct facial appearance prompting a detailed analysis which revealed a pattern of premature cranial suture fusion, retrusion of the lower jaw, increased distance between the inner corners of eyelids, and low set ears. Oral examination demonstrated a flattened palate, delayed eruption pattern, impacted maxillary teeth, and structural dental abnormalities. Analysis of skull using CT revealed that the facial bones and cranial base are predominantly affected. Hearing was affected in 4 of 5 patients tested likely due to bony growth in the middle ear interfering with normal sound conduction. Comparison with age-matched controls revealed narrowing of the facial nerve canal in 5 patients-one of whom developed progressive facial nerve paralysis. All patients had significant upper airway narrowing-2 were diagnosed with obstructive sleep apnea. In summary, patients with JMC have a distinct facial appearance associated with hearing loss, facial nerve palsy, premature fusion of skull bones, delayed eruption of teeth, and airway stenosis. Patients and physicians should be aware of these issues for appropriate monitoring and treatment.