Obiezu Fiona, Almpani Konstantinia, Kim Hung Jeffrey, Zalewski Christopher, Chu Emily, Jahanmir Golnar, Roszko Kelly L, Boyce Alison, Farhadi Faraz, Weinstein Lee S, Gafni Rachel I, Ferreira Carlos R, Jüppner Harald, Collins Michael T, Lee Janice S, Jha Smita
Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, United States.
Craniofacial Anomalies and Bone Regeneration Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, United States.
JBMR Plus. 2024 Nov 26;9(2):ziae156. doi: 10.1093/jbmrpl/ziae156. eCollection 2025 Feb.
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.
詹森干骺端软骨发育不良（JMC）是一种由1型甲状旁腺激素受体（PTH1R）的组成性激活引起的极为罕见的疾病。我们试图对该病患者的颅面表型进行特征描述。6例经基因确诊的JMC患者接受了全面的颅面表型分析，结果显示出独特的面部外观，这促使进行头影测量分析，结果显示出下颌后缩的模式。口腔检查发现腭部扁平且浅、萌出模式延迟以及上颌牙阻生。在研究的5例患者中，有4例存在亚临床和/或轻度听力损失。最常见的病因是传导性的，可能是由于鼓室上隐窝过度拥挤，阻碍了听小骨对声音的正常振动。6例患者中有5例出现鼻窦闭塞。对颅面骨进行计算机断层扫描（CT）评估发现双侧对称的膨胀性病变，主要累及神经嵴细胞（NCC）衍生的骨骼。与年龄匹配的对照组相比（6例患者中有5例），双侧面神经管狭窄，尤其是在迷路段；1例患者出现进行性面神经麻痹。6例患者中有5例存在矢状缝早闭——其中1例在婴儿期有全颅缝早闭的颅骨重建病史。所有患者均表现出明显程度的上气道狭窄以及舌骨更向前移位。2例患者被诊断为阻塞性睡眠呼吸暂停。18F - 氟化钠正电子发射断层扫描（PET）-CT显示所有患者的颅底和颌骨摄取增加。总之，对JMC患者颅面表型的首次详细系统评估显示出一种独特且明显的表型，主要影响NCC衍生的颅骨，表明PTH1R信号在其发育中起关键作用。这些影响可导致与疾病相关的显著发病率，包括听力损失、神经受压、颅缝早闭、牙颌面错合畸形和气道受损；所有这些都需要密切监测。
