CCD is a rare skeletal disorder characterized by hypoplastic clavicles, delayed closure of fontanelles, delayed eruption of primary and permanent dentition, and short stature. It is diagnosed clinically. The prevalence is 1 in 1,000,000. The gene responsible for pathogenesis is RUNX2 located on the short arm of chromosome 6p21. Genetic analysis reveals a heterozygous mutation of RUNX2 in almost 70% of patients . RUNX2 is a transcription factor belonging to the Runx family (Runx1, Runx2, Runx3), and is expressed in osteoblasts and chondrocytes. RUNX2 is essential for the differentiation of multipotent mesenchymal cells to osteoblasts. It cooperates with Sp7 and canonical Wnt pathway . Bone is formed through two types of ossification: intramembranous or endochondral. For endochondral ossification, RUNX1 and RUNX3 can compensate for the RUNX2 function to some extent, even if the expression of RUNX2 is halved due to mutation. However, for intramembranous ossification, RUNX2 is crucial. Thus, open fontanelles and sutures, together with hypoplastic clavicles, are characteristic findings in CCD since the formation of these bones is related to intramembranous ossification . A report in Argentina stated that out of 37 cases studied, 95% had skull abnormalities, 75% had single clavicle alterations, and 100% had bilateral clavicle alterations . The present case also has open fontanelles and hypoplastic clavicles. Interestingly, her mother and brother have open fontanelles, but not hypoplastic clavicles, even though they have the same mutation. This clearly shows that mutations in RUNX2 could lead to various phenotypic features even in the same family, as previously reported .
The present case has a short stature (− 3.2 SD), one of the characteristic features of CCD. The final height of patients with CCD is reported to be − 1.47 SD for men and − 1.89 SD for women . In terms of height, the genotype-phenotype correlation exists in patients with CCD. Patients with mutations in Runt domain have significantly short statures, but patients with intact Runt domain have milder manifestations . The RUNX2 mutation in the present case is a novel nonsense mutation with intact Runt domain. Her short stature could be attributable to a nonsense mutation. However, her mother with the same mutation has a normal height. This is compatible with a previous paper reporting probable intrafamilial variabilities in height . Her significant short stature could be partially due to GHD. Despite being otherwise healthy, the results of GH provocation tests showed a GHD. The complication of GHD delayed the diagnosis of CCD in the present study. In fact, the early diagnosis of CCD is somewhat difficult because of mild symptoms . A detailed patient history and physical examination are necessary for the early diagnosis of CCD. There are few papers reporting data on rhGH treatment for patients with CCD. The approved therapeutic dose of rhGH to GHD in Japan, 0.175 mg/kg/week, improved the growth velocity in this case . Some papers report the benefit of rhGH treatment in patients with CCD , while others refute it . However, the dose used is inconsistent. Thus, it remains unclear whether rhGH treatment can improve the final height . The effect of rhGH might be varying depending on the genotype, as CCD has a wide variability in phenotype. GH produces IGF1, the mediator of protein anabolic and linear growth promoting effect, through Janus activating kinase 2 (JAK2)/ Signal transducer and activator of transcription 5 (STAT5) signaling. STAT5 interacts with RUNX2 for the differentiation of osteoblast . Thus, if transcriptional activity of RUNX2 decreases due to gene mutation, GH signaling does not work properly and leads to growth hormone deficiency. Additionally, the effect of rhGH might vary depending on the activity of RUNX2 based on the genotype. Randomized controlled studies are needed to evaluate the effects of rhGH therapy inpatients with CCD.
In the present study, we have reported a case of CCD with a novel mutation in RUNX2 and GHD. The family history should be evaluated in detail, and characteristic features of CCD, such as clavicle hypoplasia and open fontanelles, should be checked for when a patient with short stature is encountered. There is a risk of misdiagnosis because of mild symptoms due to variation in phenotypes. Although rhGH treatment was effective in our case, further studies, such as randomized controlled trials, are warranted to reveal the effectiveness and safety of rhGH treatment in CCD patients.