Introduction
Cleidocranial dysplasia (CCD), also known as cleidocranial dysostosis, is an autosomal dominant disorder characterized by defective ossification leading to hypoplastic or absent clavicles, delayed closure of cranial sutures, and multiple dental anomalies.We present a family first reported with these findings in 1962. Whose genetic answer was identified in 2024 underscoring the extraordinary progress of scientific knowledge in one’s lifespan. Ultimately culminating in the resolution of a family’s 62-year diagnostic odyssey.

Case Presentation
A 25-year-old male presented with a primary indication of CHD2-related neurodevelopmental disorder manifested by autism and seizures. While gathering history, he was noted to also have hypoplastic clavicles and dental abnormalities in the setting of a maternal family history of CCD without molecular confirmation. Four individuals in three generations were reported to have CCD: our patient, his mother, grandmother, and maternal great aunt. The primary findings include aplastic/hypoplastic clavicle[s] and variable dental abnormalities. Additionally, a maternal uncle and first cousin also had symptoms of CCD without an official clinical diagnosis.

Diagnostic Workup
Molecular testing in our patient identified a missense variant in the RUNX2 gene (c.355C>A; p.Pro119Thr), initially classified as a variant of uncertain significance (VUS). To date, this variant has not been reported in population databases, ClinVar, or the scientific literature. Predictive modeling suggests the variant disrupts protein function. Subsequent testing revealed that the patient’s mother, grandmother, and maternal great-aunt also harbor this genetic change. Despite its clear segregation with cleidocranial dysplasia (CCD) within the family, the variant's classification remains uncertain. 



 

Discussion
The earliest report of CCD is attributed to Meckel in 1760. In 1898, cleidocranial dysostosis was first coined as a syndrome [1]. Sixty-five years later, our patient’s family was published as a case report in 1962 when CCD described as “an abnormal condition inherited as a dominant Mendelian factor,” was merely a suggestion [2]. Over 30 years after their initial case report, the function of the CCD determinate gene RUNX2 was first described. RUNX2 encodes a transcription factor essential for osteoblast differentiation and bone formation leading to impaired skeletal development as seen in CCD [1]. Ongoing efforts aim to perform additional segregation studies to provide evidence for reclassification of this novel RUNX2 variant as pathogenic, highlighting its potential role in CCD.



This case underscores the complexities of variant classification, where clinical correlation, computational predictions, and variant curation intersect. It exemplifies the challenges inherent in interpreting novel genetic variants and emphasizes the need for ongoing investigation, informed by both historical context and advancing technologies. Ultimately, it advocates for the persistence of clinical intuition and the careful balance of evidence in the pursuit of answers for rare disorders.



 

 

Conclusion
The power of modern genomics in resolving decades-long diagnostic mysteries is exemplified through this family's journey. It serves as a reminder to genetic professionals to consider secondary genetic diagnoses, even in the presence of a primary condition. Tracing the genetic narrative of Cleidocranial Dysplasia (CCD) in this multigenerational case illustrates the synergy between clinical observation and molecular genetics, reflecting the remarkable progress in scientific knowledge achieved over one’s lifetime.