Mapping JATD to CEP120: Clinical and Radiological Insights

Introduction

Jeune asphyxiating thoracic dystrophy is a rare skeletal dysplasia typically presenting with a narrow thorax, short limbs, and variable polydactyly. Affected individuals often display complications such as pulmonary insufficiency and multiorgan involvement. Recent mapping efforts have implicated CEP120 as a novel genetic determinant in JATD, suggesting that defects in centrosome and cilia functions may underlie the abnormal skeletal formation observed in these patients [1]. The integration of advanced radiological techniques and genomic analytics has paved the way for a more precise molecular diagnosis. Understanding the clinical ramifications, evolutionary conservation of the underlying mechanisms, and variable phenotypic spectrum of CEP120‐related dysplasia is essential to improve long‐term outcomes. This review synthesizes multiple streams of evidence from clinical case reports to molecular genetic studies, offering an in‐depth perspective on how CEP120 mutations manifest as a distinct subset of JATD with characteristic clinical and radiological features.

Clinical Features of JATD and CEP120‐Related Dysplasia

Patients with JATD present with characteristic features such as a markedly narrow thorax, short ribs that are both horizontal and markedly reduced in length, and often a combination of polydactyly and limb shortening. In the context of CEP120 mutations, additional dysmorphic features have been described. For instance, affected individuals may exhibit relative macrocephaly, hypertelorism, scant eyebrows, and midface hypoplasia. Other craniofacial anomalies can include cleft lip (or mild notching), along with tongue abnormalities such as lobulation or bifid formations. Limb involvement is typically severe, with shortened long bones, dysplastic pelvic bones, and digital anomalies including synpolydactyly and pre-axial polydactyly [1]. The presence of these anomalies indicates a disruption not only in skeletal patterning but possibly in the developmental processes regulated by centrosomal integrity and ciliogenesis. Additionally, CEP120‐related dysplasia can be associated with extra‐skeletal manifestations. Some patients demonstrate evidence of brain malformations, such as cerebellar hypoplasia and Dandy–Walker malformation, which may be reflective of the unified role of CEP120 in neural as well as skeletal development [1].

The clinical presentation varies widely even among affected family members. Some individuals present in the perinatal period with life-threatening respiratory insufficiency as a result of a severely narrow thorax, whereas others may survive into infancy or early childhood but develop progressive respiratory, cardiac, or neurological complications. The variability in clinical severity hints at possible modifier genes or further molecular heterogeneity even within the CEP120 mutation spectrum. Despite the variation, a unifying clinical picture is observed when closely analyzing dysmorphic features: an extremely narrow chest combined with limb shortening and digital anomalies remains the diagnostic hallmark. In several families, detailed clinical evaluation has revealed additional soft-tissue abnormalities, most notably tongue hamartomas or partially bifid tongues, which are not typical for classic JATD but rather point toward specific CEP120 involvement in craniofacial development [1].

Radiological Findings and Skeletal Manifestations

Radiological evaluation of patients with suspected CEP120-related JATD provides critical insights into the severity and distribution of skeletal dysplasia. Plain radiographs typically reveal a narrow, bell-shaped thorax with extremely short, horizontal ribs. The spine may appear relatively normal or may show subtle signs of dysplasia. Pelvic imaging characteristically demonstrates dysplastic and small pelvic bones with a narrow sciatic notch that may be bilaterally symmetric. Long bones, such as the femur, often show a rounded appearance at the ends with marked shortening and tapering of the diaphyses. Limb radiographs may also reveal pre-axial polydactyly, and the phalanges are frequently hypoplastic, particularly in the middle and distal segments [1].

Advanced imaging, including three-dimensional computed tomography (3D CT) and magnetic resonance imaging (MRI), can highlight additional details of the dysplasia. In some cases, brain MRI is performed, not only to exclude other syndromic causes of skeletal dysplasia but also to evaluate associated brain abnormalities. For instance, in one family a patient was noted to have cerebellar hypoplasia with a classic “molar-tooth” appearance on midline sagittal images, suggesting a concurrent central nervous system malformation that may have implications for long-term neurological outcomes [1]. These radiological findings provide a non-invasive window into the severity of the disease and can guide both genetic testing and management decisions.

Below is a summary table cataloging the key clinical and radiological features from four families that illustrate the phenotypic diversity of CEP120-related JATD:

The above table underscores the radiological heterogeneity observed in patients with CEP120 mutations, illustrating both classic and atypical features that contribute to the overall clinical presentation.

Genetic Mapping and Molecular Analysis of CEP120

The mapping of JATD to CEP120 has provided a significant breakthrough in the understanding of the molecular pathogenesis underlying this severe skeletal dysplasia. CEP120 encodes a centrosomal protein that plays a vital role in centriole elongation and the proper formation of primary cilia. Cilia are essential for embryonic skeletal development, as they mediate key signaling pathways including Hedgehog signaling. Disruption of CEP120 has been shown to impair ciliogenesis, and studies have suggested that even subtle defects in this process can translate into significant skeletal dysplasia [1].

Molecular genetic studies have involved a combination of linkage analysis, exome sequencing, and functional studies in cellular and animal models. Patients with JATD associated with CEP120 mutations typically harbor either missense or truncating mutations that disrupt the protein’s function. Functional assays in vitro have demonstrated that these mutations lead to defective centriole elongation and impaired ciliary formation, underscoring the mechanistic link between centrosome function and skeletal morphogenesis [1]. Recent advances in molecular cytogenetics have also allowed for the integration of genomic data with high-resolution radiological phenotypes by leveraging ontologies of rare diseases and radiological diagnosis. Such framework integration has helped refine the genotype-phenotype correlations and improve diagnostic accuracy [2].

At the molecular level, CEP120 interacts with other centrosomal and ciliary proteins, serving as a hub necessary for the correct assembly of the centriole. Structural studies and network analyses have pointed to a disruption in the CEP120 interaction network as the molecular basis for the observed clinical manifestations. Because these interactions are indispensable for the regulation of the Hedgehog pathway—a critical regulator of skeletal patterning—the defective formation of primary cilia in CEP120-mutant cells ultimately culminates in the narrow thorax and dysplastic limb formation that define the JATD phenotype [1]. The convergence of genetic mapping techniques and functional cellular assays has not only confirmed CEP120 as a causative gene but has also provided insights into potential therapeutic targets that may aid in modulating the disease course.

Case Studies and Phenotypic Variability Overview

An important aspect of understanding any genetic disorder is the examination of clinical variability among affected individuals. Multiple case studies have been documented in which patients with CEP120 mutations exhibit a broad range of phenotypes. Clinical and radiological reports have detailed cases involving severe neonatal presentations as well as cases where individuals progress into infancy with less dramatic chest constriction but with other associated anomalies. In one set of case studies, four different families were evaluated and detailed clinical images, radiographic examinations, and magnetic resonance imaging studies were obtained to document the phenotype. In Family 1, the index case was a female stillbirth whose severe skeletal abnormalities included not only the characteristic narrow thorax and short limbs but also distinct craniofacial features that set her apart from classic JATD cases. Family 2’s index case demonstrated not only similar skeletal dysplasia but also an omphalocele and tongue hamartoma, further underscoring the heterogeneity of the disorder. Family 3 and Family 4 exhibited additional digital anomalies and even unique cranial malformations such as unilateral craniosynostosis, illustrating that the mutational spectrum of CEP120 results in a continuum of phenotypic presentations [1].

Such intrafamilial and interfamilial phenotypic variability suggests that while CEP120 mutations are necessary to cause the disease, other genetic modifiers and environmental factors likely influence the ultimate clinical presentation. As the number of documented cases grows, it has become clear that a careful radiological assessment combined with thorough genetic testing is required to encompass the full spectrum of CEP120-related disorders. The integration of clinical data with molecular findings has led to improved classification, providing clarity in distinguishing CEP120-related JATD from other types of skeletal dysplasias that may share overlapping radiological or clinical features.

Notably, the differences observed in radiographic severity, the presence or absence of specific craniofacial abnormalities, and the variability in extra-skeletal involvement must guide clinical management and prognostic counseling. Based on current evidence, early diagnosis is critical to providing appropriate life-supporting measures for neonates with life-threatening chest constriction, while long-term follow-up is necessary for survivors who may develop progressive respiratory or neurological problems later in life [1].

Implications for Diagnosis and Management Strategies

The identification of CEP120 as the causative gene in a subset of JATD cases has profound implications for both diagnosis and management. From a diagnostic standpoint, clinicians are now able to incorporate targeted genetic testing for CEP120 mutations in patients suspected of having JATD based on their clinical and radiological findings. In neonates with a narrow thorax, short limbs, and digital anomalies, prompt molecular diagnosis can facilitate early decision-making regarding respiratory support, potential surgical interventions, and genetic counseling for families at risk [1].

Imaging studies play a pivotal role in delineating the severity of skeletal anomalies. Radiological assessment not only confirms the diagnosis in many cases but also rules out other conditions in the differential diagnosis, such as other ciliopathies or skeletal dysplasias with overlapping manifestations. Advanced imaging modalities, including high-resolution 3D CT and MRI, may reveal subtle skull abnormalities, as well as brain malformations such as cerebellar hypoplasia or Dandy–Walker malformation, further reinforcing the diagnosis of CEP120-related dysplasia [1, 2].

Management strategies for CEP120-related JATD are largely supportive in nature. For neonates, respiratory support is often the immediate priority due to the severely constricted thorax. Surgical planning may be warranted in certain cases to address life-threatening complications. In addition, long-term follow-up is necessary to monitor for the emergence of complications such as cardiopulmonary insufficiency or neurodevelopmental delays. Early intervention services, including physical and occupational therapy, can help optimize quality of life and developmental outcomes. Finally, genetic counseling is an essential component of management. Given the autosomal recessive inheritance pattern observed in many families, informing parents about recurrence risk in subsequent pregnancies is crucial. Future therapies may focus on modulating ciliary function or even targeted gene therapy approaches, but at present, clinical care remains primarily supportive [1].

Conclusion

Mapping Jeune asphyxiating thoracic dystrophy to CEP120 has significantly advanced our understanding of the molecular underpinnings of this severe skeletal dysplasia. This review has highlighted the critical clinical features observed in patients with CEP120 mutations, the characteristic radiological findings that support the diagnosis, and the molecular genetic techniques that have facilitated the mapping of the disease. Case studies reveal a broad phenotypic variability, underscoring the interrelated roles of centrosomal and ciliary dysfunction in skeletal and craniofacial development. The integration of high-resolution imaging with genetic testing plays an indispensable role in the early recognition, accurate diagnosis, and management of affected patients, ultimately guiding supportive care and informing prospective therapeutic strategies. As research in this field continues to evolve, multidisciplinary collaboration and long-term patient follow-up are essential to improve clinical outcomes in this challenging group of disorders [1, 2].

Frequently Asked Questions (FAQ)

What is Jeune asphyxiating thoracic dystrophy (JATD)?
JATD is a rare skeletal dysplasia characterized by a narrow thorax, short limbs, and often digital anomalies. It can result in severe respiratory complications in the neonatal period due to a constricted chest cavity. The condition may also present with various extra-skeletal findings.

How is CEP120 related to JATD?
CEP120 encodes a centrosomal protein that is essential for centriole elongation and ciliogenesis. Recent studies have mapped JATD to mutations in CEP120, showing that disruptions in the protein’s function lead to impaired ciliary formation, which is critical for proper skeletal development.

What are the key radiological findings in patients with CEP120-related dysplasia?
Radiological evaluation typically reveals a narrow, bell-shaped thorax with very short, horizontal ribs, dysplastic pelvic bones, and shortening of long bones. Advanced imaging may show additional features including brain malformations such as cerebellar hypoplasia or Dandy–Walker malformation in some patients.

How does genetic mapping of CEP120 help in managing the disease?
Genetic mapping allows clinicians to confirm the diagnosis through targeted gene testing, which helps in differentiating CEP120-related JATD from other skeletal dysplasias. Early diagnosis informs timely respiratory support and other necessary interventions, and it facilitates informed genetic counseling regarding recurrence risks.

What are the treatment options for individuals with CEP120-related JATD?
Currently, treatment is largely supportive. Neonates may require respiratory support and possibly surgical intervention. Longer-term strategies include monitoring for complications, early intervention therapies (physical and occupational), and genetic counseling. Future therapies may involve targeted approaches to restore ciliary function.

Is there phenotypic variability among patients with CEP120 mutations?
Yes, significant variability exists. While the core features such as a narrow thorax and limb shortening are common, additional anomalies such as craniofacial dysmorphism, digital anomalies, and even brain malformations vary greatly among affected individuals, suggesting roles for modifier genes and environmental factors.

References

1. Unknown. (n.d.). JATD is mapped to CEP120: Clinical and Radiological Insights [Reference excerpt]. Retrieved from (No URL provided)
2. Malpani, S., & colleagues. (2001). Integrating ontologies of rare diseases and radiological diagnosis. Retrieved from https://pubmed.ncbi.nlm.nih.gov/11737837/