Introduction

Spondylocarpotarsal synostosis (SCTS) is a rare genetic disorder characterized by distinct clinical features that affect bone development and growth. SCTS is associated with progressive vertebral fusion, short stature, scoliosis, and carpal and tarsal abnormalities. It may also manifest as facial dysmorphism, dental enamel hypoplasia, joint laxity, cleft palate, and hearing impairment [1].

The FLNB gene plays a crucial role in skeletal development, particularly in cartilage growth and vertebral condensation, and FLNB mutations are known to cause SCTS in an autosomal recessive manner [1,2].

However, our case of SCTS appears to be the first instance of mutations in the GMNN and DLL1 genes. Therefore, we aimed to report this finding and provide a review of GMNN and DLL1. Prior to publication, informed consent was obtained for the use of the patient’s clinical details and images.

Case

Ethics statement: This study was exempted from review by the Institutional Review Board (IRB) of Sahmyook Medical Center (IRB No: 116286-202307-HR-02). Written informed consent was obtained from the patient to participate in the study.

A 28-year-old male patient presented to the Department of Rehabilitation Medicine with persistent neck and shoulder pain. The patient reported experiencing discomfort in his right shoulder for approximately 1 year, which subsequently worsened 6 months ago along with neck pain and restricted range of motion. The patient did not report numbness in his upper extremities; however, he had a congenital condition known as radioulnar synostosis (RUS), which limited the supination and pronation of the right forearm. During the examination, he informed us of his medical history of polydactyly, which had been surgically corrected in childhood (Fig. 1). Physical examination revealed normal muscle strength and sensation; however, a notable limitation was observed in neck rotation of approximately 30° to the right and 35° to the left. Radiographic examination of the right elbow confirmed the presence of RUS (Fig. 2), whereas cervical spine radiography revealed scoliosis with a Cobb angle of 23.8° (Fig. 3). Cervical spine computed tomography revealed agenesis of the posterior arch of C1 (Fig. 4).

The patient reported that none of his relatives exhibited these phenotypic features. There was no family history of congenital skeletal or genetic abnormalities.

The patient underwent weekly manual therapy sessions for 3 months, focusing on right neck and shoulder myofascial release and self-release education. Following treatment, the patient reported a reduction in pain of 7 to 2 on the Numerical Rating Scale. The patient has not received subsequent treatment for pain and has not experienced recurrence or worsening of symptoms.

To determine the cause of SCTS, genetic analysis was performed using DNA extracted from peripheral blood leukocytes. Five thousand eight hundred and seventy Mendelian genes were sequenced using DNA Expert Sequence analysis. The results revealed two missense mutations: a GMNN mutation (c.611A>T) resulting in p.Asp204Val, and a DLL1 mutation (c.289G>C) resulting in p.Gly97Arg.

Discussion

Skeletal system-associated genetic disorders constitute a diverse group of clinically distinct and genetically heterogeneous conditions. Traditionally, these disorders have been classified as dysostosis or osteochondrodysplasia. However, advances in molecular pathology and embryology have enabled a more refined categorization, allowing these disorders to be further subdivided based on skeletal patterning, condensation, and differentiation of skeletal precursor structures, growth, and homeostasis [3]. SCTS is related to the skeletal patterning domain and is a rare genetic disorder characterized by fused vertebrae and abnormal spine segmentation [4].

Several disorders exhibit skeletal features overlapping with SCTS, including Klippel–Feil syndrome [5], spondyloepiphyseal dysplasia congenita [6], Myhre syndrome [7], and Larsen syndrome [8]. These conditions commonly present as vertebral anomalies, joint fusions, and short stature. Although they involve different genetic mutations that affect skeletal development, their clinical presentations can closely resemble those of SCTS, complicating differential diagnosis.

To the best of our knowledge, this is the first reported case of SCTS that is not primarily associated with FLNB mutations but rather with mutations in GMNN and DLL1. Previous reports have identified frameshift mutations in FLNB on chromosome 3p14 as the main cause of SCTS, resulting in considerably decreased protein levels, total loss of dimerization, and accumulation of the mutated protein in the Golgi complex. The inheritance pattern of these mutations is typically autosomal recessive [2,9].

Geminin (GMNN) is a multifunctional protein. It is involved in the regulation of DNA replication, particularly during S phase of the cell cycle. Furthermore, through multiple protein-protein interactions, GMNN enhances the activity of hematopoietic stem cells and triggers the activation of development-associated genes that are vital for appropriate embryonic and tissue development [10]. Mutations in GMNN have been associated with various developmental abnormalities, including Meier–Gorlin syndrome, which is characterized by dwarfism, ear abnormalities, and a narrow nose [11].

DLL1 is a crucial member of the Notch signaling pathway that plays a significant role in embryonic development and tissue differentiation [12]. Mutations in DLL1 may cause skeletal deformities and spinal irregularities through their influence on the Notch signaling pathway during bone formation, osteoclastogenesis, and angiogenesis [13].

In our case, the presence of RUS, cervical scoliosis, agenesis of the posterior arch of C1, and polydactyly align with known skeletal manifestations of SCTS. However, the absence of other features typically associated with SCTS, such as tarsal fusion or significantly short stature, suggests a variant or incomplete presentation of the syndrome.

While FLNB mutations are well established as the primary genetic cause of SCTS, our findings indicate that mutations in GMNN and DLL1 may represent alternative genetic pathways that contribute to the phenotypic variability in this disorder. Importantly, DLL1 mutations have been reported to be associated with skeletal deformities and spinal irregularities, supporting their potential role in the observed abnormalities.

The exact roles of GMNN and DLL1 mutations in the agenesis of the posterior arch of the atlas and development of RUS are not yet fully understood. Further investigations are required to clarify the underlying molecular mechanisms and pathways. Importantly, the identified gene mutations may disrupt normal skeletal development and bone structure. Although not observed in our case, SMAD6 mutations have been associated with axial skeletal malformations, RUS, and polydactyly [14].

To summarize, although the patient did not exhibit all the classic characteristics of SCTS, the combination of vertebral and limb anomalies, along with genetic findings, supported the diagnosis of SCTS, possibly expanding the known phenotypic spectrum of the syndrome. Further research is needed to explore the role of these mutations in skeletal development and refine the diagnostic criteria for SCTS.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization: BR, YK; Data curation: JL, YK; Supervision: EL; Visualization: YK; Writing-original draft: BR, JL; Writing-review & editing: BR, EL.

Fig. 1.

Image shows scars on both thumbs (arrows) resulting from polydactyly surgery performed in childhood.

Fig. 2.

Lateral view of the right elbow X-ray shows the fusion of the right proximal radius and ulna.

Fig. 3.

Anterior posterior view of the cervical spine X-ray reveals scoliosis.

Fig. 4.

Cervical spine computed tomography (CT) scan show agenesis of the posterior arch of the atlas. (A) Axial view of cervical spine CT image and (B) three-dimensional reconstructed image (arrow).

References

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Figure & Data

References

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