SPONASTRIME dysplasia is a rare genetic disorder characterized by short stature, facial abnormalities, vertebral issues, and bone striations, caused by recessive mutations in the TONSL gene. We reported a 6-year-old boy with characteristic clinical features of SPONASTRIME dysplasia, accompanied by neutropenia. Genetic analysis revealed biallelic variants in TONSL: mother-inherited c.1289del (p.Gln430ArgfsTer13) and father-inherited c.1961G > C (p.Arg654Pro), both of which were previously unreported. We predicted the c.1289del (p.Gln430ArgfsTer13) variant as likely pathogenic in silico analysis, while the c.1961G > C (p.Arg654Pro) variant as uncertain pathogenicity in silico analysis, and the pathogenicity was confirmed by functional studies in transfected HEK 293 T cells. Six-month growth hormone therapy was administered to the patient after confirmed diagnosis, with limited improvement. These findings have important implications for the diagnosis and treatment of the disease.

Sponastrime dysplasia is an extremely rare autosomal recessive spondyloepimetaphyseal dysplasia characterized by short stature, midface hypoplasia, nasal alterations, and dental anomalies. This is, to date, the first comprehensive report on oral and craniofacial findings, and on subjective oral health-related quality of life as clinically and radiologically examined in two adults with sponastrime dysplasia. Both subjects had typical features of sponastrime dysplasia with disproportionate short stature, hypertelorism and midface hypoplasia, and variants in the TONSL gene. One had a severe phenotype (adult height 91 cm), whereas the other exhibited moderate severity (adult height 135 cm). The notable variation in the disorder severity was also expressed in dental manifestations. Dentin dysplasia type I-like abnormalities were seen in tooth eruption and morphology. Dental roots were shortened in both individuals. The individual with severe growth failure had lost several permanent teeth and reported a moderate level of discomfort and impairment due to oral health issues, as evaluated with the Oral Health Impact Profile questionnaire. In contrast, the other individual had a full permanent dentition and minimal negative impact on oral health-related quality of life. Both had short jaw lengths and face height. The anteroposterior jaw relationships were normal. The jaws of the individual with a severe phenotype were retrognathic in relation to the skull base. Both had prominent forehead. Due to significant craniofacial and dental involvement, individuals with sponastrime dysplasia should be regularly followed by a multidisciplinary medical team including a dentist, to maintain individuals' oral health and oral health-related quality of life.

To explore the clinical features and genetic etiology of a child with SPONASTRIME dysplasia (SD). A 9-month-old female who had presented at the Linyi People's Hospital in August 2022 for short stature was selected as the study subject. Clinical data of the child were collected, and whole exome sequencing (WES) was carried out. Sanger sequencing was used for validating the candidate variants. The child has manifested short stature, mid-face hypoplasia, joint laxity, internal knee rotation, irregularities in the metaphysis of long bones, and flat and concave lumbar vertebrae. WES revealed that she has harbored compound heterozygous variants of the TONSL gene, namely c.3088G>T (p.Glu1030*) and c.3053G>A (p.Arg1018His), which were inherited from her phenotypically normal parents. Neither variant was reported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.3088G>T variant was classified as likely pathogenic (PVS1+PM2_Supporting), whilst the c.3053G>A was classified as a variant of uncertain significance (PM2_Supporting+PM3+PP3). The c.3088G>T and c.3053G>A compound heterozygous variants of the TONSL gene probably underlay the pathogenesis in this patient. Above finding has facilitated the clinical diagnosis and genetic counseling for her family.

SPONASTRIME dysplasia is an ultrarare spondyloepimetaphyseal dysplasia featuring short stature and short limbs, platyspondyly, depressed nasal bridge with midface hypoplasia and striated metaphyses. In 2019, an autosomal recessive inheritance was demonstrated by the identification of bi-allelic hypomorphic alleles in TONSL. The encoded protein has a critical role in maintaining genome integrity by promoting the homologous recombination required for repairing spontaneous replication-associated DNA lesions at collapsed replication forks. We report a 9-year-old girl with typical SPONASTRIME dysplasia and resulted in carrier of the novel missense p.(Gln430Arg) and p.(Leu1090Arg) variants in TONSL at whole-exome sequencing. In silico analysis predicted that these variants induced thermodynamic changes with a pathogenic impact on protein function. To support the pathogenicity of the identified variants, cytogenetic analysis and microscopy assays showed that patient-derived fibroblasts exhibited spontaneous chromosomal breaks and flow cytometry demonstrated defects in cell proliferation and enhanced apoptosis. These findings contribute to our understanding of the molecular pathogenesis of SPONASTRIME dysplasia and might open the way to novel therapeutic approaches.

SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of wild-type TONSL. In addition, in vitro cell-based assays and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in (KI) Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of TONSL in embryonic development and postnatal growth.