Pathogenic variants in the trafficking protein particle complex subunit 2 (TRAPPC2) gene are known to cause X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT), a rare hereditary cause of childhood short stature. Genetic diagnosis is critical in early diagnosis and management of the disease. Majority of the pathogenic variants are predicted to cause premature truncation. However, few have been functionally studied. In this study, we reported a Chinese pedigree with multiple affected remarkably short stature males and described the novel variant by in-vitro functional study. To complete precise molecular diagnosis and subsequent genetic counseling of a large Chinese pedigree with remarkably short stature. Trio whole exome sequencing was performed on the proband and his parents and phenotype-driven data analysis was conducted. The potentially pathogenic variant was verified by Sanger sequencing in parent-offspring trio and other family members. In vitro experiments involving minigene splicing study and protein expression assay were performed for the potentially disease-causing noncanonical splice variant. Using whole exome sequencing, we identified a novel intronic variant, c.94-11C>G, located in intron three of the TRAPPC2 gene. Minigene analysis confirmed that this variant resulted in abnormal splicing, leading to a frameshift insertion of 10 nucleotides and a subsequent loss of TRAPPC2 protein expression. This variant has never been reported. Our findings highlight the pathogenic nature of a novel noncanonical splicing variant, thus expanding the genetic spectrum of TRAPPC2-related disorder. Furthermore, this discovery has important implications for genetic counseling, prenatal genetic diagnosis, and follow-up care for affected individuals in this family.

Spondyloepiphyseal dysplasia tarda (SEDT) is a rare X-linked skeletal disorder affecting the spine and long bones, leading to short stature, spinal deformities, and joint stiffness. It is caused by genetic mutations, and primarily affects males. Diagnosis is confirmed by imaging and genetic testing. We report the case of a 33 years old patient with a history of X-linked SEDT, who presented with pain in the lower limbs and pelvis, accompanied by limited mobility. Bone scan with 99mTc-methylene diphosphonate (MDP) revealed a polyostotic SEDT involvement, periarticular ossifications, and bony bridges in the active phase. The authors highlight the role of bone scan with 99mTc-MDP in diagnosing this rare disease. Spondiloepifizyal displazi tarda (SEDT), omurga ve uzun kemikleri etkileyen, kısa boy, omurga deformiteleri ve eklem sertliğine yol açan nadir bir X’e bağlı geçiş gösteren iskelet hastalığıdır. Genetik mutasyonlardan kaynaklanır ve öncelikli olarak erkekleri etkiler. Tanı, görüntüleme ve genetik testlerle doğrulanır. Alt ekstremitelerde ve pelviste ağrı ve hareket kısıtlılığı ile başvuran, X’e bağlı SEDT öyküsü olan 33 yaşında bir hastayı bildiriyoruz. 99mTc-metilen difosfonat (MDP) ile yapılan kemik taraması, poliostotik SEDT tutulumunu, periartiküler ossifikasyonları ve aktif fazda kemik köprüleri gösterdi. Yazarlar, bu nadir hastalığın tanısında 99mTc-MDP ile yapılan kemik taramasının rolünü vurgulamaktadır.

Spondyloepiphyseal dysplasia tarda (SEDT) is an inherited disorder that is typically diagnosed in childhood or adolescence. It is characterized by disproportionate short stature and premature osteoarthritis, and it frequently affects males. Here, we described a novel nonsense mutation, c.406A>T; p(Lys136Ter), in TRAPPC2 (NM_001011658.4) in a Turkish patient with X-linked SEDT. A 15-year-old boy, born to non-consanguineous Turkish parents, exhibited a decline in height velocity over 3 years and complained of back pain despite minimal physical activity. Growth and development were normal until adolescence, with the patient's weight at 35 kg (SDS -3.85), height at 134 cm (SDS -5.44), and a predicted adult height of 137.6 cm. Dysmorphic facial features, microtia, synophrys, hypotelorism, and barrel chest were noted. Radiological examination revealed osteopenic bone structure, hypoplastic odontoid process, platyspondyly, scoliosis, short femoral necks, and coxa vara. Genetic analysis identified a hemizygous novel stop codon mutation (c.406A>T; pLys136Ter) in TRAPPC2, also detected as heterozygous in the patient's mother. In adolescence or childhood, X-linked SEDT should be considered in cases of disproportionate short stature, short trunk, osteoarthritis, and a family history that is appropriate for X-linked inheritance. Skeletal survey should be performed to suspect SEDT, and radiological findings may support diagnosis.

Developing increased independence is a primary goal of the transition to adulthood. Individuals with disabilities may face additional challenges in developing and maintaining independence during this transition. While clinical presentations associated with many skeletal dysplasias have been documented, recent research investigating how skeletal dysplasia affects independence in young adulthood is limited. We sought to understand and describe how young adults with short stature and skeletal dysplasia define independence, the barriers they face in achieving and maintaining independence, and the resources they leverage to support their independence. We conducted virtual semi-structured qualitative interviews with 10 young adults (ages 18-28 years) with short stature and skeletal dysplasia. Interviews were transcribed and analyzed using a modified constructivist grounded theory methodology. Skeletal dysplasia diagnoses among the interviewed cohort include achondroplasia, osteogenesis imperfecta, spondyloepiphyseal dysplasia tarda, spondyloepimetaphyseal dysplasia, and acromicric/geleophysic dysplasia. Participants' experiences with independence are described through four major categories: prioritizing self-sufficiency, accommodating tension, identifying obstacles, and incorporating facilitators. Considering these categories, we propose that for young adults with short stature and skeletal dysplasia, independence is a balancing act between self-sufficiency and accepting needed assistance. Based on these results, providers can recognize independence as a balancing act between competing priorities, and investigate and support patients' individual priorities. Providers can also explore patients' coping strategies, provide anticipatory guidance, connect individuals to others with shared experiences, learn about available adaptive equipment, and evaluate their clinic environments for accessibility.

Aplasia Cutis Congenita with Ectrodactyly Skeletal Syndrome (ACCES, OMIM #619959) is an extremely rare multiple congenital anomalies syndrome caused by haploinsufficiency of the UBA2 gene. This syndrome presents with growth retardation, dysmorphic facial features, neurodevelopmental delay, skeletal problems including ectrodactyly, developmental dysplasia of the hip (DDH) and scoliosis, skin findings such as aplasia cutis, and some internal organ abnormalities. Our 13-year-old female patient and her 38-year-old father had a skeletal dysplasia phenotype with disproportionate short stature, bilateral DDH, mild epiphyseal involvement, scoliosis, and increased lumbar lordosis. Both were neurodevelopmentally normal and had mild dysmorphic facial features and mild ectodermal findings. The dominant inheritance pattern in the pedigree suggested a pre-diagnosis of spondyloepiphyseal dysplasia tarda. The exome sequencing analysis of the patient has identified a novel heterozygous variant, NM_005499.2:c.460-2A >G, in the UBA2 gene, and the father was found heterozygous either. The isolated spondyloepiphyseal involvement of our patients was an unusual presentation compared to patients with ACCES syndrome previously reported in the literature. Considering the highly variable expressiveness of ACCES syndrome and the co-occurrence of familial hip dysplasia and vertebral problems, we suggest that this syndrome can also be classified under "Spondyloepi(meta)physial dysplasia (SE(M)D)" in the nosology of genetic skeletal disorders.