RICTOR is a key component of the mTORC2 signaling complex which is involved in the regulation of cell growth, proliferation and survival. RICTOR is highly expressed in neurons and is necessary for brain development. Here, we report eight unrelated patients presenting with intellectual disability and/or development delay and carrying variants in the RICTOR gene. The phenotypic presentation is diverse with associated features including growth failure, feeding difficulties, abnormal behavior, seizure, hypertonia, brain anomalies and various other congenital organ and skeletal malformations. All patients carried de novo or heterozygous variants inherited from one affected parent, including three missense variants, four loss-of-function variants and one 3 kb deletion encompassing RICTOR. The mTORC2 pathway was hyperactivated in a patient's fibroblasts carrying a missense variant, while the expression of RICTOR remained unchanged, indicating a gain-of-function mechanism. RNA sequencing on RICTOR knock-out mouse embryonic fibroblasts confirmed the potential role of RICTOR in neuronal cell development.

Neuropathic skeletal injuries in children are common manifestations of conditions associated with sensory impairment. The underlying aetiologies may be rare entities such as congenital insensitivity to pain or more prevalent disorders such as spinal dysraphisms. While the imaging manifestations of such injuries have been described in adults, the paediatric literature is sparse, primarily comprising case reports and case series with insufficient imaging data. Characteristic imaging findings in patients with neuropathic skeletal injuries include neuropathic arthropathy, avascular necrosis, joint dislocation, repeated fractures with exuberant callus formation, epiphyseal separation, and acro-osteolysis. Conventional radiography, MRI, and CT all contribute to the comprehensive assessment of paediatric neuropathic lesions. This pictorial essay illustrates the spectrum of imaging findings in children with neuropathic skeletal injuries of varying aetiologies as well as their natural evolution and treatment. CRITICAL RELEVANCE STATEMENT: This essay addresses a critical gap in the literature on paediatric neuropathic skeletal injuries, providing a detailed overview of their imaging manifestations, natural progression, and relevant treatment strategies, through contemporary imaging techniques such as radiography, MRI, and CT. KEY POINTS: Unrecognised neuropathic skeletal injuries cause progressive permanent deformities, impacting quality of life. Suspect neuropathic arthropathy in children with sensory loss presenting with painless inflamed joints. Neuropathic injuries may be mistaken for osteomyelitis, septic arthritis, or other disorders.

myo7aa, the homolog of the human Usher 1B syndrome pathogenic gene, myo7A, plays an important role in stereociliary development and maintenance, therefore, is critical for hearing and balance. However, the molecular mechanisms that myo7aa regulate hearing and balance still need to be studied. In this study, we generated two independent zebrafish myo7aa knockout lines using CRISPR/Cas9 technology. To investigate the effects of myo7aa on hearing, YO-PRO-1 staining and startle response assay were used. To gain insight into the specific molecular mechanisms by which myo7aa affects hearing, transcriptome sequencing and bioinformatics analysis were employed. Our study showed that hair cells of myo7aa-/- zebrafish can not take up YO-PRO-1 fluorescent dye and are insensitive to acoustic stimulation in myo7aa-/- zebrafish compared to wild type. Genes related to the Rho GTPase signaling pathway, such as arhgap33, dab2ip, and arghef40, are significantly down-regulated in myo7aa-/- zebrafish embryos at 3 dpf. GTP and ATP compensation can partially rescue the hair cell defects in myo7aa knockout zebrafish. Our findings suggest that zebrafish myo7aa affects congenital hearing by regulating Rho GTPase signaling, and loss of myo7aa leads to abnormal Rho GTPase signaling and impairs hair cell function. myo7aa, myo7A, arhgap33, dab2ip, arghef40 and myo7aa-/- fonts in the abstract are italicized. -/- is a superscript format.

Congenital insensitivity to pain with anhidrosis is an extremely rare disorder characterized by congenital generalized loss of pain and thermal sensation, decreased sweating, intellectual disability, and self-mutilating behavior. Skeletal complications can develop even after minor trauma or an unknown cause, and management is difficult and sometimes unsuccessful, leading to the development of Charcot joints. We report 3 patients whose hip instability was treated with a hip action brace (HAB) that allowed for free abduction but prevented adduction. In 2 patients, metal attachments were added to bilateral joint units to prevent the patient's hip joints from flexing over 90 degrees. The HAB was well tolerated by all patients, and no adverse effects, such as pressure ulcers, occurred during this treatment. Of the 6 hips with instability, 1 remained dislocated, and 5 were stabilized after several years of HAB application. However, 3 joints in 2 patients aged between 14 and 16 years were subluxated or dislocated, leading to joint destruction. The follow-up period from the application of HAB until the most recent visit ranged from 10 to 13 years, and all patients reached skeletal maturity. Our experience suggests that HAB treatment is effective in reducing hip instability and maintaining stability for at least several years in children with congenital insensitivity to pain with anhidrosis.

Congenital insensitivity to pain with anhidrosis (CIPA) with Charcot arthropathy is a rare combination in orthopaedic clinical practice. The experience dealing with such patients is limited. Here with this case of approximately 10 years follow-up, we wish to shed light on the choices of strategies of surgeries and alerting clinicians with post-surgery complications. The possible underlying reasons for the recurrent Charcot arthropathies as well as strategies for peri-operative management for such surgical cases are also discussed. The patient underwent a surgery to correct her severe kyphosis caused by CIPA-related Charcot spine. Multiple post-surgery complications occurred during her follow-up, including hardware migration, adjacent segment disease (ASD), and loosening pedicle screws. Five revision surgeries were conducted consequently. From the limited experience on the management of CIPA-related Charcot spine, surgical correction is still the first-line treatment. Of all the 16 cases reviewed (including our case), loosening pedicle screws, hardware migration, and ASDs are the common post-surgery complications. Large-scale removal of damaged vertebrae and subsequent reconstruction are not recommended, which might increase the risk of hardware migration. A 360° long-segment fusion might be of help to reduce the risk of ASDs. In the meantime, comprehensive management including careful nursing, proper rehabilitation exercises, and treatments targeting bone mineral metabolism is also critical.