Anxiety symptoms are elevated among people with joint hypermobility. The underlying neural mechanisms are attributed theoretically to effects of variant connective tissue on the precision of interoceptive representations contributing to emotions. To investigate the neural correlates of anxiety and hypermobility using functional neuroimaging. We used functional magnetic resonance neuroimaging to quantify regional brain responses to emotional stimuli (facial expressions) in people with generalised anxiety disorder (GAD) (N = 30) and a non-anxious comparison group (N = 33). All participants were assessed for joint laxity and were classified (using Brighton Criteria) for the presence and absence of hypermobility syndrome (HMS: now considered hypermobility spectrum disorder). Participants with HMS showed attenuated neural reactivity to emotional faces in specific frontal (inferior frontal gyrus, pre-supplementary motor area), midline (anterior mid and posterior cingulate cortices) and parietal (precuneus and supramarginal gyrus) regions. Notably, interaction between HMS and anxiety was expressed in reactivity of the left amygdala (a region implicated in threat processing) and mid insula (primary interoceptive cortex) where activity was amplified in people with HMS with GAD. Severity of hypermobility in anxious, compared with non-anxious, individuals correlated with activity within the anterior insula (implicated as the neural substrate linking anxious feelings to physiological state). Amygdala-precuneus functional connectivity was stronger in participants with HMS, compared with non-HMS participants. The predisposition to anxiety in people with variant connective tissue reflects dynamic interactions between neural centres processing threat (amygdala) and representing bodily state (insular and parietal cortices). Correspondingly, interventions to regulate amygdala reactivity while enhancing interoceptive precision may have therapeutic benefit for symptomatic hypermobile individuals.

3M syndrome is a rarely inherited autosomal recessive disorder caused by mutations in cullin-7 (CUL7), obscurin-like 1 (OBSL1), and coiled-coil domain containing protein 8 (CCDC8). It is associated with multiple dysmorphic features, including characteristic facial dysmorphism (a face that is triangular, full lips, frontal bossing, a nasal tip that is fleshy, long philtrum, protruding ears and macrocephaly), severe growth retardation prenatally and postnatally and normal intelligence. Although there are multiple skeletal manifestations of the syndrome, such as joint laxity, there is no mention of developmental dysplasia of the hip (DDH) to be associated with it anywhere in the literature. Therefore, we present the first case of bilateral DDH in a patient with 3M syndrome, which was managed similarly to other DDH cases with operative reduction, pelvic osteotomies, and femoral shortening, with a satisfactory outcome after 3 years of follow-up.

Cutis laxa (CL) is a rare connective-tissue disorder characterized by loose, inelastic skin due to defects in elastic fiber production or structure. Acquired cutis laxa (ACL) typically develops in adulthood and may follow inflammatory or immune-mediated events, though idiopathic cases remain uncommon. We report a 29-year-old male with a 10-year history of progressive skin laxity affecting the face, neck, and upper back. There were no preceding infections, drug exposures, or inflammatory skin conditions. Medical, surgical, and family histories were unremarkable. Examination revealed redundant, wrinkled skin with markedly reduced recoil in the involved areas, without joint hypermobility or systemic features suggestive of connective-tissue disease. Laboratory tests and imaging were normal. Histopathology demonstrated diminished and fragmented elastic fibers throughout the dermis, confirmed by Verhoeff-Van Gieson staining, consistent with ACL. This case represents an idiopathic, localized adult-onset form of ACL. The characteristic histological findings, along with the absence of systemic involvement, support the diagnosis. It is important to distinguish this condition from others, such as Ehlers-Danlos syndrome, anetoderma, and pseudoxanthoma elasticum, since overlapping clinical features can lead to misdiagnosis. Idiopathic ACL is rare and often under-recognized, and this case represents the first reported regional idiopathic instance, to the best of our knowledge, from Saudi Arabia. Overall, this case highlights the value of careful clinical assessment and histological evaluation in patients with slowly progressive, non-inflammatory skin laxity.

Coffin-Siris syndrome 12 (CSS12) is a recently described neurodevelopmental disorder caused by heterozygous pathogenic variants in BICRA, a gene encoding a core subunit of the non-canonical BAF (ncBAF) chromatin-remodeling complex. The condition is characterized by developmental delay, hypotonia, hypertrichosis, and joint laxity. However, long-term data remain limited, and systemic manifestations are incompletely defined. We report a 22-year-old male with a de novo BICRA frameshift variant, c.2479_2480delinsA (p.Ala827Thrfs*15), previously included in the original cohort reported by Barish et al. Longitudinal follow-up revealed an expanded phenotype extending beyond neurodevelopmental features. Early findings included global developmental delay, growth hormone deficiency, short stature, and joint hypermobility. In adolescence and adulthood, he developed severe intestinal dysmotility requiring total colectomy, recurrent spontaneous pneumothoraces from bilateral apical bullous disease, and portal-vein thrombosis, representing visceral and vascular complications not previously emphasized in BICRA-related disorders. The identified BICRA variant truncates the coiled-coil domain critical for BRD9/BRD4 interaction, consistent with a loss-of-function mechanism. The patient's systemic features suggest that BICRA haploinsufficiency affects not only neurodevelopmental pathways but also smooth-muscle and connective-tissue integrity. This case expands the phenotypic spectrum of BICRA-related CSS12, demonstrating that visceral and vascular involvement can occur alongside neurodevelopmental and connective-tissue features. Recognition of these broader manifestations underscores the need for lifelong multidisciplinary surveillance and contributes to understanding the diverse biological roles of the ncBAF complex in human development.

Kabuki syndrome (KS) is a rare congenital disorder characterized by distinctive facial features, intellectual disability, and multiple musculoskeletal anomalies, including scoliosis, kyphosis, and generalized ligamentous laxity. The combination of connective tissue fragility and complex spinal deformity may predispose these patients to post-operative complications, such as proximal junctional kyphosis (PJK), though this association has not previously been reported. We report a 15-year-old male with genetically confirmed KS who presented with severe thoracic hyperkyphosis (95°). Posterior spinal fusion and correction were performed, resulting in initial improvement. Within 8 months, the patient developed PJK above the upper instrumented vertebra, requiring multiple revision procedures. Post-operative infection with Staphylococcus aureus and rapid recurrent kyphosis further complicated management. A staged revision strategy, combining halo-gravitational traction followed by extended fusion and careful sagittal realignment, achieved stable correction and functional improvement at 1-year follow-up. The association between these conditions has, to our knowledge, not yet been reported in literature. This case highlights the multifactorial etiology of PJK in KS, where intrinsic ligamentous laxity, immune dysfunction, and extensive deformity correction converge to increase mechanical vulnerability. Soft-tissue preservation at the upper instrumented level, careful sagittal contouring, and infection control are key preventive strategies. Due to inherent ligamentous laxity and connective tissue abnormalities, patients with KS could be predisposed to proximal junctional failure after spinal deformity correction. Pre-operative recognition of connective tissue and immunologic abnormalities, together with detailed surgical planning, is essential to minimize complications and optimize long-term outcomes. PIK3R1-related SHORT syndrome is a mnemonic for short stature, hyperextensibility, ocular depression (deep-set eyes), Rieger anomaly, and teething delay. It is now recognized that the features most consistently observed in PIK3R1-related SHORT syndrome are a characteristic facial gestalt (triangular face, broad forehead, deep-set eyes, narrow nasal tip, thin nasal alae, low-hanging columella, downturned corners of the mouth, chin dimple, and prominent ears), delayed dentition, mild intrauterine growth restriction, mild-to-moderate short stature, and partial lipodystrophy (evident in the face and later in the chest and upper extremities, often sparing the buttocks and legs). Insulin resistance may be evident in mid-childhood or adolescence, although diabetes mellitus typically does not develop until early adulthood. Other frequent features include Axenfeld-Rieger anomaly or related ocular anterior chamber dysgenesis, vision issues, other dental issues, and sensorineural hearing loss. Cardiac anomalies, connective tissue findings (joint laxity, inguinal hernia), and frequent infections have also been reported. The diagnosis of PIK3R1-related SHORT syndrome is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in PIK3R1 identified by molecular genetic testing. Treatment of manifestations: Treatment for glucose intolerance and diabetes mellitus per endocrinologist; glaucoma treatment by ophthalmologist to reduce and stabilize intraocular pressure and preserve vision; standard management for other ocular findings; treatment for dental anomalies may include crowns and dental prostheses; standard hearing aids for sensorineural hearing loss; speech therapy as needed; treatment of cardiac anomalies per cardiologist; standard treatments for joint laxity, inguinal hernia, and frequent infections. Surveillance: Assess growth including height, weight, and body mass index every six to 12 months; screening for insulin resistance by oral glucose tolerance test every five years in the absence of diabetes; fasting glucose, insulin, and hemoglobin A1c annually beginning at age ten years; eye examinations to include measurement of intraocular pressure annually; dental examination every six months; hearing assessment every two to three years; assess for joint laxity, hernias, and frequent infections annually. Agents/circumstances to avoid: Administration of human growth hormone as it may exacerbate insulin resistance. Three individuals with PIK3R1-related SHORT syndrome had worsening insulin resistance when treated with metformin. Pregnancy management: If present, diabetes mellitus is managed as appropriate. PIK3R1-related SHORT syndrome is inherited in an autosomal dominant manner. Some individuals diagnosed with PIK3R1-related SHORT syndrome have an affected parent; 70% of affected individuals have the disorder as the result of a de novo pathogenic variant. Each child of an individual with PIK3R1-related SHORT syndrome has a 50% chance of inheriting the pathogenic variant. Once the PIK3R1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.