Open research questions in Connective tissue disorders research

What the literature leaves open

• 6% femoral neck), but did not prevent progression of acro-osteolysis; this further supports the concept that suppression of RANKL-mediated osteoclast activity is insufficient to counteract sustained Notch2 signaling.

  Hajdu–Cheney Syndrome in a Two-Generation Family: Longitudinal Skeletal Progression and Differential Therapeutic Responses in a Mother and Her Son · 2026 · DOI

• However, data are scarce in adults and trials with asfostase-alfa are limited to adult HPP patients who have been symptomatic since childhood. Although HPP treatment with teriparatide remains controversial, we cannot be sure that our patient had a juvenile-onset form of HPP; therefore, consider- ing that asfotase-alfa may not be indicated, we opted for ter- iparatide.

  Weaving bone resilience: a case of co-occurrence of osteogenesis imperfecta and hypophosphatasia · 2026 · DOI

• Analyses that combine conventional histolog y with polarized light collagen assessment and Raman molecular profiling across diverse OI cases have not been extensively reported.

  Histological and Molecular Characterization of Bone Integrity in Osteogenesis Imperfecta: A Case Series across Genetic Subtypes · 2026 · DOI

• It is not yet known whether early treatment can reduce the incidence or severity of foramen magnum stenosis, spinal stenosis, lower-limb deformity, or the need for orthopedic surgery. The potential influence of vosoritide and future disease-modifying therapies on struc- tural complications remains uncertain. At present, standardized protocols for combining these interventions are lacking. The psychosocial experience of parents remains poorly studied.

  Healthcare and Psychosocial Needs in Achondroplasia Across the Lifespan: Developmental Functioning, Multidisciplinary Care, and Family-Centered Outcomes · 2026 · DOI

• Precision therapies have changed the direction of achondroplasia management by introducing the possibility of modifying parts of the disease course, rather than only treating its consequences. This shift is important, but it should not be overstated. Achondroplasia remains a multisystem condition, and future treatment will still need to be integrated into long-term monitoring, functional support, psychosocial care, and patient advocacy. A major priority is the collection of real-world evidence. As more infants and young children begin treatment early, routine clinical data will become essential for understanding long- term safety and effectiveness outside trial settings. This is especially relevant for children treated in the neonatal period or early infancy, where experience remains limited. Current recommendations will likely need revision as evidence accumulates. One unresolved question is whether treatment can influence structural complications, not only growth velocity. Outcomes such as foramen magnum stenosis, spinal canal development, limb deformities, and axial skeletal growth remain incompletely defined. For cranio-cervical abnormalities, longitudinal MRI studies will be needed to clarify growth patterns, refine screening intervals, and link imaging findings more accurately with clinical decisions. Future research will also need to move beyond a narrow focus on longitudinal growth and MAPK inhibition. FGFR3 remains central, but other pathways, including PI3K/AKT, Wnt/β-catenin, BMP, hedgehog, and retinoid signaling, may contribute to growth plate biology and skeletal development [7]. Single-cell analyses, multi-omics approaches, and improved animal models may help define the cellular complexity of the disease and identify more precise therapeutic targets. The relationship between pharmacological therapy and orthopedic management is another open area. If emerging treatments alter skeletal growth or deformity progression, they may also change the timing and indications for guided growth, limb lengthening, or corrective osteotomies. At present, there are no universal protocols for combining these approaches. Prospective data and multidisciplinary decision- making will be needed, with patients and families involved in defining realistic goals and acceptable trade-offs. https://doi.org/10.3390/children13081121 Children 2026, 13, 1121 20 of 23 The combination of vosoritide with orthopedic interventions remains particularly uncertain. Earlier treatment may plausibly improve final height and body proportions and perhaps reduce some complications, but it is not yet clear whether it decreases surgical need, changes deformity recurrence, or affects bone healing after osteotomy [6]. Until stronger evidence is available, decisions should remain individualized according to residual growth, functional priorities, and patient preference. New molecular targets are also beginning to expand the field beyond FGFR3-centered strategies. Dysregulation of Wnt/β-catenin signaling has been implicated in craniofacial development, and DKK1 inhibition has shown promising effects on mandibular growth and chondrocyte differentiation in experimental models. These findings suggest that future treatment may become more region-specific, addressing craniofacial or axial abnormalities as well as long-bone growth. Gene-based and epigenetic strategies are still speculative, but they may be transfor- mative in the longer term. Experimental work suggests that reducing FGFR3 expression, rather than correcting the mutation itself, can improve skeletal development. Targeting cartilage-specific enhancers such as -29E has produced preclinical improvements in long bone growth, vertebral development, and foramen magnum size. Approaches such as CRISPR-mediated enhancer modulation, RNA interference, or other gene-silencing strate- gies are promising in concept, but major barriers remain: delivery to avascular cartilage, sufficient targeting of relevant cells, and identification of the safest and most effective timing. Future treatment will also need to address adherence and treatment burden. Expe- rience with vosoritide shows that long-term benefit depends not only on biological efficacy but also on the ability of families and patients to sustain daily injections, monitoring, and follow-up. Because treatment is elective and can be stopped without immediate medical harm, shared decision-making remains central. Families need realistic expectations, clear communication, and ongoing support. The future of achondroplasia care is unlikely to depend on a single definitive therapy. A more plausible model is individualized care com- bining pharmacological, orthopedic, rehabilitative, and possibly genetic strategies, adapted to age, phenotype, complications, and patient priorities. As the field evolves, evidence will need to be re-evaluated continuously and integrated carefully into clinical practice.

  From FGFR3 Hyperactivation to Disease-Modifying Therapy in Pediatric Achondroplasia: Molecular Mechanisms, Clinical Evidence, and Emerging Treatments · 2026 · DOI

• The limitations of this study include the small sample size of patients with premature consolidation, the monocentric nature of the cohort subjected to selection bias, the absence https://doi. 2026, 15, 6610 8 of 9 of a comparison group of achondroplastic patients without premature consolidation to evaluate which parameters differ, the impossibility of performing qualitative histological assessments of the premature consolidation zones following calloclasis, and the absence of standardized outcomes (particularly regarding complications, fixation duration, HI, and regenerate quality) that could be examined in future studies.

  Premature Consolidation of Regenerated Bone During Limb Lengthening with External Fixation in Achondroplastic Patients: Case Series and Literature Review · 2026 · DOI

• Current evidence remains insufficient to establish whether revision rates, implant survival or complication profiles differ significantly from those observed in more severe phe- notypes, and prospective phenotype-stratified studies are required. Although type-I-specific evidence remains limited, available phenotype-stratified and mixed-cohort data support the feasibility of Fassier–Duval fixation in selected patients with mild OI.

  Minimally Invasive Fassier–Duval Telescopic Rodding of the Lower Limb in Pediatric Osteogenesis Imperfecta: Current Evidence and Implications for Type I (Non-Deforming) Disease · 2026 · DOI

• Furthermore, few studies stratify outcomes according to Sillence classification, resulting in limited evidence specific to patients with type I (Lobstein) disease [7,14].

  Minimally Invasive Fassier–Duval Telescopic Rodding of the Lower Limb in Pediatric Osteogenesis Imperfecta: Current Evidence and Implications for Type I (Non-Deforming) Disease · 2026 · DOI

• Consequently, penetrance and expressivity vary widely, reflecting the complex interplay of genetic and non-genetic determinants in type II collagen disorders.

  Somatic Mosaicism Modulating Clinical Severity in COL2A1-Related Skeletal Dysplasia: A Case of Profound Skeletal Asymmetry · 2026 · DOI

• Determinants of this phenotypic heterogeneity are not fully understood; however, variants that disrupt critical steps in collagen synthesis are generally associated with more severe mani- festations. To our knowledge, such marked skeletal asymmetry has not been described among previously reported mosaic COL2A1-related disor- ders. Overall, molecular mechanisms underlying this variabil- ity remain incompletely understood, therefore, phenotypic heterogeneity is thought to arise from the influence of envi- ronmental factors and polymorphisms in disease-modify- ing genes or regulatory elements. 2 Schematic representation illustrating right-sided mosaicism expressivity vary widely both between and within affected families [15, 16]. While mosaicism is well documented in other skeletal dysplasias, most notably osteogenesis imperfecta and achondroplasia [12], its occur- rence in COL2A1-related disorders is uncommon and likely underrecognized.

  Somatic Mosaicism Modulating Clinical Severity in COL2A1-Related Skeletal Dysplasia: A Case of Profound Skeletal Asymmetry · 2026 · DOI

• While the optimal TBS value for preventing bone fractures in OI remains unknown, we believe that, in combination with BMD measurements, the TBS may serve as an indicator for setting appropriate protocols and goals for BIS treatment in children with OI based on the disease severity.

  Trabecular bone scores in children with osteogenesis imperfecta respond differently to bisphosphonate treatment depending on disease severity · 2024 · DOI

• Emerging therapies, such as anti-TNF agents, show a promising rationale during disease flares; however, robust clinical data are still lacking.

  Hajdu–Cheney Syndrome in a Two-Generation Family: Longitudinal Skeletal Progression and Differential Therapeutic Responses in a Mother and Her Son · 2026 · DOI

• Nevertheless, the magnitude of these benefits varies, and their long-term durability remains uncertain. Fur- ther investigation into the molecular mechanisms by which modulation of these genes affects bone quality and fracture healing is warranted.

  Balancing osteogenesis and adipogenesis in osteogenesis imperfecta: PLIN2 and E2F2 as key targets for mesenchymal stem cell therapy · 2026 · DOI

• The same recent series also reported pseudotumor cerebri in a substantial proportion of affected patients, suggesting that raised intracranial pressure may be an underrecognized complication of pycnodysostosis.

  Pycnodysostosis: Report of Two Novel CTSK Variants in a Child · 2026 · DOI

• Therefore, although a molecular diag- nosis could not be established, the clinical and radiological presen- tation strongly supported the diagnosis of osteopetrosis.

  Neonatal hypocalcemia and hydrocephalus as early manifestations of intermediate osteopetrosis: successful hematopoietic stem cell transplantation despite negative genetic testing: a case report · 2026 · DOI

• Multidisciplinary surveillance remains es- sential because the long-term effects of disease-modifying therapies on final height, skeletal proportionality, cranio-spinal complications, and orthopedic outcomes remain uncertain.

  From FGFR3 Hyperactivation to Disease-Modifying Therapy in Pediatric Achondroplasia: Molecular Mechanisms, Clinical Evidence, and Emerging Treatments · 2026 · DOI

• From the perspective of genome-editing research, achondroplasia remains an attrac- tive target for etiology-directed genetic therapy because of its well-defined molecular cause, but delivery to growth plates remains the key limitation.

  Achondroplasia: Current Disease-Modifying Therapies and Genome Editing Strategies · 2026 · DOI

• BACKGROUND: While data support that fluoroquinolones exacerbate lethal sequela in some types of aortic pathology, the potential danger of these drugs has not been studied in the context of vEDS.

  Ciprofloxacin Exposure Promotes Aortic Dissection and Arterial Rupture in a Mouse Model of Vascular Ehlers-Danlos Syndrome · 2026 · DOI

• Elastin-like polypeptides (ELPs) are promising drug delivery vehicles, yet their bioactivities remain underexplored, likely due to the lack of applicable protein delivery systems.

  Beta-Glucan Nanogels Mediate Intracellular Delivery of Elastin-Like Polypeptides for Efficient Macrophage Polarization · 2026 · DOI

• Future research should explore alternative treatment paradigms and develop guidelines tailored to the distinct risks in this population.

  1041 Treat or Observe? Real-World Outcomes of Unruptured Aneurysm Management in Marfan and Ehlers-Danlos Syndrome Patients · 2026 · DOI

• Pregnancy-related outcomes and timing of LDS diagnosis remain poorly characterized.

  Pregnancy-Related Vascular Outcomes in Loeys–Dietz Syndrome: A Retrospective Cohort Study and Case Series · 2026 · DOI

• These results demonstrate the Aga2/+ model responded to PTH and support further investigation into whether PTH is effective in adult individuals with moderate/severe OI who have limited treatment options.

  PTH treatment is effective in the Aga2/+ mouse model of moderate to severe osteogenesis imperfecta · 2026 · DOI

• BACKGROUND: Ventricular arrhythmias are increasingly recognized in Marfan syndrome, but associated clinical and structural features remain incompletely defined.

  Ventricular Arrhythmias in Marfan Syndrome: Prevalence and Clinical Correlates in a Multicenter Cohort · 2026 · DOI

• • Previous studies have reported inconsistent findings regarding the relationship between joint hypermobility and physical activity levels.

  Lower-limb joint hypermobility and associations with physical performance in school-aged children: a cross-sectional study · 2026 · DOI

• Abstract Lower-limb joint hypermobility has been associated with alterations in physical function; however, its independent relationship with physical performance in asymptomatic school-aged children remains unclear.

  Lower-limb joint hypermobility and associations with physical performance in school-aged children: a cross-sectional study · 2026 · DOI

Most-cited papers in Connective tissue disorders research

• Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines · PEDIATRICS · 2010 · 508 citations
• Reconstruction of Mandibular Continuity Defects With Bone Morphogenetic Protein-2 (rhBMP-2) · Journal of Oral and Maxillofacial Surgery · 2008 · 229 citations
• Nationwide age references for sitting height, leg length, and sitting height/height ratio, and their diagnostic value for disproportionate growth disorders · Archives of Disease in Childhood · 2005 · 220 citations
• Joint hypermobility and genetic collagen disorders: are they related? · Archives of Disease in Childhood · 1999 · 217 citations
• Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and the association with Sweet syndrome in two siblings · The Journal of Pediatrics · 1989 · 200 citations
• Evaluation of oral problems in an osteogenesis imperfecta population · Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology · 1999 · 162 citations
• Growth charts for Down's syndrome from birth to 18 years of age · Archives of Disease in Childhood · 2002 · 153 citations
• Etiologies and Early Diagnosis of Short Stature and Growth Failure in Children and Adolescents · The Journal of Pediatrics · 2014 · 144 citations
• Longitudinal growth changes in untreated subjects with Class II Division 1 malocclusion · American Journal of Orthodontics and Dentofacial Orthopedics · 2008 · 139 citations
• The Fibrillin‐1/VEGFR2/STAT2 signaling axis promotes chemoresistance via modulating glycolysis and angiogenesis in ovarian cancer organoids and cells · 癌症：英文版 · 2022 · 132 citations

Most recent work

• Histone Lactylation–Mediated Metabolic Remodeling in Vascular Smooth Muscle Cells Aggravates Aortic Aneurysm and Dissection by Promoting Lactate Accumulation · Circulation · 2026
• Bio‐Inspired Smart Elastin‐Like Polypeptides (ELPs) for Precision Drug Delivery: Molecular Strategies, Thermal Responsiveness, and Translational Advances · Advanced Healthcare Materials · 2026
• Phase 3 Trial of Oral Infigratinib in Children with Achondroplasia · New England Journal of Medicine · 2026
• UK consensus guidelines for multidisciplinary care of children and young people with achondroplasia: a modified Delphi process · Archives of Disease in Childhood · 2026
• Multiscale analysis and functional validation of the cellular and genetic determinants of skeletal disease · bioRxiv · 2026
• Teriparatide Plus Zoledronic Acid for Osteogenesis Imperfecta · JAMA · 2026
• Revealing FPR1 as a potential pathogenic biomarker for aortic dissection based on Mendelian randomization, single-cell transcriptome and clinical data analysis · Biology Direct · 2026
• An overview of the International Consensus Statement on achondroplasia · Orphanet Journal of Rare Diseases · 2026
• A Phase II Basket Trial of Vosoritide in Children with RASopathies, ACAN and NPR2 Deficiency · The Journal of Clinical Endocrinology & Metabolism · 2026
• Pathways to Facilitate Early Recognition and Diagnosis of Hypochondroplasia · Advances in Therapy · 2026

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