Fibroblast growth factors and their receptors (FGFR) have major roles in both human growth and oncogenesis. In adults, therapeutic FGFR inhibitors have been successful against tumors that carry somatic FGFR mutations. In pediatric patients, trials testing these anti-tumor FGFR inhibitor therapeutics are underway, with several recent reports suggesting modest positive responses. Herein, we report an unforeseen outcome in a pre-pubescent child with an FGFR1-mutated glioma who was successfully treated with FDA-approved erdafitinib, a pan-FGFR inhibitor approved for treatment of Bladder tumors. While on treatment with erdafitinib, the patient experienced rapid skeletal and long bone overgrowth resulting in kyphoscoliosis, reminiscent of patients with congenital loss-of-function FGFR3 mutations. We utilized normal dermal fibroblast cells established from the patient as a surrogate model to demonstrate that insulin-like growth factor 1 (IGF-1), a factor important for developmental growth of bones and tissues, can activate the PI3K/AKT pathway in erdafitinib-treated cells but not the MAPK/ERK pathway. The IGF-I-activated PI3K/AKT signaling rescued normal fibroblasts from the cytotoxic effects of erdafitinib by promoting cell survival. We, therefore, postulate that IGF-I-activated P13K/AKT signaling likely continues to promote bone elongation in the growing child, but not in adults, treated with therapeutic pan-FGFR inhibitors. Importantly, since activated MAPK signaling counters bone elongation, we further postulate that prolonged blockage of the MAPK pathway with pan-FGFR inhibitors, together with actions of growth-promoting factors including IGF-1, could explain the abnormal skeletal and axial growth suffered by our pre-pubertal patient during systemic therapeutic use of pan-FGFR inhibitors. Further studies to find more targeted, and/or appropriate dosing, of pan-FGFR inhibitor therapeutics for children are essential to avoid unexpected off-target effects as was observed in our young patient.

This case report sheds light on the management of skeletal deformity in a young child with X-linked hypophosphatemia (XLH), emphasizing the significance of a timely orthotic intervention alongside pharmacological treatment, which is a strategy not frequently highlighted in the XLH literature. The patient, a 2-year-and-7-month-old female, presented with classic XLH symptoms, including short stature, pronounced genu varum, and hypophosphatemia, with deformities observed in both the coronal and sagittal planes of the femur and tibia. Despite initial reliance on pharmacotherapy, which proved insufficient for skeletal realignment, the integration of orthotic treatment at age 3 marked a pivotal turn in the management strategy. By the age of 5 years and 9 months, this combined approach yielded significant improvements: the deformities in the femur and tibia were notably corrected, tibial torsion was addressed, and enhanced limb alignment was achieved, as corroborated by radiographic evidence. This case underscores the effectiveness of orthotic intervention as a critical and underemphasized adjunct to pharmacological therapy in managing XLH in early childhood. It advocates for the early inclusion of orthotic measures to optimize treatment outcomes and expand the range of management strategies for limb deformities.

Skeletal deformity is characterized by an abnormal anatomical structure of bone and cartilage. In our previous studies, we have found that a substantial proportion of patients with skeletal deformity could be explained by monogenic disorders. More recently, complex phenotypes caused by more than one genetic defect (i.e., dual molecular diagnosis) have also been reported in skeletal deformities and may complicate the diagnostic odyssey of patients. In this study, we report the molecular and phenotypic characteristics of patients with dual molecular diagnosis and variable skeletal deformities.
From 1108 patients who underwent exome sequencing, we identified eight probands with dual molecular diagnosis and variable skeletal deformities. All eight patients had dual diagnosis consisting of two autosomal dominant diseases. A total of 16 variants in 12 genes were identified, 5 of which were of de novo origin. Patients with dual molecular diagnosis presented blended phenotypes of two genetic diseases. Mendelian disorders occurred more than once include Osteogenesis Imperfecta Type I (COL1A1, MIM:166200), Neurofibromatosis, Type I (NF1, MIM:162200) and Marfan Syndrome (FBN1, MIM:154700).
This study demonstrated the complicated skeletal phenotypes associated with dual molecular diagnosis. Exome sequencing represents a powerful tool to detect such complex conditions.

Multiple osteochondromas (MO) is a rare disorder, characterized by benign osteocartilaginous tumors (osteochondromas), arising from the perichondrium of bones. The osteochondromas increase during growth, frequently causing deformities and limitations. Our study aims to analyze the data captured by the Registry of Multiple Osteochondromas, to refine Istituto Ortopedico Rizzoli (IOR) Classification, providing a representative picture of the phenotypic manifestations throughout the lifespan. We conducted a single-institution cross-sectional study. Patients were categorized according to IOR Classification, which identifies three patients\' classes on the presence/absence of deformities and/or limitations. The present dataset was compared with our previously published data, to refine the classification. Nine hundred sixty-eight patients were included: 243 children (<10 years), 136 adolescents (10-15 years), and 589 adults. Of the entire population, half patients presented at least one deformity, and one quarter reported at least one limitation. Compared with our previous study, the amount of children was more than doubled and the percentage of mild/moderate cases was notably increased, giving a better disease overview throughout the lifespan and suggesting a different cut-off for dividing Class II in subclasses. We confirmed that MO is characterized by phenotypic heterogeneity, suggesting that an early classification of the disease may offer a useful tool to follow disease pattern and evolution, to support clinical practice, and to propose timely interventions.

UNASSIGNED: Homocystinuria has a wide range of clinical presentations ranging from near normal intelligence and appearance with just lens dislocation and minimal skeletal deformities to severe mental retardation with gross skeletal deformities. In this background, we describe one such case with skeletal deformity managed comprehensively.
UNASSIGNED: A 17-year-old boy presented with complaints of deformity of the left lower limb since childhood more evident for the past 5 years along with a history of blurring of vision. On examination the pubis-heal length > crown-pubis length along with genu valgum of left lower-limb with 16 cm intermalleolar distance. He also had a superolateral subluxation of the lens in both eyes. Valgus angle was 16° on the left leg compared to 6° on the right. The diagnosis of homocystinuria was confirmed by biochemical investigations. The left side genu valgum was addressed with medial closing wedge osteotomy and fixed with distal femur locking compression plating. Lens subluxation was treated with posterior chamber intra-ocular lens surgery. He was also given medical treatment and on regular monitoring of his homocysteine levels. The patient had good functional outcome at 2-year follow-up.
UNASSIGNED: Homocystinuria is a rare disease that needs early identification and effective management to avoid complications. Skeletal complications are common and include genu valgum, pes cavus, chest wall deformities, and skeletal deformities such as kyphosis and scoliosis. Skeletal deformities can be avoided when identified early and associated osteoporosis which is managed effectively. A holistic approach is needed in the management of such patients with inter-departmental coordination to bring quality to the life of patients with homocystinuria.

BACKGROUND: Hemifacial microsomia (HFM) is the second most common craniofacial congenital anomaly following cleft lip and palate. Because of the various phenotypic spectra and the severity of the deformity, a wide range of treatment approaches have been proposed. Recently, the surgery-first approach (SFA) was introduced to treat mild to moderate HFM, and it yielded a balanced facial appearance. The SFA not only promotes rapid improvement in facial aesthetics but also considerably reduces the overall treatment time.
METHODS: A female patient, aged 25 years old, sought orthodontic treatment with the chief complaint of dental and facial asymmetry. After a comprehensive physical examination and imaging analysis were performed, the patient was diagnosed with mild HFM that was primarily attributed to unilateral abnormal development of the maxilla-mandibular. The SFA was carried out to correct the skeletal deformity. The palatal suture was used as the midline of the maxilla in the surgical plan to center the maxilla, and the chin was also properly positioned to obtain a relatively symmetrical facial appearance. Four weeks after the surgery, the patient was referred for postsurgical orthodontics to decompensate the dentition and stabilize the occlusion. After 20 mo of treatment, all orthodontic appliances were removed. The posttreatment photographs of the patient and her smile confirmed good aesthetic and occlusal results.
CONCLUSIONS: Mild HFM can be corrected by SFA, which not only promotes rapid improvement in facial aesthetics but also considerably reduces the overall treatment time.

The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders characterized by abnormal accumulation of glycosaminoglycans (GAGs) in cells and tissues. MPS patients frequently exhibit failures of endochondral ossification during postnatal growth leading to skeletal deformity and short stature. In this review, we outline the current understanding of the cellular and molecular mechanisms underlying failures of endochondral ossification in MPS and discuss associated treatment challenges and opportunities.
Studies in MPS patients and animal models have demonstrated that skeletal cells and tissues exhibit significantly elevated GAG storage from early in postnatal life and that this is associated with impaired cartilage-to-bone conversion in primary and secondary ossification centers, and growth plate dysfunction. Recent studies have begun to elucidate the underlying cellular and molecular mechanisms, including impaired chondrocyte proliferation and hypertrophy, diminished growth factor signaling, disrupted cell cycle progression, impaired autophagy, and increased cell stress and apoptosis. Current treatments such as hematopoietic stem cell transplantation and enzyme replacement therapy fail to normalize endochondral ossification in MPS. Emerging treatments including gene therapy and small molecule-based approaches hold significant promise in this regard. Failures of endochondral ossification contribute to skeletal deformity and short stature in MPS patients, increasing mortality and reducing quality of life. Early intervention is crucial for effective treatment, and there is a critical need for new approaches that normalize endochondral ossification by directly targeting affected cells and signaling pathways.

OBJECTIVE: To measure the factors that affect functional leg length of Crowe type IV Developmental dysplasia of the hip (DDH) patients and to review our own methods to balance leg length discrepancy (LLD) in Crowe type IV DDH patients.
METHODS: This was a prospective observational study which started in June 2017 and ended in August 2019. Inclusion criteria included: (i) Crowe type I or Crowe type IV hip dysplasia patients who underwent total hip arthroplasty (THA) in the Department of Orthopaedics at our institution between July 2017 and June 2018; (ii) the patients were treated with our specific leg length balance strategy; and (iii) the related outcomes of patients were completely recorded. Finally, 18 consecutive Crowe type I patients (20 hips) and 14 consecutive Crowe type IV patients (18 hips) were selected and divided into two groups according to Crowe types. All patients received THA, and patients with a longer affected side and inferior anatomical acetabular positions in Crowe type IV group also received subtrochanteric osteotomy. During operation and after hip reduction, leg lengths were compared while two legs were in an extended position and the operative leg was on top of the non-operative one. Additional leg length adjustment was applied when leg length was considered to be unequal. Prior to surgery, subluxation height of the femoral head on the affected side, functional LLD, bony length of lower limbs, and distance from teardrops to the lowest point line of the sacroiliac joint were recorded. After surgery, cup sizes, functional LLD, and height of hip rotational centers were measured. Clinical evaluations, such as Harris Hip Score (HHS) and SF-12 scale, were also obtained before and after surgery for all patients.
RESULTS: At the last follow-up, functional LLD and clinical measurements of both Crowe type IV group and Crowe type I group were significantly improved. Compared with Crowe type I patients, Crowe type IV patients had a significantly lower MCS, a significantly longer leg lengthening length and a significantly lower hip center height after surgery. Significant differences of tibia length, leg length, and teardrop position were found between affected side and healthy side of Crowe type IV patients. Only three of 14 Crowe type IV patients remained under 1 cm functional LLD. Five patients in the Crowe type IV group developed lower limb numbness immediately following surgery, and they all recovered within 6 months. The average follow-up period for either group was 14 months, and all patients were followed-up at 1, 3, 6, and 12 months then yearly after surgery until the final follow-up.
CONCLUSIONS: After detailed leg length balance process, THA combined with transverse sub-trochanter osteotomy could be an effective method to achieve equal function leg length with most Crowe type IV patients.

X-linked hypophosphatemia (XLH), the most prevalent heritable renal phosphate (Pi) wasting disorder, is caused by deactivating mutations of PHEX. Consequently, circulating phosphatonin FGF23 becomes elevated and hypophosphatemia in affected children leads to rickets with skeletal deformity and reduced linear growth while affected adults suffer from osteomalacia and forms of ectopic mineralization. In 2015, we reported uniquely mild XLH in six children and four of their mothers carrying the non-coding PHEX 3\'-UTR mutation c.*231A>G. Herein, we characterize this mild XLH variant by comparing its features in 30 individuals to 30 age- and sex-matched patients with XLH but without the 3\'-UTR mutation. The \"UTR\" and \"XLH\" groups, both comprising 17 children (2 to 17 years, 3 girls) and 13 adults (23 to 63 years, 10 women), had mean ages of 23 years. Only 43% of the UTR group versus 90% of the XLH group had received medical treatment for their disorder, including 0% versus 85% of the females, respectively (ps < .0001). The UTR group was taller: mean ± SD height Z-score (HZ) -1.0 ± 1.0 versus -2.0 ± 1.4 (p = .0034), with significantly greater height for females (-0.9 ± 0.7 versus -2.3 ± 1.4; p = .0050) but not males (-1.2 ± 1.1 versus -1.9 ± 1.5; p = .1541), respectively. Mean ± SD \"arm span Z-score\" (AZ) did not differ between the UTR -0.8 ± 1.3 versus XLH -1.3 ± 1.8 groups (p = .2269). Consequently, the UTR group was more proportionate with a mean ∆Z (AZ - HZ) of 0.1 ± 0.6 versus 0.7 ± 1.0 (p = .0158), respectively. Compared to the XLH group, the UTR group had significantly higher fasting serum Pi and renal tubular threshold maximum for phosphorus per glomerular filtration rate (TmP/GFR) (ps ≤ .0060), serum FGF23 concentrations within the reference range (p = .0068), and similar serum alkaline phosphatase levels (p = .6513). UTR lumbar spine bone mineral density Z-score was higher (p = .0343). Thus, the 3\'-UTR variant of XLH is distinctly mild, especially in girls and women, posing challenges for its recognition and management. © 2020 American Society for Bone and Mineral Research.

BACKGROUND: Among the most prominent health problems marring the global poultry industry for several decades are skeletal abnormalities. The aim of this study was to investigate a recent emergence of a novel form of skeletal deformity affecting cervical spine in broiler chickens. This work presents the natural history of this newly emerging skeletal anomaly along with long term observations of epidemiological trends in commercial broiler flocks, and clinical and pathological features.
RESULTS: In distinction from other forms of skeletal deformities commonly reported in broiler chickens, this new form of cervical spine anomaly have been observed in newly hatched chicks and in fully developed embryos that died in the shell. On clinical and post mortem examination this condition presents characteristic features consistent with congenital cervical scoliosis and torticollis (CCST). The pathogenesis of CCST appears to be linked to pathological remodeling of the cervical vertebrae bone associated with excessive activity of osteoclasts. Long term observations indicate that the incidence of CCST showed increasing epidemiological trends over time. More recently CCST has been observed in newly hatched chicks with incidence ranging from 0.1 to > 1%, and in fully developed embryos that failed to hatch about 4 to 5%.
CONCLUSIONS: The increasing trends in incidence of CCST in commercial broiler flocks are of concern from an economic perspective, and also represent a very specific and important aspect of animal welfare.