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European Journal of Pediatrics Jun 2024Achondroplasia (ACH; MIM #100,800), caused by a heterozygous gain of function pathogenic variant in the fibroblast growth factor receptor 3 gene (FGFR3; MIM*134,934), is...
Achondroplasia (ACH; MIM #100,800), caused by a heterozygous gain of function pathogenic variant in the fibroblast growth factor receptor 3 gene (FGFR3; MIM*134,934), is the most prevalent and most readily identifiable cause of disproportionate short stature that is compatible with life. In addition, individuals with achondroplasia face significant medical, functional, and psychosocial challenges throughout their lives. This study assessed associated morbidities in patients with achondroplasia at a single center in Turkey. In this study, the clinical findings and associated morbidities of a group of patients with achondroplasia (n = 68) with clinical multidisciplinary follow-up at a single center between the years 2005-2023 are evaluated retrospectively. A total of 68 patients, 30 male (44.1%) and 38 female (55.9%), were evaluated. In the majority (84.2%) of patients, shortness of extremities was detected in the prenatal period at an average of 28.7 gestational weeks (± 3.6 SDS) with the aid of ultrasonography. More than half (n = 34/63, 54%) of the patients had a father of advanced paternal age (≥ 35 years). Among the complications, respiratory system manifestations, including obstructive sleep apnea (70%), ear-nose-throat manifestations including adenoid hypertrophy (56.6%) and otitis media (54.7%), neurological manifestations due to foramen magnum stenosis (53.2%), and skeletal manifestations including scoliosis (28.8%), are represented among the most common. The mortality rate was 7.3% (n = 5/68).Conclusion: This study not only represents the first retrospective analysis of the associated morbidities of patients with achondroplasia from a single center in Turkey but also will provide a reference point for future studies.
PubMed: 38879704
DOI: 10.1007/s00431-024-05643-y -
Cureus May 2024Achondroplasia, characterized by short stature and skeletal abnormalities, is caused by a gain-of-function variant in the fibroblast growth factor receptor 3 gene....
Achondroplasia, characterized by short stature and skeletal abnormalities, is caused by a gain-of-function variant in the fibroblast growth factor receptor 3 gene. Vosoritide, a C-type natriuretic peptide analog, is an emerging treatment for achondroplasia that functions by promoting endochondral ossification. Vosoritide was approved for the treatment of achondroplasia in Europe and the United States in 2021, and in Japan, the following year. However, vosoritide is associated with a risk of hypotension and vomiting after subcutaneous injection due to its vasodilating effect. Herein, we present two cases of cardiovascular adverse events in infants following vosoritide injection. Case 1 involved a one-month-old female infant with achondroplasia who received the first subcutaneous injection of vosoritide 30 minutes after her last formula intake. Following injection, she developed transient symptomatic hypotension accompanied by vomiting. Although established guidelines recommend that injections be administered after approximately 30 minutes (Europe/Japan) or within one hour (USA) following the last feeding, an extended interval of 1.5 to two hours was required to prevent hypotension-associated vomiting. Case 2 involved a three-month-old female infant with achondroplasia. The first subcutaneous vosoritide injection was administered four hours after the last formula intake, and she subsequently developed prolonged compensated shock with marked tachycardia requiring intervention, including repetitive bolus saline injection. These cases indicate the need to monitor patients for cardiovascular adverse events following subcutaneous injection of vosoritide in early infancy.
PubMed: 38841012
DOI: 10.7759/cureus.59695 -
Asian Journal of Endoscopic Surgery Jul 2024Thanatophoric dysplasia (TD) is a rare and severe type of skeletal dysplasia. Typical clinical findings include macrocephaly, shortening of the four limbs,...
Thanatophoric dysplasia (TD) is a rare and severe type of skeletal dysplasia. Typical clinical findings include macrocephaly, shortening of the four limbs, underdeveloped lungs, and thoracic hypoplasia. Neonates with TD develop severe respiratory problems due to thoracic hypoplasia and require respiratory management for survival. Despite the resolution of respiratory problems, long-term survival cases are rare. Previous studies have reported that surgical procedures in patients with TD are limited to those necessary for survival, including tracheostomy, laminectomy, and ventricular shunt. A 1-year-old boy with TD was treated with laparoscopic herniorrhaphy. To the best of our knowledge, this is the first report of TD treated with laparoscopic procedure.
Topics: Humans; Male; Laparoscopy; Hernia, Inguinal; Herniorrhaphy; Thanatophoric Dysplasia; Infant
PubMed: 38839103
DOI: 10.1111/ases.13325 -
Journal of Biomedical Research May 2024Achondroplasia is a genetic condition characterized by skeletal dysplasia that results in characteristic craniofacial and spinal abnormalities. It is the most common...
Achondroplasia is a genetic condition characterized by skeletal dysplasia that results in characteristic craniofacial and spinal abnormalities. It is the most common form of short-limbed skeletal dysplasia. Additionally, a pregnant patient who is morbidly obese warrants specific anatomical and physiological considerations, such as a difficult airway with potential hypoxia, full stomach precautions, and a reduced functional residual capacity. Achondroplasia increases the risks of maternal and fetal complications. Although neuraxial techniques are generally preferred for cesarean sections, there is no consensus among patients with achondroplasia. We aimed to discuss the anesthetic challenges in an achondroplastic patient and report our regional anesthesia approach for an elective cesarean section.
PubMed: 38832540
DOI: 10.7555/JBR.37.20230301 -
Archives of Disease in Childhood May 2024Foramen magnum stenosis in achondroplasia carries a risk of sudden death. A proportion of these patients benefit from foramen magnum decompression (FMD). The...
INTRODUCTION
Foramen magnum stenosis in achondroplasia carries a risk of sudden death. A proportion of these patients benefit from foramen magnum decompression (FMD). The Achondroplasia Foramen Magnum Score (AFMS) was developed to stratify those most at risk. We hypothesise that this score may be reflected in neurophysiological findings.
METHODS
Patients with achondroplasia who had undergone FMD (n=20) were retrospectively grouped into AFMS 2, 3 and 4. Amplitude from tibialis anterior (TA) and the percentage change in somatosensory evoked potential (SSEP) latency after FMD were reported.
RESULTS
Baseline motor evoked potential amplitudes for patients with AFMS=4 were significantly lower left (p=0.0017 and p=0.02 for right and left TA, respectively) compared with AFMS grades 2 and 3. Median reduction (% change) in SSEP latency (ms) after surgery was not significantly different in any of the patients.
CONCLUSIONS
This short report cross-references AFMS to intraoperative neuromonitoring. Baseline amplitudes were noticeably lower in the most severe AFMS group. This observation supports the notion that AFMS can help risk stratify patients and aid in surgical selection.
PubMed: 38816068
DOI: 10.1136/archdischild-2023-326360 -
EClinicalMedicine May 2024Hypochondroplasia is a rare autosomal dominant skeletal dysplasia due to activating variants in . It presents with disproportionate short stature with a wide range of...
BACKGROUND
Hypochondroplasia is a rare autosomal dominant skeletal dysplasia due to activating variants in . It presents with disproportionate short stature with a wide range of clinical severity. There are currently no approved medications to treat short stature in children with hypochondroplasia. Vosoritide is a C-type natriuretic peptide analog that was recently approved for improving growth in children with achondroplasia. We aimed to evaluate the safety and efficacy of vosoritide in children with hypochondroplasia.
METHODS
We conducted a single-arm, phase 2, open-label trial at a single centre in the USA and enrolled 26 children with hypochondroplasia. The trial consists of a 6-month observation period to establish a baseline annualized growth velocity followed by a 12-month intervention period during which vosoritide is administered daily via subcutaneous injection at a dose of 15 μg/kg/day. The trial's co-primary endpoints included the incidence of adverse events and the change from baseline in age-sex standardized annualized growth velocity and height standardized deviation score (SDS) after 12 months of treatment. This trial is registered with ClinicalTrials.gov (NCT04219007).
FINDINGS
Twenty-four participants with a mean age of 5.86 years received vosoritide therapy. The first participant was enrolled on August 4, 2020, and the final participant completed the 18-month trial on September 8, 2023. Vosoritide was well tolerated with no treatment-related serious adverse events. Injection site reactions occurred in 83.3% of participants. No participants discontinued therapy due to an adverse event. Annualized growth velocity increased by 2.26 standard deviations (SD) and height SDS increased by 0.36 SD during the treatment period versus the observation period. Hypochondroplasia specific height SDS increased by 0.38 SD. There was a 1.81 cm/year increase in absolute annualized growth velocity.
INTERPRETATION
Vosoritide was safe and effective in increasing growth velocity in children with hypochondroplasia. Efficacy was similar to what has been reported in children with achondroplasia.
FUNDING
This study was supported by an investigator-initiated grant from BioMarin Pharmaceutical.
PubMed: 38813446
DOI: 10.1016/j.eclinm.2024.102591 -
Neurosurgery May 2024Adults with achondroplasia are more vulnerable to suffer from neurogenic claudication because of a congenital narrow spinal canal, which makes them susceptible to lumbar...
BACKGROUND AND OBJECTIVES
Adults with achondroplasia are more vulnerable to suffer from neurogenic claudication because of a congenital narrow spinal canal, which makes them susceptible to lumbar spinal stenosis (LSS). The study aims to investigate the correlations between sagittal alignment parameters and the degree of LSS in patients with achondroplasia with LSS.
METHODS
The radiological data of adult achondroplasts presented to the neurosurgical clinic of our medical center from 2019 to 2022 were collected. Lumbar stenosis was graded using the Schizas scale, and the dural sac cross-sectional area (DSCA) was measured. The angles defining the spinopelvic parameters comprising lumbar lordosis, thoracolumbar kyphosis, sagittal vertical axis, pelvic tilt, sacral slope, and pelvic incidence were measured. Spearman or Pearson correlation was used to investigate the association between sagittal misalignment and LSS.
RESULTS
A total of 34 achondroplastics were enrolled, with a median age of 44.3 ± 15.5 years, ranging from 18.6 to 78.5 years. Larger thoracolumbar kyphosis was associated with more severe stenosis according to the Schizas scale of the L12 lumbar level (r = 0.44, P = .020, 95% CI [0.08, 0.70]). Larger sagittal vertical axis correlated with a smaller DSCA at L23 (r = -0.53, P = .036, 95% CI [-0.81, -0.04]) and L45 (r = -0.66, P = .004, 95% CI [-0.87, -0.26]). Larger pelvic tilt was demonstrated to be associated with a smaller DSCA of the L34 lumbar level (r = -0.42, P = .027, 95% CI [-0.68, -0.05]) and the L45 lumbar level (r = -0.47, P = .011, 95% CI [-0.71, -0.12]).
CONCLUSION
The upper LSS may be attributed to an increased kyphosis of the thoracolumbar spine. On the contrary, the lower LSS seemed to be correlated with a more backward tilt of the pelvis.
PubMed: 38809018
DOI: 10.1227/neu.0000000000003007 -
Taiwanese Journal of Obstetrics &... May 2024We present perinatal imaging findings of a fetus with Pfeiffer syndrome and a heterozygous c.1019A>G, p.Tyr340Cys (Y340C) mutation in FGFR2 presenting a cloverleaf...
Perinatal imaging findings of a fetus with Pfeiffer syndrome and a heterozygous c.1019A>G, p.Tyr340Cys (Y340C) mutation in FGFR2 presenting a cloverleaf skull, craniosynostosis and short limbs on prenatal ultrasound mimicking thanatophoric dysplasia type II.
OBJECTIVE
We present perinatal imaging findings of a fetus with Pfeiffer syndrome and a heterozygous c.1019A>G, p.Tyr340Cys (Y340C) mutation in FGFR2 presenting a cloverleaf skull, craniosynostosis and short limbs on prenatal ultrasound mimicking thanatophoric dysplasia type II (TD2).
CASE REPORT
A 37-year-old, gravida 2, para 1, woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XY. However, craniofacial anomaly was found on prenatal ultrasound at 21 weeks of gestation, which showed a cloverleaf skull with severe craniosynostosis and relatively short straight long bones. Fetal magnetic resonance imaging (MRI) analysis at 22 weeks of gestation showed a cloverleaf skull, proptosis and relatively shallowing of the sylvian fissures. Prenatal ultrasound at 24 weeks of gestation showed a fetus with a cloverleaf skull with a biparietal diameter (BPD) of 6.16 cm (equivalent to 24 weeks), an abdominal circumference (AC) of 18.89 cm (equivalent to 24 weeks) and a femur length (FL) of 3.65 cm (equivalent to 21 weeks). A tentative diagnosis of TD2 was made. The pregnancy was subsequently terminated, and a 928-g malformed fetus was delivered with severe craniosynostosis, proptosis, midface retrusion, a cloverleaf skull, broad thumbs and broad big toes. The broad thumbs were medially deviated. Whole body X-ray showed a cloverleaf skull and straight long bones. However, molecular analysis of FGFR3 on the fetus revealed no mutation in the target regions. Subsequent whole exome sequencing (WES) on the DNA extracted from umbilical cord revealed a heterozygous c.1019A>G, p.Tyr340Cys (Y340C) mutation in the FGFR2 gene.
CONCLUSION
Fetuses with a Y340C mutation in FGFR2 may present a cloverleaf skull on prenatal ultrasound, and WES is useful for a rapid differential diagnosis of Pfeiffer syndrome from TD2 under such a circumstance.
Topics: Humans; Female; Acrocephalosyndactylia; Pregnancy; Ultrasonography, Prenatal; Adult; Receptor, Fibroblast Growth Factor, Type 2; Craniosynostoses; Thanatophoric Dysplasia; Mutation; Diagnosis, Differential; Magnetic Resonance Imaging; Heterozygote; Infant, Newborn; Skull
PubMed: 38802203
DOI: 10.1016/j.tjog.2024.03.005 -
The Journal of Arthroplasty May 2024Total knee arthroplasty (TKA) in patients who have skeletal dysplasia is a technically challenging surgery due to deformity, joint contracture, and associated...
BACKGROUND
Total knee arthroplasty (TKA) in patients who have skeletal dysplasia is a technically challenging surgery due to deformity, joint contracture, and associated co-morbidities. Patients presenting with this condition have traditionally been treated with conservative measures, leading to poor outcomes. The aim of this study was to follow up on patients who had skeletal dysplasia following total knee arthroplasty, specifically with regards to clinical outcomes.
METHODS
A total of 31 knees (22 patients) with skeletal dysplasia that had undergone total knee arthroplasty in our institution were included in our study. The mean follow-up from index surgery was 110.3 months (range; 20 to 291). The type of dysplasia, implant used, and clinical outcomes with patient-reported outcome measures (PROMs) are presented.
RESULTS
There were eight patients (36.3%) who had a diagnosis of achondroplasia, followed by multiple epiphyseal dysplasia (31.8%) and spondyloepiphyseal dysplasia (22.7%). There were fourteen men and eight women who had a mean age of 51 years (range, 28 to 73). Custom implants were required in twelve cases (38.7%), custom jigs were used in six cases (19.4%), and robotic assisted surgery was used in two (6.5%) total knee arthroplasties. Hinged prostheses were used in seventeen cases (54.8%), posterior stabilized in nine (29.0%), and cruciate retaining implants in five (16.1%). There was one patient who sustained an intra-operative medial tibial plateau fracture treated with concomitant open reduction and internal fixation. There was one revision that occurred during the follow-up period with a patella resurfacing for continued anterior knee pain. Post-operatively, Oxford knee scores improved on average by 12.2 points. The 10- and 20-year all-cause revision-free survival was 96.8 respectively.
CONCLUSION
Despite the technical challenges and complexity associated with this unique patient cohort, we demonstrated excellent implant survivorship and clinical outcomes post-total knee arthroplasty with mid- to long-term follow up of over 20 years. We recommend pre-operative cross-sectional imaging for precise planning and implant templating with multidisciplinary team decision-making. Despite our results, functional outcomes remain inferior to primary arthroplasty within the general population, though we still recommend this treatment modality to appropriately counseled patients.
PubMed: 38797447
DOI: 10.1016/j.arth.2024.05.051 -
Advances in Therapy Jul 2024Achondroplasia is a lifelong condition requiring lifelong management. There is consensus that infants and children with achondroplasia should be managed by a...
Achondroplasia is a lifelong condition requiring lifelong management. There is consensus that infants and children with achondroplasia should be managed by a multidisciplinary team experienced in the condition. However, many people are lost to follow-up after the transition from paediatric to adult care, and there is no standardised approach for management in adults, despite the recent availability of international consensus guidelines. To address this, the European Achondroplasia Forum has developed a patient-held checklist to support adults with achondroplasia in managing their health. The checklist highlights key symptoms of spinal stenosis and obstructive sleep apnoea, both among the most frequent and potentially severe medical complications in adults with achondroplasia. The checklist acts as a framework to support individuals and their primary care provider in completing a routine review. General advice on issues such as blood pressure, pain, hearing, weight, adaptive aids, and psychosocial aspects are also included. The checklist provides key symptoms to be aware of, in addition to action points so that people can approach their primary care provider and be directed to the appropriate specialist, if needed. Additionally, the European Achondroplasia Forum offers some ideas on implementing the checklist during the transition from paediatric to adult care, thus ensuring the existing multidisciplinary team model in place during childhood can support in engaging individuals and empowering them to take responsibility for their own care as they move into adulthood.
Topics: Adult; Humans; Achondroplasia; Checklist; Europe; Sleep Apnea, Obstructive; Spinal Stenosis; Transition to Adult Care
PubMed: 38748332
DOI: 10.1007/s12325-024-02880-3