Prenatal and neonatal phenotype of Larsen of La Réunion Island syndrome (B4GALT7-linkeropathy).

Larsen of La Réunion Island syndrome (LRS) is an autosomal recessive condition associated with multiple large joint dislocations, clubfeet, severe dwarfism, and distinctive facial features. LRS is caused by a recurrent homozygous variant in B4GALT7 gene with a founder effect in La Réunion population. Proteoglycans (PG) that are a major component of the extracellular matrix, are composed of a core protein connected to a glycosaminoglycans side chain via a tetrasaccharide linker region. B4GALT7 encodes galactosyltransferase I, one of the enzymes involved in the biosynthesis of the linker region. Conditions caused by pathogenic biallelic variants in genes implicated in the synthesis of the tetrasaccharide linker of PG are known as linkeropathies. Prenatal features are rarely described in this group of chondrodysplasias. We present a series of 12 unpublished patients having LRS and describe the perinatal phenotype. All the patients had a prenatal growth restriction with brevity of limbs. The other features revealed by ultrasounds were increased nuchal translucency at 10-12 weeks of gestation (50 %), feet abnormalities (clubfeet or metatarsus varus) (25 %), dislocation affecting at least one large joint (elbow, knee, wrist) (25 %). Bilateral bowing of femora was noted for two fetuses. Fibular hypertrophy was noted for one fetus. Prenatal helical computed tomography (CT) performed in three pregnancies showed additional data such as bowing of the forearm bones, proximal radio-ulnar synostosis, or dislocation of large joints. Prenatal sonographic and helical CT findings led to the prenatal diagnosis of LRS in four patients. We confirm that the neonatal clinical picture of LRS has an important overlap with that reported in patients with B4GALT7 deficiency outside La Réunion Island and other linkeropathies. The core of the phenotypic spectrum combines low birth height, micromelia, hypermobility, dislocation of at least one large joint, facial features with prominent eyes, microstomia, depressed nasal bridge, and midface hypoplasia. Other clinical features include clubfeet (33%), bifid thumb in one patient, and cardiac abnormalities in two patients. Radiological findings include radio-ulnar synostosis (75%), metaphyseal flaring, precocious carpal ossification, and a Swedish key appearance of the proximal femora. Finally, we also report radiological features rarely described in B4GALT7-linkeropathies, including bowing of the femora and fibular hypertrophy. Our results confirm the phenotypic continuum of LRS within linkeropathies with some additional findings, including a high frequency of clubfeet usually described in B3GALT6-linkeropathies, the presence of congenital heart diseases usually described in B3GAT3-linkeropathies, and a high frequency of metaphyseal flaring usually reported in B3GALT6 or XITLT1-linkeropathies. This is the first study that describes the perinatal phenotype in a cohort of patients with LRS. This study can help improve the prenatal diagnosis of the linkeropathies and add this group of conditions to the differential diagnosis of chondrodysplasias with multiple dislocations. In view of the founder effect for LRS in La Réunion Island, this disease should be suspected in fetuses with growth restriction and micromelia. Thus in case of LOH which include B4GALT7 identified in SNP-array, we recommend performing a targeted Sanger sequencing for the recurrent mutation c.808C > T; p. (Arg270Cys).

Larsen Syndrome and Associated Spinal Deformities.

Larsen syndrome is a rare genetic disorder that affects the connective tissue within the body. The present narrative review aims to examine the genetic basis of Larsen syndrome, clarify its symptoms, and define all the existing therapeutic approaches. A comprehensive search was performed in the PubMed database. Inclusion criteria considered molecular and clinical studies, management and surgical treatment of related deformities, case reports of patients with the syndrome, reviews of the associated anomalies, articles whose full text is available in PubMed, and articles published in the English language. Larsen syndrome is caused by mutations in the FLNB gene, which encodes the cytoskeletal protein filamin B, crucial in the development of the skeleton. Symptoms include joint dislocations, characteristic facial features and anomalies of the spine. Larsen syndrome may be conservatively treated initially, although surgical intervention is usually required. Various surgical techniques, including posterior spinal fusion, anterior decompression, circumferential arthrodesis, and single-stage 360° fixation, have been proposed along with growth-sparing procedures. Preoperative and postoperative care and education ensure optimal results. Further research is needed to identify novel therapeutic modalities for this condition.

Staged Bilateral Total Hip Arthroplasty in a Patient With Larsen Syndrome.

Larsen syndrome is a rare genetic disorder characterized by weak connective tissues and various musculoskeletal abnormalities. This is a case report of a 39-year-old patient with Larsen syndrome who presented with over a decade of bilateral hip pain and difficulty ambulating. This patient has a prior history of bilateral congenital hip dislocations that were treated with open reduction and spica casting as a child with good result. Years later, she went on to develop bilateral hip osteoarthritis with significant remodeling of the proximal femur. The goal of this case presentation is to demonstrate the utility of total hip arthroplasty for this patient and discuss surgical challenges and considerations.

Anesthetic challenges in the management of Larsen syndrome: A rare congenital anomaly.

Larsen syndrome is a rare inherited disease associated with dislocations of multiple joints, typical syndromic facies, and multiple spine abnormalities. They often required multiple corrective orthopedic surgeries to regain their functional ability, thus needing repeated anesthesia. Apart from skeletal deformities, they have predicted difficult airway and need extreme care during intubation and positing of the patient. Abnormal posturing due to spinal deformity and poor pulmonary reserve due to kyphoscoliosis creates an extremely challenging situation for the anesthetist to manage the case during the perioperative period. Here we are describing the perioperative anesthetic management of a patient with Larsen syndrome.

A Further Case of Larsen's Syndrome: Clinical and Genotypic Challenges in Diagnosis.

Larsen's syndrome is characterized by dislocation of multiple large joints, digital anomalies, craniofacial dysmorphism, and short stature. In this paper, we describe a case of a 5-month-old boy with a triad of cardinal features in association with other signs. The diagnosis was confirmed by exome sequencing, which led to the identification of a novel missense variant NM_001457.4:c.4928C > G (p.Ala1643Gly) in the FLNB gene. We describe the role of protein modelling for the establishment of pathogenicity of this variant. We also outline the challenges in genetic diagnosis due to variable expressivity of the variant and discuss the clinicogenetic profile of previously reported patients with Larsen's syndrome in India.

Surgical management of cervical kyphosis in larsen syndrome. Case report and review of literature.

INTRODUCTION: and importance: Larsen syndrome is a rare genetic disorder that is characterized by multiple joint dislocations, flat faces that can also be referred to as "dish face", kyphoscoliosis, and anomalies of the vertebrae. Patients with this syndrome frequently develop various spinal deformities, one of them being kyphosis of the cervical spine. This deformity can lead to serious health manifestations if not surgically treated. CASE PRESENTATION: We report a case of a 6-month-old female, diagnosed with Larsen syndrome. She presented with progressive upper and lower limbs spasticity, flexed neck, and bilateral resistant developmental dysplasia of the hip. A C3 corpectomy with iliac crest allograft was done and 2.7 plates with screws in C2 and C4 were placed. An abduction brace (Pavlik harness) was used for 3 months after the surgery to prevent early collapse. CLINICAL DISCUSSION: Our patient was the youngest patient reported in the literature to be operated on. Although the type of surgery for patients with Larsen who suffer from spinal deformities is dictated by the severity of the deformity; the literature agrees that surgical intervention is the most important step in its management. CONCLUSION: If cervical kyphosis in a patient with Larsen syndrome is left untreated; the progression of the condition can eventually lead to paralysis. Early surgical correction can spare the patient future deterioration due to chronic cord compression.

Congenital knee dislocation, case report and review of the literature.

Congenital dislocation of the knee (CDK) is characterized by hyperextension of the knee with forward displacement of the proximal tibia. It is associated with other joint dislocations and deformities and may occur isolated or as part of different systemic syndromes. Despite its characteristic postnatal morphology, prenatal descriptions are very scarce. We report a case of CDK diagnosed at 20 weeks, discuss its physiopathology, diagnosis and management and review the current literature.

Management Dilemma of a Neuropathic Knee in a Known Case of Larsen Syndrome: A Case Report.

Introduction: Larsen syndrome (LS) is a rare genetic disorder affecting mainly the connective tissues. It is characterized by characteristic facial anomalies, cervical kyphosis, cardiorespiratory disorders, and multiple joint dislocations. We present a case of a 15-year-old male with unstable neuropathic knee joint instability in a known case of LS. The paucity of literature on the management of this rare condition puts an orthopedician in dilemma regarding the optimal treatment. Case Report: A 15-year-old male, known case of LS, presented to our outpatient department with pain and instability in the right knee for 2 years. Clinically, the patient was having syndromic facies. The diagnosis of LS was confirmed on gene mapping. The right knee was swollen with medial joint line tenderness and restricted flexion. The patient had coronal plane valgus instability. The hypertrophied synovium eroded the articular surface. The radiograph of knee was suggestive of neuropathic arthropathy in fragmentation stage. Conclusion: Orthopedician should be aware of such rare entity with its bony and soft-tissue manifestations. Neuropathic knee is not an absolute contraindication to total knee replacement, especially with advanced prosthesis. Primary arthrodesis to be considered in young adults with instability.

Transcaval aortic valve implantation in a patient with Larsen syndrome: technical and anesthetic challenges.

Transcatheter aortic valve implantation has emerged as a therapeutic option for patients with symptomatic severe aortic stenosis who are inoperable, or at very high risk of open-heart surgery. Recently, we encountered a patient with aortic stenosis and Larsen syndrome, who had short stature, obesity, kyphoscoliosis, multiple musculoskeletal deformities, and severe restrictive lung disease. An open-heart surgery in such a patient involves substantial peri-operative risk. A successful transcaval aortic valve implantation was done under general anesthesia.

An orthodontic perspective on Larsen syndrome.

BACKGROUND: Larsen syndrome (LS) is a rare disorder of osteochondrodysplasia. In addition to large-joint dislocations, craniofacial anomalies are typical characteristics. In this report, we performed orthodontic analyses, including skeletal and occlusal evaluations, to examine whether the craniofacial skeletal morphology leads to the craniofacial anomalies in LS. CASE PRESENTATION: A 5 year old Japanese girl who was clinically diagnosed with LS was referred to the orthodontic clinic in the Fukuoka Dental College Medical and Dental Hospital because of a malocclusion. Clinical findings at birth were knee-joint dislocations, equinovarus foot deformities, and cleft soft palate. The patient showed craniofacial anomalies with hypertelorism, prominent forehead, depressed nasal bridge, and flattened midface. To evaluate the craniofacial skeletal morphology, cephalometric analysis was performed. In the frontal cephalometric analysis, the larger widths between bilateral points of the orbitale were related to hypertelorism. The lateral cephalometric analysis revealed the midface hypoplasia and the retrognathic mandible. These findings were responsible for the flattened appearance of the patient's face, even if the anteroposterior position of the nasion was normal. Her forehead looked prominent in relation to the face probably because of the retrognathic maxilla and mandible. Both the study model and the frontal cephalometric analysis indicated constriction of the upper and lower dental arches. The posterior crossbite facilitated by the premature contacts had developed in association with the constriction of the upper dental arch. CONCLUSIONS: This patient had some craniofacial anomalies with characteristic appearances in LS. It was evident that the underlying skeletal morphology led to the craniofacial dysmorphism.

Novel GZF1 pathogenic variants identified in two Chinese patients with Larsen syndrome.

GZF1 was recently reported as a genetic factor associated with Larsen syndrome. Two patients presenting hip dislocation, scoliosis and severe myopia, as well as hearing loss and other abnormal features, were found to carry two novel compounds heterozygous variants in GZF1 (c.397400del, p. Leu133fs; and c.1474del, p. Met492fs) through whole-exome sequencing. The mRNA expression level of L133fs-GZF1 did not significantly differ from that of WT-GZF1. However, no HA-conjugated mutant protein was detected by western blotting, which was also confirmed by immunofluorescence staining. In addition, both mRNA transcription and protein expression levels of M492fs-GZF1 were significantly lower than those of wild type, and HA-tagged M492fs-GZF1 was mainly distributed in the cytoplasm of HEK 293 T cells. These results suggested that the two variants could lead to loss of function of GZF1. Our study was the second to report the association between GZF1 variants and Larsen syndrome. We also provided functional evidence for the pathogenicity of GZF1 variants, which expands the mutation spectrum and offers a basis for functional research on the role of GZF1 in the development of Larsen syndrome.

Deciphering the Role of Filamin B Calponin-Homology Domain in Causing the Larsen Syndrome, Boomerang Dysplasia, and Atelosteogenesis Type I Spectrum Disorders via a Computational Approach.

Filamins (FLN) are a family of actin-binding proteins involved in regulating the cytoskeleton and signaling phenomenon by developing a network with F-actin and FLN-binding partners. The FLN family comprises three conserved isoforms in mammals: FLNA, FLNB, and FLNC. FLNB is a multidomain monomer protein with domains containing an actin-binding N-terminal domain (ABD 1-242), encompassing two calponin-homology domains (assigned CH1 and CH2). Primary variants in FLNB mostly occur in the domain (CH2) and surrounding the hinge-1 region. The four autosomal dominant disorders that are associated with FLNB variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of FLNB variants contributing to the LS-AO-BD disorders, the genotype-phenotype correlation is still enigmatic. In silico prediction tools and molecular dynamics simulation (MDS) approaches have offered the potential for variant classification and pathogenicity predictions. We retrieved 285 FLNB missense variants from the UniProt, ClinVar, and HGMD databases in the current study. Of these, five and 39 variants were located in the CH1 and CH2 domains, respectively. These variants were subjected to various pathogenicity and stability prediction tools, evolutionary and conservation analyses, and biophysical and physicochemical properties analyses. Molecular dynamics simulation (MDS) was performed on the three candidate variants in the CH2 domain (W148R, F161C, and L171R) that were predicted to be the most pathogenic. The MDS analysis results showed that these three variants are highly compact compared to the native protein, suggesting that they could affect the protein on the structural and functional levels. The computational approach demonstrates the differences between the FLNB mutants and the wild type in a structural and functional context. Our findings expand our knowledge on the genotype-phenotype correlation in FLNB-related LS-AO-BD disorders on the molecular level, which may pave the way for optimizing drug therapy by integrating precision medicine.

A 360-Degree Surgical Approach for Correction of Cervical Kyphosis and Atlantoaxial Dislocation in the Case of Larsen Syndrome.

Larsen syndrome is chronic debilitating disease that presents with multiple joint dislocations and severely affects the cervical spine in the form of cervical kyphosis and atlantoaxial dislocation. Children usually present in early with a myriad of deficits, compressive myelopathy being the most common. In addition to a bony compression, there is sometimes a soft tissue component, which is seldom addressed. We present here a case of atlantoaxial dislocation with cervical kyphosis due to Larsen syndrome, and along with our previous experience on syndromic atlantoaxial dislocations, we try to define an algorithm for the treatment approach of these onerous challenges. The importance of early intervention is also emphasized with a literature review of similar cases. In addition to the obvious physical damage, early intervention can also avoid the more sinister socioeconomic face of this debilitating disease.

Craniovertebral junction instability in Larsen syndrome: An institutional series and review of literature.

OBJECTIVE: Larsen syndrome (LS) is characterized by osteo-chondrodysplasia, multiple joint dislocations, and craniofacial abnormalities. Symptomatic myelopathy is attributed to C1-C2 instability and sub-axial cervical kyphosis. In this article, we have analyzed the surgical outcome after posterior fixation in LS with craniovertebral junction instability. METHODS: Ten symptomatic pediatric patients, operated between 2011 and 2019, were included, and the clinical outcome was assessed by Nurick grade, neurological improvement, and complications. The requirement of anti-spasticity drugs, the degree of bony fusion, and restriction of neck movement were also noted. At last follow-up, patient satisfaction score (PSS) and back to school status were studied. We also reviewed the literature and categorized two types of presentation of reported LS patients and discussed the pattern of disease progression among both. RESULTS: Ten patients, age range 1.5-16 years, underwent 12 surgeries (6 C1-C2 fixation, 4 long-segment posterior cervical fixation, and 2 trans-oral decompressions as the second stage); the mean follow-up was 23 (range, 6-86 months). All the ten patients in our study had the characteristic "dish-" like face and nine patients had acral anomalies. The median Nurick grade improved from preoperative (median = 4) to follow-up (median = 3). The requirement of anti-spasticity drugs decreased in seven patients and the neck-pain improved in nine patients. The median satisfaction at follow-up was good (median PSS = 2); five patients were going back to school. CONCLUSION: Craniovertebral junction instability in LS is rare and surgically challenging. Early posterior fixation showed a promising outcome with a halt in the disease progression.

A case study of atypical Larsen syndrome with absent hallmark joint dislocations.

BACKGROUND: A family with skeletal and craniofacial anomalies is presented. Whole-exome sequencing (WES) analysis indicated a diagnosis of Larsen syndrome, although their clinical presentation does not include the hallmark joint dislocations typically observed in Larsen syndrome. METHODS: Patient consent for the sharing of de-identified clinical and genetic information, along with use of photographs for publication, was obtained. WES and variant segregation analysis by WES were performed by commercial laboratory, GeneDx (Gaithersburg, MD), on peripheral blood samples from the proband, her brother, and her parents using methods detailed on their website for test XomeDx Whole Exome Sequencing Trio (https://www.genedx.com/test-catalog/available-tests/xomedx-whole-exome-sequencing-trio/). WES uses next-generation sequencing (NGS) technology to assess for variants within the coding regions, or exons, of approximately 23,000 genes. For the FLNB gene (NM_001457.3), 100% of the coding region was covered at a minimum of 10x. GeneDx uses Sanger sequencing to confirm NGS variants. RESULTS: WES revealed a heterozygous pathogenic variant, p.Glu227Lys (c.679G>A), in the FLNB gene in three out of the four family members tested. This variant is associated with Larsen syndrome, a skeletal dysplasia condition with a wide range of phenotypic variability that usually includes congenital joint dislocations. CONCLUSION: This is a highly unusual presentation of Larsen syndrome in which the identifying hallmark trait is absent in the patients' phenotypes.

FEVR findings in patients with Loeys-Dietz syndrome type II.

BACKGROUND: Loeys-Dietz syndrome (LDS) is a connective tissue disorder that has phenotypic overlap with Marfan syndrome. In LDS, the aortic root dissections can be more aggressive and occur at a younger age than Marfan syndrome. MATERIALS AND METHODS: Review of two cases. RESULTS: A 7-year old boy with history of LDS was found to have a vitreous hemorrhage in the right eye. Further examination showed findings of Familial Exudative Vitreoretinopathy (FEVR). Both eyes were found to have peripheral non-perfusion and neovascularization. A non-related 25-month-old boy with no molecularly confirmed connective tissue disorder was found to have bilateral peripheral non-perfusion and bilateral tractional retinal detachments. The boy was clinically diagnosed with Larsen syndrome, Ehlers-Danlos syndrome kyphoscoliotic form, and Marfan syndrome before presentation. The FEVR lead to consideration of LDS that was molecularly confirmed. Consequently, he was monitored for aortic root dilation. CONCLUSION: FEVR findings may lead to diagnosis of LDS and patients with LDS may present with proliferative retinopathy.

Clinical diagnosis of Larsen syndrome, Stickler syndrome and Loeys-Dietz syndrome in a 19-year old male: a case report.

BACKGROUND: Larsen syndrome is a hereditary disorder characterized by osteochondrodysplasia, congenital large-joint dislocations, and craniofacial abnormalities. The autosomal dominant type is caused by mutations in the gene that encodes the connective tissue protein, filamin B (FLNB). Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by arterial aneurysms, dissections and tortuosity, and skeletal, including craniofacial, manifestations. Mutations in five genes involved in the transforming growth factor beta (TGF-ß) signaling pathway cause five types of LDS. Stickler syndrome is a genetically heterogeneous arthro-ophthalmopathy caused by defects in collagen, exhibiting a wide specter of manifestations in connective tissue. A rare case is reported that was diagnosed with all these three hereditary connective tissue disorders. CASE PRESENTATION: A 19 year-old, Norwegian male with a clinical diagnosis of Larsen syndrome and with healthy, non-consanguineous parents attended a reference center for rare connective tissue disorders. Findings at birth were hypotonia, joint hypermobility, hyperextended knees, adductovarus of the feet, cervical kyphosis, craniofacial abnormalities, and an umbilical hernia. From toddlerhood, he required a hearing aid due to combined conductive and sensorineural hearing loss. Eye examination revealed hyperopia, astigmatism, and exotropia. At 10 years of age, he underwent emergency surgery for rupture of an ascending aortic aneurysm. At 19 years of age, a diagnostic re-evaluation was prompted by the findings of more distal aortic dilation, tortuosity of precerebral arteries, and skeletal findings. High throughput sequencing of 34 genes for hereditary connective tissue disorders did not identify any mutation in FLNB, but did identify a de novo missense mutation in TGFBR2 and a nonsense mutation in COL2A1 that was also present in his unaffected father. The diagnosis was revised to LDS Type 2. The patient also fulfills the proposed criteria for Stickler syndrome with bifid uvula, hearing loss, and a known mutation in COL2A1. CONCLUSION: LDS should be considered in patients with a clinical diagnosis of Larsen syndrome, in particular in the presence of arterial aneurysms or tortuosity. Due to genetic heterogeneity and extensive overlap of clinical manifestations, genetic high throughput sequencing analysis is particularly useful for the differential diagnosis of hereditary connective tissue disorders.

Comparative analysis of the two extremes of FLNB-mutated autosomal dominant disease spectrum: from clinical phenotypes to cellular and molecular findings.

Non-randomly distributed missense mutations of Filamin B (FLNB) can lead to a spectrum of autosomal dominant-inherited skeletal malformations caused by bone hypoplasia, including Larsen syndrome (LS), atelosteogenesi-I (AO-I), atelosteogenesi-I (AO-III) and boomerang dysplasia (BD). Among this spectrum of diseases, LS causes a milder hypoplasia of the skeletal system, compared to BD's much more severe symptoms. Previous studies revealed limited molecular mechanisms of FLNB-related diseases but most of them were carried out with HEK293 cells from the kidney which could not reproduce FLNB's specificity to skeletal tissues. Instead, we elected to use ATDC5, a chondrogenic stem cell line widely used to study endochondral osteogenesis. In this study, we established FLNB-transfected ATDC5 cell model. We reported a pedigree of LS with mutation of FLNBG1586R and reviewed a case of BD with mutation of FLNBL171R . Using the ATDC5 cell model above, we compared cellular and molecular phenotypes of BD-associated FLNBL171R and LS-associated FLNBG1586R . We found that while both phenotypes had an increased expression of Runx2, FLNBL171R-expressing ATDC5 cells presented globular aggregation of FLNB protein and increased cellular apoptosis rate while FLNBG1586R-expressing ATDC5 cells presented evenly distributed FLNB protein and decreased cellular migration. These findings support our explanation for the cause of differences in clinical phenotypes between LS and BD. Our study makes a comparative analysis of two extremes of the FLNB-mutated autosomal dominant spectrum, relating known clinical phenotypes to our new cellular and molecular findings. These results indicated next steps for future research on the role of FLNB in the physiological process of endochondral osteogenesis.

Otologic manifestations of Larsen syndrome.

OBJECTIVE: To describe and discuss otologic manifestations of Larsen syndrome, based on a case report and a systematic review of the literature. MATERIALS AND METHODS: We performed a PubMED database search, and we selected studies reporting otolaryngologic manifestations secondary to Larsen syndrome. The selected articles were read in full, and three researchers independently extracted data from the studies. In parallel, we report the case of a 14-year-old patient who had hearing loss secondary to Larsen syndrome. RESULTS: Fifteen studies met our selection criteria. Seven studies reported hearing loss in patients with Larsen syndrome (4 had conductive hearing loss and 3 had mixed hearing loss). The conductive hearing loss may be secondary to ossicular malformations and/or middle ear effusions. Other causes for conductive hearing loss are mesenchymal remnants in the middle ear, Eustachian tube dysfunction, and cleft palate. Surgical management of the hearing loss is possible in selected cases, although the surgical and anesthetic risks should be considered. Hearing aids seem to be safe and effective treatment options for the hearing loss secondary to Larsen syndrome. CONCLUSION: Although rare, patients with Larsen syndrome may have hearing loss. The most frequent type of deficit is conductive, either secondary to malformation of the ossicles or middle ear effusion. Possible surgical correction of these abnormalities should be weighed against the anesthetic risks of these patients.