Skeletal syndromes and dysplasias include more than 150 entities, most often of genetic origin. Some of them cause abnormalities in the cervical spine, with or without instability, distortion or compression of the spinal cord. These abnormalities must be detected and treated if necessary because they can have serious consequences such as quadriplegia. Up to 30% of patients with Down syndrome are affected by occipitocervical or atlantoaxial instability. Dynamic cervical spine radiographs are the most common screening tool. Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage diseases that result in the accumulation of glycosaminoglycans sometimes responsible for craniocervical instability and cervical spinal canal stenosis. Their monitoring requires an MRI every two years. Neurofibromatosis type 1 and syndromes with connective tissue abnormalities (Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danlos syndrome) can cause severe and unstable cervical spine deformities that may remain asymptomatic for a long time. Cervical X-rays should therefore be performed if there is the slightest doubt. Some rare chondrodysplasias (punctate chondrodysplasia, Larsen syndrome, Metatropic dysplasia) or segmentation anomalies (Klippel Feil syndrome, Sprengel's disease) have cervical spine abnormalities that should be looked for. In case of progression of a deformity (usually kyphosis) or stenosis of the cervical spine, it is important to consider surgical treatment with correction and stabilization. Sometimes preceded by a period of Halo traction, the instrumentation must have "wide" limits and exceed the anatomical limits of the spinal deformity by at least 2-3 levels to prevent the development of an adjacent deformity. The increasing use of surgical navigation techniques allows for greater corrections and more efficient stabilizations, including severe cervical spinal deformities. Vigilance and the detection of these abnormalities remain the key to early and preventive treatment of the complications of these spinal anomalies on often difficult terrain. LEVEL OF EVIDENCE: >V (expert opinion). The FLNB-related disorders can be divided into two groups of conditions caused by loss of function or gain of function of filamin-B. Biallelic loss-of-function pathogenic variants in FLNB cause spondylocarpotarsal synostosis syndrome (FLNB-SCT). Monoallelic gain-of-function pathogenic variants in FLNB cause a spectrum of phenotypic severity ranging from apparently isolated clubfoot to Larsen syndrome (FLNB-LS), atelosteogenesis type 3 (FLNB-AO3), and atelosteogenesis type 1 (FLNB-AO1), which is perinatal lethal. For the purposes of this GeneReview, the previously described entities Piepkorn dysplasia and boomerang dysplasia are subsumed under the FLNB-AO1 spectrum. FLNB-SCT is characterized by postnatal disproportionate short stature; scoliosis and lordosis due to vertebral fusions; carpal and tarsal synostosis; and, variably, clubfeet, hearing loss, and dental enamel hypoplasia. FLNB-LS is characterized by combinations of congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis (which can be associated with a cervical myelopathy); short, broad, spatulate distal phalanges; distinctive craniofacial features (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal ossification centers. Individuals with FLNB-LS may also present with midline cleft palate and hearing loss. FLNB-AO1 and FLNB-AO3 are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. FLNB-AO1 is lethal in the perinatal period. At its most severe, the spectrum of phenotypes assigned FLNB-AO1 can present with perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges); macrobrachycephaly; prominent forehead; hypertelorism; and proptosis. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. In individuals with FLNB-AO3, survival beyond the neonatal period is possible with intensive and invasive respiratory support. The diagnosis of FLNB-SCT is established in a proband by identification of biallelic loss-of-function pathogenic variants in FLNB by molecular genetic testing. The diagnosis of other FLNB-related disorders (LS, AO1, AO3) is established in a proband by identification of a heterozygous gain-of-function pathogenic variant in FLNB by molecular genetic testing. Treatment of manifestations: Cervical spine instability in asymptomatic infants can be successfully managed with posterior arthrodesis. Function can be stabilized (if not improved) in infants with myelopathic signs by a combination of anterior decompression and circumferential arthrodesis. Hip dislocation in individuals with FLNB-LS usually requires operative reduction. Scoliosis and clubfeet are managed in a routine manner. Anesthetic agents that allow more rapid induction and recovery are preferred in those with laryngotracheomalacia. When possible, cleft palate and hearing loss are best managed by multidisciplinary teams. Surveillance: Annual orthopedic evaluation for progressive scoliosis; feeding and growth assessment for those with cleft palate by a multidisciplinary team; annual audiologic and dental evaluations. Pregnancy management: Delivery of an affected infant has the potential to be complicated by extended breech presentation due to dislocation of the hips and knees. FLNB-SCT is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FLNB pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial FLNB pathogenic variants. Heterozygous sibs of a proband with FLNB-SCT can exhibit mild reductions in stature but no other medically significant phenotypic manifestations. Once the FLNB pathogenic variant(s) have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible. FLNB-LS, FLNB-AO1, FLNB-AO3, and FLNB-related apparently isolated clubfoot are inherited in an autosomal dominant manner. Comparatively mild (e.g., FLNB-LS) and severe (e.g., FLNB-AO3) forms of the autosomal dominant FLNB-related disorders can occur in the same family. Some individuals diagnosed with an autosomal dominant FLNB-related disorder have the disorder as the result of a pathogenic variant inherited from a heterozygous or mosaic parent. Some individuals have the disorder as the result of a de novo pathogenic variant (the vast majority of lethal FLNB conditions are the result of de novo pathogenic variants). Each child of a proband who is heterozygous for an FLNB pathogenic variant has a 50% chance of inheriting the pathogenic variant. Each child of a proband with somatic mosaicism for an FLNB pathogenic variant has up to a 50% chance of inheriting the pathogenic variant. Offspring who inherit an FLNB pathogenic variant from a proband with somatic mosaicism may be more severely affected than the proband. Once the FLNB pathogenic variant has been identified in an affected family member, prenatal/preimplantation genetic testing are possible.

Larsen syndrome is a rare genetic condition characterized by facial dysmorphism and skeletal deformities. It is caused by heterozygous pathogenic variants in the Filamin B encoding gene (FLNB). FLNB is a cytoskeletal protein that plays a key role in bone morphogenesis; however, the skeletal phenotype of Larsen syndrome has not been described in detail. Here, we studied the skeletal presentation in two subjects with Larsen syndrome. A case-study including a 63-year-old women and her 33-year-old daughter with Larsen syndrome, both carrying a novel FLNB c.688G > T, p.(Val230Phe) variant. The bone morphologic evaluation included, radiographs, bone mineral density assessment, and high-resolution peripheral quantitative tomography (HR-pQCT). In addition, a transiliac crest bone biopsy from the mother was evaluated by µCT, histomorphometry, and in situ examination of FLNB expression within physiological human bone remodeling sites of controls. Both women were diagnosed with severe osteoporosis (T-score < -5). The HR-pQCT analysis showed a low trabecular bone volume, as well as a low cortical thickness compared to a healthy cohort. Histomorphometry and µCT analysis of the iliac bone biopsy confirmed low cortical thickness, and revealed a high density of small eroded and quiescent intracortical pores. The trabecular bone remodeling was not affected, while cortical remodeling events accumulated as small eroded pores and quiescent pores with an improved infilling. The FLNB variant is associated with low bone mineral density reflecting severe osteoporosis and an altered trabecular and cortical bone structure, while bone turnover was less affected at the time of analysis.

Superior herniation of the mediastinal thymus is a rare cause of neck mass, characterized by intermittent migration of normal thymic tissue into the suprasternal region due to increased intrathoracic pressure. Generally, thymus resection is discouraged to avoid inducing athymia and subsequent immunodeficiency in the child. To date, no prior cases of tracheostomy combined with partial thymectomy have been reported. We present a case in which partial resection of the thymus was necessary to facilitate a tracheostomy. A 3-month-old female infant diagnosed with Larsen syndrome, a rare congenital connective tissue disorder, presented with respiratory failure necessitating mechanical ventilation at birth. Despite successful extubation and subsequent management with noninvasive positive pressure ventilation, she experienced recurrent episodes of apnea and oxygen desaturation. Examination revealed an anterior midline neck swelling, synchronized with respiratory movements, originating from the suprasternal notch. Ultrasound, computed tomography, and magnetic resonance imaging of the neck confirmed the presence of a normal mediastinal thymus extending into the suprasternal region. Given the risk of upper airway stenosis after the otolaryngological evaluation, an early tracheostomy under general anesthesia was planned. Upon incising the thickened cervical fascia, the thymus was visualized on the anterior surface of the trachea. The thymus and its surrounding adhesions were separated, with resection of the upper pole, followed by closure of the hernia orifice. The tracheostomy was then performed as planned. The postoperative course was uneventful, marked by gradual respiratory improvement and resolution of the intermittently visible swelling during inspiration. Cannula exchanges were completed without complications, and the patient was discharged home with a heat moisture exchanger 3 months after surgery. We encountered a case of superior herniation of the normal mediastinal thymus in a patient with Larsen syndrome. While speculative, connective tissue abnormalities may contribute to this condition. In cases requiring tracheostomy, partial thymectomy and closure of the hernia orifice may be necessary to maintain fistula patency postoperatively. Chondrodysplasia with congenital joint dislocations, CHST3-related (CDCJD-CHST3) is characterized by short stature of prenatal onset, joint dislocations (knees, hips, radial heads), clubfeet, and limitation of range of motion that can involve all large joints. Kyphosis and occasionally scoliosis with slight shortening of the trunk develop in childhood. Minor heart valve dysplasia has been described in several persons. Intellect and vision are normal. The diagnosis of CDCJD-CHST3 is established in a proband with characteristic clinical and radiographic features and biallelic pathogenic variants in CHST3 identified by molecular genetic testing. Treatment of manifestations: Surgical correction of the abnormal joints is the only treatment modality; however, surgical correction is often only partially successful and multiple procedures are needed. Physical therapy has not been effective. Treatment of cardiac manifestations as needed per cardiologist; treatment of dental anomalies as needed per dentist. Surveillance: Clinical joint and spine evaluation with orthopedist with experience in skeletal dysplasia; radiographs as recommended per orthopedist; if normal at the time of diagnosis, echocardiogram should be repeated per cardiologist or every five years; follow up with dentist annually or as needed. Agents/circumstances to avoid: Activities with a high impact on joints (e.g., jogging) and obesity. CDCJD-CHST3 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CHST3 pathogenic variant, each sib of an affected individual has a 25% chance at conception of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the CHST3 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing for a pregnancy at increased risk are possible.