Clinical characteristics: The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD).
SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions.
Larsen syndrome is characterized by 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 craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss.
AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support.
Piepkorn osteochondrodysplasia (POCD) is a 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, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic.
Diagnosis/testing: The diagnosis of SCT is established in a proband by identification of biallelic pathogenic variants in FLNB on molecular genetic testing. The diagnosis of other FLNB disorders (Larsen syndrome, AOI, AOIII, and Piepkorn osteochondrodysplasia) is established in a proband by identification of a heterozygous pathogenic variant in FLNB on molecular genetic testing.
Management: 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 Larsen syndrome usually requires operative reduction. Scoliosis and clubfeet are managed in a routine manner. Anesthetic agents that exhibit more rapid induction and recovery are preferred in those with laryngotrachiomalacia. 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.
Genetic counseling: AOI, AOIII, Piepkorn osteochondrodysplasia, and Larsen syndrome are inherited in an autosomal dominant manner. The proportion of autosomal dominant FLNB disorders caused by de novo pathogenic variants is unknown, although the vast majority of lethal FLNB conditions are caused by de novo events. In rare instances, a parent with low-level mosaicism transmits the causative pathogenic variant to an affected offspring. Each child of an individual with an autosomal dominant FLNB disorder has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk for autosomal dominant FLNB disorders is possible if the pathogenic variant in the family is known.
SCT syndrome is inherited in an autosomal recessive manner. At conception, each sib of an individual with SCT syndrome has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for SCT syndrome are possible once the pathogenic variants have been identified in the family.
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