The FLNB-related disorders include a spectrum of phenotypes ranging from mild (spondylocarpotarsal synostosis [SCT] syndrome and Larsen syndrome) to severe (atelosteogenesis types I [AOI] and III [AOIII], boomerang dysplasia). SCT syndrome is characterized by disproportionate short stature, block vertebrae, scoliosis and lordosis, carpal and tarsal fusion, club feet, hearing loss, dental enamel hypoplasia, and mild facial dysmorphisms. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; club feet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; and distinctive craniofacies (prominent forehead, depressed nasal bridge, flattened midface, and ocular hypertelorism). Both can have midline cleft palate and conductive hearing loss. AOIII and AOI are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and club feet. AOI is lethal in the perinatal period.
Diagnosis is based on clinical and radiographic findings and confirmed with FLNB molecular genetic testing.
AOI, AOIII, boomerang dysplasia, and Larsen syndrome are inherited in an autosomal dominant manner. The proportion of autosomal dominant FLNB-related disorders caused by de novo mutations is unknown, although the vast majority of lethal FLNB-related conditions are caused by de novo events. In rare instances, a parent with low-level mosaicism transmits the causative mutation to an affected offspring. Each child of an individual with an autosomal dominant FLNB-related disorder has a 50% chance of inheriting the mutation. Prenatal testing for pregnancies at increased risk for autosomal dominant FLNB-related disorders is possible if the disease-causing mutation 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 an asymptomatic 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 disease-causing mutations have been identified in the family.