Related Disorders

CLINICAL CHARACTERISTICS

The 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 cause spondylocarpotarsal synostosis syndrome (-SCT). Monoallelic gain-of-function pathogenic variants in cause a spectrum of phenotypic severity ranging from apparently isolated clubfoot to Larsen syndrome (-LS), atelosteogenesis type 3 (AO3), and atelosteogenesis type 1 (-AO1), which is perinatal lethal. For the purposes of this GeneReview, the previously described entities Piepkorn dysplasia and boomerang dysplasia are subsumed under the -AO1 spectrum. -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. -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 -LS may also present with midline cleft palate and hearing loss. -AO1 and -AO3 are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. -AO1 is lethal in the perinatal period. At its most severe, the spectrum of phenotypes assigned -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 -AO3, survival beyond the neonatal period is possible with intensive and invasive respiratory support.

DIAGNOSIS/TESTING: The diagnosis of -SCT is established in a proband by identification of biallelic loss-of-function pathogenic variants in by molecular genetic testing. The diagnosis of other related disorders (LS, AO1, AO3) is established in a proband by identification of a heterozygous gain-of-function pathogenic variant in by molecular genetic testing.

MANAGEMENT

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 -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. Annual orthopedic evaluation for progressive scoliosis; feeding and growth assessment for those with cleft palate by a multidisciplinary team; annual audiologic and dental evaluations. 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

-SCT is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an 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 pathogenic variants. Heterozygous sibs of a proband with -SCT can exhibit mild reductions in stature but no other medically significant phenotypic manifestations. Once the pathogenic variant(s) have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible. -LS, -AO1, AO3, and related apparently isolated clubfoot are inherited in an autosomal dominant manner. Comparatively mild (e.g., -LS) and severe (e.g., AO3) forms of the autosomal dominant -related disorders can occur in the same family. Some individuals diagnosed with an autosomal dominant -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 pathogenic variant (the vast majority of lethal conditions are the result of pathogenic variants). Each child of a proband who is heterozygous for an pathogenic variant has a 50% chance of inheriting the pathogenic variant. Each child of a proband with somatic mosaicism for an pathogenic variant has up to a 50% chance of inheriting the pathogenic variant. Offspring who inherit an pathogenic variant from a proband with somatic mosaicism may be more severely affected than the proband. Once the pathogenic variant has been identified in an affected family member, prenatal/preimplantation genetic testing are possible.