Flnb Disorders

Spondylocarpotarsal Synostosis Syndrome

Spondylocarpotarsal synostosis (SCT) syndrome should be suspected in individuals with the following clinical and radiographic features [Langer et al 1994].

Clinical features

• Postnatal disproportionate short stature
• Scoliosis, lordosis
• Clubfeet
• Other manifestations: midline cleft palate, conductive and sensorineural hearing loss, joint stiffness, dental enamel hypoplasia

Radiographic features

• Fusion of adjacent vertebrae and posterior elements that can involve noncontiguous areas of the cervical, thoracic, and lumbar spine
  Note: (1) Asymmetric fusion of the posterior elements can result in "a unilateral unsegmented vertebral bar." (2) More complex bilateral and midline-fused structures have also been reported. (3) Although frequently referred to as "segmentation defects," the process of segmentation is normal in SCT syndrome and the fusion of adjacent vertebral elements relates to a defect in a separate morphologic process that occurs later in development. (4) Basilar impression with or without foramen magnum stenosis have been recurrently observed.
• Carpal and tarsal synostosis. Carpal synostosis is usually capitate-hamate and lunate-triquetrum [Langer et al 1994].
• Delayed ossification of epiphyses (especially of carpal bones) and bilateral epiphyseal dysplasia of the femur; reported in two individuals [Honeywell et al 2002, Mitter et al 2008]

Larsen Syndrome

Larsen syndrome should be suspected in individuals with the following clinical and radiographic features [Larsen et al 1950].

Clinical features

• Congenital dislocations of the hip, knee, elbow, and (occasionally) shoulder
• Clubfeet (equinovarus or equinovalgus foot deformities). This may be the only clinically apparent sign in some individuals [Yang et al 2016].
• Scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy
• Short, broad, spatulate distal phalanges, particularly of the thumb
• Craniofacial anomalies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes)
• Other manifestations: midline cleft palate, hearing loss (often resulting from malformations of the ossicles)

Radiographic features in early childhood

• Vertebral anomalies: hypoplasic vertebrae, hemivertebrae, spondylolysthesis, bifid posterior processes
• Supernumerary (accessory) carpal and tarsal bone ossification centers; possibly a universal finding [Bicknell et al 2007]

Atelosteogenesis Type I

Atelosteogenesis type I (AOI) should be suspected in individuals with the following clinical and radiographic features.

Clinical features

• Perinatal lethal short-limbed dwarfism
• Severe, dislocated hips, knees, and elbows; clubfeet

Radiographic features

• Marked platyspondyly
• Hypoplastic pelvis
• Thoracic hypoplasia
• Incomplete or absent, shortened, or distally tapered humeri and femora; absent, shortened, or bowed radii; shortened and bowed ulnae and tibiae; absent fibulae
• Unossified or partially ossified metacarpals and middle and proximal phalanges
• Occasionally, extraskeletal manifestations including encephalocele and omphalocele [Bicknell et al 2005]

Note: Individuals with a diagnosis of boomerang dysplasia (perinatal-lethal bone dysplasia with close similarities to AOI) are probably now best subsumed under a diagnosis of AOI. Bowing of the femora was previously considered a differentiating feature between these two conditions but following the definition of their molecular pathogenesis, it is unlikely that this clinical sign adequately differentiates two distinct conditions.

Piepkorn Osteochondrodysplasia

Piepkorn osteochondrodysplasia (POCD) should be suspected in individuals with the following clinical and radiographic features.

Clinical features

• Perinatal-lethal micromelic dwarfism with flipper-like limbs
• Polysyndactyly. Complete syndactyly of all fingers and toes with missing or hypoplastic thumbs and halluces. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octodactyly.
• Pronounced cranofacial dysmorphism including macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos
• Other manifestations: Cleft palate, omphalocele, cardiac and genitourinary defects

Radiographic features (at 15-21 weeks' gestation). Absent ossification of all long bones, vertebrae, pelvis, metacarpals, and metatarsals. Some ossification of the pubic bones, pedicles, ribs, scapulae, skull, and clavicles can be observed.

Atelosteogenesis Type III

Clinical features

• Milder than AOI; survival beyond the neonatal period is possible with intensive and invasive respiratory support [Schultz et al 1999].
• Laryngotracheobronchomalacia
• Dislocated hips, knees, and elbows; clubfeet

Radiographic features

• Mild vertebral hypoplasia
• Distal tapering of the humeri and femora
• Short and broad tubular bones of the hands and feet

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of FLNB disorders, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of FLNB detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found (or only one pathogenic variant is identified in a proband with features characteristic of SCT syndrome), perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  Note: To date, such variants have not been identified as a cause of Larsen syndrome, AOI, POCD or AOIII. Multiexon FLNB deletions have been identified in two individuals with SCT syndrome (see Table 1).
• A multigene panel that includes FLNB and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other skeletal dysplasias, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

Note: To date such variants have not been identified as a cause of Larsen syndrome, AOI, POCD, or AOIII. Multiexon FLNB deletions have been identified in two individuals with SCT syndrome (see Table 1).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Spondylocarpotarsal Synostosis (SCT) Syndrome

Individuals with SCT syndrome have normal or near-normal birth length; however, progressive vertebral fusion results in poor growth of the trunk and short stature becomes evident postnatally. Stature is typically 3-6 SD below the mean.

Scoliosis is common, but variable in severity and time of onset because of the extent and pattern of vertebral fusion. Some authors have observed deformity at birth, although the phenotype may only become evident later in childhood. The irregular nature of the vertebral anomalies can also give rise to other complications such as cervical spine instability [Seaver & Boyd 2000] and basilar impression.

Clubfeet, pes planus, and cleft palate have been described in a small number of individuals with SCT syndrome. Some authors have reported mild craniofacial dysmorphism as part of this condition but the majority of individuals with SCT syndrome do not exhibit these features.

SCT syndrome has been associated with retinal anomalies [Steiner et al 2000] and sensorineural deafness [Langer et al 1994, Coêlho et al 1998]. The cataracts and retinal abnormalities described in one family with SCT syndrome were not severe enough to impair vision [Steiner et al 2000] and have not been observed in subsequently described individuals and so may not represent primary manifestations of the condition.

Dental enamel hypoplasia has been reported in at least two unrelated instances [Mitter et al 2008].

Intelligence is normal.

Larsen Syndrome

Larsen syndrome is compatible with survival into adulthood [Bicknell et al 2007]. Intelligence is normal.

Intrafamilial variation in Larsen syndrome can be remarkable. In a large family segregating one of the recurring pathogenic variants leading to Larsen syndrome, some individuals had cleft palate and multiple large joint dislocations, whereas others who had no major anomalies had short stature and very mild clinical and radiographic features, such as short distal phalanges and supernumerary carpal and tarsal bones [Bicknell et al 2007]. Clinical variability can also result from the presence of somatic mosaicism for a causative pathogenic variant in a mildly affected parent and the presence of a germline pathogenic variant in more severely affected offspring.

In their study of 20 unrelated families with a total of 52 affected individuals, Bicknell et al [2007] determined that all probands had dislocations or subluxations of the large joints (80% hip, 80% knee, and 65% elbow). The most mildly affected proband had subluxation of the shoulders as her only large joint manifestation. Clubfoot was present in 75% of affected individuals.

Stature is mildly affected. In 14 of 20 probands height was below the tenth centile; height was rarely below the first centile and in one individual was above the 97^th centile [Bicknell et al 2007].

Spinal abnormalities were observed on x-rays in 16 (84%) of 19 probands. Cervical kyphosis was noted in 50%, usually from subluxation or fusion of the bodies of C2, C3, and C4, which was commonly associated with posterior vertebral arch dysraphism (i.e., dysplasia of the vertebral laminae and hypoplasia of the lateral processes of all cervical vertebrae). Individuals with Larsen syndrome and cervical spine dysplasia are at significant risk for cervical cord myelopathy and secondary tetraparesis [Bicknell et al 2007]. The incidence of myelopathy is at least 15%. Evidence suggests that preemptive posterior stabilization of the cervical spine in individuals with Larsen syndrome with cervical spine dysplasia may prevent this complication and that combined anterior and posterior stabilization can lead to clinical improvement in individuals with evidence of myelopathy [Sakaura et al 2007].

Craniofacial anomalies are found in all individuals with FLNB Larsen syndrome. These include a prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes. Cleft palate occurs in 15% of affected individuals.

Deafness is common [Herrmann et al 1981, Stanley et al 1988, Maack & Muntz 1991]. Conductive deafness, often with malformation of the ossicles of the middle ear, was observed in four (21%) of 19 probands [Bicknell et al 2007].

Although laryngotracheomalacia has been reported in association with Larsen syndrome, few individuals with Larsen syndrome and a documented FLNB pathogenic variant are severely affected.

Short, broad, spatulate distal phalanges, particularly of the thumb, are a common (67%; Bicknell et al [2007]) but not invariable manifestation of Larsen syndrome.

Atelosteogenesis Type I (AOI) / Boomerang Dysplasia

On prenatal ultrasound examination, the findings of boomerang dysplasia and AOI consist of thoracic hypoplasia and limb shortening with delayed or absent ossification of vertebral and appendicular elements. Joint dislocations may be evident. Definitive diagnosis by ultrasound examination alone is possible [Tsutsumi et al 2012]. Polyhydramnios can complicate the pregnancy. Neonates with boomerang dysplasia or AOI die soon after birth from cardiorespiratory insufficiency. Occasionally, extraskeletal manifestations including encephalocele and omphalocele are encountered [Bicknell et al 2005].

Atelosteogenesis Type III (AOIII)

The most conspicuous finding of AOIII is joint dislocations. A specific diagnosis of AOIII is seldom possible by prenatal ultrasound examination alone.

Infants with AOIII can survive the neonatal period but may require intensive and invasive support to do so. The infant reported by Schultz et al [1999] had significant problems with respiratory insufficiency as a result of laryngotracheomalacia and thoracic hypoplasia. Her mother, who was intellectually normal, had similar but milder respiratory problems in the neonatal period. The manifestations of AOIII overlap with those of Larsen syndrome: large joint dislocations, club feet, short stature, and spinal anomalies. The observation of a distally tapering humerus on x-ray is indicative of AOIII, and of a stronger likelihood of significant laryngotracheobronchomalacia, the major differentiating feature between these two diagnoses.

Infants with AOIII have been born to parents with milder phenotypes (similar to Larsen syndrome). In these instances, the parents probably have a mild phenotype associated with somatic mosaicism, whereas their offspring with a non-mosaic germline pathogenic variant have a severe phenotype.

Neurodevelopment is mildy affected in some long-term survivors with AOIII [Schultz et al 1999], although the authors assumed this to be a secondary consequence of orthopedic and respiratory complications of the primary disorder.

Piepkorn Osteochondrodysplasia (POCD)

POCD is a form of perinatal-lethal micromelic dwarfism described in fewer than five individuals in the literature. The condition is characterized by flipper-like limbs, a characteristic form of polysyndactyly with complete syndactyly of all fingers and toes. The thumbs and halluces are either hypoplastic or absent. The intermediate and distal phalanges of all fingers are duplicated, resulting in distal octodactyly. Craniofacial features include macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, cardiac anomalies, and genitourinary defects including sex reversal. The radiographic features of POCD at mid-gestation are characteristic: absent ossification of all long bones, vertebrae, pelvis, metacarpals, and metatarsals. Some ossification of the pubic bones, pedicles, ribs, scapulae, skull, and clavicles can be observed.

Mosaicism

Clinical evidence suggests that somatic mosaicism can complicate the presentation of these conditions [Petrella et al 1993, Bicknell et al 2007, Bernkopf et al 2017]. Most notably, somatic mosaicism for an FLNB pathogenic variant can be associated with Larsen syndrome, whereas the same pathogenic variant in the germline state can be associated with AOIII.