Larsen syndrome, as originally described, comprises multiple large‐joint dislocations, midface hypoplasia and spatulate fingers.1
Variable features included cleft palate and vertebral defects, especially in the cervical region. Since then the diagnosis has been applied to a wide spectrum of phenotypes characterised by joint dislocations, including some with severe extraskeletal manifestations and perinatal lethality. The description of mutations in FLNB
underlying autosomal dominant Larsen syndrome, in addition to the allelic entities spondylocarpotarsal syndrome, AOI, AOIII and boomerang dysplasia, facilitates the study of this heterogeneous category afresh and offers an opportunity to re‐define the phenotype.
Some phenotypic features are consistently present in FLNB
‐related, dominantly inherited, Larsen syndrome. Although multiple joint dislocations, digit and craniofacial abnormalities have previously been considered to be the defining features of autosomal dominant Larsen syndrome,1,2,3,4,6,13,15
the presence of other manifestations such as short stature, anterior thoracic wall deformity (either pectus excavatum or pectus carinatum) and spatulate fingers (most notable in the thumb) collectively improve the diagnostic specificity for dominant Larsen syndrome caused by mutations in FLNB
. In this series, the only invariant feature observed in all cases of Larsen syndrome assessed at a sufficiently advanced age was the presence of accessory ossification centres in the carpus or tarsus or both. Individuals who carried a pathogenic mutation in FLNB
but did not manifest one or more features previously thought to be obligatory for the diagnosis—large‐joint dislocations (case 3, family 5, cases III2 and IV9), spatulate fingers (family 5, cases III2, IV3, IV7 and III8), midface hypoplasia (case 12) and stature below the 10th centile (cases 3, 4, 7 and 13)—were identified (table 1). Intrafamilial variability in severity of phenotypic expression reiterates previous observations in other reported cases of Larsen syndrome.11,14,15,56
MCPP analysis indicates that autosomal dominant Larsen syndrome is characterised by a distinctive acral patterning defect. The mean MCPP profile for Larsen syndrome is similar to the mean MCPP profile of males with otopalatodigital syndrome type 1 (OPD1), a condition caused by mutations in the paralogous gene, FLNA
This similarity is most pronounced in the distal phalanges and suggests that such clinical relatedness between these two conditions reflects commonalities in their aetiopathogenesis.
Cervical spine anomalies, often leading to cervical kyphosis, have long been recognised complications of Larsen syndrome, but their true incidence and associated risk of myelopathy have not been quantified. In this study, 10 of 16 individuals had cervical vertebral anomalies, most typically fusion of C2 and C3 sometimes accompanied by subluxation of C3 on C4, and posterior arch defects within the cervical spine. Occasionally, anomalies can be considerably more extensive than this (fig 4). In this series, 3 of 20 probands (15%) manifested a myelopathy. The pronounced morbidity associated with myelopathy warrants spinal investigation on all individuals diagnosed with Larsen syndrome.
In the light of the above observations, does a recessive form of Larsen syndrome exist? These data support Mostello et al,31
who stated that no clinical, radiographic or histological marker separates several reports compatible with a recessively inherited entity13,26,31
from those that describe the dominantly transmitted phenotype, now known to be caused by mutations in FLNB
. These putative recessive entities may represent further instances of parental germline mosaicism for a heterozygotic FLNB
The entity described in the La Réunion Island isolate57,58
is clearly phenotypically discrete (stature –5 SD, polydactyly, advanced skeletal maturation, radioulnar synostosis, diaphyseal bowing, metacarpophalangeal and interphalangeal dislocations, lack of accessory carpal and tarsal bones), clearly distinguishing this phenotype from autosomal dominant Larsen syndrome due to FLNB
mutations. Nevertheless, on the basis of current evidence, a recessive form of Larsen syndrome cannot be ruled out.5,20,26,28
Clinical and radiological analysis can distinguish bona fide
Larsen syndrome from other joint dislocation syndromes. Desbuquois syndrome shows autosomal recessive inheritance, advanced carpal ossification and prominent deformities of the hands.37,59
Accessory ossification centres are associated with the metacarpals and phalanges as opposed to the carpus. Pseudodiastrophic dysplasia is similar to Larsen syndrome with midface hypoplasia and clubfoot, but patients can be distinguished by the presence of rhizomelia, prominent dislocations of the interphalangeal joints and most often perinatal lethality.60
Ehlers–Danlos syndromes (arthrochalasia types; formerly termed Ehlers–Danlos types VIIA and VIIB) are characterised by large‐joint dislocations, but are radiographically distinct from Larsen syndrome.61
Importantly, a principal phenotypic feature in these conditions is that of hyperelastic skin, a feature not found in Larsen syndrome.
This series reports 20 patients who were heterozygous for mutations in FLNB
. All mutations were either missense or produced small inframe deletions.42
The predicted substitutions/deletions were clustered, one cluster comprising exons 2–4 encoding CH2 and the other comprising exons 25–33 encoding filamin repeats 13–17 (fig 6). The interfamilial phenotypic variation between patients with recurring mutations was wide.
The most recurrent mutation, predicting the substitution G1691S, was noted in six unrelated patients, with variable consequences. These ranged from a mild phenotype comprising dislocated knee joints, flat facies, stature >97th centile and no cervical spine abnormalities (case 13), to severe cases with myelopathy (case 16). Farrington‐Rock et al43
described another infant with this mutation and a distally tapering humerus, cervical kyphosis and multiple joint dislocations indicating overlap with AOIII. The phenotypic relatedness between Larsen syndrome and AOIII is reinforced by reports of survival in individuals with the AOIII entity,62
although a diagnosis of AOIII is still appropriate in instances where incomplete ossification of skeletal elements (such as the phalanges) or long‐bone modelling defects such as distally tapering humeri are prominent features.
A second recurrent mutation leading to the substitution E227K is similarly associated with variable expression. Study of a family segregating this mutation over four generations and having 30 affected members demonstrated that very few phenotypic components are obligatory requirements for the diagnosis (table 2). An unrelated case (case 4) has also been identified as having the same 679G→A mutation. His phenotype is comparatively mild, comprising elbow dislocations, an anterior thoracic wall deformity, supernumerary ossification centres and spatulate fingers.
There are many phenotypic and genetic similarities between the FLNB
‐related conditions and the OPD spectrum disorders, which are caused by mutations in the X‐linked gene, FLNA
. The FLNA
‐related entity bearing the most similarity to Larsen syndrome is OPD. Multiple large‐joint dislocations have not been described in this entity, and therefore differential diagnosis should be problematic only in males with Larsen syndrome who do not have this feature. The observation that mutations cluster in FLNB
in a distribution similar to that observed in FLNA
suggests parallels in the pathogenesis of these conditions and a functional relationship between these two filamin proteins. Some of the mutations reported to lead to the FLNA
groups of conditions occur at exactly homologous residues and produce identical amino acid substitutions (fig 5). The observation that filamin A and filamin B may heterodimerise in neuronal cells63
and are co‐expressed in the hypertrophic zone of the growth plate42
lends weight to this hypothesis, but evidence exists that conflicts with these data.64
Despite the observation of intense clustering of mutations causative of Larsen syndrome, the pathogenic mechanism leading to this disorder remains unclear. Mutations in CH2 in the actin‐binding domain may alter the regulation of the binding of filamin to actin. However, the substitutions identified in the filamin repeat domains do not correlate with binding sites of known filamin B protein interactants. All proteins known to interact with the repeat domains of filamin B bind to the region extending from hinge 1 to the C terminus. Whether the mutations disrupt protein interactions or facilitate novel interactions with filamin B is unclear. Over 30 proteins bind to filamin A65
and a similar diversity of binding partners may exist for filamin B, some possibly participating in the secretion of matrix components. Histological studies of the joint capsule and tracheal cartilage of an infant with Larsen syndrome who died of tracheobronchomalacia showed paucity of capsular collagen and cartilage that was thinned, hypocellular and contained shortened, “dysmature” collagen fibrils. In another patient histology of the epiphyseal growth plate showed disorganisation of the chondrocyte columns.31
Additionally, presenilins 1 and 2, components of the Notch signalling pathway that is critical for somite segmentation and the formation of the vertebrae,66
interact with filamin B.45
Disruption of presenilin–filamin B binding might be one mechanism that leads to the vertebral anomalies observed in Larsen syndrome (table 1, fig 4).
This work has defined autosomal dominant Larsen syndrome as a clinically and radiographically characteristic condition with pronounced intrafamilial and interfamilial variability. The identification of the basis of its aetiopathogenesis as clustered missense mutations in the cytoskeletal protein FLNB provides a valuable adjunct to the diagnosis of this clinically highly variable disorder.