A molecular and clinical study of Larsen syndrome caused by mutations in FLNB

Article (PDF Available)inJournal of Medical Genetics 44(2):89-98 · March 2007with88 Reads
DOI: 10.1136/jmg.2006.043687 · Source: PubMed
Abstract
Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied. Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated. The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G-->A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13-17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.
ORIGINAL ARTICLE
A molecular and clinical study of Larsen syndrome caused by
mutations in FLNB
Louise S Bicknell, Claire Farrington-Rock, Yousef Shafeghati, Patrick Rump, Yasemin Alanay,
Yves Alembik, Navid Al-Madani, Helen Firth, Mohammad Hassan Karimi-Nejad, Chong Ae Kim,
Kathryn Leask, Melissa Maisenbacher, Ellen Moran, John G Pappas, Paolo Prontera, Thomy de Ravel,
Jean-Pierre Fryns, Elizabeth Sweeney, Alan Fryer, Sheila Unger, L C Wilson, Ralph S Lachman, David
L Rimoin, Daniel H Cohn, Deborah Krakow, Stephen P Robertson
...................................................................................................................................
See end of article for
authors’ affiliations
........................
Correspondence to:
S P Robertson, Department
of Paediatrics and Child
Health, Dunedin School
of Medicine, PO Box 913,
Dunedin, New Zealand;
stephen.robertson@
stonebow.otago.ac.nz
Received 4 May 2006
Revised 25 May 2006
Accepted 29 May 2006
Published Online First
26 June 2006
........................
J Med Genet 2007;44:89–98. doi: 10.1136/jmg.2006.043687
Background: Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint
dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense
mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate
the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected
relatives were evaluated for mutations in FLNB and their phenotypes studied.
Methods: Probands were screened for mutations in FLNB using a combination of denaturing high-
performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and
radiographical features of the patients were evaluated.
Results and discussion: The clinical signs most frequently associated with a FLNB mutation are the presence of
supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the
thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense
or small inframe deletions. Three mutations are recurrent, with one mutation, 5071GRA, observed in 6 of 20
subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading
to substitutions in the actin-binding domain and filamin repeats 13–17 being the most common cause of
Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate
clustering of causative mutations in FLNB.
L
arsen syndrome (Online Mendelian Inheritance in Man
(OMIM) 150250) was first described as an entity compris-
ing congenital large-joint dislocations and characteristic
craniofacial abnormalities.
1
The cardinal features of the condi-
tion are dislocations of the hip, knee and elbow joints, with
equinovarus or equinovalgus foot deformities. Spatula-shaped
fingers, most marked in the thumb, are also present.
Craniofacial anomalies include hypertelorism, prominence of
the forehead, a depressed nasal bridge and a flattened
midface.
1–4
Cleft palate and short stature are often associated
characteristics.
1356
Spinal anomalies include scoliosis and
cervical kyphosis; cervical kyphosis can be associated with a
myelopathy.
67
Hearing loss is a well-recognised complication
8–10
often caused by malformations of the auditory ossicles.
11 12
Supernumerary carpal and tarsal bones (representing second-
ary ossification centres—for example, in the calcaneus)
213
are a
useful diagnostic feature in early childhood. Intrafamilial
variation in Larsen syndrome is a prominent feature of the
disorder.
14 15
There is clear evidence for an autosomal dominant form of
Larsen syndrome, with multiple instances of male-to-male
transmission being described
2111617
in addition to linkage data
that defines a locus at 3p21.1–14.1.
17
Instances of sibling
recurrence to unaffected parents have been retrospectively
explained by parental germline mosaicism on subsequent
observation of vertical transmission of the phenotype.
18–20
Other instances of sibling recurrence to unaffected parents
may reflect the same underlying mechanism.
13
Presentations
consistent with somatic mosaicism have also been reported.
921
Other conditions labelled as Larsen syndrome or Larsen-like
entities have been described (OMIM 245650), many with a
more severe phenotype including additional extraskeletal
features. Associated malformations include cardiac defects,
22–28
laryngotracheomalacia,
29–34
brain abnormalities (microcephaly,
pachygyria, colpocephaly, corpus callosum agenesis)
29 30 33–35
and inguinal herniae.
25 26 29
Some of these phenotypes segre-
gated in a fashion consistent with autosomal recessive
inheritance, prompting some to recognise a recessive form of
Larsen syndrome despite many cases having major phenotypic
dissimilarities with the entity Larsen et al
1
initially described.
Many have noted more severe skeletal and extraskeletal
phenotypic features including perinatal lethality in presumptive
recessively inherited cases, implying that it is possible to
clinically distinguish these heterogeneous entities from auto-
somal dominant Larsen syndrome.
26 36
However, clear criteria
that definitively delineate recessively inherited forms of Larsen
syndrome from the dominantly inherited entity have not been
established.
13 31
Laville et al
36
and Bonaventure et al
37
described several large
families, from La Re´union Island, which segregated a pheno-
type resembling Larsen syndrome, but with severe short
stature, advanced skeletal maturation, diaphyseal bowing and
lethality in childhood. Recurrence of the phenotype to
unaffected parents in an isolated population firmly implicates
an autosomal recessive mode of inheritance. Other similar
cases have since been reported.
28
This clinical presentation has
more similarities to Desbuquois dysplasia than to Larsen
syndrome.
37
Abbreviations: FLNA, filamin A gene; FLNA, filamin B gene; MCPP,
metacarpophalangeal pattern; OMIM, on-line mendelian inheritance in
man; OPD, otopalatodigital syndrome
89
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Clinical similarities between Larsen syndrome and a group of
lethal osteochondrodysplasias including atelosteogenesis types
I (AOI, OMIM 108720) and III (AOIII, OMIM 108721), and
boomerang dysplasia (OMIM 112310) suggested that they
represent an allelic series of conditions.
38 39
These more severe
dysplasias are characterised by underossification of skeletal
elements, hypoplastic or absent limb bones, joint dislocations
and craniofacial abnormalities. These observations, with the
phenotypic similarities between Larsen syndrome and otopala-
todigital syndrome type 1 (OPD1), an X-linked skeletal disorder
caused by mutations in FLNA,
40
the gene encoding filamin A,
led to the description of mutations in the paralogous gene
filamin B gene (FLNB) underlying Larsen syndrome, AOI, AOIII
and boomerang dysplasia.
41 42
Mutations leading to AOI and
AOIII were clustered in calponin homology domain 2 (CH2)
and repeats 13–17.
43
Filamin B is a cytoskeletal protein that is important in
modulation of the cellular cytoskeleton and signal transduc-
tion. It is composed of two calponin homology domains at the
N-terminal forming an actin-binding domain, and 24 structu-
rally homologous repeats, separated by two hinge regions
located between repeats 15 and 16, and 23 and 24. Four
missense mutations and one inframe deletion were identified
associated with Larsen syndrome and localised to portions of
the gene encoding the actin-binding domain and repeats 14
and 15. Mutations leading to AOI and AOIII were also clustered
in FLNB, in contrast with nonsense and frameshift mutations
leading to spondylocarpotarsal syndrome, which were more
randomly located throughout the gene.
42
In vivo, filamins form dimers, with repeat 24 acting as a
dimerisation domain. The hinge regions confer flexibility on the
filamin dimer structure, enabling orthogonal actin cross-
linking. Several proteins bind to the C-terminal portion of
filamin B. The physiological relevance of filamin binding to
many of these interacting proteins, including integrin b1A and
b1D subunits, presenilins 1 and 2, glycoprotein Iba, filamin-
binding LIM protein 1 and epithin, is unclear,
44–48
but emerging
evidence supports a role for filamins in the integration of cell
signalling and cytoskeletal remodelling.
49
In this paper a cohort of 20 unrelated families with Larsen
syndrome is reported, comprising 52 affected individuals. We
note the clinical features associated with the presence of a
FLNB mutation and examined for genotype–phenotype correla-
tions for this disorder. Mutations were non-randomly distrib-
uted and some were recurrently observed. In addition, a
characteristic clinical phenotype for Larsen syndrome asso-
ciated with mutations in FLNB was delineated.
METHODS
Patient ascertainment
Patients or families with a diagnosis of Larsen syndrome were
ascertained by doctor-initiated referral. Informed consent was
obtained from participants or their legal guardians. Patients
and family members were examined by their doctor. Clinical
photographs and a full skeletal radiographic survey were
obtained where possible. For some patients, full radiographic
and clinical details were not obtainable. Ethical approval for
this study was obtained from the Otago Ethics Committee.
Molecular analysis
Genomic DNA from cases to be examined was extracted from
whole blood using standard procedures. FLNB exons and exon–
intron boundaries were amplified using polymerase chain
reaction as described previously.
42
Primers and polymerase
chain reaction conditions are available on request. Amplified
DNA was subject to denaturing high-performance liquid
chromatography on a WAVE DNA fragment analysis system
(Transgenomic, Omaha, Nebraska, USA) according to the
manufacturer’s instructions. Amplicons showing anomalous
traces were re-amplified and cycle-sequenced on an ABI 3100
sequencer. Where mutations were shown to have arisen de novo,
declared relationships were verified by genotyping both parents
and the patient at six microsatellite loci. Where parental
samples were not available or the trait was familial, the
mutation was shown to be absent in 100 control chromosomes.
Metacarpophalangeal pattern profiles
Metacarpophalangeal pattern (MCPP) profile analyses were
performed as described previously.
50
Bone lengths of the 19
individual bones of the hand were measured in millimetres,
expressed in standard deviation (SD) units (z scores) relative to
age-specific and gender-specific mean bone lengths, and
corrected for age, gender and height using ANTRO software
(V.4.83E).
50–52
To quantify the altered structure of a hand, a
pattern variability index (s
Z
) was calculated,
53
which describes
the variance of z scores of an MCPP profile. The mean s
Z
of the
normal population is approximately 0.5. A s
Z
value .0.8 (the
95th centile) is considered to be suggestive of a malformation
syndrome.
RESULTS
Clinical presentation
Table 1 shows the clinical descriptions of patients with a FLNB
mutation. There were 8 male and 12 female probands; 16
isolated cases and 4 familial cases. All probands had disloca-
tions or subluxation of the large joints (65% with elbow, 80%
with hip and 80% with knee dislocations). The most mildly
affected proband (case 3) manifested subluxable shoulders as
her only large-joint symptom. Clubfoot was present in 75%.
Anterior thoracic wall deformities (pectus excavatum or pectus
carinatum) were present in 55% of patients. Short stature was
common (14/20 cases recording height below the 10th centile).
Height less than the first centile was rare and some individuals
were of above-average stature (case 13 was 179 cm; .97th
centile). The majority of individuals had the characteristic
prominent forehead, hypertelorism, midface hypoplasia and
depressed nasal bridge (fig 1), although exceptions were
observed (case 13; fig 1D). All but one individual with
mutations in FLNB had spatulate fingers, most specifically in
the thumb (fig 2). Conductive deafness, often with noticeable
malformation of the ossicular chain, was observed in 4 of 19
(21%) individuals.
Skeletal anomalies
Radiologically, apart from secondary abnormalities attributable
to chronic joint dislocation, the metaphyses and diaphyses of
the long bones were normal. A minority of patients (eg, case 6),
with more pronounced short stature and craniofacial anoma-
lies, exhibited distal humeral hypoplasia and thus exemplify an
overlap phenotype between Larsen syndrome and AOIII.
43
In
this cohort, supernumerary carpal and tarsal ossification
centres were universally observed features in individuals for
whom relevant radiographs were available (fig 3), although
these signs may be absent in some individuals with the allelic
condition atelosteogenesis III, suggesting that they may not be
completely sensitive indicators for Larsen syndrome. Distal
phalangeal abnormalities, most severely and consistently
affecting the thumb, were similarly common (fig 3). Spinal
abnormalities were observed in 16 of 19 (84%) individuals.
Cervical kyphosis was noted in 50% of probands (fig 4), usually
on the basis of subluxation or fusion of the C2–C3–C4 vertebral
bodies. A common accompaniment was posterior vertebral arch
dysraphism, dysplasia of the vertebral laminae and hypoplasia
of the lateral processes of all cervical vertebrae. Clinical
90 Bicknell, Farrington-Rock, Shafeghati, et al
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Table 1 Phenotypic features of Larsen syndrome due to mutations in FLNB
Case/
family
Proband
sex Mutation Protein
Protein
domain Diagnosis
Number
affected
Familial/
sporadic
Consan-
guinity
Stature
,10th
centile
Midface
hypoplasia
Cleft
palate Deafness
Congenital joint dislocation
Clubfoot Scoliosis
Anterior
thoracic
wall
deformity
Spatulate
fingers
Cervical spinal anomalies
Distal
tapering
of
humerus
Accessory
ossification
centres
Cardiac
defects
Neurodeve-
lopmental
delayElbows Hips Knees
Vertebral
fusion
Vertebral
dislocation
Posterior
arch
defects
Myelo-
pathy
1 M 482TRG F161C* CH2 LS 2 f 2 ++ 22 2 ++ 2 + 2 + 22222+ 22
2 F 502GRA G168S CH2 LS 2 f 22+ 22 ++2 +++++2 + 2 ++ 22
3 F 700CRG L234V CH2 LS 1 s 22+ 22 2222 + 22NA NA NA 2 NA NA 22
4 M 679GRA E227K* CH2 LS 1 s 22+ 22 + 22 + - ++22222+ 22
5 M 679GRA E227K* CH2 LS 30 f 2 ++ +2 ++++ + + + + 2 + 22 + 22
6 F 1081GRA G361S* Rpt 2 LS-AOIII 1 s 2 ++ 2 +++++22 ++2 + 2 ++ 2 +
7 F 1088GRA G363E Rpt 2 LS 1 s 22+ 22 2 22 + 22 + NA NA NA 2 NA 222
8 M 4292TRG L1431R* Rpt 13 LS 1 s 2 ++ 2 ++++2 ++ + NA NA NA 22 + 22
9F
4711_
4713delAAT 1571delN* Rpt 14 LS 1 s 2 ++ 22 ++++ + + + 2222NA + 22
10 M 4756GRA G1586R* Rpt 14 LS 1 s 2 ++ 22 ++++ 2 ++22+ 22 + 22
11 M 4775TRA V1592D Rpt 14 LS 2 f 2 ++ ++ ++++ + 2 +++++2 + 22
12 M 4808CRT P1603L Rpt 14 LS 1 s 2 + 222+++222 + 22+ 22 + 22
13 F 5071GRA G1691S* Rpt 15 LS 1 s 22+ 22 2 2+ 22++22222+ 22
14 F 5071GRA G1691S* Rpt 15 LS 1 s 22+ 22 ++++ + 2 +++++2 NA 2 +
15 F 5071GRA G1691S Rpt 15 LS 1 s 2 ++ 2 + 2 +++++++2 + 22 ++2
16 M 5071GRA G1691S* Rpt 15 LS 1 s 2 ++ +22++ + + + NA ++++2 + 2 +
17 F 5071GRA G1691S Rpt 15 LS 1 s +++ 22 2 ++ + 22 + 22222+ 22
18 F 5071GRA G1691S Rpt 15 LS 1 s 2 ++ 22 ++++ + + + 22222NA 22
19 F 5500G.RA G1834R Rpt 17 LS 1 s 2 ++ 2 NA ++++ + + NA NA NA NA 2 NA NA 22
20 F 5500GRA G1834R Rpt 17 LS 1 s +++ 22 ++++ 22 ++2 + 2 ++ 22
Proportion of total patients 2/20 14/20 19/20 3/20 4/19 13/20 16/20 16/20 15/20 12/20 11/20 17/18 8/16 3/16 10/16 3/20 3/16 15/16 1/20 3/20
Percentage 10 70 95 15 21 65 80 80 75 60 55 94 50 19 63 15 19 94 5 15
AOIII, atelosteogenesis type III; CH2, calponin homology domain 2; F, female; LS, Larsen syndrome; M, male; NA, not assessed; Rpt, filamin repeat; +, present; 2, absent.
Phenotypes listed in familial cases are cumulative for all affected members, not solely the proband. *Mutation proved de novo by examination of parental samples. Mutation previously reported.
42
Molecular and clinical study of Larsen syndrome 91
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myelopathy, complicated by secondary ischaemic encephalo-
pathy, was observed in 3 of 20 individuals (fig 4).
Thoracolumbar scoliosis was noted in 60%, but was not
attributable to underlying vertebral anomalies on radiographs.
Molecular analysis
Heterozygotic mutations in FLNB were found in 20 probands
(table 1). Ten had arisen de novo and four segregated within
families. Most mutations were missense; there was one small
inframe deletion, 4711_4713delAAT (1571delN). Three muta-
tions were recurrent, leading to the substitutions E227K
(n = 2), G1691S (n = 6) and G1834R (n = 2). ClustalW align-
ment showed that the predicted amino acid substitutions in
Larsen syndrome occurred at sites that are highly conserved in
paralogous and orthologous forms of the protein (fig 5).
Mutations were non-randomly distributed throughout the
gene. Two clusters of mutations were evident, those in exons
2–4 encoding CH2, and those in exons 25–33 encoding filamin
repeats 13–17 (fig 6). Two patients had mutations in a region
outside these hotspots, predicting the substitutions G361S and
G363E in filamin repeat 2. One of these patients presented with
a phenotype intermediate between AOIII and Larsen syndrome
(case 6; figs 1A and 3G). There were no phenotypic differences
between patients with mutations located in the 59 compared
with the 39 hotspot of FLNB.
Intrafamilial variation for the Larsen syndrome phenotype
was studied in a large kindred segregating the recurrent
mutation 679GRA, leading to the substitution E227K, in 30
individuals over three generations (case 5). Table 2 shows the
clinical manifestations present in each member examined in this
family. Numerous clinical symptoms and signs seen in Larsen
syndrome were variable in this family. The most remarkable
example of this is III2, who has no large-joint dislocations, yet all
her children are affected to different degrees. All affected
members in the pedigree show the typical facies, with
hypertelorism absent in a minority. Cleft palate (8%) is relatively
rare in this family. Typical features such as spatulate fingers and
supernumerary carpal bones are present in the majority of the
ABC D
Figure 2 Clinical images from individuals with Larsen syndrome showing spatulate digits of (A–C) hands and (D) feet. (A) Case 15; (B) father of case 11;
(C) case 12; (D) case 8. Informed consent was obtained from all patients/guardians for publication of this figure.
A
B
C
D
E
F
Figure 1 Facial characteristics from patients with filamin B gene mutations and diagnoses of (A) Larsen syndrome/atelosteogenesis III or (B–F) Larsen syndrome.
(A)Case6;(B)case5;(C)affectedfatherofcase11;(D)case13;(E)case11; (F) case 20. Informed consent was obtained for publication of this figure.
92 Bicknell, Farrington-Rock, Shafeghati, et al
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affected family members. However, the first metacarpal and first
metatarsal are disproportionately broad in some subjects
(figs 7D,G,H). Some metacarpals and phalanges of affected
individuals are overtubulated (Fig 7C,D,G,H).
MCPP analysis was performed for eight members in family 5
and also for case 15 (fig 8). The MCPP profiles generated were
similar to the profiles reported previously for patients with
Larsen syndrome.
54 55
The pattern is characterised by short
metacarpals (especially the second to fifth metacarpals) and
short distal phalanges (especially the first, third and fourth).
The mean pattern variability index (s
Z
) was 1.36 for males and
1.35 for females (range 1.09–1.81) from family 5. A value .0.8
is indicative of a malformation syndrome.
DISCUSSION
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,
1–4 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
A
B
CE
DF
GH
Figure 4 Anomalies of the cervical spine in Larsen syndrome. (A) Cervical kyphosis; (B,D) vertebral fusion and failure of fusion of the posterior neural arch
are depicted. Family 5, case IV20 demonstrating (E) multiple accessory ossification centres of the vertebral laminae; (F) deficiency of elements of the
posterior vertebral arches. Case 16 (G,H) showing cervical kyphosis complicated by cord compression and myelopathy (arrows). (A) Case 15; (B,D) case
20; (C) case 8; (E,F) family 5, case IV20; (G,H) case 16.
ABCE
D
F
G
Figure 3 Radiographic features of Larsen syndrome. (A,B) Shortening and broadening of the distal phalanges, most notable in the thumb. Supernumerary
carpal bones and a bifid calcaneal ossification centre are commonly observed. Individuals with an overlap of Larsen syndrome and atelosteogenesis type III
show more severe skeletal malformations, such as a distally tapering humerus (E). (A) Case 15, (B,E,F) case 20 (aged 1 year), (C,D) case 20 (aged 14
years), (G) case 6.
Molecular and clinical study of Larsen syndrome 93
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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 disloca-
tions (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 observa-
tions 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.
55
This similarity is most pronounced
in the distal phalanges and suggests that such clinical
relatedness between these two conditions reflects commonal-
ities 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 war-
rants 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
1571delN
G1586R
V1592D
P1603L
F161C
G168S
E227K
L234V
G361S
G363E
L1431R G1691S G1834R
COOHNH
2
+
+
+
+
+
+
+
+
+
+
Figure 6 Location of predicted Larsen syndrome substitutions in filamin B. Schematic of filamin B, with two N-terminal calponin homology domains, and
repeats 1–24 with hinge regions interposed between repeats 15 and 16, and 23 and 24. Above each domain is the predicted amino acid substitutions
found in patients with Larsen syndrome.
`
Substitutions previously reported by Krakow et al.
42
Figure 5 ClustalW alignment of homologous filamins from human, mouse, Gallus gallus, Drosophila melanogaster and Anopheles gambiae. Residues
predicted to be substituted in Larsen syndrome in filamin B (bold) and otopalatodigital syndrome spectrum disorders in filamin A (italic) are indicated. Hyp-
Fln, hypothetical filamin.
94 Bicknell, Farrington-Rock, Shafeghati, et al
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inherited entity
13 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 mutation.
18–20
The entity described in the La Re´union
Island isolate
57 58
is clearly phenotypically discrete (stature –5
SD, polydactyly, advanced skeletal maturation, radioulnar
synostosis, diaphyseal bowing, metacarpophalangeal and inter-
phalangeal 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.
5202628
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 distin-
guished 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 radiographi-
cally 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 al
43
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 679GRA mutation. His pheno-
type 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
Table 2 Phenotypic characteristics of family 5 segregating Larsen syndrome
ID
Age
(in years) Sex
Affected
parent
Short
stature
Prominent
forehead
Frontal
bossing Hypertelorism
Depressed
nasal
bridge
Flat
midface
Cleft
palate Deafness
Congenital joint dislocation
Clubfoot
Joint
laxity
Spinal
anomalies
Spatulate
thumbs
Long/cylindric
fingers
Spatulate
1st toes
Developmental
delayElbows Hips Knees
III 2
37 F
II 1
++ ++ + +
2
+ 222+ 22 2 2 + 2
IV 1
15 M
III 2
2 +++ ++
2
+ 2 ++ + 2 +++ 22
IV 2
6M
III 2
++ ++ + +
2
2 ++++ +2 + 222
IV 3
2F
III 2
NA +++ ++
+
222++ 22 2 ++2
III 3
39 M
II 1
++ +2 ++
2
2 + 2 + 2 ++ + 222
III 4
37 M
II 1
++ +2 ++
2
2 + 2 + 2 ++ + 222
IV 7
14 F
III 4
2 ++2 ++
2
222++ +22+ 22
IV 8
19 F
III 4
++ +2 ++
2
222+ 2 + 2 + 2 + 2
IV 9
8M
III 4
2 + 2 +++
2
22222+ 2 + 222
III 8
40 F
II 2
++ ++ +
+ 2
++++22222 + 2
IV 18
20 F
III 8
++ ++ +
+ 2
22++ + 22 ++ +2
IV 20
17 M
III 8
2 +++ +
+ 2
22++ + 2 +++ +2
IV 21
14 F
III 8
2 +++ +
+ 2
22++ NA 2 NA ++ +2
Proportion of cases
7/12 13/13 12/13 9/13 13/13 13/13 1/13 3/13 4/13 6/13 11/13 7/12 6/13 4/12 9/13 6/13 7/13 0/13
Percentage
58 100 92 69 100 100 8 23 31 46 85 58 46 34 69 46 54 0
F, female; M, male; +present; 2absent; NA, not assessed.
Molecular and clinical study of Larsen syndrome 95
www.jmedgenet.com
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 and FLNB 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 cells
63
and are co-
expressed in the hypertrophic zone of the growth plate
42
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 A
65
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, hypocel-
lular 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.
ACKNOWLEDGEMENTS
We are grateful to the families for their participation in this study.
Authors’ affiliations
.......................
L S Bicknell, S P Robertson, Department of Paediatrics and Child Health,
University of Otago, Dunedin, New Zealand
C Farrington-Rock, R S Lachman, D L Rimoin, D H Cohn, D Krakow,
Medical Genetics Institute, David Geffen School of Medicine at UCLA, Los
Angeles, California, USA
Y Shafeghati, Genetics Research Centre, University of Welfare Science &
Rehabilitation, Evin, Tehran, Iran
P Rump, Department of Clinical Genetics, University Medical Centre,
Groningen, The Netherlands
Y Alanay, Clinical Genetics Unit, Department of Pediatrics, Faculty of
Medicine, Hacettepe University, Ankara, Turkey
Y Alembik, Department of Clinical Genetics, CHRU de Strasbourg,
Strasbourg, France
N Al-Madani, M H Karimi-Nejad, Karimi-Nejad Najmabadi Genetics
Centre, Shahrake Gharb, Tehran, Iran
H Firth, Department of Medical Genetics, Addenbrookes Hospital,
Cambridge, UK
C A Kim, Pediatria-Gene´tica, Hospital das Clı´nicas da Faculdade de
Medicina, Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil
K Leask, Department of Clinical Genetics, St Mary’s Hospital, Manchester,
UK
6
4
2
0
_
2
_
4
_
6
Corrected z scores
MC1
MC2
MC3
MC4
MC5
PP1
PP2
PP3
PP4
PP5
MP2
MP3
MP4
MP5
DP1
DP2
DP3
DP4
DP5
Family 5
Case 15
Figure 8 Metacarpophalangeal pattern profiles from family 5 and case
15. The mean (SEM) is shown for family 5.
A
B
C
D
E
F
G
H
Figure 7 Intrafamilial phenotypic variability in Larsen syndrome. Clinical and radiographic images of hands and feet from different members of family 5.
Variation in the degree of hypoplasia of the distal phalanx of the thumb (compare A and C with B and D). (A,C) IV20, (B,D,F) IV21, (E,G) IVI, (H) III3.
Informed consent was obtained from all patients/guardians for publication of this figure.
96 Bicknell, Farrington-Rock, Shafeghati, et al
www.jmedgenet.com
M Maisenbacher, Department of Pediatrics, University of Florida, Florida,
USA
E Moran, Department of Genetics, NYU-Hospital for Joint Diseases, New
York, New York, USA
J G Pappas, Human Genetics Program, New York University School of
Medicine, New York, New York, USA
P Prontera, Universita degli Studi di Ferrara, Genetica Medica, Ferrara,
Italy
T de Ravel, J-P Fryns, Department of Clinical Genetics, University Medical
Center, Leuven, Belgium
E Sweeney, A Fryer, Alder Hey Children’s Hospital, Liverpool, UK
S Unger, Institute for Human Genetics, University of Freiburg, Freiburg,
Germany
L C Wilson, Clinical Genetics Unit, Great Ormond Street Hospital and
Institute of Child Health, London, UK
Funding: SPR is supported by the Child Health Research Foundation of New
Zealand and the Health Research Council of New Zealand.
Competing interests: None declared.
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98 Bicknell, Farrington-Rock, Shafeghati, et al
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    • "This registry has enabled us to collaborate with different research centers of the world. Many scientific contributions were made through clinical and radiographic delineation of conditions such as; Larsen syndrome [Alanay et al., 2006b; Bicknell et al., 2007], cartilage-hair-hypoplasia [Turkkanı-Asal et al., 2009] , odonto- chondrodysplasia, Schneckenbecken dysplasia [Furuichi et al., 2009], Bruck syndrome [Ha-Vinh et al., 2004; Andiran et al., 2008], 3M syndrome [Huber et al., 2010] , Desbuquois dysplasia [Huber et al., 2009; Kim et al., 2010] , spondyloocular syndrome [Alanay et al., 2006a], Torg-Winchester syndrome [Gok et al., 2010]. The underlying genes were identified in Cousin syndrome [Lausch et al., 2008] and spondyloenchondrodysplasia [Renella et al., 2006; Lausch et al., 2011] and recessive OI. "
    [Show abstract] [Hide abstract] ABSTRACT: This study shares data on 417 patients with genetic disorders of skeleton including 10 fetal autopsies encountered in a 5-year period at a tertiary university hospital in Ankara, Turkey. We included patients with osteochondrodysplasias, excluding overgrowth syndromes, dysostoses, and craniofacial syndromes. When grouped according to the "International Skeletal Dysplasia Society 2010 classification" the most frequent group is "FGFR3 group" (achondroplasia). "Decreased bone density group" takes the second place, consistent with the literature. We also demonstrated, a relatively higher frequency of recessively inherited skeletal dysplasias when the diagnosis is an entity other than achondroplasia or osteogenesis imperfecta. The literature on the incidence of genetic disorders of skeleton from the Middle East and Eastern Mediterranean is limited to fetal and neonatal autopsies or birth prevelance reports. The higher rate of consanguineous marriages which increases the frequency of autosomal recessive entities makes it difficult to apply data from other parts of the world. Total consanguinity rate among parents in our study was 53% and there were regional differences. The highest (79%) was among parents from South-east Anatolia. This study is the first broad retrospective analysis of genetic disorders of skeleton from our region. We aim to provide a descriptive source for future studies and discuss our findings in comparison to reports from other parts of the world. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Apr 2015
    • "Scoliosis, clubfeet, spatulate tips of digits, and the anomalous toes (short 1st, 3rd, and 4th toes) are shared with filamin A-related disorders [Robertson, 2007; Santos et al., 2010]. Mild joint laxity of fingers, scoliosis, clubfeet, midface retrusion, and elbow joint dislocation are commonly seen in filamin B-related Larsen syndrome [Bicknell et al., 2007]. We are not sure whether the malformation of elbows was secondary to dislocation during intrauterine life. "
    [Show abstract] [Hide abstract] ABSTRACT: We report on an adolescent girl with sparse scalp hair, wide columella extending below alae nasi, webbing at elbows, broad finger tips, short distal phalanx of fingers, swan neck deformity of fingers, scoliosis, tall vertebrae, short fibulae, short fourth metatarsal bone, abnormal distal humeri, and unilateral clubfoot at birth. The combination of these features represents a novel phenotype. We sequenced the protein-coding regions of the FLNA and FLNB genes and did not observe any pathogenic sequence variation. Chromosomal microarray revealed a de novo copy number variation of uncertain clinical significance on 7p22.3. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Apr 2014
    • "However mechanical forces also may play an important role in STWS. Congenital bowing of the long bones is a hallmark feature of STWS [1], but it is not unique to STWS and manifests in other syndromes including type IX Ehlers-Danlos syndrome, Campomelic Displasia, Larsen syndrome and other conditions.109110111112. Some have suggested that prenatal bowing of the long bones results from the mechanical forces of imbalanced muscles acting on structurally weak bones in utero113114115. "
    [Show abstract] [Hide abstract] ABSTRACT: Stuve-Wiedemann syndrome (STWS; OMIM #610559) is a rare bent-bone dysplasia that includes radiologic bone anomalies, respiratory distress, feeding difficulties, and hyperthermic episodes. STWS usually results in infant mortality, yet some STWS patients survive into and, in some cases, beyond adolescence. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomally recessive pattern. Most LIFR mutations resulting in STWS are null mutations which cause instability of the mRNA and prevent the formation of LIFR, impairing the signaling pathway. LIFR signaling usually follows the JAK/STAT3 pathway, and is initiated by several interleukin-6-type cytokines. STWS is managed on a symptomatic basis since there is no treatment currently available.
    Full-text · Article · Mar 2014
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