Frontometaphyseal dysplasia: Mutations in FLNA and phenotypic diversity

� 2006 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 140A:1726–1736 (2006)

Frontometaphyseal Dysplasia:Mutations in FLNA and Phenotypic Diversity

Stephen P. Robertson,1* Zandra A. Jenkins,1 Timothy Morgan,1 Lesley Ades,2,3 Salim Aftimos,4

Odile Boute,5 Torunn Fiskerstrand,6 Sixto Garcia-Minaur,7 Arthur Grix,8 Andrew Green,9

Vazken Der Kaloustian,10 Ray Lewkonia,11 Brenda McInnes,11 Mieke M. van Haelst,12

Grazia Macini,12 Tamas Illes,13 Geert Mortier,14 Ruth Newbury-Ecob,15 Linda Nicholson,16

Charles I. Scott,16 Karolina Ochman,17 Izabela Brozek,17 Deborah J. Shears,18

Andrea Superti-Furga,19 Mohnish Suri,20 Margo Whiteford,21

Andrew O.M. Wilkie,22 and Deborah Krakow23

1Department of Paediatrics and Child Health, Dunedin School of Medicine, Dunedin, New Zealand2Department of Medical Genetics, The Children’s Hospital at Westmead, Sydney, Australia

3Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia4Northern Regional Genetics Service, Auckland, New Zealand

5Genetics Service, Jeanne de Flandre Hospital, Lille, France6Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

7Genetics Service, Western General Hospital, Edinburgh, United Kingdom8Permanente Medical Group, Sacramento, California

9Department of Medical Genetics, Our Lady’s Hospital for Sick Children, Dublin, Ireland10Division of Medical Genetics, McGill University, Montreal Children’s Hospital, Montreal, Canada

11Department of Medical Genetics, Alberta Children’s Hospital, Calgary, Canada12Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

13Department of Orthopedic Surgery, University of Pecs, Pecs, Hungary14Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

15Clinical Genetics Service, United Bristol Hospitals Trust, Bristol, United Kingdom16Division of Medical Genetics, DuPont Hospital for Children, Wilmington, Delaware

17Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland18Clinical and Molecular Genetics Unit, Institute for Child Health, London, United Kingdom

19Department of Paediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany20Clinical Genetics Service, City Hospital, Nottingham, United Kingdom

21Ferguson-Smith Centre for Medical Genetics, Glasgow, United Kingdom22Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, United Kingdom

23Cedars Sinai Medical Research Institute, Los Angeles, California

Received 26 February 2006; Accepted 26 April 2006

Frontometaphyseal dysplasia is an X-linked trait primarilycharacterized by a skeletal dysplasia comprising hyperos-tosis of the skull and modeling anomalies of the tubularbones. Extraskeletal features include tracheobronchial,cardiac, and urological malformations. A proportion ofindividuals have missense mutations or small deletions inthe X-linked gene, FLNA. We report here our experiencewith comprehensive screening of the FLNA gene in a groupof 23 unrelated probands (11 familial instances, 12 simplexcases; total affected individuals 32) with FMD. We foundmissense mutations leading to substitutions in the actin-binding domain and within filamin repeats 9, 10, 14, 16, 22,and 23 of filamin A in 13/23 (57%) of individuals in thiscohort. Some mutations present with a male phenotype that

is characterized by a severe skeletal dysplasia, cardiac, andgenitourinary malformations that leads to perinatal death.Although no phenotypic feature consistently discriminatesbetween females with FMD who are heterozygous for FLNAmutations and those in whom no FLNA mutation can beidentified, there is a difference in the degree of skewing of X-inactivation between these two groups. This observationsuggests that locus heterogeneity may exist for this disorder.� 2006 Wiley-Liss, Inc.

Key words: frontometaphyseal dysplasia; otopalatodigitalsyndrome; filamin A; skeletal dysplasia

Grant sponsor: Child Health Research Foundation of New Zealand.*Correspondence to: Stephen P. Robertson, Department of

Paediatrics and Child Health, Dunedin School of Medicine, P. O. Box913, Dunedin, New Zealand.

E-mail: [email protected] 10.1002/ajmg.a.31322

How to cite this article: Robertson SP, Jenkins ZA, Morgan T, Ades L, Aftimos S, Boute O, Fiskerstrand T,Garcia-Minaur S, Grix A, Green A, Kaloustian VD, Lewkonia R, McInnes B, van Haelst MM, Macini G, Illes T,Mortier G, Newbury-Ecob R, Nicholson L, Scott CI, Ochman K, Brozek I, Shears DJ, Superti-Furga A, Suri M,

Whiteford M, Wilkie AOM, Krakow D. 2006. Frontometaphyseal dysplasia: Mutations in FLNA andphenotypic diversity. Am J Med Genet Part A 140A:1726–1736.

INTRODUCTION

The otopalatodigital syndrome spectrum disorders(OPSD) are a group of X-linked malformationsyndromes than span a broad range of clinicalseverity [Verloes et al., 2000]. The manifestations ofthese conditions range from otopalatodigital syn-drome type 1 (OPD1; OMIM 311300) which ischaracterized in affected males by cleft palate,conductive and/or sensorineural hearing loss, cra-niofacial abnormalities and a skeletal dysplasia[Dudding et al., 1967], to Melnick–Needles syn-drome (MNS, OMIM 309350) which demonstratesskeletal deformities in females and embryonic orperinatal lethality in males [Melnick and Needles,1966; Donnenfeld et al., 1987]. Within this spectrumare two other disorders, otopalatodigital syndrometype 2 (OPD2; OMIM 304120), and frontometaphy-seal dysplasia (FMD; OMIM 305620).

Frontometaphyseal dysplasia was first described asa sporadic condition in a male and subsequentlymultiple isolated and familial cases have beendescribed [Gorlin and Cohen, 1969; Holt et al.,1972; Danks and Mayne, 1974; Weiss et al., 1975;Medlar and Crawford, 1978; Kanemura et al., 1979;Jend-Rossmann et al., 1984; Leggett, 1988; Nishimuraet al., 1995; Ehrenstein et al., 1997; Kung and Sloan,1998; Boduroglu and Tuncbilek, 1999; Vinay et al.,2000; Takahashi et al., 2002; Morava et al., 2003;Zenker et al., 2004; Stefanova et al., 2005]. Thecardinal manifestations of the condition includesupraorbital hyperostosis, hypertelorism, down-slanting palpebral fissures, and a generalized skeletaldysplasia that manifests with thickening of thecalvarium, agenesis of the frontal, ethmoidal,and sphenoidal sinuses together with bowing andundermodeling of the diaphyses and metaphyses ofthe tubular bones. Extraskeletal manifestationsinclude cardiac defects (atrial septal defects, ven-tricular septal defects, pulmonary stenosis, vascularaneurysms), laryngeal stenosis, and ureteric andurethral stenosis. Underdevelopment of the muscu-lature of the upper limb girdle and the intrinsicmuscles of the hands has been a recurrent observa-tion. Although the initial descriptions of FMD were inmales, females have been described since withpronounced phenotypic expression, suggesting tosome authors the possibility of autosomal dominantinheritance [Kassner et al., 1976; Weiss et al., 1976].Notably, male-to-male transmission of the disorderhas never been described.

Formal proof of allelism ofOPD1,OPD2, FMD, andMNS came with the demonstration that mutations

within the X-linked gene FLNA, encoding thecytoskeletal protein filamin A, were found inindividuals from all four diagnostic categories[Robertson et al., 2003]. Filamin A is a 280-kDaprotein that binds actin fibrils through an N-terminalactin-binding domain and participates in the mod-ulation of the cytoskeleton. This actin-bindingdomain is composed of two calponin homologydomains. The remainder of the molecule comprises24 immunoglobulin—like folds, the most C-terminalof which mediates dimerisation between filaminmonomers. Loss-of-function mutations in FLNA hadbeen previously associated with periventricularnodular heterotopia (PVNH; OMIM 300049) [Foxet al., 1998; Sheen et al., 2001]. Pedigrees segregatingPVNH feature excessive rates of miscarriage and anunder-representationofmales suggestiveof embryo-nic lethality in individuals who are hemizygous for amutant allele [Eksioglu et al., 1996].

The mutations in FLNA underlying the OPSD are allpredicted to preserve the translational reading frameand most have been clustered within three discreteregions of the gene [Robertson et al., 2003]. Of all theOPSD, mutations leading to FMD are the mostdispersed over the length of the gene, with mutationspredicting substitutions in repeats 10, 14, and 23[Zenker et al., 2004; Giuliano et al., 2005; Stefanovaet al., 2005].

This study comprises a molecular and clinicalanalysis of an expanded series of 23 unrelatedindividuals or families with FMD. Our analysisreveals a range in the severity of phenotypes thatmay be related to the position of the causativemutation within the FLNA gene and suggest thatlocus heterogeneitymay explain the observation thathalf of the individuals with FMD analyzed in thisstudy do not have an identifiable FLNA mutation.

METHODS

Patient Ascertainment

Patients or families with phenotypes with an OPSDwere ascertained by physician-initiated referral.Informed consent was obtained from participantsor their legal guardians. Subjects and familymemberswere examined by their physician. Clinical photo-graphs and a full skeletal radiographic survey wereobtained. Ethical approval for this study wasobtained from the Otago Ethics Committee. Toobtain a consistent set of diagnostic criteria for thediagnosis of FMD, all reports of male patients

FRONTOMETAPHYSEAL DYSPLASIA 1727

American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

previously diagnosed with the condition anddescribed in sufficient detail were evaluatedand phenotypic characteristics tabulated [Gorlinand Cohen, 1969; Holt et al., 1972; Danks andMayne, 1974; Sauvegrain et al., 1975; Weiss et al.,1975, 1976; Kassner et al., 1976; Medlar andCrawford, 1978; Sellars and Beighton, 1978; Kane-mura et al., 1979; Ullrich et al., 1979; Beighton andHamersma, 1980; Fitzsimmons et al., 1982; Jend-Rossmann et al., 1984; Leggett, 1988; Glass andRosenbaum, 1995; Nishimura et al., 1995; Ehrensteinet al., 1997; Franceschini et al., 1997; Kung and Sloan,1998; Boduroglu and Tuncbilek, 1999; Vinay et al.,2000; Morava et al., 2003; Zenker et al., 2004;Stefanova et al., 2005] (Tables I and II). Character-istics were divided into mandatory, major and minorfeatures on account of their frequency and specificityfor the disorder. A clinical diagnosis of FMD wasconsidered secure if males met all mandatory andmajor criteria; or alternatively, all mandatory, onemajor and two or more minor criteria (Table I).This clinical diagnosis must be supported by allmandatory radiological features. Affected femalesdemonstrated all mandatory clinical and radiologicalfeatures (Table II). For familial cases an index male(if available) was used to assign the diagnosis.

Screening of FLNA for Mutations

Genomic DNA was extracted from blood usingstandard techniques. Exons 2–48 of FLNA, includingintron–exon boundaries were amplified by PCRusing primers and reaction conditions published

elsewhere [Robertson et al., 2003]. Productswere visualized by agarose gel electrophoresis forsize discrepancies; amplified products obtainedusing DNA from a healthy control male wereadded to those of male subjects, and heteroduplexformation and denaturing high-performance liquidchromatography was performed according to themanufacturer’s instructions (Transgenomic, Inc.,Omaha, NE). Anomalous waveforms were identifiedusing Navigator 1.6 software (Transgenomic, Inc.),the PCR product re-amplified from the genomic DNAtemplate and sequenced using BigDye terminatorchemistry and resolved on an ABI 3100 sequenceanalyzer. Sequence changes were designated patho-genic if they arose de novo by the examinationof parental samples and confirmation of parentalrelationships by the segregation of six unlinkedmicrosatellitemarkers.Whereparental sampleswerenot available or the variant segregated with thedisease phenotype in a family, the mutation wasshown to be absent in a panel of 100 X chromosomesfrom healthy male and female individuals.

X-Inactivation Analysis

Skewing of X-inactivation was measured usinga modified version of the AR triplet repeat assayas previously described [Allen et al., 1992]. Pre-digestion of genomic DNA (1 mg) with RsaI, either inthe presence (þ) or absence (�) of the methylation-sensitive enzyme HpaII (20 IU) was performed. Theproducts were analyzed on an ABI 377 sequencerusing GeneScan software. Differences in peak areas

TABLE I. Diagnostic Criteria for Frontometaphyseal Dysplasia—Males

Clinical Radiological

Mandatory criteria Pronounced supraorbital hyperostosis Undermodeling of metatarsals, metacarpals and phalangesHypertelorism Abnormally modeled metaphyses/diaphyses

Skull base sclerosisMajor criteria Flexion contractures of fingers

Ulnar deviation of handsMinor criteria Subglottic stenosis Advanced bone age

Urethral stenosis/atresia Carpal and tarsal coalitionMicrognathia Absence of the frontal sinusesLong fingers Anteroinferior mandibular spurDistal phalangeal hypoplasia thumb Fusion of cervical vertebral bodiesScoliosis Posterior vertebral arch deficiency

Coat hanger ribsScoliosis

TABLE II. Diagnostic Criteria for Frontometaphyseal Dysplasia—Females

Clinical Radiological

Mandatory criteria Pronounced supraorbital hyperostosis Skull base sclerosisHypertelorism

Major criteria Flexion contractures of fingersUlnar deviation of hands

Minor criteria Micrognathia Absence of the frontal sinusesDistal phalangeal hypoplasia thumbLong fingers

1728 ROBERTSON ET AL.


for the two alleles in the HpaII (þ) assay werecorrected for differences in amplification efficiencymeasured in the HpaII (�) assay, the final resultsbeing expressed as a percentage.

RESULTS

Patient Cohort

Twenty-three probands were ascertained as eithersingleton (five males, seven females) or familial(probands: five males, six females) cases of FMDaccording to the diagnostic criteria presented inTables I and II. Clinical and radiographic assessmentof affected relatives of probands increased the totalnumber of individuals in the study to 32. There wereno instances of male-to-male or father-daughtertransmission of the trait. Clinical and radiologicalfeatures of all 32 subjects are presented alongsidethose obtained from the literature survey in Table III.

Identification of Mutations

Thirteen unrelated individuals or families (57%)had mutations identified within the coding regions ofFLNA (12 missense mutations, one in-frame 3 bpdeletion; 8 familial, 5 isolated; Table IV). Mutationsfound in three individuals had previously been

reported in tabular form (3476A>C, 3557C>T,4858-4860del) [Robertson et al., 2003]. All 13 muta-tions are predicted to maintain the translationalreading frame. The distribution of mutations over thegene correspond broadly to four regions of thefilamin A protein: the actin-binding domain, filaminrepeats 9–10, 14–16, and 22–23 (Fig. 1). Onemutation (3557C>T, S1186L) recurred in threeunrelated individuals in addition to being describedpreviously [Giuliano et al., 2005].

Mutations in the Actin-Binding Domain

Case 1. The most 50 mutation in FLNA wasidentified in a mother and son. The mother’s brotherhad hydrocephalus diagnosed in infancy and a shuntwas inserted. The male proband was of normalstature (178 cm, 75th centile) with macrocephaly(OFC 61 cm: >95th centile). He has downslantingpalpebral fissures, apparent hypertelorism, promi-nent supraorbital ridges, mandibular prognathism,a high-arch palate, and dental crowding. Digitalcontractures were present, most marked in digit V.There was bilateral restriction in wrist dorsiflexion,elbow extension and supination, and knee exten-sion. Muscle bulk in the limbs was poor. The feethad broad short first toes with II–III syndactyly.Thoracic kyphosis and a deep pectus excavatum

TABLE III. Clinical and Radiological Features of Individuals With FMD From the Literature and From theMutation Positive and Mutation-Negative Cohorts (Expressed as Percentages)

Clinical feature

FLNA mutationpositive

FLNA mutationnegative

Literature % (n) Males Females Males Females

Clinical Males n¼ 9 n¼ 11 n¼ 3 n¼ 9Prominent supraorbital ridges 100 (20) 100 91 100 100Down slanting palpebral fissures 95 (19) 100 64 100 89Dental anomalies 100 (13) 100 18 33 11Deafness 90 (20) 67 27 100 33Restricted elbow movements 100 (15) 100 45 100 44Interphalangeal joint contractures(digit II less affected than digit V)

100 (18) 89 90 100 67

Camptodactyly 93 (15) 89 81 100 44Long slender digits 100 (20) 89 45 100 56Muscular underdevelopment 86 (15) 100 9 100 67Scoliosis 53 (15) 56 18 33 33Tracheal stenosis 25 (20) 11 9 0 11Urethral obstruction 32 (19) 22 0 0 0Cardiac defect 24 (21) 22 0 66 22Craniosynostosis 5 (20) 11 0 0 0Cleft palate 0 (21) 0 9 0 11Height <10th centile 21 (14) 0 0 0 22Impaired intelligence 0 (21) 0 0 0 0

RadiologicalSupraorbital hyperostosis 100 (21) 100 100 100 100Absent frontal sinuses 93 (14) 89 54 100 67Fusion C2/3 and/or subluxation C3/4 29 (17) 33 0 66 11Bowed long bones 94 (18) 56 18 100 11Dislocated radial heads 46 (13) 44 9 100 11Carpal fusions 33 (15) 0 9 66 0Poorly modeled phalanges 94 (17) 100 36 100 44



TABLE IV. Mutations Associated With Frontometaphyseal Dysplasia Including Previously Published Cases

Associated phenotype

MutationPredicted

substitution/deletionProteindomain Conservation* De novo/familial ReferenceMale Female

FMD FMD 733G>A E245K CH2 B,C,G,D Familial Case 1FMD FMD 759C>G D253E CH2 B,C,G,D Familial Case 2? FMD 3446C>T P1149L 9 B,C,G,D Unknown Case 3FMD FMD 3476A>C D1159A 10 B,C,G,D Familial Case 4, Robertson et al. [2003]FMD FMD 3557C>T S1186L 10 B,C,G,D Familial Case 5, Robertson et al. [2003]FMD FMD 3557C>T S1186L 10 B,C,G,D Familial Case 6FMD FMD 3557C>T S1186L 10 B,C,G,D De novo Case 7FMD FMD 3557C>T S1186L 10 B,C,G,D Familial Giuliano et al. [2005]Lethal FMD FMD 3668C>T P1223L 10 B,C,D De novo in mother Case 8Lethal FMD FMD 3746T>C V1249A 10 B,C,G,D Familial Case 9FMD ? 4858_4860del I1620del 14 C,G,D De novo Case 10, Robertson et al.

[2003]Lethal FMD FMD 4904_4912del R1635_V1637del 14 B,C,G,D Familial Stefanova et al. [2005]? FMD 5363T>G L1788R 16 C,G De novo Case 11? FMD 7058T>C F2353S 22 B,C,G,D Familial Case 12? FMD/PVNH 7315C>A L2439M/delL2439-G2445 23 B,C,G,D De novo Zenker et al. [2004]? FMD 7447del9 2483_2485del YRV 23 B,C,G,D De novo Case 13

?, no individual of this gender ascertained with this mutation.*Identical residue in human FLNB (B), FLNC (C),Gallus gallus (G),Drosophila melanogaster (D); conservation at deletions is recorded if at least one deleted residue isidentical in the homologue indicated.

FIG. 1. A cartoon of the filamin A protein monomer, indicating the position and identity of the predicted substitutions and small in-frame deletions that are associatedwith FMD. Below the protein are clinical and radiographic images from individuals with the corresponding mutations. In the upper row are images of males, belowthese are images of female subjects. A boxwith a question mark indicates no individual of this gender could be identified. A, B: case 2; (C) case 3; (D) case 7; (E, F) case 8;(G, H) case 9; (I) case 11; (J) case 12; (K) case 13. Mutations predicting S1186L, R1635_V1637del, and L2439M have been reported previously by others [Zenker et al.,2004; Giuliano et al., 2005; Stefanova et al., 2005].



were present. Radiographs demonstrated calvarialthickening, skull base sclerosis, prominent supra-orbital ridges, non-aeration of the frontal sinuses, adextroconvex scoliosis, and distal digital phalangealhypoplasia. Family photographs of her brothershowed facial and acral features similar to theproband. A mutation, 733G>A, predicting thesubstitution E245K was identified in the probandand his mother.Case 2. The male proband, presented with the

typical craniofacial appearance associated with FMD(Fig. 1A) in addition to bicoronal craniosynostosis,which was surgically corrected. There was nohistory of cardiac, respiratory tract, or genitourinarymalformations apart from bilateral cryptorchidismand an umbilical hernia. He had a bifid uvula,microretrognathia, high-set, sloping shoulders withaxillary webbing, and restricted pronation-supina-tion and flexion-extension of both elbows. Therewas marked thenar and hypothenar muscularwasting, camptodactyly of digits II–V, partial cuta-neous syndactyly, and distal digital phalangealhypoplasia. Radiographs showed skull base sclero-sis, perisutural sclerosis, and non-aeration of thefrontal sinuses. The vertebrae, ribs, and pelvis werenormal but there were mild modeling abnormalitiesof the long bone diaphyses. The metacarpals,metatarsals, and phalanges were all undertubulated,especially in the preaxial digits. The proband’s twosisters and mother (Fig. 1B) exhibited moderatesupraorbital hyperostosis, and bilateral camptodac-tyly of digits II–V. The mutation 759C>G, whichpredicts the substitution D253E within the calponinhomology domain 2 of the actin-binding domain,segregated with the phenotype.

Filamin Repeats 9–10

Six unrelated individuals were identified withmutations in exon 22 of FLNA associated with anFMD phenotype.Case 3. Patient 3, a female, had no family

history of skeletal disorders. Her clinical featuresincluded prominent supraorbital ridges, downslant-ing palpebral fissures and micrognathia. She hadmicrodontia and oligodontia, a normal palate, andmoderate conductive hearing loss. Both elbowflexion-extension and supination-pronation werereduced. The fingers were long with contractures atthe distal interphalangeal joints, and the intrinsicmuscles of the hands and the shoulder girdle werehypoplastic. Bilateral metatasus varus was present.Stridor accompanied by recurrent chest infectionswas investigated by bronchogram at age 5 years(Fig. 1C). Numerous abnormally tapered regionsof the distal trachea, left main stem bronchusand multiple segmental bronchi were observedconsistent with tracheobronchomalacia. Radio-graphs showed supraorbital hyperostosis with

aerated frontal sinuses and an anterior mandibularspur (Fig. 1C). The radial heads were dislocated, themetacarpals and phalanges were poorly modeledand there was distal phalangeal hypoplasia. Thecausative mutation, 3446C>T leading to P1149Lwithin filamin repeat 9, had arisen de novo.Case 4. This family segregating a mutation,

3476A>C leading to the substitution D1159A,has been described elsewhere [Morava et al., 2003].The male proband presented with an asthenichabitus, typical dysmorphism, conductive deafness,myopia (�5 diopters) and a history of neonatalmicrognathia and urethral obstruction that did notrequire surgery. Echocardiogram demonstratedmitral valve prolapse. Skeletal signs included thor-acolumbar scoliosis, restricted pronation of theforearms, and flexion contractures of the elbows.Progressive contractures of both the interphalangealand metacarpophalangeal joints of the hands werenoted, affecting digits III, IV, and V most severely.Radiographs demonstrated skull base sclerosis,cranial vault thickening, absent frontal sinuses,dislocated radial heads, and deficient modeling ofthe phalanges and metacarpals. His younger brotherhad a similar build and craniofacial appearance andflexion contractures of the elbows, knees and withinthe small joints of the hands, again most pronouncedin digits III–V. Radiographs were similar to those ofhis brother. A maternal uncle was reported to besimilarly affected. The clinical manifestations in theobligate carrier mother included supraorbital hyper-ostosis, mild thoracic scoliosis, flexion contracture ofdigit V bilaterally, and perisutural sclerosis.Case 5. A male presented with asthenic

build, supraorbital hyperostosis, hypertelorism,downslanting palpebral fissures, and micrognathia.He had combined conductive and sensorineuraldeafness and bilateral hydronephrosis with mega-ureters due to urethral stenosis. There were flexioncontractures at both elbows and the knees were heldin rigid extension. Wrist adduction was limitedbilaterally. There was camptodactyly of the proximaland distal interphalangeal joints of digits III–V. Hismother, who was shown to be heterozygous for thesame mutation, had supraorbital hyperostosis but noother significant clinical anomalies. A recurrentmutation, 3557C>T leading to S1186L was foundin the proband and his mother.Case 6. The second instance of this mutation

(3557C>T) was observed in two brothers withsupraorbital hyperostosis and digital contractures.Their mother had typical craniofacial manifestationsof the condition, but no radiology was available onher. The older subject had attention deficit hyper-activity disorder, pulmonary stenosis, atrial septaldefect, hypodontia, and an inguinal hernia. He haddownslanting palpebral fissures, mixed hearing loss,restriction of extension at the elbows, knees andhips, a mild scoliosis, absent distal interphalangeal



joint creases, and camptodactyly bilaterally. Musclebulk was reduced, most notably in the calves,but strength was normal. A skeletal survey showedsupraorbital hyperostosis, non-pneumatisation ofthe frontal and sphenoidal sinuses, vertebral (C2–C3) fusion, bowed tibiae, and undermodeled meta-carpals and phalanges. The younger sibling hadsupraorbital hyperostosis, hypertelorism, hypodon-tia, sensorineural hearing loss, and restrictionof elbow, hip and knee extension, and forearmsupination. The distal phalanges of the thumbs wereshort and broad. There were flexion contractures ofthe interphalangeal joints of the hands and campto-dactyly. Radiographs demonstrated fusion of C2 andC3, undermodeling of the metacarpals and pha-langes and short, broad femoral necks. There wasgeneralized muscular hypoplasia.Case 7. This same mutation (3557C>T) arose

denovo in anunrelated 6-year-oldmale (Fig. 1D).Hehad a neurogenic bladder with diverticulae asso-ciated with hypospadias, left-sided megaureter, andvesicoureteric reflux. No obstructive lesion withinthe urethra was identified. His height was 121 cm(þ1.5 SD) and his OFC was 55 cm (þ3 SD). His facieswere triangular with apparent hypertelorism, down-slanting palpebral fissures, and supraorbital hyper-ostosis. He had hypodontia and hypermetropia. Hehad a scoliosis, flexion contractures of the elbows,and limited abduction at the wrists. His thumbs andhalluces were both broad with distal phalangealhypoplasia. He had a small atrial septal defect thatrequired no intervention. Radiographs showedbilateral radial head dislocation and bowing of thetibiae andfibulae. Therewerepronouncedmodelingdeformities of the phalanges and metacarpals,particularly of the first digits. There was skull basesclerosis and hypoplasia of the frontal sinuses. Therewas no deafness or cleft palate. His neurodevelop-ment was normal.Case 8. This woman presented with prominent

supraorbital ridges, macrocephaly, micrognathiaand limited supination of the forearms and extensionof the elbows and knees, bilateral ulnar deviationof the hands, arachnodactyly, and bilateral genurecurvatum (Fig. 1F). The right thumb had ahypoplastic distal phalanx with dystrophy of thenail. Her second pregnancy, which was complicatedby oligohydramnios, resulted in male who diedwithin a few hours of delivery at 37 weeks’ gestationwith multiple congenital anomalies (Fig. 1E). He wasgrowth retarded and dysmorphic (low set ears,coarse features, hypertelorism and downslantingpalpebral fissures, bilateral epicanthus, pointedchin). He had pulmonary hypoplasia and bilateralmulticystic dysplastic kidneys with dilated uretersand bilateral cryptorchidism. The bladder wallwas hypertrophied but there was no unequivocalevidence for bladder outlet obstruction. He hadtricuspid atresia, pulmonary stenosis with right

ventricular hypoplasia, rocker bottom feet, flexioncontractures of elbows and knees, and ulnar devia-tion of the wrists. Radiographs showed hypominer-alization of the calvaria and no radiological evidencefor supraorbital hyperostosis. The long bones of thelower limbs were mildly bowed with metaphysealundermodeling. The causative mutation 3668C>T,predicting the substitution P1223L, had arisen denovo in the mother of this infant.Case 9. A 55-year-old woman exhibited pro-

nounced supraorbital hyperostosis, midface hypo-plasia, and micrognathia (Fig. 1H). Additionally shehad a left-sided Poland anomaly, bilateral cubitusvalgus, a valgus deformity of the right leg, andbilateral genu recurvatum. She had surgery to correcta pectus deformity. Her first-born son died shortlyafter birth with macrocephaly and a severelydistended abdomen. Autopsy revealed left hydrone-phrosis and renal cysts, ascites, hepatomegaly,and abnormal genitalia (Fig. 1G). The mutation3746T>C which is predicted to lead to the substitu-tion V1249A was found upon analysis of a samplefrom this infant and his mother.


Case 10. This male presented with conductivehearing loss soon after birth. A fixed stridor wasnoted throughout the first year of life. He hadhypodontia and never developed any secondarydentition. At aged 30 years, his height was 190 cm(þ2.5 SD). He had supraorbital hyperostosis, appar-ent hypertelorism, and downslanting palpebralfissures. His eyes were deep set and his pinnae werelarge and dysplastic. There was no cleft palate.Extension, supination, and pronation of the elbowjoint and abduction and extension at shoulders werelimited bilaterally. His thumbs were broad with distalphalangeal hypoplasia. There was camptodoctyly ofdigits II–V and flexion contractures at the proximaland distal interphalangeal joints, more pronouncedin digits IV–V. Skull radiographs showed sclerosisof the skull base and enlargement of the frontalsinuses. A de novo mutation, 4858_4860del, which ispredicted to lead to the in-frame deletion, I1620delwithin filamin repeat 14, was found in the proband[Robertson et al., 2003].Case 11. The female proband presented

with conductive deafness, nasal speech, malocclu-sion, dysmorphism (supraorbital hyperostosis,hypertelorism, triangular facies, micrognathia), bilat-eral thenar hypoplasia, and normal intelligence(Fig. 1I). Neurologic examination and brain MRIwere normal. There was limitation of flexion atthe elbows and knees, flexion contractures, andcamptodactyly of the fingers, most pronounced indigit V, metatasus varus deformities and spatulatetoes. Radiographsdemonstrated calvarial expansion,supraorbital hyperostosis, undermodeling of the



diaphyses of the long bones, particularly pro-nounced in the hands, and progressive carpal bonefusion (Fig. 2). A de novo heterozygous mutation,5363T>G, which is predicted to lead to thesubstitution, L1788R, within filamin repeat 16, wasfound in the proband.


Case 12. This 36-year-oldwomanwasbornwitha cleft palate, bilateral club feet, and sensorineuralhearing loss (Fig. 1J). She had undergone surgical re-contouring of her forehead previously. She had deepset eyes and supraorbital hyperostosis. There werepartial flexion contractures of the proximal and distalinterphalangeal joints of the hands and shorthalluces. She had one affected daughter who wasdysmorphic (downslanting palpebral fissures, mildmalar hypoplasia, and low set ears), in addition tobilateral sensorineural hearing loss and flexioncontractures of the digits. She did not have a cleftpalate or club feet but was born with bilateraldislocation of the hips. Both females were hetero-zygous for the mutation 7058T>C which predictsthe substitution F2353S within filamin repeat 22.Case 13. A female with a history of idiopathic

epilepsy and myopia (�2,5 diopters) presented witha hypoplastic midface, prominent supraorbitalridges, deep set eyes, a broad nasal bridge, micro-retrognathia, and hypodontia (Fig. 1K). Her psycho-motor development and hearing were normal.Additional findings included an asthenic habitus,scoliosis, dolichostenomelia, flexion contractures ofthe knees and elbows and arachnodactyly. Radio-graphs showed supraorbital hyperostosis, calvarialthickening, and modeling anomalies of the pha-langes and metacarpals. An MRI of the brain wasnormal. She was heterozygous for the de novomutation 7447del9, which is predicted to lead to theinframe deletion, 2483_2485delYRV within filaminrepeat 23.

Patients in Whom no Mutation was Identified

After comprehensive screening of the codingsequences and splice site consensus sequences of

FLNA by DHPLC and direct sequencing, 10 of23 individuals (43%; 3 males, 7 females) did nothave an identified FLNAmutation to account for theirphenotype. Long-range, overlapping PCR amplicons(2–3.5 kb) were designed across the entire FLNAlocus, and products from the female individuals fromthis mutation-negative cohort were analyzed byagarose gel electrophoresis for the presence of small(100–500 bp) deletions and insertions. No bands ofan abnormal size were detected. In addition, samplesfrom four of seven female individuals with no FLNAmutation identifiable were examined by Southernanalysis. No anomalous bands were detected.

A phenotypic analysis of individuals with FMD butno identifiable mutation in FLNA did not identify anyclinical or radiological characteristic that consistentlydifferentiates them from the cohort in whom muta-tions were found (Table III). Two previouslydescribed families segregating FMD are within thiscategory [Fitzsimmons et al., 1982; Morava et al.,2003]. No samples other than from a single affectedfemale were available from one family [Fitzsimmonset al., 1982] and the second consisted of a singlemother-daughter dyad, precluding segregation ana-lysis to exclude the FLNA locus.

X-Inactivation Studies

A total of 22 females (16 familial, 6 sporadic) with aclinical diagnosis of FMD were analyzed for thepresence or absence of skewing of X-inactivation.Thirteen (59 %) of these females were shown to becarriers of a FLNA mutation. Previous work hadidentified a correlation between the degree ofskewing of X-inactivation and the severity of theassociated OPSD diagnosis in females who wereheterozygous for FLNA mutations [Robertson et al.,2003]. In this cohort, 11 of 13 heterozygotes forFLNA mutations, and 9 of 10 mutation negativeindividuals were informative in this assay. The resultsof this analysis confirmed previous observationsthat heterozygosity for a FLNA mutation that leadsto FMD is associated with pronounced skewing ofX-inactivation (mean 92.0%� 2.9 (SEM)). This resultis significantly different from that obtained in femaleswith a typical FMD phenotype but no identifiable

FIG. 2. Metacarpal, carpal and phalangeal manifestations of FMD in a female with the mutation 5363T>G at ages (A) 1 month; (B) 15 months; (C) 4 years, and (D) 8years. There is progressive fusion of the carpal bones (most notably the hamate and capitate), and undermodeling of the metacarpals and phalanges most pronouncedon the preaxial side of the hands. The evolution of camptodactyly is shown and a contractural process involving the digits is demonstrated by the progressive flexion ofthe interphalangeal joints of digits IV and V.



FLNA mutation (mean 74.7% � 6.2 (SEM)), P¼ 0.05(Mann–Whitney U-test) (Fig. 4).

DISCUSSION

The molecular pathology of the OPD spectrumdisorders is remarkable for the clustering of muta-tions that are predicted to lead to preservation of thetranslational reading frame [Robertson et al., 2003;Zenker et al., 2004; Giuliano et al., 2005; Stefanovaet al., 2005]. Here we note that mutations, whichunderlie FMD, although dispersed over the gene,still cluster in specific regions, namely exons 3–5(encoding the actin-binding domain), 22 (encodingfilamin repeats 9 and 10), 28–33 (encodingfilamin repeats 14–16), and 43–45 (encoding filaminrepeat 22–23).

The clinical data presented here indicate that themost pronounced skeletal characteristic in FMDremains supraorbital hyperostosis associated withsclerosis of the skull base. Undermodeling of themetacarpals and phalanges, most prominent on theradial side of the hand, is also an invariantradiological sign in affected males. Vertebral bodyfusion and posterior arch deficiency, usually in theupper cervical region, are the most common spinalanomalies. Scoliosis can occur in both male hemi-zygotes and female heterozygotes for FLNA muta-tions [Morava et al., 2003].

The literature review and tabulation of phenotypicfeatures in patients with FMD identify two extra-skeletal features that may facilitate recognition ofthe disorder. Muscular hypoplasia, particularly of theintrinsic muscles of the hands and the shoulder girdleis common in males, but not in females with FMD.This clinical finding is congenital and not progres-sive. Muscular strength is not affected and musclebiopsy and enzymology offer little insight into thepathogenesis of this clinical sign [Fitzsimmons et al.,1982]. A characteristic contractural process of thehand (Fig. 3) is a similarly common finding in bothmales and females with FMD (Table III).

This study indicates that obstructive lesions of theureters and urethra are common accompanimentsof FMD and should be specifically sought for, andexcluded, in individuals in whom the diagnosis is

being considered. Malformations of the tracheo-bronchial tree may underlie the frequent observationof recurrent respiratory tract infections in individualswith FMD.Thedescription of themalformation in therespiratory tract in case 3 in this series is the firstdocumentation of the possible basis for the frequentreport of respiratory symptoms in individuals [Holtet al., 1972; Leggett, 1988].

Several instructive observations emerged from ananalysis of the genotype–phenotype relations in thispatient cohort. We describe the first individuals witha diagnosis of FMD who had mutations leading tosubstitutions in the actin-binding domain of filaminA. One male (with a mutation that predicts thesubstitution D253E) exhibits tall stature and bicor-onal craniosynostosis reinforcing our observationthat mutations in FLNA associated with FMD do notcommonly lead to short stature despite strongexpression in the epiphyseal growth plate [Krakowet al., 2004]. No mutation-positive individual had afinal adult height below the 10th centile.

Mutations conferring substitutions within filaminrepeat 10 are noteworthy for variation in the severityof the associated phenotype. Two mother-son pairsconfirm the existence of a severe lethal form of FMDin males (cases 8 and 9). Stefanova et al. [2005]previously reported a similar phenotype associatedwith a deletion in exon 29. The findings in the twounrelated males reported here included cardiacdefects (tricuspid atresia, pulmonary stenosis),obstructive uropathy, arachnodactyly, mild campo-melia, and joint contractures. No qualitative pheno-typic feature in related carrier females unequivocallypredicts this lethal phenotype over more viable malephenotypes associated with the substitutionsD1159A and S1186L in the same protein fold. Themale phenotype associated with MNS is clinicallydistinct from that described in this report and byothers [Stefanova et al., 2005] despite the causativemutations being located in the same FLNA exon.Sons of women with typical MNS phenotypeshave skeletal (absent halluces, marked thoracichypoplasia, micrognathia) and extraskeletal anoma-lies (omphalocoele, cardiac, and genitourinarydefects) not seen in the FMD-associated male-lethalphenotype described here. However, some overlap

FIG. 3. Contractures of the fingers in FMD. A, B: Male patient, aged 17 years, with the mutation 759C>G. Note the cutaneous syndactyly, the absence of the digitalflexion creases that is more pronounced on the ulnar side of the hand and hypoplasia of the intrinsic musculature of both hands. C: More pronounced contractures in a12-year-old with no identifiable mutation in FLNA.



betweenMNSandFMDcertainly exists, reflecting theallelic nature of the conditions. A second female witha mutation that predicts the substitution P1149L(described here in a sporadic female with FMD—case 3) has been ascertained (SPR, TM, A Green,unpublished data) with a clinical diagnosis of MNS,but is not presented within this dataset due toincomplete phenotypic characterization. She hadtwo sons with a lethal disorder that includedmicrognathia, cleft palate, absent halluces, absentdistal phalanges of the thumbs, thoracic hypoplasia,and anal stenosis—aphenotype that is reminiscent ofmale-lethal MNS [Donnenfeld et al., 1987].

It is notable that no males with FMD have beendescribed with mutations leading to substitutionswithin filamin repeats 16–23, although females withthis diagnosis have mutations in exons encodingthis region (cases 12, 13) [Zenker et al., 2004]. Thisobservation may be related to the distribution ofdescribed binding sites within the filamin protein fora large number of proteins [Stossel et al., 2001]alteration of which in the male hemizygote may notbe tolerated during embryonic development.Although no convincing evidence for excessivemiscarriage or relative infertility exists to supportthis hypothesis, this may merely be an ascertainmentissue.

Previously, phenotypic similarities between OPD1and FMD have suggested that the two conditions arethe same entity [Gimelli and Superti-Furga, 1987;Verloes et al., 2000]. Several observations run counterto this hypothesis. Shortening of the first ray,particularly in the feet together with a long secondtoe, as seen in OPD1 are infrequent findings in FMD.The progressive contractural process affecting theproximal and distal interphalangeal joints, mostsevere on the ulnar side of the hand, is unique toFMD. Obstructive urological lesions have not beenreported in OPD1 and cleft palate is a more commonaccompaniment in OPD1 than FMD. Muscle hypo-plasia is also a common observation in FMD butnot in OPD1. All classically affected males with

OPD1 have had mutations identified solely withinexons 3–5 of FLNA, whereas, as noted above,mutations underlying FMD lie within clusters dis-persed over the length of the gene.

The data presented here shows that a significantproportion of individuals with FMD have noidentifiable mutation in FLNA. Although it is con-ceivable that our mutation screening strategy is notcompletely sensitive, it is unlikely to account for allinstances of failure to identify a causative mutationin individuals who otherwise have a typical FMDphenotype. Four of these individuals have beenpreviously reported in work that contributed to theclinical definition of FMD as an entity and representtypical phenotypes for the condition [Danks et al.,1972; Fitzsimmons et al., 1982; Gimelli and Superti-Furga, 1987; Morava et al., 2003]. Considering thatloss-of-function mutations in FLNA lead to PVNH,it is unlikely that a substantial proportion of the10 unrelated individuals with FMD in whom noexonic or splice-site consensus sequence mutationwas identifiable in this study harbor a disease-causing mutation outside the coding regions ofthe FLNA locus scanned in this study. Suggestiveevidence supportive of this contention is theproportion of females cases (both sporadic andfamilial) who do not show the characteristic skewedX-inactivation pattern observed in individuals whoare heterozygous for FLNA mutations. Skewing of X-inactivation can occur for stochastic reasons and ismore prevalent in older females, an observation thatmay explain results obtained from some individualsin this cohort with skewed X-inactivation but noidentifiable FLNA mutation. Mosaicism for a FLNAmutation could also conceivably explain some ofthese observations, but familial instances of FMDwithin this cohort rule out this hypothesis as auniversal explanation. Further study of these FLNAmutation-negative patients may identify furthergenes that functionally interact with filamin A andprove invaluable in expanding our understanding ofthe aetiopathogenesis of the OPSD phenotypes.

ACKNOWLEDGMENTS

We are grateful to all the individuals and familieswho participated in this study. S.R., T.M., and Z.A.J.are supported by the Child Health Research Founda-tion of New Zealand.

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Frontometaphyseal dysplasia: Mutations in FLNA and phenotypic diversity