Artrogriposis Distal Descubrimientos Clinicos y Geneticos 2012

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REGULAR ARTICLE

Distal arthrogryposis: clinical and genetic findingsEva Kimber1,2, Homa Tajsharghi3, Anna-Karin Kroksmark2, Anders Oldfors3, Mr Tulinius ([email protected])2

1.Department of Womens and Childrens Health, Uppsala University Childrens Hospital, Uppsala, Sweden2.Department of Paediatrics, Institute of Clinical Sciences, University of Gothenburg, The Queen Silvia Childrens Hospital, Gothenburg, Sweden

3.Department of Pathology, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden

Keywords

Arthrogryposis, Distal arthrogryposis 1 and 2,Multiple congenital contractures, Muscle weakness,Muscular disease

Correspondence

Mar Tulinius, Department of Paediatrics, Universityof Gothenburg, The Queen Silvia Childrens Hospital,SE-416 85 Gothenburg, Sweden.Tel: +46-31-3434780 |Fax: +46-31-843010 |Email: [email protected]

Received

13 March 2012; revised 5 April 2012;accepted 12 April 2012.

DOI:10.1111/j.1651-2227.2012.02708.x

ABSTRACT

Aim: Distal arthrogryposis is characterized by congenital contractures predominantlyin hands and feet. Mutations in sarcomeric protein genes are involved in several types of

distal arthrogryposis. Our aim is to describe clinical and molecular genetic findings in indi-

viduals with distal arthrogryposis and evaluate the genotype-phenotype correlation.Method: We investigated 39 patients from 21 families. Clinical history, includingneonatal findings, joint involvement and motor function, was documented. Clinical exami-

nation was performed including evaluation of muscle strength. Molecular genetic investiga-

tions were carried out in 19 index cases. Muscle biopsies from 17 patients were analysed.Results: A pathogenic mutation was found in six families with 19 affected family

members with autosomal dominant inheritance and in one child with sporadic occurrence.In three families and in one child with sporadic form, the identified mutation was de novo.

Muscle weakness was found in 17 patients. Ambulation was affected in four patients and

hand function in 28. Fourteen patients reported pain related to muscle and joint affection.Conclusion: The clinical findings were highly variable between families and alsowithin families. Mutations in the same gene were found in different syndromes suggesting

varying clinical penetrance and expression, and different gene mutations were found in the

same clinical syndrome demonstrating genetic heterogeneity.

INTRODUCTION

Distal arthrogryposis (DA) belongs to a group of syndromes

called arthrogryposis multiplex congenita (AMC), definedas congenital contractures in more than two joints and inmultiple body areas (1). There are more than 200 described

AMC syndromes. The incidence is between 14300 and

15100 (24). DA syndromes are characterized mainly by

distal congenital joint contractures, that is, of the hands andfeet. Twenty-one per cent of patients in a Swedish study of

AMC in children and adolescents were diagnosed with DA

syndromes, which indicates an incidence of about 120 000

(2). In 1982, DA syndromes were delineated as arthrogrypo-

sis with mainly congenital hand and foot involvement (5):

type I with only distal joint involvement and characteristichands at birth with flexed and overlapping fingers, and type

IIA-IIE with distal limb contractures and additional charac-teristic manifestations. A revised and extended classification

was made by Bamshad et al. (6). In this classification, DA isdefined as an inherited primary limb malformation disorder

characterized by congenital contractures of two or more dif-

ferent body areas and without primary neurological andor

muscle disease affecting limb function. Included disorders

are characterized by distal joint involvement, limited proxi-

mal joint involvement, autosomal dominant inheritance,reduced penetrance and variable expressivity. Nine different

clinical forms are originally described, with a 10th

syndrome defined in 2006 (68). The DA syndrome classifi-

cations are shown in Table 1.

The most commonly described forms of DA are DA1 andDA2B. DA1 is characterized by clenched fists at birth, ulnar

deviation, medially overlapping fingers and club feet or

other foot malpositions. The hips may be affected, calves

may be small and the opening of the mouth mildly limited

(9). DA2A, the FreemanSheldon syndrome, is character-ized by small mouth, facial contractures, scoliosis, mainly

distal joint contractures and short stature (10). DA2B, the

SheldonHall syndrome, is similar to DA2A but milder.

Typical findings in DA2B are vertical talus, ulnar deviation,

severe camptodactyly, triangularly shaped face, prominent

Key notes

We investigated 39 patients from 21 families with distalarthrogryposis.

Clinical findings were found to be highly variablebetween families and also within families.

Mutations in the same gene were found in differentsyndromes suggesting varying clinical penetrance andexpression, and different gene mutations were found inthe same clinical syndrome demonstrating genetic het-erogeneity.

Acta Pdiatrica ISSN 08035253

2012 The Author(s)/Acta Pdiatrica 2012 Foundation Acta Pdiatrica 2012101, pp. 877887 877


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nasolabial folds, down-slanting palpebral fissures, smallmouth and prominent chin (11). Foot deformities may be

asymmetric (12).

Mutations in genes encoding sarcomeric muscle proteins

are found in several DA syndromes: Sung et al. (13,14)described mutations in beta-tropomyosin (TPM2) in DA1,

and mutations in fast troponin I (TNNI2) and fast troponinT (TNNT3) in DA2B. Toydemir et al. (15) described muta-

tions in embryonic myosin heavy chain 3 (MYH3) in DA2A,

the FreemanSheldon syndrome, and in DA2B, the Shel-

donHall syndrome. Further, a mutation in the foetal myo-sin heavy chain (MYH8) has been described in DA7, the

trismus-pseudocamptodactyly syndrome (16). Recently,DA1 has been associated with mutations in the slow-twitch

skeletal muscle myosin-binding protein C1 (MYBPC1) (17).Myopathic findings have previously been demonstrated in

DA12B with mutations in TNNI2 (18). Muscle weakness

has been demonstrated in patients with DA2B and muta-

tions in MYH3 and TPM2 (19). A defective function of

contractile muscle proteins during foetal life influencing

the mobility of the foetus seems to be the common causeof congenital joint contractures in these syndromes

(15,16,20).

The purpose of this study is to describe the clinical find-

ings in individuals with DA, to classify them into different

DA syndromes, to describe molecular genetic findings in theinvestigated individuals and to evaluate the genotype-phe-

notype correlation.

MATERIALS AND METHODS

SubjectsIn a national Swedish study of 131 children, adolescents

and young adults with AMC, 27 individuals with DA were

identified from 21 families. Including the affected parents

and extended family members, 39 individuals with familial

or sporadic DA were examined. The 27 patients were identi-fied via paediatric rehabilitation centres or, in a few cases,

via the orthopaedic surgeon or the Swedish AMC-associa-

tion. Affected relatives were contacted by the investigators

after an interview with and examination of the patients.From each of the 21 families, one patient was defined as the

index case (Tables 24).Written informed consent was obtained from adult par-

ticipating individuals and from the parents. The study was

approved by the Ethical Review Board at the Universities of

Gothenburg, Uppsala, Stockholm, Umea, Orebro, Malmo,Lund and Linkoping, and by the heads of the Paediatric

departments in the Swedish health-care regions.

Clinical investigationA detailed clinical examination was carried out of the origi-

nally identified 27 individuals, including physical examina-

tion by the same paediatric neurologist (EK) and

physiotherapist (A-KK). The physical examination included

a general examination, evaluation of facial involvement,

other associated signs and symptoms, and a neurologicalexamination.

Medical charts were studied, and results from previous

investigations, including orthopaedic procedures and mus-

cle biopsies, were recorded. A structured interview with the

27 patients was carried out and included their family his-tory, prenatal and perinatal history, neonatal findings,

developmental milestones, associated medical problems,

treatment and outcome.

Affected adult family members were examined by the

same physician and physiotherapist, and information ontheir family history was obtained through personal inter-

views. Family members who were found to be asymptomatic

carriers of the pathogenic gene mutation were seen and

interviewed personally to exclude the presence of previ-

ously undiagnosed distal joint involvement.

Table 1 Classification of distal arthrogryposis syndromes

Key distinguishing features

Classification

Bamshad Classification Hall Other name OMIM number

Overlapping fingers neonatally, ulnar deviation DA1 DA type I Digitotalar dysmorphism 108120

Facial contractures, small pursed mouth DA2A FreemanSheldon syndrome, FSS 193700

Intermediate DA12A DA2B SheldonHall syndrome 601680

Cleft palate, short stature DA3 DA type IIA Gordon syndrome 114300

Scoliosis DA4 DA type IID Arthrogryposis with severe scoliosis 609128Cleft lip DA type IIC

Ptosis, limited ocular mobility DA5 DA type IIB Arthrogryposis with oculomotor limitation

and electroretinal abnormalities

108145

Sensorineural hearing loss DA6 Arthrogryposis-like hand anomaly and

sensorineural hearing loss

108200

Trismus, facultative finger contractures DA7 Trismus-pseudocamptodactyly syndrome,

Hecht syndrome

158300

Multiple pterygium DA8 AD multiple pterygium syndrome 178110

Ear deformity, long fingers DA9 Beals syndrome, congenital contractural

arachnodactyly, CCA

121050

Plantar flexion contractures DA10 Short tendo calcaneus 187370

DA, Distal arthrogryposis.

DA: clinical and genetic findings Kimber et al.

878 2012 The Author(s)/Acta Pdiatrica 2012 Foundation Acta Pdiatrica 2012 101, pp. 877887


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The diagnostic criteria used to distinguish the different

forms of DA are, according to Bamshad et al. from 1996 (6),

described in Table 1.Ambulation was classified according to Hoffer (21), using

the four categories of community ambulator, household

ambulator, nonfunctional ambulator and nonambulator

(22).Passive range of motion was measured with an ordinary

goniometer. Isometric muscle strength was measured with a

hand-held dynamometer using a method standardized by

Eek et al. (23), or, in children too young to participate in

this, by clinical evaluation. Motor function was assessed

according to Scott et al. (24), using a scale designed for chil-dren with muscle disease. In adults and in children younger

than one year, gross and fine motor function was evaluated

by inspection and interview.

Hand function was assessed by classification into one offour categories as follows:

1 Normal function

2 Able to perform all tasks completely but with compen-

satory strategies

3 Able to perform all tasks but incompletely and with

compensatory strategies

4 Able to perform tasks incompletely, very limited hand

function

The tasks evaluated in children included grasping a

paper, holding a pen and writingdrawing, assembling Legoand Duplo bricks, threading beads on a string and screwing

together a nut and bolt (22).

Hand function and gross motor function were videotaped

to facilitate evaluation and comparisons.

Short stature was defined as below 3 SD.

Muscle pathologyMuscle biopsy specimens were obtained from eleven indi-

viduals and analysed by the same pathologist (AO). Staining

techniques included haematoxylin-eosin, Gomori tri-

chrome, myofibrillar ATPase, oxidative enzymes (NADH-tetrazolium reductase, succinate dehydrogenase and cyto-

chrome oxidase), glycogen, lipids and major histocompati-

bility complex class 1 antigen. In another six patients,

results from previously performed muscle biopsies wererecorded from medical charts.

Table 2 Eight patients in three families with DA owing to mutations in embryonic myosin heavy chain,MYH3

Case

Familyindividual 1:1 1:2 (IC) 2:1 2:2 (IC) 2:3 2:4 3:1 3:2 (IC)

Age at investigation

(years)

49 21 41 10 10 8 7 4

Male(M)female(F) F F M F F M M M

Facial involvement + + + + ) ) ) )

Impairedmouth opening + + + + + + ) )

Joint involvement

Hands + + + + + + + +

Feet + + + + + + + +

Proximal joints + + + + + + + )

Asymmetric legsfeet + + ) ) + ) + (+)

Smooth palms ) ) + + + + ) )

Scoliosiskyphosis + + ) ) ) ) ) ))

Short stature + + ) ) ) ) ) )

Muscle weakness + + ) ) ) ) ) )

Level of ambulation* 2 2 1 1 1 1 1 1

Hand function** 3 2 2 2 1 2 1 2

No of orthopaedic

hand surgeries

220 30 00 00 20 20 00 00

Pain problems + + ) ) ) ) ) )

Additional signs

symptoms

Lip hem-angioma

hypertonia

Lip hemangioma Inguinal

hernia

keratoconus

Cleft palate Mental

retardation

ADHD

Cleft palate, CHD,

ADHD duodenal

atresia

Muscle pathology + + ) NA NA NA ) NA

DA classification DA2B DA2B DA2B DA2B DA1 DA1 DA1 DA1

Mutation found MYH3

D462G

MYH3

D462G

MYH3

A234T

MYH3

A234T

MYH3

A234T

MYH3

A234T

MYH3

A1752T

MYH3

A1752T

NA, not analyzedlacking information; ADHD, attention deficit hyperactivity disorder; CHD: congenital heart disease; IC, index case in the family; +: present; ): not

present; *1: community ambulator; 2: household ambulator; 3: nonfunctional ambulator; 4: nonambulatory; **1: able to perform tasks completely; 2: able to per-

form tasks completely but with compensatory strategies or aberrant function; 3: able to perform tasks incompletely; 4: not able to perform tasks.

Kimber et al. DA: clinical and genetic findings



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Table

3

Twopatientsinone

fam

ilyw

ithDAow

ingtomutationsb-tropomyos

in,

TPM2an

dn

inepatientsintwo

fam

iliesw

ithDAduetomutations

intropon

in1

,TNNI2

Case

Fam

ilyindividua

l

4:1

4:2

(IC)

5:1

5:2

5:3

5:4

5:5

(IC)

5:6

6:1

6:2

(IC)

6:3

Ageatinvestigation

(years)

65

28

64

38

34

30

5

0,7

26

6

1

Male(M)female(F)

F

F

M

F

M

M

F

F

F

F

M

Facialinvolvement

+

+

)

+

)

)

)

)

+

+

+

Impairedmouth

opening

+

+

+

+

+

)

)

+

NA

+

)

Jointinvolvement

Hands

+

+

+

+

+

+

+

+

+

+

+

Feet

+

+

+

+

+

+

+

+

+

+

+

Proximaljoints

+

+

+

+

+

+

)

)

NA

+

+

Asymmetriclegsfeet

+

+

)

)

+

)

)

)

NA

)

)

Smoothpalms

+

+

+

+

+

)

)

+

NA

+

NA

Scoliosiskyphosis

+

+

)

+

)

)

)

)

NA

+

)

Shortstature

+

+

)

)

)

)

)

)

)

+

)

Muscleweakness

+

+

)

)

)

)

)

)

NA

+

NA

Levelofambulation*

1

1

1

1

1

1

1

)

1

1

1

Handfunction**

2

2

2

2

2

1

1

2

3

2

NA

Nooforthopaedic

handsurgeries

00

30

60

60

60

00

30

10

>20

12

10

Painproblems

+

)

+

)

)

+

)

)

NA

)

)

Additionalsigns

symptoms

Reduced

hearing

Reduced

hearing

Neckpterygium

)

)

)

Reduced

hearing,

inguinal

hernia

Inguinal

hernia

Neck

pterygium

NA

Cranio-stenosis

Pelvo-uretheral

stenos

is

Inguinalhernia,

retentiotestis

Musclepathology

+

+

+

+

+

+

NA

NA

NA

NA

NA

DAclassification

DA2B

DA2B

DA1

DA2B

DA1

DA2B

DA1

DA2B

DA2B

DA2B

DA2B

Mutationfound

TPM2

R133W

TPM2

R133W

TNNI2

K176del

TNNI2

K176

del

TNNI2

K176del

TNNI2

K176del

TNNI2

K176del

TNNI2

K176del

TNNI2

R174Q

TNNI2

R174Q

TNNI2

R174Q

NA,notanalyzedlackinginformation;IC,

indexcaseinthefamily;+:present;:notp

resent;*1:communityambulator;2:household

ambulator;3:nonfunctionalambulator;4:nonambulatory;**1:abletoper-

form

taskscompletely;2:abletoperfor

m

taskscompletelybutwithcompensatorystrate

giesoraberrantfunction;3:abletoperform

task

sincompletely;4:notabletoperform

tasks.




5/12

Molecular genetic investigationBlood samples for genetic analysis were obtained from 19 of

the 21 index patients and from their relevant family mem-bers. In two index patients, no blood sample was obtained

(12:1 and 21:1).

Extraction of DNA, polymerase chain reaction (PCR)

and sequence analysis were performed as previouslydescribed (17,19,20). The entire coding region of MYH3,

TPM2and TNNI2was sequenced in 15 index patients using

the previously described primers (15,16,20). The presence

of each mutation was confirmed in each affected individual

by restriction fragment length polymorphism (RFLP) analy-

sis. RFLP analysis was also used to screen for the presenceof each mutation in 200 control chromosomes. In addition,

in five of the 15 index patients in whom mutations in

MYH3,TPM2and TNNI2were excluded, the entire coding

region of other sarcomeric thin filament componentsincluding TNNI1, TNNT3, TNNC1, TNNC2 and TNNT1was also analysed. Furthermore, additional sarcomeric

genes were considered as the plausible cause of the disease

based on similarities in the clinical features with previously

reported cases. This included one patient with multiple

pterygium syndrome where the acetylcholine receptor gene

gamma and the entire coding region ofGHRNGwere anal-

ysed in addition to TPM2. The entire coding region of the

slow-twitch skeletal muscle myosin-binding protein C (MY-BPC1) was also analysed in two index patients, and the

entire coding region of both MYH8 and MYH3was analy-

sed in one index patient.

RESULTS

SubjectsWe identified 27 patients, children and young adults, and

twelve affected relatives. Of the 39 affected individuals, 22

were male and 17 were female. The age span was from ninemonths to 65 years at the time of investigation. There were

ten families with a total of 28 affected individuals: in one

family three generations were affected, in eight families two

generations and in one family one generation. In four fami-lies there were two affected siblings, and in one family three

affected siblings. Eleven cases were sporadic.

Perinatal dataPerinatal data were available for 26 of the 27 patients. Data

were missing for one child who was adopted at three years

Table 4 Nine patients in four families with familial DA with no identified mutations

Case Familyindividual 7:1 7:2 (IC) 8:1 8:2 (IC) 8:3 9:1 9:2 (IC) 10:1 10:2 (IC)

Age at investigation

(years)

50 18 34 7 3 36 1 38 4

Male(M)female(F) F M M M M M M F M

Facial involvement + + + + + ) ) ) +

Impaired mouth

opening

+ + NA + + ) ) ) )

Joint involvement

Hands + + + + + + + + +

Feet + + + + + + + + +

Proximal joints + + NA + + + + + +

Asymmetric legsfeet + ) + + + ) + ) )

Smooth palms + + + + + + + ) )

Scoliosiskyphosis ) ) + + ) ) ) ) +

Short stature ) ) NA ) ) ) ) ) )

Muscle weakness NA + NA + + ) ) ) )

Level of ambulation* 1 1 1 1 1 1 NA 1 1

Hand function** 2 2 2 2 2 2 2 1 1

No of orthopaedic

hand surgeries

411 55 10 01 20 120 10 10 00

Pain problems + + + + ) + ) ) )

Additional signs

symptoms

High blood

pressure

Reduced hearing

Urether stenosis,

Urolithiasis Ing.

hernia

Ing. hernia Ing. hernia

Retentio

testis

Ing. hernia

Retentio

testis

Myopia Bowed

lower leg

Crumpled

ears

Crumpled

ears

Muscle pathology + NA NA + NA NA NA NA NA

DA classification DA2B DA2B DA2B DA2B DA2B DA1 DA1 DA9 DA9

Mutation found None found None found None

found

None

found

None

found

None

found

None

found

None

found

None

found

NA, not analyzed lacking information; IC, index case in the family; +: present; : not present; *1: community ambulator; 2: household ambulator; 3: nonfunc-

tional ambulator; 4: nonambulatory; * *1: able to perform tasks completely; 2: able to perform tasks completely but with compensatory strategies or aberrant func-

tion; 3: able to perform tasks incompletely; 4: not able to perform tasks.




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of age. Birth was by Caesarean section in 14 patients, eight

of whom were in breech position. One child had intrauter-ine growth retardation, and two were born prematurely 32

gestational weeks. Feeding problems during the neonatal

period were reported for 15 patients.

Joint involvement at birthInformation regarding joint position at birth was available

for 33 of the 39 individuals. In the remaining six individuals,congenital, mainly distal, joint contractures were described,

but no detailed information was available. Hand involve-

ment included ulnar deviation (n = 16), adducted thumbs(n = 15), clenched fists (n = 13), contractures of the fingers

(n = 12), contractures of the wrists (n = 10) and overlap-

ping fingers (n = 6). Foot involvement included pes equi-

novarus (n = 18), pes calcaneovalgus (n = 11) and otherfoot malpositions (n = 8). Involvement of proximal joints

included contractures of the hips (n = 12), knees (n = 10),shoulders (n = 7) and elbows (n = 6), dislocation of the

hips (n = 5), scoliosiskyphosis (n = 3) and torticollis

(n = 3).

Other neonatal findingsReported neonatal findings included facial haemangioma

(n = 4), epicanthic folds (n = 4), asymmetric face (n = 3),

microphthalmia (n = 3), low-set ears (n = 3), hypertelo-rism (n = 2), micrognathia (n = 1) and small mouth

(n = 1). Cleft palate was described in two patients, one of

whom also had multiple malformations including duodenal

atresia and congenital heart vitium with ventricular septum

defect and anomalous outlet of the pulmonary veins. One

patient with DA2A, the FreemanSheldon syndrome, had

severe facial contractures with blepharophimosis and anextremely small and puckered mouth. Inguinal hernia was

present in four patients, and diaphragmatic hernia in onechild who was later identified as having a multiple ptery-

gium syndrome. Congenital pterygias were described intwo patients.

Clinical findings at follow-upThe clinical findings are described in Tables 25 and illus-

trated in Figure 1. The number of patients with facial

involvement and joint involvement of the hands, feet andproximal joints is shown in Table 6.

Facial involvement was found more frequently in familial

than in sporadic cases. The most frequent findings, in

decreasing order, were impaired mouth opening (mild con-

tractures of the temporomandibular joints), low-set ears,high arched palate, micrognathia, high nose bridge, down-

slanting andor narrow palpebral fissures, facial asymmetry,

small mouth and epicanthic folds.

Flexion or, more rarely, extension contractures of the

wrists were the most frequent findings in the hands, fol-lowed by ulnar deviation of the wristsfingers. Smooth

palms with absent flexion creases and contractures in meta-

carpophalangeal (MCP) and finger joints resulting in cam-

ptodactyly were also seen frequently. Adducted thumbs andother thumb malpositions were also found.

The most common types of foot involvement, in order offrequency, were ankle contractures, adductionmetatarsus

varus, prominent heel pads, overlapping toes, short Achilles

tendons, pes planovalgus and equinus feet. Asymmetric

involvement of the feet was a common finding, while asym-

metric foot size was found in only a few patients.

The proximal joints were more often affected in the upperlimbs than in the lower limbs, with elbow and shoulder con-

tractures being the most common finding. Prominent radialheads were found in combination with impaired prona-

tionsupination, while impaired flexionextension of the

elbows was less commonly found. Contractures of the kneeswere less frequently seen than contractures of the hips.

Asymmetric leg length andor muscle bulk especially of the

calves was also seen.

Additional signs and symptoms

Inguinal hernia occurred in seven familial cases and onesporadic case, and cryptorchism in three familial and three

sporadic cases. Ureteric stenosis was found in two familial

cases. Attention deficit hyperactivity disorder (ADHD) was

present in two brothers one of whom also had mental retar-dation, while the other brother had multiple malformations

(palate, heart, duodenum). Reduced hearing, unilat-

eralbilateral, was present in four familial cases. Multiple

pterygias were present in the two patients with DA8, andmild neck pterygium was found in a further three familial

cases. Malformation of the outer ear (crumpled ear) was

present in the two familial cases with DA9. Dimples over

affected joints were present in 11 familial and in six spo-

radic cases.

Orthopaedic surgeryThe number of orthopaedic surgical interventions varied

between one and 22 in 31 patients, 21 familial cases and tensporadic cases. When malpositioning of the feet had beenpresent at birth, orthopaedic surgery had generally been

performed during the first year of life.

PainPain, either generalized muscle pain or localized pain, was

present in 14 patients: ten familial and four sporadic cases.Pain was more frequent in the patients with more severe

joint contractures, and in the patients who had undergone

multiple orthopaedic surgeries. Muscle fatigue and pain on

exertion were described in several of the adult patients.

Gross motor function and hand functionAmbulation was affected in four patients: a mother and

daughter with DA2B, one sporadic case with DA2B and

one sporadic case of DA8. Ambulation could not be evalu-

ated in two children less than one year of age.

Hand function was mildly affected (able to perform thetasks completely but with compensatory strategies) in 23

patients, 19 familial and four sporadic cases and severely

affected (able to perform the tasks incompletely and with

compensatory strategies) in five patients, two familial andthree sporadic cases.




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Table

5

Patientsw

ithspora

dica

llyoccurring

DA

,onew

ithmutation

inem

bryon

icmyos

inheavy

cha

in,

MYH3an

dtenpatientsw

ithno

identifie

dmutations

Case

Fam

ilyindividua

l

11:1

12:1

13:1

14:1

15:1

16:1

17:1

18:1

19:1

20

:1

21:1

Ageatinvestigation

(years)

4

16

17

13

10

5

3

18

11

4

10

Male(m)female(f)

M

M

F

F

F

M

M

M

M

F

M

Facialinvolvement

+

+

)

)

)

+

)

+

+

+

+

Impairedmouth

opening

++

+

)

)

)

+

)

+

+

)

+

Jointinvolvement

Hands

+

+

+

+

+

+

+

+

+

+

+

Feet

+

+

+

+

+

+

+

+

+

+

+

Proximaljoints

+

+

+

+

)

+

+

+

+

+

+

Asymmetriclegsfeet

)

+

+

)

)

)

)

)

)

+

+

Smoothpalms

)

+

+

+

+

+

)

)

+

)

)

Scoliosiskyphosis

+

+

)

)

)

)

)

+

+

)

+

Shortstature

+

+

)

)

)

)

)

)

+

)

+

Muscleweakness

+

+

+

+

+

)

+

+

+

)

+

Levelofambulation*

1

2

1

1

1

1

1

1

1

2

1

Handfunction**

2

3

2

2

2

1

1

3

3

1

1

Nooforthopaedic

handsurgeries

31

14

05

122

06

00

01

52

03

20

01

Painproblems

)

)

+

+

)

)

)

+

+

)

)

Additionalsigns

symptoms

CHDPtosis

Ptosis,pubertas

praecox,

retentiotestis

)

)

)

Facial

hemangioma

)

Inguinal

herniaMild

neckpterygium

Ptosis,

retentiotestis

Multiple

pterygium

Multiple

pterygium

retentiotestis

Musclepathology

+

+

NA

)

NA

NA

)

)

NA

NA

NA

DAclassification

DA2A

DA2B

DA1

DA1

DA1

DA2B

DA1

DA7

DA3

DA

8

DA8

Mutationfound

MYH3T178M

NA

Nonefound

Nonefoun

d

Nonefound

Nonefound

Nonefou

nd

Nonefound

Nonefound

NA

NA

NA,notanalyzedlackinginformation;CHD,congenitalheartdisease;+:present;):n

otpresent;*1:communityambulator;2:house

holdambulator;3:nonfunctionalambulator;4:

nonambulatory;**1:ableto

perform

taskscompletely;2:abletope

rform

taskscompletelybutwithcompensatorystrategiesoraberrantfunction;3:abletoperform

tasksincompletely;4:notabletoperform

tasks.




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Muscle involvementMuscle weakness was found in 17 individuals, eight familial

and nine sporadic cases.

Muscle morphologyMorphological findings in skeletal muscle are illustrated in

Figure 2. Muscle pathology was demonstrated in twelve of17 patients. In two patients with DA2B and TPM2 muta-

tion, there was minor type-1 fibre predominance. In the

patient with DA2A and MYH3 mutation, marked type-1

fibre predominance and scattered small type-1 fibres were

found. In two patients with DA2B and MYH3 mutation,

increased variability in fibre size owing to the presence offrequent small type-1 fibres was found. In four familial cases

with DA1 or DA2B and TNNI2 mutation, muscle biopsy

specimens showed findings of myopathy with changes

mainly restricted to type-2 fibres. In one patient with DA2B

with no known mutation, a previously performed musclebiopsy showed type-1 fibre predominance.

Molecular geneticsMolecular genetic investigations revealed pathogenic muta-tions in one sporadic and 19 familial cases. Three de novomutations were identified, including a D462G mutation in

MYH3in family 1, a R133W mutation in TPM2in family 4

and a K176del mutation in TNNI2in family 5. In addition,

A234T and A1752T mutations in MYH3 were identified in

family 2 and 3, respectively. Two asymptomatic carrierswere identified in these families, the paternal grandfather in

family 2 with A234T mutation in MYH3 and the father in

Figure 1 Clinical features in patients with Distal arthrogryposis2B (SheldonHall syndrome) with mutations of different sarcomeric protein genes: from right to left

patient with mutation of fast troponin I (TNNI2), embryonic myosin heavy chain (MYH3),b-tropomyosin (TPM2) and a patient with no identified mutation. Note asym-

metric lower legs and feet.

Table 6 Facial involvement, involvement of hands, feet and proximal joints according to inheritance in 28 familial and 11 sporadic patients with distal arthrogryposis syndromes

Facial involvement F S Hand involvement F S Foot involvement F S Involvement of proximal joints F S

Impaired mouth opening 14 5 Ulnar deviation 15 5 Metatarsus varus 13 11 Shoulder contractures 14 7

Low-set ears 12 4 Wrist contractures 16 4 Ankle contractures 13 8 Elbows impaired prosup 15 6

High arched palate 14 0 Smooth palms 13 1 Prominent heel pads 7 1 Elbow flexext

contractures

7 3

Micrognathia 8 3 Contractures in MCP joints 12 2 Overlapping toes 6 1 Elbow hyperextension 2 2

High nasal bridge 7 2 Contractures in finger joints 9 4 Short Achilles tendons 2 3 Prominent radial heads 5 0

Down-slanting eyes 6 1 Thumbs in hands 7 2 Curlyadducted toes 3 2 Contractures in hips 7 4

Narrow palpebral fissures 6 1 Proximal syndactyly 3 0 Pes planovalgus 3 1 Hip dislocation 1 0

Asymmetric facejaw 5 1 Hyperextended PIP-joints 2 1 Equinus feet 1 3 Hip hypermobility 0 1

Small mouth 5 1 Laterallow-set thumbs 3 1 Proximal syndactyly 1 0 Contractures in

knee joints

7 4

Epicanthal folds 4 0 Short dorsal extensor

tendons

1 1 Cavus feet 0 1 Patellar luxation 2 0

Lip hemangioma 3 0 Sublux thumbs 1 0Down-pressed tip of nose 2 0

Ptosis 0 2

Cleft palate 2 0

Hypertelorism 2 0

Prominent chin 1 0

F, familial; S, sporadic; MCP, metacarpophalangeal; PIP, proximal interphalangeal; pro, pronation; sup, supination.




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family 3 with A1752T mutation inMYH3. The latter patient

had a history of contractures of the feet as a child, but was

asymptomatic at the time of investigation. Notably, two

nonsynonymous single-nucleotide polymorphisms at posi-

tion 1752 (A1752S and A1752T) have been identified(rs34393601). No mutations were found in TNNC1,

TNNC2,TNNT1,GHRNG, MYBPC1andMYH8.

Distal arthrogryposis classificationThirteen patients, nine familial and four sporadic cases,

were classified as having DA1. Seventeen patients, 15 famil-

ial and two sporadic cases, were classified as having DA2B.

In two familial patients, the clinical findings were interme-

diate between DA1 and DA2B. Clinically, the dividing line

between these two syndromes was not clear-cut.One child was classified as having DA2A, FreemanShel-

don syndrome, one child as DA3, Gordon syndrome, and

one young man as DA7, trismus-pseudocamptodactyly syn-drome. All three were sporadic cases. DA8, multiple ptery-gium syndrome, was found in two sporadic cases, and DA9,

Beal syndrome, in one family with an affected mother and

son.

In seven patients with DA2B, five familial cases from two

families and two sporadic cases, and in six patients with

DA1, two familial and four sporadic cases, no mutation wasidentified. The clinical findings in these cases did not differ

from the findings in patients with DA1 or DA2B in whom

pathogenic mutations were identified.

DISCUSSION

Distal arthrogryposis syndromes, at least DA1, DA2A and

DA2B, may be regarded as diseases caused by sarcomeric

protein dysfunction causing foetal myopathy and secondary

congenital joint contractures. The involvement is predomi-nantly distal in milder cases, but with more severe affection

all joints are involved, proximal and distal, and facial devel-

opment is also affected. Our findings indicate that familialcases are often more severe.

The phenotypic variability was found to be wide, varying

from unaffected carriers to severely affected individuals.

The correlation between genotype and phenotype was low.

Facial involvement and involvement of proximal joints were

seen as expressions of increasing severity rather than of clin-ically separate syndromes. DA1 and DA2B appear as differ-

ent clinical expressions of the same genetic mutation in two

of our investigated families: family 2 with mutation in

MYH3and family 5 with mutation in TNNI2.In this study, there was not a strict genotype-phenotype

correlation. Dysfunction of several different sarcomeric pro-

teins during foetal life results in similar clinical features, and

the presence of so far nonidentified gene mutations can

cause the same clinical symptoms as the mutations identi-

fied inMYH3,TPM2andTNNI2.

The likelihood of identifying a genetic cause of DA wasfound to be far greater in familial than in sporadic cases. A

pathogenic mutation causing sarcomeric protein dysfunc-

tion was found in 19 familial cases but only in one sporadic

Figure 2 Muscle pathology in three patients with Distal arthrogryposis2B (SheldonHall syndrome) owing to mutations in different sarcomeric protein genes: In the

biopsy specimen from the patient with fast troponin I (TNNI2) mutation, there are myopathic changes affecting mainly type 2 fibres and minor increase in interstitial con-

nective tissue. In the biopsy specimen from the patient with embryonic myosin heavy chain (MYH3) mutation, there is variability in fibre size with many small type 1

fibres. In the biopsy specimen from the patient with -tropomyosin (TPM2)mutation, there is type 1 fibre predominance as the only pathologic change.




10/12

case. The only sporadic case of DA with an identified patho-

genic mutation in our study was a child with DA2A, theFreemanSheldon syndrome. However, in three families

with familial DA ade novomutation could be demonstrated

in the oldest affected individual, which indicates that patho-

genic sarcomeric gene mutations may also be present in

other sporadic cases. One of the de novo mutations was in

MYH3 (family 1), one was in TPM2 (family 4) and one in

TNNI2(family 5).Asymptomatic carriers were found in two extended fami-

lies, demonstrating varying penetrance. In family 2, the

unaffected paternal grandfather carried the same mutationin MYH3 as his affected son and three affected grandchil-

dren. In family 3, also with a mutation in MYH3, the father

was an asymptomatic carrier with the same mutation as that

found in the two affected children. The father had a historyof contractures of his feet as a child.

Muscle involvement in childhood and in adult life wasvariable, with muscle weakness present in some families but

not in others. In some instances, the muscle weakness

affected only the hands and feet, and in others all the mea-

sured muscle groups. Muscle weakness was found in bothfamilial and sporadic DA. Interviews did not indicate any

clear progression of muscle weakness over time, but

affected adults described increasing muscle fatigue with age.

Generalized muscle pain was more common in older thanin young individuals. Where pain was reported in children,

it seemed, in most of the cases, to be a consequence of

repeated surgical interventions, especially in the feet. Pain

of the hands was rarely reported.

Limitations to daily life seemed to be correlated mainly to

pain and muscle fatigue, but in some cases also to quitesevere limitations of joint mobility. Joint contractures of the

hands were sometimes a problem in daily life. Finger con-

tractures were more easily compensated for by using thehands in a different manner one man was a skilled manual

worker in spite of quite severe finger contractures whileimpaired function of the thumbs, especially thumb-finger

opposition, was more difficult to compensate for. Difficulty

of pronation and supination was also found to cause practi-

cal problems in daily life, such as difficulty of receiving small

objects (for example loose change) in the palm of the hand,

and difficulty of pushing or applying pressure using thepalms of the hands. Feet malpositions were more often trea-

ted surgically, as plantigrade position of the feet is necessary

for ambulation.

We found pathological changes in muscle biopsy speci-

mens from patients with DA2A and DA2B. Whether thesefindings are specific for the respective gene mutations is not

known, and requires further muscle morphologic studies in

DA patients.

Several of the DA syndromes, DA1, DA2A, DA2B and

DA7, have recently been shown to be caused by sarcomericprotein dysfunction (1316,1820). DA3, DA4, DA6 and

DA10 also include clinical findings that can be present in

DA syndromes where the cause is known to be sarcomeric

protein dysfunction. Mitochondrial dysfunction has beenfound in DA5 with ophthalmoplegia and retinal

pigmentation (5,25). Pulmonary disease has also beendescribed in this syndrome (26,27). Autosomal dominant

multiple pterygium syndrome is classified as DA8 (6). In

multiple pterygium syndrome, the Escobar syndrome, muta-

tions of embryonic acetylcholine receptor genes (28,29) or

absence ofb-tropomyosin (30) are described. Overlapping

clinical findings have been described in DA8 and DA2B(31). In DA9 (contractural arachnodactyly, Beal syndrome),

a pathogenic mutation of a fibrillin gene, FBN2, has beendescribed (32), indicating collagen dysfunction.

In conclusion, we suggest that DA syndromes be defined

according to the pathogenic background, that is, sarcomericprotein dysfunction, connective tissue dysfunction or other

pathology. DA1, DA2B and DA2A may be regarded as a

continuum of increasingly severe forms of myopathy,

caused by foetal sarcomeric protein dysfunction. Moleculargenetic and muscle morphological investigations, in addi-

tion to careful clinical evaluation, including evaluation ofmuscle strength and joint involvement, are of importance in

patients with DA syndromes, to further define and under-

stand these disorders.

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