159

GENETIC COUNSELING, Vol. 25, No 2, 2014, pp 159-168

SYNDROMES PRESENTING ADDUCTED THUMB WITH/WITHOUT CLUBFOOT AND DUNDAR SYNDROME

BY A. SUBASIOGLU UZAK 1, J.P. FRYNS 2 AND M. DUNDAR 1

(1) Department of Medical Genetics, Erciyes University School of Medicine, Kayseri, Turkey.(2) Departments of Human Genetics, Catholic University of Leuven, Leuven, Belgium.

INTRODUCTION

A congenital flexed adducted thumb has been called variously as con-genital clasped thumb, thumb in palm deformity or flexion adduction deformity of the thumb. This condition can be an isolated anomaly or associated with several genetic disorders. Congenital clasped thumb refers to a wide spectrum of thumb anomalies. It can be a result of mild deficiencies of the thumb extensor mechanism (extensor pollicis brevis or longus or both) or severe abnormalities of the extrinsic and intrinsic muscles, web space and soft tissue and joint contractures (3). According to the most useful classification that proposed; type 1 is supple clasped thumb with absence of hypoplasia of the extensor mus-cles, the thumb can passively abducted and this condition is seen with-out other digital abnormalities. Type II clasped thumb is a complex type with additional findings of hand contractures as joint contractures and collateral ligament abnormalities. In this form the thumb cannot be passively abducted and extended. Also other digital anomalies can be seen. Type III clasped thumb is associated with related syndromes especially arthrogryposis group. In this type the extensor mechanism can be deficient or normal (17, 20, 28). This condition should alert the

Summary: Syndromes presenting adducted thumb with/without clubfoot and Dundar syndrome: Congenital adducted thumb has been called variously as congenital clasped thumb, thumb in palm deformity or flexion adduction deformity of the thumb. This condition can be an isolated anomaly or associated with several genetic disorders. The syndromes that include adducted thumb as a cardinal feature such as Dundar Syndrome are few in the literature. This syndrome is an autosomal-recessive very rare disorder characterized by typical facial appearance with dysmorphic features that includes wasted build, hyperextensible, thin and translucent skin with atrophic scarring, severe congenital contractures of fingers and thumbs, club feet, severe kyphoscoliosis, joint instability, muscular hypotonia, and ocular involvement. Heart, kidney, and/or intestinal defects can also be observed. Up to date the syndrome is described in few families in the literature. Here we discuss the syndromes that include adducted thumb as a cardinal feature and also the differential diagnosis of the Dundar Syndrome according to the literature.

Key-words: Adducted thumb - Adducted thumb-clubfoot syndrome - Dundar syndrome - Ehlers-Danlos syndrome musculocontractural type.

160

GENETIC COUNSELING

clinician for various genetic syndromes (30).Dundar Syndrome (Ehlers-Danlos Syndrome, Musculocontractural Type), Christian Adducted Thumbs Syndrome, Escobar or multiple pterygia syndrome, MASA Syndrome, Arthrogryposis Multiplex Con-genita, Distal, Type I, Arthrogryposis, Distal, Type 2a are some of the most common syndromes that include adducted thumb as a cardinal feature.

SYNDROMES

Dundar Syndrome (Ehlers-Danlos Syndrome, Musculocontractural Type, Adducted Thumb – Club Foot Syndrome, Arthrogryposis, Dis-tal, with Peculiar Faces and Hydronephrosis, MIM ID #601776) is a rare syndrome that was originally described by Dundar et al. in male and female first cousins (4). Later on Sonoda and Kouno and Janecke et al. reported similar cases (10, 26). Up to date there are few reports published related with the syndrome. This syndrome embraces a broad spectrum of features. It is characterized by typical facial appearance that comprises frontal bossing, late-closing anterior fontanelle, tele-canthus, downslanting palpebral fissures and deep set/ posteriorly ro-tated ears, downturned angles of mouth, facial clefting. The dysmor-phic features include wasted build, thin and translucent skin, ocular anterior chamber abnormalities, distal arthrogryposis with arachnodac-tyly and adducted thumbs, club feet, joint instability and coagulopathy. The heart, kidney, and/or intestinal defects can also be observed (4, 5). Dundar et al. performed a genome-wide linkage scan, sequenced two candidate genes on chromosome 15q15, and identified homozygous mutations in the CHST14 gene in each family (5). The CHST14 gene encodes N-acetylgalactosamine 4-O-sulfotransferase 1 (D4ST1), which catalyzes the 4-O-sulfation of N-acetylgalactosamine (Gal-NAc) residues in dermatan sulfate and it is determined that loss of der-matan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome. Later on Müller et al. demonstrated locus heterogeneity in the syndrome (23). They provided evidence for the important role of dermatan sulfate in human development besides extracellular matrix maintenance (23). As a result the syndrome is the first metabolic de-fect specific (restricted) to dermatan sulfate biosynthesis and it is a form of congenital disorder of glycosylation (9). Miyake et al. demon-strated abnormal collagen bundle formation at a group of patients and suggested that this can be a main pathology associated with a decorin glycosaminoglycan abnormality (21). Dundar Syndrome has an auto-somal recessive inheritance pattern and is caused by homozygous or

161

compound heterozygous mutations (5). To date nine CHST14 variants have been determined which are all related with the syndrome (5, 14, 16, 18, 21).

Adducted Thumbs Syndrome (Thumbs, Congenital Clasped, MIM ID 201550) that characterized by arthrogryposis, dysmyelination, cra-niostenosis, and cleft palate. The syndrome was originally described by Christian et al. in three infants from an inbred Amish pedigree and consisting of adducted thumbs, craniosynostosis and severe neurolog-ical abnormalities (2). Striking dysmorphic features include prominent sutures, a prominent occiput, telecanthus, an antimongoloid eye slant, strabismus, a narrow, high, or cleft palate with a bifid uvula, posteriorly rotated ears, and micrognathia. There are multiple joint contractures of the large joints, but also of the index fingers, in addition to the adduct-ed thumbs. Muscle bulk was reduced and the infants were hypotonic (2). Kunze et al. reported a similar female infant who died at the age of 3 months. She had difficulty in swallowing with an ophthalmoplegia, hypotonia, and areflexia. There were multiple joint contractures with camptodactyly and adducted thumbs, but apparently no craniosynos-tosis (15). The genetic basis of this syndrome remains unknown but it was observed to have an autosomal recessive inheritance pattern.

Multiple pterygia syndrome (MIM ID 265000) is a form of arthro-gryposis multiplex congenita which is an autosomal recessive condi-tion and shows clinical heterogeneity. Initially it is categorized into two types; prenatally lethal and nonlethal (22). The nonlethal type, called Escobar syndrome (ES) (MIM #265000) characterized by ex-cessive webbing (pterygia, especially of the neck, antecubital and pop-liteal areas), congenital joint contractures (arthrogryposis), scoliosis, syndactyly and camptodactyly of the fingers, and foot deformities (2, 15). Other variable features include intrauterine death, congenital re-spiratory distress, growth retardation, short stature, kyphoscoliosis and other vertebral anomalies, a mild to moderate degree of facial dysmor-phism, ptosis, antemongoloid slant of eyes, low-set ears, cleft palate, cryptorchism, arachnodactyly and congenital contractures (4, 10, 11, 26). The syndrome was first reported by Bussiere in 1902 and since then, more than 60 families have been reported (11, 13).Hoffmann et al. and Morgan et al. reported that both variants of multi-ple pterygium syndrome can be caused by mutations in the gamma, or fetal, subunit of the nicotinergic acetylcholine receptor (AChR) gene located at chromosome 2q33–q34 (8, 22). Further, it was observed that mutations in two other related genes, CHRND and CHRNA1, also can cause the lethal type of MPS (19).

162

GENETIC COUNSELING

MASA Syndrome (Mental Retardation, Aphasia, Shuffling Gait, And Adducted Thumbs, Spastic Paraplegia, Type 1, Clasped Thumb and Mental Retardation, Thumb, Congenital Clasped, With Mental Retardation, Adducted Thumb with Mental Retardation, Gareis-Ma-son Syndrome, Crash Syndrome, MIM ID #303350) was originally described by Bianchine and Lewis (1). The cardinal clinical features of the syndrome are mental retardation, aphasia, shuffling gait, and adducted thumbs was summarized by the acronym MASA (1). The shuffling gait is thought to be caused by spasticity of the lower limbs. The clinical features also include; short stature, microcephaly, macro-cephaly, strabismus, kyphosis, lordosis, pes cavus, talipes equinovarus increased reflexes and the delayed onset of speech. Structural brain abnormalities can also be seen such as agenesis of the corpus callosum, enlarged cerebral ventricles and hydrocephalus (1, 32). The condition has an X-linked recessive inheritance pattern. This syndrome is caused by mutation in the L1 cell adhesion molecule (L1CAM) gene (31).

Arthrogryposis Multiplex Congenita, Distal, Type 1a (MIM ID #108120) belongs to a highly heterogeneous group. In this type the affected parts of the limbs are usually the distal parts especially hands and feet. The fingers are medially overlapping, fists are clenched and also camptodactyly, ulnar deviation of the fingers and the positional foot deformities can be seen. The other joints contractures are variable. In this type of arthrogryposis there are no associated visceral anoma-lies. Besides this, the patients’ intelligence is normal (7). The classic form is always sporadic but there are some authors that described fam-ilies that have dominant inheritance (7, 12). The causative factor of this type of artrogryposis was demonstrated by Sung et al. and TPM2 gene that encodes beta-tropomyosin was determined (27).

Arthrogryposis, Distal, Type 2a (Freeman-Sheldon Syndrome, Whis-tling Face-Windmill Vane Hand Syndrome, Craniocarpotarsal Dys-trophy, Craniocarpotarsal Dysplasia, MIM ID #193700) syndrome is originally described by Freeman and Sheldon (6). The syndrome has an autosomal dominant inheritance pattern and includes skeletal mal-formations and facial characteristics. Abnormal x-ray appearance of the floor of the anterior cranial fossa of the skull, microcephaly, camp-todactyly with ulnar deviation, adducted thumbs, kyphoscoliosis, hip dislocation, talipes equinovarus, contracted toes, and vertical talus; are the common skeletal abnormalities. Facial characteristics include full forehead, mask like facies, deep-set eyes with hypertelorism and tele-canthus, epicanthal folds, increased philtrum length, small nose with

163

hypoplastic alae nasi and a small mouth (6). Toydemir et al. screened 28 FSS probands for mutations in genes that encode myosin heavy chains and a mutation in the MYH3 gene in 26 of 28 FSS cases was reported (29).

DISCUSSION

At the genetic evaluation of a case with adducted thumbs the clini-cian must be careful while making the final decision between non syn-dromic adducted thumbs and syndromic forms (Table I). In a study in which twenty-five patients were included, additional features were observed in 88% of the cases (30). Neurological evaluation must be done carefully as neurologic abnormalities are commonly associat-ed with the condition. Brain imaging should be performed and be-sides mental status should be evaluated (30). Up to date 27 genetic syndromes have been identified in which adducted thumbs can be a possible clinical clue (30). Before the molecular analyses, cytogenetic analyses must be performed as cytogenetic abnormalities such as inter-stitial 1p36 deletion, 2q inverted duplication/ deletion, 3p26 deletion found to be associated with adducted thumbs (30). Dundar syndrome represents a recognizable pattern with generalized connective tissue disorders with facial dysmorphic features. Effected individuals in each of the families shared phenotypic characteristics that are atypical for previously described syndromes such as Christian Adducted Thumbs Syndrome, Escobar or multiple pterygia syndrome, MASA Syndrome, Arthrogryposis Multiplex Congenita, Distal, Type 1a, Arthrogrypo-sis, Distal, Type 2a. With the presence of characteristic features such as typical facial appearance, wasted build, thin and translucent skin, ocular anterior chamber abnormalities, arachnodactyly and distal ar-throgryposis with severely adducted thumbs, club feet, joint instability and coagulopathy, Dundar Syndrome must be investigated by perform-ing molecular analysis for the responsible gene, CHST14 which is on chromosome 15q15. Shimizu et al. presented a comprehensive review of all 20 reported patients (25). They mentioned that, at birth some re-markable features can be seen such as large fontanelle, hypertelorism, downslanting palpebral features, multiple congenital contractures with adducted thumbs, talipes equinovarus, and cylindrical fingers and as the cases grew older spinal deformities, marfanoid body habitus, and recurrent joint dislocations can be seen. Dermatologic features can be remarkable also such as hyperextensibility, and fragility that can cause atrophic scars. Abnormal platelet function which can cause bleeding,

164

GENETIC COUNSELING

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166

GENETIC COUNSELING

Skin

Hype

rexten

sible

skin,

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Skin

Hist

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Fine

colla

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pred

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nt in

reticu

lar to

papil

lary d

ermis,

thin

colla

gen b

undle

sEl

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copy

Colla

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brils

disp

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in re

ticula

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smoo

th, ro

und c

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rils

Mus

cle, S

oft T

issue

Hema

tomas

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t large

subc

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s, low

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cle m

ass,

hypo

tonia

Myo

pathy

Redu

ced m

uscle

mas

sM

ild m

uscle

wea

knes

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mus

cle bi

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sh

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ber s

ize va

ria-

bility

; type

1 fib

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e pr

edom

inanc

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all ty

pe

1 fibe

rs, in

creas

ed in

ter-

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Meta

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Fea

ture

sHy

perp

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ia, us

ually

as-

socia

ted w

ith an

esthe

sia,

malig

nant

hype

rtherm

iaNe

urolo

gicGr

oss m

otor d

evelo

pmen

tal de

layDy

smye

linati

-on

with

exce

ss my

elin-

depe

nden

t gli

osis,

mye

lin

solub

iliza

tion,

ge-

neral

ized h

ypoto

nia,

velop

hary

ngea

l ins

uffic

iency

Norm

al int

ellige

nce

Men

tal

retard

ation

, ap

hasia

, sh

uffli

ng

gait,

lower

limb s

pasti

-cit

y, ag

enes

is of

the c

orpu

s ca

llosu

m,

enlar

ged

cereb

ral

ventr

icles

, hy

droc

ep-

halus

Norm

al int

ellige

nce

Men

tal re

tarda

tion,

seizu

res

Mole

cular

Bas

isCH

ST14

, 608

429.0

001

CHRN

G, 10

0730

.0001

L1CA

M,

3088

40.00

04TP

M2,

1909

90.00

01M

YH3,

1607

20.00

01

Table

I: C

ontin

ued

167

REFERENCES

1. ABIANCHINE J.W., LEWIS R.C. JR.: The MASA syndrome: a new heritable mental retardation syn-drome. Clin. Genet., 1974, 5, 298-306.

2. CHRISTIAN J.C., ANDREWS P.A., CONNEALLY P.M., MULLER J.: The adducted thumbs syndrome. An autosomal recessive disease with arthrogrypo-sis, dysmyelination, craniostenosis, and cleft palate. Clin. Genet., 1971, 2, 95-103.

3. COOPER C.: Fundamentals of Hand Therapy: Clin-ical Reasoning and Treatment Guidelines for Com-mon Diagnoses of the Upper Extremity. Elsevier Health Sciences, 2007.

4. DUNDAR M., DEMIRYILMAZ F., DEMIRYILMAZ I., KUMANDAS S., ERKILIC K., KENDIRCI M., TUNCEL M., OZYAZGAN I., TOLMIE J.L.: An autosomal recessive adducted thumb-club foot syn-drome observed in Turkish cousins. Clin. Genet., 1997, 51, 61-64.

5. DUNDAR M., MULLER T., ZHANG Q., PAN J., STEINMANN B., VODOPIUTZ J., GRUBER R., SONODA T., KRABICHLER B., UTERMANN G., BAENZIGER J.U., ZHANG L., JANECKE A.R.: Loss of dermatan-4-sulfotransferase 1 function re-sults in adducted thumb-clubfoot syndrome. Am. J. Hum. Genet., 2009, 85, 873-882.

6. FREEMAN E.A., SHELDON J.H.: Cranio-carpotar-sal dystrophy: undescribed congenital malformation. Arch. Dis. Child., 1938, 13, 277-283.

7. HALL J.G., REED S.D., GREENE G.: The distal arthrogryposes: delineation of new entities--review

and nosologic discussion. Am. J. Hum. Genet., 1982, 11, 185-239.

8. HOFFMANN K., MULLER J.S., STRICKER S., MEGARBANE A., RAJAB A., LINDNER T.H., CO-HEN M., CHOUERY E., ADAIMY L., GHANEM I., DELAGUE V., BOLTSHAUSER E., TALIM B., HORVATH R., ROBINSON P.N., LOCHMÜLLER H., HÜBNER C., MUNDLOS S.: Escobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunit. Am. J. Hum. Genet., 2006, 79, 303-312.

9. JANECKE A.R., BAENZIGER J.U., MULLER T., DUNDAR M.: Loss of dermatan-4-sulfotransferase 1 (D4ST1/CHST14) function represents the first dermatan sulfate biosynthesis defect, “dermatan sul-fate-deficient adducted thumb-clubfoot syndrome”. Hum. Mutat., 2011, 32, 484-485.

10. JANECKE A.R., UNSINN K., KRECZY A., BALD-ISSERA I., GASSNER I., NEU N., UTERMANN G., MULLER T.: Adducted thumb-club foot syndrome in sibs of a consanguineous Austrian family. J. Med. Genet., 2001, 38, 265-269.

11. JONES K.L.: Smith’s Recognizable Patterns of Hu-man Malformation. 5th ed. Philadelphia, WB Saun-ders, 1997.

12. KLEMP P., HALL J.G.: Dominant distal arthrogry-posis in a Maori family with marked variability of expression. Am. J. Hum. Genet., 1995, 55, 414-419.

13. KODAGANUR S.G., TONTANAHAL S.J., SARDA A., SHAH M.H., BHAT V., KUMAR A.: Clinical phe-

congenital cardiac defects, ophthalmological complications, and uro-lithiasis also reported (25).Like all the syndromes early clinical diagnosis will be helpful for pre-diction of prognosis, the assessment of the other clinical problems of the patients and for the follow-up and therapy of the clinical conditions related with the syndrome. It is important to identify the mutation in order to inform the families for prenatal and preimplantation genetic diagnosis and as the syndrome has an autosomal recessive inheritance pattern, detailed genetic counseling must be given to families accord-ing to the literature.

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GENETIC COUNSELING

notype and the lack of mutations in the CHRNG, CHRND, and CHRNA1 genes in two Indian fam-ilies with Escobar syndrome. Clin. Dysmorphol., 2013, 22, 54-58.

14. KOSHO T., MIYAKE N., HATAMOCHI A., TAKA-HASHI J., KATO H., MIYAHARA T., IGAWA Y., YASUI H., ISHIDA T., ONO K., KOSUDA T., IN-OUE A., KOHYAMA M., HATTORI T., OHASHI H., NISHIMURA G., KAWAMURA R., WAKUI K., FUKUSHIMA Y., MATSUMOTO N.: A new Ehlers-Danlos syndrome with craniofacial charac-teristics, multiple congenital contractures, progres-sive joint and skin laxity, and multisystem fragili-ty-related manifestations. Am. J. Med. Genet., 2010, 152, 1333-1346.

15. KUNZE J., PARK W., HANSEN K.H., HANEFELD F.: Adducted thumb syndrome: report of a new case and a diagnostic approach. Eur. J. Pediatr., 1983, 141, 122-126.

16. MALFAIT F., SYX D., VLUMMENS P., SYMOENS S., NAMPOOTHIRI S., HERMANNS-LE T., VAN LAER L., DE PAEPE A.: Musculocontractural Ehlers-Dan-los syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a sin-gle clinical entity caused by mutations in the der-matan-4-sulfotransferase 1 encoding CHST14 gene. Hum. Mutat., 2010, 31, 1233-1239.

17. MCCARROLL H.R.: Congenital flexion deformities of the thumb. Hand Clin., 1985, 1, 567-575.

18. MENDOZA-LONDONO R., CHITAYAT D., KAHR W. H. A., HINEK A., BLASER S., DUPUIS L., GOH E., BADILLA-PORRAS R., HOWARD A., MITTAZ L., SUPERTI-FURGA A., UNGER S., NISHIMURA G., BONAFE L.: Extracellular matrix and plate-let function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene. Am. J. Med. Genet., 2012, 158, 1344-1354.

19. MICHALK A., STRICKER S., BECKER J., RUPPS R., PANTZAR T., MIERTUS J., BOTTA G., NARET-TO V. G., JANETZKI C., YAQOOB N., OTT C. E., SEELOW D., WIECZOREK D., FIEBIG B., WIRTH B., HOOPMANN M., WALTHER M., KÖRBER F., BLANKENBURG M., MUNDLOS S., HELLER R., HOFFMANN K.: Acetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disorders. Am. J. Hum. Genet., 2008, 82, 464-476.

20. MIH A. D.: Congenital clasped thumb. Hand Clin., 1998, 14, 77–84.

21. MIYAKE N., KOSHO T., MIZUMOTO S., FURUI-CHI T., HATAMOCHI A., NAGASHIMA Y., ARAI E., TAKAHASHI K., KAWAMURA R., WAKUI K., TAKAHASHI J., KATO H., YASUI H., ISHIDA T., OHASHI H., NISHIMURA G., SHIINA M., SAITSU H., TSURUSAKI Y., DOI H., FUKUSHIMA Y., IKE-GAWA S., YAMADA S., SUGAHARA K., MATSU-MOTO N.: Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome. Hum. Mutat., 2010, 31, 966-974.

22. MORGAN N.V., BRUETON L.A., COX P., GREAL-LY M.T., TOLMIE J., PASHA S., ALIGIANIS I.A., VAN BOKHOVEN H., MARTON T., AL-GAZALI L., MORTON J.E., OLEY C., JOHNSON C.A., TREM-BATH R. C., BRUNNER H.G., MAHER E.R.: Muta-tions in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar vari-ants of multiple pterygium syndrome. Am. J. Hum. Genet., 2006, 79, 390-395.

23. MULLER T., MIZUMOTO S., SURESH I., KOMAT-SU Y., VODOPIUTZ J., DUNDAR M., STRAUB V., LINGENHEL A., MELMER A., LECHNER S., ZSCHOCKE J., SUGAHARA K., JANECKE A.R.: Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syn-drome. Hum. Mol. Genet., 2013, 22, 3761-3772.

24. ONLINE MENDELIAN INHERITANCE IN MAN, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), { Updated 30 August 2013 }. World Wide Web URL: http://omim.org/

25. SHIMIZU K., OKAMOTO N., MIYAKE N., TAIRA K., SATO Y., MATSUDA K., AKIMARU N., OHASHI H., WAKUI K., FUKUSHIMA Y., MATSUMOTO N., KOSHO T.: Delineation of dermatan 4-O-sulfotrans-ferase 1 deficient Ehlers-Danlos syndrome: observa-tion of two additional patients and comprehensive review of 20 reported patients. Am. J. Hum. Genet., 2011, 155, 1949-1958.

26. SONODA T., KOUNO K.: Two brothers with distal arthrogryposis, peculiar facial appearance, cleft pal-ate, short stature, hydronephrosis, retentio testis, and normal intelligence: a new type of distal arthrogryp-osis?. Am. J. Hum. Genet., 2000, 91, 280-285.

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ADDRESS FOR CORRESPONDENCE: Munis Dundar, M.D., Ph.D. Erciyes University, School of Medicine Department of Medical Genetics Kayseri, Turkey Phone: 90 352 4370600 E-mail: dundar@erciyes.edu.tr

27. SUNG S. S., BRASSINGTON A.M., GRANNATT K., RUTHERFORD A., WHITBY F.G., KRAKOWIAK P.A., JORDE L.B., CAREY J.C., BAMSHAD M.: Mutations in genes encoding fast-twitch contractile proteins cause distal arthrogryposis syndromes. Am. J. Hum. Genet., 2003, 72, 681-690.

28. TEMTAMY S., MCKUSICK V.: The Genetics of Hand Malformation. New York, Alan R. Liss, 1978.

29. TOYDEMIR R.M., RUTHERFORD A., WHIT-BY F.G., JORDE L.B., CAREY J.C., BAMSHAD M.J.: Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat. Genet., 2006, 38, 561-565.

30. VERHAGEN J.M., SCHRANDER-STUMPEL C.T., BLEZER M.M., WEBER J.W., SCHRANDER J.J., RUBİO-GOZALBO M.E., BAKKER J.A., STEG-MANN A.P., VOS Y. J., FRINTS S. G.: Adducted thumbs: a clinical clue to genetic diagnosis. Eur. J. Med. Genet., 2013, 56, 153-158.

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