American Journal of Medical Genetics 112:379–383 (2002)

Clinical and Genetic Heterogeneity ofSeckel Syndrome

L. Faivre,1 M. Le Merrer,1 S. Lyonnet,1 H. Plauchu,2 N. Dagoneau,1 A.B. Campos-Xavier,1

J. Attia-Sobol,2 A. Verloes,3 A. Munnich,1 and V. Cormier-Daire1*1Departement de Genetique et INSERM U393, Hopital Necker Enfants Malades, Paris, France2Service de Genetique Medicale, Hotel Dieu, Lyon, France3Unite de Genetique Medicale, Liege, Belgique

Seckel syndrome is a rare autosomal reces-sive condition belonging to the group ofosteodysplastic primordial ‘‘dwarfism’’ andcharacterized by the association of 1) sev-ere pre- and postnatal growth retardation,2) microcephaly with mental retardation,and 3) specific dysmorphic features. Recen-tly, two disease loci have been mapped tochromosomes 3q22.1-q24 and 18p11.31-q11.2,respectively, by homozygosity mapping inconsanguineous families. Here, we report onthe exclusion of these loci in five consangui-neousandonemultiplexnonconsanguineousSeckel syndrome families and in two consan-guineous families presenting type II osteo-dysplasticprimordialdwarfism.Theseresultssupport the view that Seckel syndrome is aclinically and genetically heterogeneouscondition. � 2002 Wiley-Liss, Inc.

KEY WORDS: Seckel syndrome; geneticheterogeneity; chromosome3q22.1-q24; chromosome18p11.31-q11.2

INTRODUCTION

Seckel syndrome (MIM 210600) is characterized bythe association of proportionate short stature of pre-natal onset and specific dysmorphic features, includingsevere microcephaly, a receding forehead, large eyes, abeak-like protrusion of the nose, a narrow face, a reced-ing lower jaw, micrognathia, mental retardation, and

autosomal recessive inheritance [Majewski andGoecke,1982]. More than 100 cases have been hitherto diag-nosed based on the recognition of specific clinicalfindings. Interestingly, increased chromosomal break-age has been occasionally reported [Butler et al., 1987].NoX-ray features are characteristic of Seckel syndrome,but delayed bone age, hip dysplasia, and elbow disloca-tion are currently observed in this disease. In addition, anumber of Seckel-like syndromes have been recognizedbased on the association of a typical facial appearancewith short stature, particularly the microcephalicosteodysplastic dwarfism types II and III [Majewskiet al., 1982].

In 2000, a gene for Seckel syndrome was mapped tohuman chromosome 3q22.1-q24 in two inbred Pakistanifamilies originating from the same village [Goodshipet al., 2000]. Another locus has been recently mapped tochromosome 18p11.31-q11.2 in one inbred Iraqi family[Borglum et al., 2001]. Here, we report the exclusion ofboth loci in six Seckel syndrome families from variousethnic origins and in two families with type II micro-cephalic osteodysplastic primordial dwarfism.

PATIENTS

A total of 11 affected individuals belonging to sixfamilies of European (one), North African (four), andWest African (one) origin were included in this study.Clinical data of the affected individuals are shown inTable I and Figure 1. Pseudodominance is the mostlikely mode of inheritance in family 5. The clinicalpresentation of patient 2 in family 5 was mild, allowinghim to have a family. He had special education at school,didnot knowhow to read, couldnotwritewords, andwascurrently a carpenter. All patients had normal standardcytogenetic examination. Six of our patients had a com-plete endocrine workup, including growth hormone,insulin growth factor 1, cortisol, prolactine concentra-tions, and thyroid function tests, and all results werenormal, except low IgF1 in one case. Two consangui-neous families with type II microcephalic osteodysplas-tic dwarfism [Verloes et al., 1987] were also included inthis study.

*Correspondence to: Dr. Valerie Cormier-Daire, Departementde Genetique, Hopital Necker-Enfants Malades, 149, rue deSevres, 75015 Paris, France. E-mail: cormier@necker.fr

Received 4 January 2001; Accepted 29 April 2002

DOI 10.1002/ajmg.10677

� 2002 Wiley-Liss, Inc.

METHODS AND RESULTS

DNA extraction andmicrosatellite analyses were per-formed as previously described [Belin et al., 1998], andprimers for short-tandem repeat polymorphism mar-kers on chromosomes 3q22.1-q24 and 18p11.31-q11.2were chosen from the Genethon map [Dib et al.,1996] with an average spacing of 5 cM (D3S1309 toD3S1268 for chromosome 3, and D18S478 to D18S452for chromosome 18, from centromere to telomere,respectively).

TABLE

I.ClinicalFea

turesof

the11Patien

tsRep

ortedHereWithSeckel

Syndrome

Family1

Family2

Family3

Family4

Family5

Family6

12

12

11

12

31

2

Ethnicalorigin

NA

NA

NA

NA

ANA

NA

NA

NA

EE

Sex

FF

FF

MF

MM

MF

MAge(yea

rs)

8TOP

23

15

712

13

40

36

46

40

Birth

length

(cm)

38

TOP

40

40

40.5

41

42

??

??

Typicalfacial

dysm

orphism

þþ

þþ

þþ

þþ

þþ

þ

Men

talretard

ation

Mild

TOP

Mod

erate

Mod

erate

þMild

Mild

Mild

Mild

Mod

erate

Mod

erate

Size(SD)

�8

�6

�4

�4

�4

�4

�5

�5

�6

�4

�4

OFC

(SD)

�8

�6

�4

�5

�8

�4

�4

�5

�4

�8

�6

Cafe

aulaitsp

ots

�TOP

��

�þ

þ�

��

�Other

features

Microdon

tia

Pyelicdilatation

Delayed

puberty

Cataract

Abnormal

gyration

VSD

Bifidkidney

Osteosa

rcom

aSmallpen

isDiabetes

Diabetes

��

Pancytopen

ia�

TOP

��

��

��

��

�

NA,North

Africa;E,Europe;

A,Africa;TOP,Termination

ofpregnancy;SD,Standard

dev

iation

;?,In

form

ation

not

available;VSD,Ven

tricularseptaldefect.

Fig. 1. Clinical features of patients 1 (C) and 2 (A and B) in family 1,patient 1 (D and E) in family 3, patient 1 (F) in family 5, and patients 1(H) and 2 (G) in family 6. Note microcephaly with a receding forehead, abeak-like protrusion of the nose, a narrow face, a receding lower jaw, andmicrognathia.

380 Faivre et al.

The first published locus on chromosome 3q22.1-q24was excluded in the six families reported here usingmanual haplotype analysis under the assumptions ofautosomal recessive inheritance, full penetrance, and a0 value for the phenocopy rate (Fig. 2). In families 1–5,none of the affected individuals were homozygous bydescent and/or identical by descent to their affected sib.In family 6, genotypes of both affected patients wereidentical, but the same haplotype was found in theirunaffected sib. Similar results were found when study-ing linkage to chromosome 18p11.31-q11.2 (Fig. 3). Infamilies 1–3 and 5, none of the affected patients werehomozygous by descent and/or geno-identical to theiraffected sib. Only patient 1 in family 4 was homozy-gous for two adjacent markers at loci D18S116 andD18S1104, but the analysis of another marker of thisinterval (D18S53) showed heterozygosity. In family 6,haplotypes of both affected patients were different. Wealso excluded both loci in the two consanguineousfamilies with type II osteodysplastic primordial dwarf-ism (data not shown).

DISCUSSION

Here, we exclude six families with Seckel syndromefrom linkage to chromosomes 3q22.1-q24 and 18p11.31-q11.2. We also exclude from linkage to chromosomes3q22.1-q24 and 18p11.31-q11.2 two families withmicro-cephalic osteodysplastic dwarfism type II. The diag-nosis of Seckel syndrome is based on clinical findingsonly. Reviewing a series of 60 cases of Seckel syndrome,Majewski and Goecke [1982] emphasized the broadinterfamilial clinical heterogeneity of this condition,as confirmed by other authors later [Thompson andPembrey, 1985;Parent et al., 1996]. Interfamilial clinicalheterogeneity has also been noted in the families in-cluded in linkage studies. Indeed, in the Pakistani fami-lies linked to chromosome 3q22.1-q24 [Goodship et al.,2000], the probands presented with a height of �5 SDand severe microcephaly (occipitofrontal circumference[OFC],�12 SD), severe mental retardation, and the ab-sence of spontaneous or induced chromosome breakage.In the Iraqi family linked to chromosome 18p11.31-

Fig. 2. Haplotypes of the six families with Seckel syndrome at the 3q22.1-q24 locus.

Genetic Heterogeneity in Seckel Syndrome 381

q11.2 [Borglum et al., 2001], the probands’ heightsranged from �3.5 to �5.5 SD, and they had less severemicrocephaly (OFC, �5 SD), milder mental and motorretardation, cafe-au-lait spots, spindle-shaped fingers,and increased spontaneous and induced chromosomebreakage. Similar clinical heterogeneity was found inour patients (Table I). Interestingly, two affectedindividuals from families 4 and 6 presented with cafe-au-lait spots, as described in the patients reported byBorglum et al. [2001], a clinical feature that is rarelydescribed in Seckel syndrome. One patient of our seriespresented with an osteosarcoma, which to our knowl-edge has not been reported in Seckel syndrome.

A number of Seckel-like syndromes have also beenidentified on the basis of a typical facial appearance andshort stature, most notably microcephalic osteodysplas-tic dwarfism types II and III and microcephalic osteo-dysplastic dysplasia. It has been argued that types I andIII reflect the phenotypic variability of a same type ofosteodysplastic primordial dwarfism. Type II microce-phalic osteodysplastic dwarfism has been recognized as

a separate entity, mainly based on X-ray features,including short limbs with preferential distal involve-ment, coxa vara, epiphysiolysis, and metaphyseal flar-ing with V-shaped distal femora metaphyses [Majewskiet al., 1982]. In fact, a complete radiological survey in thefirst year of life is necessary to distinguish betweenSeckel syndrome and type II microcephalic osteodys-plastic dwarfism.

The exclusion of both loci in our families suggests thatat least one additional locus accounts for Seckelsyndrome and argues in favor of further heterogeneityin this syndrome.

REFERENCES

Belin V, Cusin V, Viot G, Girlich D, Toutain A, Moncla A, Vekemans M,Le Merrer M, Munnich A, Cormier-Daire V. 1998. SHOX muta-tions in dyschondrosteosis (Leri-Weill syndrome). Nat Genet 19:67–69.

Borglum AD, Balslev T, Haagerup A, Birkebaek N, Binderup H, Kruse TA,Hertz JM. 2001. A new locus for Seckel syndrome on chromosome18p11.31-q11.2. Eur J Hum Genet 9:753–757.

Fig. 3. Haplotypes of the six families with Seckel syndrome at the 18p11.31-q11.2 locus.

382 Faivre et al.

Butler MG, Hall BD, Maclean RN, Lozzio CB. 1987. Do some patients withSeckel syndrome have hematological problems and/or chromosomebreakage? Am J Med Genet 27:645–649.

Dib C, Faure S, Fizames C, Samson D, Drouot N, Vignal A, MillasseauP, Marc S, Hazan J, Seboun E, Lathrop M, Gyapay G, MorissetteJ, Weissenbach J. 1996. A comprehensive genetic map of thehuman genome based on 5,264 microsatellites. Nature 380:152–154.

Goodship J, Gill H, Carter J, Jackson A, Splitt M, Wright M. 2000.Autozygosity mapping of a Seckel syndrome locus to chromosome3q22.1-q24. Am J Hum Genet 67:498–503.

Majewski F, Goecke T. 1982. Studies of microcephalic primordial dwarfism.I. Approach to a delineation of the Seckel syndrome. Am J Med Genet12:7–21.

Majewski F, Ranke M, Schinzel A. 1982. Studies of microcephalicprimordial dwarfism. II. The osteodysplastic type II of primordialdwarfism. Approach to a delineation of the Seckel syndrome. Am J MedGenet 12:23–35.

Parent P, Moulin S, Munck MR, de Parscau L, Alix D. 1996. Bird headeddwarfism in Seckel syndrome. Nosologic difficulties. Arch Pediatr 3:55–62.

Thompson E, Pembrey M. 1985. Seckel syndrome: an overdiagnosedsyndrome. J Med Genet 22:192–201.

Verloes A, Lambrechts L, Senterre J, Lambotte C. 1987. Microcephalicosteodysplastic dwarfism (type II-like) in siblings. Clin Genet 32:88–94.

Genetic Heterogeneity in Seckel Syndrome 383