Seckel syndrome: an overdiagnosed syndrome - Journal of Medical

Journal of Medical Genetics 1985, 22, 192-201

Seckel syndrome: an overdiagnosed syndromeELIZABETH THOMPSON AND MARCUS PEMBREY

From the Mothercare Unit of Paediatric Genetics, Institute of Child Health, 30 Guilford Street, LondonWC]N IEH.

SUMMARY Five children in whom a diagnosis of Seckel syndrome had previously been made were

re-examined in the genetic unit. One child had classical Seckel syndrome, a sib pair had thefeatures of the syndrome with less severe short stature, and in two children the diagnosis was notconfirmed. Seckel syndrome is only one of a group of low birth weight microcephalic dwarfismand careful attention should be paid to fulfilment of the major criteria defined by Seckel beforethe diagnosis is made. There remains a heterogeneous group of low birth weight microcephalicdwarfism yet to be defined.

Seckell first defined the syndrome as severe in-trauterine growth retardation (IUGR); severe shortstature which is proportionate; severe microcephaly;a 'bird headed' profile with a receding chin andforehead and large beaked nose; mental retarda-tion; and various associated congenital anomalies,which is inherited in an autosomal recessive manner.Although an excessively rare condition, the name isknown to most paediatricians and it appears to be acondition that is overdiagnosed.

Majewski and Goecke2 reviewed the 60 publishedcases of the syndrome and found only 17 whofulfilled the original diagnostic criteria. Theyadopted strict criteria and found that the averagebirth weight at term was 1543 g (range 1000 to 2055g). The approximate mean postnatal growth re-tardation in 16 of the 17 was -7 1 SD (range -5-1 to-13-3). The mean occipitofrontal head circumfer-ence (OFC) was -8-7 SD (range -4-1 to -14.3 SD);in half the OFC was as retarded as height and in halfmore retarded than height. All were mentallyretarded, nearly half with an IQ of less than 50. Inaddition, they compiled a list of the variableassociated abnormalities of the syndrome.The purpose of this report is to document further

evidence for the heterogeneity of low birth weightmicrocephalic dwarfism and to present a sib pairwith Seckel syndrome who are taller than previouslyreported cases. Useful diagnostic features amongthe associated abnormalities are also illustrated.Detailed anthropometric measurements have beenrecorded (appendix 1 and 2).

Received for publication 1() April 1984.Accepted for publication 2 August 1984.

Case reportsCASE 1

This patient, a male aged 14 years, was the first born

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FIG 1 Extract ofgrowth records of cases 1 to 5. (Standardsof Tanner et al. Arch Dis Child 1966;41:613.)

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Seckel syndrome: an overdiagnosed syndrome

of twins; the co-twin died at three days of age of aheart defect. The birth weight of case 1 was 1701 g.Further information about the pregnancy and peri-natal period was not available; the child was ininstitutional care for the first 11 years of life and wasthen fostered. He had a cleft palate which wasrepaired and suffered from frequent upper respira-tory tract infections while in institutional care.Orthodontic treatment and tooth extractions hadbeen required for crowded teeth. The mental agewas assessed as 5 years 9 months at a chronologicalage of 9 years and he attends a special school for theeducationally subnormal. Only one previous heightmeasurement (supplied by his foster mother) wasavailable (fig 1). On examination he was veryamiable and cooperative. The height was 127-4 cm(-5-1 SD), weight 20 5 kg, and head circumference

44 5 cm (-6.6 SD). The short stature was prop-ortionate, that is, the leg to trunk length ratio wasnormal (appendix 1). There was micrognathia, areceding forehead, a large curved nose, and small,lobeless ears (fig 2a, b).The face was asymmetrical, the teeth crowded,

and the palpebral fissures small. The eyes appearedwidely spaced but there was telecanthus and theinterpupillary distance was proportionate to facewidth (appendix 2). The frontal hairline was Vshaped. The total hand length was small butcompatible with height and the fingers were shortrelative to palm length (fig 2c, appendix 1). Therewas camptodactyly involving the proximal inter-phalangeal joints. The feet were small for age butrelatively large for height (appendix 1). There waspes planus, the toes were short and tapered with a

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Elizabeth Thoinpson and Marcus Pembrey

gap between the right first and second toes, andthere was a left hallux valgus. The toes could not beflexed. The heads of the radii were clinically andradiologically dislocated. There was mild flexion atthe hips and knees, giving a characteristic standingposture (fig 2d). The cardiovascular system andgenitalia were normal and there was no hirsutism.

CASE 2

This patient, a male aged 15 years 8 months, was thefirst child of healthy unrelated English parents. Thefetus was small for dates throughout pregnancy.Delivery at 37 weeks was normal and there was no

birth asphyxia. Birth weight was 1980 g. A congen-ital right talipes equinovarus was treated surgically.Early feeding and respiratory problems led to care

in the hospital special nursery for the first six weeksof life. From the ages of 5½/2 months to 5 years therewere frequent attacks of bronchitis. Insulin depen-dent diabetes mellitus developed at 12 years. Hewears hearing aids and has had dental extractionsand orthodontic treatment for crowded teeth. He

attends a special school for the severely education-ally subnormal and has behaviour problems. Pre-vious height measurements supplied by the localhospital are charted in fig 1. The maternal andpaternal heights were 152 cm and 189 cm respective-ly. Mid-parental height correcting for maternal sex

was 176-75 cm, which is just above the 50th centilefor an adult male.On examination, the height was 150.2 cm (-3-3

SD), weight 43 1 kg, and head circumference 44-2cm (-7 3 SD). The short stature was proportionate(appendix 1). The face was round and asymmetrical,the nose large and curved, the chin small, theforehead receding, and the ears small and lobeless(fig 3a). The palate was high and narrow, the teethcrowded, and the palpebral fissures small withtelecanthus. The interpupillary distance was prop-

ortionate to face width (fig 3b, appendix 2). Thehands and feet were proportionate to height butwith relatively short fingers (appendix 1). There was

clinobrachydactyly of the fifth fingers (fig 3c) andclinodactyly of the second left toe and a wide gap

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between the first and second toes. Previous handx-rays showed a pseudoepiphysis at the base of thesecond and fifth metacarpals and fusion of thetrapezium and scaphoid bones and of the triquet-rium and lunate bones (fig 3d). A previous chestx-ray revealed 12 ribs. The heads of the radii wereclinically and radiologically dislocated. Slight fixedflexion of the hips and knees produced the samestanding posture as in case 1.

CASE 3This patient, a female, the only sib of case 2, wasseen at 12 years 5 months. She was born at term,weighing 1814 g, and remained in hospital for amonth to gain weight. She had 'bronchitis' at 7weeks. She has had orthodontic treatment forcrowded teeth. A Stanford-Binet assessment at achronological age of 3 years 11 months showed amental age of 2 years 9 months. She attends a schoolfor the educationally subnormal and is of a particu-larly outgoing and happy disposition. Previousheight and weight measurements supplied by thelocal hospital are charted in appendix 1. On ex-amination the height was 132-4 cm (-3-4 SD),weight 30-2 kg, and head circumference 40-9 cm(-9-4 SD). The short stature was proportionate

(appendix 1). Fig 4a and b show the large curvednose, receding forehead and chin, small lobelessears, asymmetrical face, and crowded teeth. Thepalpebral fissures were small with telecanthus andthe interpupillary distance was normal relative toface width (appendix 2). The hands and feet wereproportionate to height and the fingers propor-tionate to palm length (appendix 1), apart frombrachydactyly of the fifth fingers (fig 4c). There wasclinodactyly of the second left toe and a gap betweenthe first and second toes. The heads of the radii wereclinically dislocated, with inability to fully supinatethe forearms and a tendency to hold the elbowsflexed. The same stance as in cases 1 and 2 waspresent. There was no clitoromegaly or hirsutism.Fig 4d shows the sibs at a younger age when theirfacial features were less angular and the eyesappeared to bulge, particularly in the girl.

CASE 4

This patient, a male aged 7 years 8 months, was bornof the first pregnancy of healthy unrelated Englishparents. He was born at term of a normal delivery.Birth weight was 1500 g, length 41 cm, and headcircumference 29 cm. Seckel syndrome was firstdiagnosed at 5 months of age when he weighed 2-5 kg

FIG 4 Side view (a), front view (b), and hands (c) ofcase 3. (d) Sibs, cases 2 and 3, at 5 and 2 years respectively.

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Elizabeth Thompson and Marcus Pembrey

TABLE Summary ofmanifestations.

Seckel svyndrome Published cases Unidiagnrosed dwarfism

Case I Case 2 Case 3 Case 4 Case 5

Intrauterine growthretardation (hw <2055 gat term) + + + 17/17 + +

Short statureHeight-5 SD + 16/17 +Height-3 SD + + +

Proportionate trunk toleg length + + + 17/17 - +

Microcephaly + + + 17/17 + +Mental retardation + + 17/17 + +Face

Micrognathia + + + 17/17 - -Large curved nose + + + 17/17 - -Receding forehead + + + 17/17 - -Asymmetry + + + NR

EyesSmall palpebral fissures + + + NR +Telecanthus + + + NR - +Bulging eves - + + 1(1/16 large eyes

(at a young aige)Antimongoloid slant - - - 7/11 + +

PalatcHigh arched - + - 4/10) + +Cleft + - - 2/17 - -

EarsSmall + + + NR +Lobeless + + + 1(0/12 dysplastic-

TeethCrowded + + + NRMalocclusion + + + NR + +

SkeletonHand abnormalitics* + + + 8/ clinodactyly V - +Foot abnormalities* + + +Dislocated heads of

radii + + + 3/6 -Hips: fixed flexion + + + 5/9 hip 'dysplasta -

Hips: congenital dislocation - -+Knees: fixed flexion + + + NR -

Dislocation - + - NR -

GenitaliaCryptorchidism - - 3/4 +Clitoromegaly - 3/7

*See text for specific abnormalities. NR=not recorded.

and was 50-5 cm in length, with a head circumferenceof 34 cm. He had bilateral radical mastoid-ectomies at 5 years. Although early motor milestoneswere normal, intellectual handicap became apparentand he attends a school for the severely educationallysubnormal. Previous measurements from the hospi-tal file are given in fig 1. It was the mother whonoticed dissimilarities between him and other chil-dren with Seckel syndrome. The maternal andpaternal heights were 156 cm and 181-5 cm respec-tively; mid-parental height correcting for maternalsex was 175-0 cm which is on the 50th centile for anadult male. There was one sib, a normal girl. Onexamination, the height was 95-7 cm (-5.1 SD),weight 11-0 kg, and head circumference 42-5 cm(-7-3 SD). The short stature was not proportionateas the trunk was relatively short compared to the

legs (appendix 1). Fig 5a shows the child at 5½12 yearswith his 31/2 year old sister. The nose was not undulyprominent or curved and the forehead and chin didnot recede (fig 5b, c). The palpebral fissures weresmall and appeared closely spaced but the interpu-pillary distance was proportionate to the verynarrow face width (appendix 2). The ears werenormally shaped and the palate was high arched.The hands and feet were proportionately small andthe fingers were in proportion to palm length andnormally shaped (appendix 1). The elbows, hips,and knees were normal. There was bilateral cryptor-chidism and no hirsutism. A dental report indicatedthat several teeth were absent and a class IIImalocclusion was present. A chromosome karyo-type (G banded) was normal (46,XY) and therewere no increased numbers of sister chromatid

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(a) (b) (c)

FIG 5 (a) Case 4 at 51½2 years with normal sister aged 3½12years and parents. (b) Side view and (c) front view ofcase 4.

exchanges (SCE) with bromodeoxyuridine in theculture.

CASE 5This patient, a female aged 7 years 9 months, wasborn of the first pregnancy of healthy unrelatedEnglish parents. There was one sib, a girl, who hadhad a right congenital dislocated hip but was otherwisehealthy. Delivery was at term after a normalpregnancy. The birth weight was 1899 g and length40 6 cm. Bilateral hip dislocations were diagnosed atsix months and were corrected with splinting.Repeated chest infections occurred during infancy,and eczema and asthma were diagnosed at three years.She attends a school for the educationally subnor-mal and is hyperactive. Previous height measure-ments were not available. On examination she wasoveractive with mild truncal and limb ataxia. Theheight was 107-3 cm (-2.9 SD), weight 20 6 kg (10th

FIG 6 Case 5.

centile), and head circumference 46-7 cm (-4.0SD). The trunk to leg length proportions werenormal (appendix 1). The nose was large but notcurved, the chin and forehead were normal, and theears large and simple with small lobes (fig 6). Therewas a mild antimongoloid eye slant and a leftconvergent strabismus and telecanthus (appendix2). The palate was high arched. The hands and feetwere proportionally small and the fingers prop-ortionate to palm length, apart from clinodactyly ofthe fifth fingers (appendix 1). The heads of the radiiwere clinically dislocated and the elbows could notbe fully supinated. The Achilles tendons wereshortened so that the heel could not be placed flat onthe floor. Chromosome karyotype (G banded) wasnormal (46,XX) and there were no increasednumbers of SCE on chromosome culture withbromodeoxyuridine. Immunoglobulins andalphafetoprotein were normal.

Discussion

Diagnostic problems arise when children manifestmany, but not all, the classical features of Seckelsyndrome. Our approach has been to evaluate allfive cases on the same day, comparing each childwith case 1, who presents a classical case of Seckelsyndrome, meeting the most stringent criteria. Inaddition to intrauterine growth retardation, prop-ortionate short stature, microcephaly, and mentalretardation, the sib pair (cases 2 and 3) had astrikingly similar facial appearance to case 1, togetherwith small lobeless ears (cases 1, 2, and 3); smallhands (with shortening of the fingers relative to the

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Elizabeth Thompson and Marcus Pem:brey

palm length in cases and 2); small feet with a widegap between the first and second toes (cases 1, 2,and 3); dislocation of the heads of the radii (cases 1,

2, and 3); and a characteristic stance with fixedflexion at the hips and knees. On the basis of thesediscrete dysmorphic features shared in common withcase 1 we concluded that the sib pair do have Seckelsyndrome and that therefore a height above -5 SDdoes not exclude the diagnosis, as suggested byMajewski and Goecke.2 Two sibs originally re-

ported by Frijns and Van den Berghe,3 excluded byMajewski and Goecke as being too tall for theSeckel syndrome, are similar to our sibs. They are a

female aged 23 years and a male aged 14 years withbirth weights at term of 1400 g and 1700 g

respectively, heights of -4-7 SD and -2 1 SDrespectively, and microcephaly and severe mentalretardation. The boy's face is less typical and he ismildly retarded.3The table compares the salient features of our

cases 1, 2, and 3 with the 17 cases drawn frompublished reports by Majewski and Goecke.2 It isseen that we confirm several previously recognisedassociations as well as draw attention to severalothers not previously emphasised. Facial asym-metry, not emphasised by Majewski and Goecke,2 ispresent in our three cases and in the sibs describedby Harper et al.4 'Large' eyes have been commonlyreported (table) and variously described as 'pro-truding, 'proptosed' and 'bulging',6 suggestingthat the globes are large relative to the bony orbits.Ocular measurements have not previously beenreported. Our cases 1, 2, and 3 have short palpebralfissures with marked telecanthus; the appearance ofbulging eyes was seen in the sibs only at a young age.Widely spaced eyes have been previously reported.In our cases, interpupillary distance is proportionateto the narrow face. Dysplastic ears are common; theabnormality in about half the published cases islobeless ears, as in our three cases. 4 7-9 The dentalovercrowding and malocclusion presumably relateto the small jaws. Enamel hypoplasia, anothercommonly reported feature, is absent in our cases

since it mainly affects the first dentition.5 Abnormal-ities of the hands and feet, and joints, such as theelbows, hips, and knees, are an important mani-

festation of the syndrome. The most common

abnormality of the hands is clinodactyly of the fifthfingers (table). Abnormal finger flexion creases, as

in our case 1, have been reported in four cases.1 4 9General shortening of fingers relative to palm length(cases 1 and 2) has not previously been reported inSeckel syndrome. Carpal bone fusion (case 2)occurred in Seckel's case 1; the pseudoepiphyses(particularly of the second finger) are a non-specificfinding. The wide gap between the first and second

toes of our cases 1, 2, and 3 was reported by Seckelland Harper et al.4 Dislocation of the heads of theradii is characteristic and combined with fixedflexion at the hips and knees produces a typicalstanding posture, noted previously by de la Cruz.7Our case 4 does not have Seckel syndrome.

Similarities include very low birth weight, severeshort stature, microcephaly, and mental retardation.Not consistent are the relatively small trunk to leglength ratio, the normally proportioned foreheadand mandible, and the small but otherwise normalextremities and joints (appendix 1). The eyemeasurements are proportionate to the narrow facewidth in contrast to the Seckel group in whom thereis marked relative widening of the inner canthaldistance. The high palate and malocclusion mayrelate to an extremely narrow face, and cryptorchid-ism is non-specific. The features are not those ofother low birth weight microcephalic dwarfisms, forexample Cornelia de Lange, Russell-Silver, Dubo-witz, or Fanconi syndromes. Bloom syndrome isexcluded by normal SCE. "' The osteodysplasticprimordial dwarfism types I, II, and III described byMajewski et all1-13 are excluded, as the craniofacialabnormalities in these conditions are the same as inSeckel syndrome and, in addition, in type lI thelimbs are relatively short. The cause of the problemsof case 4 remains unknown.

Case 5 has a disorder different from both Seckelsyndrome and from case 4, with low birth weight,microcephaly, and mental retardation, but in con-trast to Seckel syndrome moderate short stature, anormally proportioned chin and forehead, andrelatively large ears. The high palate, downwardslanting palpebral fissures, telecanthus, strabismus,clinodactyly, and dislocated radii and hips arereminiscent of Seckel syndrome. Ataxia is not afeature of Seckel syndrome. Absence of telangiecta-sia and normal immunoglobulins and alphafetopro-tein exclude ataxia-telangiectasia. The precise di-agnosis for case 5 is unknown.

In conclusion, Seckel syndrome is only one of agroup of low birth weight microcephalic dwarfismsand can be overdiagnosed. There is a continuingneed to report cases that have been documentedcarefully, so that the full range of expression of thisautosomal recessive syndrome can be delineated.

Addendum

After this report was submitted, another child withSeckel syndrome was seen, who is briefly describedsince he is much younger than our other cases. Hewas an 18 month old boy who had a birth weight atterm of 2-18 kg, a height of -5-2 SD with propor-tionate body ratios, a head circumference of -4-6

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F

FIG 7 See addendum.

SD, and developmental retardation. The nose waslarge with a prominent nasal bridge and the chinsmall, but the forehead was less receding comparedto the older children with Seckel syndrome (fig 7).He demonstrated several features emphasised in thisreport, namely facial asymmetry, narrow palpebralfissures, telecanthus, and small ears (which did havelobes). In addition there was clinodactyly of the fifthfingers and third toes bilaterally, tapered fingers,and a dislocated right radial head clinically and onx-ray. There were pseudoepiphyses at the bases ofthe second metacarpals and no ossification of themiddle phalanges of the toes. The testes wereundescended. Further details are available from theauthors on request.Although there is little doubt that this child does

have Seckel syndrome, he demonstrates that it isprobably more difficult to make the diagnosis in theyounger child before the typical facial profile hasfully evolved.

The authors thank Dr Michael Donmall for takingthe anthropometric measurements, Dr MichaelBaraitser for helpful discussions, and Mrs Linda

Burn for typing the manuscript. We also thank MrsJane Berg for her enthusiasm in gathering thepatients together, and the families for their coopera-tion. Dr Maurice Super kindly allowed us to reportthe child in the addendum. Dr E Thompson issupported by a Wellcome Training Fellowship.

References

Seckel HPG. Bird-headed dwarfs. Springfield. Illinois: C CThomas. 1960.

2 Majewski F, Goecke T. Studies of microcephalic primordialdwarfism. I. Approach to a delineation of the Seckel syndrome.Ain J Med Gentet 1982;12:7-21.Frijns JP, Van den Berghe H. Familial bird headed dwarfism.Acta Paediatr Belg 1976;29:12t-2.

4 Harper RG, Orti E, Baker RK. Bird headed dwarfs (Seckel'ssyndrome). J Pediatr 1967;70: 799-804.

5 Sauk JJ, Litt R, Espiritu CE, Delaney IR. Familial bird-headeddwarfism (Seckel's syndrome). J Med Genet 1973:10:196-8.Lambotte C, Dony G, Bonnet F. Seckel syndrome-birdheaded dwarfism. Acta Paediatr Belg 1976;29:79-82.

7 de la Cruz F. Bird headed dwarf: a case report. Am J Ment Defic1963;68:54-62.Szalay GC. Intrauterine growth retardation versus Silver'ssyndrome. J Pediatr 1964;64:234-40.Cervenka J, Tsuchiya H, Ishiki M, Suzuki M, Mori H. Seckel'sdwarfism: analysis of chromosome breakage and sister chroma-tid exchanges. Ain J Dis Child 1979;133:555-6.

". German J. Schonberg S. Lonic E, Chaganti RSK. Bloom'ssyndrome. IV. Sister chromatid exchanges in lymphocytes. Am JHum Geniet 1977;29:248-55.Majewski F, Spranger J. Uber einen neuen Typ des primordiarenMinderw uchscs: der brachymcle primordiale Mindcrwuchs.Monatsschr Kinderheilkd 1976;124:499-503.

2 Majewski F, Ranke M, Schinzel A. Studies of microcephalicprimordial dwarfism 11. The osteodysplastic type II of primordialdwarfism. Am J Med Geniet 1982;12:23-35.

3 Majewski F, Stoeckenius M, Kemperdick H. Studies of mic-rocephalic primordial dwarfism III. An intrauterine dwarf withplatvspondyly and anomalies of pclvis and clavicles-osteodysplastic primordial dwarfism type III. Am J Med Genet1982;12:37-42.

Correspondence and requests for reprints to Dr EThompson, Mothercare Unit of Paediatric Genetics,Institute of Child Health, 30 Guilford Street,London WC1N IEH.

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