CORSELLO, Giovanni

DE SIMONE G

GIUFFRE, Mario

PERITORE M

PICCIONE F

PICCIONE, Maria

PIERLUIGI M

Archivio istituzionale della ricerca - Università di Palermo

55ITAL J PEDIATR 2006;32:55-59Key wordsLeri-Weill syndrome •Dischondrosteosis • SHOX gene •Skeletal dysplasiaParole chiaveSindrome di Leri-Weill •Discondrosteosi • Gene SHOX •Displasia scheletricaSubmitted: November 19, 2004Accepted: March 14, 2005Correspondence:Prof. Giovanni CorselloClinica Pediatrica e Terapia Intensiva NeonataleDipartimento Materno InfantileUniversità di Palermovia Cardinale Rampolla,190142 Palermo, ItalyTel. +39 091 6555424Fax +39 091  6555423E-mail: giocors@aliceposta.itCASE REPORTCASO CLINICOLeri-Weill’s syndrome: clinical, radiological and genetic investigations in five patientsDiscondrosteosi di Leri-Weill: valutazione clinica, radiologica e geneticain cinque pazientiM. PICCIONE, F. PICCIONE, M. GIUFFRÈ, G. DE SIMONE, M. PERITORE,M. PIERLUIGI*, G. CORSELLODipartimento Materno Infantile, Università di Palermo, Palermo; * Laboratorio diGenetica Umana, Ospedali “Galliera” di Genova, GenovaSummaryThe Authors describe five patients, all females, affected by Leri-Weill dischondrosteosis,a skeletal dysplasia due to mutations of the SHOX gene. All patients showed the charac-teristic clinical features of dischondrosteosis: short stature, mesomelia and Madelung wristdeformity. Cytogenetic analysis showed a normal karyotype in patients 1, 2, 3 and 4,whereas in patient 5 a non-familial unbalanced X;Y translocation was evident, with dele-tion of the pseudoautosomal region of the X chromosome, where the SHOX gene is lo-cated. In all patients FISH analysis with cosmids for the pseudoautosomal region of the Xand Y chromosomes showed the deletion of the SHOX gene. In consideration of the phe-notypical heterogeneity of the clinical spectra, an accurate clinical and imaging evaluationof patients and a careful investigation of their relatives were performed in order to identi-fy familial cases.RiassuntoGli Autori descrivono cinque pazienti di sesso femminile affetti da discondrosteosi diLeri-Weill, una displasia scheletrica dovuta a mutazioni del gene SHOX. Tutti i pazientimostrano le peculiari caratteristiche cliniche della discondrosteosi: bassa statura, meso-meria e deformità del polso tipo Madelung. L’analisi citogenetica ha mostrato un cario-tipo normale nei pazienti 1, 2, 3, e 4, mentre nel paziente 5 ha evidenziato una traslo-cazione X;Y sbilanciata non familiare, con delezione della regione pseudoautosomicadel cromosoma X, dove è localizzato il gene SHOX. In tutti i pazienti l’analisi FISH concosmici per la regione pseudoautosomica dei cromosomi X e Y ha mostrato la delezionedel gene SHOX. In considerazione della eterogeneità fenotipica del quadro clinico, ènecessaria una accurata valutazione clinica e strumentale dei pazienti ed un attento stu-dio dei parenti al fine di identificare i casi familiari.IntroductionLeri-Weill Dyschondrosteosis (DCS) is a skeletal dysplasia whose main fea-tures are Madelung wrist deformity, mesomelia and short stature 1.Although the 4:1 female-to-male ratio 2 initially suggested a dominant X-linked inheritance, the occurrence of a male-to-male transmission in variousfamilies has supported the dominant autosomal way of inheritance with few-er signs in affected males 3.DCS has recently been related to a haploinsufficiency on the SHOX (shortstature homeobox containing gene) located on the pseudoautosomal region(PAR) of the Xp and Yp chromosomes (locus Ypter-p11.2; Xpter-p22.3) 1 4-8.We now report on 5 new patients, 3 of them belonging to the same family inwhich a wide range of clinical features has been observed.Clinical reportPatient 1: female, 13 years old, 2nd child of non-con-sanguineous and apparently healthy parents; from theprevious pregnancy a normal male child had been born.The pregnancy had been regular with spontaneous de-livery at term. The patient’s birth-weight was 3,300 g,and length 50 cm.On admission the patient weighed 46.7 kg (50th per-centile) and was 144 cm tall (3rd percentile, - 2.13 SD).She had short limbs and forearms, carpal deformitymore evident on the left side, and bilateral tibia vara.X-rays of the upper limbs showed homerus varus andbilateral shortening of the antibrachial bones that weremore evident on the left side. On the left side the radi-al diaphysis was bent on the frontal plain and the ulnaon the lateral plain, with the distal extremities dorsallydislocated (Fig. 1). Hypoplasia and lateral and dorsalbowing of the radius and ulna with consecutive trian-gulation of the carpal bones were evident (Fig. 2), withthe apex at the level of the wedged semilunar bone inthe radius-ulnar space. On the right side the above-mentioned features could be found, although withmilder expressivity. The X-ray of the lower limbsshowed bilateral coxa valga with the angle of the cer-vical diaphyses at 140°, bilateral genu varum, esostoseson the medial metaphyseal border of the tibia (Fig. 3),hypoplasic peroneal heads and peroneal diaphysisslightly bent with back convexity. The chromosomeswere normal (46,XX). FISH (fluorescence in situ hy-bridization) analysis using 34F5 cosmids for thepseudoautosomal region of the X and Y chromosomesshowed the deletion of the SHOX locus (Fig. 4).Patients 2, 3, 4: patient 2 is an 11 year old girl. She wasthe second child of non-consanguineous parents; shewas delivered at 36 weeks of gestation. She showed IU-GR and growth retardation since the first months ofM. PICCIONE ET AL.56Fig. 1. Ventrally bent and dorsally dislocated ulna.Fig. 2. Hypoplasia and lateral and dorsal bowing of the radiusand ulna with triangulation of the carpal bones.Fig. 3. Esostoses on the medial metaphyseal border of the tibia.Fig. 4. FISH analysis shows only one copy of the SHOX gene onthe X chromosomes.postnatal life. Her birth-weight was 1,800 g and herlength 40 cm. The mother (patient 3) was 145 cm tall(< 3rd percentile, - 2.87 SD) and the sister (patient 4, 19years old) 142 cm tall (< 3rd percentile, - 3.37 SD), bothshowing mesomelia and short forearms.On admission to our institute the child weighed 25.8 kg(3rd percentile, - 2 SD) and was 123.5 cm tall (< 3rd per-centile, - 3.05 SD). She showed severe discordantgrowth retardation and small limbs, mesomelia with abroadening of the distal epiphyses of the wrist joints,reduced extension of the elbows and limited prono-supination of the forearms.The X-rays showed short upper limbs due to a short ra-dius and ulna, with the diaphyses bent so as to deter-mine a widening of the space between the bones (Fig.5). The ulna was bent on the sagittal plain with dorsaldislocation and consecutive triangulation of the carpalbones (Madelung deformation). The lower limbsshowed bilateral short tibia and fibula. The chromo-somes were normal (46,XX). FISH analysis using 34F5cosmids for the pseudoautosomal region of sexualchromosomes showed the deletion of the SHOX locus.In consideration of the phenotype of both mother andsister (patients 3 and 4), X-rays were carried out onboth, showing most of the features present in theproband. In addition, the FISH analysis showed in bothof them the deletion of the SHOX locus.The acquisition of an accurate anamnesis allowed us tocompose the pedigree of 3 generations with a familialform of DCS (Fig. 6).Patient 5: female child aged 1 year and 4 months at thefirst observation and 8 years at the second. The parentswere non-consanguineous and apparently healthy. Thepregnancy had been regular with spontaneous deliveryat term. Birth-weight was 2,970 g; birth-length was 48cm. On the first admission the child weighed 8.6 kg (3rdpercentile, -2 SD) and was 71 cm (< 3rd percentile, -3.17 SD) tall.Cytogenetic investigations: the karyotype was46,X,del(X)t(X;Y)(p22.3;q11.2) in all the metaphasesexamined (Fig. 7). The parents’ karyotype was normal.On the second observation, when the child was 8 yearsold, weight was 18.5 kg (< 3rd percentile, - 3 SD) andheight 107 cm (< 3rd percentile, - 3.14 SD). Her staturewas short with mesomelia, hyperlordosis and bilateraltibia vara.The X-rays of the upper limbs showed short radius withdiaphysis bent on the frontal plain, obliquity of the dis-tal articular extremity from top down and from the in-side to the outside, with triangulation of the carpalbones. On the lower limbs there was hypoplasia of theperoneal heads more evident on the left and bilateraltibia vara.FISH analysis with cosmids 34F5 for the pseudoauto-somal region of Xp and Yp of X and Y chromosomesshowed the deletion of the SHOX locus.57LERI-WEILL SYNDROMEFig. 5. The widening of the space between radius and ulna.Fig. 6. Pedigree of the familial Leri-Weill Dyschondrosteosis forpatient 2.Fig. 7. Cytogenetic analysis of X/Y and X chromosomes in pa-tient 5 with karyotype 46,X,del(X)t(X;Y)(p22.3;q11.2).DiscussionMutations of the SHOX gene have recently been associ-ated with idiopathic short stature, mild rizomelic bodydisproportions, and short stature in patients with Turn-er’s syndrome and in most patients with DCS 1 4 5 7 9 10.In 2.4% of children with short stature, mutations ofSHOX gene (silent, missense, nonsense, small dele-tion, etc.) have been detected 11, although various stud-ies have shown that idiopathic short stature not associ-ated with mesomelia of the limbs does not require flu-orescence in situ hybridization analysis of the SHOXgene 12.In some subjects who clinically show DCS, the dele-tion of the SHOX locus is not underlined, confirming agenetic heterogeneity in DCS 13. Different mutations invarious regions of the SHOX gene can play an impor-tant role in the pathogenesis of DCS 14, confirming thathaploinsufficiency is the most frequent mechanism inDCS 14 15.DCS has been described in subjects with X;Y unbal-anced translocation 6 16.The incidence of DCS is underestimated, above all inmales because of the milder clinical signs 2 associatedwith muscular hypertrophy 13.Several hypotheses have been proposed to explain thevarying phenotypic expressivity and the relatively lowincidence (7%) of the Madelung deformity in patientswith Turner’s syndrome, who almost all have haploin-sufficiency of the SHOX gene and short stature 2. Re-cently attention has been turned to the role of estrogens17 18.Estrogens have been shown to accelerate the pro-grammed senescence of the growth plate, causing ear-lier fusion: they may have asymmetric effects on thegrowth plate, interacting with specific SHOX deficientareas 19. In patients with haploinsufficiency of theSHOX gene and normal ovarian function 20 the auxo-logical anomalies correlated with mesomelia are evi-dent since childhood and worsen during puberty be-cause of the skeletal maturing effects of  ovarian estro-gens. This would explain why in subjects with Turner’ssyndrome the evidence of DCS is rare, insofar as thelack of estrogens would have a protective effect 2.The patients described are all females and show thecharacteristic clinical features of DCS (short stature,mesomelia and Madelung wrist deformity) with pheno-typic inter- and intra-familial heterogeneity (Tab. I) asfrequently described in the literature 2 4 5 13. Many hy-potheses have been formulated to explain this clinicalvariability, including modifier genes, intragenic se-quence alterations, long range effects, epistasis, andepigenetic interactions.In patients 1, 2, 3, and 4, the cytogenetic analysisshowed a normal karyotype, while FISH analysisshowed the deletion of the SHOX locus. In patient 5, anon-familial unbalanced X;Y translocation was evi-dent, with deletion of the pseudautosomal region of theX chromosome (Xp22.3) where the SHOX gene ismapped and correlated to DCS. The clinical features ofDCS in all patients become evident during adoles-cence, suggesting the usefulness of a follow-up in allsubjects with short stature 6. In all the cases with chro-mosomal anomalies involving the pseudoautosomal re-gions of the sex chromosomes, even in the presence ofonly short idiopathic stature, FISH analysis for theSHOX gene must be carried out.ConclusionIn consideration of the phenotypical heterogeneity ofthe clinical spectra due to mutations of the SHOX gene,an accurate clinical and imaging evaluation of patientsis recommended along with careful familial anamnesisand investigation of the relatives in order to identify fa-milial cases with varying clinical expressivity and ele-vated risk of recurrence (50%).M. PICCIONE ET AL.58Tab. I. Phenotypical variability in the 5 patients presented.Patient 1 Patient 2 Patient 3 Patient 4 Patient 5Short stature X X X X XHomerus varus XMesomelia X X X X XDorsal dislocation of the distal ulna X X X X XTriangulation of carpal bones X X X X XReduced extension of the forearms XCoxa valga XEsostoses on the metaphyseal border of tibia XShort tibia X X X X XGenu varus X XReferences1 Belin V, Cusin V, Viot G, Girlich D, Toutain A, Moncla A, et al.SHOX mutations in dyschondrosteosis (Leri-Weill syndrome). NatGenet 1998;19:67-9.2 Ross JL, Scott C Jr, Martilla P, Kowal K, Nass A, Papenhausen P,et al. Phenotypes associated with SHOX deficiency. J Clin EndMet 2001;86:5674-80.3 Lichtenstein JR, Sundaram M, Burdge R. Sex-influenced expres-sion of Madelung’s deformity in a family with dyschondrosteosis.J Med Genet 1980;17:41-3.4 Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A, et al.Pseudoautosomal deletions encompassing a novel homeoboxgene cause growth failure in idiopathic short stature and Turnersyndrome. Nat Genet 1997;16:54-63.5 Shears DJ, Vassal HJ, Goodman FR, Rodger WP, Reardon W, Su-perti-Furga A, et al. Mutation and deletion of the pseudoautoso-mal gene SHOX cause Leri-Weill dyschondrosteosis. Nat Genet1998;19:70-3.6 Calabrese G, Fishetto R, Stuppia L, Capodiferro F, Mingarelli R,Causio F, et al. X/Y translocation in a family with Leri-Weilldyschondrosteosis. Hum Genet 1999;105:367-8.7 Grigelioniene G, Eklof O, Ivarsson SA, Westphal O, NeumeyerL, Kedra D, et al. Mutations in short stature homeobox contain-ing gene (SHOX) in dyschondrosteosis but not in hypochon-droplasia. Hum Genet 2000;107:145-9.8 Ezquieta B, Cueva E, Oliver A, Gracia R. SHOX intragenic mi-crosatellite analysis in patients with short stature. J Ped End Met2002;15:139-48.9 Palka G, Stuppia L, Guanciali Franchi P, Chiarelli F, Fischetto R,Borrelli P, et al. Short arm rearrangements of sex chromosomeswith haploinsufficiency of the SHOX gene are associated withLeri-Weill dyschondrosteosis. Clin Genet 2000;57:449-53.10 Zinn AR, Wei F, Zhang L, Elder FF, Scott CI Jr, Marttila P, et al.Complete SHOX deficiency causes Langer mesomelic dysplasia.Am J Med Genet 2002;110:158-63.11 Rappold GA, Fukami M, Niesler B, Schiller S, Zumkeller W, Bet-tendorf M, et al. Deletions of the Homeobox gene SHOX (shortstature homeobox) are an important cause of growth failure inchildren with short stature. J Clin End Met 2002;87:1402-6.12 Musebeck J, Mohnike K, Beye P, Tonnies H, Neitzel H, SchnabelD, et al. Short stature homeobox-containing gene deletion screen-ing by fluorescence in situ hybridisation in patients with shortstature. Horm Res 2001;55:71-6.13 Schiller S, Spranger S, Schechinger B, Fukami M, Merker S,Drop SLS, et al. Phenotypic variation and genetic heterogeneityin Leri-Weill syndrome. Eur J Hum Genet 2000;8:54-62.14 Huber C, Cusin V, Le Merre M, Mathieu M, Sulmont V,Dagoneau N, et al. SHOX point mutations in dyschondrosteosis. JMed Genet 2001;38:323.15 Ross JL, Bellus G, Scott CI Jr, Abboudi J, Grigelioniene G, ZinnAR. Mesomelic and rhizomelic short stature: the phenotype ofcombined Leri-Weill dyschondrosteosis and achondroplasia orhypochondroplasia. Am J Med Genet 2003;116A:61-5.16 Stuppia L, Calabrese G, Borrelli P, Gatta V, Morizio E, MingarelliR, et al. Loss of the SHOX gene associated with Leri-Weilldyschondrosteosis in a 45,X male. J Med Genet 1999;36:711-3.17 Ogata T, Matsuo N, Nishimura G. SHOX haploinsufficiency andoverdosage: impact of gonadal function status. J Med Genet2001;38:1-6.18 Binder G, Ranke MB, Martin DD. Auxology is a valuable instru-ment for the clinical diagnosis SHOX haploinsufficiency inschool-age children with uneplained short stature. J Clin EndMet 2003;88:4891-6.19 Weise M, De-Levi S, Barnes KM, Gafni RI, Abad V, Baron J. Ef-fects of estrogen on growth plate senescence and epiphyseal fu-sion. Pro Natl Acad Sci USA 2001;98:6871-6.20 Fukami M, Matsuo N, Hasegawa T, Sato S, Ogata T. Longitudi-nal auxological study in a female with SHOX (short stature home-obox containing gene) haploinsufficiency and normal ovarianfunction. Eur J End 2003;149:337-41.59LERI-WEILL SYNDROME

Leri-Weill’s syndrome: clinical, radiological and genetic investigations in five patients

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Leri-Weill’s syndrome: clinical, radiological and genetic investigations in five patients

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