Letter to the Editor

An Unusual Radiological Finding in ThanatophoricDysplasia Type 1 With Common Mutation of theFibroblast Growth Factor Receptor-3 (FGFR3)Gene (Arg248Cys)

To the Editor:

Thanatophoric dysplasia (TD), the most common le-thal form of dwarfism, is characterized by markedshortness of the limbs, with several skin folds, rela-tively normal trunk length, narrow thorax, and dispro-portionately large head with frontal bossing [Marote-aux et al., 1967; Centa and Camera, 1969]. TD can beassociated with cloverleaf skull deformity [Partingtonet al., 1971; Camera et al., 1973]. Langer et al. [1987]subdivided TD into two types. In type 1, the humeriand femora are curved (femora with ‘‘telephone re-ceiver’’ appearance), vertebral bodies are very flat andribs very short. In type 2, the short femora are straight,with proximal medial spike, vertebral bodies are not asflat and ribs are not as short as in type 1, and cloverleafskull is virtually always present. Usually, cloverleafskull is lacking in type 1 and, when present, is mild.There has been disagreement on this issue. For ex-ample, Norman et al. [1992] found no previous reportsof cloverleaf skull in type 1. Tavormina et al. [1995],who first discovered mutations in TD, separated their55 cases into two groups. Patients with short, curvedfemora with or without cloverleaf skull have been re-ferred to as TD1, whereas those with straight femoraand severe cloverleaf skull have been referred to asTD2. Therefore, according to these authors, the findingof curved femora is crucial in distinguishing the twotypes of TD. Of 39 patients with TD1, 22 had mutationsat codon 248, causing an arginine to cysteine substitu-

tion (Arg248Cys) and one had a Ser371Cys change,while all the 16 cases of TD2 had a mutation at codon650, leading to a lysine to glutamic acid change(Lys650Glu) [Tavormina et al., 1995]. Subsequently,mutations in the stop codon (807) were found in fiveadditional patients with TD1 [Rousseau et al., 1995].Recently, Ser249Cys, Tyr373Cys, and Gly370Cyschanges were detected in TD1 cases [Tavormina et al.,1995; Rousseau et al., 1996].

We have examined a foetus with TD at 21 weeks ofgestation. On radiographs (Fig. 1), he showed shortlong bones, narrow thorax, short ribs, marked platy-spondyly, horizontal inferior margins of the iliac bones,without cloverleaf skull. His relatively short femorawere slightly curved without proximal medial spike. Amolecular study was performed by direct sequencinganalysis of FGFR3 gene. The presence of a C-T hetero-zygous base substitution at position 742, which pre-dicts an Arg248Cys change, was detected in exon 7.The result was confirmed by restriction analysis ofPCR product by Bsi HKA I enzyme. Examination ofexon 10, exon 14, and of the stop codon at the end ofhexon 19 showed no mutation.

Therefore, the foetus reported here, who showedfemora without a ‘‘telephone receiver’’ appearance andvery flat vertebral bodies, had the mutation most com-monly reported in TD type 1. His radiological findingswere similar, except for the skull deformity, to those ofthe case 1 reported by Norman et al. [1992] as TD type2. Because the molecular studies have showed that clo-verleaf skull deformity and, in our case, minimallycurved femora can be present also in TD 1, the radio-logical findings differentiating the two types of TDshould be more clearly defined.

A very narrow thorax, very flat vertebral bodies, andfemora which usually have a ‘‘telephone receiver’’ ap-pearance but which can also be straight without proxi-mal medial spike, represent, in our opinion, the radio-logical findings typical of TD type 1.

*Correspondence to: Dr. Gianni Camera, Servizio di GeneticaClinica e Dismorfologia, Ospedali Galliera, Mura delle Cappuc-cine 14, 16128 Genoa, Italy.

Received 22 June 1996; Accepted 14 October 1996

American Journal of Medical Genetics 71:122–123 (1997)

© 1997 Wiley-Liss, Inc.

REFERENCESCamera G, Mantegazza F, Damiani S (1973): Associazione tra cranio a

trifoglio e nanismo tanatoforo. Pathologica 65:181–187.

Centa A, Camera G (1969): Il cosiddetto nanismo tanatoforo. Min Pediat21:447–453.

Langer LO, Yang SS, Hall JG, Sommer A, Kottamasu SR, Golabi M,Krassikoff N (1987): Thanatophoric dysplasia and cloverleaf skull. AmJ Med Genet Suppl 3:167–179.

Maroteaux P, Lamy M, Robert JM (1967): Le nanisme thanatophore.Presse Med 75:2519–2524.

Norman AM, Rimmer S, Landy S, Donnai D (1992): Thanatophoric dys-plasia of the straight-bone type (type 2). Clin Dysmorphol 1:115–120.

Partington MW, Gonzales-Crussi F, KhaKee SG, Wollin DG (1971): Clo-verleaf skull and thanatophoric dwarfism. Report of four cases, two inthe same sibship. Arch Dis Child 46:656–664.

Rousseau F, El Ghouzzi V, Delezoide AL, Legeai-Mallet L, Le Merrer M,Munnich A, Bonaventure J (1996): Missense FGFR3 mutations createcysteine residues in thanatophoric dwarfism type I (TD1). Hum MolGenet 5:509–512.

Rousseau F, Sangier P, Le Merrer M, Munnich A, Delezoide AL, Marote-

aux P, Bonaventure J, Narcy F, Sanak M (1995): Stop codon FGFR3mutations in thanatophoric dwarfism type 1. Nat Genet 10:11–12.

Tavormina PL, Rimoin DL, Cohn DM, Zhu Y-Z, Shiang R, Wasmuth JJ(1995): Another mutation that results in the substitution of an un-paired cysteine residue in the extracellular domain of FGFR3 in thana-tophoric dysplasia type I. Hum Mol Genet 4:2175–2177.

Tavormina PL, Shiang R, Thompson LM, Zhu Y-Z, Wilkin DJ, LachmanRS, Wilcox WR, Rimoin DL, Cohn DH, Wasmuth JJ (1995): Thanato-phoric dysplasia (types I and II) caused by distinct mutations in fibro-blast growth factor receptor 3. Nat Genet 9:321–328.

Gianni Camera*Maurizia BaldiMaria BafficoSilvano PozzoloService for Clinical Genetics

and DysmorphologyOspedali GallieraGenoa, Italy

Fig. 1. Skeletal x-ray of the foetus at 21 weeks of gestation. A: Short long bones; narrow thorax; iliac bones short in the vertical diameter; slightlycurved femora without proximal medial spike. B: Narrow thorax due to very short ribs; very marked platyspondyly.

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