Grebe Syndrome: Clinical and Radiographic Findings inAffected Individuals and Heterozygous Carriers

Teresa Costa,1 Gale Ramsby,2 Fatima Cassia,3 Klaus-Ruediger Peters,2 Jose Soares,4Jordao Correa,5 Antonio Quelce-Salgado,6 and Petros Tsipouras7*1Departments of Pediatrics and Genetics, Hospital for Sick Children, Toronto, Canada2Department of Diagnostic Imaging and Therapeutics, University of Connecticut Health Center, Farmington,Connecticut

3Department of Pediatrics, Hospital Asa Norte, Brasilia, Brazil4Department of Radiology, Hospital SAMUR, Vitoria da Conquista, Bahia, Brazil5Laboratory of Genetics, State Hospital, Sao Paulo, Brazil6Department of Experimental Psychology, Paulist State University, Assis, Brazil7Department of Pediatrics, University of Connecticut Health Center, Farmington, Connecticut

Grebe syndrome is a recessively inheritedacromesomelic dysplasia. We studied, clini-cally and radiographically, 10 affected indi-viduals, originating from Bahia, Brazil. Thephenotype is characterized by a normalaxial skeleton and severely shortened anddeformed limbs, with a proximo-distal gra-dient of severity. The humeri and femorawere relatively normal, the radii/ulnae andtibiae/fibulae were short and deformed, car-pal and tarsal bones were fused, and severalmetacarpal and metatarsal bones were ab-sent. The proximal and middle phalanges ofthe fingers and toes were invariably absent,while the distal phalanges were present.Postaxial polydactyly was found in severalaffected individuals. Several joints of thecarpus, tarsus, hand, and foot were absent.Heterozygotes presented with a variety ofskeletal manifestations including polydac-tyly, brachydactyly, hallux valgus, andmetatarsus adductus. Grebe syndrome iscaused by a missense mutation in thegene encoding cartilage-derived morphoge-netic protein-1. Am. J. Med. Genet. 75:523–529, 1998. © 1998 Wiley-Liss, Inc.

KEY WORDS: Grebe syndrome; acromeso-

melic dysplasia; dispropor-tionate dwarfism; bone apla-sias and hypoplasias; poly-dactyly; cartilage-derivedmorphogenetic protein-1

INTRODUCTION

Grebe syndrome is a recessively inherited disorder oflimb development (MIM 200700). It exhibits increasingseverity in a proximo-distal gradient and is thereforeclassified as a form of acromesomelic dysplasia in theInternational Classification of Osteochondrodysplasias[Spranger, 1992]. The phenotype is characterized by anormal axial skeleton, relatively normal humeri andfemora, short and deformed radii/ulnae and tibiae/fibulae, and severe abnormalities of hands and feet.The digits are reduced to globular appendages, andhexadactyly is common.

Few cases have been reported since 1952, whenGrebe [1952] first described the phenotype in 2 Ger-man sisters. The highest concentration of affected in-dividuals, 47 cases belonging to 21 sibships in 6 kin-dreds, was identified in a small geographic area duringthe course of a survey of genetic disorders in the stateof Bahia, Brazil [Quelce-Salgado, 1964, 1968]. Twenty-two other cases, one with no recorded family history[Langer et al., 1989] and 21 others belonging to 7 un-related families, were reported from India [John andGundappa, 1963; Meera Khan and Khan, 1982], En-gland [Kumar et al., 1984], Puerto Rico [Garcia-Castroand Perez-Comas, 1975], the USA [Romeo et al., 1977;Freire-Maia and Lenz, 1969], and China [Curtis, 1986].In addition to the Brazilian families, 2 others were in-bred kindreds [Meera Khan and Khan, 1982; Curtis,1986], and in 2 sibships the parents were consanguin-eous [Grebe, 1952; Garcia-Castro and Perez-Comas,1975]. The rarity of the condition and the high fre-quency of consanguinity in the reported cases suggest

Contract grant sponsor: Coles Family Foundation; Contractgrant sponsor: N.I.H.; Contract grant number: HD-22610.

Teresa Costa is presently at the Department of Pediatrics,IWK-Grace Health Center, Dalhousie University, Halifax, NovaScotia, Canada.

*Correspondence to: Petros Tsipouras, M.D., Department of Pe-diatrics, University of Connecticut Health Center, 263 Farming-ton Ave., Farmington, CT 06030. E-mail: tsipouras@nso1.uchc.edu

Received 25 August 1997; Accepted 10 October 1997

American Journal of Medical Genetics 75:523–529 (1998)

© 1998 Wiley-Liss, Inc.

that the mutation frequency is low in the general popu-lation.

The pattern of malformations in Grebe syndrome issimilar to that seen in Hunter-Thompson type ‘‘ac-romesomelic dysplasia’’ [Hunter and Thompson, 1976;Langer et al., 1989] and in mouse mutant brachypo-dism [Gruneberg and Lee, 1973], disorders which havebeen shown to be caused by mutations in bone morpho-genetic proteins, and in growth and differentiation fac-tor-5 (Gdf-5) in the mouse and its human homologue,cartilage-derived morphogenetic protein-1 (CDMP-1)[Storm et al., 1994; Thomas et al., 1996]. Recently, werevisited the population originally studied by Quelce-Salgado [1964, 1968] with the objectives of furtherdocumenting the phenotype and of collecting bloodsamples for molecular studies. We provide here a de-tailed description of the phenotype of affected individu-als and obligate carriers. The results of the mutationanalysis of CDMP-1 was outlined in a companion paper[Thomas et al., 1997].

PATIENTS AND METHODS

By history we identified 20 individuals with Grebesyndrome, all members of the original families firstreported by Quelce-Salgado [1964, 1968]. Ten affectedindividuals and their families were available for study.Their physical appearance suggested mixed European,African, and Amerindian ancestry, which is typical ofinhabitants of the state. Seven belonged to 5 sibships ina single kindred (Fig. 1, Family 1), while the otherswere divided among 3 seemingly unrelated families(Fig. 1, Families 3–5). Of interest, in family 1 themother of IV-13 was related to family 2. Eight affected

individuals and 16 relatives, including 9 obligate car-riers, agreed to have blood drawn for molecular studies;these investigations are described separately [Thomaset al., 1997]. Eight affected individuals, 4 females (ages13, 15, 25, and 35 years) and 4 males (ages 10, 13, 34,and 51 years), were examined clinically (family 1: III-9;IV-8, IV-9, V-2, V-3; family 3: IV-1; family 4: III-2; fam-ily 5 II-1). Three affected individuals underwent fullradiographic skeletal surveys (family 1: IV-8, V-3; fam-ily 3: IV-1), while 4 others underwent limited studiesexcluding spine and skull (family 1: III-9, IV-9; family4: III-2; family 3: II-1). In addition, the 10-year-old af-fected boy (family 3: IV-1) underwent an MRI of theright upper limb. Seven obligate heterozygotes (family1: II-7, III-6, III-7, IV-2; family 3: II-2; family 4: IV-1;family 5: I-2) were examined clinically, and 5 had ra-diographs of hands and feet (family 1: III-6, III-7, IV-2;family 4: IV-1, family 5: I-2). A metacarpophalangealindex was derived from the hand radiographs of obli-gate carriers, using the method described by Poznanskiet al. [1972]. Informed consent was obtained from eachparticipant in the study. The investigation was re-viewed and approved by the Institutional ReviewBoard of the University of Connecticut Health Center.

The radiographs were digitized to 15-bit with a CCDflatbed scanner (Scanmaster DX, Howtek, Inc., Hud-son, NH) and displayed as seen on a light screen, ap-plying a new kind of digital signal processing (VisualImaging Workstation Pixision, JEOL USA, Inc., Pea-body, MA). This technology is based on nonlinear pointprocessing, using the hysteresis properties of images aslocal modifier [Peters, 1996]. Conventional image pro-cessing was not used.

RESULTSClinical Findings

Affected individuals. Affected individuals hadnormal intelligence and were fully independent andproductive members of their community. They hadadapted surprisingly well to the hand malformationsby handling objects between their ‘‘thumbs.’’ Onewoman was a proficient housekeeper and could evencrochet. Her brother repaired small appliances. Allwere ambulatory, and one young boy even played soc-cer.

All had strikingly similar phenotypes, with dispro-portionately short and deformed limbs (Fig. 2). Adultstanding height averaged 95.5 cm and 100.5 cm, sittingheight 77.5 cm and 86.0 cm, and arm spans 81.5 cm and95.5 cm for females and males, respectively. Abnormalfindings were limited to the limbs, where the defectswere symmetrical and of increasing severity distally(Fig. 2). In the upper limb, the proximal segment wasshort (20.7 cm and 22.5 cm for adult females and males,respectively), while the middle segment was relativelyshorter and bowed (8.5 cm and 6.8 cm, female andmale, respectively). The hands were short (8.8 and10 cm, female and male, respectively), and the fingerswere replaced by globular appendages about 2 cm longwhich appeared to be joined to the hand by a bridge ofsoft tissue, without apparent articulation at the meta-carpophalangeal joints. There was no apparent devel-

Fig. 1. Pedigrees of the affected individuals identified by history. Al-though no links could be found between the 5 families, they all originatedfrom the same geographic area.

524 Costa et al.

opment of the thumb. Nails were short but otherwisenormal. Five individuals had hexadactyly. The range ofmovement at the shoulder was normal. At the elbow,no supination or pronation was evident, except for lim-ited movement in 1 case; but there was full flexion andextension in 6/7, while 1/7 had mild limitation of ex-tension of the right side. At the wrist there was noapparent bony articulation on palpation, but the ‘‘joint’’could be moved through hyperextension and full flex-ion. Patients had a peculiar movement of the fingers,with simultaneous slight extension and proximalmovement (‘‘telescoping’’) but no real flexion or exten-sion. There was some adduction of the radial digit(‘‘thumb’’).

In the lower limb, the proximal segment was short(20.1 and 14.2 cm, female and male, respectively), andthe middle segment relatively shorter (10.8 and 10.4cm, female and male, respectively). Muscles were bulkyand extended to the ankle without evidence of a popli-teal fossa. The patellae were not palpable. Movementat the hips was normal. There was limited extensionand flexion at the knee, and limited plantar flexion anddorsiflexion of the ankle. The hindfoot was inverted.There was no apparent articulation of the toes withfoot, and no movement of the toes. None had polydac-tyly of the feet, but 4 individuals had a history of au-toamputation of toes (Fig. 2).

Relatives. Obligate heterozygotes were of normalheight. Clinically, 2 males had normal limbs (family 1:II-7, III-6). The other 5 (4 female, 1 male) had minoranomalies. These included: bilateral simian creases,unilateral metatarsus adductus, and unilateral halluxvalgus (family 1: III-7); postaxial polydactyly left foot(family 1: IV-2) (Fig. 3C); unilateral short fifth meta-tarsal (family 3: II-2); unilateral simian crease andshort fifth metacarpals (family 4: IV-1); and bilateral

simian creases, short fifth metacarpals, flexion con-tracture of the fifth proximal interphalangeal joint ofthe right hand, short fifth metatarsals, unilateral hal-lux valgus, and valgus deformity of toes 1–4 on the left(family 5: I-2).

Five relatives of unknown status were examined.Two had minor abnormalities, obvious brachydactyly(Fig. 3A,B), short fifth metacarpals, flexion contractureof the fifth proximal interphalangeal joints (Fig. 3A),valgus deformities of toes (Fig. 3B), and short fifthmetacarpals (family 1: III-8); and flexion contracture ofthe proximal interphalangeal joints on the right, withmild flexion contraction of the fourth proximal inter-phalangeal joint on the left (family 1: IV-13). Both in-dividuals (III-8 and IV-13) were found to be heterozy-gotes for the common C400Y mutation identified inGrebe syndrome [Thomas et al., 1997]. Other relativeswere reported to have hand abnormalities but wereunavailable for examination.

Imaging Studies

Affected individuals. Evaluation of skeletal ra-diographs demonstrated a plethora of abnormalities.Although the middle and distal segments of the lowerlimbs were the most severely affected, the femora pre-sented with a number of abnormalities. A marked de-crease in the length of the femoral diaphysis was in-variably observed, associated with disproportionatelysized greater and lesser trochanters, external rotationof the femoral shafts, and asymmetry of the femoralcondyles (Fig. 4a,b). The middle segment was severelydeformed, with a partially formed medial tibial plateaualigning with the medial tibial condyle, absent tibialand fibular diaphyses, and absence of the lateral mal-leolus (Fig. 4a,b). The patellae were either hypoplastic

Fig. 2. A: Affected woman (family 4, III-2) with her unaffected 4-year-old son. Close-up of the palms of the hands (B) and feet (C). Note markedly shortlimbs, loss of normal palmar landmarks, polydactyly of the hands, and oligodactyly of the right foot due to autoamputation.

Grebe Syndrome 525

or absent. The identity of the tarsals was difficult todiscern; however, the talo-navicular and calcaneo-cuboid articulations were normal (Fig. 4d). Partial fu-sion of the navicular and cuneiform and of the talusand calcaneus was observed in certain individuals (Fig.4d). The metatarsals were fused, and the proximal andmiddle phalanges were absent in several instances(Fig. 4c). A fusion of the metatarsals to the phalangeswas also observed (Fig. 4c).

Review of radiographs of the upper limbs showed ashallow trochlear depth of the humerus (Fig. 5A). Themiddle segment was severely involved, with hypoplasia

of the ulna which appeared to terminate abruptly (Fig.5A). The radial head was malformed, while the shaftwas angulated in the middle and at the neck, the distalradius was fully formed (Fig. 5A). The second carpalrow was fused, and the metacarpals were short (Fig.6a,b). The proximal and middle phalanges were absentin most instances, although the distal phalanx wasreadily recognizable (Fig. 5A, 6a,b).

A magnetic resonance scan of the middle and distalsegment of the upper limb of a 10-year-old child dem-onstrated the presence of fibrous tissue in the distalulnar segment (Fig. 5B). Cartilage was present in thearticular surfaces of the elbow joint, but not betweenthe mesenchymal ghost of the carpus and the remain-ing skeletal structures (Fig. 5B).

Obligate heterozygotes. Abnormalities were de-tected in the radiographs of all 5 obligate carriers stud-ied, even in one man who had no noticeable clinicaldefects (Fig. 7a–d). The metacarpophalangeal index(Fig. 8) indicates that the tubular bones are short, es-

Fig. 3. Manifestations in heterozygotes. Adult male with molecular evi-dence of heterozygosity (family 1, III-8) has brachydactyly, flexion contrac-ture of the fifth proximal interphalangeal joints (A), and valgus deformityof the forefoot and short fifth metacarpals (B). C: An obligate carrier adultfemale (family 1, IV-2) has postaxial polydactyly of the left foot.

Fig. 4. Radiographs of the lower limbs of affected adults. a, b: Shortfemur diaphysis and short femoral neck, as well as short and triangularlyshaped tibia short fibula. c: Abnormally shaped and misplaced tarsalbones. d: Short and abnormal metatarsals, and absent proximal andmiddle phalanges.

526 Costa et al.

pecially the metacarpals and the middle phalanges; theproximal and distal phalanges are relatively spared.There is considerable variation among subjects, as evi-denced by the large standard deviations. However,there was surprising symmetry with the measure-ments of the left and right hands, virtually superim-posable for any one individual. Of interest, therewas significant delay in bone age in a 4-year-old boy(Fig. 7a).

Molecular Studies

As published elsewhere [Thomas et al., 1997], aG→A transition at nucleotide 1199 was detected in theaffected individuals. This missense mutation, G1199A,predicts the substitution of a highly conserved cysteineresidue by tyrosine (C400Y). Six of the 7 affected indi-viduals studied were found to be homozygous for thismutation. The seventh (family 1, III-9), a man indis-tinguishable clinically and radiographically from theothers, was a compound heterozygote for this mutationand for a deletion of a G at position 1144, DG1144[Thomas et al., 1997].

DISCUSSIONThe complex mechanisms of limb morphogenesis

have been conserved in all tetrapods for the past four

million years [Hogan, 1996]. Three principal axes de-fine the developmental patterning of the limb: dorsal-ventral, proximal-distal, and anterior-posterior[Hogan, 1996]. This patterning is generated through anetwork of reciprocal interactions of the tissues in-volved [Hogan, 1996]. A variety of signaling moleculeshave been identified as mediators of the patterningprocess, including the cartilage-derived morphogeneticprotein-1 (CDMP-1) [Chang et al., 1994; Storm et al.,1994] Cartilage-derived morphogenetic protein-1 is amember of the TGF-b superfamily of signaling mol-ecules, and it is expressed predominantly at sites ofcartilage differentiation in developing limbs, where itfunctions as a signal for chondrogenesis [Chang et al.,1994; Storm et al., 1994]. In addition, CDMP-1 is ex-pressed at the position of future joint spaces [Chang etal., 1994]. CDMP-1 is synthesized in a precursor formwhich is processed to its mature configuration, formingdimers with itself or other bone morphogenetic pro-teins [Thomas et al., 1997].

Homozygous mutations in CDMP-1 and its mousehomologue, Gdf-5, are associated with limb malforma-tions characterized by: (1) symmetrical limb abnor-malities with a proximal-distal gradient of severity andpostaxial polydactyly; (2) abnormal ossification pre-senting as bone aplasias, hypoplasias, and delayedbone age; and (3) abnormal joint formation [Storm et

Fig. 5. Radiograph (A), MR scan (B), and schematic representation (C)of the right arm and hand of a 10-year-old male A, B: Hypoplastic andangulated radius. B, C: The ulnar diaphysis terminates abruptly, and itsdistal segment is composed of fibrous tissue, as indicated by arrow. B: MRscan shows cartilage in the articular surfaces of the elbow but not betweenthe remaining skeletal structures. A: Absence of proximal and middle pha-langes.

Fig. 6. Radiographs of hands of an affected adult. Comparison of digi-tized film images without (a) and with (b) visual contrast display. Notepolydactyly, fusions of the carpal bones, short and abnormal metacarpals,and presence of distal phalanges.

Fig. 7. Radiographs of heterozygotes. a: Delayed bone age in a 5-year-old male. b: Short first, third, fourth, and fifth metacarpal, with shortmiddle phalanx of second and fifth digits. c: Duplication of the middle anddistal phalanges of the fifth toe, broad proximal phalanx, and abnormallyshort middle and distal phalanges of toes 2–5. d: Abnormally short of themiddle phalanx of toes 2–5. Note abnormal shape of distal phalanx.

Grebe Syndrome 527

al., 1994; Thomas et al., 1996, 1997]. The CDMP-1 mis-sense mutation in the Brazilian families with Grebesyndrome is associated with severe limb defects. Amilder phenotype was reported in a single family witha 22-base pair tandem duplication within the codingsequence of CDMP-1, which creates a frameshift andresults in a functionally null mutation [Thomas et al.,1996]. The affected brother and sister had short limbswith multiple dislocations; the digits were short but notglobular, as seen in Grebe syndrome [Langer et al.,1989]. Because of similarities with a sporadic case pre-viously reported by Hunter and Thompson [1976], theywere labeled as having ‘‘Hunter-Thompson-type ac-romesomelic dysplasia.’’ In the mouse model, brachy-podism, several distinct frameshifts in the coding se-quence of the Gdf-5 gene were identified, resulting infunctionally null mutations [Storm et al., 1994].

Obligate carriers in the Brazilian families had a va-riety of mild abnormalities of hands and feet, namelybrachydactyly, polydactyly, and positional deformities.Although no single defect was pathognomonic of thecarrier state, it is of interest to note that the clinicalfindings led us to suspect heterozygosity in 2 individu-als whose genotypic status could not be predicted bypedigree analysis (family 1: III-8, IV-13) but who wereshown to carry the C400Y CDMP-1 mutation on mo-lecular studies [Thomas et al., 1997]. A variety of mis-sense and null CDMP-1 gene mutations were identifiedin several families with brachydactyly C [Polinkovskyet al., 1997]. Both phenotypes are inherited as domi-nant traits, suggesting a complex pattern of molecularinteractions of CDMP-1 with other proteins.

Significant delay in bone age was observed in ahealthy and well-grown 4-year-old boy whose mother isa homozygous affected individual (Fig. 2). We presumethis to be an expression of his heterozygous state.Quelce-Salgado [1968] had already alluded to abnor-malities in relatives of affected individuals; 2 parentsstudied radiographically had absence of or abnormalphalanges of the toes, and other family members had‘‘talipes equinovarus, polydactyly, and double hallu-ces.’’ In a Chinese family, one obligate carrier had post-axial polydactyly of the feet, and a relative of undeter-mined genotype had a duplicated hallux [Curtis, 1986].Brachydactyly was implicated as a manifestation of thecarrier state for Grebe syndrome in two families, one

English and one Chinese [Kumar et al., 1984; Curtis,1986]. In the single English individual studied radio-graphically, the bony elements involved were the firstmetacarpals and the middle phalanges of the secondand fifth fingers, while in the 3 members of the Chinesefamily, the third, fourth, and fifth metacarpals and themiddle phalanges of the second and fifth fingers wereshortened. This pattern is similar to that seen in thefamily which we studied, as illustrated in the metacar-pophalangeal profile (Fig. 8). It is not known whetherthe allelic condition, Hunter-Thompson dysplasia, mayhave heterozygote manifestations, as the parents of thesibs reported with this condition were not studied[Langer et al., 1989; Thomas et al., 1996].

During development, ossification of skeletal ele-ments progresses in a proximo-distal direction [Hogan,1996]. The humerus ossifies before the radius and ulna,and those two before any elements of the hand. Inter-estingly, the skeletal abnormalities observed in bothGrebe and Hunter-Thompson syndromes correspond toelements which ossify late in development. The proxi-mal-distant gradient of severity seen in the two disor-ders would be consistent with a CDMP-1 expressiongradient or with a higher abundance of other bone mor-phogenetic protein molecules, which in some waymight be acting as diluters of the C400Y CDMP-1 lev-els [Thomas et al., 1997]. It is a reasonable assumptionthat the distal ossification center of the ulna neverformed due to a malfunctioning signaling mechanismduring a critical phase of development (Fig. 5B). Recentstudies showed that a CDMP-1 chain with the C400Ymutation has the ability to form not only homodimersbut also heterodimers, with other bone morphogeneticproteins rendering them biologically inactive sincethey cannot be secreted from the cells [Thomas et al.,1997]. This hypothesis offers a common mechanism un-derlying the hypoplasia of other bones observed inGrebe syndrome.

ACKNOWLEDGMENTS

The authors express their gratitude to the many in-dividuals who participated in this study. Without theirwholehearted participation this study would not havebeen possible. We thank Dr. Michael Kilpatrick (Farm-ington, CT), Dr. Frank Luyten (Besthesda, MD), andDr. John Opitz (Salt Lake City, UT), for their com-ments and invaluable insight. This work was sup-ported in part by NIH HD-22610 and by the Coles Fam-ily Foundation to P.T.

REFERENCES

Chang SC, Hoang B, Thomas JT, Vukicevic S, Luyten FP, Ryba NJP,Kozak CA, Reddi AH, Moos M (1994): Cartilage-derived morphogeneticproteins. J Biol Chem 269:28227–28234.

Curtis D (1986): Heterozygote expression in Grebe chondrodysplasia. ClinGenet 29:455–456.

Freire-Maia N, Lenz WD (1969): Discussion. Alan R. Liss, BD: OAS V(4):14–16.

Garcia-Castro JM, Perez-Comas A (1975): Nonlethal achondrogenesis(Grebe-Quelce-Salgado type) in two Puerto Rican sibships. J Pediatr87:948–952.

Grebe H (1952): Die Achondrogenesis. Ein einfach rezessives Erbmerkmal.Folia Hered Pathol (Pavia) 2:23–29.

Fig. 8. Metacarpophalangeal profile of 5 obligate heterozygotes.

528 Costa et al.

Gruneberg H, Lee AJ (1973): The anatomy and development of brachypo-dism in the mouse. J Embryol Exp Morphol 30:119–141.

Hogan BLM (1996): Bone morphogenetic proteins: Multifunctional regula-tors of vertebrate development. Genes Dev 10:1580–1594.

Hunter AGW, Thompson MW (1976): Acromesomelic dwarfism: Descrip-tion of a patient and comparison with previously reported cases. HumGenet 34:107–113.

John K, Gundappa MP (1963): Congenital deformities of limbs in differentmembers of a family. J Indian Med Assoc 41:559.

Kumar D, Curtis D, Blank CE (1984): Grebe chondrodysplasia and brachy-dactyly in a family. Clin Genet 25:68–72.

Langer LO, Cervenka J, Camargo M (1989): A severe autosomal recessiveacromesomelic dysplasia, the Hunter-Thompson type, and comparisonwith the Grebe type. Hum Genet 81:323–328.

Meera Khan PM, Khan A (1982): Grebe chondrodysplasia in three genera-tions of an Andhra family in India. Prog Clin Biol Res 104:69–80.

Peters K-R (1996): Collection of deficiencies of SEM signal collection con-trasts measured and corrected by differential hysteresis processing.Scanning 18:539–555.

Polinkovsky A, Robin NH, Thomas JT, Irons M, Lynn A, Goodman F,Reardon W, Kant SG, Brunner HG, van der Burgt I, Chitayat D,Luyten FP, Warman ML (1997): Mutations in the morphogen CDMP-1cause autosomal dominant brachydactyly C. Nat Genet 17:18–19.

Poznanski AK, Garn SM, Nagy JM, Gall JC (1972): Metacarpophalangeal

pattern profiles in the evaluation of skeletal malformations. Radiology104:1–11.

Quelce-Salgado A (1964): A new type of dwarfism with various bone apla-sias and hypoplasias of the extremities. Acta Genet (Basel) 14:63–66.

Quelce-Salgado A (1968): A rare genetic syndrome. Lancet 1:1430.Romeo G, Zonana J, Rimoin DL, Lachman RS, Scott CI Jr, Kaveggia EG,

Spranger JW, Opitz JM (1977): Heterogeneity of nonlethal severeshort-limbed dwarfism. J Pediatr 91:918–923.

Spranger J (1992): International classification of osteochondrodysplasias.Eur J Pediatr 151:407–415.

Storm EE, Huynh TV, Copeland NG, Jenkins NA, Kingsley DM, Lee S-J(1994): Limb alterations in brachypodism mice due to mutations in anew member of the TGFb superfamily. Nature 368:639–643.

Thomas JT, Lin K, Nandetkar M, Camargo M, Cervenka J, Luyten FP(1996): A human chondrodysplasia due to a mutation in a TGF-b su-perfamily member. Nat Genet 12:315–317.

Thomas JT, Kilpatrick M, Lin K, Erlacher L, Lembessis P, Costa T, Tsi-pouras P, Luyten FP (1997): Disruption of human limb morphogenesisby a dominant negative mutation in cartilage-derived morphogeneticprotein-1. Nat Genet 17:58–64.

Tsipouras P, Thomas JT, Costa T, Kilpatrick MW, Cassia F, Correa Neto J,Soares Filho J, Vuckov A, Lembessis P, Quelce-Salgado A, Luyten FP(1996): Acromesomelic dysplasia Grebe-Quelce Salgado type is causedby a mutation in the cartilage-derived morphogenetic protein gene. AmJ Hum Genet 59:290.

Grebe Syndrome 529