An Autosomal Dominant or X-LinkedOsteodysplastic Disorder With SevereCervical Involvement

Stephen P. Robertson,1* Robert Dickens,2 Ravi Savarirayan,1 and John G. Rogers1

1Victorian Clinical Genetics Service, Royal Children’s Hospital, Parkville, Victoria, Australia2Department of Orthopaedics, Royal Children’s Hospital, Parkville, Victoria, Australia

A disorder affecting bone and cartilagegrowth is described in a mother and her3-year-old son. A dysplastic process involv-ing the vertebral bodies, most pronouncedin the cervical region and leading to cervi-cal dislocation in the first of these two pa-tients, is the most significant complicationof this disorder. This entity appears unre-lated to other previously described skeletaldysplasias with cervical kyphosis as a majormanifestation. This disorder is most likelyautosomal dominant. Am. J. Med. Genet. 83:17–22, 1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: osteodysplasia; cervical dis-location; skeletal dysplasia

INTRODUCTIONCervical kyphosis is a described component of sev-

eral skeletal dysplasias and can represent a threat tothe neurological integrity of patients with these disor-ders [Lachman, 1997]. We report on a mother and sonwith a skeletal dysplasia that is dominantly transmit-ted and has cervical kyphosis as a prominent manifes-tation. Additional characteristics include milder in-volvement of the thoracic spine caudal to the cervicalspine, an abnormal pelvis, hypoplastic distal phalan-ges, and dysplasia of some extra-skeletal cartilaginousstructures such as the pinnae of the ears and the tra-cheobronchial tree that suggest a generalized disorderof bone and cartilage growth.

CLINICAL REPORTSPatient 1

Patient 1, the fourth child of healthy nonconsan-guineous parents, was born after a normal pregnancy

and delivery. Paternal height was 183 cm and mater-nal height was 170 cm. Two brothers and a sister werewell and of normal stature. Birth weight was 2,500 g(<3rd centile), and length was 46 cm (3rd centile). Atbirth her pinnae were prominent and cupped with ab-sent lobes, and her external auditory canals weresmall. Brachydactyly of hands and feet with hypoplasiaof the distal phalanges was present. The thumbs wereboth proximally inserted, toenails and fingernails as-sumed a clubbed appearance, and there was interdigi-tal webbing in the hands. Bilateral talipes equinovaruswas present and required several operations.

Abnormalities in the cervical spine were first appre-ciated at age 3 years (Fig. 1A). A marked cervical ky-phosis developed principally because of block disloca-tion of the upper cervical vertebrae from C6 rostrally(Fig. 1B). There was an associated deficiency of theposterior elements of vertebrae C1–5 (Fig. 1C). Exces-sive atlanto-axial mobility was present with the odon-toid process appearing hypoplastic and mobile on flex-ion-extension lateral radiographs. Other skeletal ab-normalities apart from those in the cervical spine werealso present. Both radial heads became dislocated andwere excised. The knee joints were noted to be hyper-extensible. A thoracolumbar scoliosis was evident fromage 12 years with the apex of the curve being located atT12-L1 with underlying dysplasia of the vertebral bod-ies. The interpedicular distance in the thoracolumbarspine was widened, and the pelvis was hypoplastic andvertically orientated (Fig. 2).

Progressive dislocation at the C5/C6 level led to theperformance of a spinal fusion using a bone graftingprocedure at age 13 years with a good functional result.Subsequently the spine has demonstrated no clinicalevidence of instability and there have been no furtherjoint dislocations or fractures. No neurological deficitwas demonstrable at any stage.

Her postoperative course was complicated by tra-cheobronchomalacia that was demonstrated endoscopi-cally. There was excessive collapse of both the lowertrachea and both main bronchi on inspiration. Follow-ing her recovery, no problems with upper airway col-lapse or stridor have been encountered. Height and

*Correspondence to: Dr. Stephen Robertson, Victorian ClinicalGenetics Service, Royal Children’s Hospital, Flemington Rd.,Parkville 3052, Victoria, Australia. E-mail: robertss@cryptic.rch.unimelb.edu.au

Received 18 August 1998; Accepted 4 November 1998

American Journal of Medical Genetics 83:17–22 (1999)

© 1999 Wiley-Liss, Inc.

weight have tracked along the 3rd centile and headcircumference has followed the 2nd centile. Presentlyat age 34 years, she has delivered two children vagi-nally. Her intellect is normal. Her peripheral bloodkaryotype was 46,XX.

Patient 2

The first child of patient 1 was born at 35 weeks ofgestation from a nonconsanguineous union. An ultra-sound scan at 18 weeks of gestation demonstrated tali-

Fig. 1. Radiographs of the cervical spine of patient 1. A: Lateral view atage 3 years. Dysplasia of all elements of vertebral bodies C1- C7 causing alordotic deformity. The odontoid process is hypoplastic. B: Progression atage 13 years. Block dislocation has occurred at the C5/C6 junction with aresultant worsening of the now kyphotic deformity. No neurological com-promise was clinically evident. C: Anterior-posterior open-mouth view. De-ficiency of the posterior elements of the upper cervical vertebral arches.

18 Robertson et al.

pes equinovarus. Birth weight was 2.3 kg (25th cen-tile). He had the same cup-shaped ears with absentlobes as his mother, as well as brachydactyly, clubbednails, and hyperextensible knees. Additional anomaliesincluded a bicuspid aortic valve, glandular hypospa-dias, and a single midline maxillary frenulum. He hadlaryngeal stridor that resolved spontaneously beforeage 12 months.

Radiographs performed at age 6 months showedplatyspondyly of the thoracic and cervical vertebralbodies, a cervical lordosis caused by vertebral body dys-plasia without accompanying subluxation or disloca-tion, and a thoracolumbar kyphosis (Fig. 3A, 3B). Theinterpedicular distances in the thoracolumbar spinewere widened. The distal phalanges on both hands andfeet were hypoplastic (Fig. 3C). The pelvis demon-strated less hypoplasia than was evident in patient 1(Fig. 3D). No accessory calcaneal ossification centrewas evident radiologically and neither mother nor sonhas midface hypoplasia or other minor anomalies.

Presently aged 31⁄2 years, his neurodevelopment isnormal and his height and weight track between the3rd and 10th centiles.

DISCUSSION

This mother and son demonstrate a generalized os-teodysplasia that manifests most severely in the spine.

Both individuals exhibit dysplasia of the cervical ver-tebral bodies leading to a kyphosis and deficiency of theposterior elements. The presence of excessive caudalwidening of the spinal canal, kyphoscoliosis, talipesequinovarus, and abnormalities of the phalanges in thehands and feet of both patients suggest that a heritablecondition with widespread phenotypic manifestationsis present in these two patients.

Several other skeletal dysplasias have been reportedthat are characterized principally by a dysplastic cer-vical spine with resulting kyphosis (Table I), but theyare either lethal or demonstrate anomalies distinctfrom those described in this report. Lethal entities suchas atelosteogenesis, de la Chapelle dysplasia, and cam-pomelic dysplasia have severe deformities of the longbones among other differentiating findings and can beset apart from this milder form of chondro-osseousdys-plasia.

The presence of extraskeletal malformations such asabnormal ears, tracheobronchomalacia, and a bicuspidaortic valve in this family suggest these abnormallyformed cartilaginous structures are components of thephenotype and are related to the skeletal deformities.In this respect this entity shares elements with dias-trophic dysplasia [Horton et al., 1978] in which a defectin a sulfate transporting protein leads to deformities inskeletal and cartilaginous structures including cervicalkyphosis. Although it is conceivable that a similar mo-

Fig. 2. Other skeletal manifestations in patient 1, age 6 years. Radiographs of the hands (A) and feet (B) showing brachyphalangy. The distalphalanges of the toes are hypoplastic. C: Vertically orientated pelvis with hypoplastic iliac wings. The interpedicular distance in the lumbralised S1vertebrae is increased.

Dominant Cervical Kyphosis 19

Fig. 3. Radiographic findings in patient 2, the son of patient 1, age 2 years. A: Dysplastic vertebrae C1-C7are evident. No subluxation or clinical evidence of neurological compromise is present. B: Lateral thoraco-lumbar spine demonstrating platyspondyly. C: Right hand. No clear evidence of brachydactyly. D: Normalpelvis.

lecular defect may underlie this family’s disorder, itsdominant transmission and the lack of disorganizationof metacarpal and phalangeal ossification, chevron de-formities in the distal femora and tibia, haematomataof the pinnae and proximally inserted, and abductedthumbs, exclude diastrophic dysplasia as the diagnosisin this instance.

The most common syndrome to demonstrate severecervical spine dysplasia is Larsen syndrome [Larsen etal., 1950], in which defects in vertebral segmentationand deficiency of the posterior arches are frequentlyencountered and can lead to cervical dislocation andthe need for surgery to prevent neurological compro-mise [Muzumdar et al., 1977; Bowen et al., 1985; LeMarec et al., 1994; Johnson et al., 1996]. Although dis-located radial heads, hyperextensible knee joints, tali-pes equinovarus deformities, and laryngotracheomala-cia are found within this family and in Larsen syn-drome, the latter condition has more extensive jointdislocations and a characteristic facial and radio-graphic craniofacial appearance and therefore is not atenable diagnostic possibility in this instance [Larsenet al., 1950].

Spondyloepiphyseal dysplasia also involves odontoidhypoplasia and cervical kyphosis but the presence ofsensorineural deafness, myopia, and delayed ossifica-tion of the femoral and tibial epiphyses in these pa-tients places them apart from the family reported here[Spranger and Langer, 1970]. Rarer entities such asBurton syndrome [Burton et al., 1986], oto-facio-cervical syndrome [Fara et al., 1967], and Rolland-Desbuquois syndrome [Rolland et al., 1972] all of which

have dysplastic vertebral bodies leading to kyphotic de-formities in the cervical region also have other skeletaland minor anomalies that separate them from theclinical entity described in this report.

Berk and Tabatznik [1961] have outlined a disorderthat encompasses cervical kyphosis secondary to ante-rior wedging and subluxation of the vertebral bodiestogether with distal phalangeal hypoplasia. Additionalanomalies included spasticity and optic atrophy. Jointhyperextensibility and cartilaginous involvement werenot present in both patients reported so far with thissyndrome, and therefore it is clinically distinct fromthe condition presented here [Berk and Tabatznik,1961; Hartwell et al., 1988].

Speculation as to the pathogenesis of this disorder islimited by the nonavailability of chondro-osseous his-tology. It is most likely an autosomal dominant condi-tion as both sexes appear to be equally affected al-though a sex-linked disorder cannot be formally ex-cluded. There is some resemblance to disorders causedby defects in type II collagen and the diastrophic dys-plasia sulfate transport protein but additional elucida-tion of this disorder must await additional histologicaland biochemical tests.

REFERENCES

Berk ME, Tabatznik B. 1961. Cervical kyphosis from posterior hemiverte-brae with brachyphalangy and congenital optic atrophy. J Bone JointSurg 43B:77–86.

Bowen JR, Ortega K, Ray S, MacEwen GD. 1985. Spinal deformities inLarsen syndrome. Clin Orthop 197:159–163.

Burton BK, Sumner T, Langer LO, Rimoin DL, Adomian GE, Lachman RS,

TABLE I. Syndromes, Demonstrating, Cervical Kyphosis

Syndrome MIM Reference Inheritance and phenotype

LethalAtelosteogenesis II (de la

Chapelle dysplasia)256050 Sillence et al., 1997 AR. Severe micromelia, undermodeled tubular

bones, pulmonary hypoplasiaCampomelic dysplasia 211970 Coscia et al., 1989

Lee et al., 1972AD. Bowed long bones, cutaneous dimpling,

hypoplastic scapulae, cleft palateLethal Larsen-like syndrome 245650 Chen et al., 1982 AR. Severe laryngotracheomalacia, pulmonary

hypoplasia, large joint dislocationsNonlethal

Berk-Tabatznik syndrome Berk and Tabatznik, 1961 Optic atrophy, distal phalangeal hypoplasia,spasticity, normal cognition

Burton syndrome 245160 Burton et al., 1986 AR. Pursed lips, microstomia. bowed long bones,ectopia lentis, short and broad pelvis;Kniest-like epiphyses and metaphyses

Diastrophic dysplasia 222600 Krecak and Starshak, 1987 AR. Short stature, kyphoscoliosis, disorganisedossification of metatarsals and metacarpals,pinna hematomas, abducted thumbs, chevrondeformity distal long bones, cleft palate

Larsen syndrome 24560 Topley et al., 1994 AD and AR. Joint dislocations, dished-out150250 Larsen et al., 1950 midface, cleft palate; internal organ

malformations and vertebral segmentationdefects are possibly more common in AR form

Oto-facio-cervical syndrome 166780 Fara et al., 1967 AD. Long face, lacrimal duct stenosis or aplasia,branchial cysts, fistulae, deafness

Rolland Desbuquois syndrome 224400 Rolland et al., 1972 Short broad long bones, enlarged stiff joints,dysmorphism, vertebral dyssegmentation

Spondylo epiphyseal dysplasiacongenita

183900 Spranger and Langer, 1970 Flat facies, myopia, cleft-palate, platyspondylykyphoscoliosis, barrel chest, sensorineuralhearing loss, delayed ossification of os pubis,femoral and tibial epiphyses, talus andcalcaneus

Dominant Cervical Kyphosis 21

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Chen H, Chang C, Perrin E, Perrin J. 1982. A lethal, Larsen-like multiplejoint dislocation syndrome. Am J Med Genet 13:149–161.

Coscia MF, Bassett GS, Bowen JR, Ogilvie JW, Winter RB, Siminton SC.1989. Spinal abnormalities in camptomelic dysplasia. J Pediatr Orthop9:6–14.

Fara M, Chlupackova V, Hrivnakova J. 1967. Dysmorphia oto-facio-cervicalis familiaris. Acta Chir Plast 9:255–268.

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Horton WA, Rimoin DL, Lachman RS, Skovby F, Hollister DW, SprangerJ, Scott CI, Hall JG. 1978. The phenotypic variability of diastrophicdysplasia. J Pediat 93:609–613.

Johnson CE, Birch JG, Daniels JL. 1996. Cervical kyphosis in patients whohave Larsen syndrome. J Bone Joint Surg 78A:538–545.

Krecak J, Starshak RJ. 1987. Cervical kyphosis in diastrophic dwarfism:CT and MR findings. Pediatr Radiol 17:321–322.

Lachman RS. 1997. The cervical spine in the skeletal dysplasias and as-sociated disorders. Pediatr Radiol 27:402–408.

Larsen LJ, Schottstaedt ER, Bost FC. 1950. Multiple congenital disloca-

tions associated with characteristic facial abnormality. J Pediatr 37:574–581.

Lee FA, Issacs H, Strauss J. 1972. The ’camptomelic’ syndrome: Shortlife-span dwarfism with respiratory distress, hypotonia, peculiar facies,and multiple skeletal and cartilaginous deformities. Am J Dis Child124:485–496.

Le Marec B, Chapuis M, Treguier C, Odent S, Bracq H. 1994. A case ofLarsen syndrome with severe cervical malformations. Genet Counsel5:179–181.

Muzumdar AS, Lowry RB, Robinson CEG. 1977. Quadriplegia in Larsensyndrome. BD:OAS. Vol. 13(3C). New York: Alan R. Liss, Inc. for theNational Foundation - March of Dimes. p 202–211.

Rolland JC, Laugier J, Grenier B, Desbuquois G. 1972. Nanisme chondro-dystrophique et division palatine chez un nouveau-ne. Ann Pediat 19:139–143.

Sillence DO, Worthington S, Dixon J, Osborn R, Kozlowski K. 1997. Atelo-steogenesis syndromes: A review, with comments on their pathogen-esis. Pediatr Radiol 27:388–396.

Spranger JW, Langer LO. 1970. Spondyloepiphyseal dysplasia congenita.Radiology 94:313–322.

Topley JM, Varady E, Lestringant G. 1994. Larsen syndrome in siblingswith consanguineous parents. Clin Dysmorph 3:263–265.

22 Robertson et al.