Temporal Aspects in Craniometaphyseal Dysplasia:Autosomal Recessive Type

Nursel Elcioglu2 and Christine M. Hall1*1Department of Radiology, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom2Department of Medical Genetics, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey

We present the clinical and radiographicfindings in a patient with the autosomal re-cessive form of craniometaphyseal dyspla-sia (CMD). The changes from infancy to theage of 17 years are illustrated and dis-cussed. Am. J. Med. Genet. 76:245–251, 1998.© 1998 Wiley-Liss, Inc.

KEY WORDS: craniotubular dysplasias;craniometaphyseal dysplasia(recessive type); bone sclero-sis; hyperostosis

INTRODUCTION

Craniometaphyseal dysplasia (CMD) is a rare disor-der of bone modelling characterised by sclerosis of theskull base, vault and facial bones, and metaphysealwidening of tubular bones. The initial symptoms oftenare progressive nasal obstruction and facial distortion.Bilateral facial weakness and progressive deafnessmay be other childhood signs. Intelligence is usuallynormal. In most families, the trait shows autosomaldominant inheritance although autosomal recessive in-heritance has been observed. The recessive form ap-pears to be more severe than the dominant. Cranialnerve deficits have been reported in infancy and earlychildhood in a few patients, but the evolution of thefindings in recessive CMD is not well documented [Gor-lin, 1994; Beighton, 1995].

We report the natural history of the skeletal changesin a 17-year-old boy with recessive CMD recognised at5 months because of optic nerve compression and in-creased bone density.

CLINICAL REPORT

The patient (RC) is the third child of healthy, non-consanguineous parents. The other children were well.

There is no family history of bone disease. He was bornnormally at term and weighed 3.7 kg with a head cir-cumference of 37 cm. Pregnancy and neonatal periodwere uneventful. He was first admitted at 3 months forfailure to thrive. At this stage, a skeletal surveyshowed some osteosclerosis and apparent widening ofhis sutures, consistent with the large head circumfer-ence. On admission at 4 1/2 months, his weight was onthe 3rd centile and head circumference (44.5 cm) was>98th centile. At this stage the optic discs were paleand there was unsteady fixation with intermittentsquint. There was bony encroachment on the optic fo-ramina and compression of the optic nerves. Repeatedvisual evoked responses (VER) showed marked dete-rioration and he underwent right optic nerve decom-pression but the VER showed no substantial change.

By the age of 10 months his weight (7.45 kg) andheight (68.4 kg) were both <3rd centile and his headcircumference (48 cm) >98th centile. He had a largehead with prominent forehead and abnormally broadand high bridge of his nose. A right divergent strabis-mus and rotatory nystagmus were present. There wasbilateral optic atrophy and he was only able to follow abright light. Repeated computed tomography of thehead showed progressive enlargement of the lateralventricles and a wide subarachnoid space. A ven-triculo-peritoneal shunt was inserted when he was 20months old. His height and weight were <10th centilebut the head circumference remained >98th centile.

Because of conductive hearing loss, grommets wereinserted at the age of 5 years and T-tubes at the age of6 years. By the age of 7 years, he could not hear normalspeech when there was any background noise, and lan-guage development was delayed.

On review at the age of 17 years, he was alreadyregistered as blind and had bilateral hearing loss forwhich he wore hearing aids. He had frontal and para-nasal bossing, a broad flat nasal bridge with a saddledeformity, and hypertelorism. He had malocclusionwith an open mouth posture (Fig. 1a,b). The palate washigh and narrow with an acquired large central fistula.The posterior part of the gums almost met in the mid-line so that they formed a closed horse-shoe, as a resultof the marked hyperostosis. His speech developmentwas normal apart from difficulties with some soundsgiving a muffled quality and hyponasal resonance. Hewas able to follow conversations and respond to ques-

*Correspondence to: Dr. Christine M. Hall, Department of Ra-diology, Great Ormond Street Hospital for Children NHS Trust,London WC1N 3JH, United Kingdom.

Received 11 September 1997; Accepted 7 November 1997

American Journal of Medical Genetics 76:245–251 (1998)

© 1998 Wiley-Liss, Inc.

tions appropriately and produced connected discoursewith a good sequencing of ideas. He was well settled ata school for physically handicapped children.

Radiological Findings

In the skull at all ages the base was sclerotic withovergrowth (Fig. 2a,b). However the vault showed pro-gressive hyperostosis, which at the age of 17 was mostpronounced in the frontal and occipital regions with avery large occipital tubercle. There was also bony en-croachment around the orbital margins and around thenasal bone causing hypertelorism. At no stage were theparanasal sinuses aerated. The mandible initially, atthe age of 4 1/2 months, showed only sclerosis, butprognathism became more pronounced due to massiveovergrowth. By the age of 17 years many of the secondteeth had been lost and the lamina dura around theroots of the teeth could not be identified. Althoughovergrowth of the maxillae was also present, the man-dibular hyperostosis became disproportionately pro-nounced (Fig. 3). CT head scans showed a striking in-crease in vault thickening.

In the spine at the age of 4 1/2 months the configu-ration of the vertebrae was normal, but there was sig-nificant sclerosis of the central vertebral bodies, and toa lesser extent of the neural arches. The vertebral end-plates and the anterior and posterior margins of thebodies were of normal of density giving rise to a ‘‘bone-in-bone’’ appearance. By the age of 17 years, the ver-tebral bodies appeared entirely normal but the pediclesand laminae were sclerotic and the spinous processeslarge (Fig. 4a,b).

In the chest, the ribs showed progressive expansion

changing from a normal contour in early infancy tobeing extremely wide by 17 years (Fig. 5a,b). The ex-pansion spared the posterior costo-vertebral ends of theribs. In parallel with change in size there was a pro-gressive decrease in bone density, from sclerosis inearly infancy to normal density by 17 years. Theclavicles initially showed minor expansion and sclero-sis of the middle thirds, but by the age of 2 years, theexpansion and sclerosis was more pronounced, involv-ing the medial two thirds of the clavicles. At 17 yearsthe clavicles were expanded medially with a thinnedcortex and relative osteopenia.

In infancy the iliac wings had sclerosis centrally andindistinct, ‘‘frayed’’ margins. In the upper femora, simi-lar changes were present with sclerotic diaphyses, butosteoporotic, frayed metaphyses (Fig. 6a). By 17 years,the pelvis was normal, with only an isolated bone is-land in the right intertrochanteric region (Fig. 6b).

The long bones showed progressive diminution ofbone density from dense diaphyseal sclerosis in infancyto osteoporosis by the age of 17 years. In infancy thecortex of the diaphyses appeared thickened and irregu-lar, with obliteration of the medullary cavities and themetaphyses were frayed, flared, and poorly ossified.The sclerosis gradually decreased and was seen as re-sidual ‘‘ghosts’’ in the diaphyses. There was progressiveexpansion associated with undermodelling, thinning ofthe cortex and osteoporosis. By the age of 2 years, themetaphyses were no longer frayed. An appearance ofperiosteal reactions along the diaphyses was related tonew bone of normal density growing around the scle-rotic areas. By the age of 17 years, the metaphyseswere wide and the tibia had a sinuous or wavy configu-ration. There was a localised area of cortical new boneon the shaft of the fibula (Figs. 7a–d, 8a,b).

Fig. 1. a,b: Facial appearance,at 17 years. Broadening of the de-pressed nasal base with paranasalbossing, short nose, and promi-nence of the facial bones, especiallythe jaw with open mouth deformityand abnormal placed teeth. Notethe external strabismus and hear-ing aid.

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Skeletal surveys on father and mother showed noskeletal abnormality.

DISCUSSION

Craniometaphyseal dysplasia (CMD) was domi-nantly inherited in several kindreds [Beighton et al.,1979]. An autosomal recessive form is recognised but isuncommon [Penchaszadeh et al., 1980]. Without a fam-ily history, differentiation between the two is difficultin infancy and early childhood. In later childhood theradiological and clinical signs improve in the dominantform, but there is progressive overgrowth and cranio-facial deformity with marked prognathism in the re-cessive form. Both forms are characterised in infancyby sclerotic diaphyses of the long bones and by sclerosis

and overgrowth of the skull base, vault, and facialbones. The appearance of the long bones graduallychanges in both types with progressive metaphysealexpansion, cortical thinning, and osteoporosis ratherthan sclerosis. In the skull, the sclerosis and over-growth in the dominant type improves with age and theonly finding in an adult may be of sclerosis along thelines of the sutures. However, considerable intra- andinter-familial variability exists. Typically both domi-nant and recessive forms have normal spine, pelvis,and ribs, with only mild expansion of the medial endsof the clavicles. Our case in early infancy showed scle-rosis of the vertebral bodies, iliac wings, and ribs, andsubsequently there was significant expansion of theribs. This may be a reflection either of the relativelysevere expression in this particular case or that theseearly appearances, which change quite rapidly, are in-frequently documented [Beighton and Cremin, 1980].

Other craniotubular disorders have been confusedwith CMD in the literature. In Pyle disease (metaphy-seal dysplasia), the skull is almost normal and bonedensity is decreased with expanded metaphyses asso-ciated with cortical thinning. Many mild examples maynever present for medical attention. Typically there isa mild sinuous or wavy deformity of the tibia as seen inour case. This is also present in other craniotubulardisorders, such as frontometaphyseal dysplasia, andosteodysplasty (Melnick-Needles syndrome) but otherspecific radiological findings differentiate these condi-

Fig. 2. Skull radiographs. a: 4 1/2 months: Mild vault sclerosis withsevere sclerosis and bony overgrowth of skull base and maxillae. b: 13years: Right ventricular shunt present. Marked sclerosis and hyperosteosisof vault, base, and facial bones. No aeration of paranasal sinuses or mas-toid air cells.

Fig. 3. Facial view at 17 years. Pronounced prognathism due to man-dibular overgrowth with sclerosis.

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tions [Beighton and Cremin, 1980; Wynne-Davies etal., 1985; Gorlin, 1994].

In infancy, CMD requires differentiation from cra-niodiaphyseal dysplasia because of the diaphyseal scle-rosis with cortical expansion and the craniofacialchanges. However, in craniodiaphyseal dysplasia,there is severe progressive craniofacial hyperostosisand the diaphyses show expansion with sparing of themetaphyses [Beighton and Cremin, 1980].

Management of patients with craniotubular disor-ders, especially those at the severe end of the spectrumwith massive craniofacial hyperostosis causing signifi-cant morbidity, is extremely difficult. Surgical manage-ment has been reported [Shafer et al., 1990; Richards

et al., 1996] but the results have been variable, somepatients developing rapidly progressive hyperostosisfollowing the operation. Whether this was the normalnatural history of the disorder or a reaction to surgeryis unclear. Progressive truncal ataxia has been identi-fied as a complication in CMD, recessive type and im-provement has been documented following posteriorcranial fossa decompression [Boltshauser et al., 1996].Attempts have been made to influence the hyperostosisby medical means over the years. Therapeutic manoeu-vres have included Calcitriol therapy with low calciumintake, biphosphonates, and also somatostatin in thehope of modifying the disease. Assessment of thesetherapeutic measures has been hampered by a lack of

Fig. 4. Spine. a: 4 1/2 months. Central sclerosis of vertebral bodies giving a ‘‘bone-in-a-bone’’ appearance. Sclerosis also affects the neural arches.b: 17 years. Normal configuration and density of vertebral bodies. Marked sclerosis of pedicles and laminae and large spinous processes.

248 Elçioglu and Hall

knowledge of the natural evolution of the disorders inindividual patients but none have been associated withconvincingly beneficial results. Somatostatin may havea role in slowing the progressive hyperostosis [Rich-ards et al., 1996].

An early and accurate diagnosis and knowledge ofthe natural history of the recessive form of CMD is vitalin predicting the prognosis and instituting appropriatemanagement of complications and possible preventa-tive therapeutic regimes. Only by a better understand-ing of the temporal changes can an affected individual’soutcome be improved.

ACKNOWLEDGMENTS

The authors thank the many physicians and sur-geons involved in the care of the patient at Great Or-mond Street Hospital for Children-London, in particu-lar to Mr. B. Jones of the craniofacial unit, and to thepatient and his parents for permission to publish theclinical photographs.

Fig. 5. Thorax. a: 2 years. Expansion and sclerosis of medial two thirdsof clavicles and all the ribs. Thin cortex and decreased bone density ofupper humeral metaphyses. b: 17 years. Marked rib expansion, with rela-tive sparing of the posterior costo-vertebral ends. No sclerosis. Expansionof the medial thirds of clavicles.

Fig. 6. Pelvis. a: 4 1/2 months. Central sclerosis of iliac wings. Sclerosisalso of upper femoral diaphyses and metadiaphyses. Normal density ofpubic rami and ischia. b: 17 years. Normal bone modelling and density.Localised bone island in upper right femoral intertrochanteric region.

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Fig. 7. Limbs. a: Upper limb at 4 1/2 months. Undermodelled long bones with diaphyseal expansion, cortical irregularity, and sclerosis. Flared, frayedmetaphyses of normal or decreased bone density. b: Lower limb at 4 1/2 months. Sclerosis and mild expansion of all diaphyses. Decreased bone densityof metaphyses, epiphyses, and tarsal bones. Metaphyses flared and irregular with a frayed appearance. c: Lower limbs at 2 years. Expansion ofmetaphyses, especially lower femoral with normal bone density. Diaphyses sclerotic. d: Lower limb at 17 years. Undermodelled with mild expansion ofmetaphyses. Thinned metaphyseal cortex with osteoporosis. ‘‘S-shaped’’ or wavy configuration of tibial shaft. Localised cortical new bone on shaft of fibula.

250 Elçioglu and Hall

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Fig. 8. Hands. a: 2 years. Undermodelled, wide metacarpals and pha-langes. Sclerotic distal shafts of phalanges and discrete sclerotic foci indistal metacarpal diaphyses. Expanded metaphyses lower radius and ulnawith thin cortex. Sclerotic shafts. b: 17 years. Undermodelled short longbones with thin cortex and decreased bone density.

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