37 Med Genet 1995;32:370-374

Syndrome of the month

Craniometaphyseal dysplasia (CMD),autosomal dominant form

P Beighton

The autosomal dominant form of cranio-metaphyseal dysplasia (CMD) (MIM 123000)is a well defined disorder in which mild tomoderate overgrowth of the craniofacial bonesleads to asymmetry of the mandible, cranialnerve compression, variable hearing loss, andfacial palsy. Between 50 to 100 affected personshave been documented, including several largemultigeneration families.The autosomal recessive form of CMD

(MIM 218400) is a rare, severe condition inwhich marked bone overgrowth leads to dis-tortion of the facies with blindness, deafness,and facial palsy. Fewer than 10 cases havebeen reported and syndromic boundaries areill defined.

Historical backgroundIn 1954 Peter Jackson, an English physicianon the staff of Groote Schuur Hospital, Uni-versity of Cape Town, took a fellowship inendocrinology with Fuller Albright at Mas-sachusetts General Hospital, Boston. As part ofa study of constitutional and metabolic skeletal

disease, Jackson, Albright, and colleagues re-viewed disorders of osseous modelling andidentified a specific syndrome which compriseddysplasia of the metaphyses, sclerosis of thebase of the skull, and overgrowth of the cranio-facial bones. They culled five previously re-ported cases, added two of their own, andtermed the condition "craniometaphyseal dys-plasia". l Of the five previously reportedpatients, three had been designated "os-teopetrosis" and two "leontiasis ossea". (Thisarchaic, non-specific descriptive term pertainsto a "lion-like facies", which has many causesand it does not denote any particular disorder.)

Following the delineation of CMD, Moriand Holt' documented three affected persons,using the title "familial metaphyseal dysplasia".One of these patients had three affected rel-atives, with generation to generation trans-mission. Subsequently, Spranger et al' reporteda similar family, while other authors describedsporadic cases or sets of sibs with a muchmore severe form of the condition, in whichinheritance was apparently autosomal re-cessive." The nosological situation was cla-rified in 1969, when Gorlin et al,8 in theirseminal review of the sclerosing bone dys-plasias, clearly established the separate syn-dromic identity of the AD and AR forms ofCMD. Since that time, there have been manyreports of CMD and it has become evident

MRC Research Unitfor Medical Genetics,Department of HumanGenetics,Medical School,University of CapeTown,Observatory 7925,South AfricaP Beighton

Figure 1 The proband, aged 39 years. He had bilateralperceptive deafness and facial weakness which had beenpresent since childhood. A mandibular recession operationhad been performed at the age of 18 years.

Figure 2 The daughter of the proband, aged 2 years.Gross paranasal bossing is evident.

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Craniometaphyseal dysplasia (CMD), autosomal dominant form

Figure 3 The brother of the proband aged 47 years. Themandible is prominent and somewhat asymmetrical. Aright sided facial palsy is present.

that the AD form is relatively mild and com-paratively common, while the AR form is rare,severe, and possibly heterogeneous.

Clinical features and natural historyIn the AD form of CMD affected personsusually enjoy good general health, stature isnormal, intellect is unimpaired, and there areno systemic ramifications. The bones are notfragile and dyshaematopoiesis does not occur.The clinical manifestations are summarisedbelow. In themselves they do not permit firmdiagnosis, for which radiographic studies arenecessary.910 The clinical and radiographic fea-tures of a family with AD CMD are depictedin figs 1 to 9.

FACIAL DISTORTIONProgressive bone overgrowth in AD CMD cancause mild to moderate mandibular pro-

gnathism and malalignment of the teeth. Bycontrast, distortion of the facies in AR CMDis very severe.The AD form of CMD may present in in-

fancy with bony paranasal bossing. This curiousfeature tends to regress with growth, and byadolescence or early adulthood it may be vir-tually absent. Some degree of nasal obstructionmay be present and mouth breathing is fre-quent.

CRANIAL NERVE COMPRESSIONBone overgrowth and sclerosis at the base ofthe skull leads to variable compression of theseventh and eighth cranial nerves. Unilateralor bilateral facial palsy may occur at any age; inearly childhood, involvement is often fluctuantbut by adulthood facial palsy may be per-manent. This complication is common but vari-able and not all persons withAD CMD developpermanent facial palsy.

If the auditory nerve and inner ear are com-promised by bone overgrowth, unilateral orbilateral deafness may develop. Involvement ofthe bony components of the middle ear andchronic otitis media and upper respiratory tractinfection owing to minor anatomical ab-normalities of the airway and sinuses may com-pound the hearing loss, which is often "mixed"in type. Fortunately, deafness, if present at all,is usually partial and rarely profound.

In AR CMD, cranial nerve compression issevere, and in addition to facial palsy and deaf-ness, visual loss may result from involvementof the optic nerve. This latter complicationdoes not occur in AD CMD.

RAISED INTRACRANIAL PRESSUREHyperostosis of the calvarium leads to a po-tentially lethal rise in intracranial pressure inseveral of the sclerosing bone dysplasias, not-ably sclerosteosis and AR CMD. As the cal-varium is not significantly widened in ADCMD, this complication is rare but not un-precedented. Indeed, an affected girl knownto the author underwent craniectomy in latechildhood for this complication.

Figure 4 The affected children of the patient depicted in fig 3, from left to right at the respective ages of 3, 8, and 15years. Paranasal bossing and age related mandibular overgrowth are evident.

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Beighton

Figure 8 Anteroposterior radiograph of the knees of anaffected girl, aged 7 years. Defective modelling of the lowerfemoral metaphyses has produced a "flask shaped"configuration.

Figure 5 The proband' affected sister with her two affected children. Apart frommandibular prominence, their facies are not markedly abnormal but each had thecharacteristic radiological features.

Figure 6 Lateral skull radiograph of the affected girlaged 3 years. The base of the skull is sclerotic, and thecalvarium is similarly involved, to a lesser extent.

Figure 9 Anteroposterior radiograph of the knees of theproband' brother at the age of 47years. The lowerfemoral metaphyses are "club shaped". In distinction tothe skull, the long bones are not sclerotic; indeed, as shownin this radiograph, their cortices are thin.

Figure 7 Lateral skull radiograph of the proband, aged39 years. The base and calvarium are very sclerotic,without significant hyperostosis.

Radiographic featuresDiagnosis ofAD CMD is dependent upon therecognition of the characteristic sclerosis ofthe skull and non-sclerotic widening of themetaphyses of the tubular bones. The radio-graphic changes, which are age related, havebeen reviewed by Holt9 and Spiro et al."0

In AD CMD, the base of the skull issclerotic and the calvarium is similarly affectedto a lesser degree. In adulthood, sclerosismay be especially evident along the cranialsutures. The air sinuses may be obliteratedand paranasal bony bossing, which is mostevident in early childhood, may give aspurious appearance of hypertelorism. Man-

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Craniometaphyseal dysplasia (CMD), autosomal dominant form

Clinical and radiological features of the craniometaphyseal dysplasias and Pyle diseaseCMD CMD PyleAD type AR type disease

Reported cases 50+ 10+ 20+Clinical features

Facial distortion + + + +Cranial nerve palsy + + +Bone fEragility +

Radiographic featuresCranial sclerosis + + + + + +Modelling defects in long bones + + + + +Configuration of distal femora Club shaped Club shaped Erlenmayer flask

dibular prognathism and asymmetry may alsobe present.Widening of the metaphyses of the long

bones is a major feature of CMD. These bonesare not sclerotic, and in the affected regionsthe cortices are thin. These changes are mostobvious at the lower end of the femur whichhas an "Erlenmeyer flask" configuration inchildhood and a "club" shape in adulthood.The spine and pelvis are normal and in the

chest the only significant changes are very mildmodelling defects of the medial portions of theclavicles and costochondral junctions.

In ARCMD the radiographic manifestationsare severe, especially in the skull, which issclerotic and hyperostotic. The metaphyses ofthe long bones are widened, but not sclerotic;the skeleton is otherwise essentially normal.

Differential diagnosisCMD has been the source of considerablesemantic confusion. In particular, the term"metaphyseal dysplasia" has been applied toPyle disease, which is a distinctive AR conditionwith gross metaphyseal expansion, but lackingany significant cranial sclerosis" 12 (table). Aspreviously mentioned, the non-specific de-scriptive term "leontiasis ossea" has been ap-plied to persons with the severe AR CMD.In the same way, the term "osteopetrosis" or"Albers-Sch6nberg" disease has often beenused in a non-specific sense for many sclerosingbone dysplasias, including CMD.'3

Other conditions which bear some re-semblance to CMD include craniodiaphysealdysplasia (CDD), AD and AR forms, fronto-metaphyseal dysplasia, and sclerosteosis. Thesedisorders can all be distinguished radiologicallyby the extent and anatomical distribution ofthe skeletal changes.'4 The AR form of CMDmust be distinguished from conditions in whichovergrowth of the craniofacial skeleton is ex-treme; the AR type of CDD is the most com-mon of these rare entities.

GeneticsAutosomal dominant transmission of CMDwas present in a kindred reported by Ko-mins,'5 in which four affected persons in twogenerations were documented under the er-roneous title "Familial metaphyseal dysplasia(Pyle disease)". A multigeneration family withCMD was also reported by Mori and Holt2under the same misnomer. A father and daugh-ter with the condition were described by Stool

and Caruso,'6 and in 1979 Beighton et al'7published an account of 15 affected persons infive generations of a South African family ofBritish stock. Other reports concerned a Mex-ican family with typical AD CMD in threegenerations'8 and an Australian kindred withnine affected persons in four generations.'9 An-other large kindred with AD CMD was doc-umented by Rimoin et al20 but the correct title"craniometaphyseal dysplasia" was marred bythe addition of the erroneous eponymic term"Pyle disease".

In all the above mentioned families, the ratiosof males to females and affected to unaffectedpersons were in general conformity with auto-somal dominant inheritance; equally there wereseveral instances ofmale to male transmission.2'There was no obvious sex influence on pheno-typical expression, but some variation in se-verity was evident in several of the affectedfamilies. Indeed, in the Mexican family'8 atleast two persons were unaware that they wereaffected until the diagnosis was confirmed byradiological demonstration of metaphysealwidening.The AR form of CMD is rare, ill defined,

and probably heterogeneous, and often difficultto diagnose with precision.6 Nevertheless in thefew reports concerning this disorder or groupof disorders, there is good evidence for ARinheritance. Parental consanguinity has beenmentioned5 and sets of affected sibs have beennoted.4622 Additional stigmata which may in-dicate further heterogeneity include wormianbones23 and bone fragility.24 The syndromicsignificance of complications such as isolatedaccounts of hydrocephalus,25 cervical spine de-formity,26 and mental retardation27 is uncertain.There are several reports of sporadic patients

with severe CMD; it is likely that many ofthemhave the AR form, but in the absence ofpositivegenealogical data, and in view of the pheno-typical variability, it is difficult for this diagnosisto be clinched.

Basic defectThe nature of the basic defect in AD CMD isunknown. The cranial sclerosis and the ab-normal modelling of the metaphyses have beenattributed to the defective osteoclastic activitybut at present this view is speculative.28

In AR CMD the metabolic responses of twoaffected children to therapy with calcitonin29and calcitrol30 may indicate that the basic defectinvolves dysfunctional osteoclasts. This issueis clouded, however, by problems concerning

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Beighton

possible heterogeneity and these observationsmust be interpreted with caution. The pa-thophysiology of CMD was investigated in anaffected boy aged 3 years, possibly with ARCMD, by Yamamoto et al.3 Using specificmonoclonal antibodies these workers showedthat osteoclast-like cells derived from the bonemarrow lacked expression of the osteoclast va-cuolar proton pump.A possible clue to the chromosomal location

of the faulty gene in CMD is provided by theobservation of an affected female child with atranslocation between chromosomes 12 and18, with the regions ql3;ql2 being involved.26As with many sporadic examples of CMD,however, it is uncertain which form of thedisorder was implicated.

I am grateful to Mrs Gillian Shapley and Mrs Greta Beightonfor typing the manuscript. This work was supported by grantsfrom the Medical Research Council for South Africa, the CooperLowveld Foundation, the Mauerberger Foundation, and theUniversity of Cape Town Staff Research Fund. The illustrationsin this article are derived from Beighton P, Hamersma H, HoranF. Clin Genet 1979;15:252-258 and Beighton P, Cremin B.Sclerosing bone dysplasias. Heidelberg: Springer. They are re-produced with the publishers' permission.

1 Jackson WPU, Albright F, Drewery G, Hanelin J, Rubin ML.Metaphyseal dysplasia, epiphyseal dysplasia, diaphysealdysplasia and related conditions. Arch Intern Med 1954;94/6:871-85.

2 Mori PA, Holt JF. Cranial manifestations of familial me-taphyseal dysplasia. Radiology 1956;66:335-43.

3 Spranger J, Paulsen J, Lehmann W. Die kraniometaphysaereDysplasie (Pyle) Z Kinderheilkd 1965;93:64-79.

4 Lehmann ECH. Familal osteodystrophy of the skull andface. .7 Bone 3toint Surg (Br) 1957;39:313-15.

5 Lievre JA, Fischgold DH. Leontiasis ossea chez l'enfant(osteopetrose partielle probable). PresseMed 1956;64:763-5.

6 Millard DR, Maisels DD, Batsone JHF, Yates BW. Cranio-facial surgery in craniometaphyseal dysplasia. Am Surg1967;113:615-21.

7 Ross MW, Altman DH. Familial metaphyseal dysplasia.Review of the clinical and radiologic features of Pyle'sdisease. Clin Pediatr 1967;63:143-9.

8 Gorlin RJ, Spranger J, Koszalka MF. Genetic craniotubularbone dysplasias and hyperostoses. A critical analysis. BirthDefects 1969;5(4):79-95.

9 Holt JF. The evolution of crani-metaphyseal dysplasia. AnnRadiol (Paris) 1966;9:209-14.

10 Spiro PC, Hamersma H, Beighton P. Radiology of the

autosomal dominant form of craniometaphyseal dysplasia.S Afr Med_. 1975;49:839-42.

11 Heselson NG, Raad MS, Hamersma H, Cremin BJ,Beighton P. The radiological manifestations of meta-physeal dysplasia (Pyle disease). Br3rRadiol 1979;52:431-40.

12 Raad MS, Beighton P. Autosomal recessive inheritance ofmetaphyseal dysplasia (Pyle disease). Clin Genet 1978;14:251-6.

13 Beighton P, Horan F, Hamersma H. A review of the os-teopetroses. Postgrad Med ] 1977;53:507-16.

14 Greenspan A. Sclerosing bone dysplasias - a target-siteapproach. Skeletal Radiol 199 1;20:561-83.

15 Komins C. Familial metaphyseal dysplasia (Pyle's disease).Br ] Radiol 1954;27:670-5.

16 Stool SE, Caruso VG. Cranial metaphyseal dysplasia. ArchOtolaryngol 1973;97:410.

17 Beighton P, Hamersma H, Horan F. Craniometaphysealdysplasia - variability of expression within a large family.Clin Genet 1979;15:252-8.

18 Camevale A, Grether P, del Castillo V, Takenaga R, Or-zechowski A. Autosomal dominant craniometaphysealdysplasia. Clinical variability. Clin Genet 1983;23:17-22.

19 Taylor DB, Sprague P. Dominant craniometaphyseal dys-plasia - a family study over five generations. AustralasRadiol 1989;33:84-9.

20 Rimoin DL, Woodruff SL, Holman BL. Craniometaphysealdysplasia (Pyle's disease): autosomal dominant inheritancein a large kindred. Birth Defects 1969;4:96-104.

21 Bricker SL, Langlais RP, van Dis ML. Dominant cranio-metaphyseal dysplasia. Literature review and case report.Dentomaxillofac Radiol 1983;12:95- 100.

22 Penchaszadeh VB, Gutierrez ER, Figueroa E. Autosomalrecessive craniometaphyseal dysplasia. Am .7 Med Genet1980;5:43-55.

23 Langer LO Jr, Brill PW, Afshani E, Williams CA, Thomas IT,Frias JL. Radiographic features of craniometadiaphysealdysplasia, wormian bone type. Skeletal Radiol 1991;20:37-41.

24 Ventruto V, Ametrano 0, D'Avanzo G, et al. A case ofautosomal recessive form of craniometaphyseal dysplasiawith unusual features and with bone fragility. AustralasRadiol 1987;31:79-82.

25 Hudgins RJ, Edwards MS. Craniometaphyseal dysplasiaassociated with hydrocephalus: case report. Neurosurgery1987;20:617-18.

26 Yamada H, Yamanaka T, Tanaka Y, Nakamura S. Cervicalspinal deformity in craniometaphyseal dysplasia. Surg Ne-urol 1987;27:284-290.

27 Portnov VA, Marincheva GS, Gorbachevskaia NL. Familialcraniometaphyseal dysplasia associated with mental re-tardation. Zh Nevropatol Psikhiatr 1985;85:404-9.

28 Cole DE, Cohen MM Jr. A new look at craniometaphysealdysplasia. 7 Pediatr 1988;112:577-9.

29 Fanconi S, Fischer JA, Wieland P, et al. Craniometaphysealdysplasia with increased bone turnover and secondaryhyperparathyroidism: therapeutic effect of calcitonin. 7Pediatr 1988;112:587-91.

30 Key LL Jr, Volberg F, Baron R, Anast CS. Treatment ofcraniometaphyseal dysplasia with calcitriol. JPediarr 1988;112:583-7.

31 Yamamoto T, Kurihara N, Yamaoka K, et al. Bone marrow-derived osteoclast-like cells from a patient with cranio-metaphyseal dysplasia lack expression of osteoclast-re-active vacuolar proton pump. Clin Invest 1993;91:362-7.

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