Pediatr Radiol (1994) 24:392-406

Pediatric Radiology 9 Springer-Verlag 1994

Craniotubular bone disorders R. L Gorlin Department of Oral Pathology and Genetics, University of Minnesota, Malcolm Moos Health Sciences, 515 Delaware Street S.E., Minneapolis, MN 55455, USA

Introduction 1. Craniometaphyseal dysplasia 2. Craniodiaphyseal dysplasia 3. Frontometaphyseal dysplasia 4. Craniometadiaphyseal dysplasia 5. Osteopetrosis 6. Dysosteosclerosis 7. Oculodentoosseous dysplasia (oculodentodigital syndrome) 8. Osteopathia striata 9. Autosomal dominant otosclerosis (endosteal hyperostosis, Worth type) 10. Van Buchem disease 11. Sclerosteosis 12. Progressive diaphyseal dysplasia (Camurati-Engelmann disease) 13. Hyperphosphatasemia 14. Stanescu osteosclerosis syndrome

Almost 25 years have passed since Gorlin et al. [1] classified genetic craniotubular bone dysplasias and hyperostoses. I thought it worthwhile to review this group of conditions in order to evaluate errors of judgment and to examine present biases concerning these conditions. We originally divided craniotubular dysplasias into Pyle's disease, craniometaphyseal dysplasia, craniodiaphyseal dysplasia, frontometaphyseal dysplasia, Schwarz-L61ek syndrome, osteopetrosis, dysosteosclerosis, and oculodento-osseous dysplasia. The craniotubular hyperostoses that we considered in 1969 included Van Buchem disease, sclerosteosis, congenital hyperphosphatasia, autosomal dominant osteosclerosis, and Camurati-Engelmann disease. In part, present biases have been covered by Gorlin et al. [2] and a further work is in preparation [3]. It was really Pyle's disease that initially piqued my interest. I was a neophyte in the field of bone dysplasias Correspondence to: R. J. Gorlin

and I needed to critically examine this group of disorders for the second edition of our syndrome text. A 6month visit by Jtirgen Spranger catalyzed my study. Dr. Koszalka referred to me for diagnosis the cases of two brothers with Pyle's disease for reasons that elude me, as I had never met him. To my surprise I found in the literature that all sorts of disorders were called Pyle's disease, primarily among them true metaphyseal dysplasia (Pyle) and craniometaphyseal dysplasia. At this point, I do not think of Pyle's disease as a craniotubular dysplasia as the skull is so mildly involved.

References (Introduction) 1. Gorlin RJ, Spranger L Koszalka MF (1969) Genetic craniotubular bone dysplasias and hyperostoses: a critical analysis. Birth Defects 5:79-95 2. Gorlin RJ, Cohen MM Jr, Levin LS (1990) Syndromes of the head and neck, 3rd edn. Oxford University Press, New York 3. Gorlin RJ, Toriello HO, Cohen MMJ (1995) Hereditary hearing loss and its syndromes. Oxford University Press, New York (in press)

Craniometaphyseal dysplasia This disorder, in earlier years often erroneously reported as Pyle's disease, is characterized by unusual facies and club-shaped metaphyseal flaring of long bones. Autosomal dominant [4-24] and recessive [25-34] inheritance patterns have been observed. About 80 cases have been reported [4-34].

Clinical findings

Usually within the first year of life, the root of the nose begins to broaden and an elevated wing of bone gradually extends bilaterally over the nasal bridge to the zygomas. Increasing bony sclerosis narrows the nasal lumen,

393 leading to obstruction, with resultant o p e n m o u t h [8, 9, 14]. In about 30 % of patients there is peripheral facial nerve paralysis, headache, or vertigo [4, 6, 15]. H y p e r telorism is a constant feature. Nystagmus is common. Rarely, there is visual loss because of optic atrophy [12, 15]. This suggests bony e n c r o a c h m e n t on the optic foramina. The alveolar ridges m a y be thickened. Occasionally there is delayed eruption of p e r m a n e n t teeth. B o n y alterations in the t e m p o r a l bone and pyramid produce mixed hearing loss. In about one-half of the cases, it b e c o m e s evident in childhood. It is slowly progressive until there is moderate to severe (30-90 dB) loss by the fourth decade [4, 6,

13,15]. Radiographic findings Hyperostosis and sclerosis involve the frontal and occipital portions of the calvaria, base of skull, and, less often, mandible. There is increased bone deposit on the walls of the paranasal sinuses and u n d e r p n e u m a t i z a t i o n of mastoid cells. Most m a r k e d is frontonasal hyperostosis. The ribs are widened and dense. Long bones have clubshaped m e t a p h y s e a l flare that is far milder than that seen in Pyle's disease and m a y be minimal during the first years of life. Cortical hyperostosis of diaphyses is n o t e d in t h e young, but disappears with age. Short tubular bones exhibit the same changes as those noted in long bones.

10. Guibaud R Hermier M, Ajacques JC, Beuf JR Larbre F (1973) La dysplasie cranio-m6taphysaire. Pddiatrie 28:149-161 11. Holt JF (1966) The evolution of cranio-metaphyseal dysplasia. Ann Radiol (Paris) 9:209-224 12. Jend HH (1981) Cranio-metaphyseal stratiform dysplasia conventional radiography and CT findings. Eur J Radiol 1: 261-265 13. Keitzer G, Paparella MM (1969) Otolaryngological disorders in craniometaphyseal dysplasia. Laryngoscope 79:921-941 14. Key LL, Volberg F, Baron R, Anast CS (1988) Treatment of craniometaphyseal dysplasia with calcitriol. J Pediatr 112: 583-586 15. Kletzker GR, Smith PG Kelleen TE (1989) Otolaryngologic features of craniometaphyseal dysplasia. Otolaryngol Head Neck Surg 96:548-553 16. Martin FW (1977) Craniometaphyseal dysplasia. J Laryngol Otol 91:159-169 17. Morgan DW, Aldran C, Hoare TJ (1990) Hearing loss due to cranio-metaphyseal dysplasia. J Laryngol Otol 104:807-808 18. Puliafito CA, Wray SH, Murray JE, Boger WP III (1981) Optic atrophy and visual loss in craniometaphyseal dysplasia. Am J OphthalmoI 92:696-701 19. Rimoin DL, Woodruff SL, Holman BL (1969) Cranio-metaphyseal dysplasia (Pyle's disease): autosomal dominant inheritance in a large kindred. Birth Defects 5:96-104 20. SchrOder C, Quirin A, Oppermann HC, Oldigs HD (1992) Craniometaphysfire Dysplasie - characterische R0ntgenbefunde. Klin P~idiatr 204:174-176 21. Shea J, Gerbe R, Ayane N (1981) Cranio-metaphyseal dysplasia: the first successful surgical treatment for associated hearing loss. Laryngoscope 91:1369-1374 22. Spiro PC, Hamersma H, Beighton P (1975) Radiology of the autosomal dominant form of craniometaphyseal dysplasia. S Afr Med J 49:839-842 23. Spitzer W, Steinhauser EW (1981) Die kraniometaphys~ire Dysplasie. Dtsch Zahn~irztl Z 36:96-100 24. Taylor DB, Sprague P (1989) Dominant craniometaphyseal dysplasia - a family study over five generations. Australas Radio133:87-89

Current bias E x t r e m e variability in the dominant f o r m does not allow for differentiation f r o m the recessive form. Although s o m e recessive cases a p p e a r to be m o r e severe than d o m i n a n t examples, in a sporadic case it is not possible to clinically distinguish b e t w e e n the two forms [17, 28].

References ( C r a n i o m e t a p h y s e a l dysplasia, dominant) 4. Beighton R Hamersma H, Horan F (1979) Craniometaphyseal dysplasia: variability of expression within a large family. Clin Genet 15:252-258 5. Carlson DH, Harris GBC (1972) Craniometaphyseal dysplasia: a family with three documented cases. Radiology 103:147-151 6. Carnevale A, Greither R del Castitlo V, Takenaga R, Orzechowski A (1983) Autosomal dominant craniometaphyseal dysplasia: clinical variability. Clin Genet 23:17-22 7. Colavita N, Kozlowksi K, Sprague P (1988) Cranio-metaphyseal dysplasia. Australas Radiol 32:257-262 8. Cole DEC, Cohen MM Jr (1988) A new look at craniometaphyseal dysplasia. J Pediatr 112:577-579 9. Fanconi S, Fischer JAA, Wieland R Giedion A, Bolshauser E, Olah AJ, Landolt AM, Prader A (1988) Craniometaphyseal dysplasia with increased bone turnover and secondary hyperparathyroidism: therapeutic effect of calcitonin. J Pediatr 112: 587-590

References (Craniometaphyseal dysplasia, recessive) 25. Graf K (1965) Die Bedeutung des Pyle-Syndroms (Leontiasis ossea) ftir die Oto-Rhino-Laryngologie. Z Laryngol Rhinol 44: 438445 26. Jackson WPU, Albright F, Drewry G, Hanelin J, Ruben MI (1957) Metaphyseal dysplasia, epiphyseal dysplasia, diaphyseal dysplasia and related constitutions. Arch Intern Med 94: 871-885 27. Lehmann ECH (1957) Familial osteodystrophy of the skull and face. J Bone Joint Surg [Br] 39:313-315 28. Li6vre JA, Fischgold H (1956) Leontiasis ossea chez l'enfant (osteopetrose partielle probable). Presse M~d 64:763-765 29. Millard DR, Maisels DO, Batstone JHF, Yates BW (1967) Craniofacial surgery in craniometaphyseal dysplasia. Am J Surg 113:615-621 30. Nicolo A, Briani 8 (1966) La displasia craniometafisaria. Ann Radiol Diagn 39:185-202 31. Penchaszadeh VB, Gutierrez ER, Figueroa EP (1980) Autosomal recessive craniometaphyseal dysplasia. Am J Med Genet 5:43-55 32. Ross MW, Altman DH (1967) Familial metaphyseal dysplasia: review of the clinical and radiological features of Pyle's disease. Clin Pediatr (Phila) 6:143-149 33. Sommer F (1954) Eine besondere Form einer generalisierten Hyperostose mit Leontiasis ossea faciei et cranii. Radiol Clin (Basel) 23:65-75 34. Wemmer V, B6ttger E (1978) Die kraniometaphys~ire Dysplasia (Jackson). R6fo 128:66-69

394

Craniodiaphyseal dysplasia Joseph et al. [39], in 1958, first used the term craniodiaphyseal dysplasia to designate a severe bone disorder characterized by massive generalized hyperostosis and sclerosis involving, in particular, the skull and facial bones [35, 36, 48, 38-42, 43 (case 1), 44, 47]. Kaitila et al. [41] and Kirkpatrick et al. [42] described the same case. The patient described by Gemmell [37] possibly had a mild form of the disease and the patient reported by Schaefer et al. [47] really had craniometaphyseat dysplasia of the dominant type. The movie Mask was about a patient with craniodiaphyseal dysplasia.

Clinical features Facial and cranial thickening, distortion, and enlargement are severe. Nasal obstruction and recurrent upper respiratory infection appear within the first few years or over the first few months of life. H e a d circumference is increased. Marked bony thickening, hypertelorism, nasal flattening, occlusion of lacrimal ducts, and severe dental malocclusion generally follow. Bilateral choanal stenosis can be demonstrated within the first few years. All patients have severe hypertelorism, lacrimal duct obstruction resulting from bony overgrowth, and diminished visual acuity or blindness as a result of optic atrophy. Compression of cranial nerves results from bony overgrowth. This relentless process is associated with headache, progressive mental retardation, and seizures. Developmental milestones, including speech, are delayed [37, 38, 43, 45, 46]. Often there is lack of sexual maturation. Stature has been retarded in several cases [37, 42, 49], and early death has occurred in about 50 %.

Radiographic findings The skull and facial bones as well as the mandible are severely sclerotic and hyperostotic. The paranasal sinuses and mastoids do not develop. There is moderate thickening and marked sclerosis of the ribs and clavicles. The long tubular bones do not exhibit metaphyseal flare, but rather have a policeman's nightstick shape and show diaphyseal endostosis. The short tubular bones of the hands and feet, particularly the first metapodial, exhibit cylindrization. A few investigators have found elevated levels of serum alkaline phosphatase, but normal levels of calcium and phosphorus. Hearing loss, generally mixed, has been described in almost all cases, but extensive documentation has been sparse. Halliday [38] reported sensorineural hearing deficit.

Current bias The role of inheritance is confusing. Male and female sibs were reported by de Souza [48]. The parents of

Hallidays's [38] patients were consanguineous. This would suggest autosomal recessive inheritance. However, Brueton and Winter [35] opined that the sibs described by de Souza [48] really had Van Buchem syndrome. The rest of the cases were isolated examples. We suspect that there is a great heterogeneity in this group of cases.

References (Craniodiaphyseal dysplasia) 35. Brueton LA, Winter RM (1990) Craniodiaphyseal dysplasia. J Med Genet 27:701-706 36. Fosmoe RJ, HoIm RS, Hildreth RC (1968) Van Buchem's disease (hyperostosis corticalis generalisata familiaris). Radiology 90:771-774 37. Gemmell JH (1935) Leontiasis ossea: a clinical and roentgenographical entity. Radiology 25:723-729 38. Halliday J (1949-1950) A rare case of bone dysplasia. Br J Surg 37:52-63 39. Joseph R, Lefebre J, Guy E, Job JC (1958) Dysplasie craniodiaphysaire progressive: ses relations avec la dysplasie diaphysaire progressive de Camurati-Engelmann. Ann Radiol (Paris) 1:477-490 40. Kaitila I, Stewart RE, Landow E, Lachman R, Rimoin DL (1975) Craniodiaphyseal dysplasia. Birth Defects 11:359-361 41. Kirkpatrick DB, Rimoin DL, Kaitila I, Goodman SJ (1977) The craniotubular bone modeling disorders: a neurosurgical introduction to rare skeletal dysplasias with cranial nerve compression. Surg Neurol 7:221-232 42. Levy MH, Kozlowksi K (1987) Cranio-diaphyseal dysplasia. Australas Radio131:431-435 43. Macpherson RI (1974) Craniodiaphyseal dysplasia, a disease or group of diseases? J Can Assoc Radiol 25:22-23 44. McKeating JB, Kershaw CR (1987) Craniodiaphyseal dysplasia. J R Nav Med Serv 73:81-93 45. Menichini G, Scarfo GB, Cantore GR Marchetti PG, Tomaccini D (1977) Singolare caso di malattia iperostosica del tipo "displasia cranio-diafisaria". Minerva Pediatr 29:1485-1489 46. Scarfo GB, Tomaccini D, Capaccioli L, Gambacorta D (1979) Idrocephalo associato a displasia cranio-diafisaria. Radiol Med (Torino) 65:249-252 47. Schaefer B, Stein S, Oshman D, Rennert O, Thurnau G, Walt J, Bodensteiner J, Brown O (1986) Dominantly inherited craniodiaphyseal dysplasia. A new craniotubular dysplasia. Clin Genet 30:381-391 48. Souza O de (1927) Leontiasis ossea. Porto Alegre (Brazil) Faculdade de Med Rev Dos Cursos 13:47-54 49. Stransky E, Mabelangan I, Lara RT (1962) On Paget's disease with leontiasis ossea and hypothyreosis starting in early childhood. Ann Paediatr 199:393-408

Frontometaphyseal dysplasia Gorlin and Cohen [56], in 1969, separated frontometaphyseal dysplasia from other craniotubular dysplasias. The condition consists of pronounced bony supraorbital ridges, mixed hearing loss, and generalized skeletal dysplasia. A b o u t two dozen cases have been subsequently described by numerous authors [50-55, 58-63, 65-71]. A probable earlier example is that of Lischi [64].

395

Clinical findings

Current bias

The m a r k e d supraorbital ridge, wide nasal bridge, downward slanting palpebral fissures, and small pointed chin give the patient a striking appearance. Enlargement of the supraorbital ridge becomes evident before puberty. Missing p e r m a n e n t teeth and retained deciduous teeth [51, 54, 56] may occur with most patients having malocclusion. There is both primary and secondary wasting of hand muscles. Dorsiflexion of the wrist and extension of the elbows are reduced, with pronation and supination being extremely limited. Flexion deformities of the fingers and ulnar deviation of the wrist are progressive. Finger mobility is essentially limited to the metacarpophalangeal joints. The thumbs tend to be broad. Hammer toes have also been noted. Urinary tract anomalies (hydroureter and hydronephrosis) [55, 61, 62, 68] and obstructive airway disease [51, 55, 56] are probably relatively c o m m o n complications. Mitral valve prolapse has been reported [67] as well as bands of soft tissue extending from the medial edge of the scapula to the vertebral column [69]. Hirsutism of the buttocks and thighs is common. Progressive mixed hearing loss has been reported [51, 56, 68, 70, 71].

Inheritance is X-linked with variable expression in carrier females [51, 57, 60]. Although some authors have suggested autosomal dominant inheritance [53, 63, 71], there has been no male-to-male transmission. P r o n o u n c e d supraorbital ridges are found in otopalatodigital ( O P D ) syndrome, type I and to a lesser degree in Melnick-Needles syndrome, but those disorders are otherwise clearly distinguished. O P D syndrome has X-linked inheritance. Melnick-Needles syndrome is Xlinked dominant, lethal in the male.

Radiographic findings These include a thick torus-like frontal ridge, absence of frontal sinuses, " H e r s h e y kiss" or "top of the mosque" defects of supraorbital rims, arched superior borders of maxillary sinuses, short maxilla, elongated cranial base, and antegonial notching of the mandible with marked hypoplasia of the angle and condyloid process [51, 56, 59, 61, 63, 68]. The foramen magnum is greatly enlarged, and numerous vertebral anomalies have been noted; for example, the odontoid process is located too far anteriorly, the atlas has no posterior arch, and the lumbar vertebrae are flattened. There is fusion of the second and third cervical vertebrae, and subluxation of the third and fourth vertebrae. The shoulders may be highly positioned. Scoliosis is usually m a r k e d with resultant shortening of the trunk. The long bones manifest increased density in the diaphyseal region, with lack of modeling in the metaphyseal area producing an Erlenmeyer-flask deformity. The legs may be laterally bowed. Marked flaring of the iliac bones and coxa valga are noted, as well as fused and eroded carpal bones, wide elongated middle phalanges, and increased interpediculate distances in the lumbar region of the spine [54, 56, 60, 64, 69, 71]. The ribs and vertebrae are irregularly contoured [59] and the lower ribs are "coat hanger" in form. A characteristic metacarpophalangeal profile has been suggested [60].

References (Frontometaphyseal dysplasia) 50. Abuelo DN, Ehrlich D, Schwartz A, Feingold M (1983) Frontometaphyseal dysplasia Am J Dis Child 137:1017-1018 51. Arenberg JK, Shambaugh GE Jr, Valvasorri GE (1974) Otolaryngologic manifestations of frontometaphyseal dysplasia. The Gorlin-Holt syndrom e. Arch Ototaryngol Head Neck Surg 99:52-58 52. Balestrazzi P (1985) H6r6dit6 li6e au sexe dans la dysplasia frontometaphysaire. J Genet Hum 33:419-425 53. Beighton R Hamersma H (1980) Frontometapyhseal dypslasia: autosomal dominant or X-linked. J Med Genet 17:53-56 54. Danks DM, Mayne V, Hall RK, McKinnon MC (1972) Frontometaphyseal dysplasia. Am J Dis Child 123:254-258 55. Fitzsimmons JS, Fitzsimmons EM, Barrow M, Gilbert GB (1982) Frontometaphyseal dysplasia: further delineation of the clinical syndrome. Clin Genet 22:195-205 56. Gorlin RJ, Cohen MM Jr (1969) Frontometaphyseal dysplasia: a new syndrome. Am J Dis Child 118:487-494 57. Gorlin RJ, Winter RB (1980) Frontometaphyseal dysplasia evidence for X-linked inheritance. Am J Med Genet 5:81-84 58. Holt JF, Thompson GR, Arenberg IK (1972) Frontometaphyseal dysplasia. Radiol Clin North Am 10:225-243 59. Jend-Rossman I, Jend HH, Ringe JD, Gundlach KKH (1984) Frontometaphyseal dysplasia: symptoms and possible mode of inheritance. J Oral Maxillofac Surg 42:743-748 60. Jervis GA, Jenkins EC (1975) Frontometaphyseal dysplasia. Syndrome Ident 3:18-19 61. Kanemura T, Orii T, Ohtani M (1979) Frontometaphyseal dysplasia with congenital urinary tract malformations. Clin Genet 16:399-404 62. Kassner EG, Haller JO, Reddy VH, Mitarotunda A, Katz I (1976) Frontometaphyseal dysplasia: evidence for autosomal dominant inheritance. Am J Roentgenol 127:927-933 63. Kleinsorge H, B6ttger E (1977) Das Gorlin-Cohen-Syndrom (frontometaphys~ire Dysplasie). R6fo 127:451-458 64. Lischi G (1967) Le torus supraorbitalis: variation cranienne rare. J Radiol Electro148:463-466 65. Medlar RC, Crawford AH (1978) Frontometaphyseal dysplasia presenting as scoliosis: a report of a family with four cases. J Bone Joint Surg [Am] 60:392-394 66. Mersten A, Merstenovfi E, Pichani~ M, Sterbovg E (1980) Craniometaphyseal dysplasia. Radiol Diagn 21:70-74 67. Park JM, Contreras EA, Garcia RR (1986) Mitral valve prolapse in a patient with frontometaphyseal dysplasia. Clin Paediatr 25:469-471 68. Sauvegrain J, Lombard M, Gaul L, Truscelli D (1975) Dysplasie frontometaphysaire. Ann Radiol 18:155-162 69. Ullrich E (1979) Frontometaphyseal dysplasia: report of two familial cases. Australas Radiol 23:265-271 70. Walker BA (1969) A craniodiaphyseal dysplasia or craniometaphyseal dysplasia, ? type. Birth Defects 5:298-300 71. Weiss L, Reynolds WA, Szymanowski RT (1975) Frontometaphyseal dysplasia - evidence for dominant inheritance. Birth Defects 11:55-56

396

Craniometadiaphyseal dysplasia

Osteopetrosis

Craniometadiaphyseal dysplasia is an autosomal recessive disorder described initially by Schwarz [74] in 1960 but far more extensively by Williams [75] in 1988 and Langer et al. [72] in 1991.

Osteopetrosis is a group of disorders characterized by failure of resorption of the primary spongiosa by osteoclasts, resulting in increased osseous density in which cortical and cancellous bone cannot be distinguished radiographically. Histologically, there is an increased number of osteoclasts [81, 88, 115, 118]. Osteopetrosis has been traditionally divided into two groups: congenital (malignant) autosomal recessive type and adult (benign) autosomal dominant form. However, there is considerable further genetic heterogeneity: (a)severe autosomal recessive osteopetrosis (Albers-Sch6nberg disease), (b) mild autosomal recessive osteopetrosis, (c) autosomal recessive osteopetrosis with renal tubular acidosis (carbonic anhydrase II deficiency), and (d) benign autosomal dominant osteopetrosis, types I and II. We suspect that still other forms exist [82].

Clinical findings The disorder is characterized by large head ( > 98th centile) with prominent forehead, relatively large eyes, lowset pinnae and natal teeth.

Radiographic findings Multiple wormian bones, wide long tubular bones without normal metaphyseal flaring, wide short tubular bones without normal diaphyseal constriction and, in some cases, expansion and with wide ribs and clavicles are seen radiographically. Langer et al. and Williams studied the same two sibs and found, in infancy, a large anterior fontanelle as well as thinning of the calvaria with wormian bones, hyperostosis and mild sclerosis of the skull, particularly in the frontal and occipital areas as well as the maxilla and mandible. The paranasal sinuses were obliterated. Teeth were hypoplastic and occipital horns were noted. Fractures of long bones were noted in both sibs.

Current bias Schwarz-Ldlek syndrome has disappeared. The patient reported by Schwarz [74] apparently has craniometadiaphyseal dysplasia and that of L61ek [73] probably represents a severe example of craniometaphyseal dysplasia or perhaps an entity unto its own. Craniometadiaphyseal dysplasia has autosomai recessive inheritance, there being affected sibs and parental consanguinity [72, 75].

References (Craniometadiaphyseat dysplasia) 72. Langer LO Jr, Bull PW, Afshani E, Williams CA, Thomas IT, Frias JL (1991) Radiographic features of craniometadiaphyseal dysplasia, wormian bone type. Skeletal Radiol 20: 3742 73. Ldlek I (1962) Camurati-Engelmann'sche Erkrankung. Fortschr Rontgenstr 94:393408 74. Schwarz E (1960) Craniometaphyseal dysplasia. Am J Roentgeno184:461-466 75. Williams CA (1988) A new syndrome of craniotubular dysplasia having diaphyseal and metaphyseal modeling defects and increased susceptibilityto fracture. March of Dimes Birth Defects Conference, Baltimore, July 1988

Severe autosomal recessive osteopetrosis (AlbersSchOnberg disease) This disorder is characterized by increased density of nearly all bones and the complications that occur from failure of resorption of the primary spongiosa and its resultant persistence: anemia, hepatosplenomegaly, blindness, hearing loss, facial paralysis, and osteomyelitis [84]. There is failure to thrive and reduced host defense [87]. Life span is rarely more than a few years [93]. Involved bones are expanded, splayed, and dense, with epiphysis, metaphysis, and diaphysis being involved to a similar degree. Cortical and cancellous bones are indistinguishable radiographically. Pathogenesis has been extensively discussed by Reeves et al. [87]. Over 400 cases have been reported. It may be recognized in utero.

Clinical findings All tubular bones may be involved, but growth is usually normal. The skull is thickened and dense, mainly at its base, but the calvaria and paranasat sinuses are poorly aerated, and the facial bones appear denser than normal [86]. Long bone fractures are common. Defective vision and nystagmus are extremely common. Optic atrophy resulting from pressure of bone on optic veins is a relatively common complication. Facial paralysis results from the pressure of dense bone on the foramen of the seventh cranial nerve [83]. Mental retardation occurs in about 20 % of patients [83]. Between 25% and 50% of patients have moderate mixed sensorineural and conductive hearing loss beginning in infancy [76, 85, 91]. There is often a history of otitis media. Osteomyelitis of the jaws seems to be a significant complication of dental extraction, presumably the result of deficient blood supply [79, 90, 92]. The infection may lead to extraoral fistulas. Primary molars and all

397 permanent teeth are greatly distorted and remain totally or partially embedded in basal bone [77]. Although the liver and spleen are normal at birth, in over 50 % of the cases they enlarge in childhood because of extramedullary hematopoiesis. Hemolytic anemia and thrombocytopenia are found and generalized lymphadenopathy has been noted in about 20 %. Bone marrow transplantation has been carried out for therapy [78, 89]. A particularly severe form of osteopetrosis was reported in two sibs by E1 Khazen et al. [80]. There were in utero fractures, hip dislocation, hydrocephaly, and hypoplasia of the cerebellum. No osteoclasts were found.

Radiographic findings All of the recessive osteopetroses have thick and dense skull, most marked at the base. The skeleton is uniformly dense. Alternate radiolucent bands can be seen in the metaphyses and diaphyses of long bones.

Mild autosomal recessive osteopetrosis This rare form is characterized by short stature, increased upper/lower segment ratio, mandibular prognathism, fractures following minimal trauma, mild to moderate anemia with extramedullary hematopoiesis, unerupted teeth, and osteomyelitis [94--102]. Autosomal recessive inheritance has clearly been established, but I suspect that this group is heterogeneous.

Clinical findings The calvaria is thick and sclerotic. About 20 % of patients manifest conductive hearing loss. Osteomyelitis of the mandible occurs in about 10-20 % as do cranial nerve palsies of II, III, and VII [111, 112, 115-117]. There is usually some lack of remodeling, particularly in the femur and tibia. Elevated serum acid phosphatase [112, 114,118] has been noted.

Radiographic findings The condition appears "silently" within the first few years of life, being manifest by increased radiopacity of the skull. Density is most marked at the diaphyseal ends of long bones, gradually extending to the epiphyses and to the marrow cavity [112]. In type I autosomal dominant osteopetrosis, sclerosis and thickening of the calvaria are marked. There is no endplate sclerosis of vertebral bodies, and no "bone within bone" appearance in the ilia. There is usuaIly some lack of remodeling, particularly in the femur and tibia [108,110]. In type II, the skull base is thickened. Endplate thickening of vertebral bodies is a hallmark as are "bone within bone" alterations. Narrowing of foramina of the skull bone results in cranial nerve abnormalities. Most commonly, the condition is discovered on routine radiographs of the chest or upon radiographic survey of the family of a patient with known disease.

Current bias Autosomal recessive osteopetrosis with renal tubular acidosis (carbonic anhydrase II deficiency) Several families have been reported with severe osteopetrosis, short stature, mental retardation, basal ganglia calcification, visual impairment, hepatosplenomegaly, renal tubular acidosis, extramedullary hemopoiesis, pancytopenia and sensorineural hearing loss [103-106]. Inheritance is autosomal recessive. In one family the molecular basis for the defective carbonic anhydrase II has been ascertained [104].

Benign autosomal dominant osteopetrosis, types I and H Dominant forms of osteopetrosis are more common than recessive forms and are not associated with anemia, hepatosplenomegaly, blindness, or mental retardation. At least 40 % are asymptomatic, being diagnosed radiologically [112]. The dominant forms usually become manifest somewhat later in life than autosomal recessive types [108, 109]. The condition is rarely associated with fractures following minor trauma [112-114, 119, 120].

Classification into dominant and recessive forms was simplistic [107]. Surely there are many forms in addition to the four presented here. References (Severe autosomaI recessive osteopetrosis) 76. Bejaiou M, Barakat M, Sfar MT, Ferchiou A (1992) La forme r6cessive de l'osteop6trose. Arch Fr P6diatr 49:627-631 77. Bjorvatn K, Gilhuus-Moe O, Aarskog D (1979) Oral aspects of osteopetrosis. Scand J Dent Res 87:245-252 78. Coccia PF, Krivit W, Cervenka J (1980) Successful bone marrow transplantation for infantile malignant osteopetrosis. N Engl J Med 302:701-708 79. Dyson DP (1970) Osteomyelitis of the jaws in Albers-Sch6nberg disease. Br J Oral Surg 7:178-187 80. E1 Khazan N, Faverly D, Vamos E, Van Regemorter N, Flament-Durand J, Carton B, Cremer-Perlmutter N (1986) Lethal osteopetrosis with multiple fractures in utero. Am J Med Genet 23:811-819 81. Greenspan A (1991) Sclerosing bone dysplasias - a target site appraisal. Skeletal Radio120:562-583 82. Jagadha V, Halliday WC, Becker LE, Hinton D (1988) The association of infantile osteopetrosis and neuronal storage disease in two brothers. Acta Neuropathol (Berl) 75:233-240 83. Lehman RA, Reeves JD, Wilson WB, Wesenberg RL (1977) Neurological complications of infantile osteopetrosis. Ann Neurol 2:378-384 84. Lorfa-Cort4s R, Quesada-Calvo E, Cordero-Chaverri C (1977) Osteopetrosis in children. A report of 26 cases. J Pediatr 91:43--47

398 85. Myers EN, Stool S (1969) The temporal bone in osteopetrosis. Arch Otolaryngol 89:460-469 86. Paulose KO, A1 Khalifa S, Shenoy PK, Harris S, Sharma RK (1988) Osteopetrosis (marble bone disease) - agenesis of paranasal sinuses. J Laryngol Otol 102:1047-1051 87. Reeves J, Arnaud S, Gordon S, Subryan B, Block M, Huffer W, Arnaud C, Mundy G, Haussler M (1981) The pathogenesis of infantile malignant osteopetrosis. Bone mineral metabolism and complications in five infants. Metab Bone Dis Res 3: 135-142 88. Shapiro F, Key LL, Anast C (1988) Variable osteoclast appearance in human infantile osteopetrosis. Calcif Tissue Int 43:67-76 89. Sieff CA, Levinsky RJ, Rogers DW (1983) Allogenic bone marrow transplantation in infantile malignant osteopetrosis. Lancet I. 437-441 90. Steiner M, Gould AR, Means WR (1983) Osteomyelitis of the mandible associated with osteopetrosis. J Oral Maxillofac Surg 41:395-405 91. Suga IF, Lindsay JR (1976) Temporal bone histopathology of osteopetrosis. Ann Otol Rhinol Laryngo185:15-24 92. Wong ML, Balkomy TJ, Reeves J (1978) Head and neck manifestations of malignant osteopetrosis. Trans Am Acad Ophthalmol Otolaryngol 86:585-594 93. Younai IV, Eisenbnd L, Sciubba JJ (1988) Osteopetrosis. A case report including gross and microscopic findings in the mandible at autopsy. Oral Surg 65:214-221

References (Mild a u t o s o m a l recessive osteopetrosis) 94. Beighton R Hamersma H, Cremin B (1979) Osteopetrosis in South Africa. The benign, lethal and intermediate forms. S Afr Med J 55:659-665 95. Bejaiou M, Barakat M, Sfar MT, Ferchiou A (1992) La forme r6cessive de l'osteop~trose. Arch Fr P6diatr 49:627-631 96. Boyko A, Smylski PT (1974) Osteopetrosis. J Oral Surg 32: 859-863 97. Dorantes LM, Me]ia AM, Dorantes S (1986) Juvenile osteopetrosis: effects on blood and bone of prednisone and a low calcium, high phosphate diet. Arch Dis Child 61:666-670 98. Hasenhuttl K (1962) Osteopetrosis. Review of the literature and comparative studies in a case with a 20 year follow-up. J Bone Joint Surg [Am] 44:359-370 99. Hawke M, Jahn AF, Bailey D (1981) Osteopetrosis of the temporal bone. Arch Otolaryngol 107:278-282 100. Horton WA, Schimke N, Iyama T (1980) Osteopetrosis: further heterogeneity. J Pediatr 97:580-585 101. Kahler SG, Burns JA, Aylesworth AS (1984) A mild autosomal recessive form of osteopetrosis. Am J Med Genet 17:451-464 102. Trias A, Ferry A (1974) Osteopetrosis in adults. Rev Chir Or thop 60:593-606

References (Benign a u t o s o m a l d o m i n a n t osteopetrosis, type I and II) 107. Anderson PE, Bollerslev J (1987) Heterogeneity of autosomal dominant osteopetrosis. Radiology 164:223-224 108. Bollerslev J (1987) Osteopetrosis. A genetic and epidemiological study. Clin Genet 31:86-90 109. Bollerslev J, Grodum E, Grcntved A (1987) Autosomal dominant osteopetrosis. J Laryngol Otol 101:1088-1091 110. Bollerslev J, Gr0ntved A, Andersen PE (1988) Autosomal dominant osteopetrosis. An otoneurological investigation of the two radiological types. Laryngoscope 98:411-413 111. Chindia ML, Ocholla TJ, Imalingat B (1991) Osteopetrosis presenting as paroxysmal trigeminal neuralgia. Int J Oral Maxillofac Surg 20:198 200 112. Johnston CC, Lavy N, Lord FV, Merrit AD, Deis WP (1968) Osteopetrosis: a clinical, genetic, metabolic and morphologic study of the dominantly inherited benign form. Medicine (Baltimore) 47:149-167 113. Kuhlencordt F, Kruse HR Lozano-Tankin C, Hirth L, Goedde HW, Schneider C, Wieners H, Otte P (1977) Die Osteopetrosis Albers-SchOnberg. Ergeb Inn Med Kinderheilkd 39: 135-160 114. Kukla LF (1977) Dominant osteopetrosis. Clin Pediatr (Phila) 16:846-847 115. Milgram JW, Jasty M (1982) Osteopetrosis. A morphological study of twenty-one cases. J Bone Joint Surg [Am] 64:912-929 116. Milroy CM, Michaels L (1990) Temporal bone pathology of the adult type osteopetrosis. Arch Otolaryngol Head Neck Surg 116:79-84 117. Miyamoto RT, House WE Brackmann DE (1980) Neurologic manifestations of osteopetrosis. Arch Otolaryngol 106: 210214 118. Shapiro F, Glimscher MJ, Holtrop ME, Tashjian AH, Brickley-Parsons D, Kenzora JE (1980) Human osteopetrosis. A histologic, ultrastructural and biochemical study. J Bone Joint Surg [Am] 62:384-399 119. Svoboda P J, Mendieta C, Reeve CM (1983) Albers-Sch6nberg disease complicated with periodontal disease. J Periodontol 54:592-597 120. Yu JS, Oates RK, Walsh KH, Stuckey SJ (1971) Osteopetroses. Arch Dis Child 46:257-263

Dysosteosclerosis Dysosteosclerosis is c h a r a c t e r i z e d b y d i s p r o p o r t i o n a t e ly short and b e n t tubular b o n e s with thickening of the skull [121,122, 125, 127, 128, 131,133-136, 138].

Clinicalfindings References ( A u t o s o m a l recessive osteopetrosis with renal t u b u l a r acidosis) 103. Leone G (1982) Osteopetrosi recessiva con calcificazioni cerebrali. Radiol Med (Torino) 68:373-378 104. Roth DE, Venta PJ, Tashian RE, Sly WS (1992) Molecular basis of human carbonic anhydrase II deficiency. Proc Natl Acad Sci USA 89:1804-1808 105. Sly WS, Whyte MR Sundaram V, Tashian RE, Hewett-Emmett D, Sakafi N, Ohtson A (1985) Carbonic anhydrase II deficiency in 12 families with the autosomat recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. N Engl J Med 313:139-145 106. Whyte MR Murphy WA, Falon MD, Sly WJ, Teitelbaum SL, McAlister WH, Avioli LV (1980) Osteopetrosis, renal tubular acidosis, and basal ganglia calcification in three sisters. Am J Med 69:64-74

T h e anterior fontanelle tends to r e m a i n open. T h e r e is frontal and biparietal bossing and n a r r o w chin. Oligodontia, p o o r l y calcified teeth with late e r u p t i o n and prem a t u r e loss have b e e n described [124, 1 2 8 , 1 3 2 , 1 3 3 , 1 3 6 , 137]. Natal teeth have also b e e n noted. Progressive otosclerosis has b e e n seen [121,127]. T h e patient is short and there is a t e n d e n c y to b o n e fractures [127, 134, 135J, The limbs are d i s p r o p o r t i o n ately s h o r t e n e d in c o m p a r i s o n to the t r u n k and s o m e what bowed. Pectus c a r i n a t u m is occasionally found. M a c u l a r a t r o p h y of the skin has b e e n seen [122, 123, 132, 133,136]. D u r i n g early childhood, there m a y be cranial nerve i n v o l v e m e n t such as optic atrophy, a b d u c e n s palsy, and

399 facial paralysis. Some degree of spasticity and exaggerated reflexes have been evident [122, 123, 127, 133]. Other patients have manifested progressive mental retardation. Intracerebral calcifications have been reported [121].

Radiographic findings Radiographically, the calvaria and skull base are thickened. There is sclerosis of the orbital roofs, absent paranasal sinuses, and constriction of the foramina. The clavicles, scapulae, and ribs are sclerotic. The vertebral bodies are flattened and irregularly dense. Long tubular bones are bent in the region of the shortened, thickened diaphyses. The metaphyses are bottle shaped. The epiphyses and metaphyses are sclerotic, but the submetaphyseal areas are clear and their trabecular structure is coarse and irregular. Short tubular bones exhibit similar changes. Iliac bones are hypoplastic and sclerotic. Osteomyelitis of the mandible has been noted [130] (same case as [1251).

Current bias Affected sibs [122, 123, 129, 135] and parental consanguinity [122, 123,125, 133,138] clearly indicate autosomal recessive inheritance. However, there certainly appears to be an Xqinked recessive form [132] and some of the isolated male cases may be examples of the Xlinked form.

132. Pascual-Castroviejo I, Casas-Fernandez C, Lopez-Martin V, Martinez-Bermejo A (1977) X-linked dysosteosclerosis. Four familial cases, Eur J Pediatr 126:127-138 133. Roy C, Maroteaux E Kremp L, Courtecuisse V, Alagille D (1968) Un nouveau syndrome osseux avec anomalies cutan6es et troubles neurologiques. Arch Fr P6diatr 25:893-905 134. Spranger J, Albrecht C, Rohwedder HJ, Wiedemann HR (1968) Die Dysosteosclerose - eine Sonderform der generalisierten Osteosklerose. Fortschr Geb Rontgenstr 109:504-512 135. Stehr L (1942) Pathogenese und Klinik der Osteosklerosen. Arch Orthop Unfallchir 41:156-182 136. Temtamy SA, Rega M, E1-MeligyM, Badramy HS, Sami Abdel Meguid M, Safwat HM (1974) Metaphyseal dysplasia, anetoderma and optic atrophy: an autosomal recessive syndrome. Birth Defects 10:61-71 137. Utz W (1970) Manifestation der Dysosteosklerose im Kieferbereich. Dtsch Zahnfirztl Z 25:48-50 138. Venetruto V, Ametrano O, D'Avanzo G, Della Bruna M, Stabile M, Lonardo F (1987) A case of autosomal recessive form of cranio-metaphyseal dypslasia with unusual features and with bone fi-agility.Australas Radiol 31:79-81

Oculodentoosseous dysplasia (oculodentodigital syndrome) Although reported as early as 1920 by L o h m a n n [153], Meyer-Schwickerath et al. [154], in 1957, were the first to fully describe a syndrome characterized by narrow nose with hypoplastic alae and thin nostrils, microcornea with iris anomalies, syndactyly and/or camptodactyly of postaxial fingers, hypoplasia or aplasia of middle phalanx of fifth fingers and toes, and enamel hypoplasia. A b o u t 100 cases have been reported to date.

Clinical findings

References (Dysosteosclerosis) 121. Chitayat D, Silver K, Azouz EM (1992) Skeletal dysplasia, intracerebral calcifications, optic atrophy, hearing impairment, and mental retardation: nosology of dysosteosclerosis. Am J Med Genet 43:517-523 122. Ellis RWB (1933-1934) Osteopetrosis. Proc R Soc Med 27: 1563-1571 123. Field CE (1938-1939) Albers-Sch6nberg disease: an atypical case. Proc R Soc Med 32:320-324 124. Fryns JR Vinken L, Claessens S, Marien J, Bentjiens J, van den Berghe H (1980) Dysosteosclerosis in a mentally retarded boy. Acta Paediatr Belg 33:53-56 125. Houston CS, Gerrard JW, Ives EJ (1978) Dysosteosclerosis. Am J Roentgenol 130:988-991 126. Kaitila I, Rimoin DL (1976) Histologic heterogeneity in the hyperostotic bone dysplasias, Birth Defects 12:71-79 127. Kirkpatrick DB, Rimoin DL, Kaitila I, Goodman SJ (1977) ]-he craniotubular bone modeling disorders: a neurological introduction to rare skeletal dysplasias with cranial nerve compression. Surg Neurol 7:221-232 128. Leisti J, Kaitila I, Lachman RS, Asch MJ, Rimoin DL (1975) Dysosteosclerosis. Birth Defects 11:349-351 129. Nema HV (1974) Craniometaphyseal dysplasia. Br J Ophthalmo158:107-109 130. Pakota GV, Shiffman J, Hall JM (1993) Osteomyelitis of the mandible in a patient with dysosteosclerosis. Oral Surg Oral Med Oral Patho171:145-147 131. Parascandolo S, Grulliero A, Tortora R Marasea F (1985) Su un caso clinico di displasia cranio-metaphisaria. Minerva Stomatol 34:671-675

Short narrow palpebral fissures, epicanthal folds, and long thin nose with prominent nasal bridge and hypoplastic alae nasi produce a characteristic physiognomy. The pinnae may be abnormally modeled and/or outstanding. Dry lusterless hair that fails to grow to normal length has been noted in 30 % of patients [148, 152, 154, 160,162]. Striking eye changes are seen consisting of short narrow palpebral apertures, microcornea (6-9 m m in diameter), and epicanthal folds in childhood [142, 145, 146, 151]. Remnants of the pupillary m e m b r a n e may be present along the iris margin rather than across the pupil [141,143, 148, 154]. Several patients have exhibited secondary glaucoma [145, 150, 157, 160]. Generalized enamel hypoplasia has been noted by a n u m b e r of investigators [143,144, 159, 161]. The alveolar ridge of the mandible may be wider than normal [148, 150, 158, 163]. Cleft lip-palate [144, 147, 155, 163] and microdontia [145, 149, 163] have been observed by several authors. Most patients have a gracile build. Camptodactyly of the fifth or, less often, of the fourth fingers is a c o m m o n finding. Clinically, the fifth finger appears to be shortened. Bilateral syndactyly of the fourth and fifth fingers (rarely the third) with ulnar clinodactyly and syndactyly of the third and fourth toes are often present [157, 159].

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Radiographic findings Hyperostosis of the skull is occasionally noted [141, 159]. The middle phalanx of the fifth finger is cuboid or deltoid or occasionally absent [162] and there is aplasia or hypoplasia of the middle phalanx of one or more toes [140]. Lack of modeling of the metaphyseal area of long bones is relatively c o m m o n [141, 142, 144, 148,

152, 158]. Current bias The syndrome is considered to show autosomal dominant inheritance with new mutations representing approximately 50 % of cases [142, 156, 159]. Although affected sibs with normal parents have been described [143, 147], these cases can be attributed to the variable expressivity of the disorder or gonadal mosaicism. There may, however, be genetic heterogeneity. Patients described by Farman et al. [146] and reported by Beighton et al. [139] exhibited marked cranial hyper0stosis, massive mandibular overgrowth, gross medial clavicular widening, blindness, microphthalmia, calcification of basal ganglia, cataracts, cleft lip-palate, and spastic quadriplegia. Perhaps this represents an autosomal recessive form.

References [Oculodentoosseous dysplasia (oculodentodigital syndrome)] 139. Beighton R Hamersma H, Raad M (1979) Oculo-dento-osseous dysplasia: heterogeneity or variable expression? Clin Genet 16:169-177 140. Brueton LA, Huson SM, Farren B, Winter RM (1990) Oculodentodigital dypslasia and type III syndactyly: separate genetic entities or disease spectrum? J Med Genet 27:169-175 141. David JEA, Palmer PES (1958) Familial metaphyseal dysplasia. J Bone Joint Surg [Br] 40:87-93 142. Dudgeon J, Chisolm JA (1974) Oculo-dento-digital dysplasia. Trans Ophthalmol Soc UK 94:203-210 143. Eidelman E, Chosack A, Wagner ML (1967) Orodigitofacial dysostosis and oculodentodigital dysplasia. Oral Surg 23: 311-319 144. FSra M, Horak I, HrivnfikovfiJ (1977) Oculodentodigital dysplasia. Acta Chit Plast 19:110-122 145. Ffira M, Gorlin RJ (1981) The question of hypertetorism in oculodentoosseous dysplasia. Ant J Med Genet 10:101-102 146. Farman AG, Smith SN, Nortj6 CJ (1977) Oculodentodigital dysplasia. Br Dent J 142:405-408 147. Gillespie FD (1964) Hereditary dysplasia oculodentodigitalis. Arch Ophthalmol 71:187-192 148. Gorlin RJ, Meskin LH, St. Geme JW (1963) Oculodentodigital dysplasia. J Pediatr 63:69-75 149. Haines JO, Rogers SC (1975) Oculodento-digital dysplasia: a rare syndrome. Br J Radio148:932-936 150. Judisch GF, Martin-Casck A, Hanson J, Olin WH (1979) Oculodentodigital dysplasia. Arch Ophthalmol 97:878-884 151. Kadrnka-Lovrencic M, Jurkovic S, Reiner-Banovac Z (1973) Die oculo-dento-digitale Dysplasie (Das Meyer-Schwickerath-Syndrom). Monatsschr Kinderheilkd 121:595-599 152. Kurlander GJ, Lawy NW, Campbell JA (1966) Roentgen differentiation of the oculodentodigital syndrome and the Hallermann-Streiff syndrome of infancy. Radiology 86:77-85

153. Lohmann W (1920) Beitrag zur Kenntnis des reinen Mikrophthalmus. Arch Augenheilkd 96:136-141 154. Meyer-Schwickerath G, Gr(iterich E, Weyers H (1957) Mikrophthalmussyndrome: Klin Monatsbl Augenheilkd 131: 18-30 155. Nivelon-Chevallier, Audry D, Audry F, Dumas R (1981) Dysplasie oculo-dento-digitale. J G6n6t Hum 29:171-179 156. Patton MA, Laurence KM (1985) Oculodentoosseous syndrome. J Med Genet 22:386-389 157. Pitter J, Svejda J (1952) Ober den Einfluss der R6ntgenstrahIen auf die Entstehung von Missbildungen der menschlichen Frucht. Ophthalmologica 123:386-393 158. Rajic DS, de Veber LL (1966) Hereditary oculodentoosseous dysplasia. Ann Radiol 9:224-231 159. Reisner SH, Kott E, Bornstein B, Salinger H, Kaplin J, Gorlin RJ (1969) Oculodentodigital dysplasia syndrome. Am J Dis Child 118:600-607 160. Sugar HS (1978) Oculodentodigital dysplasia syndrome with angle-closure glaucoma. Am J Ophthalmol 86:36-38 161. Sugar HS, Thompson JR David JD (1966) The oculo-dentodigital dysplasia syndrome: Am J Ophthalmo161:1448-1451 162. Thod6n CJ, Ry6ppy S, Kuitunen P (1977) Oculodentodigital dysplasia syndrome. Acta Paediatr Scand 66:635-638 163. Weintraub DM, Baum JL, Pashayan HM (1975) A family with oculodentodigital dysplasia. Cleft Palate J 12:323-329

Osteopathia striata Osteopathia striata or striated skeleton was first described by Voorhoeve [179] in 1924. The syndrome has been extensively reviewed by Winter et al. [180], in 1980, and by de Keyser et al. [171], in 1983. About 40 cases have been described.

Clinical findings The cranium is enlarged, even from birth. Adult head circumference is often 60-65 cm. There is frontal bossing and the face appears somewhat squared. Nasal obstruction may be evident in infancy [167, 169, 176, 178]. The nasal bridge is broad and the eyes appear widely set. Facial palsy [167, 172] or other cranial nerve defects [171,176, 180] have been noted. Mild mental retardation has been found in about 30 % of patients [164, 167-170, 176]. Cleft palate or bifid uvula occurs in about 50 %. Abbreviated tooth roots or unerupted teeth have been described [167]. Progressive hearing loss, found in about 50 %, is usually mixed, variable in severity and often involves both low and high frequencies [164, 166, 167, 169, 175-177].

Radiographic findings Radiographically there is hypostosis of the cranial vault with marked increase in density of the cranial base [173, 174]. The sinuses may be obscured and the mastoid air cells diminished. The anterior fontanelle closes late. The ribs and medial clavicles are somewhat broad. The long bones and iliac wings appear combed, hence the name osteopathia striata. Occasionally there is generalized increased bone density. Scoliosis is present in

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at least 15 % of patients [169]. Spina bifida occulta in the lumbar region is c o m m o n [169].

Current bias This disorder was not discussed in our 1969 paper. Autosomal dominant inheritance [165, 168, 180] is a p p a r e n t although females o u t n u m b e r males by 2.5F : 1M.

that is, widened and d e e p e n e d mandible with increased gonial angle [181, 183-196, 198, 199]. ([193] and [184] are reports of the same case.) Changes begin at p u b e r t y and plateau with cessation of growth. Possibly, torus palatinus is m o r e frequently associated with the condition [183, 190, 194, 198, 199]. In contrast to Van Buc h e m disease, there is usually no compression of cranial nerves as a result of foraminal e n c r o a c h m e n t or elevation of serum alkaline phosphatase, with rare exception [183, 185, 189, 191]. A b o u t 50 cases have b e e n reported.

References ( O s t e o p a t h i a striata) 164. Bass HN, Weiner JR, Goldman A, Smith LE, Sparkes RS, Crandall BF (1980) Osteopathia striata syndrome: clinical, genetic and radiologic considerations. Clin Pediatr (Phila) 19: 369-373 165. Cortina H, Vallcanera A, Vidal J (1981) Familial osteopathia striata with cranial condensation. Pediatr Radiol 11:87-90 166. Culver G J, Thumasathit C (1972) Osseous changes of osteopathia and Pyle's disease occurring in a patient with 11 year follow-up. Am J Roentgenol 116:640-643 167. Franklyn PR Wilkinson D (1978) Two cases of osteopathia striata, deafness and cranial osteopetrosis. Ann Radio121:91-93 168. Gehweiler JA, Bland WR, Carden TR, Daffner RH (1973) Osteopathy striata - Voorhoeve's disease. Review of the roentgen manifestations. Am J Roentgenol 118:450-455 169. Horan FT, Beighton PH (1978) Osteopathia striata with cranial sclerosis: an autosomal dominant entity. Clin Genet 13:201-206 170. Hurt RL (1953) Osteopathia striata - Voorhoeve's disease: report of a case presenting features of osteopathia striata and osteopetrosis. J Bone Joint Surg [Br] 35:89-96 171. Keyser J de, Bruyland M, De Greeve J, Leemans J, Ebinger G (1983) Osteopathia striata with cranial sclerosis. Clin Neurol Neurosurg 85:41-48 172. Kornreich L, Grunebaum M, Ziv N, Shuper A, Mimouni M (1988) Osteopathia striata, cranial sclerosis with cleft palate and facial nerve palsy. Eur J Pediatr 147:101-103 173. Mohan V, Gupta SK, Bhushan B (1990) Osteopathia striata with cranial sclerosis. Australas RadioI 34:249-252 174. Nakamura T, Yokomizo Y, Kanda S, Harada T, Naruse T (1985) Osteopathia striata with cranial sclerosis affecting three family members. Skeletal Radiol 14:267-269 175. Odrezin GT, Krazikov N (1993) CT scan of the temporal bone in a patient with osteopathia striata and cranial sclerosis. AJNR 14:72-75 176. Paling MR, Hyde I, Dennis NR (1981) Osteopathia striata with sclerosis and thickening of the skull. Br J Radiol 54: 344-348 177. Piechowiak H, Goebel FD, Hirsche U, Tyrell R (1986) Cranial sclerosis with striated bone disease (osteopathia striata). Klin Padiatr 198:418-424 178. Robinow M, Unger F (1984) Syndrome of osteopathia striata, macrocephaly, and cranial sclerosis. Am J Dis Child 138: 821823 179. Voorhoeve N (1924) L'image radiologique non encore d6crite d'une anomalie du squelette. Acta Radiol 3:407-427 180. Winter RM, d~. Crawfurd M, Meire HB, Mitchell N (1980) Osteopathia striata with cranial sclerosis: highly variable expression within a family including cleft palate in two neonatal cases. Clin Genet 18:462-474

Autosomal dominant osteosclerosis (endosteal hyperostosis, Worth type)

Clinical findings Worth and Wollin [199] described this disorder in 1966. Clinical changes are essentially limited to square jaw,

Radiographic changes Endosteal sclerosis of the n e u r o c r a n i u m seen with loss of the diploE, osteosclerosis, and hyperostosis of the mandible with absence of the normal antegonial notches, endosteal sclerosis of the diaphyses of long bones (including metacarpals and metatarsals), and osteosclerosis of the pelvis. The vertebral bodies, ribs, and clavicles are involved to a minor degree.

Current bias T h e r e is autosomal dominant inheritance [187]. Charrow et al. [182] and Stoll et al. [197], however, described an autosomal recessive s y n d r o m e of endosteal osteosclerosis and cerebellar hypoplasia. The condition was characterized by microcephaly, delayed development, missing or a b n o r m a l teeth, and neurologic changes secondary to the cerebellar hypoplasia (hypotonia, ataxia, nystagmus, congenital hip dislocation). H e a r i n g loss was noted in possibly two of four patients affected. The disorder described by N a k a m u r a et al. [192] certainly resembles cherubism.

References [Autosomal dominant osteosclerosis (endosteal hyperostosis, Worth type)] 181. Beals RK (1976) Endosteal hyperostosis. J Bone Joint Surg [Am] 58:1172-1173 182. Charrow J, Poznanski Ak, Unger FM, Ribonow M (1991) Autosomal recessive cerebellar hypoplasia and endosteal hyperostosis. Am J Med Genet 41:464468 183. Demonchy A, Valat JR Neveur CA, Le Chevallier PL (1978) Hyperostose corticale g6n6ralis4e. Nouv Presse M6d 7: 28492851 184. Dyson DP (1972) Van Buchem's disease (hyperostosis corticalls generalisata). Br J Oral Surg 9:237-245 185. Eastman JR, Bixler D (1977) Generalized cortical hyperostosis (Van Buchem disease): nosologic considerations. Radiology 125:297-304 186. Gelman MI (1977) Autosomal dominant osteosclerosis. Radiology 125:289-296 187. Gorlin RJ, Glass L (1977) Autosomal dominant osteosclerosis. Radiology 125:547-548 188. Jacobs P (1977) Van Buchem disease. Postgrad Med J 53: 497505 189. Lapresle J, Maroteaux P, Kuffer R, Said G, Meyer O (1976) EIyperostose corticalis g6ndralis~e dominante avec atteinte multiple des nerfs craniens. Nouv Presse Meal 5:2703-2706

402

190. Maroteaux R Fontaine G, Scharfman W, Farriaux JP (1971) L'hyperostose corticle g6n6ralisde a transmission dominante. Arch Fr P6diatr 28:685-698 191. Moretti C, D0sualdo F, Modesto A, Benedetti A, Corsi M (1982) Iperostosi endostale a transmissione dominante. Descrizione di 8 casi in 3 generazioni dello stesso nucleo familiare. Radiol Med (Torino) 68:151-158 192. Nakamura T, Yamada N, Nonaka R, Sasaki M (1987) Autosomal dominant type of endosteal hyperostosis with unusual manifestations of sclerosis of the jaw bones. Skeletal Radiol 16:48-51 193. Owen RJ (1976) Van Buchem's disease (hyperostosis corticalis generalisata). Br J Radiol 48:126-132 194. Ruckert WE, Caudill RJ, McCready PJ (1985) Surgical treatment of Van Buchem's disease. J Oral Maxillofac Surg 43: 801-805 195. Russell WJ, Bizzozero OJ, Omori Y (1968) Idiopathic osteosclerosis: a report of six related cases. Radiology 90:70-76 196. Segond E Menkes GJ, Maroteaux P (1973) Le retr6cissement du canal m6dullaire des os a transmission dominante. Nouv Presse M6d 2:2728-2732 197. Stoll C, Talon R Alembik Y, Levy JM (1986) Hypoplasie c6rdbelleuse cong6nitale avec lesions osseuses. Ann P6diatr (Paris) 33:417-421 198. Vayssairat M, Prier A, Meisel C (1976) Nouveaux cas familiaux d'hyperostose corticale g6n6ralis6e a transmission dominante (type Worth). J Radiol Electro137: 719-724 199. Worth HM, Wollin DG (1966) Hyperostosis corticalis generalisata congenita. J Can Assoc Radiol 17:67-74

Van Buchem disease Van Buchem disease (generalized cortical hyperostosis) is characterized by osteosclerosis of skull, mandible, clavicles, and ribs and by hyperplasia of diaphyseal cortex of long and short bones. The most extensive monograph is that of Van B u c h e m in 1976 [206].

Clinical findings Facial changes develop slowly, but usually b e c o m e apparent before the second decade. A most striking finding is a wide and thickened mandible, suggesting acromegaly. Rarely, skull circumference is enlarged. Occasionally there is mild exophthalmos. Patients experience headache, unilateral or (rarely) bilateral facial paralysis, and optic atrophy. Elevated serum alkaline phosphatase has been noted in most cases. Virtually all fifteen patients described had bilateral symmetric hearing loss. Gradual impairment of hearing began at about 15 years of age [206, 207]. Some patients showed sensorineural hearing loss whereas others manifested mixed hearing loss.

vere cases, the medullary cavity is occluded. The transverse diameter of the diaphysis is normal or increased.

Current bias The disorder is believed to show autosomal recessive inheritance [201-207]. Most examples have been in South Africans of Dutch ancestry. The patient described by Dixon et al. [200] has a separate disorder. I have seen the same disorder in sibs and have coined the term pseudo-Van Buchem disease. Autosomal dominant osteosclerosis is clearly separated from Van B u c h e m disease, with which it is sometimes confused in the literature. In the former condition, there are no neurological complications (such as hearing loss), and no exophthalmos, hypertelorism, or elevated alkaline phosphatase. The relationship between Van Buchem disease and sclerosteosis is discussed in the next section.

References (Van Buchem disease) 200. Dixon JM, Cull RE, Gamble P (1982) Two cases of Van Buchem's disease. J Neurol Neurosurg Psychiatry 45:913-918 201. Jacobs P (1977) Van Buchem disease. Postgrad Med J 53: 4975O5 202. Sala O (1953) ORL importance of some aspects of osteopetrosis. Boll Mal Orecch 71:577-592 203. Toledo F (1982) Hiperostosis endosteal (enfermedad de Van Buchem). Radiologia (Madr) 24:49-52 204. Van Buchem FSR Hadders HN, Ubbens R (1955) Hyperostosis corticalis generalisata familiaris. Acta Radio144:109-114 205. Van Buchem FSR Hadders HN, Hansen JF, Woldring MG (1962) Hyperostosis corticalis generalisata: report of seven cases. Am J Med 33:387-397 206. Van Buchem FSR Hadders HN, Hansen JF (1976) Hyperostosis corticalis generalisata familiaris (Van Buchem's disease). Elsevier, New York 207. Van der Wouden A (1968) Deafness caused by hyperostosis corticalis generalisata. Pract Otorhinolaryngo130:91-92 Sclerosteosis Sclerosteosis was described as early as 1929 by Hirsch [217]. Several other reports of the disorder [214, 216, 218-220, 222, 225, 226] antedate Hansen's [215] definition of sclerosteosis. The disorder is characterized by generalized osteosclerosis with hyperostosis of the calvaria, mandible, clavicles, and pelvis, rather different from that observed in Van Buchem disease. Usually there is syndactyly and other abnormalities of the digits. A b o u t 60 cases have been described. The kindred reported in [218] and [226] are the same.

Radiographic findings Clinical findings Changes include thickening of the calvaria and increased density of the skull base. The body of the mandible is greatly enlarged in all measurements; the angle is obtuse. The long tubular bones exhibit diaphyseal thickening and are roughly textured. The cortical hyperostosis is predominantly endosteal in character. In se-

The typical facies, evident by the age of 5 years, is characterized by frontal prominence, hypertelorism, and broad flat nasal root. The mandible is prognathic, broadened and squared, and dental malocclusion is frequent [224]. The face may be distorted with relative midfacial hypo-

403 plasia. H e a d circumference is enlarged. Facial nerve paralysis, transient in infancy, is c o m m o n in adulthood. Characteristically, it is unilateral for many years. There is increased intracranial pressure in 80 % of patients [109, 212, 223]. Ataxia has been reported [219, 223]. Exophthalmos, optic atrophy, reduced visual fields, convergent strabismus, nystagmus, chronic headache, and decreased sensory function of the trigeminal nerve have been described in adults. Visual loss occurs in 30 % of patients; only rarely, however, is there total blindness. Several patients have died suddenly from impaction of the medulla in the foramen magnum [209, 213]. Final height attainment is over 180 cm in 70 % of patients. In about 75 % there is asymmetric partial or complete cutaneous syndactyly of the index and middle fingers. There may be radial deviation of the distal phalanx of the index fingers. The nails on the involved digits are hypoplastic in 80 %. Bilateral sensorineural, mixed, or conductive hearing loss - a constant feature of the disorder - may appear early in infancy, during childhood, or late in adolescence [210, 221].

Radiographic findings The calvaria becomes thickened and sclerotic in infancy. This gradually increases until about the age of 30 years. The base is dense and the foramina obliterated. The mandible is massive, prognathic, often asymmetric, and with an obtuse angle. The clavicles and ribs are broadened and dense because of cortical thickening. The scapulae, pelvis, and vertebral endplates and pedicles are uniformly sclerotic. The tubular bones, in addition to increased density, exhibit a lack of diaphyseal modeling. The index finger may have no middle phalanx or only a small triangular bone (delta phalanx) producing radial deviation. Bony syndactyly may involve the second and third fingers [210].

Current bias Inheritance is autosomal recessive. Most patients have been of South African Dutch ancestry [208, 211, 212, 214, 219]. Prevalence has been estimated to be about 1 in 60,000 in Afrikaners [208]. Heterozygotes exhibit increased calvarial width and density (R Beighton, personal communication). Patients with Van Buchem disease tend to be of normal height and never have involvement of digits. Most are also of Dutch ancestry. Sclerosteosis tends to be more severe in its manifestations. Hearing loss (90 % of cases) and raised intracranial pressure (80 % of cases) are more c o m m o n than in those with Van Buchem disease. Beighton et al. [212], having examined 80 Afrikaners with sclerosteosis in South Africa and 15 patients with Van Buchem disease in Holland, suggested that the two disorders are the same, the difference being the occurrence of an additional epistatic gene in South African suffers.

References (Sclerosteosis) 208. Beighton E Hamersma H (1979) Sclerosteosis in South Africa. S Afr Med J 55:783-788 209. Beighton R Durr L, Hamersma H (1976) The clinical features of selerosteosis: a review of the manifestations in twenty-five affected individuals. Ann Intern Med 84:393-397 210. Beighton R Cremin BJ, Hamersma H (1976) The radiology of sclerosteosis. Br J Radiol 49:934-939 211. Beighton R Davidson L, Durr L, Hamersma H (1977) Sclerosteosis - an autosomal recessive disorder. Clin Genet 11:1-7 212. Beighton R Barnard A, Hamersma H, van der Wouden A (1984) The syndromic status of sclerosteosis and Van Buchem disease. Clin Genet 25:175-181 213. Epstein S, Hamersma H, Beighton P (1979) Endocrine function in sclerosteosis. S Aft Med J 55:1105-1110 214. Falconer AW, Ryrie BJ (1937) Report on a familial type of generalized osteoscterosis. Presse Med 195:12-14 215. Hansen HG (1967) Sklerosteose. In: Opitz H, Schmid F (eds) Handbuch der Kinderheilkunde, vol 6, Springer, Berlin Heidelberg New York, pp 351-355 216. Higinbotham NL, Alexander SF (1941) Osteopetrosis: four cases in one family. Am J Surg 53:444-454 217. Hirsch IS (1929) Generalized osteitis fibrosa. Radiology 13: 44-84 218. Kelley CH, Lawlah JW (1946) Albers Sch6nberg disease: a familial survey. Radiology 147:507-513 219. Klintworth GK (1963) Neurologic manifestations of osteopetrosis (Atbers-Sch6nberg's disease). Neurology 13:512-519 220. Kretzmar JH, Roberts RA (1926) Case of Albers-Sch~Snberg disease. BMJ 1:837-838 221. Nager GT, Hamersma H (1986) Sclerosteosis involving the temporal bone. Clinical and radiologic aspects. Am J Otolaryngol 7:1-16 222. Pietruschka G (1958) Weitere Mitteilungen fiber die Marmorknochenkrankheit (Albers-SchSnbergsche Krankheit) nebst Bemerkungen zur Differentialdiagnose. Klin Monatsbl Augenheilkd 132:509-525 223. Stein SA, Witkop C, Hills S, Fallon MD (1983) Sclerosteosis: neurogenic and pathophysiologic analysis of an American kinship. Neurology 33:267-277 224. Sugiura Y, Yasuhara T (1975) Sclerosteosis. J Bone Joint Surg [Am] 57:273-276 225. Truswell AS (1958) Osteopetrosis with syndactyly. A morphological variant of Albers-Sch6nberg disease. J Bone Joint Surg [Br] 40:208-218 226. Witkop CJ Jr (1965) Genetic disease of the oral cavity. In: Tiecke RW (ed) Oral Pathology, McGraw-Hill, New York

Progressive diaphyseal dysplasia (Camurati-Engelmann disease) Progressive diaphyseal dysplasia, a sclerotic and hyperostotic disorder of bone, was described by Camurati [228] in 1922 and Engelmann [234] in 1929. A n earlier example is that of Cockayne [229] in 1920. More than 100 cases have been reported.

Clinical findings The most c o m m o n clinical findings include delayed ambulation, bone pain, generalized neuromuscular weakness, flat feet, broadly based waddling gait, thin musculature with disproportionately long limbs, and bowed tibiae. This condition can be manifest as early as the 3rd5th years of life, although the mean age is about 15-

404 20 years [227, 236-238, 254]. There may be genua vara, genua valga, lumbar lordosis, or scoliosis. Less often there is hepatosplenomegaly [231]. Secondary sexual development is poor. Some patients exhibit frontal bossing, exophthalmos, papilledema, epiphora, optic atrophy, and headache [239, 244, 245, 251], while some lose sense of taste and smell [241]. Mixed hearing loss based on stenosis has been noted in 5 - 7 % of patients [230-233, 235, 241, 242, 243 (cases 2 and 3), 244, 246, 247, 250, 252, 253]. Sparkes and G r a h a m [250] recorded slit-like internal auditory canals. Vestibular disturbances can be noted [232, 241, 243,2531 . Serum alkaline phosphatase, urinary hydroxyproline, and erythrocyte sedimentation rate may be elevated [236,239,249]. A n e m i a is relatively frequent. The scintigraphic changes are striking and not always correlated with radiographic changes [240].

Radiographic findings There is symmetric irregular spindle-shaped, sclerotic cortical thickening of the mid-diaphyses of long tubular bones and narrowing of medullary cavities. With age, the process extends proximally and distally toward the metaphyses which are rarely involved. The epiphyses are not affected. The base of the skull and calvaria are sclerotic in 70 % of patients. The mandible is sclerotic in 25 % and occasionally is significantly enlarged. The cervical vertebrae, clavicles, pelvic bones, hand and foot bones, and ribs are affected in about 2 0 % [244, 248].

Current bias There is nothing significantly changed. Inheritance is autosomal dominant with considerable variation in expression. New mutations account for about 5 0 % of cases (235).

References [Progressive diaphyseal dysplasia (Camurati-Engelmann disease)] 227. Beighton R Cremin BJ (1980) Sclerosing Bone Dysplasias. Springer, New York Berlin Heidelberg 228. Camurati M (1922) Di un raro di osteite simmetrica ereditaria degli arti inferiori. Clin Organi Mov 6:622-665 229. Cockayne EA (1920) Case for diagnosis. Proc R Soc Med 13: 132-136 230. Cohen J, States JD (1956) Progressive diaphyseal dysplasia. Lab Invest 5:492-508 231. Crisp A J, Brenton DP (1982) Engelmann's disease of bone - a systemic disorder? Ann Rheum Dis 41:183-188 232. Dannenmaier B, Weber B (1989) Beobachtungen zum Camurati-Engelmann-Syndrom. R~Sfo151:175-178 233. Demas PN, Sotereanos GC (1989) Facial skeletal manifestations of Engelmann's disease. Oral Surg Oral Med Oral Pathol 68:686-690 234. Engelm~ann G (1929) Ein Fall von Osteopathia hyperostotica (sclerosis) multiplex infantiles. Fortschr Roentgenol 39: 1011-1116

235. Fallon MD, Whyte ME Murphy WA (1980) Progressive diaphyseal dysplasia (Engelmann's disease). J Bone Joint Surg [Am] 62:465-472 236. Hundley JD, Wilson FC (1973) Progressive diaphyseal dysplasia. J Bone Joint Surg [Am] 55:461-474 237. Kaitila I, Stewart RE, Landow E (1975) Craniodiaphyseal dysplasia. Birth Defects 11:359-362 238. Kirkpatrick DB, Rimoin DL, Kaitila I, Goodman SJ (1977) The craniotubular-bone modelling disorders: a neurosurgical introduction to rare skeletal dysplasias with cranial nerve decompression. Surg Neurol 7:221-232 239. Kuhlencordt F, Kruse HP, Hellner KA, Montz R (1981) Diaphysfire Dysplasie (Camurati-Engelmann-Syndrom) mit fortschreitendem Visusverlust. Dtsch Med Wochenschr 106: 617621 240. Kumar B, Murphy WA, Whyte MP (1981) Progressive diaphyseal dysplasia (Engelmann's disease): scintigraphic radiographic-clinical correlations. Radiology 140:87-92 241. Lenarz T, GiJlzow J (1983) Neurootologische Frt~hsymptome der Camurati-Engelmann-Krankheit. Laryngol Rhinol Otol 62:463-467 242. Lennon EY, Schechter MM, Hornabrook RW (1961) Engelmann's disease. J Bone Joint Surg [Br] 43:273-284 243. Miyamoto RT, House WF, Brackmann DE (1980) Neurotologic manifestations of the osteopetroses. Arch Otolaryngol 106:210-214 244. Morse PH, Walsh FB, McCormick JR (1969) Ocular findings in hereditary diaphyseal dysplasia (Engelmann's disease). Am J Ophthalmol 68:100-104 245. Naveh Y, Kaftori JK, Alon U, Ben-David J, Berant M (1984) Progressive diaphyseal dysplasia: genetics and clinical and radiologic manifestations. Pediatrics 74:399-405 246. Nelson M, Scott CI (1969) Engelmann's disease (a form of craniodiaphyseal dysplasia). Birth Defects 5:301 247. Paul LW (1953) Hereditary multiple diaphyseal sclerosis (ribbing). Radiology 60:412-416 248. Ramon Y, Buchner A (1966) Camurati-Engelmann's disease affecting the jaws. Oral Surg 22:592-599 249. Smith R, Walton RJ, Corner BD, Gordon RS (1977) Clinical and biochemical studies in Engelmann's disease (progressive diaphyseal dysplasia). Q J Med 46:273-294 250. Sparkes RS, Graham CB (1972) Camurati-Engelmann disease. J Med Genet 9:73-85 251. Tucker AS, Klein L, Antony GJ (1976) Craniodiaphyseal dysplasia: evolution over a five-year period. Skeletal Radiol 1: 47-55 252. Trunk G, Newman A, Davis TE (1969) Progressive and hereditary diaphyseal dysplasia. Arch Intern Med 123:417-422 253. Van Dalsem VF, Genent HK, Newton TH (1979) Progressive diaphyseal dysplasia. J Bone Joint Surg [Am] 61:596-598 254. Yoshioka H, Mino M, Kiyosawa N, Hirasawa Y (1980) Muscular changes in Engelmann's disease. Arch Dis Child 55: 716-719

Hyperphosphatasemia Hyperphosphatasemia (juvenile Paget's disease) is characterized by swelling of the limbs during early infancy followed by fracture and bending with enlargement of the calvaria.

Clinical findings Hyperphosphatasemia is characterized clinically by fever, bone pain, and swelling of extremities during the 1st year of life [262]. Later, enlargement of the calvaria and often numerous fractures and bending of the bones

405 of the extremities occur, particularly anterior bowing of legs and general broadening of diaphyseal areas of tubular bones. H e a d a c h e and hypertension are frequent [269, 270]. The sclerae may be blue [265]. Intelligence is normal. Progressive mixed hearing loss is c o m m o n as is angioid streaking of the retina [265, 270, 278]. The skin exhibits pseudoxanthoma elasticum [261,263, 267, 270, 273]. Histologically, there is intensive metaplastic fibrous bone formation as well as increased osteoblastic and osteoclastic activity, very similar to that seen in Paget's disease but without typical mosaic or regression lines. Since chondral ossification is not markedly disturbed (epiphyses are normally formed and joints are not involved), growth is not seriously diminished. Muscle weakness is frequent, which retards walking, running, and jumping [266, 271,272, 274, 280].

Radiographic findings The skull reveals changes ("cotton ball patches") remarkably like those seen in Paget's disease. There is flattening of vertebral bodies. Long bones exhibit bending, overcylindricalization, and generalized cortical widening. Bone trabeculation is coarse and bone density diminished. Short bones are involved to a lesser degree, mostly on the endosteal side. The facial bones, except in the patient reported by Marshall [269], have not been involved. Scintigraphic changes are striking [268]. Teeth are shed early due to root resorption [265]. The blood picture is generally normal, although anemia was described in Swoboda's [277] patients. Serum alkaline phosphatase may exceed 500 King-Armstrong units ( K A U ) (normal < 25 K A U ) [255, 271]. Serum acid phosphatase (normal 1.5-3.5 K A U ) as well as urinary hydroxyproline (normal 6-22 mg/24 h per m 2) and leucine aminopeptidase [255,260] are elevated.

Current bias Tile condition is considered to show autosomal recessive inheritance [258, 259, 264, 265, 268, 275, 277, 278]. A b o u t half of the patients have been of Puerto Rican origin [256, 257, 265,276,278].

260. Desai MR Joshi NC, Shah KN (1973) Chronic idiopathic hyperphosphatasia in an Indian child. Am J Dis Child 126: 626628 261. Dohler JR, Souter W, Beggs I, Smith G (1986) Idiopathic hyperphosphatasia with dermal pigmentation - a 20-year follow-up. J Bone Joint Surg [Br] 68:305-310 262. Dunn V, Condon VR, Rallison ML (1979) Familial hyperphosphatasemia: diagnosis in early infancy and response to human thyrocalcitonin therapy. AJR 132:541-545 263. Eng AM, Bryant J (1975) Clinical pathologic observations in pseudoxanthoma elasticum. Int J Dermatot 14:585-605 264. Eroglu M, Taneli NN (1977) Congenital hyperphosphatasia (juvenile Paget's disease) - eleven years' follow-up of three sisters. Ann Radiol (Paris) 20:145-150 265. Eyring EL Eisenberg E (1968) Congenital hyperphosphatasia. J Bone Joint Surg [Am] 50:1099-1117 266. Fanconi G, Moreira G, Uehlinger E, Giedion A (1964) Osteochalasia desmalis familiaris. Helv Paediatr Acta 19: 279-295 267. Fretzin DF (1975) Pseudoxanthoma elasticum in hyperphosphatasia. Arch Dermatol 111:271-272 268. Iancu TC, Almagor G, Friedman E, Hardoff R, Front D (i978) Chronic familial hyperphosphatasemia. Radiology 129:669-676 269. Marshall WC (1962) A case of progressive osteopathy with hyperphosphatasia. Proc R Soc Med 55:238-239 270. Mitsudo SM (1971) Chronic idiopathic hyperphosphatasia associated with pseudoxanthoma elasticum. J Bone Joint Surg [Am] 53:303-314 271. Pazzadlia VE, Barbieri D, Beluffi G (1989) Chronic idiopathic hyperphosphatasic and fibrous dysplasia in the same child. J Pediatr Orthop 9:70%716 272. Saraf SK, Gupta SK (1989) Juvenile Paget's disease. Australas Radiol 33:189-191 273. Saxe N, Beighton P (1982) Cutaneous manifestations of osteoectasia. Clin Exp Dermatol 7:605-609 274. Silverman F (1985) Caffey's pediatric X-ray diagnosis, 8th edn, Year Book, Chicago, p 651 275. Sorrel E, LeGrand-Lambling (1938) Dystrophie osseuse g6n6ralisde. Bull Soc Pediatr Paris 36:89-92 276. Stemmermann GN (1966) A histologic and histochemical study of familial osteoectasia. Am J Pathol 48:641-651 277. Swoboda W (1958) Hyperostosis corticalis deformans juvenilis: ungew6hnliche generalisierte Osteopathien bei zwei Geschwistern. Helv Paediatr Acta 13:292-312 278. Thompson RC, Gaull GE, Horwitz SJ (1969) Hereditary hyperphosphatasia: studies in three siblings. Am J Med 47: 209-219 279. Whalen JR Worwith M, Krook L (1977) Calcitonin treatment in hereditary bone dysplasia with hyperphosphatasemia: a radiographic and histologic study of the bone. Am J Roentgenol 129:29-35 280. Woodhouse N, Fisher MT, Sigurdsson G, Japlin GF, MacIntyre I (1972) Paget's disease in a 5-year-old: acute response to human calcitonin. BMJ 4:267-268

References (Hyperphosphatasemia) 255. Antoniades K, Karakasis D, Karpetanos G, Lasaridis N, Tzarou V (1993) Chronic idiopathic hyperphosphatasemia. Oral Surg Oral Med Oral Pathol 76:200-204 256. Bakwin H, Eiger MS (1956) Fragile bones and macrocranium. J Pediatr 49" 558-564 257. Bakwin H, Golden A, Fox S (1964) Familial osteoectasia with macrocranium. Am J Roentgenol 91:609-617 258. Blanco O, Stivel M, Mautalen C, Schajowicz F (1977) Familial idiopathic hyperphosphatasia. J Bone Joint Surg [Br] 59: 421427 259. Choremis C, Yannakos D, Papadatos C, Baroutsoy E (1958) Osteitis deformans (Paget's disease) in an H-year-old boy. Helv Paediatr Acta 13:185-188

Stanescu osteosclerosis syndrome Stanescu et al. [284], in 1963, first reported what has become known as Stanescu type osteosclerosis. A second family was reported in 1984 [281].

Clinical findings Features include: short stature, brachycephaly, hypoplastic midface, ocular proptosis, micrognathia, and bra-

406 chydactyly. Other findings have included depression of the frontoparietal and occipitoparietal sutures.

Radiographic findings The cortices of long bones are dense. Lack of pneumatization of frontal and sphenoidal bones, small crowded teeth with enamel hypoplasia, sacralization of S1, and exostoses are seen. Patients appear to have craniosynostosis, judging from photographic and radiographic documentation of craniofacial shape [283], although no specific mention has been made of this in the texts of the three articles on the subject to date [281,283,284]. Further documentation is needed in future reports of the disorder.

Clinical bias Stanescu et al. [284] described 11 effected individuals. Maximilian et al. [283] examined the same family, reporting three new individuals with the disorder. Dipi-

erri and Guzman [281] described an affected mother and daughter. The current bias is that inheritance is clearly autosomal dominant. Hall [282] noted a sporadic instance of a patient with some similarities, although differences included lack of brachydactyly and severe involvement of the spine and thorax with pectus excavatum and kyphoscoliosis. Hall's patient may represent a different entity.

References (Stanescu osteosclerosis syndrome) 281. Dipierri JE, Guzman JD (1984) A second family with autosomal dominant osteosclerosis - type Stanescu. A m J Med Genet 18:13-18 282. Hall JG (1974) Craniofacial dysostosis - either Stanescu dysostosis or a new entity. Birth Defects 10:521-523 283. Maximilian C, Dumitriu L, Ioanitiu D, Ipsas I, Duca D (1981) Syndrome de dysostose craniofaciale avec hyperplasie diaphysaire. J Gdndt Hum 29:129-139 284. Stanescu V, Maximilian C, Poenaru S, Stanescu R (1963) Syndrome h6r6ditaire dominant, rdunissant une dysostose craniofaciale de type particulier, une insuffisance de croissance d'aspect chrondrodystrophique et un 6paissement massif de la corticale des os longs. Rev Fr Endocrinol Clin 4:219-231

Literature in pediatric radiology American Journal of Roentgenology

(Baltimore)

Neonatal subependymal cysts delected by sonography: prevalence, sonographic findings, and clinical significance. Larcos, G. et al. (Dept. of Nucl. Med. and Ultrasound, Hosp., Westmead, New South Wales2145, Australia) 162:953 (1994) Diagnosis of pulmonary complications associated with lung transplantation in children: value of CT vs histopathologic studies. Medina, L.S. etal.(Siegel, M.J., The Mallinckrodt Inst. of Rad., Washington Univ. School of Med., Dept. of Rad., 510 S. Kingshighway Blvd., St. Louis, Mo 63110, USA) 162:969 (1994) CT findings in inflammatory bowel disease in children. Jabra, A.A. et al.(The Russell H. Morgan Dept. of Rad. and Rad. Science, The Johns Hopkin's Med. Inst., 600 N.Wolfe St., Baltimore, MD 21287, USA) 162:975 (1994) Abnormalities of the bladder in children: imaging findings. Fernbach, S.K., Feinstein, K.A. (Dept. of Rad., The Children's Memorial Hosp., 2300 Children's Plaza, Box #9, Chicago, IL 60614, USA) 162:1143 (1994) Tailored low-dose fluoroscopic voiding cystourethrography for the reevaluation of vesicoureteral reflux in girls. Kleinman, P.K. et al. (Dept.of Rad., Univ. Med. Center, 55 Lake Av. N., Worcester, MA 01655, USA) 162:1151 (1994) Re: tailored low-dose fluoroscopic voiding cystourethrography for the reevaluation of vesicoureteral reflux in girls. Lebowitz, R.L. (Dept. of Rad., Children's Hosp., Harvard Med. School, 300 Longwood Av., Boston, MA 02115, USA) 162:1155 (1994) Colonic volvulus in children: value of barium enema for diagnosis and treatment in 14 children. Mellor, M.EA., Drake, D.G. (Emergency Dept., Children's Hosp., 345 N.Smith Av., St. Paul, MN 55102, USA) 162:1157 (1994)

Continued from p. 391 Neonatal disseminated primitive neuroectoderreal tumor. Mitchell, C.S. (Wood, B. E, Dept. of Rad., Children's Hosp., 4650 Sunset Blvd., Los Angeles, CA 90027, USA) 162 : 1160 (1994) Bone disease in adolescents with ache fulminans and severe cystic acne: radiologic and scintigraphic findings. Laasonen, L.S. et al. (Dept. of Dermatol., Univ., SF-90220 Oulu, Finland) 162:1161 (1994) MR imaging diagnosis of central precocious puberty: importance of chances in the shape and size of the pituitary gland. Sharafuddin, M. J. A. et al. (Dept. of Rad., Univ. Med. Center, 3635 Vista Av. at Grand Blvd., St. Louis, MO 63110, 'USA) 162:1167 (1994) Transrectal sonographically guided drainage of deep pelvic abscesses. Alexander, A.A, et al. (Div. of Diagn. Ultrasound, Dept. of Rad., Jefferson Med. College, Thomas Jefferson Univ. Hosp., 7th Flr., Main Bldg., 132 S. 10th St., Philadelphia, PA 19107, USA) 162:1227 (1994) Archives of Pediatrics & Adolescents Medicine

(Chicago) Radiological case of the month: congenital hiatal hernia. Biehl, D.A. et al. (Wood, B.R, Dept. of Rad., MS81, Children's Hosp., 4650 Sunset Blvd., Los Angeles, CA 90027, USA) 148:421 (1994) Radiological case of the month: esophageal coins. Dowd, M.D. (Wood, B.E, Dept. of Rad., MS81, Children's Hosp., 4650 Sunset Blvd., Los Angeles, CA 90027, USA) 148:423 (1994) Radiological case of the month: congenital neuroblastoma. Souid, A. K. et al. (Wood, B. P., Dept. of Rad., MS#81, Children's Hosp., 4650 Sunset Blvd., Los Angeles, CA 90027, USA) 148:525 (1994) Radiological case of the month: Yersinia enterocolitica masquerading as appendicitis. Chand-

let, N.D., Parisi, M.T. (Wood, B.R,Dept. of Rad., MS#81, Children's Hosp., 4650 Sunset Blvd., Los Angeles, CA 90027, USA) 148:527 (1994) Archives of Surgery (Chicago)

Congenital cystic disease of the tracheobronchial tree in infants and children. Experience with 44 consecutive cases. Coran, A.G., Drongowski, R. (Univ. of Ped. Surg. Associates, F3970 C.S.Mott Children's Hosp., Ann Arbor, MI 48109-0245, USA) 129:521 (1994) Clinical Nuclear Medicine

(Philadelphia)

Nephrotic syndrome as an unusual paraneoplastic syndrome of Hodgkin's disease demonstrated on gallium-67 scan. Juweid, M., et al. (Heyman, S., Children's Hosp.,Dept. of Nucl. Med., 34th & Civic Center Blvd., Philadelphia, PA 19104, USA) 19:224 (1994) Kidney-to-liver ratio: a simple scintigraphic parameter for routine individual renal function assessment in children. Yung, B. C. K., Sostre, S. (Sostre, S., Div. of Nucl. Med., Dept. of Rad., The John's Hopkins Med. Inst., 600 N. Wolfe St., Nelson Tower Basement, Baltimore, MD 21287, USA) 19:228 (1994) Scintigraphic detection of the loss of one kidney following en bloc transplantation of paired pediatric kidneys. Rosen, J. M. et al. (Div. of NucI. Med., Dept. of Rad., Mount Sinai Med. Center, Box 1141, One Gustave Levy Place, New York, NY 10029, USA) 19:233 (1994) Scintigraphic findings of osteomyelitis after intraosseous infusion in a child. Barron, B.J. et al. (Univ. Med. School, Dept. of Rad., 6431 Fannin, Suite 2.132, Houston, TX 77030, USA) 19:307 (1994)

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