Pediatric Radiology

Pediatr Radiol (1988) 18:399-404

© Sptinger-Vedag 1988

The osteoporosis pseudoglioma syndrome. Update and report on two affected siblings W. Swoboda 1 and F. GrilF 1Ludwig Boltzmann Institute for Paediatric Endocrinology and z Department of Paediatrics, Orthop/idisches Spital, Vienna, Austria

Abstract. Two siblings (male, 29 years, and female, 13 years) with the rare autosomal recessive osteoporosis pseudoglioma syndrome are reported in detail. All essential signs and symptoms o f the full clinical picture were present and are d o c u m e n t e d by impressive X-ray pictures. Some aspects o f our patients are compared with relevant findings o f previous reports. Collagen studies (skin biopsies) failed to reveal any significant disorder o f the main collagen types composition. Striking similarities with established genetic disorders o f collagen (like the osteogenesis imperfecta group and the Ehlers-Danlos syndrome) suggest, however, that the OPS could be a primary collagen disorder. Genetic counselling and devoted socio-medical care for these handicapped children is presently the only help which can be offered.

The osteoporosis pseudoglioma syndrome (OPS) is a very rare, genetically determined disorder that occurs in the development o f the skeleton and the eyes and is accompanied by some degree o f laxity o f ligaments. In contrast to osteogenesis imperfecta (OI), where ocular affection is occasionally present to a varying degree, severe primary damage o f the chorioretinal parts o f the eye with consecutive destruction o f the entire eye is an essential part o f the OPS. The syndrome received its present denomination from McKusick [1, 2]. Autosomal recessive inheritance was suggested and confirmed by him as well as by other authors before and after his own observations [3-13]. Published cases are considered as very rare, and in 1984 the frequency was stated as This study is dedicated to Walter Teller, MD, Professor of Paediattics and Director of the Childrens' Hospital, University of Ulm, FRG, with sincere feelings of friendship on the occasion of his forthcoming 60th birthday!

"less than 10 reported cases" [14]. Our presentation o f two siblings (male and female) is intended as a contribution towards spreading the knowledge o f a widely u n k n o w n syndrome. In addition, this p a p e r provides information about the long-term effects of the disease, as one o f our patients belongs to the older age group that has not often been reported. A comprehensive overview was published recently [12], so we shall not discuss the literature in detail.

Case reports

Family history The parents are healthy with no known consanguinity. Patient 1, male, born in 1957, is the first of four children of the couple. Patient 2, female, born in 1973, is number three. The two other children, both males, are unaffected.

Patient 1 This patient was born after an uneventful pregnancy "without detectable abnormality", but by the 2nd month, a turbidity of the eyes was noticed which was followed by progressive atrophy of both eyes. The patient has been practically blind since early infancy. He has had six bone fractures between 4 and 19 years. Deformities of the spine and legs developed gradually together with retardation of longitudinal growth. Bone histology was taken at an operation on the femur at age 16. The pathologist's report was: osteogenesis imperfecta, Lobstein's type. Physical examination: primary teeth in bad condition, secondary teeth in good state. No ligament weakness was noticed and muscular, neurologic, intellectual and hearing development was normal. Performance in an institution for the blind was good; the patient even learned stenotyping. Presently he is working satisfactorily as a telephone operator in an institution for handicapped persons. Examination at age 29: height 148 cm (!), weight 59 kg. Despite a significant kyphoscoliosis and pronounced deformities of the legs he does not complain about locomotor difficultiesor any noteworthy pain. The X-ray films (Figs.1-3) show severe secondary signs of osteoporosis as well as residuals after fractures and operation upon the femora, but there is no indication of active

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W. Swoboda and F. Grill: Osteoporosis pseudoglioma syndrome

Figs.1 and 2. Patient I at age 29. Vertebral column showing mild skoliosis, osteoporosis, and severe deformities of the vertebral bodies, mainly in the thoracic region

metabolic bone disease. This situation is supported by the serum chemistry: calcium 2.41 mmol/1, inorganic phosphate 1,0 mmol/ 1, alkaline phosphatase 254 U/l, parathyroid hormone (PTH) 2.7mU/l, 25-hydroxy-cholecalciferol (25-OH-CC) 5.2ng/ml. Examination of the eyes: complete blindness due to bilateral "phthisis bulbi", and significantly thickened corneae with calcified inclusions; deeper parts cannot be examined. (Identical findings had been obtained by the same examiner at age 6.) In the skull X-ray, intraocular calcifications are visible (Fig.4a).

Patient 2 She is the younger sister of patient 1. Pregnancy and birth are reported as uneventful. Immediately after birth the parents noticed the absence of eye reactions with light stimulation. At the age of 3 months, an ophthalmologic examination revealed slight thickening and some calcifications of the cornea, atrophy of the iris and turbidity of the right lens. Left side: lens still clear, behind the lens there is yellowish membrane-like tissue. (In retrospect, the ophthalmologist interprets his previous findings as being in agreement with the diagnosis of a "pseudogliomatous degeneration of the eye".) Except for one fracture of a clavicle, no history of, or tendency for bone fractures was reported. At age 10 an orthopedic examination was performed because of consistent back

pain. X-ray suggested juvenile osteoporosis or osteogenesis imperfecta tarda. The development of ligaments, teeth and hearing was normal. At age 3 years, the patient suffered three attacks of generalized convulsions. Antiepileptic treatment, together with calcium and vitamin D medication was started and brought the convulsive disorder under control. At age 12 the EEG was normal. Intellectual development was above average with strong interest in music (plays piano and flute), and excellent performance in an institution for blind children. Examination at age 13: height 129 cm (2 cm below 3rd centile), weight 25 kg (average for height). There was significant thoracic kyphosis but pain was brought under full control with a corset. No deformities or pain in the legs were observed. X-ray showed generalized osteoporosis (Fig. 5) with pronounced "codfish" vertebrae (Fig.6). Serum chemistry within normal range: calcium 2.2mmol/1, inorganic phosphate 1.7mmol/1, alkal.phosphatase 600 U/1 PTH 2.1 mU/1, 25-OH-CC 41 ng/ml (elevated due to daily vitamin D supplement). Urine: normal excretion of calcium, slightly elevated hydroxyprolinuria. Examination of eyes: both corneae were significantly thickened with belt-like calcifications and bilateral atrophy of iris lenses with high density. Full blindness was due to bilateral phtisis bulbi. Again, intraocular calcifications can be seen on the skull X-ray (Fig.4b).

W. Swoboda and F. Grill: Osteoporosis pseudoglioma syndrome

Special investigations It is well known that m a n y types o f osteoporosis/ osteopenia as well as osteogenesis imperfecta (OI) do not present with abnormal blood mineral chemistry findings, because collagen metabolism is primarily involved. To date, we have not obtained permission to do b o n e biopsy in either patient. Moreover, there was no indication for open bone surgery. However, skin biopsies were possible and cultured

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skinfibroblasts were examined by Professor B. Pontz (University o f Mainz, Children's Hospital, FRG). The summary o f the results o f his investigation reads as follows: "The separated components of the collagens (alpha-1 and alpha-2 chains, respectively, of type I collagen as well as of type II collagen) show normal electrophoretic mobility. The type III collagen is 12.6% of the total collagen synthesis,which is within the normal range. The relation of alpha-1 to alpha2-chains of type I collagen was 2.13, which is also within the normal range (theoretical standard value 2.0). In summary, we did not find any abnormality relating to the distribution of fibroblast types or of the constitution of the type I collagen. This, however, does not exclude a possible minor increase in lysine hydroxylation, since we used only proline but not lysine as a marker. Personally, I could envisage a disorder of the collagen metabolism in your patient."

Discussion Incidence and genetics

Fig.3. Patient 1. Severe osteoporosis of the knee region with secondary deformities of the joint constituents

The OPS, probably described for the first time in 1955 [8], but then interpreted as "atypical osteogenesis imperfecta", has been reported with increasing frequency in the past decade. Relevant cases were observed in France, Greece, Italy, the USA and now in Austria. A higher gene frequency in mediterranean countries was suggested [12]. The autosomal recessive transmission by phenotypically healthy parents is so obvious that the few sporadic cases can be ignored in this respect. Moreover, genetic calculations do not leave any doubt [12].

Fig.4. a Skull of patient 1 showing massive intraocular calcification on the right side. b Skull of patient 2 at age 12, showing marked calcification of the right eye ball, and beginning deposition of calcified material in the left eye

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W. Swoboda and F. Grill: Osteoporosis pseudoglioma syndrome

Fig.5. Patient 2, showing generalized osteoporosis but without significant deformities at age 12 Fig.6. Patient 2. Severe osteoporosis of the spine with remarkable deformations and height-reductions of thoracic (and, not shown here, also upper lumbar) vertebrae ("codfish type")

Clinical picture and diagnosis The leading clinical sign is definitely the severe damage of the eyes which usually occurs in the prenatal period. Therefore this characteristic becomes evident very early in life, often immediately after birth, as in patient 2. This fact explains why some cases were primarily published in the ophthalmologic literature [6, 11, 13]. The identification of the typical eye lesions may be difficult in the beginning. They were classified as "hyalorentinal dysplasia" [4]. After a rapid progression, atrophy of the entire eye-ball ("phtisis bulbi") develops, comprising degeneration and calcifications of all parts of the eye. Misinterpretation of such findings as retinoblastoma [3] led to enucleation of the eye and consequently to the underlying pathology of "pseudoglioma", used until now for characterizing the syndrome. The finding of calcifications in the skull X-ray is not unique. It was also seen by others [7, 12] and can thus support the diagnosis. The osteoporosis or osteopenia differs in severity as well as time of onset of clinical symptoms. Manifestation of bone fragility is reported not before the age of 4 years. Number and severity of fractures are rather variable, as our two patients demonstrate. Though many characteristics of the OPS support a relationship with OI, it may well be that the main symptoms of "idiopathic juvenile osteoporosis" (shortening of the trunk with kyphosis and back pain) are the first

skeletal complaints that lead to radiological examination. So, the X-ray findings can either resemble those of OI or those of juvenile osteoporosis, respectively, but in combination with the presence of blindness the correct diagnosis cannot be missed. Accessory signs of impaired development of connective tissue were noticed in a number of cases, manifested as laxity of ligaments and mild muscular weakness. Development of teeth is usually not disturbed. Parallel to the severe damage of the eyes, further damage of nervous tissue might be expected, and in fact this was observed in some patients, although in the majority only to a mild extent: Microcephaly, mental retardation, convulsions (as in patient 2), and others. As mentioned in most case reports, and confirmed by our own observations, biochemical examinations do not yet contribute to the diagnosis. As could be expected, no significant abnormalities in the parameters reflecting the mineral metabolism were found. Hydroxyprolinuria and hypercalciuria, present in some stages of the disease, are non-specific findings, occurring in a number of different osteopenic/osteoporotic/osteomalacic conditions.

Course and prognosis Since blindness is permanent by its very nature, we can focus on the skeletal situation. The course of the bone disease seems to follow individual factors.

W. Swoboda and F. Grill: Osteoporosis pseudoglioma syndrome

It also depends on the number and localisation of previous fractures as well as on the quality of their respective treatment. We do not know if prolonged brace treatment of the spine will prevent progressive damage of the vertebrae, or if it is only effective in reducing pain. In contrast to idiopathic juvenile osteoporosis, spontaneous reconstitution of the deformed vertebral bodies is unlikely in the OPS (compare patient 1). Adult height depends on the correct development of the spine as well as on that of the legs. Our patients were of short stature, despite average height of both parents, and our young man was to some extent "dwarfed". Significant deformities of the legs as well as the short spine contributed to this outcome, and short stature as such seems to be a frequent [12] though not essential part of the syndrome, as can be seen in the oldest patients with this syndrome reported on [5]. Intellectual development is often reported as poor. Our own cases show the contrary. School performance and social adjustment are average or even above. The discrepancies in the literature about this aspect may not only depend on the difference of possible involvement of the nervous system, or its connective tissue, in the metabolic disorder. Inadequate sociointellectual adjustment might very well be secondary to blindness, thus representing a type of "pseudomental deficiency", a well-known phenomenon in children who are blind for other reasons.

Pathology The biochemical background of the OPS is unknown. Basically it is a connective tissue disorder, manifesting itself predominantly in the eyes, the bones and to some extent in the ligaments. Research in the biosynthesis of collagen was started only in the early 1970s, and the understanding of some hefttable disorders in this field has made great progress since [15, 16]. Although at least eight different types of collagen have been identified biochemically [17], only types I and III have been the subject of extensive laboratory research. Type I is the predominant collagen of the body, found in tendons, bone, teeth and skin, type III is prominent in vascular and visceral structures. In a number of syndromes, well-known to the pediatrician, defects in the formation and transformation of collagen components could be established and localised. This has, for a long time, been recognised as the heterogeneity within the OI group, clinically and genetically. It could also be explained biochemically: the different types of OI are associated with different structural disorders of type I collagen or procollagen. In contrast, type III collagen disorders were found in some forms of the Ehlers-Danlos syndrome, a heritable disorder with great variability

403 of clinical signs and symptoms, including severe ocular damage in type IV of the disease. The complexity of collagen formation makes it understandable that all investigations in this field require very sophisticated laboratory methods, and that not infrequently the results obtained do not provide satisfactory explanations. In addition, the distribution of the respective collagen types in various types of tissue or organs seems to be different. This means that a specimen of skin fibroblasts does not necessarily reflect the situation in other parts of the body, e.g. the eye or the bone. For the syndrome under consideration it might be of importance that type I collagen contributes 80 to 85%, and type III collagen 15 to 20%, to the total dermal collagen. In contrast to this, type II collagen is the predominant compound in cartilage and the vitreous mass of the eye, while type V is related to the cornea [17].

As described above, an attempt to clarify the collagen situation in our patients with the help of skin fibroblasts was not successful. Moreover, due to technical difficulties, the investigations unfortunately remained incomplete with respect to present standards. It has to be added that for ethical reasons a substantial examination of the organs primarily involved, namely the eyes and the bone, was not possible. Parallel to the OI and the Ehlers-Danlos syndrome we speculate, however, that also in the OPS the primary disorder is in the formation a n d / or composition of the collagen structure. Possibly one type, which contributes to the collagen specific for the eye tissue, might be the basic pathology.

Treatment Active treatment is not available, of course. Enucleation of the eye(s) should be prevented, being a mutilating and - as malignancy need not be feared an unnecessary operation. Orthopedic measures should remain as conservative as possible. Surgical corrections might be necessary in some situations, but on the other hand they may lead to undesirable results due to the individual variability of the course of the disease. Mental deficiency and other nervous symptoms should not be overestimated as they may be due to inadequate socio-medical care for the blind patients.

Conclusion

The pathology of OPS shows a significant correlation with the OI group. With high probability it can be postulated that the basic disorder is a genetically determined structural dysplasia of collagen component(s). With this mechanism, the osteopathy together with the destruction of the eyes and the laxity of ligaments is reasonably explained. In contrast to the different types of OI, the OPS shows a very homogeneous clinical picture as well as a regular auto-

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somal recessive transmission. The severe damage of the eyes, observed in all patients very early in life, underlines the specific type of collagen disorder. To date, no biochemical findings are available to explain the selective severe eye damage. The present description of this rare syndrome attempts to spread the knowledge about the OPS in the hope that thorough biochemical and other sophisticated investigations will be done whenever an occasion (e. g. bone surgery) presents. Moreover, the improved knowledge should in turn improve genetic counseling. Acknowledgements. We are indebted to Prof. J. Stepanik, Vienna, for the ophthalmologic examinations, and to Prof. B.Pontz, Mainz, for the connective tissue studies.

References 1. McKusick VA (1972) Heritable disorders of connective tissue, 4th edn. Mosby, Saint Louis, p 433 2. McKusick VA (1975) Mendelian inheritance in man, 4th edn. John Hopkins University Press, Baltimore 3. Bianchine JW, Murdoch JI (1969) Juvenile osteoporosis (9.) in a boy with bilateral enucleation of the eyes for pseudoglioma. Birth Defects 4:225 4. Chrisostomidou OM (1973) Retinohyaloid dysplasia with osteoporosis and hypotonia: a syndrome with autosomal recessive transmission in a Greek family. Excerpta Med Int Congr Ser 297:69 5. Neuhauser G, Kaveggia EG, Opitz JM (1976) Autosomal recessive syndrome of pseudogliomatons blindness, osteoporosis and mild mental retardation. Clin Genet 9: 324 7. Bartsocas CS, Zeis PM, Elia M, Papadatos CJ (1982) Syndrome of osteoporosis with pseudogliorna. Ann Genet 25: 61

W. Swoboda and F. Grill: Osteoporosis pseudoglioma syndrome 8. Meyer H (1955) Atypical osteoporosis imperfecta. Lobstein's disease. Arch Pediatr 72:182 9. Sauvegrain J, Duffer JL, Vacher H, Chariot JC, LeHoang Phuc, Haye C (1981) Degrnrrescence hyaloido-retienne avec osteoporose et fragilit6 osseuse. J Radiol 62:537 10. Heide T (1981) Ein Syndrom bestehend aus Osteogenesis imperfecta, Makrozephalus mit Schaltknochen und prominenten Stirnhrckern, Brachytelephalangie, Gelenkfiberstreckbarkeit, kongenitaler Amaurose und Oligophrenie bei drei Geschwistern. Klin P~tdiatr 193:334 11. Lomickova H, Seemanova E, Strobl O, Zaban P (1984) The "osteoporosis pseudoglioma" syndrome. Cesk Oftalmol 40: 89 12. Frontali M, Stomeo C, Dallapiccola B (1985) Osteoporosispseudoglioma syndrome: report on three affected sibs and an overview. Am J Med Genet 22:35 13. Mellor D (1983) Osteoporosis pseudoglioma syndrome. Ophthalmic Pediatr Genet 3:141 14. Kozlowska K, Beighton P (1984) Gamut index of skeletal dysplasias. An aid to radiodiagnosis. Springer, Berlin Heidelberg New York Tokyo 15. Prockop D J, Kivirikko KI, Tuderman L, Guzman NA (t979) The biosynthesis of collagen and its disorders. N Engl J Med 301: 13; 177 16. Prockopp DJ, Kivirikko KI (1984) Heritable diseases of collagen. N Engl J Med 311:376 17. Pinnel SR, Murad S (1983) Disorders of collagen. Chapter 63. In: Stanbury JB, Wyngaarden JB, Frederickson DS, Goldstein JL, Brown MS (eds) The metabolic basis of inherited disease, 5th edn. McGraw-Hill, New York Received: 13 February 1987; accepted: 15 April 1987 Prof. Dr. W. Swoboda Ludwig-Boltzmann Institut far P~idiatrische Endokrinologie Universit~itskinderklinik W~ihringer Gfirtel 18-20 A-1090 Wien/Austria

Literature in pediatric radiology (continued from p. 398) The use of midazolam for sedation of infants and children. Diament, M.J., Stanley, P. (Dept. of Rad., Children's Hosp., 4650 Sunset Blvd., Los Angeles, CA 90027-6089, USA) 150, 377 (1988) Factors affecting visualization of posterior rib fractures in abused infants. Kleinrnan, P. K. et al. (Dept. of Rad., Univ. of Massachusetts Med. Center, 55 Lake Ave. N., Worchester, MA 01655, USA) 150, 635 (1988) Balloon dilatation of esophageal stenosis in children. Sato, Y. et al. (Dept. of Rad., The Univ. Hosp. and Clinics, Iowa City, IA 52242, USA) t50, 639 (1988) Acute scrotal abnormalities in children: Diagnosis by combined sonography and scintigraphy. Mueller, D.L. et al. (Dept. of Rad., Children's Hosp., 1820 Richmond Rd. S.W., Calgary, Alberta, T2T 5C7, Canada) 150, 643 (1988) Sonographic evaluation of ovarian torsion in childhood and adolescence. Grail', M., Itzchak, Y. (The Chaim Sheba Med. Centre and Sackler School of Med., Tel Aviv Univ., Tel Hashomer 52621, Israel) 150, 647 (1988) Clinical Nuclear Medicine (Philadelphia)

Detection of an ileal cavernous hemangiorna by technetiurn-99m red blood cell imaging. Holloway, H. et al. (Sandier, M., Dept. of Nuclear Mexi., Vanderbilt Univ. Med. Center, Nashville, TN 37232, USA) 13, 32 (1988) Correlation between iodine-131 MIBG imaging and biological markers in advanced neuroblastoma. Yeh, S.D.J. et al. (Nuclear Med., Serv., Me-

morial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA) 13, 46 (1988) Clinical Pediatrics (Philadelphia) Multiple sclerosis presenting at 4 years of age: clinical and MRI correlations. DiMario, Jr., F.J., Berman, EH. (Div. of Neurology, Children's Hosp., 34th & Civic Center Blvd., Philadelphia, PA 19104, USA) 27, 32 (1988) Review of urachal anomalies: An unusual presentation of an infected urachat cyst. Boyle G. et al. (Rosenberg, H., Dept. of Rad., The Children's Hosp., 34th St. and Civic Center Blvd, Philadelphia, PA 19104, USA) 27, t30 (1988) Journal of Bone and Joint Surgery American Volume (Boston)

Disorders of the saero-iliac joint in children. Reilly, J.P. (Gross, R.H., Dept. of Orthop. Surgery, Med. Univ., 171 Ashley Av., Charleston, SC 29425-2239, USA) 70-A, 31 (1988) Traumatic dislocation of the hip caused by capsular interposition in a child. Cinats, J.G. et al. (Moreau, M.J., Univ., 10118-111 Street, Edmonton, Alberta T5K 11(6, Canada) 70-A, 130 (1988) Multiple non-ossifying fibromas. Blau, R.A. et at. (Div. of Orthop., State Univ. Hosp., 410 West 10th Ave., N/843, Columbus, OH 43210, USA) 70-A, 299 (1988) (cominued on p. 415)