Osteoporosis-pseudoglioma syndrome

A m e r i c a n Journal of M e d i c a l Genetics 4530-37 (1993)

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Osteoporosis-Pseudoglioma Syndrome Anne De Paepe, Jules G. Leroy, Lieve Nuytinck, FranGoise Meire, and Jan Capoen Department of Medical Genetics (A.D.P.,J.G.L., L.N.), Department of Ophthalmology (F.M.),and Department of Radiology (J.C.),University Hospital Gent, Belgium

Two patients with osteoporosis pseudoglioma syndrome are described. Both are single children, born to nonconsanguineous, healthy parents. The first patient, a 17-year-old girl, had serious visual impairment since birth. She is severely dwarfed and has major skeletal deformities resulting in inability to walk since age 2 years. The second patient is an 18-year-old girl with unilateral neonatal blindness, short stature and deformities, mainly of pelvis and lower limbs. She has been able to walk with support up to now. The clinical and radiological findings in these 2 patients reflect the clinical variability of the condition. Results of collagen studies in both patients are normal and differentiate this condition clearly from severe osteogenesis imperfecta, which it resembles. o 1993 Wiley-Liss, Inc.

KEY WORDS: osteoporosis, pseudoglioma, blindness, skeletal deformities, autosomal recessive, collagen type I INTRODUCTION Osteoporosis-pseudoglioma syndrome, a rare nosological entity, consists of premature, generalised osteoporosis leading to bone deformity and fracturing and is associated with progressive vitreoretinal degeneration and phthisis bulbi [Neuhauser et al., 1976; Bartsocas et al., 19821. In 1985, F’rontali et al. reviewed the clinical findings in 21 patients from 8 sibships. Congenital blindness or loss of vision in the first years of life is nearly constant. The skeletal changes soon impair ambulation and result in major physical handicap and short stature. The syndrome appears to be caused by the homo-

Received for publication January 22, 1992; revision received May 7, 1992. Address reprint requests t o Dr. Anne De Paepe, University Hospital Gent, Faculty Center Medical Genetics (OK5), De Pintelaan 185, B-9000Gent, Belgium.

0 1993 Wiley-Liss, Inc.

zygous state of a single mutant gene [Neuhauser et al., 1976; F’rontali et al., 19851. Its pathogenesis remains unknown, but the clinical manifestations strongly suggest that this condition is a connective tissue disorder. CLINICAL REPORTS Patient A This is a 17-year-oldgirl (Fig. 11,the only daughter of nonconsanguineous, healthy parents. The father was 28, the mother 26 years old at the patient’s birth. She was born a t 41 weeks of gestation after an uneventful pregnancy and delivery. Within the first weeks of life, visual impairment was noticed: the eyelids remained constantly closed and pupillary light reflexes were absent. An eye examination at 10 weeks showed bilateral large and cloudy corneae, absence of the anterior eye chamber, iris atrophy, posterior synechiae and lens opacities. The presence of retrolental white masses was demonstrated echographically. The eye abnormalities were diagnosed as “Reese type retinal dysplasia.” At that time, weight was 5,120 g (50-75th centile), length 59 cm (75-90th centile) and OFC 38 cm I:10-25th centile). Except for the eye anomalies and blindness, no physical abnormalities were noticed. Psychomotor development was recorded as normal up to age 2 years. At that age, she was admitted for a seizure with concomitant fracture of the right thigh which was treated with immobilisation and casting. She was never able to stand or walk independently thereafter and became progressively more dependent on walking aids. She suffered a few other fractures, developed progressive bowing of the legs and became wheelchair-bound at age 11 years. Consecutive radiographs showed severe osteoporosis with bowing and deformities of the lower limbs, especially of tibiae and femora. These findings led to the diagnosis of osteogenesis imperfecta (01). The patient was referred to the genetic clinic through the 01 patient organisation at age 17 years. She was totally blind, unable to walk or sit alone and had to be transported in a specially designed wheelchair. She had a broad face with prominent mouth. The sclerae were white, the irises blue. Both corneae was opacified. She had photophobia and lateral nystagmus. Severe obesity and short stature (length 116 cm) were present. The OFC was 54 cm. The neck was short. The upper thorax and limbs were relatively well developed,

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Fig. 1. Patient A at ages 18 months (a) and 17 years (b),respectively.

but the lower trunk and lower limbs were extremely short, bowed and deformed. She had a thoracolumbar scoliosis with lumbar hyperlordosis and sacral hyperkyphosis. The pelvis was severely deformed. The right knee was fixed completely in extension. Although she had received little schooling, she was apparently of normal intelligence. A neurologic examination showed no abnormalities. A radiologic skeletal survey (Fig. 2) disclosed severe, generalised osteoporosis of all bones. The skull cortex was thin with radio-opaque densities in both orbits. The vertebral bodies were flattened with concave end-plates. All long bones showed extreme osteoporosis and thinning of the cortex with cystlike dilatations in the metaepiphyseal regions. An ophthalmologic reexamination showed bilateral microphthalmia, complete opacification of the corneae and obliteration of the anterior chamber with hypoplastic irises and cataract. The posterior eye structures had completely disintegrated, presenting the image of “phthisis bulbi .” CT-scan of the orbits (Fig. 3) confirmed the microphthalmia and the complete disarray of all ocular structures. No abnormalities of the brain were seen. Blood and urinalysis, particularly levels of calcium, phosphorus, magnesium and alkaline phosphatase, were normal.

Patient B This is the 18-year-old daughter (Fig. 4) of a nonconsanguineous, healthy couple. The father was 26 and the mother 33 years old a t the patient’s birth. There were no other sibs. The patient was born at 39 weeks of gestation after an uneventful pregnancy and delivery. Birth weight was 3,300 g, birth length 52 cm. Visual problems were noted neonatally. An opthalmologic examination showed bilateral microphthalmia with atrophy of the left eye. In the right eye, a cystic, vascularised mass was found, extending posteriorly from the papillary region into the anterior part of the eye. Peripheral retinal dystrophy was seen. At age 3 years, visual acuity was decreased to 5/10 in the right eye; in the left eye, light perception was completely absent. During the first years of life, psychomotor development was normal, except for a mild delay in walking. She suffered a first fracture of the left femur a t 11 years. Radiographic examination documented marked osteoporosis of all bones and confirmed the presence of a fracture in the upper third of the left femur. The diagnosis of 01 was established on the basis of the clinical history and radiologic findings. Despite surgical repair with intramedullary rodding of the left femur, the fracture did not heal. A stress fracture of the right femur followed shortly afterwards. During the next years, the

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Fig, 2. Radiographs of patient A, respectively, of the skull (a), femora (b),pelvis (c), and hands (d) showing marked osteoporosis,deformitiesof pelvis and long bones, and cystic dilatation of meta-epiphyseal regions.

patient fractured her left arm twice and her right arm once, in each instance after minor trauma. Despite successive operations, the femoral fractures never consolidated completely. Because of increasing walking difficulties, she started to use walking aids a t the age of 15 years. Mental development of the patient was completely normal and she performed excellently at school. At 16 years, the visual problems in the right eye

worsened as the result of a vitreous hemorrhage. Ophthalmologic reexamination at that time confirmed total absence of visual perception in the left eye, with corneal opacification. The corneal diameter measured 9 to 10 mm in the right and 6 to 7 mm in the left eye. The visual acuity of the right eye was decreased to 3/10; no marked abnormalities were seen on cornea, iris and anterior chamber, but persistence of the primary vitreous was

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Fig. 3. Orbital CT-scan of patient A showing disintegration of orbital structures with intraocular calcifications and phthisis bulbi.

noticed. A retrolental dense mass, diagnosed as “pseudoglioma” was documented ultrasonographically in the right eye, while in the left eye, total phthisis of the eye structures was seen. At 19 years, she was referred to the genetic clinic. She was short (length 145 cm) and obese (weight 46 kg). OFC was 53.5 cm. She had a rather broad face and prominent mouth, bilateral microphthalmia and lateral nystagmus. Her sclerae were white, the irises blue and the left cornea was opacified. Her trunk and limbs were well developed and not deformed, except for a mild thoracoscoliosis and a moderate lumbar torsion-scoliosis. She was able to stand independently, but walked with support only. Numerous striae cutis distensae were present on breasts and thighs and scars on the left thigh were red and hypertrophic. There was no joint hyperlaxity and mobility of the limbs was normal. She appeared to be an intelligent girl and attended the last year of senior high school. Roentgenographic skeletal survey (Fig. 5) showed severe, generalised osteoporosis of all bones. The skull was small with respect to the prominent jaws and showed impressiones digitatae. The spine showed global osteoporosis, but the shape of the vertebral bodies was preserved. There was a mild dextroconvex thoracoscoliosis with a prominent sinistroconvex lumbar torsionscoliosis. An old fracture was seen on the seventh rib. The shape of the first ribs was bilaterally irregular, showing a pseudarthrosis on the left side. Multiple grow arrest lines were visible in the pelvis and in the metaphyseal region of all long bones. Although the pelvis was somewhat asymmetric, its general shape was relatively well preserved. All long bones were thin and showed marked osteoporosis. Epi-metaphyseal regions were widened with respect to the diaphyses. Intramedullary rods were present in both femora and unconsolidated femoral fractures were seen bilaterally, with pseudar-

throsis formation on the right side. A cystlike zone with sclerotic margins was seen in the proximal diaphysis of the right tibia. “he fibulae were very thin and showed mild bowing, but otherwise, no marked deformity of the long bones was present. CT-scan of the orbits (Fig. 6) showed virtual obliteration of the left eye structures, while the volume of the right eye was still normal. MATERIALS AND METHODS Microscopical Studies Skin biopsy specimens were taken from the upper arm in both patients and their parents, except for the mother of the first patient who refused the minor procedure. One part of the skin specimen was prepared for morphological examination. Fibroblast cultures were set up from the other part for biochemical collagen analysis. Biochemical Studies Skin fibroblast cultures were established from explants of skin biopsies. The cells were maintained in Optimen-1 (Gibco-BRL, Gibco Ltd, Prisley, Scotland, U.K.) supplemented with 2% Ultroser G (Gibco-BRL, Gibco Ltd, U.K.) and 5% foetal calf serum under conditions as described [Nuytinck et al., 19921. Cultured fibroblasts at confluency were incubated for 20 hours in medium containing 25pg/ml ascorbic acid and 50 pCi/ml 14-C proline. After labelling of the cells, the medium and cell layer were removed and investigated separately. Procollagens were prepared by standard methods [Bonadio et al., 19851 and separated by 5%SDS-polyacrylamide gel electrophoresis [Laemmli, 19701. Collagens were obtained by proteolysis of 14-Cproline labelled procollagens with pepsin (50 p,g/ml at 15°Cfor 6 hours), separated on 5% SDS-polyacrylamide gels and processed for fluorography [Laskey and Mills, 19751.

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Fig. 4. Patient B at age 18 years: the face (a)and patient standing with support (b).

Pepsin-digested procollagens were treated with cyanogen bromide (CNBr) and separated in the second dimension on 3-10% SDS-polyacrylamide gels with 0.5 mol/l urea [Bonadio et al., 19851. For investigation of the collagen processing, procollagens were extracted from the medium, following the harvest at, respectively, 5 hours and 24 hours, and subsequently each day up to day 11. They were analysed by 5% SDS-polyacrylamide gel electrophoresis.

RESULTS Morphological Studies In both patients, light microscopical characteristics of the skin were normal. Electron microscopical examination confirmed a normal shape and periodicity of the collagen fibrils without significant variability in fibril diameter (7,500to 8,500 nm). In some places, smaller bundles without periodicity were seen. No abnormalities of the elastic fibres were noticed. Biochemical Studies No differences could be detected in the electrophoretic pattern of the pro-a and a-chains of procollagen and collagen type I and 111, neither in the medium nor in the cells obtained from the patients and their parents, as compared to control samples.

Also, both patients showed a normal two-dimensional peptide pattern after digestion of collagens with cyanogenbromide, as compared to a normal control sample (data not shown). In addition, SDS-polyacrylamide gel electrophoresis of collagens and procollagens harvested at different times during the processing experiment yielded completely normal results in both patients (data not shown).

DISCUSSION Although the patients present the characteristic skeletal and ocular abnormalities of osteoporosis pseudoglioma syndrome (OPS), they both had been diagnosed initially as a severe form of 01. As such, the first patient was referred through the Belgian 01 foundation of which she and her parents had been members for several years. Phenotypic confusion between OPS and 01 has indeed been reported in other instances [Beighton et al., 1985; Stoss, 1986;Superti-F’urga,1986; Teebi et al., 19881. The clinical and radiological characteristics of the patients are very similar but they present marked differences in the severity of the clinical phenotype and in the degree of bone deformity. The first patient was completely blind, almost from birth. An eye examination disclosed complete obliteration of all ocular structures, precluding observation of the ophthalmologic features typical of this condition at

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Fig. 5. Radiographs of patient B, respectively, of skull (a),knees (b),pelvis ( c ) ,and spine (d)showing osteoporosis, growth arrest lines in metaphyseal regions of long bones and pelvis and cystic lesion in tibia.

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Fig. 6. Orbital CT-scan of patient B: severe obliteration of the left ocular structures, while right eye is well preserved.

the time of diagnosis. Fortunately, records from the eye examination shortly after birth were available to confirm the presence of the typical ocular changes of OPS: absent anterior eye chamber, posterior synechiae, iris atrophy, lens opacities and white retrolental masses. In the second patient, only the left eye was severely affected at birth, while the typical ocular abnormalities of OPS were still recognizable in the right eye at age 16 years. Both patients had white sclerae. In both of them the ocular findings had initially been interpreted as “Reese retinal dysplasia”, a condition consisting of retinal malformation with persistence of primary vitreous substance, as found, e.g., in Norrie disease. The skeletal changes in the first patient were severe: she was very short and able to stand with support by age 2 years, but she never learned to walk unaided. However, in the second patient the degree of osteoporosis with fractures and deformity was less pronounced. She was able to walk independently up to age 16 years. This illustrates the clinical variability of the condition in accordance with other observations reported in the literature [Frontali et al., 1985; Somer et al., 19881. The mental status of both patients is normal. The second patient is an excellent student. Therefore, mental retardation is not consistent in this entity. The pathogenesis of OPS remains unclear. In view of the phenotypic resemblance to 01, the possibility of a biosynthetic defect of type I collagen was suggested, but not proved [Beighton et al., 1985; Somer et al., 19881. One report [Somer et al., 19883 deals with biochemical investigations on collagen biosynthesis in a brother and a sister with OPS.No abnormalities of procollagen and collagen type I production were detected. The biochemical findings in the present patients confirm this observation. Normal results are obtained by SDS-poly-

acrylamide gel electrophoresis of procollagens and collagens in first and second dimension, as well as by the investigation of collagen processing. These results suggest that, unlike 01,a genetic defect of type I collagen is not the primary defect in OPS. Therefore, different pathogenetic mechanisms underlie OPS and 01, respectively. Retinal detachment and vitreo-retinal degeneration may be found in some chondrodysplasias, such as Stickler syndrome and spondiloepiphyseal dysplasia congenita. Both have been linked to the collagen type I1 gene, located on chromosome 2 [F’rancomano et al., 1987; Anderson et al., 19901. Collagen type I1 is a major structural component of cartilage and vitreous body. However, severe osteoporosis is not prominent in these chondrodysplasias. In our patients, no cartilage biopsies were available for collagen type I1 studies. In conclusion, we illustrate that OPS is a variable nosological entity with clinical resemblance to, but distinct from, severe 01. Most likely it has a different pathogenesis, not primarily involving structural defects of type I collagen.

REFERENCES Anderson IJ, Goldberg RB, Marion RW, Upholt WB, Tsipouras P (1990):Spondyloepiphysealdysplasia congenita: Genetic linkage to type I1 collagen (COL2A1). Am J Hum Genet 46:896-901. Bartsocas CS, Zeis PM, Elia M, Papadatos CJ (1982): Syndrome of osteoporosis with pseudoglioma. Ann GBn6t 25:1:61-62. Beighton P, Winship I, Behari D (1985):The ocular form of osteogenesis imperfecta: A new autosomal recessive syndrome. Clin Genet 2869-75. Bonadio J, Holbrook K, Gelinas R, Jacob J, Byers P (19851:Altered triple helical structure of type I procollagen in lethal perinatal osteogenesis imperfecta. J Biol Chem 260:1734-1742. Francomano CA, Lieberfarb RM, Hirose T, Maumenee H, Streeten EA,

Osteoporosis-PseudogliomaSyndrome Meyers DA, Pyeritz RE (1987):The Stickler syndrome: Evidence for close linkage to the structural gene for type I1 collagen. Genomics 1:293-296. Fkontali M, Stomeo C, Dallapiccola B (1985): Osteoporosis-pseudoglioma syndrome: Report of three affected sibs and a n overview. Am J Med Genet 22:35-47. Laemmli UK (1970):Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 226:680-685. Laskey R, Millis A (1975):Quantitative film detection of 3H and 14Cin polyacrylamide gels by fluorography. Eur J Biochem 56:335-341. Neuhauser G , Kaveggia E, Opitz J M (1976):Autosomal recessive syndrome of pseudogliomatous blindness, osteoporosis and mild retardation. Clin Genet 9324-332.

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Nuytinck L, Narcisi P, Nicholls A, &nard JP, Pope FM, De Paepe A (1992):Detection and characterisation of an over-modified type 111 collagen by analysis of non-cutaneous connective tissues in a patient with Ehlers-Danlos syndrome IV. J Med Genet 29:375-380. Somer H, Palotie A, Somer M, Hoikka V, Peltonen L (1988): Osteoporosis-pseudoglioma syndrome: Clinical morphological, and biochemical studies. J Med Genet 25543-549. Stoss H (1986):Letters to the editors: Osteogenesis imperfecta or osteoporosis-pseudoglioma syndrome. Clin Genet 30:447-448. Superti-Furga A (1986): Letters to the editors. Clin Genet V:29. Teebi AS, Al-Awadi SA, Marafie MJ, Bushnaq RA, Satyanath S (1988): Osteoporosis-pseudoglioma syndrome with congenital heart disease: A new association. J Med Genet 2532-36.