Hyperphosphatasia with massive osteoectasia: a 45-year follow-up

Skeletal Radiol (2007) 36: S2–S6 DOI 10.1007/s00256-006-0176-3 E. F. McCarthy G. H. Sack Received: 7 April 2006 Revised: 9 May 2006 Accepted: 2 June 2006 Published online: 17 August 2006 # ISS 2006 E. F. McCarthy (*) Department of Pathology and Orthopaedic Surgery, Division of Surgical Pathology, The Harry & Jeanette Weinberg Building, 401 N. Broadway / Room 2242, Baltimore, MD 21231-2410, USA e-mail: [email protected] Tel.: +1-410-6143653 Fax: +1-410-6143766 G. H. Sack Department of Internal Medicine, 600 N., Wolfe Street, Baltimore, MD 21231, USA Tel.: +1-410-9552374 Fax: +1-410-9558095 CASE REPORT Hyperphosphatasia with massive osteoectasia: a 45-year follow-up Abstract Hyperphosphatasia is a heterogeneous group of disorders characterized by a generalized skeletal disease and increased alkaline phosphatase. Increased bone remodeling secondary to increased osteoclastic activity appears to be the underlying feature of these disorders. These disorders include juvenile Paget’s disease, expansile skeletal hyperphosphatasia, hyperostosis generalisata with striations, and CamuratiEngelmann’s disease, type II. The genetic mutations for a number of these disorders have been identified. We present a patient with congenital hyperphosphatasia whose clinical and radiographic features were somewhat different from these other well-defined syndromes. The patient was followed for 45 years until his Introduction In 1953 Bakwin and Eiger described a child with skeletal fragility, generalized expanded bones with coarse trabeculae, and an elevated alkaline phosphatase [1]. They felt that the changes in this patient were similar to those of Paget’s disease, and this condition came to be known as juvenile Paget’s disease. However, because adult’s Paget’s disease is a distinct entity, the generalized skeletal disease seen in children is now known as congenital hyperphosphatasia. In addition to terms like juvenile Paget’s disease or congenital hyperphosphatasia, other names have been used to describe this disorder. These include chronic idiopathic hyperphosphatasia, familial osteoectasia, osteitis deformans in children, and chronic progressive osteopathy with hyperphosphatasia. These diagnostic labels describe a death of at age 49. The patient had massive osteoectasia with dense striations involving the entire shaft of his long bones. His spine, pelvis, short tubular bones, and calvarium were also involved. He suffered hearing loss and optic atrophy, but he kept his teeth throughout his life. He was tall with a marfanoid habitus, and he had hypogonadism and hypothyroidism. There was no evidence of mental retardation, and other laboratory studies where within normal limits. This case, as well as other manifestations of hyperphosphatasia, attests to the complexity of the bone remodeling system. Keywords Hyperphosphatasia . Osteoectasia . Juvenile Paget’s disease number of diseases with overlapping phenotypes. Their common feature is hyperphosphatasia, a reflection of increased bone turn-over. We are presenting a case of a patient followed for 45 years with diffuse severe osteoectasia and hyperphosphatasia. Case history The patient was a product of a 33-week gestation complicated by placenta previa. He weighed 6 pounds at birth and had no obvious deformities. A sibling with no deformities had died at 3 days after a 6-month pregnancy. There was no family history of skeletal disease. At the age of 4 years, the patient presented to the pediatric neuromuscular clinic with muscle wasting and weakness, and a S3 muscular dystrophy was diagnosed. By age 13, the muscular weakness and hypotonia persisted. However, radiographs showed diffuse skeletal abnormalities which were interpreted as being Camurati-Engelmann’s disease. They showed diaphyseal widening and coarse trabeculae. As he grew, he developed muscular and bone pain with stiffness. The patient had an elevated alkaline phosphatase. Throughout his entire life, his alkaline phosphatase was from three to ten times the normal value. Other laboratory values were normal. He was treated intermittently with corticosteroids. The patient developed a marfanoid habitus and reached a height of 6’2”. Bone pain and stiffness continued, and in adult life the patient required chronic methadone treatment. Involvement of the calvarium eventually led to pseudo-tumor cerebri with papilledema and mild optic atrophy, and, starting in adolescence, he began to experience hearing loss. The patient kept his teeth throughout his life. He also showed long-standing hypogonadism and hypothyroidism. The expansion of his bones eventually caused skin ulcerations, most severe in the lower extremities. This led to cellulitis, sepsis, and pneumonia, and he died at the age of 49. An autopsy was performed. In addition to the skeletal changes, pneumonia and cellulitis, the autopsy showed optic atrophy as well as hypoplasia of the testes, thyroid, and prostate. The pituitary was small. Radiographs showed that the entire skeleton was affected by an expansile osteodystrophy. This included the long bones, spine, the calvarium, the pelvis, and the short tubular bones. The long bones were uniformly affected throughout their entire length, including the epiphysis at both ends. In some long bones, the expansion of the medullary cavity was severe. For example, the Fig. 2 Specimen radiograph of the radius and ulna removed at autopsy. Both long bones are expanded, and there are radiodense striations. The interosseous space has been obliterated diameter of the medullary cavity at the mid-shaft of the tibia was 12 cm (Fig. 1). Normal for this area is 1.5 cm. The plain radiographs of the long bones showed areas of radiolucency alternating with broad bands of radiodensity which extended linearly down the length of the bone. This is especially evident in the specimen radiograph of the radius and ulna (Fig. 2). The CT images show extensive expansion with rarefaction at the periphery with marked cortical thinning (Fig. 3). There were zones of radiodensity which Fig. 1 AP radiograph of the tibia. The entire shaft is expanded, and there are broad longitudinal radiodense striations Fig. 3 Two CT images of the tibia showing extreme osteoectasia with radiodense striations in the central portion of the bone. Peripherally there is osteopenia. The distinction between the tibia and the fibula is not apparent S4 Fig. 4 AP radiograph of the pelvis showing extreme radiodensity with coarsening of the trabeculae. There is severe osteoarthritis of both hips corresponded to the streaks of radio-density seen on radiographs. There was severe bilateral osteoarthritis of the hip (Fig. 4) and spondylosis of the spine. The skull was moderately thickened throughout (Fig. 5). Histologic features varied, depending on whether tissue was sampled from a radiodense area or a radiolucent area. Radiolucent areas showed thin cortices and trabeculae separated by fatty marrow (Fig. 6). The broad bands of radiodensity showed dense lamellar bone with increased remodeling lines suggesting high turnover (Fig. 7). High turnover seemed to be the main pathologic process rather Fig. 5 CT scan of the skull showing thickening throughout the entire circumference near the skull base Fig. 6 Low power (H&E, × 40) of the bone in a peripheral area of osteopenia and expansion. The cancellous bone is osteopenic, and there extensive fatty marrow. This section is taken from the peripheral zone beneath the periosteum then a defect in either membranous or endochondrae bone formation. However, osteoblasts and osteoclasts were not prominent. Other areas showed myxoid changes in the marrow with woven bone formation. Discussion Congenital idiopathic hyperphosphatasia is a group of disorders with overlapping phenotypes. The genetic mutations have been identified for some of these disorders. The constellation of clinical and radiographic features in the current case has not yet been described. In summary, the patient had severe expansile osteodystrophy with dense Fig. 7 Medium power photomicrograph (H&E, × 60) showing the histologic features of a radiodense striation. There is extreme density of the bone with evidence of numerous remodeling lines reflecting high bone turnover. Osteoclasts and osteoblasts are not prominent S5 medullary striations involving the entire shaft of the long bones. The spine, pelvis, calvarium and short tubular bones were also involved. Diffuse involvement of the skull resulted in pseudotumor cerebri as well as deafness and optic atrophy. He was tall with a marfanoid habitus, and he had hypogonadism and hypothyroidism. He did not lose his teeth. Aside from his hyperphosphatasia, laboratory studies relating to calcium and phosphorus balance were normal. For many years this patient carried the diagnosis of Camurati-Engelmann’s disease, a disorder which occasionally is accompanied by hyperphosphatasia [2]. However, patients with Camurati-Engelmann’s disease have marked endosteal and periosteal thickening of the diaphysis [3], and the epiphyses are spared. This was not present in our case. Also, in Camurati-Engelmann’s disease, the short tubular bones are not usually involved. CamuratiEngelmann’s disease has been shown to be a mutation in a gene which upregulates TGI β1, and it is inherited as an autosomal dominant pattern [4]. The most frequently reported syndrome of congenial hyperphosphatasia has similar phenotypic features to the original case reported in 1956. This disorder is most commonly referred to as juvenile Paget’s disease. Patients with this disorder show wide osteoporoatic bones with coarse trabeculae. They have a short stature with enlargement of the head, and most patients have severe hearing impairment. There is often vertebral osteoporosis, and fractures may be common [5]. This disorder has been shown to be due to an inactivating mutation of the gene encoding osteoprotegrin [6, 7]. Osteoprotegrin is synthesized by osteoblasts, and is a competitor for RANK-L. Without osteoprotegrin, there is uncontrolled activation of osteoclast differentiation and resulting high bone turnover [8]. This mutation is inherited as an autosomal recessive pattern. Another disorder which has been recently characterized is expansile skeletal hyperphosphatasia [9]. This disorder, transmitted in an autosomal dominant pattern, is characterized by severe expansion of the long bones. The skull is involved and early deafness results. However, unlike our current case, the teeth in expansile skeletal hyperphosphatasia are lost very early. The genetic mutation this disorder is an activating mutation of the gene coding RANK protein resulting in increased osteoclastic activation and high levels of alkaline phosphatase [10]. A similar mutation occurs in another disorder known as familial expansile osteolysis [11]. This disorder is characterized by deafness, tooth loss and expansile osteopenic zones in bones, similar to lytic Paget’s disease [12]. This disorder may begin in childhood [13]. Another sclerosing bone dysplasia associated with hyperphosphatasia is known as hyperostosis generalisata with striations [14]. This disease is characterized by widening of the entire shaft of the long bones with dense medullary coarse striations, features similar to those of the current case. However, in this disorder, cranial involvement is often minimal and cranial nerve palsy is rare. Another disease, possibly a variant of hyperostosis generalisata with striations, is Camurati-Engelmann’s disease type II [15]. Radiographic features are similar to the current case, except skull involvement is minimal and cranial nerve involvement is not present. However, as in the present case, patients have extreme bone pain and a marfanoid habitus with delayed sexual development. The exact classification of this present case is not possible. The clinical and radiographic features overlap with many of the other disorders characterized by bone dysplasia and hyperphosphatasia. All of these disorders are characterized by high bone turnover. Probably many mutations are involved in this group of disorders. The fact that many separate mutations can lead to increased bone remodeling and hyperphosphatasia attest to the complexity of the remodeling system. References 1. Bakwin H, Eiger M. Fragile bones and macrocranium. J Pediatr 1956; 49 (5):558–64. 2. Whyte M. 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