How to cite this article: Kantaputra PN, Limwongse C, Koolvisoot A, Ausawamongkolkul A, Tayavitit S. 2006. A newly recognized polyosteolysis/hyperostosis syndrome. Am J Med Genet Part A 140A:2640–2645.
We report a patient with polyostotic expansile osteolysis affecting the long bones and iliac bones, hyperostosis of the skull and thoracic cage, pectus carinatum, gigantiform synovial masses of the elbows and knees, ASD, cardiomegaly, cryptorchidism, and mental retardation. To our knowledge, this constellation of findings has not been described previously; it may represent a newly recognized autosomal recessive syndrome.
An 11-year-old Thai boy was first seen for multiple joint swellings. He was the oldest of four children from a first cousin marriage. Two younger brothers and sister were normal (Fig. 1a). Another sister was deceased from an unrelated cause.
Ten days after birth, his elbows and knees began to swell and became larger with age. At 7 months, he was noted to be cyanotic when crying. Clubbing of the fingers and toes was observed. A small ASD and cardiomegaly were detected at 3 years. At 4 years, his mother noted that he tired easily. Hepatomegaly was detected at that time. He became anemic and occasionally required a blood transfusion. Limited extension of his fingers was observed. He fell and broke his left arm at 9 years. At 11 years, the swollen elbows and knees became greatly enlarged. His parents noted that, at times, his periarticular regions were warmer than other parts of his body.
At 12 years, his weight, height, and OFC were 30.5 kg (25th–50th centile), 128 cm (3rd centile), and 49 cm (3rd centile), respectively. His cheeks were full and his tongue was pale. Cervical and submandibular lymphadenopathy was noted and was most likely due to multiple dental abscesses and chronic periodontitis. Protruding abdomen with hepatoplenomegaly and umbilical hernia were observed (Fig. 1a). The left testis was palpable in the inguinal canal. His right testis was within the scrotal sac and was 1 cm in diameter. Stretched penile length was 4.5 cm. Pubic hair was not observed. His elbows and knees were symmetrically swollen with a soft cystic consistency (left elbow, 31 cm in diameter; right elbow, 27 cm in diameter; left knee, 41 cm in diameter; right knee, 40 cm in diameter) (Figs. 1a and 2a). The skin over the swellings was warm and had finely dilated superficial veins. Mild limitation of flexion and extension of the fingers, elbows, and knees was observed. His ankles were swollen medially. His fingers and toes exhibited clubbing (Fig. 1b,c). Wasting of the upper muscles of the upper arms was noted (Fig. 1a).
Developmental evaluation at birth appeared to be normal. He sat, stood, and walked at 6 months, 1 year, and 2 years, respectively. After 2 years, his parents noted gradual developmental delay. He spoke his first word at 2 years. At 7 years, he attended school for 2–3 months and then stopped because of motor difficulty. At 12 years, mental development was severely delayed with an IQ of 24 (Stanford-Binet). He appeared to have more advanced receptive language compared to his minimally expressive language skills.
The patient had chronic hypochromic, microcytic anemia. Hemoglobin electrophoresis yielded a normal hemoglobin type. Other findings included mild elevation of serum phosphorus (5.9 mg/dl: norm 2.2–5.0 mg/dl), but age-appropriate levels of calcium (8.1 mg/dl; norm 8.1–10.4 mg/dl), alkaline phosphatase (151 U/L; norm 39–117 U/L), and parathyroid hormone. Urinalysis, liver function tests, serum BUN (7 mg/dl: norm 5–25 mg/dl), and creatinine (0.4 mg/dl: norm 0.5–1.5 mg/dl) were normal. Elevated levels of beta crosslap (1.56 ng/ml: norm 0.00–0.32) and osteocalcin (196.80 ng/ml: norm 1.00–35.00 ng/ml) indicated increased osteoclastic activity. Synovial tapping of the left knee yielded 150 ml of a clear yellowish joint fluid. Joint fluid studies disclosed a glucose of 95 mg/dl and a very low number of white blood cells, consistent with a non-inflammatory cause of the swelling.
The patient underwent total synovectomy of the left knee at 13 years. The external surface of the synovium appeared as white fibrous tissue with areas of fatty tissue. The internal surface had a smooth and shiny grayish-white surface. The synovial mass contained numerous large yellowish villi (Fig. 2b). The cut surface showed rubbery, grayish-white homogeneous tissue. After removing the synovium, the distal femoral cartilage appeared erosive. Histological study of the synovium disclosed non-specific chronic synovitis with fatty infiltration (Fig. 2c). Bone marrow biopsy at the distal femur showed areas of hyper- and hypo-cellularity and adequate numbers of precursor cells; there was no evidence of a tumor or a granuloma. Two years after total synovectomy, the knee joint was reported to have enlarged to the same size as noted previously.
Affected bones grouped according to skeletal pathology are listed in Table I. Radiographic findings of the skull included thick cranial tables with a widened medullary space and a hair-on-end appearance, hyperostotic cranial vault, and hyperostotic cranial base. The posterior cranial base was flat (Figs. 3a,b). A panoramic radiograph disclosed an underdeveloped mandible, multiple dental caries, and taurodontism of the maxillary second permanent molars. There were multiple areas of unusual and severe bone loss resulting from dental infection (Fig. 3c). Chest radiograph showed a hyperostotic thoracic cage and broad ribs (Fig. 4b). The medial portion of each clavicle showed a thick cortex and narrow medullary space. The lateral portion of each clavicle appeared small. Cardiomegaly was present. The vertebrae were unremarkable (Figs. 4b and 5b).
Table I. Skeletal Findings
Distal phalanges of digits
Expansion without osteolysis
Osteolysis without expansion
Thoracic cage and ribs
Proximal end of femur
Diaphyseal/metaphyseal expansion was somewhat symmetric with multiple osteolytic lesions and very thin cortices. Expansile osteolytic lesions were present at the distal ends of the humeri and proximal ends of the radii and ulnae; all had extremely thin cortices. Trabecular septae had an irregular pattern (Fig. 6a,b). The distal radii, ulnae, and carpal bones were unremarkable except for thin cortices. Large soft tissue masses were evident at the elbows (Figs. 6a,b). Radiographs of the hands at 11 and 12 years showed medially dislocated distal phalanges of both thumbs and narrow proximal interphalangeal joint spaces of digits 2–4. The middle phalanges of fingers 2–5 did not appear to have broad ends. Progressive acro-osteolysis was observed in the distal phalanges of the thumbs and fingers 2–5. The distal phalanx of fingers 5 on both sides appeared tapered (Fig. 4a).
A pelvic radiograph showed multiple large osteolytic lesions of the iliac bones particularly the iliac wings. The cortices appeared very thin. Expansion of iliac bones was not observed. The pubic bones, ischium, and patella were unremarkable. The proximal femoral diaphyses were severely affected by large expansile osteolytic lesions. The cortical bones were extremely thin (Figs. 4d and 7a,b). The diaphyses and metaphyses of the tibiae and fibulae appeared expanded but without evidence of osteolytic lesions. Multiple, opaque transverse lines were noted in the middle portions of the tibiae and fibulae. (Figs. 4d and 5a). An MRI of the knees disclosed large soft tissue masses occupying the synovial cavities of the joints. Some areas of the mass had a low signal, which was consistent with fluid content. There were infiltrative lesions in the medullary cavities of the long bones, including the tibiae, fibulae, and femora with expansion of the metaphyses and diaphyses (Fig. 8). Acro-osteolysis was severe in the distal phalanges of the toes. Distal symphalangism was noted on the left fifth toe. The tarsal bones were unremarkable (Fig. 4c).
Mutational Analysis of TNFRSF11B
TNFRSF11B encodes osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) receptor superfamily, and which acts as a decoy receptor that can bind to RANKL. A high frequency of OPG favors increased bone mass, whereas a low frequency of OPG favors bone resorption. Mutations in TNFRS11B are known to cause juvenile Paget disease [Cundy et al., 2002, 2005; Whyte et al., 2002a; Chong et al., 2003; Teitelbaum and Ross, 2003; Janssens et al., 2005]. Because our patient shared some features in common with juvenile Paget disease, such as thickened cranium, polyostotic osteolytic lesions, thin cortical bones, and expansion of long bones, we thought that mutational analysis of TNFRSF11B was indicated even though our patient had some manifestations not found in juvenile Paget disease.
Genomic DNA was isolated from peripheral blood samples. Amplification of the entire coding sequence was performed using primer sequences and PCR conditions described elsewhere [Cundy et al., 2002]. Direct sequencing did not identify a TNFRSF11B mutation.
We have reported an intriguing bone disorder consisting of polyostotic expansile osteolysis affecting long bones and iliac bones; hyperostosis of the skull, thoracic cage, and medial portion of the clavicle; pectus carinatum; gigantiform synovial masses of the elbows and knees; ASD; cardiomegaly; cryptorchidism; and mental retardation. Affected bones grouped according to skeletal pathology are listed in Table I. General groupings include (1) expansile osteolysis, (2) expansion without osteolysis, (3) osteolysis without expansion, and (4) hyperostosis. Unaffected bones (5) are also listed in Table I.
We were unable to obtain a bone biopsy from either an expansile osteolytic lesion or a hyperostotic lesion. The gigantiform synovial lesion was diagnosed as benign synovial villous hypertrophy. Such lesions occurred very soon after birth and gradually enlarged, causing joint effusion and a limited range of motion at the elbows and knees because of chronic synovitis.
To our knowledge, this represents a newly recognized polyosteolysis/hyperostosis syndrome that is at variance with any previously reported bone disorder, including familial expansile osteolysis [Hughes et al., 2000; Palenzuela et al., 2002;OMIM, 2006], juvenile Paget disease [Golob et al., 1996; Whyte et al., 2002a; OMIM, 2006], and McCune–Albright syndrome (and polyostotic fibrous dysplasia) [Cohen and Howell, 1999; de Sanctis et al., 1999; OMIM, 2006].
The parents were first cousins, suggesting that this polyosteolysis/hyperostosis syndrome may have autosomal recessive inheritance.
We are grateful to the patient and his family for their participation, generosity, kindness, and especially patience. We thank Suchart Benjarasmeeroj, Department of Pathology, Faculty of Medicine Siriraj Hospital for histopathological study of the synovium, and Somyod Tayavitit who introduced the patient to us. This work is dedicated to the patient and his family.