Osteoprotegerin Deficiency (Juvenile Paget’s Disease): Responses to Oral and IV Bisphosphonates in 3 Children Deborah Wenkert1, Marc D. Natter2, Mayumi Otsuka3, Natalya E. Fish2, Jorge M. Lopez-Benitez2, Morri Markowitz4, William McAlister5, Steven Mumm5, Michael P. Whyte5 1Shriners Hospt Children, St Louis, MO, USA, 2Tufts-New Eng Med Ctr, Boston, MA, USA, 3N. Navajo Med Cntr, Shiprock, NM, USA, 4Montefiore Hospt, Bronx, NY, USA, 5Wash U Sch Med, St Louis, MO, USA.

Abstract Patient 1 Patient 2 Patient 3 Discussion Osteoprotegerin (OPG) deficiency, the principal variant of juvenile Paget’s disease, is a rare, JPD, previously called idiopathic or hereditary hyperphosphatasia, presents in infancy, young childhood or, rarely, autosomal recessive osteopathy featuring markedly accelerated bone turnover. Here, we assess in late childhood. It causes deafness, bone pain, fracture, and deformity with x-rays showing undertubulation of responses of 3 affected, unrelated children to bisphosphonate (BP) therapy (Table). long bones with a disorganized trabecular pattern and thin cortices. Rapid rates of skeletal remodeling are demonstrated by histopathology as well as by biochemical markers of bone turnover, including especially Pt #1: A 4 yr old boy of Cypriot descent suffered leg swelling, periosteal elevation, and ESR=74 impressive hyperphosphatasemia. Most JPD patients are homozygous for a loss-of-function mutation in from "Caffey disease" diagnosed at age 1 mo. Alkaline phosphatase (ALP) reached 2470 U/l. TNFRSF11B encoding OPG, including missense defects, insertions/deletions, and frame shifts.(4,5,7,8,11) OPG acts Hearing (normal at birth) was lost by 21 mo. Three fxs and warm, bony expansions deformed all 3 11/12 yrs as a decoy receptor for RANK Ligand, thus suppressing bone turnover. With OPG deficiency, this suppression is limbs. Growth, except head size (OFC), was stunted. On referral, he had weakness, torticollis, lacking or diminished, and thus bone turnover is accelerated. chest and limb deformity, could not sit, and cried when moving. X-rays showed markedly expanded bones, “bowtie” vertebrae, thickened diploic space, and marked coxa vara. One wk OPG deficiency differs from classic Paget’s disease of bone (PDB; OMIM #167250)(1) which typically presents in after 1/3 mg/kg pamidronate (PAM), he sat; 3 weeks after the first 3-dose cycle (total ~2 mg/kg), 7 7/12 yrs 10 11/12 yrs middle-age, and increased skeletal turnover occurs in only one or a few bones.(12) In OPG deficiency, greatly he crawled. After 3 cycles, he stood. Stamina, appetite, mood, torticollis, and mobility 11 3/12 yrs accelerated remodeling manifests in childhood, affects the entire skeleton, and interferes with normal bone growth remarkably improved along with radiographic improvement. and modeling.(2,4,5) In addition, familial Paget’s disease of bone is an autosomal dominant disorder with variable C penetrance, whereas OPG deficiency is autosomal recessive. Pt #2: A 7 yr old girl of Puerto Rican descent seemed well until an atraumatic femoral fx at age The clinical severity of OPG deficiency in our 3 patients seemed to correlate with the anticipated effects of the 2. X-rays showed limb deformities from "Engelmann disease" (ALP 1963 U/l). By referral, she V (4) had 4 fxs (25% ht, 20% wt, 5% arm span, < 5% sitting ht, and > 95% OFC), mild deafness, and S A A specific homozygous TNFRSF11B deletion or mutation. This has been reported in other cases. Our patient 3 is homozygous for deletion of TNFRSF11B (Navajo mutation). (5) In him, lack of OPG biosynthesis engenders high arm pain; leg pain limited walking. Femurs and tibias were bowed. X-rays showed periosteal 4 5/12 yrs (5) elevation, osteopenia, and expanded bones. At age 10, after 1.5 yrs of alendronate, knee pain 7 7/12 yrs 10 11/12 yrs circulating concentrations (and presumably skeletal tissue levels) of unbound RANKL. Our patient 2 is was minimal along with radiographic improvement. 3 11/12 yrs 1 9/12 yrs homozygous for TNFRSF11B c.349T>C,p.F117L [Iberian mutation] found in four patients of Spanish, Portuguese, 1 yr 4 yrs 10 11/12 yrs Argentinian,(4) or Puerto Rican heritage.(4,8) One would predict she would make an altered OPG, thus explaining This 6 lb 9 oz fraternal twin, fussy from birth, screamed when his Pt #3: An 11 yr old, dwarfed, deaf, Navajo boy (NEJM 2002: 347:175) had macrocephaly, and (5) her milder disease. Patient 1 is homozygous for a unique deletion predicted to express no functional OPG, and legs were lifted. Progressive leg swelling at 4 weeks of age was 7 7/12 yrs 7 7/12 yrs This 7lb 7 oz, 19 inch Navajo boy, previously reported, appeared well until a misshapen chest and limb deformity. He became poorly compliant for calcitonin, and declined risedronate. skull and thorax were noted at age 5 mo. At age 1 year, failure to thrive, bone deformities, indeed presented with disease as severe as seen in patient 3. At age 7, PAM was begun (ALP max 2716) with symptom and x-ray improvement. Pt 1 and 2 diagnosed as Caffey’s disease when a radiograph showed and radiographic findings (Fig) led to a diagnosis of JPD. He lost his first tooth at 1 year of 11 3/12 yrs Early attempts to improve the bone quality in JPD included use of sodium fluoride (13) with only mildly encouraging had different, homozygous, loss-of-function defects in exon 2 of TNFRSF11B encoding OPG. Pt periosteal elevation. At 4 mo of age, ESR was 74 and serum This 6 lb 7 oz girl of Puerto Rican descent walked at 14 mo of age and alkaline phosphatase (ALP) was 857 IU/l (150 - 350 nl). At 9 mo age. He was small (below the 3rd percentile for length, and in the 5th percentile for weight), results, and synthetic human calcitonin with some regression of bony abnormalities in childhood. (14,15,16) #1 had a frame-shift, single base deletion (c.278delT), likely forming no functional protein, was well until age 2 2/12 yrs when minimal trauma fractured a femur. of age, a humeral fracture healed with deformity, and refractured tachypneic and weak, and had a disproportionately large head (75th percentile), short humeri, laterally bowed femora, consistent with severe disease. Pt #2 had a missense mutation (c.T349C, p.Phe117Leu) Skeletal survey showed mild “deformity to her extremities”, and she was (17) at 21 mo of age. At 13 mo of age, symptoms improved with 1 mo anterior curved tibiae, markedly delayed gross motor skills, and poor muscle tone. Radiographs showed deformed and In 1992, Spindler et al. reported a positive response to pamidronate in a 38-year-old woman with mild JPD. causing a less severe phenotype. Pt #3 is deleted for OPG. thought to have Engelmann’s disease (progressive diaphyseal of prednisone (0.2 mg/kg), but radiographs worsened. He widened osteopenic long bones with coarse trabeculae and indistinct cortical medullary junctions. There were flattened Elevated serum ALP and urine total hydroxyproline both decreased in response to oral pamidronate. This patient dysplasia). vertebral bodies. His parents were healthy, both of Navajo heritage, with no known consanguinity. Biochemical markers of had previously been given etidronate (EHDP) without a good response. We found six subsequent reports of Children with OPG deficiency show varying responsivity to BPs, reflecting the underlying OPG received Naprosyn for 2 yrs. ALP reached a maximum of 2470 IU/l. Four subsequent fractures occurred (clavicular, humeral, and two radial mineral homeostasis were remarkable for hypercalciuria and increased skeletal turnover. Intermittent compliance with daily bisphosphonate use (etidronate, pamidronate IV and oral, ibandronate, and alendronate) for JPD. In each case, mutation. breaks) and she had persistently elevated ALP (1,553 - 1,963) at times subcutaneous injections of synthetic salmon calcitonin to age 7 led to radiographic and clinical improvement, but with bisphosphonates improved x-ray appearance, increased mobility, and lowered markers of bone turnover; in some At 7 mo of age, he frequently scratched his ears, seemed to be in without a known fracture. persistently active bone disease (Fig). His ALP reached a maximum of 2,716 IU/L. cases, into the normal range. (6, 18, 19, 20-22) pain, and had bloody otorrhea. Hearing, normal at birth (by ABR), Introduction was impaired by 1 ½ years. She lost her first tooth early (age 4) with teeth “discolored and eaten He developed medullary nephrocalcinosis by age 5 which resolved by age 12. Deafness is a known feature of JPD. Computed tomography of our patient 1 showed absence of ossicles despite away.” normal hearing at birth. This is consistent with observations in OPG knockout mice in whom auditory ossicles are JPD, previously called idiopathic hyperphosphatasia (OMIM #239000)(1), is an autosomal By 30 mo of age, he had had recurrent, red, hot, bony expansions resorbed and otic capsules are abnormally remodeled.(5,23) Thus, early intervention to protect hearing seems recessive disorder featuring remarkably accelerated bone turnover affecting the entire (never joint-centered) with residual deformity of all 4 extremities as Skull radiographs showed a thick diploic space and basilar impression. necessary. skeleton.(2) Approximately 50 cases are described in the medical literature.(1,3,4) JPD is well as 3 long bone fractures. Cranial CT for bilateral hearing loss showed abnormal inner ear characterized biochemically by greatly increased serum alkaline phosphatase (ALP) activity structures. The severity of JPD can vary greatly among patients. Thus, the choice of bisphosphonate regime (drug, dose, (hyperphosphatasemia), skeletal deformities, fractures, bone pain, and childhood deafness.(2,5,6) At referral at age 3 11/12 yrs (Fig), he had anorexia, fatigue, and frequency, i.v., oral) should be tailored to each patient based on disease severity and response to treatment. Loss-of-function mutation of TNFRSF11B, the gene encoding osteoprotegerin (OPG), accounts weakness. He first rolled over at 21 mo, but could neither sit up On referral at age 7 8/12 yrs (Fig), she complained of anorexia, fatigue, Knowledge of the particular OPG mutation may offer insight into the predicted outcome. (4,5,7,8) (9) on his own, nor stand. He cried with kneeling, crawling, and being dyspnea, unilateral clavicular, arm and bilateral lower limb pain for most patients, thus their disorder can now be called “OPG deficiency.” JPD can be In the only report of JPD treated with recombinant OPG,(24) it seemed well tolerated. X-rays showed improvement, fatal by early adult life if untreated with antiresorptives.(5,10) placed in a stander. exacerbated by touch or use. She could walk only 2 blocks. She had mild bilateral hearing loss and a difficulty in reading and comprehension. ALP levels normalized, and both patients reported a decrease in bone pain. No antibodies to the OPG-Fc were Here, we describe 3 patients with JPD due to different homozygous OPG deletions or other His parents were both of Cypriot extraction and in good health. detected. Since the majority of JPD patients have an OPG defect, it would be logical to treat this disease with mutations whose severity and response to oral or IV bisphosphonate therapy seem in keeping He had three siblings, all in good health. Family history was remarkable for alopecia totalis in her mother. Both OPG, rather than treat just the skeletal manifestations of the disease with bisphosphonates. The bisphosphonates, with their genotype. parents were of Puerto Rican descent, but without known consanguinity. as shown here, as well as by others, clearly have a positive impact on bone by decreasing the rapid remodeling All growth parameters were significantly below those of his 7 yrs 10 11/12 yrs that occurs with this disease. However, with bisphosphonate use, bone remains abnormal and other clinical fraternal twin and age-matched norms, except for head Physical examination (Fig) showed normal height, weight, and arm span, but with a diminished sitting height manifestations of the disease, including vascular calcifications resembling pseudoxanthoma elasticum, as well as circumference (Table). He kept his head cocked to one side. He At age 6, daily Actonel was prescribed but retinal disease that can lead to blindness remain untreated. Indeed, our experience with a 60-year-old Greek man Biochemical and DXA response to Bisphosphonates in 3 children with OPG deficiency had a barrel-shaped chest, and long limb deformities. Hips had and macrocephaly (Table). Her forehead was high, prominent in the central region, with general not taken and therefore pamidronate i.v. was enlargement of the skull. She had a high-arched, elongated palate, and decreased hearing and strength. who received 20 years of bisphosphonate therapy and developed retinal blindness supports the need for the use of minimal motion. He had bilateral knee flexion contractures, and substituted a half year later to insure OPG rather than bisphosphonates to fully control this disease.(21) enlargement of fingers sparing the joints. compliance. PATIENT 1 PATIENT 2 PATIENT 3 Obvious anterior bowing of bilateral femurs and tibiae were present with pseudo-flexion contractures of the knees, and decreased internal rotation of hips. She was tender to palpation of her extremities. Decreased On physical exam, at age Radiographs (Fig) showed osteopenia, expansion of all major long 3 11/12 yrs 4 5/12 yrs References Pamidronate (i.v.) Alendronate (p.o.) Pamidronate (i.v.) 1 yr 2 3/12 yrs 7 yrs 10 11/12 yrs 7 years, he had scoliosis, (6 mo of 8 mg/kg/6 mo) (1.5 yr of 35 mg (3.5 yr of ~ 8 mg/kg/yr) bones, poorly defined cortices, marked coxa vara with a hairpin motion occurred at the wrists and elbows. She had a prominent bowed left clavicle and scoliosis. EKG was (after Calcitonin) normal. Ophthalmologic exam showed no retinal abnormalities. Her P, ALP, urinary calcium excretion, and progressive anterior 1. Online Mendelian Inheritance in Man (OMIM™). Web site. Available at: www.ncbi.nlm.nih.gov/omim/. Accessed October 23, 2006. twice/wk) bend in his proximal femora, and deformed ribs and bowtie bowing of both tibiae, 2. Cole DEC, Whyte MP. 1996 Hyperphosphatasia syndromes. In: Cohen MM Jr, Baum BJ (eds.) Studies in stomatology and craniofacial biology. IOS Press, Amsterdam, ESR were elevated (Table). Netherlands, pp. 245-272. shaped vertebrae. Skull radiographs showed thickened diploic decreased abduction of 3. Cundy T. 2002 Idiopathic hyperphosphatasia. Semin Musculoskelet Radiol. 6:307-12. 3 11/12 yrs 4 5/12 yrs 7 7/12 yrs 10 1/12 yrs 7 10/12 yrs 10 11/12 yrs Response to Treatment space and basilar invagination. Cranial CT showed a thick diploic Radiographs (Fig) showed 'railroad tracking' with osteopenia, shaping abnormalities, poor cortical medullary hips, flexion contractures 4. Chong B, Hegde M, Fawkner M, Simonet S, Cassinelli H, Coker M, Kanis J,Seidel J, Tau C, Tuysuz B, Yuksel B, Love D, Cundy T. 2003 The International Hyperphosphatasia Collaborative space and a dilated and grossly abnormal cochlea (C), vestibule of the knees (75°), elbows Group Idiopathic hyperphosphatasia and TNFRSF11B mutations: Relationships between phenotype and genotype. J Bone Miner Res 18:2095-104. definition, and expanded bone affecting her entire skeleton. She had mild platybasia, significant protrusio Hearing seemed to improve between ages 7 and 8 years. Between ages 5. Whyte MP, Obrecht SE, Finnegan PM, Jones JL, Podgornik MN, McAlister WH, Mumm S. 2002 Osteoprotegerin deficiency and juvenile Paget’s disease. N Engl J Med 347:175-84. Height Z-score -4.1 -4.0 0 -0.8 -7.2 -7.1 (V) and semicircular canals (S) and malformed ossicles (Figure). 8 and 9 years, he walked without a walker for 7 mo ( 5 - 10 feet at a time) and hips, an expanded 6. Tau C Mautalen C Casco C Alvarez V Rubinstein M. 2004 Chronic idiopathic hyperphosphatasia: normalization of bone turnover with cyclical intravenous pamidronate therapy. acetabuli, and a moderate levoscoliotic curve over the lumbar spine. humerus, and enlargement Bone. 35:210-6. until he jumped off a forklift and fractured his right femur. After recovery, 7. Cundy T, Hegde M, Naot D, Chong B, King A, Wallace R, Mulley J, Love DR, Seidel J, Fawkner M, Banovic T, Callon KE, Grey AB, Reid IR, Middleton-Hardie CA, Cornish J. 2002 Weight Z-score -1.9 -0.6 -1 -0.9 -4.1 -0.6 His serum P, ALP, urinary calcium excretion, CRP, and ESR were DEXA showed an L1 through L4 Z-score of -3.1. his endurance was greatest after a pamidronate infusion, and he would and stiffness in the cartilage of his ears A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Hum Mol Genet 11:2119-27. 8. Mumm S, Banze S, Pettifor J, Tau C, Schmitt K, Ahmed A, Whyte MP. 2003 Juvenile Paget’s disease: Molecular analysis of TNFRSF11B encoding osteoprotegerin indicates homozygous all elevated (Table). DXA of L1-L4 showed a Z score of -6.8. stop walking two weeks before his next dose. At age 9 9/12 years, bilaterally. Mutational analysis showed deactivating mutations from consanguinity as the predominant etiology (abstract). J Bone Miner Res 18(Suppl):S286. Arm Span Z-score -3.1 -2.3 -1.5 -1.7 -5.8 -5.0 (5) Mutational analysis showed a homozygous missense mutation (Phe117Leu) in exon 2 predicting an altered Actonel 5 mg once per week was prescribed. By age 10, he reported complete deletion of OPG. 9. Whyte MP. 2006 Paget’s disease of bone and genetic disorders of RANKL/OPG/RANK/NF-?B signaling. Ann NY Acad Sci 1068:143-64. Head Circumference % 50% 50% > 98% > 98% > 98% > 98% Mutational analysis of TNFRSF11B showed a homozygous protein and less severe phenotype (“Iberian mutation”). increased endurance, and walked for a total of two hours a day. 10. Mitsudo SM. 1971 Chronic idiopathic hyperphosphatasia associated with pseudoxanthoma elasticum. J Bone Joint Surg Am 53:303-14. 11. Janssens K, de Vernejoul MC, de Freitas F, Vanhoenacker F, Van Hul W. 2005 An intermediate form of juvenile Paget’s disease caused by a truncating TNFRSF11B mutation. frameshift, single base deletion (likely forming no functional Physical examination at age 10 11/12 years showed Bone 36:542-48. Dietary Ca (mg/day) 565 540 993 600 870 846 protein) consistent with severe disease. 12. Kanis JA. 1998 Pathophysiology and treatment of Paget’s disease of bone. Blackwell Science, Malden, MA, USA. Response to Treatment only 8 teeth, hardened ear cartilage, anterior tibial 13. Eyring EJ, Eisenberg E. 1968 Congenital hyperphosphatasia: A clinical, pathological, and biochemical study of two cases. J Bone Joint Surg Am 50:1099-117. ALP (50 - 420 IU/L) 720 247 1232 303 1927 436 bowing, flexion contractures of his knees, elbows and 14. Woodhouse NJ, Fisher MT, Sigurdsson G, Joplin GF, MacIntyre I. 1972 Paget's disease in a 5-year-old: acute response to human calcitonin. Br Med J 4:267-9. hips, decreased abduction of the hips, and scoliosis. 15. Doyle FH, Woodhouse NJ, Glen AC, Joplin GF, MacIntyre I. 1974 Healing of the bones in juvenile Paget’s disease treated by human calcitonin. Br J Radiol 47:9-15. BAP (47 - 181 IU/L) 369 111 - 154 - 229 She received alendronate at age 8 at a dose of 35 mg orally twice weekly. She had one interim fracture of 16. Blanco O, Stivel M, Mautalen C, Schajowicz F. 1977 Familial idiopathic hyperphosphatasia: a study of two young siblings treated with porcine calcitonin. J Bone Joint Surg Br. 59-B:421-7. Response to Treatment Strength scores by grip and pinch had increased 17. Spindler A Berman A Mautalen C Ubios J Santini AE. 1992 Chronic idiopathic hyperphosphatasia. Report of a case treated with pamidronate and a review of the literature. her left humerus which healed uneventfully. Her hearing was reevaluated, and she was fitted with a hearing J Rheumatol. 19:642-5. Phosphate (3.1 - 5.9 mg/dL) 6.8 7.3 5.9 5.3 5 5.6 aid. significantly over the past year. Radiographs (Fig) 18. Cundy T Wheadon L King A. 2004 Treatment of idiopathic hyperphosphatasia with intensive bisphosphonate therapy. J Bone Miner Res. 19:703-11. One week after 1/3 mg/kg i.v. of Pamidronate, he could sit up by showed continued improvement in the appearance of 19. Demir E Bereket A Özkan B Topcu M. 2000 Effect of alendronate treatment on the clinical picture and bone turnover markers in chronic idiopathic hyperphosphatasia. PTH (10 - 69 pg/mL) 32 11 19 25 14 13 himself. Three weeks after the first treatment cycle (2 additional J Pediatr Endocrinol & Metab 12:217-21. At reevaluation at age 10 ½ years, she complained of leg pain occurring only once a week after prolonged the bones including previous lytic area of his right distal 20. Singer F Siris E Shane E Dempster D Lindsay R Parisien M. 1994 Hereditary hyperphosphatasia: 20 year follow up on response to disodium etidronate. J Bone Miner Res. 9:733-8. doses of 0.75 mg/kg/dose once per week) he started crawling. walking, but fatigue and shortness of breath persisted. She was doing well in school. humerus, as well as decreased anterior bowing of his 21. Whyte MP, Singhellakis P Petersen MB Davies M Totty WG Mumm S. 2007 Juvenile Paget’s disease: The second reported oldest patient is homozygous for the Osteocalcin (13 - 81 mg/g) 31 79 53 97 197 142 TNFRSF11B “Balkan” mutation (966_969delTGACinsCTT) which elevates circulating immunoreactive osteoprotegerin levels. J Bone Miner Res. 22:938-46. tibias by approximately 10 degrees bilaterally. In the 22. Cassinelli HR Mautalen CA Heinrich JJ Miglietta A Bergada C. 1992 Familial idiopathic hyperphosphatasia (FIH): response to long-term treatment with pamidronate (APD). Urine Ca/Cr (< 220 mg/g) 488 515 373 85 489 715 Reevaluation after 3 cycles (age 4 5/12 years) (Fig) showed he could push himself up to stand. He had Physical exam showed her height 21st percentile, arm span 4th percentile, and weight 18th percentile. The spine, there was increased vertebral bodies heights and Bone Miner. 19:175-84. a remarkable improvement in stamina, appetite, mood, and mobility. Torticollis nearly resolved. remaining exam was remarkable for the pseudo-flexion contractures and bowing in her knees, decreased improved mineralization (Fig). He developed bilateral 23. Zehnder AF, Kristiansen AG, Adams JC, Kujawa SG, Merchant SN, McKenna MJ. 2006 Osteoprotegerin knockout mice demonstrate abnormal remodeling of the otic capsule and Deoxypyridinoline (1 - 41 nM/mm Cr) progressive hearing loss. Laryngoscope. 116:201-6. 188 72 189 > 300 173 43 range of motion in wrists, and scoliosis. Tenderness on palpation or range of motion exam had resolved. cavernous internal carotid aneurysms and had abnormal 24. Cundy T, Davidson J, Rutland MD, Stewart C, DePaoli AM. 2005 Recombinant OPG for juvenile Paget’s disease. N Engl J Med. 353:918-23. Serum P and urinary calcium excretion remained elevated, but his ESR, ALP, and CRP were normal ESR (0 - 20 mm/hr) 61 17 37 11 57 15 Serologic evaluation now showed serum ALP and phosphorus in the normal range, resolution of inner ear structures. On skull radiographs and cranial (Table). Radiographs showed a better defined bone cortices with improved mineralization of all bones hypercalciuria with mild hypocalciuria, and an ESR in the normal range (Table). Radiographic studies CT, he had a thick diploic space, developed bilateral Acknowledgements CRP (0 - 0.9 mg/dL) 2.5 < 0.5 < 0.8 < 0.5 < 0.1 0.4 and better cortical medullary differentiation (Fig). The spine was better mineralized with improved showed smoother cortical surfaces with improved definition, and thinner diaphyses with greater uniformity of cavernous internal carotid aneurysms (A) with erosion of 7 7/12 yrs 9 9/12 yrs 10 11/12 yrs vertebral heights. DXA showed L1 - L4 Z score = - 2.7. bone density in the cortices (Fig). We thank our patients and their families for their participation in our studies. Angelia English provided expert secretarial assistance. Vivienne Lim and Dawn Russell helped with illustrations. L1-L4 DXA Z-score -6.8 -2.7 -3.1 + 0.1 -3.1 + 0.4 his sphenoid bone (Fig.). There were malformed semi-circular canals, cochlea, vestibule, and ossicles. Supported by Shriners Hospitals for Children, The Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund and the Hypophosphatasia Research Fund.