Juvenile Paget’s disease: Report of a family with a novel missense mutation and unique radiological manifestations in a heterozygote

Abstract Juvenile Paget’s disease (JPD) is a rare, generalized skeletal disorder characterized by markedly increased bone turnover secondary to enhanced osteoclastic activity. The patients with JPD develop progressive, widespread skeletal involvement and non-skeletal manifestations. Objectives To identify the characteristic molecular, biochemical, radiological, and audiological findings in three siblings with JPD associated with intrafamilial phenotypic variability. Patients and Methods A Saudi family with 3 affected siblings was recruited. Biochemical measurement of serum alkaline phosphatase and markers of bone turnover were performed. Genetic testing and sequencing of a panel of 22 known genes for skeletal dysplasia with increase bone density were performed by next generation sequencing (NGS). Radiological and audiological assessment were also performed. Results Patients showed marked elevation of serum alkaline phosphatase and markers of bone turnover. A novel homozygous mutation c.433T>G (p.Cys145Gly) in exon 3 of TNFRSF11B gene was identified in the 3 affected siblings. Both parents were heterozygous for the mutation. The heterozygote father had thickening of calvarium, a radiological manifestation of JPD. The eldest child (index case) had a unique striking distortion of the skull bones as evidenced by 3-D computed tomography of skull. He had also bilateral inner ear structural deformity and severe sensorineural hearing loss. Conclusions: JPD is a rare disorder that can be highly overlooked due to phenotypic overlap with other disorders of skeletal dysplasia. Mutations affecting cysteine residues result in the most severe JPD phenotypes. NGS is useful for early diagnosis of JPD, a prerequisite for successful treatment strategy.

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Paget’s disease: clinical update

Orvosi Hetilap ◽

10.1556/oh.2011.29174 ◽

2011 ◽

Vol 152 (33) ◽

pp. 1337-1346

Author(s):

Judit Donáth ◽

Gyula Poór

Keyword(s):

Alkaline Phosphatase ◽

Serum Alkaline Phosphatase ◽

Paget’S Disease ◽

Paget's Disease ◽

Etiologic Role ◽

Osteoblast Activity ◽

Chronic Disorder ◽

Abnormal Increase ◽

Osteoclast Function ◽

High Level

Paget’s disease is a chronic disorder of bone remodeling, characterized by an abnormal increase of osteoclast and, hence, osteoblast activity. The imbalance of bone turnover results in the formation of unhealthy and fragile bone. It also leads to impairment of adjacent joints and to a risk of various complications. Current research focuses on the elucidation of the etiologic role viral infection and predisposing genetic factors. Paget’s disease is commonly discovered by chance; its suspicion is raised either by high level of alkaline phosphatase or by the X-ray of the pathological bone. Bisphosphonates have proven to be effective in controlling disease activity because they inhibit osteoclast function. Their use is recommended when bone-derived serum alkaline phosphatase is high and/or when disease localizations are highly suspected for the development of complications. Orv. Hetil., 2011, 152, 1337–1346.

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Skeletal Blood Flow in Paget's Disease of Bone and its Response to Calcitonin Therapy

Clinical Science ◽

10.1042/cs0540069 ◽

1978 ◽

Vol 54 (1) ◽

pp. 69-74 ◽

Cited By ~ 5

Author(s):

R. Wootton ◽

J. Reeve ◽

E. Spellacy ◽

M. Tellez-Yudilevich

Keyword(s):

Alkaline Phosphatase ◽

Blood Flow ◽

Serum Alkaline Phosphatase ◽

Paget’S Disease ◽

Paget's Disease ◽

Short Term ◽

Urinary Hydroxyproline ◽

Rapid Fall ◽

Hydroxyproline Excretion

1. Blood flow to the skeleton was measured by the 18F clearance method of Wootton, Reeve & Veall (1976) in 24 patients with untreated Paget's disease. In every patient but one, resting skeletal blood flow was increased. There was a significant positive correlation between skeletal blood flow and serum alkaline phosphatase and between skeletal blood flow and urinary total hydroxyproline excretion. 2. Fourteen patients were re-studied after they had received short-term (7 days or less) or long-term (7 weeks or more) calcitonin. Skeletal blood flow, alkaline phosphatase and urinary hydroxyproline excretion fell towards normal in every case. There was some evidence from the short-term studies that calcitonin produced a more rapid fall in skeletal blood flow than in alkaline phosphatase. 3. Glomerular filtration rate appeared to increase transiently in response to calcitonin.

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Paget’s disease of bone

10.1093/med/9780199642489.003.0144 ◽

2013 ◽

Cited By ~ 1

Author(s):

Stuart H. Ralston

Keyword(s):

Bone Turnover ◽

Viral Infections ◽

Serum Alkaline Phosphatase ◽

Paget’S Disease ◽

Paget's Disease ◽

Bisphosphonate Therapy ◽

Paget’S Disease Of Bone ◽

Bone Architecture ◽

Paget's Disease Of Bone ◽

Disease Extent

Paget's disease of bone (PDB) affects up to 1% of people of European origin aged 55 years and above. It is characterized by focal abnormalities of bone remodelling which disrupt normal bone architecture, leading to expansion and reduced mechanical strength of affected bones. This can lead to various complications including deformity, fracture, nerve compression syndromes, and osteoarthritis, although many patients are asymptomatic. Genetic factors play a key role in the pathogenesis of PDB. This seems to be mediated by a combination of rare genetic variants which cause familial forms of the disease and common variants which increase susceptibility to environmental triggers. Environmental factors which have been suggested to predispose to PDB include viral infections, calcium and vitamin D deficiency, and excessive mechanical loading of affected bones. The diagnosis can be made by the characteristic changes seen on radiographs, but isotope bone scans are helpful in defining disease extent. Serum alkaline phosphatase levels can be used as a measure of disease activity. Inhibitors of bone resorption are the mainstay of medical management for PDB and bisphosphonates are regarded as the treatment of choice. Bisphosphonates are highly effective at reducing bone turnover in PDB and have been found to heal osteolytic lesions, and normalize bone histology. Although bisphosphonates can improving bone pain caused by elevated bone turnover, most patients require additional therapy to deal with symptoms associated with disease complications. It is currently unclear whether bisphosphonate therapy is effective at preventing complications of PDB.

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Usefulness of biochemical markers of bone turnover in assessing response to the treatment of paget’s disease

Bone ◽

10.1016/s8756-3282(01)00592-0 ◽

2001 ◽

Vol 29 (5) ◽

pp. 447-452 ◽

Cited By ~ 46

Author(s):

L Alvarez ◽

N Guañabens ◽

P Peris ◽

S Vidal ◽

I Ros ◽

...

Keyword(s):

Bone Turnover ◽

Biochemical Markers ◽

Paget’S Disease ◽

Paget's Disease ◽

Markers Of Bone Turnover

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Relationship between biochemical markers of bone turnover and bone scintigraphic indices in assessment of Paget's disease activity

Arthritis & Rheumatism ◽

10.1002/art.1780400312 ◽

1997 ◽

Vol 40 (3) ◽

pp. 461-468 ◽

Cited By ~ 58

Author(s):

Luisa Alvarez ◽

Pilar Peris ◽

Francisca Pons ◽

Nuria Guañabens ◽

Ramón Herranz ◽

...

Keyword(s):

Bone Turnover ◽

Disease Activity ◽

Biochemical Markers ◽

Paget’S Disease ◽

Paget's Disease ◽

Markers Of Bone Turnover

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Biochemical markers of bone turnover in paget's disease of bone

Journal of Bone and Mineral Research ◽

10.1002/jbmr.5650140213 ◽

1999 ◽

Vol 14 (S2) ◽

pp. 66-69 ◽

Cited By ~ 24

Author(s):

P.D. Delmas

Keyword(s):

Bone Turnover ◽

Biochemical Markers ◽

Paget’S Disease ◽

Paget's Disease ◽

Paget’S Disease Of Bone ◽

Paget's Disease Of Bone ◽

Markers Of Bone Turnover

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MON-371 The Case of Dueling Femurs

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.198 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Richa Patel ◽

Ana Ramirez Berlioz ◽

Bhavana Chinnakotla ◽

Lilamani Romayne Goonetilleke Kurukulasuriya

Keyword(s):

Alkaline Phosphatase ◽

Lumbar Spine ◽

Bone Resorption ◽

Bone Turnover ◽

Bone Turnover Markers ◽

Paget’S Disease ◽

Paget's Disease ◽

X Ray ◽

History Of ◽

Turnover Markers

Abstract Introduction: Paget’s disease of the bone is characterized by excessive osteoclastic bone resorption followed by formation of disorganized bone; which is often focal. Bone pain and deformities are common features and it often leads to complications such as pathological fractures, deafness or neurologic deficits. Elevated bone turnover markers and alkaline phosphatase reflect ongoing exaggerated bone resorption and osteoblastic activity. We present an unusual scenario of post-menopausal osteoporosis and Paget’s disease occurring in the same patient. Clinical Case: 86-year-old female with history of Type 2 Diabetes Mellitus, Hypertension, Hypothyroidism, degenerative joint disease of lumbar spine with prior interbody fusion and laminectomy was referred to our clinic by Orthopedics for evaluation of newly diagnosed Paget’s disease. 2 months ago, she noticed severe right hip pain limiting daily activities. She denied any history of falls, fractures or family history of Paget’s. Physical exam was notable for tenderness to right sacro-iliac joint and right femoral trochanteric region. Work up included MRI of Lumbar spine and Pelvis, Pelvis X-ray, DEXA scan and routine blood work. Interestingly, her DEXA scan showed T score of +2.9 in Right hip and -3.1 in Left hip. On Pelvis X-ray cortical thickening, coarse trabecula and osteoarthritic changes were noted in right femur and hip, consistent with Paget’s disease. Left femur showed strikingly thinner cortices compared to the right, due to underlying osteoporosis. MRI of lumbar spine and pelvis was consistent with polyostotic Paget’s involving L3-L5, Sacrum and Right femur. Nuclear bone scan showed areas of uptake including anterior calvarium, lumbar spine, right hip, right femur, 8th rib, left mid tibia and 1st metatarsal of left foot. Since the distribution of uptake seemed atypical for Paget’s, a skeletal survey was obtained which was negative for bone lesions suggestive of malignancy. Laboratory testing revealed serum calcium 9.8mg/dL(8.4–10.2), 25-Hydroxy Vitamin D 30ng/dL(20–30), PTH 45.6pg/mL (15–65), Alkaline Phosphatase 370U/L (35–104), Procollagen I intact N-terminal 516mcg/L (16–96) and N-Terminal Telopeptide (NTX) 126.4 nM BCE (6.2–19). Patient received one dose of IV Zoledronic acid with modest improvement in hip and lower back pain. She continues to take Calcium carbonate 600mg twice daily and vitamin D3 1000IU once daily. We plan to see her in follow up in 3 months with repeat levels bone turnover markers. Conclusion: This is a unique case of Paget’s disease and osteoporosis, two very different diseases of metabolic bone disorder spectrum found in one patient. Treatment of Paget’s disease is indicated for pain reduction, prevention of fractures and deformities and to prevent disease progression in weight bearing areas. Bisphosphonates can target pathology of both diseases by reducing osteoclastic bone resorption.

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Paget’s disease of bone

Oxford Textbook of Rheumatology ◽

10.1093/med/9780199642489.003.0144_update_002 ◽

2013 ◽

pp. 1237-1244

Author(s):

Stuart H. Ralston

Keyword(s):

Bone Turnover ◽

Viral Infections ◽

Serum Alkaline Phosphatase ◽

Paget’S Disease ◽

Paget's Disease ◽

Paget’S Disease Of Bone ◽

Bone Architecture ◽

Paget's Disease Of Bone ◽

Disease Extent ◽

Bone Scans

Paget’s disease of bone (PDB) affects up to 1% of people of European origin aged 55 years and above. It is characterized by focal abnormalities of bone remodelling which disrupt normal bone architecture, leading to expansion and reduced mechanical strength of affected bones. This can lead to various complications including deformity, fracture, nerve compression syndromes, and osteoarthritis, although many patients are asymptomatic. Genetic factors play a key role in the pathogenesis of PDB. This seems to be mediated by a combination of rare genetic variants which cause familial forms of the disease and common variants which increase susceptibility to environmental triggers. Environmental factors which have been suggested to predispose to PDB include viral infections, calcium and vitamin D deficiency, and excessive mechanical loading of affected bones. The diagnosis can be made by the characteristic changes seen on radiographs, but isotope bone scans are helpful in defining disease extent. Serum alkaline phosphatase levels can be used as a measure of disease activity. Inhibitors of bone resorption are the mainstay of medical management for PDB and bisphosphonates are regarded as the treatment of choice. Bisphosphonates are highly effective at reducing bone turnover in PDB and have been found to heal osteolytic lesions, and normalize bone histology. Although bisphosphonates can improving bone pain caused by elevated bone turnover, most patients require additional therapy to deal with symptoms associated with disease complications. It is currently unclear whether bisphosphonate therapy is effective at preventing complications of PDB.

Download Full-text