Hypophosphatasia

1,379

Published on

definition,types ,presentation ,diagnosis ,differential diagnosis ,treatment ,prognosis

Published in: Health & Medicine
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
1,379
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
68
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide

Hypophosphatasia

  1. 1. Is it a variant of Rickets?
  2. 2. 1 st Patient • A female infant • Shortening of limbs, detected during pregnancy by ultrasonography. • Admitted to the neonatal intensive care unit because of respiratory distress. Is it a varient of Rickets? 11/3/2012 2 Prof.Dr. Saad S Al Ani
  3. 3. Cont. • A bone radiograph : hypomineralization of all bones, • Serum alkaline phosphatase was very low (10 U/L) • Seizures (focal clonic and tonic) started Is it a varient of Rickets?11/3/2012 3 Prof.Dr. Saad S Al Ani
  4. 4. Cont. • The seizures were refractory to phenobarbital and other antiepileptic drugs. • The first (EEG) showed a burst- suppression pattern. Is it a varient of Rickets?11/3/2012 4 Prof.Dr. Saad S Al Ani
  5. 5. Cont. • Pyridoxine was administered (50 mg/kg) and completely controlled the seizures. • Antiepileptic drugs were discontinued, and a maintenance dose of pyridoxine (10 mg/day) was established. Is it a varient of Rickets?11/3/2012 5 Prof.Dr. Saad S Al Ani
  6. 6. Cont. • A postpyridoxine EEG revealed the disappearance of the burst- suppression pattern. • The patient died at age 26 days. Is it a varient of Rickets?11/3/2012 6 Prof.Dr. Saad S Al Ani
  7. 7. 2nd Patient • 6 months • Persistence of a widened anterior fontanel • Diagnosis of nutritional rickets prompted high-dose vitamin D and calcium supplementation Is it a varient of Rickets?11/3/2012 7 Prof.Dr. Saad S Al Ani
  8. 8. Cont. Immediate ponderal growth failure and bulging anterior fontanel Is it a varient of Rickets?11/3/2012 8 Prof.Dr. Saad S Al Ani
  9. 9. Cont. • 8 months: Oral therapy stopped; calcium-phosphate metabolism assessments showed : *Increased calcium and phosphate values *Reduced PTH *High 25-hydroxy vitamin D levels *Hypercalciuria Is it a varient of Rickets?11/3/2012 9 Prof.Dr. Saad S Al Ani
  10. 10. Cont.• Ponderal growth failure• Bulging anterior fontanel• Blood tests confirmed above findings except normalization of 25-hydroxy vitamin D levels Is it a varient of Rickets?11/3/2012 10 Prof.Dr. Saad S Al Ani
  11. 11. Cont. • Radiograph showed : *Severe and generalized osteopenia with tongues of radiolucency *Persistence of opened anterior fontanel • Renal ultrasound showed : * Nephrocalcinosis Is it a varient of Rickets?11/3/2012 11 Prof.Dr. Saad S Al Ani
  12. 12. Radiograph of the left wrist showing tongues of radiolucency (arrows) in distal metaphysis of radius and ulna Mohan, Acta Paediatr, 2011 Is it a varient of Rickets?11/3/2012 12 Prof.Dr. Saad S Al Ani
  13. 13. Cont.• at 9 months of age, the patients history reported normal growth.• Except the absence of the central lower mandibular incisors, the oral examination was entirely normal, without inflammation of the gums. Is it a varient of Rickets? 11/3/2012 13 Prof.Dr. Saad S Al Ani
  14. 14. 3rd Patient• A 10-months-old girl• Spontaneous and unexplained loss of her primary lower central incisors Is it a varient of Rickets?11/3/2012 14 Prof.Dr. Saad S Al Ani
  15. 15. Is it a varient of Rickets?11/3/2012 15 Prof.Dr. Saad S Al Ani
  16. 16. 4 th Patient • A 30-months-old boy • Premature loss of primary teeth. • Except for eczema, the child presented with normal development. Is it a varient of Rickets?11/3/2012 16 Prof.Dr. Saad S Al Ani
  17. 17. Cont.• At 19 months of age, this child had spontaneously lost his four lower primary incisors and• The oral examination did not reveal any gingivitis or bleeding. Is it a varient of Rickets?11/3/2012 17 Prof.Dr. Saad S Al Ani
  18. 18. Is it a varient of Rickets?11/3/2012 18 Prof.Dr. Saad S Al Ani
  19. 19. Cont. • Radiographs of the skeleton revealed : * Distorted bone trabeculation * Areas of decreased radiolucency * Bone undermineralization. Is it a varient of Rickets?11/3/2012 19 Prof.Dr. Saad S Al Ani
  20. 20. Is it a varient of Rickets?11/3/2012 20 Prof.Dr. Saad S Al Ani
  21. 21. Is it a variant of Rickets? Is it a varient of Rickets?11/3/2012 21 Prof.Dr. Saad S Al Ani
  22. 22. Serum alkaline phosphatase (ALP) analysis for all these children showed low values which indicates hypophosphatasia (HPP) diagnosis. The normal ALP range is 44 to 147 IU/L. Is it a varient of Rickets?11/3/2012 22 Prof.Dr. Saad S Al Ani
  23. 23. Prof. Dr. Saad S Al AniSenior Pediatric ConsultantHead of Pediatric DepartmentKhorfakkan HospitalSharjah ,UAE saadsalani@yahoo.com Hypophosphatasia
  24. 24. Introduction Hypophosphatasia is an autosomal recessive disorder that radiographically resembles rickets and is defined by low serum alkaline phosphatase activity. Barvencik F, Beil FT, Gebauer M, et al. Skeletal mineralization defects in adult hypophosphatasia—a clinical and histological analysis. Osteoporos Int. 2011;22(10):2667-2675 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 24
  25. 25. Hypophosphatasia Prof. Dr. Saad S Al Ani11/3/2012 25
  26. 26. Cont. • It is an inborn error of metabolism in which activity of the tissue-nonspecific (liver/bone/kidney) alkaline phosphatase (TNSALP) is deficient. Hypophosphatasia Prof. Dr. Saad S Al Ani11/3/2012 26
  27. 27. Etiology •Single point mutation of the gene ↓ • Prevent expression of the TNSALP activity • >200 mutations of the gene •The most common is misssense mutation (75%) Mornet E. Hypophosphatasia. Orphanet J Rare Dis. http://www.ojrd.com/content/2/1/40. 29, 201211/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 27
  28. 28. Cont. Activity of the intestinal and placental enzyme is normal. Spranger JW, Brill PW, Poznansk A: Bone Dysplasias. An Atlas of Genetic Disorders of Skeletal Development, 2nd ed. New York, Oxford University Press, 2002 Hypophosphatasia Prof. Dr. Saad S Al Ani11/3/2012 28
  29. 29. PathophysiologyDeficient alkaline phosphatase (ALP) activity:• Disrupts bone mineralization• Impairs calcium and phosphate regulation→ leading to progressive damage to multiple vital organs Mornet E. Hypophosphatasia. Orphanet J Rare Dis. http://www.ojrd.com/content/2/1/40. Hypophosphatasia Prof. Dr. Saad S Al Ani11/3/2012 29
  30. 30. Multiple vital organs Including : • Destruction and deformity of bones • Profound muscle weakness • Seizures • Impaired renal function • Respiratory failure • Inflammation Mornet E. Hypophosphatasia. Orphanet J Rare Dis. http://www.ojrd.com/content/2/1/4011/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 30
  31. 31. Bone Matrix11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 31
  32. 32. Prevalence11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 32
  33. 33. Canadian prevalence11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 33
  34. 34. Global prevalence11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 34
  35. 35. A comparison11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 35
  36. 36. Metabolic bases of HPP Genetic mutation in the ALPL gene PPI : inorganic Deficient ALP activity pyrophosphate PLP: pyridoxal 5′-phosphate Substrates accumulation/PPI,PLP,PEA PEA : phosphoethanolamine Metabolic disease • Inhibition of hydroxyapatite crystal formation CPPD : calcium pyrophosphate • CPPD crystal deposition dihydrate • Vitamin B6 (PLP) unable to cross blood –brain barrier •Hypercalcemia ,hyperphosphatemia11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 36
  37. 37. Time of presentationThere is considerable heterogeneity in the severity of the disease11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 37
  38. 38. Cont. • Some cases appear at birth, and diagnosis has even been made in utero by radiographic examination of a fetus. Is it a varient of Rickets?11/3/2012 38 Prof.Dr. Saad S Al Ani
  39. 39. Types 1. Lethal neonatal or perinatalThere are form (congenital lethalthree types hypophosphatasia),that the 2. Severe infantile formdisease may 3. Milder form occurring inappear in: childhood or late adolescence (hypophosphatasia tarda).11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 39
  40. 40. 1.Neonatal or Perinatal form(Congenital lethal hypophosphatasia) 1. Moth-eaten appearance at the ends of the longIs characterized bones by : 2. Severe deficiency of ossification throughout the skeleton 3. Marked shortening of Seizures the long bones11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 40
  41. 41. 2.Infantile form (Severe form) The patients present during the first 6 mo of life with : * Rickets and/or * Failure to thrive11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 41
  42. 42. Cont.• Hypercalcemia is fairly common, and hypercalciuria can cause nephrocalcinosis• A low serum alkaline phosphatase is characteristic of this disorder• The serum phosphorus is normal.11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 42
  43. 43. Remember In the neonatal period, the normal to elevated alkaline phosphatase levels present in Osteogenesis imperfecta (OI) (brittle bone disease),distinguish it from hypophosphatasia.11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 43
  44. 44. 3.Childhood or Late adolescence (hypophosphatasia tarda) • Patients with the • Bowing of the legs mild disease may • Variable statural present with : shortening Also: 1. Bone pain 2. Frequent fractures 3. Milder skeletal deformities 4. Premature tooth loss11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 44
  45. 45. Bowing of the legs11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 45
  46. 46. Unusual clinical manifestationsInclude :1. Wormian bones in the calvaria2. Poor calcification of the frontal, parietal, and occipital bones3. Premature loss of deciduous or permanent teeth11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 46
  47. 47. Characteristic diagnostic tests1.↑↑↑Phosphoethanolamine (PEA) in urine2. ↑↑plasma inorganic pyrophosphate(IPP)3. ↑↑ plasma Pyroidoxal-5-phosphate (PLP) 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 47
  48. 48. Cont.• Serum levels of phosphorus are normal, and those of alkaline phosphatase are subnormal. •Mild to moderate hypercalcemia (especially the severe infantile form) Mumm S, Jones J, Finnegan P, Whyte MP: Hypophosphatasia: Molecular diagnosis of Rathbuns original case. J Bone Miner Res 2001;16:1724-2711/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 48
  49. 49. Essential diagnostic toolIn patients with HPP, serum pyridoxal 5- phosphate (PLP) is elevated and can provide additional diagnostic insight.PLP is ↓ in most other bone diseases11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 49
  50. 50. 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 50
  51. 51. Treatment No satisfactory therapy has been found • Infusion of plasma rich in alkaline phosphatase activity • Bone marrow transplantation is successful using donors with normal TNSALP values11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 51
  52. 52. Supportive therapy• Disease management focuses on supportive therapy to minimize disease-related complications:• Vitamin B6 for seizures in affected patients• Surgery to relieve increased intracranial pressure, repair of fractures• Pain management, such as NSAIDs• Dental care to preserve primary dentition11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 52
  53. 53. Prognosis• The clinical course of this condition often improves spontaneously as an affected child maturesEarly death due to1. Renal failure2. Flail chest leading to pneumonia may also occur in the severe infantile form of the disorder.11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 53
  54. 54. Hypophosphatasia (HPP):Severe, progressive complications. Lifelongmorbidities• Devastating mortality in the most vulnerable patients• Nearly 100% mortality in hypophosphatasia (HPP) patients who manifest perinatally• Approximately 50% mortality in HPP patients who manifest in infancy . Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2010;1192:190-200.11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 54
  55. 55. 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 55
  56. 56. Remember 1.High-dose vitamin D 2. Calcium supplements 3.Bisphosphonates →Can actually worsen hypophosphatasia (HPP) symptoms11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 56
  57. 57. Summary11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 57
  58. 58. 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 58
  59. 59. Cont.11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 59
  60. 60. Cont.11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 60
  61. 61. Early signs of HPP11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 61
  62. 62. Cont.11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 62
  63. 63. 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 63
  64. 64. 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 64
  65. 65. 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 65
  66. 66. 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 66
  67. 67. 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 67
  68. 68. 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 68
  69. 69. 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 69
  70. 70. 11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 70
  71. 71. Cont.11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 71
  72. 72. Cont.11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 72
  73. 73. Misdiagnosis of hypophosphatasia (HPP) can lead to inappropriate treatment that puts patients at unnecessary risk.11/3/2012 Hypophosphatasia Prof. Dr. Saad S Al Ani 73
  74. 74. Is it a varient of Rickets?11/3/2012 74 Prof.Dr. Saad S Al Ani
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×