Hypophosphatasia

1st Patient
• A female infant
• Shortening of limbs, detected during
pregnancy by ultrasonography.
• Admitted to the neonatal intensive care
unit because of respiratory distress.
3/18/2022 2
Is it a varient of Rickets?
Prof.Dr. Saad S Al Ani

• A bone radiograph :
hypomineralization of all bones,
• Serum alkaline phosphatase was
very low (10 U/L)
• Seizures (focal clonic and tonic)
started
Cont.
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• The seizures were refractory to
phenobarbital and other antiepileptic
drugs.
• The first (EEG) showed a burst-
suppression pattern.
Cont.
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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.
3/18/2022 5

Cont.
• A postpyridoxine EEG revealed
the disappearance of the burst-
suppression pattern.
• The patient died at age 26 days.
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2nd Patient
• 6 months
• Persistence of a widened anterior
fontanel
• Diagnosis of nutritional rickets
prompted high-dose vitamin D and
calcium supplementation
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Cont.
Immediate ponderal growth failure
and bulging anterior fontanel
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• 8 months:
Oral therapy stopped; calcium-phosphate
metabolism assessments showed :
*Increased calcium and phosphate values
*Reduced PTH
*High 25-hydroxy vitamin D levels
*Hypercalciuria
Cont.
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Cont.
• Ponderal growth failure
• Bulging anterior fontanel
• Blood tests confirmed above findings
except normalization of 25-hydroxy
vitamin D levels
10
3/18/2022

Cont.
• Radiograph showed :
*Severe and generalized osteopenia with
tongues of radiolucency
*Persistence of opened anterior fontanel
• Renal ultrasound showed :
* Nephrocalcinosis
11
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Radiograph of the left wrist showing tongues of radiolucency
(arrows) in distal metaphysis of radius and ulna
Mohan, Acta Paediatr, 2011
12
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Cont.
• at 9 months of age, the patient's history
reported normal growth.
• Except the absence of the central lower
mandibular incisors, the oral examination
was entirely normal, without inflammation
of the gums.
13
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3rd Patient
• A 10-months-old girl
• Spontaneous and unexplained loss of her
primary lower central incisors
14
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4th Patient
• A 30-months-old boy
• Premature loss of primary teeth.
• Except for eczema, the child presented
with normal development.
16
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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.
17
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Cont.
• Radiographs of the skeleton revealed :
* Distorted bone trabeculation
* Areas of decreased radiolucency
* Bone undermineralization.
19
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3/18/2022 20

Is it a variant of Rickets?
3/18/2022 21

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.
3/18/2022 22

Hypophosphatasia
Prof. Dr. Saad S Al Ani
Senior Pediatric Consultant
Head of Pediatric Department
Khorfakkan Hospital
Sharjah ,UAE
saadsalani@yahoo.com

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
3/18/2022 24
Hypophosphatasia Prof. Dr. Saad S Al Ani

25
3/18/2022

Cont.
• It is an inborn error of metabolism in
which activity of the tissue-nonspecific
(liver/bone/kidney) alkaline phosphatase
(TNSALP) is deficient.
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Etiology
Mornet E. Hypophosphatasia. Orphanet J Rare Dis. http://www.ojrd.com/content/2/1/40.
29, 2012
•Single point mutation of the gene
↓
• Prevent expression of the TNSALP
activity
• >200 mutations of the gene
•The most common is misssense mutation
(75%)
27
3/18/2022 Hypophosphatasia Prof. Dr. Saad S Al Ani

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
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Pathophysiology
Deficient 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.
29
3/18/2022

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/2/1/40
30

Bone Matrix
31

Prevalence
32

Canadian prevalence
33

Global prevalence
34

A comparison
35

Metabolic bases of HPP
Genetic mutation in the ALPL gene
Deficient ALP activity
Substrates accumulation/PPI,PLP,PEA
Metabolic disease
• Inhibition of hydroxyapatite crystal formation
• CPPD crystal deposition
• Vitamin B6 (PLP) unable to cross
blood –brain barrier
•Hypercalcemia ,hyperphosphatemia
PPI : inorganic
pyrophosphate
PLP: pyridoxal
5′-phosphate
PEA :
phosphoethanolamine
CPPD : calcium
pyrophosphate
dihydrate
36

Time of presentation
There is considerable heterogeneity in the
severity of the disease
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Cont.
• Some cases appear at birth, and diagnosis
has even been made in utero by
radiographic examination of a fetus.
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Types
1. Lethal neonatal or perinatal
form (congenital lethal
hypophosphatasia),
2. Severe infantile form
3. Milder form occurring in
childhood or late adolescence
(hypophosphatasia tarda).
There are
three types
that the
disease may
appear in:
3/18/2022 39

1.Neonatal or Perinatal form
(Congenital lethal hypophosphatasia)
Is characterized
by :
1. Moth-eaten appearance
at the ends of the long
bones
2. Severe deficiency of
ossification throughout
the skeleton
3. Marked shortening of
the long bones
Seizures
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2.Infantile form (Severe form)
The patients present during the first 6 mo
of life with :
* Rickets
and/or
* Failure to thrive
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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.
3/18/2022 42

Remember
In the neonatal period, the normal to
elevated alkaline phosphatase levels
present in Osteogenesis imperfecta (OI)
(brittle bone disease),distinguish it from
hypophosphatasia.
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3.Childhood or Late adolescence
(hypophosphatasia tarda)
• Patients with the
mild disease may
present with :
• Bowing of the legs
• Variable statural
shortening
Also:
1. Bone pain
2. Frequent fractures
3. Milder skeletal deformities
4. Premature tooth loss
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Bowing of the legs
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Unusual clinical manifestations
Include :
1. Wormian bones in the calvaria
2. Poor calcification of the frontal, parietal,
and occipital bones
3. Premature loss of deciduous or permanent
teeth
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Characteristic diagnostic tests
1.↑↑↑Phosphoethanolamine (PEA) in urine
2. ↑↑plasma inorganic pyrophosphate(IPP)
3. ↑↑ plasma Pyroidoxal-5-phosphate (PLP)
47

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 Rathbun's original case. J Bone Miner Res 2001;16:1724-27
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Essential diagnostic tool
In patients with HPP, serum pyridoxal 5'-
phosphate (PLP) is elevated and can
provide additional diagnostic insight.
PLP is ↓ in most other bone diseases
49

50

Treatment
• Infusion of plasma rich in alkaline
phosphatase activity
• Bone marrow transplantation is
successful using donors with normal
TNSALP values
No satisfactory therapy has been found
3/18/2022 51

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 dentition
52

Prognosis
• The clinical course of this condition often
improves spontaneously as an affected
child matures
Early death due to
1. Renal failure
2. Flail chest leading to pneumonia
may also occur in the severe infantile form
of the disorder.
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Hypophosphatasia (HPP):
Severe, progressive complications. Lifelong
morbidities
• 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.
54

55

Remember
1.High-dose vitamin D
2. Calcium supplements
3.Bisphosphonates
→Can actually worsen hypophosphatasia
(HPP) symptoms
56

Summary
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Cont.

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Cont.

Early signs of HPP
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Cont.

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Cont.

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Cont.

Misdiagnosis of hypophosphatasia (HPP) can lead to inappropriate
treatment that puts patients at unnecessary risk.
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Hypophosphatasia

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