Janatha

Dept. of Radiology
2008 aug 06
5 month old baby
 Born to 2nd gravida at term – no
neonatal complications
 Growth and development
appropriate for age
 h/o:
 Fracture of right femur no preceeding
histroy of trauma
 March 2008
 Total protien – 49 (63-82g/L)
 Na – 136 (135- 145)
 Potassium – 6.4 (3.5-5)
 Cl – 107 (101-111)
 Creatinine – 25 Umol/L (27-53)
 ALP – 681 IU/L (110-302)
 AST – 112 (22-58) IU/L
 ALT – 54 (11-39) IU/L
 March 2008
 CBP:
▪ WBC – 3.2
▪ RBC – 4.5
▪ HB – normal
▪ CRP – 2 normal
▪ Diff count
▪ Lymphocytes 80% ( 20-50%)
▪ Platelets - low

 Imp:
▪ leucoerythroblastic picture, mild thromboctopenia
 Sr. Creatinine – 42 (27-53) Umol/L
 phos – 0.8 (1.15-2.15) mmol/L
 Calcium – 2.35 (2.1 -2.6 mmol/L)
 Mg – 1.02 (0.7-1.1)
 ALP – 1450 (110-302)

 Platelets: 54 ( 150-450)
 Vi.D 25-OH: 14 (50-200nmol/L)
 Vit.D 1,25 OH: 87 (43-148pmol/L)
 Intact PTH : 29.1 (1.3-6.8)pmol/L
Patient was discharged with
aHip spica casting
Calciferol, calcitriol and Ca++

Readmitted in july 2007

 Sr. calc: 9.3 (8-  Intact PTH: 19.2
10.8) (11.1-79.5) pg/ml
 Sr.creat: 0.6mg/cl
 CBP:
 Na: 139
 Hb:10.3
 K: 4.5  RBC: 3.4 (3.7-5.3)
 Cl: 111(98-106)  Platelets 122 (200-
 Sr.Phos: 2.6 500)

(4.8-8.2) mg/dl
 Sr.Calcium & parathyroid levels –
normal

 Non union of the Rt. Femur #

 Stool exam – N
 USG abdomen:
 N. study
 Doppler of PV and Hepatic viens – N.study
 CSF anlysis:
 Normal
 CT base of skull:
 Osteopetrosis
 MRI:
 focal narrowing of optic canal due to
hypertrophy of overlying bones (greater &
lesser wing of spenoid)
 # shaft of femur – proximal 1/3rd with non
union
Generalised sclerosis * - osteopetrosis
Significantly, diffuse metaphyseal fraying and
cupping
Periosteal reaction
Increased distance between the metaphyses
and epiphyses in multiple areas (widening of
physis)
Leucoerythroblastic picture with
thrombocytopenia

 These findings, along with the lowered serum

A German radiologist, Albers-
Schönberg, first described
osteopetrosis in 1904
 Synonyms :
 Marble bone disease
 Chalk bones
 Osteopetrosis generalisata
 Osteosclerosis generalisata
A rare familial bone abnormality,
characterized by lack of resorption of
normal primitive osteochondrous
tissue.
 Overall incidence of the disease is
estimated to be 1 case in 100,000-
500,000 population
 Gender and ethnicity is not a factor for
predominance of this disease.
 However, it has been reported more
frequently in the Mediterranean
countries, Costa Rica and the Middle
 4 main types of osteopetrosis have been described:
An infantile/congenital form, AR form
Malignant
A milder recessive form

Autosomal dominant form./Tarda and

Benign
4 type due to deficiency of carbonic anhydrase II
th

 With renal tubular acidosis

 The benign form, presents in adulthood

 while the two more malignant variants, osteopetrosis
congenita and marble bone disease, present in infancy
and childhood, respectively
 The prime defect - failure of osteoclastosis
as a consequence, bone modeling and
remodeling are impaired
 Without properly working osteoclasts ,
failure of resorption of calcified cartilage
(spongiosa)
 The unchecked accumulation of osseous
tissue increases bone density and
constricts the marrow and neural foramina
 So that the patient is susceptible to
anemia, leukopenia,
thrombocytopenia, extramedullary
hematopoiesis, and multiple cranial
nerve neuropathies
 Because of these complications, few
patients with this disorder survive
childhood and the teens, unless they
have the "tarda" form of the disease.
 Theneonatal or "malignant" form
presents with severe marrow
depletion and intracranial
haemorrhage

 These
patients may live for several
decades but at are risk for
overwhelming infections &
haemorrhage
 The intermediate form appears
within the first decade of life and
does not follow a malignant course. 
 Some of the features noted in the
malignant form, such as anaemia,
dental anomalies, or disproportion
(short limb/short stature), can be
identified in milder presentations. 
Osteopetrosis Tarda (benign osteopetrosis)
 This form is that also known as Albers-SchÖnberg
disease
 It is usually detected by a family history of bone
disease or as an incidental radiologic finding
 It is asymptomatic in about 50 % of cases
 About 40 % of patients present with fractures
related to brittle osteopetrotic bones or with
osteomyelitis, especially of the mandible and
subsequent deformities such as coxa vara are
common
 The patient with the AD type has
a normal life expectancy but
many orthopaedic problems  
 Mild anemia may be present;
facial palsies and deafness can
occur, but are not necessarily
features 
 Inadult osteopetrosis (also called
benign osteopetrosis)
 Two distinct types have been
described, type I and type II, on the
basis of radiographic, biochemical,
and clinical features
Characteristic Type I Type II
Marked sclerosis Sclerosis mainly of
Skull sclerosis
mainly of the vault the base

Does not show Shows the rugger-

Spine
much sclerosis jersey appearance

Shows endobones
Pelvis No endobones
in the pelvis
Transverse
May or may not be
banding of Absent
present
metaphysis
Risk of fracture Low High
Serum acid
Normal Very high
phosphatase
 The bones are very dense. In fact,
they are so dense that nothing else
really looks like this (except for
pyknodysostosis, which is really,
really rare)

 The bones fracture easily, often with

a linear fracture plane.
 Labs
 Anemia is invariably present
 Severe thrombocytopenia
 Serum Ca+ may be N / elevated
 PTH often is elevated (secondary
hyperparathyroidism).
 Acid phosphatase and CK-BB
concentrations are often increased in
type II disease.
 Serum bone-specific alkaline
phosphatase values may be increased
 Radiologic features are usually diagnostic
 Because the disease is a heterogeneous
group of disorders, the findings vary
depending on the subtype.
 Patients usually have generalized
osteosclerosis
 Bones may be uniformly sclerotic, but
alternating sclerotic and lucent bands may
be noted in iliac wings and near ends of
long bones
 The bones might be clublike or appear like a
bone within bone (endobone).
 The entire skull is thickened and dense,
especially at the base.
 Sinuses are small and underpneumatized.
 Vertebrae are extremely radiodense.
 They may show alternating bands, known as the
rugger-jersey sign
 Radiographs may show evidence of fractures or
osteomyelitis.
 Two types of adult osteopetrosis are identified on
the basis of radiographs
 Typing the patient's disease might be important
to predict a fracture pattern because type II
disease appears to increase the risk of fracture
 Type I disease:
▪ Sclerosis of the skull mainly affects the vault with marked thickening.
The spine does not show much sclerosis.
 Type II disease:
▪ Sclerosis is found mainly in the base of the skull.
▪ The spine always has the rugger-jersey appearance, and the pelvis
always shows subcristal sclerosis.
▪ Transverse banding of metaphysis is common in patients with type II
disease
Lateral radiograph of the skull shows uniform sclerosis of calvarium
and the skull base with an enlargement of the cranial vault. There is
obliteration of the frontal sinuses and mastoids
 The process of bone marrow replacement
and extramedullary hematopoiesis often
results in leukemia.
 Repeated infections and haemorrhage
 Cranial nerve disorders due to sclerosis at
the base of the skull.
 Dental caries and osteomyelitis are
common
 Rx
 Low calcium diet and Vit. D to
activate osteoclasts
 Bone marrow transplantation has
been employed to attempt to treat
the infantile form of the disease
 Aim is to provide hematopoietic
stem cells that can differentiate into
normal osteoclasts
 The word “osteopetrorickets” is used to
indicate this unusual association
 Rickets is a paradoxical feature of malignant
infantile osteopetrosis*
 Despite a markedly positive total body calcium
balance, patients with osteopetnosis are
susceptible to rickets because the dysfunctional
osteoclasts are unable to maintain a normal
calcium-phosphorous balance in the extracellular
fluid

* Kaplan et al. reported a series of five infants with

osteopetnosis, all of whom had proven cases of rickets.
 Theserum calcium and phosphorous
product is insufficient to mineralize
the newly formed chondroid and
osteoid leading to rickets
 These patients can have hypocalcaemia,
hypophosphatemia and increased alkaline
phosphatase and parathyroid hormone
levels
 Radiographic detection of rickets is
important in these patients.
 As bone marrow transplantation is the
therapy of choice for osteopetnosis, but
the clinical response to bone marrow
transplantation is inadequate if there is
underlying rickets
 Presence of rickets has additional implications if
human leukocyte antigen-matched bone marrow
transplantation is anticipated
 The purpose of bone marrow transplantation is to
provide hematopoietic stem cells that can
differentiate into normal osteoclasts
 However, when normal bone is replaced by
hypomineralized osteoid , the effectiveness of
transplantation is severely attenuated
 Because normal osteoclasts cannot resorb
hypomineralized osteoid , rickets counteracts the
basic purpose of the transplantation, so the
patient’s clinical condition does not improve
 AJR, Donnelly et al. 164 (4): 968. (1995)

 CLINICAL PROFILE OF OSTEOPETROSIS IN

CHILDREN IN KARACHI, JCPSP 2007, Vol. 17 (3):
154-157 Syeda Shireen Gul, Syed Jamal Raza,
Muhammed Alam and Zeenat Issani

 Kulkarni ML, Matadh PS. Rickets in osteopetrosis-

a paradoxical association. Indian Pediatr
2003;40(6):561-5

 Ozsoylu S. Malignant osteopetrosis with rickets.

Eur J Pediatr 2001;160(2):137
 Since the early 20th century, ultraviolet
radiation or vitamin D ingestion has been
recognized as a cure for nutritional
rickets, although certain forms of rachitic
disease have remained refractory to this
therapy
 Study of these refractory cases has
revealed low serum phosphate
concentration as a common factor.
 Familial occurrence of this condition led to
the diagnosis of familial
 In osteopetrosis the patients are often advised to reduce
calcium intake.
 In normal subjects a lower serum calcium stimulates PTH
secretion that acts on osteoclasts to cause bone resorption
and thus increase serum calcium.
 In osteopetrosis the osteo-clasts do not respond to PTH and
the responsibility for maintaining calcium balance lies on
the kidneys and intestine.
 Patients on limited calcium intake and poor intestinal
absorption due to prednisolone, which is used for
hematological complications, result in reduced total body
calcium and phosphate levels
 Increased PTH increases calcium reabsorption but at the
expense of phosphate wasting.
 Persistance of hypo-calcemia and hypophosphatemia
results in inability to mineralize newly formed chondroid
and osteoid and the paradoxical association of rickets and
osteopetrosis.
 Inadequate levels of inorganic
phosphate impair the function of
mature osteoblasts (ie, bone matrix
ossification), because formation of
mature bone involves the
precipitation of hydroxyapatite [3-
Ca3(PO4)2 : Ca(OH)2] crystals.
 This has also been called X-linked
hypophosphatemia, primary renal
hypophosphatemic rickets or familial vitamin D-
resistant rickets.
 As one of these names implies, it is due to a
hereditary defect of the renal tubules, leading to
decreased reabsorption of phosphate (phosphate
diabetes) and therefore reduced serum
phosphate levels.
 As the name also implies, this decreased
reabsorption does not respond to usual amounts
of vitamin D.
 Inheritance: X-linked dominant.  Mutations of the
is a defective zinc metalloendopeptidase PHEX
 Clinical:  Laboratory studies reveal near-normal
levels of calcium, PTH, and vitamin D, but low
levels of serum phosphate. 
 Urinary phosphate and serum alkaline
phosphatase are elevated. 
 Affected children present with bowing of the
lower extremities, short stature, bone pain and
dental caries. 
 The disease becomes clinically apparent after 12
months of age
 Classic, vitamin D resistant rickets is
characterised by:
 Hypophosphataemia
 Renal phosphate leak as expressed as a lowered
transfer maximum of phosphate per unit volume
of glomerular filtrate (TMPO4/GFR)
 Inappropriate vitamin D metabolism in the
presence of
 low serum phosphate (low to normal serum 1,25
dihydroxy vitamin D3; calcitriol)
 High alkaline phosphatase
 Skeletal defects
 In general, this disorder exhibits
rachitic epiphyseal and
metaphyseal abnormalities
predominantly in the lower
limbs.
 No pathognomonic sign on x-ray
distinguishes hypophosphatemic
rickets from any other etiology.
 In a study of patients with
hypophosphatemia, Stickler (1969)
concluded that hypophosphatemia was
already present in the neonatal period,
that alkaline phosphatase was elevated at
1 month of age, and that early treatment
with high doses of vitamin D did not
prevent growth failure.
 Patients with the X-linked disorder do not
show muscle weakness, tetany, or
hypocalcemia
 Diagnosis at discharge:
 # Rt.femur
 Osteopetrosis with involvement of
marrow
 Hypophosphataemic rickets
 Lab Studies
 Calcium levels may be within or slightly below
the reference range
 Alkaline phosphatase levels are significantly
above the reference range.
 Serum parathyroid hormone levels are within the
reference range or slightly elevated
 while calcitriol levels are low or within the lower
reference range.
 Most importantly, urinary loss of phosphate is
above the reference range
 Lab Studies
 Findings in infantile osteopetrosis
 Serum calcium- Hypocalcemia can occur and cause rickets if it
is severe enough.
 PTH often is elevated (secondary hyperparathyroidism).
 Acid phosphatase is increased due to increased release from
defective osteoclasts.
 Levels of creatinine kinase isoform BB (CK-BB) is increased due
to increased release from defective osteoclasts.
 Findings in adult osteopetrosis
 Acid phosphatase and CK-BB concentrations are often
increased in type II disease.
 Serum bone-specific alkaline phosphatase values may be
increased