Transcript Shortened 4th and 5th Metacarpals, a differential diagnosis

SHORTENED 4TH AND 5TH METACARPALS,
A DIFFERENTIAL DIAGNOSIS
Meredith Austin-Appleton, PGY-1
CanMEDS Objectives
Scholar: improve knowledge of disorders of
calcium/phosphate metabolism as well as Turner syndrome
Medical Expert: improve differential diagnosis and
management of findings of shortened 4th and 5th
metacarpals
Health advocate: apply knowledge to best management of
individual patients
Case Presentation
• 10 year-old ZL referred
• ROS: negative
to Pediatric
Endocrinology clinic for
short 4th and 5th
metacarpal, incidental
finding on right hand
XR done for trauma to
phalanx of right 5th
digit
• Parents unclear
reason for visit, and
have no concerns
• PMH: none
• Medications: none
• Physical exam: normal
growth parameters,
subtle dip from 3rd to
4th knuckles B/L
• No other abnormalities
on exam
Differential Diagnosis
• Idiopathic
• Turner syndrome (nope!)
• Pseudohypoparathyroidism
• Pseudopseudohypoparathyroidism
• Idiopathic primary hypoparathyroidism
• Post-trauma
• Post-infective
• Isolated 5th metacarpal shortening seen in some familial
T1DM
Pseudohypoparathyroidism, Type Ia
• 4th& 5th metacarpal shortening
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seen with type Ia with Albrights
Hereditary osteodystrophy
Low Ca+, high Phos,
appropriately high PTH
Decreased urinary cAMP
response to PTH
Defect in GNAS1 gene
responsible for coding Gprotein, leading to inability of
G-protein to activate adenyl
cyclase upon PTH binding
Autosomal dominant
inheritance
http://bestpractice.bmj.com/bestpractice/monograph/1150/basics/pathophysiology.html
GNAS1
• Imprinted
• Renal expression is determined by maternal allele – only
a defect in the maternal allele will lead to defective PTH
binding
• Type Ia caused by loss-of-function mutation of
maternally inherited allele
• Maternal allele of GNAS1 expressed in thyroid, gonads,
pituitary, can lead to other hormone resistance (TSH, LH,
FSH, GnRH)
Albright Hereditary Osteodystrophy
• Combination of findings
including PHP type Ia
• Also have round facies,
short stature, obesity,
developmental delay,
subcutaneous
calcifications
• Phenotype is not related
to PTH, rather to mutation
of G-protein in other
tissues
Pseudopseudohyoparathyroidism
• Paternally transmitted
GNAS1 mutations
• Phenotype of AHO without
PTH resistance
• Normal calcium, phosphate
and PTH!
Pseduohypoparathyroidism 1b, 1c
1b
• Hypocalcemia without AHO
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phenotype
Rare
PTH resistance limited to
kidney
Some reports of TSH
resistance, though usually
no other endocrine
involvement
Mutation in regulatory
elements of GNAS1, still
maternally transmitted
1c
• Mutation affecting
coupling of PTH receptor
to G protein
• Can activate adenyl
cyclase, but no longer
coupled to PTH receptor
• Similar phenotype to 1a
Pseudohypoparathyroism type 2
• No AHO phenotype
• Urinary cAMP levels increase in response to exogenous
PTH, however have same biochemical of
pseudohypoparathyroidism
• Issue is further down the signalling pathway
• Genetics unknown
Idiopathic Primary Hypoparathyroidism
• Case reports of
shortened 4th and 5th
metacarpals with
primary
hypoparathyroidism
• Require PTH level to
differentiate from PHP
The Effects
• Patients with hypocalemia can have paraesthesias,
tetany, QT prolongation
• Hyperphosphatemia leads to calcium phosphate deposits
in kidney, brain, skin, eye leading to nephrolithiasis,
calcification of basal ganglia, subdermal calcification,
cataracts
McCune-Albright Syndrome
• Precocious puberty,
café-au-lait spots and
boney fibrous
dysplasia
• Somatic (acquired)
mutation in GNAS1
causing enhanced
function of G protein
http://emedicine.medscape.com/
Turner Syndrome
• 45X, usually maternal X
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chromosome
Usually just 4th metacarpal
shortening
½ have mosaic
chromosomes (45X and
46XX)
Short stature is only
phenotype found in all
patients (GH therapy)
Webbing of neck, shield
chest, ear abnormalities,
renal, cardiac
Hypothyroidism common
Pubertal Development
• Usually primary amenorrhea, some have secondary
amenorrhea
• Can have spontaneous pregnancy – retrospective study
showing of patients with proven Turner Syndrome, and
>90% 45X out of 50 cells, 5/276 females
• Characteristic ‘streak gonads’, however extremely
variable
• Results of autopsies on aborted fetuses indicated normal
primordial germ cells at 6 weeks gestation, at later
gestations showed decrease with more connective tissue
(accelerated apoptosis)
Back to our patient…
What investigations would you order, if any?
Investigations
• Calcium, albumin,
• PTH Infusion Test – can
phosphorus, Mg, ALP,
PTH, Cr, vitamin D
• Calcium can
occasionally be normal
in PHP, however PTH
levels will be increased
• Consider TFT,
gonadotropin levels
• ECG – looking for QT
prolongation
• Analysis of GNAS1 gene
distinguish between
hypoparathyroidism and
PHP and between PHP
type 1 and PHP type 2
• Infusion of human PTH,
measure urinary PO4,
Cr and cAMP
• Differentiating between
type 1 and 2 indicated
for genetic counseling,
though will not change
management
Investigations – Turner Syndrome
• Karyotyping – if suspecting Turner syndrome and blood
lymphocyte karyotype normal, karyotype 2nd tissue (skin)
If confirmed:
• GH testing not recommended (not growth hormone
deficient)
• TSH annually
• Echocardiography/MRI (r/o coarctation)
• Glucose, Cr, Urinalysis annually (r/o DM, renal disease)
Our patient
• All blood work normal, except slightly low phosphate
• Conclusion:
• NORMAL VARIANT!
• Positive metacarpal sign is seen in close to 10% of
normal individuals!
References
• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784883/
• http://www.ncbi.nlm.nih.gov/pubmed/8699958
• http://www.uptodate.com
• http://www.omim.org/entry/103580