Download - SHORTENED 4 TH AND 5 TH METACARPALS, A DIFFERENTIAL DIAGNOSIS Meredith Austin-Appleton, PGY-1
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SHORTENED 4TH AND 5TH METACARPALS, A DIFFERENTIAL DIAGNOSIS
Meredith Austin-Appleton, PGY-1
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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
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Case Presentation
• 10 year-old ZL referred 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
• ROS: negative• PMH: none• Medications: none• Physical exam: normal growth parameters, subtle dip from 3rd to 4th knuckles B/L
• No other abnormalities on exam
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Differential Diagnosis• Idiopathic• Turner syndrome (nope!)• Pseudohypoparathyroidism• Pseudopseudohypoparathyroidism• Idiopathic primary hypoparathyroidism• Post-trauma• Post-infective
• Isolated 5th metacarpal shortening seen in some familial T1DM
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Pseudohypoparathyroidism, Type Ia
• 4th& 5th metacarpal shortening 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 G-protein, leading to inability of G-protein to activate adenyl cyclase upon PTH binding
• Autosomal dominant inheritancehttp://bestpractice.bmj.com/best-practice/monograph/1150/basics/pathophysiology.html
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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)
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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
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Pseudopseudohyoparathyroidism• Paternally transmitted
GNAS1 mutations• Phenotype of AHO without
PTH resistance• Normal calcium, phosphate
and PTH!
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Pseduohypoparathyroidism 1b, 1c
1b
• Hypocalcemia without AHO 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
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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
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Idiopathic Primary Hypoparathyroidism
• Case reports of shortened 4th and 5th metacarpals with primary hypoparathyroidism
• Require PTH level to differentiate from PHP
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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
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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/
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Turner Syndrome
• 45X, usually maternal X 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
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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)
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Back to our patient…
What investigations would you order, if any?
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Investigations
• Calcium, albumin, 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
• PTH Infusion Test – can 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
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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)
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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!
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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