1. SHORTENED 4 TH AND 5 TH METACARPALS, A DIFFERENTIAL DIAGNOSIS Meredith Austin-Appleton, PGY-1

2. 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 4 th and 5 th metacarpals Health advocate: apply knowledge to best management of individual patients

3. Case Presentation 10 year-old ZL referred to Pediatric Endocrinology clinic for short 4 th and 5 th metacarpal, incidental finding on right hand XR done for trauma to phalanx of right 5 th digit Parents unclear reason for visit, and have no concerns ROS: negative PMH: none Medications: none Physical exam: normal growth parameters, subtle dip from 3 rd to 4 th knuckles B/L No other abnormalities on exam

5. Differential Diagnosis Idiopathic Turner syndrome (nope!) Pseudohypoparathyroidism Pseudopseudohypoparathyroidism Idiopathic primary hypoparathyroidism Post-trauma Post-infective Isolated 5 th metacarpal shortening seen in some familial T1DM

6. Pseudohypoparathyroidism, Type Ia 4 th & 5 th 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 inheritance http://bestpractice.bmj.com/best- practice/monograph/1150/basics/pathophysiology.html

7. 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)

8. 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

9. Pseudopseudohyoparathyroidism Paternally transmitted GNAS1 mutations Phenotype of AHO without PTH resistance Normal calcium, phosphate and PTH!

10. 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

11. 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

12. Idiopathic Primary Hypoparathyroidism Case reports of shortened 4 th and 5 th metacarpals with primary hypoparathyroidism Require PTH level to differentiate from PHP

13. 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

14. 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/

15. Turner Syndrome 45X, usually maternal X chromosome Usually just 4 th 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

16. 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)

17. Back to our patient… What investigations would you order, if any?

18. 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

19. Investigations – Turner Syndrome Karyotyping – if suspecting Turner syndrome and blood lymphocyte karyotype normal, karyotype 2 nd 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)

20. 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!

21. 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