Pseudohypoparathyroidism vs pseudopseudohypoparathyroidism

[Bobcat18]

I understand that the issue is with the Gs subunit which results in impaired PTH function but I'm confused as to what "with" vs "without" end-organ PTH residence means? Thanks in advance for your help!

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[StilgarMD]

Pseudohypoparathyroidism is when its as if you lack PTH-effect due to the signaling cascade downstream being non-fuctional (Gs subunit, like you said). The mutant Gs is likely in the tissues that need to respond to PTH to preserve calcium homeostasis.

Pseudopseudohypoparathyroidism (from what I can see) is when the person Looks like someone with the former ("knuckle-kunckle-dimple-dimple" hand being a notable feature) but their blood work is that of a totally normal person. It might result from some sort of chimerism that produces resistance in the cells responsible for the outward phenotype but not in the long bones and the intestines. This could lead to PTH not signaling in the hand/brain, causing the phenotype, but it is signaling in the tissues responsible for calcium homeostasis (Bone, gut, kidney), so the person's blood values are fine.

See attached for more details.

 

[StilgarMD]

So just as an update - FA says:

Pseudohypoparathyroidism is when the defect is inherited from the mother
while pseudopseudohypoparathyroidism is inherited from the father.

The Gs protein apparently experiences imprinting.

 

[stop2stop]

So just as an update - FA says:

Pseudohypoparathyroidism is when the defect is inherited from the mother
while pseudopseudohypoparathyroidism is inherited from the father.

The Gs protein apparently experiences imprinting.

That is fascinating. Any idea why imprinting would lead to the phenotype-only in the case of paternal inheritance?

 

[StilgarMD]

Imprinting is a matter of gene inactivation. The situation I describe above must happen here, except for instead of mutations taking place at different branch points of cellular differentiation, the cells in your "Calcium homeostasis tissues" must rely on your mother's gene, and be fine as long as you get a good copy from your mom, whereas the external phenotype can arise from either case.

 

[Phloston]

When you're thinking about this stuff, the first thing you need to start with is knowing what the Albright hereditary osteodystrophy (AHO) phenotype is.

Albright hereditary osteodystrophy = the clinical presentation of shortened fourth/fifth metacarpals, short stature, mild mental ******ation and round facies. That description is essentially the common tetrad you'll hear.

The second step is looking at the biochemistries. If calcium is low, phosphate high, and PTH high, then there's PTH insensitivity. We can call this biochemistry pseudohypoparathyroidism (Ca/PO4 reflect as if PTH is low, but it's actually high)

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AHO phenotype + pseudo biochemistry = pseudohypoparathyroidism type Ia

AHO phenotype + normal biochemistry = pseudopseudohypoparathyroidism (phenotype looks like pseudo Ia but biochemistries say otherwise)

Normal phenotype + pseudo biochemistry = pseudohypoparathyroidism Ib or II (in II the defect is more downstream and cAMP responses are normal in response to exogenous PTH)

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The USMLE will tell you there's pseudohypoparathyroidism and then ask for what happens when exogenous PTH is given. Normally nothing should occur because the disease is as if PTH isn't there. But if you're cornered into a situation where something has to respond, it's urinary cAMP, which will increase in type II.

 

[SeahawksFan]

When you're thinking about this stuff, the first thing you need to start with is knowing what the Albright hereditary osteodystrophy (AHO) phenotype is.

Albright hereditary osteodystrophy = the clinical presentation of shortened fourth/fifth metacarpals, short stature, mild mental ******ation and round facies. That description is essentially the common tetrad you'll hear.

The second step is looking at the biochemistries. If calcium is low, phosphate high, and PTH high, then there's PTH insensitivity. We can call this biochemistry pseudohypoparathyroidism (Ca/PO4 reflect as if PTH is low, but it's actually high)

-------

AHO phenotype + pseudo biochemistry = pseudohypoparathyroidism type Ia

AHO phenotype + normal biochemistry = pseudopseudohypoparathyroidism (phenotype looks like pseudo Ia but biochemistries say otherwise)

Normal phenotype + pseudo biochemistry = pseudohypoparathyroidism Ib or II (in II the defect is more downstream and cAMP responses are normal in response to exogenous PTH)

------

The USMLE will tell you there's pseudohypoparathyroidism and then ask for what happens when exogenous PTH is given. Normally nothing should occur because the disease is as if PTH isn't there. But if you're cornered into a situation where something has to respond, it's urinary cAMP, which will increase in type II.

Man, you are epic !