Consider revising the classification of pseudopseudohypoparathyroidism (DOID:4183)

[allenbaron]

Is your request related to a specific disease? Please describe.
pseudopseudohypoparathyroidism (DOID:4183)

Describe the proposed change(s)
It is currently a child of pseudohypoparathyroidism (DOID:4184) but its definition does not fit with that of this parent. Perhaps it should be made a sibling of its current parent.

References
pseudohypoparathyroidism (DOID:4184) definition:

A metal metabolism disorder that is characterized by end-organ resistance to parathyroid hormone.

pseudopseudohypoparathyroidism (DOID:4183) definition

A pseudohypoparathyroidism characterized by a lack of resistance to parathyroid hormone or other hormones along with the constellation of clinical features referred to as Albright hereditary osteodystrophy and that has_material_basis_in a mutation resulting in loss of function of the Gs-alpha isoform of the GNAS gene on the paternal allele. This results in expression of the Gs-alpha protein only from the maternal allele.

[allenbaron]

Hmm... looks like there might be more revision needed than just reconciling these definitions.

There's definitely a relationship betweeen pseudopseudohypoparathyroidism (PPHP) and PHP Ia, so it's not wrong per se that they are both classified as children of pseudohypoparathyroidism (PHP)¹.

However, multiple authors have described issues with the current classification at it appears in the DO¹²³.

A consortium of European experts convened around 2016 and reclassified these diseases based on their molecular mechanisms, reorganizing them under the name 'inactivating PTH/PTHrP signalling disorder' (iPPSD)², in an effort to more clearly delineate the features that distinguish these disease subtypes. Turan S discusses this and outlines a lot of the issues with distinguishing between these diseases¹.

Jüppner (2023) acknowledged the European consortium's naming convention, which now does appear in publications, but suggests it's insufficient and points out PHP/AHO (Albright’s Hereditary Osteodystrophy) are still commonly used in practice to describe these diseases³.

It seems the classification for these diseases has not yet reached clarity. This will require significant follow-up and likely the involvement of clinicians to sort out, which is beyond the scope of the DO currently.

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Moving forward now

The problem outlined here is the incompatibility between the definitions of PPHP and it's current parent term PHP. Given the relationship of PPHP and PHP Ia, it seems reasonable to keep PPHP as a child of PHP. This suggests revision of the definition of PHP, as the grouping disease, would probably be best.

I suggest we revise this disease to accommodate diseases based on the broader possible phenotypes. This would include:

1. Those physical phenotypes typically associated together as "Albright’s Hereditary Osteodystrophy", which are currently included in the definition of PHP Ia (DOID:0080053): "shortening and widening of long bones located_in the hand or located_in the foot along with short stature, obesity, and rounded face".
   • These apply in the case of PHP Ia⁴, PPHP⁵, and PHP Ic⁶.
2. Resistance to parathyroid hormone.
   • This applies to PHP Ia⁴, PHP Ic (DOID:0051013)⁶, and PHP Ib (DOID:0080222)⁷.
   • Note that there is some uncertainty if PHP Ia and PHP Ic are the same disease or not (see OMIM record for PHP Ic) and patients may exhibit resistance to hormones beyond parathyroid hormone, while PHP Ib does not.

Given this information I suggest the definition of PHP be revised to:

A metal metabolism disorder that is characterized by end-organ resistance to parathyroid hormone and/or a constellation of symptoms collectively termed Albright’s hereditary osteodystrophy, which include shortening and widening of long bones located_in the hand or located_in the foot along with short stature, obesity, and rounded face.

Genetic cause

Most of these subtypes are caused by mutations in the GNAS gene. However, PHP Ib appears to have 2 additional genetic causes: STX16 and GNASAS1 (GNAS antisense RNA).

PHP II

Wanted to note that OMIM also has another disease termed PHP II⁸, which does not include AHO phenotype and has a different pattern of parathyroid hormone resistance. The proposed definition of PHP would still be able to incorporate this disease if we choose to add it. It does not currently appear to have a known genetic cause.

Footnotes

1. Turan S. Current Nomenclature of Pseudohypoparathyroidism: Inactivating Parathyroid Hormone/Parathyroid Hormone-Related Protein Signaling Disorder. J Clin Res Pediatr Endocrinol. 2017 Dec 30;9(Suppl 2):58-68. doi: 10.4274/jcrpe.2017.S006. Epub 2017 Dec 27. PMID: 29280743; PMCID: PMC5790322. ↩ ↩² ↩³

2. Thiele S, Mantovani G, Barlier A, Boldrin V, Bordogna P, De Sanctis L, Elli FM, Freson K, Garin I, Grybek V, Hanna P, Izzi B, Hiort O, Lecumberri B, Pereda A, Saraff V, Silve C, Turan S, Usardi A, Werner R, de Nanclares GP, Linglart A. From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network. Eur J Endocrinol. 2016 Dec;175(6):P1-P17. doi: 10.1530/EJE-16-0107. Epub 2016 Jul 11. PMID: 27401862; full text. ↩ ↩²

3. Jüppner H. Pseudohypoparathyroidism: complex disease variants with unfortunate names. J Mol Endocrinol. 2023 Dec 12;72(1):e230104. doi: 10.1530/JME-23-0104. PMID: 37965945; PMCID: PMC10843601. ↩ ↩²

4. https://omim.org/entry/103580 ↩ ↩²

5. https://omim.org/entry/612463 ↩

6. https://omim.org/entry/612462 ↩ ↩²

7. https://omim.org/entry/603233 ↩

8. https://omim.org/entry/203330 ↩

[allenbaron]

Since we have need to get out a release without conflicting disease definitions, I will update the definition of PHP as described. I will also update the definition of PHP Ib to include the other genetic causes.

I will not create PHP II at this time. It seems better to first review the classification and land on a clear revision first, if possible and at least some time is needed for that.

[allenbaron]

The definition of PHB Ib was likely sufficient as it was but I added a second sentence list mutations that had been shown to cause it to be comprehensive.

I also added the acronyms for PHP and its subtypes, since they are frequently used in the literature.

[allenbaron]

Given the similarity of PHP Ia and Ic, I also chose to add a comment noting the difference on PHP Ic.

[allenbaron]

I will leave this issue open since it seems likely that these diseases need further review, perhaps in conjunction with OMIM.