pseudohypoparathyroidism, Albright Hereditary osteodystrophy

1. ფსევოიოპოფარათორეიდიზმი

2. Introduction
• Pseudohypoparathyroidism (PHP) is a heterogeneous group of rare
endocrine disorders characterized by normal renal function and
resistance to the action of parathyroid hormone (PTH), manifesting
with hypocalcemia, hyperphosphatemia, and increased serum
concentration of PTH
• There are 5 variants of pseudohypoparathyroidism: PHP type 1a
(PHP-1a), PHP type 1b (PHP-1b), PHP type 1c (PHP-1c), PHP type 2
(PHP-2), and pseudopseudohypoparathyroidism (PPHP)
• PHP type 1a is the most common subtype and represents 70% of
cases

3. History
• In 1942, Fuller Albright first introduced the term
pseudohypoparathyroidism to describe patients who presented with
PTH-resistant hypocalcemia and hyperphosphatemia along with an
unusual constellation of developmental and skeletal defects,
collectively termed Albright hereditary osteodystrophy (AHO)

4. Epidemiology
• The estimated prevalence of PHP type 1a, type1b, and PPHP is 1 per
150,000 in Italy.
• In Japan, the estimated prevalence of PHP type 1a and type 1b is 1
per 295,000.
• PHP occurs approximately twice as frequently in females as in males.
• Onset of endocrine symptoms occurs during childhood, although
cases with severe hypothyroidism at neonatal screening have been
reported

5. Type 1 Pseudohypoparathyroidism
• Diminished urinary cyclic adenosine monophosphate (cAMP)
response to exogenous PTH administration.
• There are several subtypes of PHP type 1 caused by mutations
of GNAS1, a gene encoding the alpha subunit of the G protein,
coupled to the PTH receptor .
• These gene mutations result in the G protein's inability to activate
adenyl cyclase upon the binding of PTH to its receptor.
• Activation of adenyl cyclase is required for signal transduction that
produces the end-organ response to PTH. Failure of signal
transduction results in the unresponsiveness of the end-organ

6. Type 1 a
• PHP type 1a is an autosomal dominant disease with a loss-of-function
mutation of GNAS1, leading to an inability to activate adenyl cyclase when
PTH binds to its receptor
• Maternal transmission of the mutation is required for expression of PHP
type 1a
• Albright hereditary osteodystrophy (AHO): round facies, short stature,
short fourth/fifth metacarpal bones, obesity, subcutaneous calcifications,
and developmental delay, choroid plexus calcifications, hypogonadism.
• In addition, the PTH resistance of the renal tubule leads to
hyperphosphatemia and hypocalcemia, and secondary
hyperparathyroidism and hyperparathyroid bone disease (osteitis fibrosa)

7. Brachydactyly

8. Associated defects …
• In humans, GNAS1 also is predominantly expressed from the
maternal allele in the thyroid, gonads, and pituitary glands.
• As a result, patients with PHP type 1a show resistance to various
other G-protein coupled hormones including thyroid-stimulating
hormone (TSH), luteinizing hormone (LH), follicle-stimulating
hormone (FSH), and gonadotropin-releasing hormone (GnRH), as well
as blunted response to beta-adrenergic agonists

9. Pseudo-pseudohypoparathyroidism
• Paternal transmission of a mutated GNAS1 gene results in AHO but
the normal maternal allele results in the maintenance of renal
responsiveness to PTH.
• As a result, these patients have normal calcium homeostasis
with normal concentrations of calcium, phosphate, and PTH.
• Paternally inherited inactivating GNAS1 mutations also can cause
progressive osseous heteroplasia, a related autosomal dominant
disorder characterized by extensive dermal ossification during
childhood.

10. Type 1b
• Patients with the PHP type 1b disease have hypocalcemia but do not
have the phenotypic abnormalities of AHO.
• PTH resistance appears to be confined to the kidney in this disorder,
leading to only hypocalcemia, hyperphosphatemia, and secondary
hyperparathyroidism.
• This rare autosomal dominant disorder appears to be caused by
methylation defects or mutations that affect the regulatory elements
of GNAS1, rather than mutations in GNAS1 itself.
• Type 1b is maternally transmitted.

11. Type 1c
• PHP type 1c refers to a subgroup of mutations that affect the
coupling of G protein to the PTH receptor.
• The ability to stimulate adenyl cyclase remains intact but is no longer
coupled to the binding of PTH and its receptor.
• Patients with PHP type 1c are usually phenotypically similar to those
with PHP type 1a

12. Type 2 PHP
• Patients with PHP type 2 do not have the features of AHO.
• They have normal or even elevated urinary cyclic
adenosine monophosphate (AMP) concentrations in response to
exogenous PTH administration but without a concomitant increase in
phosphate excretion.

14. Management and treatment
• Patients with pseudohypoparathyroidism infrequently develop
hypercalciuria with calcium and vitamin D therapy
• Therefore, the goal of treatment with calcium and vitamin D is to
maintain normocalcemia (rather than low-normal serum calcium as
for other forms of hypoparathyroidism).
• A typical starting dose of calcitriol is 0.25 mcg twice daily.
• The dose should be increased weekly to achieve a normal serum
calcium. Many patients require up to 2 mcg daily .
• Approximately 1 to 2 g of elemental calcium daily (in divided doses) is
recommended.

15. Quiz time!
---- Pseudohypoparathyroidism is characterized by all of the following
except :
•a) Hyperphosphatemia
•b) Low levels of parathyroid hormone
•c) Hypocalcaemia
•d) Partial defect in G protein

16. References
• Uptodate.com
• Medscape
• Omim.org (Online Mendelian Inheritance in Man )
An Online Catalog of Human Genes and Genetic Disorders