IllnessPseudohypoparathyreoidism, differential diagnosis

NGS +

[Sanger]

Pseudohypoparathyroidism (PHP) refers to a heterogeneous group of disorders whose common feature is end-organ resistance to parathyroid hormone (PTH). Clinical signs begin in childhood, and the specific symptomatology and severity vary significantly among affected individuals. PHP type Ia is caused by mutations leading to loss of function of an isoform of the maternal GNAS allele, only the paternal allele is expressed. Pseudo-PHP (PPHP) results from loss of function of the paternal GNAS allele, so that only the maternal allele is expressed. Imprinting errors can also cause differential gene expression depending on the parent from which the active allele in question is derived. PHP Ia is due to resistance also to other hormones including TSH and gonadotropins. The clinical features are termed Albright hereditary osteodystrophy (AHO) with the symptom constellation of short stature, obesity, round face, subcutaneous ossifications, brachydactyly and other skeletal abnormalities including sometimes mental retardation. PPHP is characterized by AHO without other hormone resistance. PHP type Ib is characterized by renal PTH resistance and imprinting/methylation defects at the GNAS locus, resulting in lack of expression of the maternal allele in renal tissue. These patients do not show features of AHO. PHP type Ic is characterized by PTH resistance, generalized hormone resistance and AHO (a difference from PHP type Ia involves only erythrocyte membrane protein G). PHP type II causes isolated renal PTH resistance without AHO, but the phosphaturic effect of PTH is deficient. PHP should not be confused with polyostotic fibrous dysplasia (McCune-Albright syndrome). PHP inheritance is autosomal dominant (under consideration of the imprinting phenomenon) with complete penetrance; polyostotic fibrous dysplasia is due to somatic mutations. More recent data on diagnostic yield are not available, especially since these must always be assessed in relation to the genes to be included in the differential diagnosis PHP/PPHP.

References: https://www.ncbi.nlm.nih.gov/books/NBK459117/

https://www.ncbi.nlm.nih.gov/books/NBK274564/

https://www.ncbi.nlm.nih.gov/books/NBK547709/

• Alias: Albright hereditary osteodystrophy with multiple hormone resistance
• Allelic: Osseous heteroplasia, progressive (GNAS)
• Allelic: ACTH-independent macronodular adrenal hyperplasia (GNAS)
• Allelic: Adrenocortical tumor, somatic (PRKAR1A)
• Allelic: Beckwith-Wiedemann syndrome (IGF2)
• Allelic: Blomstrand lethal chondrodysplasia (PTHR1)
• Allelic: Carney complex, type 1 (PRKAR1A)
• Allelic: Eiken syndrome (PTHR1)
• Allelic: McCune-Albright syndrome, somatic, mosaic (GNAS)
• Allelic: Myxoma, intracardiac (PRKAR1A)
• Allelic: Ollier's disease, enchondromatosis (PTHR1)
• Allelic: Pigmented nodular adrenocortical disease, primary, 1 (PRKAR1A)
• Allelic: Pituitary adenoma 3, multiple types, somatic (GNAS)
• Allelic: Primary failure of tooth eruption, PFE (PTHR1)
• Acrodysostosis 1, with/-out hormone resistance (PRKAR1A)
• Acrodysostosis 2, with/-out hormone resistance (PDE4D)
• Albright hereditary osteodystrophy-like syndrome = Chromosome 2q37 deletion syndrome
• Brachydactyly, type E2 (PTHLH)
• Brachydactyly-mental retardation (HDAC4)
• Chondrodysplasia, Blomstrand type (PTHR1)
• Guttmacher syndrome (HOXA13)
• Hand-foot-uterus syndrome (HOXA13)
• Hypertension + brachydactyly syndrome (PDE3A)
• Metaphyseal chondrodysplasia, Murk Jansen type (PTHR1)
• Osseous heteroplasia, progressive (GNAS syn. NESP55)
• Pseudohypoparathyroidism Ia, Ib, Ic (GNAS)
• Pseudohypoparathyroidism, type IB (STX16)
• Pseudopseudohypoparathyroidism (GNAS)
• Silver-Russell syndrome 3 (IGF2)