A syndrome presenting with pseudohypoparathyroidism (PHP), hypocalcemia, round face, short stature, short neck, brachydactyly, obesity, subcutaneous and intracranial calcifications, seizures, and neuromuscular problems, such as fatigue and muscle cramps.
PHP Type IA. Strictly taken, Albright Hereditary Osteodystrophy relates to PHP Type IA only. However, for completeness, PHP Type IB and IC are included here. PHP IC is basically similar to PHP IA with the exception of preserved GNAS (see below) activity in erythrocytes, fibroblasts, and platelets, which may be due to a different location of the mutation within the GNAS gene. Do not confuse Albright Hereditary Osteodystrophy with ☞McCune-Albright Syndrome.
The exact incidence is unknown; however, the estimated incidence (PHP Type IA and IB combined) in Japan is 3 to 4 per 1,000,000 live births and 6 per 1,000,000 in Italy.
Autosomal dominant and due to maternally-inherited mutations in the G-protein GNAS1 (guanine nucleotide-binding protein alpha-stimulating activity polypeptide 1)-gene. Each G-protein consists of one alpha, one beta, and one gamma subunit. In AHO (PHP Type IA), the genetic defect affects the α subunit of the stimulatory G-protein, which is either defective or produced only in minimal amounts. GNAS1 couples transmembrane signaling pathways and enhances the production of cyclic adenosine monophosphate (cAMP). The gene encoding for this α subunit of GNAS1 in AHO has been mapped to chromosome 20q13.2. (For PHP Type IC, the gene locus is chromosome 20q13.32). All patients are heterozygous, leaving them with one normal allele for the α subunit, which is not only required for parathormone, but also for several other peptide hormones (eg, thyrotropin [TSH], growth hormone-releasing hormone, glucagon, gonadotropins, antidiuretic hormone, calcitonin, epinephrine). Consequently, these patients may clinically exhibit some resistance to the effects of all these hormones. Although PHP Type IB has also autosomal dominant inheritance, the underlying defect is different. Sporadic cases have been described. The mutation has been mapped to 20q13.3 (ie, close to the GNAS1 gene region). Here however, the hormonal resistance appears to be caused by limited or absent responsiveness of the kidneys to parathyroid hormone (PTH), but the skeletal lesions in these patients are proofs of an intact bone response to PTH.
The disorder is caused by increased PTH release due to deficient end-organ responsiveness, which is caused either by a germline mutation in the GNAS1-gene with decreased expression/function of the G-protein (AHO; PHP Type IA), or presumably a defect in the parathormone receptor (PHP Type IB).
Albright Hereditary Osteodystrophy Syndrome: This infant with obesity, round face, and short neck shows some of the typical features of this disorder.
AHO is diagnosed based on clinical and x-ray ...