{"id":522568,"date":"2022-01-01T11:57:48","date_gmt":"2022-01-01T16:57:48","guid":{"rendered":"https:\/\/myendoconsult.com\/learn\/?p=522568"},"modified":"2023-03-16T06:06:46","modified_gmt":"2023-03-16T11:06:46","slug":"what-is-albrights-hereditary-osteodystrophy","status":"publish","type":"post","link":"https:\/\/myendoconsult.com\/learn\/what-is-albrights-hereditary-osteodystrophy\/","title":{"rendered":"What is Albrights Hereditary Osteodystrophy"},"content":{"rendered":"

This is a concise review of AHO, including its initial description by Fuller Albright, classic clinical features, pathophysiology, and genetic background.<\/p>\n

What is the classic phenotype of AHO?<\/h2>\n

Dr. Fuller Albright<\/strong> first described Albright’s hereditary osteodystrophy (AHO) in 1942. The classic phenotype has the following features, brachydactyly, short stature<\/em>, and round facies.<\/em> The classification system for this group of inactivating PTH\/PTHrp signaling disorders is based on the presence or absence of the classic AHO phenotype and Gs\u0251 activity in response to exogenous PTH administration[1].<\/p>\n

Short Stature<\/h3>\n

Short stature is a cardinal clinical finding in Albright hereditary osteodystrophy (AHO<\/strong>). The classic AHO phenotype is characterized by round facies, obesity, brachydactyly, and short stature[2]. Short stature in patients with pseudohypoparathyroidism<\/strong> (PHP) occurs due to rapid chondrocyte differentiation leading to premature closure of the growth plate and eventual stunting of growth[3]. Impaired activity of Gs\u0251 affects PTH mediated signaling in chondrocytes. This is even more profound during puberty and accounts for the short stature observed in patients with pseudohypoparathyroidism[4].<\/p>\n

Obesity<\/h3>\n

Most adults with PHP1A have a body mass index (BMI) >25kg\/m2[4]. The reported prevalence of obesity is more than 66%, higher than the 32% prevalence rate reported for the general population[5].<\/p>\n

    \n
  1. Melanocortin signaling pathways that regulate satiety are dependent on Gs\u0251 activity. Gs\u0251 activity is defective in PHP, which leads to impaired satiety, ultimately leading to obesity[4].<\/li>\n
  2. There are \u03b2 adrenergic receptors in adipose tissue, which presumably play a role in lipolysis. Downstream signaling of these receptors is dependent on Gs\u0251 activity; as such, decreased fat mobilization occurs in patients with PHP[6].<\/li>\n
  3. Growth hormone<\/a> (GH) deficiency is a contributory factor as well since Growth hormone-releasing hormone (GHRH) signaling is dependent on the stimulatory G-protein, Gs\u0251[5].<\/li>\n<\/ol>\n

    Brachydactyly<\/h3>\n

    The characteristic skeletal feature of PHP happens to be shortening of the metacarpals and metatarsals. This skeletal change tends to involve the fourth and fifth metacarpals and metatarsals [4, 7]. Impaired activity of Gs\u0251 affects Parathyroid hormone-related peptide<\/strong> (PTHrp) mediated signaling critical in chondrocyte proliferation in the growth plate[4].<\/p>\n

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    Figure 1. Plain radiograph of both hands depicting brachydactyly \u2013 shortening of the 4th<\/sup> metacarpals bilaterally.<\/p>\n

    Dental manifestations.<\/strong><\/p>\n

    Multiple dental abnormalities<\/strong> include delayed or even failed eruption of the teeth, blunting of the roots, hypodontia, and ankylosis[4, 8]. Patients should be referred to dentists for optimal care of their teeth[8]. Downstream signaling for PTH-1R<\/strong> in the tooth is affected due to impaired Gs\u0251 activity. This highlights the vital role of PTH in mediating tooth maturation and mineralization[4].<\/p>\n

    Pathophysiology Pearl<\/h2>\n

    PTH binds to the PTH-1R receptor, which leads to the dissociation of Gs\u0251 from the heterotrimeric G protein. Gs\u0251 subsequently activates adenylyl cyclase (AC). This is followed by AC-mediated conversion of ATP to cyclic AMP. The second messenger, cyclic AMP activates protein kinase A (PKA), which subsequently phosphorylates various target proteins involved in the transcription and translation of several downstream cyclic AMP-responsive genes.<\/p>\n

    A loss of function mutation<\/b> involving the gene encoding the alpha subunit of the Gs protein, i.e., the GNAS gene<\/strong>, results in pseudohypoparathyroidism<\/em>[4]. Resistance to PTH action in the proximal renal tubule leads to hypocalcemia<\/strong> and hyperphosphatemia<\/strong>, a biochemical profile akin to what is observed in patients with isolated hypoparathyroidism. Patients, however, have a paradoxical elevation in serum PTH, hence the name, pseudohypoparathyroidism<\/strong>[4]\n

    Pseudopseudohypoparathyroidism (PPHP).\u00a0This is a unique clinical and biochemical subtype of inactivating PTH\/PTHrp signaling disorders (iPPSD)<\/strong>. The new iPPSD <\/strong>nomenclature acknowledges the spectrum of clinicopathologic phenotypes in patients with pseudohypoparathyroidism[1].<\/p>\n

    \"\"<\/p>\n

    Figure 2. Role of tissue specific expression of Gs\u03b1 gene in determining the final clinical phenotype of pseudohypoparathyroidism.\u00a0 <\/strong>The Guanine nucleotide-binding protein, alpha stimulating<\/em> (GNAS) gene, is critical in the transcription of the stimulatory G protein (Gs\u03b1). Gs\u03b1 in most tissues is expressed in a biallelic fashion, i.e., there are distinct paternal and maternal alleles. The clinical and biochemical features are, therefore, dependent on the parent of origin of the mutant allele<\/strong>[9].<\/p>\n

    The paternal Gs\u03b1 gene in normal physiology is not expressed in the proximal renal tubule, pituitary gland, and gonadal tissue. It, therefore, plays no role in renal electrolyte (calcium and phosphorus) handling or activation of Gs\u03b1 coupled receptors such as luteinizing hormone (LH), parathyroid hormone (PTH), and thyroid-stimulating hormone (TSH). Paternal derived Gs\u03b1 gene<\/strong> is however present in bone<\/strong>. An affected child who inherits a mutated Gs\u03b1 gene from a father will, therefore, present with pseudopseudohypoparathyroidism<\/strong> PPHP (i.e., short stature with no apparent biochemical or hormonal perturbations)[9].<\/p>\n

    Maternal Gs\u03b1 gene expression determines most of the downstream effects of Gs\u03b1 coupled receptors in extra-skeletal tissues, including LH, PTH, TSH, and GHRH. Also, unlike the paternal allele, the maternal allele is expressed in several tissues including pituitary, renal, and gonadal tissues. It is noteworthy, that both maternal and paternal Gs\u03b1 genes are expressed in bone. A mutation in the maternal Gs\u03b1 gene, therefore, results in the classic Pseudohypoparathyroidism type 1A<\/strong> (PHP1A) phenotype (see table 1)[10, 11].<\/p>\n

    Pseudohypoparathyroidism type 1B<\/strong> (PHP1B) occurs when there is an imprinting (methylation) defect in the maternal GNAS gene. However in contrast to pseudopseudohypoparathyroidism<\/strong> and PHP1A, there is no mutation in the Gs\u03b1 gene[12].<\/p>\n\n\n\n\n\t\n\n\t\n\t\n\t\n\t
    iPPSD<\/th>AHO<\/th>Other hormone Resistance States.<\/th>PTH resistance<\/th>\n<\/tr>\n<\/thead>\n
    PPHP<\/td>Present<\/td>Absent<\/td>Absent [13, 14]<\/td>\n<\/tr>\n
    PHP1A<\/td>Present<\/td>Present<\/td>Present [10, 11]<\/td>\n<\/tr>\n
    PHP1B<\/td>Absent<\/td>Infrequent<\/td>Present [12].<\/td>\n<\/tr>\n
    PHP1C<\/td>Present<\/td>Present<\/td>Present [2].<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n