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Diagnosis and reasoning

This young woman has presented with two major complaints: cramping of her hands, and fatigue for several months. At first glance, these symptoms are nonspecific enough that the differential diagnosis is quite broad, encompassing electrolyte imbalances, neurovascular disorders, and even connective tissue diseases. However, her physical exam yields an important clue: a positive Trousseau's sign. This is strongly suggestive of hypocalcemia, with an electrolyte panel confirming the presence of serum total calcium levels below the norm. As a significant fraction of calcium is protein-bound, assessment of serum albumin levels is also important; the normal values seen here exclude a factitious result. It is also important to obtain an ECG, as hypocalcemia causes prolongation of the QT interval, with a subsequent increased risk for arrhythmias; however, this too is normal. The next step should be to determine and treat the underlying etiology; key causes to consider include vitamin D deficiency, decreased intestinal absorption, renal disease, hypoparathyroidism, and rarely, pseudohypoparathyroidism. Impaired calcium absorption can be due to either vitamin D deficiency or malabsorptive states such as celiac disease. However, our patient's serum vitamin D levels are normal and she has no history suggestive of malabsorption, making these etiologies unlikely. As calcium is reabsorbed in the distal nephron, diseases of the renal parenchyma often give rise to hypocalcemia. However, the presence of a normal renal function assay argues against this. Hypoparathyroidism is a possibility here; however, in such individuals, PTH levels will be low or normal; in this patient, PTH levels are elevated. Hyperparathyroidism, however, is unlikely, as overstimulation of osteoclasts by increased PTH production leads to hyper- and not hypo- calcaemia. Furthermore, increased production of PTH is a physiological response to hypocalcemia, indicative of healthy parathyroids. This leaves us with pseudohypoparathyroidism (PHP), which is due to end-organ resistance to PTH; the current findings of hypocalcemia, hyperphosphatemia, and elevated PTH levels, in a background of normal vitamin D levels and renal functions are sufficient to establish this diagnosis. To further refine our diagnosis, it is important to know that PHP is a heterogeneous group of genetic disorders characterized by mutation of the GNAS gene on chromosome 20q13. These are classified as type I and type II PHP. Type I is further divided into types Ia, Ib and Ic (PHP-Ia, PHP-Ib, and PHP-Ic, respectively). Of the above, PHP Ia and Ic are both associated with mental retardation and skeletal abnormalities in a syndrome known as Albright's hereditary osteodystrophy, and thus can be excluded. On the other hand, individuals with PHP Ib and II are both morphologically normal; that said, PHP II is very rare, and based on incidence alone, PHP Ib is far more likely here. Accurate differentiation can be established via the PTH infusion test; this involves administering exogenous PTH and estimating levels of urinary cAMP and phosphate afterwards. In this patient, the decreased cAMP and phosphorus excretion shows that this is PHP type Ib, as expected. Her management should include both calcium replacement, as well as treatment with active vitamin D metabolites (e.g. calcitriol); the dose should be adjusted to maintain normocalcemia. Her anxiety is most likely a manifestation of the hypocalcemia, and will subside with calcium replacement; diazepam is probably best avoided. Given the absence of hypomagnesaemia, there is no indication for magnesium sulfate therapy.


The term pseudohypoparathyroidism (PHP) refers to a group of rare genetic and epigenetic disorders characterized by a resistance to parathyroid hormone (PTH). While there is scant epidemiological data on the condition, the prevalence in the general population is estimated to be ~0.79 per 100,000 individuals. Based on phenotypes and genetic variations, PHP is divided into types I and II; the former is further classified into subtypes Ia, Ib and Ic; for brevity, the exact mutations are not discussed in this monograph. To appreciate the underlying pathophysiology, one must recall that PTH acts on the proximal convoluted tubule (PCT) to increase the production of 1,25-dihydroxy vitamin D3; this in turn, increases calcium and phosphate absorption from the gut. PTH also inhibits phosphate reabsorption at the PCT while increasing calcium reabsorption at the distal convoluted tubule (DCT). In all forms of PHP, there is resistance to the action of PTH at the PCT; this results in hypocalcemia, hyperphosphatemia, and elevated PTH levels due to compensatory mechanisms. However, the DCT remains sensitive to PTH and thus, a certain amount of urinary calcium is reabsorbed; while insufficient to offset the calcium loss from the PCT, this explains the normo- to hypo-calciuria seen in the condition. Signs and symptoms common to all forms of PHP include muscle cramps, fatigue, and numbness in mild to moderate hypocalcemia, and seizures, tetany and arrhythmias in severe hypocalcemia. Pediatric patients may experience growth retardation as well. Individuals with the Ia subtype also present with round facies, frontal bossing, short stature, obesity, mental retardation, brachydactyly and ectopic ossification; this is collectively called Albright's hereditary osteodystrophy (AHO). They may also have resistance to other hormones that act via the Gs alpha subunit, including thyroid-stimulating hormone (TSH), growth hormone releasing hormone (GHRH), and gonadotropins. Furthermore, superficial calcifications are present in most patients with PHP Ia and should be looked for during the general examination; shortening of the hand bones may also be seen. PHP Ic presents similarly to PHP Ia, while individuals with PHP Ib are phenotypically normal. In PHP II, patients have only PTH resistance that leads to hypocalcemia and hyperphosphatemia. Where PHP is suspected, estimation of serum calcium, phosphate and PTH levels is a suitable first step; serum calcium will be decreased, and phosphate and PTH elevated. Serum vitamin D levels, and renal functions should also be assayed; if both are normal, the presence of the previously mentioned abnormalities is essentially diagnostic of PHP. Where the above investigations are equivocal, and/or for further differentiation between the subtypes of PHP, the PTH infusion test can be performed; here, exogenous PTH is administered and levels of urinary cAMP and phosphate estimated. In normal individuals, PTH administration will result in a marked elevation of both urinary cAMP and phosphate excretion; however, in PHP I, urinary cAMP and phosphate excretion will both show a muted response. On the other hand, in PHP II, phosphate excretion alone will be affected. A hormone profile is also helpful because patients with PHP Ia can have a comorbid resistance to GHRH, TSH or gonadotropins, leading to elevated levels of these hormones. Radiographs may also reveal useful information; in PHP Ia and Ic, brachydactyly may be seen, while in PHP I, the Madelung deformity can occasionally be observed. Where performed, DNA sequencing of the Gs alpha coding gene may reveal mutations in PHP Ia and PHP Ic. Epigenetic changes by methylation analysis of the GNAS locus can be identified in PHP Ib. In all forms of PHP, the objective of treatment is to maintain serum calcium and phosphate levels within their normal ranges; this typically requires lifelong therapy. Mild to moderate asymptomatic hypocalcemia can often be treated by oral calcium alone; symptomatic or severe hypocalcemia is best corrected with intravenous calcium therapy first. Vitamin D should also be administered, in doses titrated to the requirements of the individual patient. In addition, where associated endocrinopathies are also present, appropriate treatment should be instituted.

Take home messages

  1. Pseudohypoparathyroidism (PHP) is a rare condition where there is resistance to parathormone (PTH) at the end organ (renal) level, due to mutations in the GNAS gene.
  2. These patients present with hypocalcemia, hyperphosphatemia, and elevated PTH levels; this is in contrast to hypoparathyroidism, where PTH levels are low or normal.
  3. The presence of the previously mentioned biochemical abnormalities in conjunction with normal renal functions and vitamin D levels is sufficient to establish the presence of PHP.
  4. Where investigations are equivocal or for differentiation between the subtypes of PHP, the PTH infusion test is of value.
  5. Treatment involves life-long supplementation with calcium and vitamin D in order to maintain calcium and phosphate levels within the normal range.

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