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.[1]
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). These features included short stature, rounded face, shortened fourth metacarpals and other bones of the hands and feet, obesity, dental hypoplasia, and soft-tissue calcifications/ossifications. In addition, administration of PTH failed to produce the expected phosphaturia or to stimulate renal production of cyclic adenosine monophosphate (cAMP). However, the AHO phenotype is not a feature of PHP-1b or PHP-2.
The molecular defects in the gene (GNAS1) encoding the α subunit of the stimulatory G protein (Gsα) contribute to at least 4 different forms of the disease: PHP-1a, PHP-1b, PHP-1c, and PPHP.[2] While PHP-2 is associated with renal resistance to PTH action, the genetic abnormalities causing PHP-2 remain to be identified.[3]
Diagnosis of PHP is defined by the coexistence of hypocalcemia and hyperphosphatemia with elevated PTH levels in the presence of normal vitamin D values and normal renal function and the absence of hypercalciuria. Pseudohypoparathyroidism can be diagnosed by blood or urine tests to measure the levels of calcium, phosphorous, and parathyroid hormone. Genetic testing for a mutation in the GNAS1 gene can confirm diagnosis and identify subtype.[1]
The goals of pharmacotherapy are to correct calcium deficiency, prevent complications, and reduce morbidity. Intravenous calcium is the initial treatment for all patients with severe symptomatic hypocalcemia. Administration of oral calcium and 1alpha-hydroxylated vitamin D metabolites, such as calcitriol, remains the mainstay of treatment and should be initiated in every patient with a diagnosis of PHP. Maintaining serum total and ionized calcium levels within the reference range discourages hypercalciuria and suppresses PTH levels to normal. Patients with intracranial calcifications may experience seizures related to chronic neuropathic changes, and they may need antiepileptic medications.[4, 5]
(See the image below.)
View Image
Patient with pseudohypoparathyroidism showing shortened fourth metacarpals.
A heterozygous mutation of the GNAS gene that encodes the G stimulatory α subunit (Gsα) of guanine nucleotide-binding protein leads to a loss of expression or function of the Gsα, which impairs the transmission of stimulatory signals to adenylate cyclase, limiting cyclic AMP (cAMP) generation necessary for hormone action. GNAS mutations on maternally inherited alleles (PHP-1a and PHP-1c) manifest resistance to parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), growth-hormone–releasing hormone (GHRH), and gonadotropins, as well as the the phenotypic features of Albright hereditary osteodystrophy (AHO).[3]
GNAS mutations on paternally inherited alleles (PPHP) have only the phenotypic features of AHO without hormonal resistance.[3] Davies et al reported an analysis of pedigrees of families that included patients with PHP and PPHP, suggesting that patients who inherit the defective gene from the father have pseudo-PHP, because the mutant gene is not expressed and the product of a single maternally inherited GNAS1 gene preserves normal responses to PTH and thyrotropin.[6] However, the occurrence of AHO in patients with pseudo-PHP indicates that one GNAS1 gene is not sufficient in all tissues.
Those with PHP-1b lack typical features of AHO but may have mild brachydactyly. Familial PHP-1b displays an isolated loss of methylation at exon A/B associated with a recurrent 3-kb deletion in the STX16 gene. NESP55 and NESPAS deletions have also been described leading to the loss of all maternal GNAS imprints (epimutations). Sporadic PHP-1b is characterized by complete loss of methylation at the NESPas, XLas, and A/B promoters. In some cases, paternal 20q disomies have been found.[2, 7]
PHP-2 is associated with renal resistance to PTH action and the absence of AHO phenotype; however, the genetic abnormalities causing PHP-2 remain to be identified.[3]
Testotoxicosis
Testotoxicosis with PHP-1a can occur. Gonadotropin-independent sexual precocity has been reported in 2 boys who presented in infancy with classic PHP-1a. Usually, patients with PHP-1a show resistance to luteinizing hormone, which could lead to primary testicular insufficiency. The paradoxical presentation of testotoxicosis in these boys resulted from an identical point mutation in the GNAS1 gene, which caused both a loss and gain of Gsα function.
PHP-1a, characterized by a loss of Gsα function, is caused by thermal inactivation of the mutant protein at body temperature. Testotoxicosis indicates an organ-specific gain of Gsα function, resulting from the expression of the mutant protein. The lower temperature of the testes protects the mutant protein from thermal inactivation.
Growth plate defects
A study by Sanchez et al found that an imprinting defect in GNAS may lead to growth plate defects in patients with PHP-1b, including brachydactyly and Madelung deformity. This suggests that GNAS signaling has a more extensive role in chondrocyte maturation than was previously believed.[8]
Several other peptide hormones, including thyroid-stimulating hormone (thyrotropin), antidiuretic hormone, gonadotropins, glucagons, adrenocorticotropin, and growth hormone–releasing hormone, use the α subunit of stimulatory G protein to enhance cAMP production. Patients with PHP-1a can present with resistance to the effects of any of these hormones, although in most patients, responses to corticotropin and glucagon are clinically unaffected.
The dominant pattern of inheritance of PHP-1a has been attributed to haploinsufficiency of GNAS1, meaning that the protein produced by a single normal Gsα allele cannot support normal function, although it may suffice for survival. The single normal Gsα allele preserves the responses to hormones such as corticotropin and glucagon. The haploinsufficiency of the GNAS1 gene is tissue specific, which may explain the selective resistance to hormones and the characteristic habitus of patients with PHP-1a.
Pseudo-PHP
Pseudopseudohypoparathyroidism (PPHP) is caused by GNAS mutations on paternally inherited alleles. Paternal inheritance accounts for differences in the same family where some patients with a defective GNAS1 gene inherited maternally have resistance to PTH (PHP-1a), whereas others with PPHP share with them the habitus of AHO but are not resistant to PTH.
PHP type 1b
Familial PHP-1b is caused by heterozygous deletions in STX16, NESP55, and/or AS exon. Sporadic PHP-1b is characterized by complete loss of methylation at the NESPas, XLas, and A/B promoters. In some cases, paternal 20q disomies have been found.[2] The absence of PTH resistance in the mother and maternal grandfather who carried the same mutation was consistent with current models of paternal imprinting of the GNAS1 gene.[9]
PHP type 1c
PHP-1c appears to be a variant of PHP-1a, in which the specific GNAS mutation disrupts receptor-mediated activation of adenylyl cyclase but does not affect receptor-independent activation of the enzyme. This accounts for the inability to demonstrate reduced activity of solubilized Gsα with conventional assays.[3, 7]
The estimated prevalence of PHP type 1a, type1b, and PPHP is 1 per 150,000 in Italy.[10] In Japan, the estimated prevalence of PHP type 1a and type 1b is 1 per 295,000.[11, 10] 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.[10]
Patients with pseudohypoparathyroidism (PHP) can present in infancy, especially if significant hypocalcemia occurs.
Patients with PHP type 1a present with a characteristic phenotype, collectively called Albright hereditary osteodystrophy (AHO). The constellation of findings includes the following:
Short stature
Stocky habitus
Obesity[12]
Developmental delay
Round face
Dental hypoplasia
Brachymetacarpals
Brachymetatarsals
Soft tissue calcification/ossification
Patients may develop paresthesias, muscular cramping, tetany, carpopedal spasm, or seizure. Hypocalcemia in children or adolescents is often asymptomatic.[13]
Patients with PHP-1a may have disturbances in taste, smell, vision, and hearing, and they may be hyporesponsive to the biologic effects of other peptide hormones that use Gsα to enhance cAMP production. The hormones under this class include thyrotropin, antidiuretic hormone, the gonadotropins, glucagon, adrenocorticotropin, and growth hormone–releasing hormone. Evaluate patients for signs and symptoms suggestive of deficiencies of any of these hormones. Primary hypothyroidism occurs in most patients with PHP-1a.[14, 15]
Reproductive dysfunction commonly occurs in persons with PHP-1a. Women may have delayed puberty, oligomenorrhea, and infertility.
Features of hypogonadism may be less obvious in men. Testes may show evidence of maturation arrest or may fail to descend normally. Fertility appears to be decreased in men with PHP-1a.
Within the spectrum of PHP-1a, variability exists in osteoclast responsiveness to PTH. Some patients may have osteopenia and rickets.
Mentation is impaired in approximately half of patients with PHP-1a and appears to be related to the Gsα deficiency rather than to chronic hypocalcemia, because patients with other forms of PHP and hypocalcemia have normal mentation.
Unusual presenting manifestations include neonatal hypothyroidism, Parkinson disease, and spinal cord compression. An interesting association between PHP-1a and hypercalcitoninemia without any evidence of medullary thyroid carcinoma has been described.[16] An increased prevalence of sleep apnea in children with PHP-1a has also been described.[17]
Physical examination may reveal signs of hypocalcemia, including positive Chvostek sign (ie, twitching of facial muscles after tapping the facial nerve just in front of the ear) and/or Trousseau sign (ie, carpal spasm after maintaining an arm blood pressure cuff at 20 mm Hg above the patient's systolic blood pressure for 3 minutes. Occasionally, cataracts or papilledema is present.
Patients with PHP type 1b present with hypocalcemia without AHO. The severity of hypocalcemia can vary greatly among family members of the same kindred.
Patients with pseudo-PHP have the phenotype of AHO but with normal biochemical parameters. Patients with pseudo-PHP are often found in the same kindreds as those with PHP type 1a.
Albright hereditary osteodystrophy
Obesity is a common feature of AHO, although brachydactyly is the most reliable sign in the diagnosis of this condition (see the image below). The brachydactyly may be symmetrical or asymmetrical and may involve one or both hands or feet. Shortening of the metacarpals causes shortening of the digits, particularly the fourth and fifth digits. Shortening of the metacarpals may be recognized during physical examination as dimpling over the knuckles of a clenched fist (ie, Archibald sign). Shortening of the distal phalanx of the thumb is evident as a thumb in which the ratio of the width of the nail to its length is increased (ie, so-called murderer's thumb or potter's thumb).
View Image
Patient with pseudohypoparathyroidism showing shortened fourth metacarpals.
Several other skeletal deformities have been described in AHO, including short ulna, bowed radius, deformed elbow, or cubitus valgus and coxa vara, coxa valga, genu varum, and genu valgum deformities.
Laboratory studies for the diagnosis of pseudohypoparathyroidism (PHP) include serum calcium tests (including measurement of serum total calcium and ionized calcium) to confirm a hypocalcemic state. Serum phosphate levels are elevated in PHP.
Determining the serum concentration of intact PTH, using an immunoradiometric assay (IRMA), is also diagnostic.[13] When the serum concentration of PTH in a hypocalcemic patient is increased, the patient has either a form of PHP or secondary hyperparathyroidism.
Assessment of skeletal and renal responsiveness to PTH is accomplished by measurement of changes in serum calcium, phosphorus, cAMP, and calcitriol concentrations and in urinary cAMP and phosphorus excretion after administration of the biosynthetic N-terminal fragment of PTH.
Consider thyroid function tests and measurement of gonadotropin and testosterone or estrogen levels. Also consider assessment of growth hormone function with insulinlike growth factor-1.
Freson et al concluded that platelet-based testing can effectively be used in the diagnosis of Gsα defects. In their report, on the use of platelets to diagnose Gsα hypofunction, the investigators found that platelet aggregation responses varied according to Gsα signaling defects, thus providing a reflection of a patient's phenotype and genotype.[19]
Todorova-Koteva et al demonstrated the use of commercially available recombinant PTH injections and concomitant measurement of cAMP in urine to diagnose PTH resistance, especially in nonphenotypically evident pseudohypoparathyroidism.[20]
Radiography of the hand may show a specific pattern of shortening of the bones, in which the distal phalanx of the thumb and the third through fifth metacarpals are shortened most severely. Radiography may also show small soft tissue opacities (calcifications/ossifications). Computed tomography (CT) scanning may reveal calcification of the basal ganglia.
Electrocardiogram may reveal prolongation of the QT interval secondary to hypocalcemia.
Patients with PHP type 1b may be evaluated for parathyroid-related bone disease. Consider bone mineral density (BMD) testing in this group of patients.[21]
Genetic testing and analysis of the GNAS1 gene can confirm diagnosis and identify the different variants of PHP. Patients affected by PHP-1b require testing for GNAS methylation changes; some laboratories will analyze exon A/B only as a screen, because the loss of methylation of this DMR on the maternally derived GNAS allele is present in all reported cases of both inherited and sporadic forms of PHP-1b. Patients with PHP-1b can be further analyzed for paternal uniparental isodisomy of chromosome 20q or small deletions within STX16 and GNAS; these tests have furthermore been shown to identify deletions within GNAS as the cause of some PHP-1a cases.[3]
The goals of therapy are to maintain serum total and ionized calcium levels within the reference range to avoid hypercalciuria and to suppress PTH levels to normal. This is important because elevated PTH levels in patients with PHP can cause increased bone remodeling and lead to hyperparathyroid bone disease.
All patients with severe symptomatic hypocalcemia should be initially treated with intravenous calcium. Administration of oral calcium and 1alpha-hydroxylated vitamin D metabolites, such as calcitriol, remains the mainstay of treatment and should be initiated in every patient with a diagnosis of PHP.
In adults, infuse approximately 100 mg of elemental calcium (either calcium chloride or calcium gluconate) over 10 to 20 minutes. If this measure does not alleviate the clinical manifestation, 100 mg/hr of elemental calcium can be infused (in adults), with close monitoring of calcium levels. Do not rapidly infuse calcium because of the possible adverse effects of cardiac conduction defects; cardiac monitoring may help to guide therapy.
The 2 most readily available formulations for parenteral use are calcium chloride and calcium gluconate; a 10-mL ampule of 10% calcium chloride contains 360 mg of elemental calcium, and a 10-mL ampule of 10% calcium gluconate contains 93 mg of elemental calcium.
For neonates, infants, and children, the recommended initial dose is 0.5-1 mL/kg of 10% calcium gluconate administered over 5 minutes.
Pseudohypoparathyroidism type 1b patients could develop tertiary hyperparathyroidism and/or hyperparathyroid bone disease. Therefore, it is important to treat them with sufficient doses of calcium and vitamin D to maintain serum calcium and PTH levels within or as close to the normal range as possible.[22]
Rarely, extraskeletal osteomas require surgical removal to relieve pressure symptoms. Parathyroidectomy is the treatment of choice in patients with tertiary hyperparathyroidism.
Monitor therapy through regular serum and urinary calcium measurements. Exercise caution to avoid renal or hypercalcemic complications. In addition, monitor serum PTH levels with a goal of maintaining serum PTH levels within the reference range.
The goals of pharmacotherapy are to correct calcium deficiency, to prevent complications, and to reduce morbidity. Intravenous calcium is the initial treatment for all patients with severe symptomatic hypocalcemia. Administration of oral calcium and 1alpha-hydroxylated vitamin D metabolites, such as calcitriol, remains the mainstay of treatment and should be initiated in every patient with a diagnosis of PHP. Maintaining serum total and ionized calcium levels within the reference range discourages hypercalciuria and suppresses PTH levels to normal. Patients with intracranial calcifications may experience seizures related to chronic neuropathic changes, and they may need antiepileptic medications.[4, 5]
Clinical Context:
Calcium chloride improves nerve and muscle performance by regulating the action potential excitation threshold affected by calcium deficiency.
Clinical Context:
Calcium gluconate moderates nerve and muscle performance and facilitates normal cardiac function. It can be initially administered intravenously, and calcium levels can be maintained with a high-calcium diet. Some patients require oral calcium supplementation.
Clinical Context:
Calcium carbonate is used for supplementation of intravenous therapy in hypocalcemia. Calcium moderates nerve and muscle performance by regulating the action potential excitation threshold.
Mini R Abraham, MD, Consulting Staff, Overland Park Medical Specialists
Disclosure: Nothing to disclose.
Coauthor(s)
Romesh Khardori, MD, PhD, FACP, Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School
Disclosure: Nothing to disclose.
Chief Editor
George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Stanley Wallach, MD Executive Director, American College of Nutrition; Clinical Professor, Department of Medicine, New York University School of Medicine
Stanley Wallach, MD is a member of the following medical societies: American College of Nutrition, American Society for Bone and Mineral Research, American Society for Clinical Investigation, American Society for Clinical Nutrition, American Society for Nutritional Sciences, Association of American Physicians, and Endocrine Society
Disclosure: Nothing to disclose.
Kent Wehmeier, MD Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Kent Wehmeier, MD is a member of the following medical societies: American Society of Hypertension, Endocrine Society, and International Society for Clinical Densitometry
Mantovani G. Pseudohypoparathyroidism. Orpha.net. Available at http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=12935&Disease_Disease_Search_diseaseGroup=Pseudohypoparathyroidism&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Pseudohypoparathyroidism&title=Pseudohypoparat. October 2014; Accessed: August 29, 2017.
){kind=link}