Pseudohypoparathyroidism


Article Author:
Peter Ucciferro


Article Editor:
Catherine Anastasopoulou


Editors In Chief:
Ishwarlal Jialal


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
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Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/27/2019 9:27:12 PM

Introduction

Pseudohypoparathyroidism (PHP) is a rare inherited disorder characterized by target organ resistance or unresponsiveness to parathyroid hormone (PTH). The syndrome mimics hypoparathyroidism with patients experiencing hypocalcemia and hyperphosphatemia. However, instead of having low PTH levels, elevated levels of PTH are present in serum. PHP is typically classified as either type 1 or type 2 and then type 1 is further subdivided into 1a, 1b, or 1c. Type 1 is distinguishable from type 2 by the abnormal cAMP response to G protein activation seen in type 1, whereas the cAMP response is normal in type 2. PHP 1a and 1c both can exhibit multi-hormone resistance, whereas 1b is localized only to the kidney. Of all the subtypes of PHP, type 1a is thought to be the most common subtype, but PHP type 1b recently has been found to occur with similar frequency.

Etiology

Pseudohypoparathyroidism subdivides into several categories. It first divides into PHP type 1 and PHP type 2. In general, PHP type 1 forms exhibit blunted cAMP and phosphate excretion in urine in response to PTH (cAMP being a downstream response to activation of G protein-coupled receptor for PTH). In PHP type 2, the cAMP response is normal but blunted phosphate excretion in response to PTH still occurs. Only a few cases of PHP type 2 have been documented, and its pathophysiology remains not well understood.

PHP type 1 is further divided into several subtypes a,b, and c. PHP type 1b is isolated resistance to PTH in the kidney and normal PTH response in bone without phenotypic expression of Albright hereditary osteodystrophy (AHO).[1] PHP 1a and 1c have PTH resistance, and both express a phenotype of AHO. AHO presents with short stature, frequently below normal intelligence, obesity, round face, short neck, subcutaneous ossifications, brachydactyly, and shortened metatarsals. The shortened metacarpals often cause an absence of knuckles at third, fourth and fifth or only some of those digits resulting in the classic "knuckle, knuckle, dimple, knuckle" sign.

PHP type 1a has reduced Gs alpha activity and presents with multi-hormone resistance. 

PHP type 1c, much like 1a, presents with multi-hormone resistance, but it is different from type 1a in that normal Gs alpha activity is present.[1]

Epidemiology

Pseudohypoparathyroidism and Albright hereditary osteodystrophy are very rare disorders. The estimated prevalence is between 0.3 and 1.1 cases per 100000 population depending on geographic location.[2][3]

Pathophysiology

PHP type 1a results when there is a loss of function mutation in GNASPRKAR1APDE4D, or PDE3A.[4] The result is an aberrant response in many G protein-coupled receptors leading to multi-hormone resistance or unresponsiveness. Thus far over 400 mutations within the GNAS coding region have been identified as causes of PHP 1a.[5] The mutations identified include frameshift, nonsense, missense, insertion, and deletions as well as others. Of note, research has discovered a temperature-sensitive Gs alpha mutant (p.A366S) that can cause testotoxicosis and precocious puberty.[6]

In addition to PTH resistance PHP type 1a infrequently exhibits blunted response to thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and growth hormone-releasing hormone (GHRH) resulting in primary hypothyroidism, primary hypogonadism, and short stature, depending on the affected gene. 

The inheritance of GNAS mutation is fairly complex due to paternal genetic imprinting. Individuals who acquire the mutant GNAS allele from their father only have the phenotypic expression of AHO (termed pseudopseudohypoparathyroidism) and do not have PTH resistance. Individuals who inherit the mutant allele from their mother express both AHO and multi-hormone resistance.

PHP type 1b results from abnormal methylation of GNAS regulatory elements. The abnormal methylation leads to subnormal production of Gs alpha protein expression and a blunted response to PTH. 

History and Physical

Pseudohypoparathyroidism typically gets discovered during early childhood. There may or may not be an obvious family history of the disease depending on which parent the child inherited the disease from as genetic imprinting can hide its expression. The presence of the AHO phenotype should prompt physicians to complete biochemical workup.

Patients experiencing symptoms of hypocalcemia may complain of paresthesias, peri-oral numbness, and muscle cramping or spasms. 

Physical exam for PHP type 1b would likely only find symptomatic hypocalcemia. Hypocalcemia can present with positive Chvostek sign and Trousseau sign.

Chovostek sign is positive when tapping on the facial nerve leads to the contraction of facial muscles on the same side due to the nerve's hyperexcitable state. A positive Trousseau sign is when inflation of a sphygmomanometer to higher than systolic blood pressure and maintaining that pressure for 3 minutes leads to transient ischemia and carpal pedal spasm due to hypocalcemia. 

PHP type 1a and 1c may have signs of hypocalcemia but will also exhibit the AHO phenotype.

Evaluation

Serum calcium, phosphorus, and parathyroid hormone levels should be checked together as well as 25OH Vitamin D levels. 

The presence of hypocalcemia, hyperphosphatemia, normal 25 hydroxyvitamin D, and elevated parathyroid hormone levels suggest pseudohypoparathyroidism. Synthetic PTH challenge test can be performed (Ellsworth-Howard test) but is not necessary for diagnosis. 

An electrocardiogram is likely appropriate if significant hypocalcemia is present to assess for prolonged QT interval and risk for arrhythmia.

PHP1 patients should have biochemical testing completed annually, including PTH, calcium, phosphate, TSH, and urine calcium.[2]

Monitoring of appropriate height and growth is important, and testing for growth hormone deficiency should take place even if the height is normal.[7]

Screening and treatment for other endocrinopathies such as hypogonadism should be individualized.

X-rays of upper and lower extremities to screen for brachydactyly are recommended during the initial evaluation.

In patients with PHP with AHO, genetic testing is essential. Genetic testing and counseling provide information regarding likely disease manifestations and future complications. Additionally, genetic testing can help determine inheritance patterns within families and provide insight into the possibility of affected offspring. 

Treatment / Management

The overall goals in the treatment of PHP are to maintain normal calcium, normal phosphorus, avoid hypercalciuria, and lower PTH levels to normal if possible. It is typically not possible to achieve all electrolyte and hormone level goals; however, getting them as close as possible is recommended. 

Calcium and phosphorus goals are usually attainable with the administration of calcitriol (active vitamin D metabolite) with or without calcium supplementation. Dosing is adjusted so that calcium remains in the low end of the normal range. In addition to checking serum calcium, 24-hour urine calcium levels should be maintained in the low to the mid-normal range to avoid renal calculi and impaired kidney function. 

In patients with continued hypocalcemia, treatment with calcium supplementation is a requirement. 

In the acute setting, the recommendation is for intravenous calcium Patients who are symptomatic (spasms, seizure, etc.), those with prolonged QT interval on electrocardiogram or if corrected calcium is less than 7.5mg/dL and the patient is considered to be a high risk should receive IV calcium infusion. Initially, 1 to 2 g of calcium gluconate administration should be over a 10 to 20-minute interval followed by a slow infusion of calcium. The slow infusion can be achieved by diluting 1000 mg elemental calcium into 1 L of 5% dextrose or normal saline and running at a rate of around 1 cc/kg/hr. Oral calcium and vitamin D supplementation should start as soon as possible. Oral calcium carbonate 2-8g elemental calcium/day and oral calcitriol 0.25 to 1.0 mcg twice a day are usually sufficient doses and allow calcium infusion to stop within a few hours. 

These patients will require permanent active vitamin D supplementation with or without calcium. Calcitriol 0.25-1.0 mcg/day should be used (not other forms of vitamin D due to decreased 1 alpha-hydroxylase activity which converts vitamin D to an active form). Calcium carbonate or calcium citrate should be given 2 to 8 g elemental calcium daily in divided doses to keep calcium low end of normal.

PTH levels require monitoring during treatment with the goal of reduction into the normal range or as close as possible. Lowering PTH attempts to minimize skeletal resorption and later development of osteoporosis.[1]

Treatment with parathyroid hormone or parathyroid hormone analogs is not recommended.

Differential Diagnosis

Pseudohypoparathyroidism presents with hypocalcemia, hyperphosphatemia, elevated PTH levels, normal 25 hydroxyvitamin D, and normal kidney function. Additionally, many patients express the phenotype of Albright hereditary osteodystrophy, but not always. Although no other diseases present identically, many conditions share similar characteristics providing the following differential diagnoses.

  • True hypoparathyroidism presents with hypocalcemia and hyperphosphatemia, but the PTH levels are low. True hypoparathyroidism typically classifies as either surgical or nonsurgical. The most frequent cause of hypoparathyroidism is surgical, post parathyroidectomy for treatment of hyperparathyroidism or accidental removal of parathyroid glands during other neck surgeries such as thyroidectomy. Non-surgical hypoparathyroidism can result from a variety of inherited and acquired disorders. Examples include hemochromatosis or other infiltrative diseases and mutations in PTH gene, CaSR gene and autoimmune polyendocrine syndrome type 1 (APS1) which presents with the triad of hypoparathyroidism, primary adrenal insufficiency, and mucocutaneous candidiasis.
  • Vitamin D deficiency presents with hypocalcemia and elevated PTH levels (secondary hyperparathyroidism) but obviously low 25 OH vitamin D levels.
  • Worsening chronic kidney disease (CKD) or impaired GFR presents with similar findings. The kidney is the primary site for 1-alpha-hydroxylation of 25 OH vitamin D which produces the active form of the hormone 1,25(OH)2 vitamin D. The impaired conversion to active vitamin D leads to its low levels in patients with CKD. In addition to low active vitamin D levels, higher than normal phosphate frequently accumulates in the blood due to declining GFR. The low active vitamin D levels and high phosphate levels both lead to increased release of parathyroid hormone. 

Prognosis

Prognosis of PHP is variable. In mild forms of the disease when treated appropriately with calcium and vitamin D, a normal life expectancy is not unreasonable.[3] For others with a more severe expression of AHO phenotype, the presence of obesity, sleep apnea, and mental retardation can cause significant morbidity and mortality.

Complications

Chronic hypocalcemia and hyperphosphatemia can lead to parkinsonism which may or may not resolve with appropriate calcium and vitamin D supplementation.[8]

Children with brachydactyly may suffer from difficulty with fine motor skills.

There is an increased prevalence of carpal tunnel syndrome seen in AHO patients.[9]

There are reports of higher than normal, as well as an earlier presentation of spinal stenosis, which can lead to lower extremity paraparesis.[10][11]

Finally, there is a more than four-fold increased risk for sleep apnea reported in childhood.[12]

Deterrence and Patient Education

Unfortunately, PHP is an inherited disorder, and once an individual has developed the condition; there is no cure. Genetic testing and counseling are recommendations for individuals who have PHP, especially if they plan to have children so that there can be full identification of their risk of passing on the disease. Patients with PHP should have yearly screening exams, even if they are feeling well.

Enhancing Healthcare Team Outcomes

Patients with pseudohypoparathyroidism should follow with an endocrinologist. Regular testing of serum calcium levels are necessary as well as screening for other hormone resistance. Each patient's care requires individualization to their specific expression of hormone resistance.

Diagnosing, treating, and managing pseudohypoparathyroidism requires an interprofessional healthcare team approach. The patient's family doctor will enlist the services of an endocrinologist, as stated above. A specialist in genetics is also a necessary consult. Involvement of other healthcare team members will vary based on individual patient presentation. If IV interventions are required, the nurse will be administering those, and monitoring the effectiveness of treatment, reporting their findings to the treating clinician. The pharmacist will prepare the IV, and in cases of oral therapy can counsel the patient on dosing and administration. As treatment progresses, the team must be able to adapt based on patient response and coordinate with the next steps as described above in the Treatment section. With open communication and collaborative effort, the interprofessional team can help drive outcomes to the best possible result for the patient. [Level V]


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Pseudohypoparathyroidism - Questions

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A 33-year-old male presents to the office for routine follow-up. He was diagnosed with pseudohypoparathyroidism 3 years ago he developed a seizure disorder. Three weeks ago he ran out of medications, and just this week he experienced his first seizure in over 6 months. On physical exam he has shortened fourth and fifth metatarsals, he is obese with a short neck and short stature. Which of the following additional findings would likely be present in his initial physical exam?



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A 10-year-old female presents to the emergency department after having two witnessed seizures. The child was at school and in her usual state of health when she suddenly fell to the floor and was seen convulsing. After a few minutes, she recovered but then on the way to the hospital; she had a second seizure. She has no personal history of seizure disorder, and no one else in the family has a history of seizures. Her only surgical history is tonsillectomy over a year ago without any complications. Currently, she takes no medications and is described as "a healthy 10-year-old girl" by her mother. On physical examination, her vitals are all within normal limits. Her general appearance is notable for obesity and short neck. Brachydactyly is present in both hands, and she has sub-capsular cataracts. CT scan of the head shows no hemorrhages or masses but basal ganglia perivascular calcifications are present. Which of the following abnormalities will likely also be present?



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A 16-year-old boy presents to a clinician to seek care accompanied by his grandmother. The grandmother has limited knowledge of his medical history, but states that he has seizures and "something is wrong with his thyroid." He takes no medications. On physical exam, the child is obese, has a short neck, and a round face. Additionally, he has 4th and 5th digit brachydactyly as well as palpable subcutaneous soft tissue calcifications present in his arms. A review of his medical record shows that he was seen in the emergency room last month for seizure and CT of the head revealed basal ganglia calcifications and subcapsular cataracts. Which of the following laboratory abnormalities are most likely present in this patient?



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A 16-year-old female presents to the clinic with the complaints of facial twitching for the past few days. She denies any gastrointestinal or urinary symptoms. On physical exam, her vital signs reveal a blood pressure of 100/65 mmHg; heart rate 76 beats/min, temperature 98.6 degrees Fahrenheit, and a respiratory rate 23 breaths/min. She is a short, stocky young girl but otherwise healthy in appearance. Examination of her hands and feet reveal very short fourth metacarpal and metatarsal bones. Which of the following laboratory abnormalities is most likely present in this patient?



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A 16-year-old female presents to a clinician for a consult. She was diagnosed with a calcium disorder at a young age but cannot provide any specific details about her condition. Her physical exam is remarkable for short fourth and fifth metatarsals, short stature, and seemingly low intelligence level. Currently, she takes calcium and vitamin D supplements but no other medications. She feels well and has no complaints. The patient is unaware of anyone else in the family who has similar problems. She has never had surgery before, and she does not smoke or drink alcohol. Which of the following laboratory abnormalities would you expect to find in this patient?



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Pseudohypoparathyroidism - References

References

Mantovani G,Bastepe M,Monk D,de Sanctis L,Thiele S,Usardi A,Ahmed SF,Bufo R,Choplin T,De Filippo G,Devernois G,Eggermann T,Elli FM,Freson K,García Ramirez A,Germain-Lee EL,Groussin L,Hamdy N,Hanna P,Hiort O,Jüppner H,Kamenický P,Knight N,Kottler ML,Le Norcy E,Lecumberri B,Levine MA,Mäkitie O,Martin R,Martos-Moreno GÁ,Minagawa M,Murray P,Pereda A,Pignolo R,Rejnmark L,Rodado R,Rothenbuhler A,Saraff V,Shoemaker AH,Shore EM,Silve C,Turan S,Woods P,Zillikens MC,Perez de Nanclares G,Linglart A, Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nature reviews. Endocrinology. 2018 Aug;     [PubMed]
Mantovani G,Elli FM, Inactivating PTH/PTHrP Signaling Disorders. Frontiers of hormone research. 2019;     [PubMed]
Kim YS,Park J,Park Y,Hwang K,Koo DL,Kim D,Seo DW, Intracranial Cortical Calcifications in a Focal Epilepsy Patient with Pseudohypoparathyroidism. Journal of epilepsy research. 2016 Jun;     [PubMed]
Germain-Lee EL, Management of pseudohypoparathyroidism. Current opinion in pediatrics. 2019 May 28;     [PubMed]
Shoemaker AH,Jüppner H, Nonclassic features of pseudohypoparathyroidism type 1A. Current opinion in endocrinology, diabetes, and obesity. 2017 Feb;     [PubMed]
Landreth H,Malow BA,Shoemaker AH, Increased Prevalence of Sleep Apnea in Children with Pseudohypoparathyroidism Type 1a. Hormone research in paediatrics. 2015;     [PubMed]
van Lindert EJ,Bartels RH,Noordam K, Spinal stenosis with paraparesis in albright hereditary osteodystrophy. Case report and review of the literature. Pediatric neurosurgery. 2008;     [PubMed]
Alam SM,Kelly W, Spinal cord compression associated with pseudohypoparathyroidism. Journal of the Royal Society of Medicine. 1990 Jan;     [PubMed]
Underbjerg L,Sikjaer T,Mosekilde L,Rejnmark L, Pseudohypoparathyroidism - epidemiology, mortality and risk of complications. Clinical endocrinology. 2016 Jun;     [PubMed]
Hendy GN,Cole DEC,Bastepe M, Hypoparathyroidism and Pseudohypoparathyroidism 2000;     [PubMed]
Long XD,Xiong J,Mo ZH,Dong CS,Jin P, Identification of a novel GNAS mutation in a case of pseudohypoparathyroidism type 1A with normocalcemia. BMC medical genetics. 2018 Jul 30     [PubMed]
Nakamoto JM,Zimmerman D,Jones EA,Loke KY,Siddiq K,Donlan MA,Brickman AS,Van Dop C, Concurrent hormone resistance (pseudohypoparathyroidism type Ia) and hormone independence (testotoxicosis) caused by a unique mutation in the G alpha s gene. Biochemical and molecular medicine. 1996 Jun     [PubMed]

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