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Pseudohypoparathyroidism

Pseudohypoparathyroidism (PHP) encompasses a group of conditions that are characterized by parathyroid hormone resistance.


Presentation

PHP may manifest in infancy or later with symptoms reflective of severe hypocalcemia. Signs can include paresthesias, tetany, cramps, and even seizures [5]. Moreover, the physical exam is notable for findings such as Chvostek sign and Trousseau sign.

PHP1a

The constellation of PHP1a, also referred to as AHO, consists of short stature, round face, obesity [6], brachydactyly, brachymetacarpia, soft tissue ossification, dental hypoplasia, and possibly mental delay.

Since these patients typically have hormone deficiencies, complications may include delayed puberty and infertility. Also, primary hypothyroidism is common [7] [8].

Other types

PHP1b [8] [9] and PHP2 [10] are characterized by PTH insensitivity without AHO. PHP1c is typified by both.

Fatigue
  • The patient presented with general fatigue, steppage gait, and myalgia. Physical examinations revealed muscular weakness and atrophies in the lower legs, a shortening of the bilateral Achilles' tendons and absence of deep tendon reflexes.[ncbi.nlm.nih.gov]
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 14, 2019[patientslikeme.com]
  • […] formation of cAMP normal appearance Presentation Symptom symptoms of hypocalcemia paresthesia fingertip, toes, perioral abdominal pain, biliary colic muscle cramps, tetany dyspnea (laryngospasm, bronchospasm) convulsions mental status changes anxiety, fatigue[orthobullets.com]
  • Affected individuals may also experience headaches, unusual sensations, weakness, easy fatigue, lack of energy, blurred vision, and/or abnormal sensitivity (hypersensitivity) to light.[rarediseases.org]
  • There was a history of general fatigue, poor school performance and tingling in the hands that began 2 months earlier. Physical examination showed truncal obesity, round face but no other phenotypic features of AHO.[elsevier.es]
Short Finger
  • fingers or toes 0001156 Broad 1st metacarpal Wide 1st long bone of hand 0010027 Cataract Clouding of the lens of the eye Cloudy lens [ more ] 0000518 Choroid plexus calcification 0006960 Constrictive median neuropathy 0012185 Delayed eruption of teeth[rarediseases.info.nih.gov]
  • fingers or toes 0001156 Cataract Clouding of the lens of the eye Cloudy lens [4] Last updated: 7/11/2016 Testing Resources The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition.[rarediseases.info.nih.gov]
Dyspnea
  • […] protein) normal appearance Type 2 unknown gene defect downstream defect distal to formation of cAMP normal appearance Presentation Symptom symptoms of hypocalcemia paresthesia fingertip, toes, perioral abdominal pain, biliary colic muscle cramps, tetany dyspnea[orthobullets.com]
  • 0009642 Calcinosis Calcium buildup in soft tissues of body 0003761 Chest pain 0100749 Choreoathetosis 0001266 Confusion Disorientation Easily confused Mental disorientation [ more ] 0001289 Conjunctivitis Pink eye 0000509 Depressivity Depression 0000716 Dyspnea[rarediseases.info.nih.gov]
Stridor
  • Stridor. Convulsions (usually grand mal). Syncope. Emotional lability, anxiety and depression, confusion. Memory impairment. Lethargy. Headaches. Brittle nails. Dry hair and skin. Painful menstruation.[patient.info]
Abdominal Pain
  • The patient was admitted for severe abdominal pain and vomiting associated with high plasma amylase, lipase and calcium levels.[degruyter.com]
  • pain, biliary colic muscle cramps, tetany dyspnea (laryngospasm, bronchospasm) convulsions mental status changes anxiety, fatigue, mood swings Physical exam findings of tetany dermatologic fungal nail infections hair loss blotchy skin pigment loss, vitiligo[orthobullets.com]
  • Additional symptoms and findings may include stiffness or cramps in the arms and/or legs, palpitations, and/or abdominal pain.[rarediseases.org]
  • Third, pediatric 1, repeated cold, chronic cough asthma. 2, anorexia, non-food, growth and development behind, constipation, diarrhea, abdominal pain 3, night cry, shock epilepsy, ADHD. 4, sweating, enuresis, myocarditis, purpura. 5, children with ADHD[opencare.com]
  • Signs and symptoms include muscle cramps, abdominal pain, dry skin, brittle nails, cataracts, tetany, and convulsions. Definition (NCI_CTCAE) A disorder characterized by a decrease in production of parathyroid hormone by the parathyroid glands.[fpnotebook.com]
Blurred Vision
  • Affected individuals may also experience headaches, unusual sensations, weakness, easy fatigue, lack of energy, blurred vision, and/or abnormal sensitivity (hypersensitivity) to light.[rarediseases.org]
Chvostek Sign
  • Moreover, the physical exam is notable for findings such as Chvostek sign and Trousseau sign.[symptoma.com]
  • sign contraction of facial muscles with percussion of the facial nerve C ontraction of C heek C hvostek Trousseau sign carpal spasm with occlusion of brachial artery with a blood pressure Tr icep spasm Tr ousseau sign Albright hereditary osteodystrophy[medbullets.com]
  • Latent signs of tetany in the form of positive Chvostek's sign and Trousseau's sign were present. We decided to re-evaluate him in view of late age of onset of symptoms, absence of AHO phenotype, and to confirm the diagnosis.[ijem.in]
  • sign ) or by using the cuff of a sphygmomanometer to temporarily obstruct the blood flow to the arm (a phenomenon known as Trousseau's sign of latent tetany ). [3] A number of medical emergencies can arise in people with low calcium levels.[en.wikipedia.org]
  • Clinical signs Chvostek's sign: detects latent tetany: Tapping of the fifth facial nerve in front of the ear with the patient's mouth slightly open causes contraction of the facial muscles.[patient.info]
Muscle Twitch
  • Symptoms are related to a low level of calcium and include: Cataracts Dental problems Numbness Seizures Tetany (a collection of symptoms including muscle twitches and hand and foot cramps and muscle spasms) People with Albright hereditary osteodystrophy[nlm.nih.gov]
  • This may cause cataracts (clouding of the lens of the eye), dental problems, numbness, seizures, or tetany (muscle twitches and hand and foot spasms).[rarediseases.info.nih.gov]
  • This results in cataracts, dental problems, seizures, numbness, and tetany (muscle twitches and hand and foot spasms). Symptoms are generally first seen in childhood.[rarediseases.info.nih.gov]
  • A 34-year-old male presented with recurrent carpopedal spasms of 4 years duration with perioral numbness, cramps, muscle twitching and generalized weakness for which he was evaluated 2 years back and found to have hypocalcemia, hyperphosphatemia, hypercalciuria[ijem.in]
Round Face
  • The phenotype of Albright syndrome includes 5 common features: brachydactyly, obesity, short stature, a round face, and mental retardation.[ncbi.nlm.nih.gov]
  • PHP1a The constellation of PHP1a, also referred to as AHO, consists of short stature, round face, obesity, brachydactyly, brachymetacarpia, soft tissue ossification, dental hypoplasia, and possibly mental delay.[symptoma.com]
  • The condition causes short stature, round face, obesity, developmental delay, and short hand bones. Symptoms depend on whether you inherit the gene from your mother or father. Type Ib involves resistance to PTH only in the kidneys.[nlm.nih.gov]
  • A 3-year-old boy was diagnosed with obesity, delayed pyschomotor development, and round face.[ncbi.nlm.nih.gov]
  • He and his mother were obese and had round faces, frontal bossing, small noses, flat nasal bridges, brachydactyly. His mother showed no hormonal resistance. These findings indicated that our patient had PHP type Ia and his mother had pseudoPHP.[ncbi.nlm.nih.gov]
Seizure
  • CONCLUSION: Patients with PHP have an increased risk of neuropsychiatric disorders, infections, cataract and seizures, whereas mortality among PHP patients is compatible with that in the background population. 2015 John Wiley & Sons Ltd.[ncbi.nlm.nih.gov]
  • Abstract We describe a patient who presented with epileptic seizures unresponsive to anticonvulsive treatment.[ncbi.nlm.nih.gov]
  • A 22-year-old woman presented to us with seizures of a few minutes duration. She had clinical features of Albright hereditary osteodystrophy (AHO), including hypocalcemia, hyperphosphatemia and resistance to parathyroid hormone.[ncbi.nlm.nih.gov]
  • She had occasional doubtful seizure and headache for 7 years. Initially clinicians could not reach the diagnosis due to inadequate investigations.[ncbi.nlm.nih.gov]
  • One year after the photopsia onset, the patient experienced an episode of seizures with generalized tonic-clonic movements.[ncbi.nlm.nih.gov]
Headache
  • She had occasional doubtful seizure and headache for 7 years. Initially clinicians could not reach the diagnosis due to inadequate investigations.[ncbi.nlm.nih.gov]
  • Affected individuals may also experience headaches, unusual sensations, weakness, easy fatigue, lack of energy, blurred vision, and/or abnormal sensitivity (hypersensitivity) to light.[rarediseases.org]
  • Symptoms of hypoparathyroidism may include tingling in the lips, fingers, and toes; dry hair, brittle nails , and dry, coarse skin; muscle cramps and pain in the face, hands, legs, and feet ; cataracts ; dental problems; memory loss , headaches , and[medicinenet.com]
  • […] paresthesia , an unpleasant tingling sensation around the mouth and in the hands and feet, as well as muscle cramps and severe spasms known as " tetany " that affect the hands and feet. [2] Many also report a number of subjective symptoms such as fatigue , headaches[en.wikipedia.org]
Paresthesia
  • Signs can include paresthesias, tetany, cramps, and even seizures. Moreover, the physical exam is notable for findings such as Chvostek sign and Trousseau sign.[symptoma.com]
  • […] round facies obesity short stature diminished intelligence Type 1b defect in GNAS1 (Gs α protein) normal appearance Type 2 unknown gene defect downstream defect distal to formation of cAMP normal appearance Presentation Symptom symptoms of hypocalcemia paresthesia[orthobullets.com]
  • Decreased reflex response Decreased reflexes [ more ] 0001265 Irritability Irritable 0000737 Laryngeal dystonia 0012049 Muscle spasm 0003394 Myoclonic spasms 0003739 Oligomenorrhea Light or infrequent menstrual periods 0000876 Osteoma cutis 0025027 Paresthesia[rarediseases.info.nih.gov]
  • Reversible complications include: tetany , or prolonged cramp-like spasms in the hands and fingers malformed teeth a heart arrhythmia , or irregular heartbeat paresthesia , or tingling sensations in the lips, tongue, fingers, and feet If they’re not diagnosed[healthline.com]
  • As a result, people with hypoparathyroidism can experience paresthesia , an unpleasant tingling sensation around the mouth and in the hands and feet, as well as muscle cramps and severe spasms known as " tetany " that affect the hands and feet. [2] Many[en.wikipedia.org]
Hyperreflexia
  • Hyperreflexia. Other symptoms and signs depend on the aetiology: DiGeorge's syndrome : Recurrent infections due to T-cell immunodeficiency. Congenital heart disease and its related symptoms, heart murmur. Speech delay.[patient.info]
Spastic Paraplegia
  • Examination revealed functional upper extremities with spastic paraplegia of bilateral lower extremities. The patient's neurologic function was cautiously monitored, but he deteriorated to a bed-bound state, preoperatively.[ncbi.nlm.nih.gov]

Workup

The clinical assessment consists of the patient's history, detailed physical exam, and relevant tests.

Laboratory tests

The biochemical studies are notable for hypocalcemia, hyperphosphatemia, and increased PTH levels. Since PHP is associated with various hormone deficiencies, further evaluation may include thyroid function tests, and measurements of the gonadotropin, estrogen or testosterone, growth hormone, and insulinlike growth factor-1 (IGF-1). Patients with infertility warrant a complete endocrine profile.

Imaging

If hand x-rays are obtained, remarkable findings reveal a significantly shortened distal phalanx of metacarpals located on the thumb and digits three through five. Additionally, calcification and ossification may be apparent on radiography. Finally, a head computed tomography (CT) may show basal ganglia calcification.

Soft Tissue Calcification
  • Also, soft tissue calcification will be seen.[ajnr.org]
  • tissue calcification exostoses: short metaphyseal or more central and perpendicular to long axis of a bone broad bones with coned epiphyses CNS / head and neck manifestations basal ganglia calcification sclerochoroidal calcification 4 deep white matter[radiopaedia.org]
  • The most well-known of these is Albright hereditary osteodystrophy (type Ia pseudohypoparathyroidism), an autosomal dominant disorder that classically presents with short stature, rounded face, shortened fourth metacarpals, and soft-tissue calcifications[clinicaladvisor.com]
  • tissue calcification Studies Diagnostic testing imaging hand radiograph shortening of the bones, most severe in the 4 th and 5 th metacarpals calcifications and ossifications studies serum studies calcium phosphate PTH administration of synthetic PTH[medbullets.com]
  • Medication List About Pseudohypoparathyroidism: A heritable syndrome featuring: hypocalcaemia, brachydactyly, moderate dwarfing, mental retardation, soft tissue calcifications, basal ganglia calcifications, cataracts, tetany Drugs Used to Treat Pseudohypoparathyroidism[drugs.com]
Increased Bone Density
  • bone density 0011001 Intellectual disability Mental deficiency Mental retardation Mental retardation, nonspecific Mental-retardation [ more ] 0001249 Nystagmus Involuntary, rapid, rhythmic eye movements 0000639 Obesity Having too much body fat 0001513[rarediseases.info.nih.gov]
Shortened Long Bone
  • long bone of hand 0010049 Short metatarsal Short long bone of foot 0010743 Short toe Short toes Stubby toes [ more ] 0001831 Showing of 72 Last updated: 5/1/2019 Making a diagnosis for a genetic or rare disease can often be challenging.[rarediseases.info.nih.gov]
Parathyroid Hormone Increased
  • Abstract A22 month old boy with grand-mal seizures and hypocalcemia, had an elevated serum concentration of parathyroid hormone, increased urinary excretion of cyclic AMP, and a marked rise in urinary cyclic AMP in response to exogenously administered[nejm.org]
Prolonged QT Interval
  • QT interval 0001657 Reduced bone mineral density Low solidness and mass of the bones 0004349 Sensorineural hearing impairment 0000407 Short 3rd metacarpal Shortened 3rd long bone of hand 0010041 Spinal cord compression Pressure on spinal cord 0002176[rarediseases.info.nih.gov]
  • Other possible investigations: ECG: prolonged QT interval which may progress to ventricular fibrillation or heart block. Echocardiogram: cardiac abnormalities (in DiGeorge's syndrome). Renal ultrasound: looking for renal calculi.[patient.info]

Treatment

The treatment objectives are to achieve control of the calcium and PTH levels and to manage any existing hormonal deficiencies.

Adults with profound hypocalcemia are treated with 100mg of intravenous (IV) elemental calcium at a duration of 10 to 20 minutes. If symptoms persist, additional calcium is administered while the patient undergoes calcium and heart monitoring. Children and infants are treated with 10% calcium gluconate at a dose of 0.5-1 mL/kg over a length of 5 minutes.

Following IV treatment, patients are to maintain calcium levels through oral calcium supplements, vitamin D metabolites such calcitriol, and diet.

Other

Patients with additional hormonal abnormalities should be treated accordingly.

Prognosis

If properly treated, patients are expected to have normal life expectancy.

Etiology

The cause of PHP1a, PHP1b, and pseudopseudohypoparathyroidism (pseudo-PHP) is a mutation in the GNAS1 gene, which codes for the alpha subunit of the stimulatory G protein (Gsa) [1]. Most cases of PHP1a are transmitted through an autosomal dominant pattern with parental imprinting. Maternal inheritance of this variant is associated with features of Albright hereditary osteodystrophy (AHO) and resistance to other hormones but the paternal expression does not produce the latter [1]. PHP1b is inherited spontaneously in most cases. The etiology of PHP1c and PHP2 is unclear.

Epidemiology

This rare condition exhibits a two-fold predilection for females.

Sex distribution
Age distribution

Pathophysiology

PTH regulates the plasma calcium concentration through its effect on the kidneys and bone through PTHR1, which is a receptor coupled to Gsa [2] [3]. In PHP, there is renal resistance to PTH at the level of the proximal tubule [4], which leads to less calcium reabsorption.

Prevention

Biochemical surveillance should be performed every 3 months to track calcium levels and adjust treatment as needed.

Summary

Pseudohypoparathyroidism (PHP) is a spectrum of endocrine disorders defined by the renal resistance to parathyroid hormone (PTH). The diagnosis is achieved through clinical and laboratory assessment. Treatment aims to correct the calcium levels and other hormonal abnormalities if present.

Patient Information

Pseudohypoparathyroidism is a rare disorder defined by increased parathyroid hormone and low calcium levels. Signs may include short stature, round face, obesity, short bones in the hand, and mental delay. The disorder is diagnosed with a physical exam and laboratory tests. It is treated with calcium and vitamin D. The prognosis is generally good.

References

Article

  1. Bastepe M. The GNAS locus and pseudohypoparathyroidism. Advances in Experimental Medicine and Biology. 2008; 626:27-40.
  2. Potts JT. Parathyroid hormone: past and present. Journal of Endocrinology. 2005; 18(3):311–325.
  3. Gensure RC, Gardella TJ, Jüppner H. Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochemical and Biophysical Research Communications. 2005; 328(3):666–678.
  4. Stone MD, Hosking DJ, Garcia-Himmelstine C, White DA, Rosenblum D, Worth HG. The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism. Bone. 1993; 14:727–735.
  5. Shalitin S, Davidovits M, Lazar L, et al. Clinical heterogeneity of pseudohypoparathyroidism: from hyper- to hypocalcemia. Hormone Research. 2008; 70(3):137-44.
  6. Long DN, McGuire S, Levine MA, et al. Body mass index differences in pseudohypoparathyroidism type 1a versus pseudopseudohypoparathyroidism may implicate paternal imprinting of Galpha(s) in the development of human obesity. Journal of Clinical Endocrinology and Metabolism. 2007; 92(3):1073-9.
  7. Balavoine AS, Ladsous M, Velayoudom FL, et al. Hypothyroidism in patients with pseudohypoparathyroidism type Ia: clinical evidence of resistance to TSH and TRH. European Journal of Endocrinology. 2008; 159(4):431-7.
  8. Mantovani G, Bondioni S, Linglart A, Maghnie M, Cisternino M, Corbetta S. Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type ib. Journal of Clinical Endocrinology and Metabolism. 2007; 92(9):3738-42.
  9. Liu J, Erlichman B, Weinstein LS. The stimulatory G protein subunit G s is imprinted in human thyroid glands: implications for thyroid function in pseudohypoparathyroidism types Ia and Ib. Journal of Clinical Endocrinology and Metabolism. 2003; 88(9):4336-4341.
  10. Rodriguez HJ, Villarreal H, Klahr S, Slatopolsky E. Pseudohypoparathyroidism type II: restoration of normal renal responsiveness to parathyroid hormone by calcium administration. Journal of Clinical Endocrinology and Metabolism. 1974; 39(4):693-701.

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Last updated: 2019-07-11 20:38