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]

  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]

  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]

• Weight Gain

  Patients should be screened at diagnosis and during follow-up for specific features, such as PTH resistance, TSH resistance, growth hormone deficiency, hypogonadism, skeletal deformities, oral health, weight gain, glucose intolerance or type 2 diabetes [ncbi.nlm.nih.gov]

  PHP may be connected to other hormone problems, resulting in: Low sex drive Slow sexual development Low energy levels Weight gain Contact your provider if you or your child have any symptoms of a low calcium level or pseudohypoparathyroidism. [nlm.nih.gov]

  TSH resistance and patterns of excessive intrauterine growth or weight gain at birth or during early infancy and childhood have been described 44, 51, 52. [doi.org]

• Short Finger

  finger Stubby finger Stubby fingers [ more ] 0009381 Short metacarpal Shortened 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 [rarediseases.info.nih.gov]

• Galactorrhea

  Type 1 Excludes transitory endocrine and metabolic disorders specific to newborn ( P70-P74 ) Endocrine, nutritional and metabolic diseases E20-E35 2019 ICD-10-CM Range E20-E35 Disorders of other endocrine glands Type 1 Excludes galactorrhea ( N64.3 ) [icd10data.com]

• 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]

  If the patient develops dyspnea and pneumoderma during or after this procedure, a chest radiogram or thoracoabdominal CT should be taken for diagnostic purposes. [giornalechirurgia.it]

• 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]

  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]

  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]

  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]

  Additional symptoms and findings may include stiffness or cramps in the arms and/or legs, palpitations, and/or abdominal pain. [rarediseases.org]

• Alopecia

  […] before the age of 3 years, with one or more of the following: Chronic oral candidiasis (thrush) Napkin (diaper) dermatitis Paronychia and candidal onychomycosis (nail infection ) Widespread crusted plaques on the scalp, trunk, hands and feet Scarring alopecia [dermnetnz.org]

• 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

  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]

  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]

  Physical examination showed normal vital signs; AHO, Trousseau’s and Chvostek’s signs were negative. [revistas.unal.edu.co]

  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]

  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]

• 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]

  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]

• Advanced Bone Age

  X-rays will show shortening of the fourth metacarpal (long bone of the hand) and advanced bone age. All metacarpals and metatarsals (long bones of the foot) may be affected. [rarediseases.info.nih.gov]

• Round Face

  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]

  The phenotype of Albright syndrome includes 5 common features: brachydactyly, obesity, short stature, a round face, and mental retardation. [ncbi.nlm.nih.gov]

• Seizure

  Abstract We describe a patient who presented with epileptic seizures unresponsive to anticonvulsive treatment. [ncbi.nlm.nih.gov]

  She was started on anti-seizure medications and remained seizure free since starting treatment. In the meantime her PTH levels were elevated and her vitamin D levels were significantly reduced (Table 1). [omicsonline.org]

• Convulsions

  He was admitted with hypocalcemic convulsions as well as hyperphosphatemia and elevated PTH levels suggested PTH resistance at 2.5 years of age. [ncbi.nlm.nih.gov]

  Information Case 1 Case 2 Case 3 Case 4 Final aggregate Reason for consultation Hypocalcemia Convulsion Convulsion Pathologic fracture Hypocalcemia Hypocalcemia Hypocalcemia (100%) Convulsion (50%) History Epilepsy Epilepsy Mother with AHO Hypothyroidism [revistas.unal.edu.co]

  Mental retardation, cataracts, tetany, and convulsions may also occur. pseu·do·hy·po·par·a·thy·roid·ism ( sū'dō-hī'pō-par'ă-thī'royd-izm ), [MIM*103580] A disorder resembling hypoparathyroidism, with high serum phosphate and low calcium levels but with [medical-dictionary.thefreedictionary.com]

• 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 muscle [medicinenet.com]

  Common reported side effects with ATRA treatment are headache, hypertriglyceridemia, bone pain, liver dysfunction and skin dryness [1]. Apart from these common adverse effects, rarely, ATRA associated hypercalcemia has been reported. [docksci.com]

• 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]

  Patients usually presents with neurological symptoms related to hypocalcemia like muscular cramps, paresthesia, fatigue, anxiety etc., extrapyramidal signs and seizures. [jdrntruhs.org]

  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]

  During the endocrinology consultation, the patient reported general malaise and generalized paresthesia over the last week prior to the consultation. [revistas.unal.edu.co]

• 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]

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

  In addition, such bilateral symmetric calcification can sometimes be seen within the thalami and the cortex. 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 [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]

• Shortened Long Bone

  X-rays will show shortening of the fourth metacarpal (long bone of the hand) and advanced bone age. All metacarpals and metatarsals (long bones of the foot) may be affected. [rarediseases.info.nih.gov]

• Increased Bone Density

  […] size of cheeks Large cheeks [ more ] 0000293 Growth hormone deficiency 0000824 Hypoplasia of dental enamel Underdeveloped teeth enamel 0006297 Increased bone mineral density Increased bone density 0011001 Intellectual disability Mental deficiency Mental [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]

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.

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

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.

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

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.

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

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.

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.

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