Pseudohypoparathyroidism is a condition associated primarily with resistance to the

parathyroid hormone Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration through its effects on bone, kidney, and intestine. PTH influences bone ...

. Those with the condition have a low serum

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...

and high

phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...

, but the parathyroid hormone level (PTH) is appropriately high (due to the low level of calcium in the blood). Its pathogenesis has been linked to dysfunctional

G Proteins G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their ac ...

(in particular,

Gs alpha subunit The Gs alpha subunit (Gαs, Gsα) is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding ...

). Pseudohypoparathyroidism is a very rare disorder, with estimated prevalence between 0.3 and 1.1 cases per 100000 population depending on geographic location.

Types

Types include: ;Type 1a (OMIM ) : Has a characteristic phenotypic appearance (

Albright's hereditary osteodystrophy Albright's hereditary osteodystrophy is a form of osteodystrophy, and is classified as the phenotype of pseudohypoparathyroidism type 1A; this is a condition in which the body does not respond to parathyroid hormone. Signs and symptoms The dis ...

), including short fourth and fifth

metacarpals In human anatomy, the metacarpal bones or metacarpus form the intermediate part of the skeletal hand located between the phalanges of the fingers and the carpal bones of the wrist, which forms the connection to the forearm. The metacarpal bones ar ...

and a rounded

facies In geology, a facies ( , ; same pronunciation and spelling in the plural) is a body of rock with specified characteristics, which can be any observable attribute of rocks (such as their overall appearance, composition, or condition of formatio ...

. It is most likely an

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

disorder. It is also associated with

thyroid stimulating hormone Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of ...

resistance. Caused by GNAS1 mutation. ; Type 1b (OMIM ) : Lacks the physical appearance of type 1a, but is

biochemical Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology an ...

ly similar. It is associated with a methylation defect in the A/B exon of GNAS1, caused by STX16 disruption. ; Type 2 (OMIM ) : Also lacks the physical appearance of type 1a. Since the genetic defect in type 2 is further down the signalling pathway than in type 1, there is a normal

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

response to PTH stimulation despite the inherent abnormality in calcium regulation. The specific gene is not identified. While biochemically similar, type 1 and 2 disease may be distinguished by the differing urinary excretion of cyclic AMP in response to exogenous PTH. Some sources also refer to a "type 1c" (OMIM ). The phenotype is the same as in type 1a, but red blood cells show normal Gs activity. As it is also caused by a GNAS mutation, it is not clear whether it should be considered an entity separate from Ia.

Presentation

Patients may present with features of

hypocalcaemia Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L) while levels less than 2.1 mmol ...

including carpo-pedal muscular

spasm A spasm is a sudden involuntary contraction of a muscle, a group of muscles, or a hollow organ such as the bladder. A spasmodic muscle contraction may be caused by many medical conditions, including dystonia. Most commonly, it is a muscle c ...

s, cramping,

tetany Tetany or tetanic seizure is a medical sign consisting of the involuntary contraction of muscles, which may be caused by disorders that increase the action potential frequency of muscle cells or the nerves that innervate them. Muscle cramps cau ...

, and if the calcium deficit is severe, generalized

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...

. IQ is typically mildly depressed or unaffected. Additional characteristics include short stature, obesity, developmental delay, and calcification of the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an ext ...

in the deep

white matter White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distribu ...

of the

brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...

. Type 1a Pseudohypoparathyroidism is clinically manifest by bone resorption with blunting of the fourth and fifth knuckles of the hand, most notable when the dorsum of the hand is viewed in closed fist position. This presentation is known as 'knuckle knuckle dimple dimple' sign (

Archibald's sign Archibald's sign (also known as Archibald's metacarpal sign) refers to a feature in the hand characterized by a shortening of the fourth or/and fifth metacarpals when the fist is clenched. Causes The causes of Archibald's sign are not known; howe ...

). This is as opposed to

Turner syndrome Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low h ...

which is characterized by blunting of only the fourth knuckle, and

Down syndrome Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual d ...

, which is associated with a hypoplastic middle phalanx.

Related conditions

The term pseudopseudohypoparathyroidism is used to describe a condition where the individual has the

phenotypic In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...

appearance of pseudohypoparathyroidism type 1a, but is biochemically normal.

Diagnosis

Biochemical findings

hypocalcemia Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L) while levels less than 2.1 mm ...

hyperphosphatemia Hyperphosphatemia is an electrolyte disorder in which there is an elevated level of phosphate in the blood. Most people have no symptoms while others develop calcium deposits in the soft tissue. Often there is also low calcium levels which can ...

* elevated

(

hyperparathyroidism Hyperparathyroidism is an increase in parathyroid hormone (PTH) levels in the blood. This occurs from a disorder either within the parathyroid glands (primary hyperparathyroidism) or as response to external stimuli (secondary hyperparathyroidism) ...

) * Suppressed

calcitriol Calcitriol is the active form of vitamin D, normally made in the kidney. It is also known as 1,25-dihydroxycholecalciferol. It is a hormone which binds to and activates the vitamin D receptor in the nucleus of the cell, which then increases the ...

levels

Treatment

Calcium and Calcitriol supplements, the latter with a larger dose than for treatment of hypoparathyroidism.

References

External links

{{Genomic imprinting Cell surface receptor deficiencies Rare diseases