Pseudohypoparathyroidism is a rare

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

genetic condition associated primarily with resistance to the parathyroid hormone. Those with the condition have a low serum

calcium Calcium is a chemical element; it has 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 to it ...

and high

phosphate Phosphates are the naturally occurring form of the element phosphorus. 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 orthop ...

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

G protein G proteins, also known as guanine nucleotide-binding proteins, are a Protein family, family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell (biology), ...

s (in particular, Gs alpha subunit). Pseudohypoparathyroidism is a very rare disorder, with estimated prevalence between 0.3 and 1.1 cases per 100,000 population depending on geographic location.

Types

Types include: ;Type 1a (OMIM ) : Has a characteristic phenotypic appearance ( Albright's hereditary osteodystrophy), including short fourth and fifth

metacarpals In human anatomy, the metacarpal bones or metacarpus, also known as the "palm bones", are the appendicular skeleton, appendicular bones that form the intermediate part of the hand between the phalanges (fingers) and the carpal bones (wrist, wris ...

and a rounded

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

. It is most likely an

disorder. It is also associated with thyroid stimulating hormone 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, ...

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 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 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 musc ...

s, cramping, tetany, and if the calcium deficit is severe, generalized

seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

. 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 Nucleus (neuroanatomy), nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into externa ...

in the deep

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

of the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

. 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). This is as opposed to

Turner syndrome Turner syndrome (TS), commonly known as 45,X, or 45,X0,Also written as 45,XO. is a chromosomal disorder in which cells of females have only one X chromosome instead of two, or are partially missing an X chromosome (sex chromosome monosomy) lea ...

which is characterized by blunting of only the fourth knuckle, and Down syndrome, 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 (physical form and structure), its developmental processes, its biochemical and physiological propert ...

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

Diagnosis

Biochemical findings

* hypocalcemia * hyperphosphatemia * elevated parathyroid hormone (

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 hyperparathyroi ...

) * Suppressed

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

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