Autosomal Dominant Hypocalcemia 1

Mendelian MONDO:0011013 Pathograph 19 Show in embeddings browser Endocrine disorder

ADH1 is a disease of a moved set point rather than a missing protein. The calcium-sensing receptor is a class C G-protein-coupled receptor that reads extracellular ionised calcium and, when that concentration rises, both suppresses parathyroid hormone secretion and reduces calcium reabsorption in the renal tubule. A heterozygous activating variant leaves the receptor intact and correctly located but shifts its dose-response curve to the left, so calcium concentrations that a normal receptor would read as low are read as sufficient. The consequence is hypocalcaemia that the body does not defend. PTH is not absent - it is inappropriately low for the calcium level, which is what distinguishes this from parathyroid destruction or agenesis. And because the same over-sensitive receptor is present in the renal tubule, calcium is being excreted at the same time as it is being lost from the circulation. That second limb is what makes ADH1 clinically distinct from other hypoparathyroidisms: hypercalciuria is driven both by the low PTH and by the receptor acting directly on the tubule, so it is worse than PTH deficiency alone would explain. The therapeutic consequence follows directly and is the reason the mechanism is worth stating precisely. Conventional treatment - calcium plus activated vitamin D - raises serum calcium by pushing more calcium through a kidney that is already wasting it, so correcting the symptom aggravates the renal lesion and drives nephrocalcinosis and stones. Treatments that act on the mechanism rather than the number, PTH replacement and negative allosteric modulators of the receptor, are therefore not merely alternatives but are aimed at a different point in the causal chain.

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1
Inheritance
10
Pathophys.
14
Phenotypes
3
Gaps
19
Pathograph
1
Genes
5
Medical Actions
2
Subtypes
1
Trials
1
Models
22
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
A single activating allele is sufficient, because the phenotype comes from the mutant receptor sensing calcium too well rather than from loss of the wild-type copy. De novo variants are common, so an absent family history does not argue against the diagnosis.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:7874174 SUPPORT Human Clinical
"We conclude that this extracellular domain mutation increases the receptor's activity at low Ca2+ concentrations, causing hypocalcaemia in patients heterozygous for such a mutation."
States both the dominant mechanism and that heterozygosity is sufficient.
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Subtypes

2
Isolated autosomal dominant hypocalcemia type 1
The common presentation: hypocalcaemia with inappropriately low PTH and relative hypercalciuria, without a salt-wasting tubulopathy. Severity ranges from an incidental biochemical finding to seizures.
ADH1 with Bartter syndrome type V
A minority of activating CASR alleles additionally produce a salt-wasting tubulopathy with hypokalaemic metabolic alkalosis, hyperreninaemia and hyperaldosteronaemia. The extra limb is mechanistically explained: an activated receptor in the thick ascending limb inhibits the ROMK potassium channel, which is the channel mutated in Bartter syndrome type 2. This is curated as a subtype of ADH1 rather than as a separate Bartter entity, because the primary lesion is the same receptor. Nomenclature warning: the existing Bartter_Syndrome entry in this knowledge base carries an unrelated subtype also named Type 5, for transient antenatal Bartter syndrome caused by MAGED2. Both are called type 5 in the literature and they are different diseases with different genes. The name here is qualified as "ADH1 with Bartter syndrome type V" in display_name for that reason.
Show evidence (1 reference)
PMID:12241879 SUPPORT Human Clinical
"We describe two hypocalcaemic patients with deficient parathyroid hormone secretion who also showed characteristics of Bartter's syndrome. We found activating mutations of the gene for the calcium-sensing receptor (CASR) in both patients."
The report establishing that activating CASR alleles can carry a Bartter phenotype alongside ADH1.
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Discussions and Knowledge Gaps

3
Why is the treatment target in ADH1 a low-normal serum calcium rather than a normal one?
INTERPRETATION adh1_calcium_target_is_a_tradeoff
Attached to
pathophysiology#Renal Calcium Wasting treatments#Calcitriol and Calcium Supplementation
In most hypoparathyroidism, hypercalciuria has one cause - no PTH to drive distal reabsorption - and PTH replacement addresses it. In ADH1 there are two causes, and only one of them responds to anything conventional therapy does. The renal receptor is over-sensitive whatever the PTH is doing, so every increment of serum calcium is filtered into a tubule that will not reabsorb it normally. That makes the usual therapeutic logic run backwards. Correcting serum calcium to the middle of the reference range does not restore normal physiology; it maximises the filtered load at the site of the second lesion, and the documented consequences are nephrocalcinosis, stones and declining renal function. So the accepted target is deliberately sub-normal - enough calcium to prevent tetany and seizures, not enough to normalise the number. This is why the mechanism is modelled here as two limbs converging on renal calcium wasting rather than as a single hypoparathyroid state. An entry that recorded only "hypoparathyroidism causes hypercalciuria" would make the conventional treatment look adequate.
Show evidence (2 references)
PMID:8813042 SUPPORT Human Clinical
"treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment"
The observed harm from raising calcium by the conventional route.
PMID:33112267 SUPPORT Human Clinical
"The traditional approach to treatment includes activated vitamin D but this further increases urinary calcium excretion."
States the trade-off directly as the motivation for seeking an alternative.
Why does the degree of in vitro receptor activation not predict a patient's response to a calcilytic?
KNOWLEDGE GAP adh1_in_vitro_activation_does_not_predict_response
Attached to
genetic#CASR treatments#Calcilytic (Negative Allosteric Modulator of the CaSR)
The mechanistic argument for calcilytics in ADH1 is clean: the receptor is too easily activated, so shift it back. The clinical study tested that argument in five patients with four different CASR variants and measured, in parallel, what the drug did to each variant receptor in cells. Every variant behaved as activating in vitro and every one was shifted by the drug in vitro - and yet the in vitro numbers did not correlate with any clinical parameter, and the clinical responses varied substantially between patients. That is a gap rather than a negative result. It means the assay that classifies a variant as activating - a calcium dose-response curve in a heterologous cell line - is not measuring the quantity that determines what happens in a patient. Candidate explanations include signalling that is biased between pathways in ways the readout does not capture, tissue-specific differences between parathyroid and tubule, and expression or trafficking effects that a stable overexpression system removes. Of those, biased signalling has since acquired direct evidence rather than remaining a suggestion. A de novo p.Leu723Arg variant was shown to lower the EC50 for calcium activation of G11 while leaving Gi, Gq and Gs unchanged - so a variant can be activating along one coupling route and not others. A dose-response assay that reads a single downstream output cannot distinguish that from uniform activation, and the patient carrying it presented with short stature and inconsistent hypercalciuria rather than the usual ADH1 picture. That does not close the gap, since the calcilytic study's variants were not profiled this way, but it shows the mechanism is real and that the standard assay would miss it. Recording this matters for how the genotype is used. A variant curated as "gain of function, confirmed functionally" carries less predictive information than that phrase suggests, and this entry deliberately does not let the functional classification stand in for a prognosis.
Show evidence (3 references)
PMID:31063613 SUPPORT Human Clinical
"In vitro, all mutant CaRs were half-maximally activated (EC50 ) at lower concentrations of extracellular calcium (Ca2+o ) compared to wild-type (WT) CaR; NPSP795 exposure increased the EC50 for all CaR activity readouts. However, the in vitro responses to NPSP795 did not correlate with any..."
The paired result - uniform in vitro behaviour, uncorrelated clinical behaviour - which is the gap itself.
PMID:31063613 SUPPORT Human Clinical
"Albeit all mutations appear to be activating at the CaR, in vitro observations were not predictive of the in vivo phenotype or the response to calcilytics, suggesting that other parameters impact the response to the drug."
The authors' own statement of the disconnect, quoted separately from the result that produced it.
PMID:39658204 SUPPORT In Vitro
"Transient expression studies showed the Leu723Arg variant was normally expressed but resulted in a significantly lower EC50 for extracellular calcium activation of G11 but not other G proteins (ie, Gi, Gq, Gs)."
Direct evidence that a variant can be activating for one G-protein route and not others, which is one of the candidate explanations for the assay-to-clinic disconnect.
What does ADH1 need to be distinguished from, and why does the distinction change management?
INTERPRETATION adh1_vs_adh2_and_hypoparathyroidism
Attached to
diagnosis#CASR Sequencing
Two differentials matter. The first is hypoparathyroidism from parathyroid destruction, surgery or agenesis. It looks similar - low calcium, low PTH, high phosphate - but has no renal limb, so calcium and vitamin D are appropriate treatment there and a compromise here. Distinguishing them is what the paired calcium/PTH plus a urinary calcium measurement is for, and it is why the original kindreds were relabelled from "autosomal dominant hypoparathyroidism". The second is ADH2, caused by activating variants of GNA11, the G-protein that transduces the receptor's signal. Because the lesion is one step downstream, the biochemistry is close to identical and sequencing is what separates them. The distinction is not academic for the calcilytic question: a drug that acts allosterically on the receptor has its target intact in ADH1, whereas in ADH2 the receptor is normal and the excess signalling begins beyond it - which is why the calcilytic effect in ADH2 was demonstrated in a mouse model rather than assumed to transfer. A third differential is acquired rather than inherited: activating autoantibodies against the receptor reproduce the ADH biochemistry with no CASR variant present. It is the differential a negative sequencing result should raise rather than close, and the mirror image of the inactivating autoantibodies that phenocopy familial hypocalciuric hypercalcaemia.
Show evidence (2 references)
PMID:28194447 SUPPORT Model Organism
"Heterozygous germline gain-of-function mutations of G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal dominant hypocalcemia type 2 (ADH2)."
Defines ADH2 and its relationship to the receptor, which is the basis of the differential.
PMID:20374733 SUPPORT Other
"Phenocopies of FHH or ADH are due to circulating CASR inactivating or activating autoantibodies, respectively."
A third differential the genetic test settles - an acquired autoimmune phenocopy that reproduces the biochemistry with no CASR variant at all.
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Pathophysiology

10
Heterozygous CASR Gain-of-Function Variant
A missense variant, most often in the large extracellular domain, that makes the receptor easier to activate. The protein is expressed and trafficked normally; what changes is the calcium concentration at which it signals.
Genetic context CASR hgnc:1514 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns CASR (hgnc:1514). hgnc:1514 is a gene from the HUGO Gene Nomenclature Committee. functional_impact_category: GAIN_OF_FUNCTION
calcium-sensing receptor activity GO:0004930 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves calcium-sensing receptor activity, annotated with G protein-coupled receptor activity (GO:0004930), qualified as gain of function. GO:0004930 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Left-Shifted Calcium Set Point
Show evidence (1 reference)
PMID:8813042 SUPPORT In Vitro
"Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to..."
The direct measurement of the leftward shift in the dose-response curve, which is the molecular claim this node makes. Graded IN_VITRO because it is a heterologous expression experiment in HEK-293 cells.
Left-Shifted Calcium Set Point
The receptor now reaches half-maximal signalling at a lower extracellular calcium concentration than the wild-type receptor does. Every downstream consequence follows from this one quantitative change, in whichever tissue the receptor is expressed.
calcium-sensing receptor signalling GO:0007186 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased calcium-sensing receptor signalling, annotated with G protein-coupled receptor signaling pathway (GO:0007186). GO:0007186 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Nuf mouse (Casr Leu723Gln) Mouse recapitulates A germline activating Casr variant producing the same set-point lesion, in which pharmacological reversal of the shift can be tested directly.
Downstream
Suppressed Parathyroid Hormone Secretion In the parathyroid chief cell, where receptor activation is the signal to stop secreting.
Impaired Renal Tubular Calcium Reabsorption In the renal tubule, where the same receptor independently reduces calcium reabsorption. This limb does not require the parathyroid limb.
Show evidence (1 reference)
PMID:7874174 SUPPORT In Vitro
"Xenopus oocytes expressing the mutant receptor exhibit a larger increase in inositol 1,4,5-triphosphate in response to Ca2+ than oocytes expressing the wild-type receptor."
The heterologous-expression measurement showing increased signalling output for the same calcium stimulus.
Suppressed Parathyroid Hormone Secretion
Parathyroid chief cells read the prevailing calcium as adequate and withhold PTH. Secretion is reduced, not abolished - measured PTH is typically low-normal rather than undetectable, which is precisely why the finding is described as inappropriate rather than absent.
parathyroid chief cell CL:0000446 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves parathyroid chief cell, annotated with chief cell of parathyroid gland (CL:0000446). CL:0000446 is a cell type from the Cell Ontology.
parathyroid hormone secretion GO:0035898 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased parathyroid hormone secretion (GO:0035898). GO:0035898 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hypocalcemia with Inappropriately Low PTH
Renal Calcium Wasting Loss of PTH removes the hormone's own stimulus to distal tubular calcium reabsorption. This is the limb ADH1 shares with every other hypoparathyroidism.
Hyperphosphatemia PTH is phosphaturic, so withholding it raises serum phosphate.
Show evidence (1 reference)
PMID:33112267 SUPPORT Human Clinical
"which reduces PTH secretion from parathyroid cells despite low serum calcium levels"
States the parathyroid limb explicitly, including that it operates despite low serum calcium.
Impaired Renal Tubular Calcium Reabsorption
The over-sensitive receptor in the renal tubule reduces calcium reabsorption directly. This is the limb that separates ADH1 from other causes of hypoparathyroidism, and it is why raising the filtered calcium load makes the renal picture worse rather than better. A route from the receptor to the transport defect has been traced. Claudin-14 is a negative regulator of the paracellular calcium pathway in the thick ascending limb, held in check by miR-9 and miR-374. ADH1 receptor variants repress transcription of those two microRNAs, which lifts the brake on claudin-14 and closes the paracellular route. The step is evidenced in cell and animal models rather than in patients, and is recorded here at that strength.
CLDN14 hgnc:2035 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CLDN14 (hgnc:2035). hgnc:2035 is a gene from the HUGO Gene Nomenclature Committee.
renal tubular calcium ion transport GO:0070588 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased renal tubular calcium ion transport, annotated with calcium ion transmembrane transport (GO:0070588). GO:0070588 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Renal Calcium Wasting
Impaired Vasopressin-Dependent Water Reabsorption The same receptor is expressed in the collecting duct, where its activation opposes vasopressin action. This is a second renal consequence, parallel to the calcium one rather than downstream of it.
Show evidence (4 references)
PMID:33112267 SUPPORT Human Clinical
"the presence of CaSRs with increased sensitivity to calcium in the renal tubule also impairs reabsorption of calcium"
The renal limb stated as a mechanism independent of the parathyroid limb.
PMID:37754292 SUPPORT Human Clinical
"Gain-of-function CASR variants increase the sensitivity of the CaSR to extracellular calcium, reducing PTH secretion and renal calcium reabsorption and resulting in hypocalcemia, hyperphosphatemia, hypomagnesemia, and hypercalciuria."
States both limbs and, importantly, names hypomagnesaemia among the cardinal biochemical consequences rather than as a Bartter-subtype feature.
PMID:25071082 SUPPORT Model Organism
"The genetic mutations in the calcium-sensing receptor from patients with autosomal dominant hypocalcemia (ADH) repressed the transcription of miR-9 and miR-374 genes, and treatment with an HDAC inhibitor rescued the phenotypes of cell and animal models of ADH."
The claudin-14 route stated for ADH variants specifically, with a pharmacological rescue in cell and animal models. This is the citation for the CLDN14 descriptor on this node; the descriptor was previously carried on the strength of a deep-research lead alone, which PR review correctly flagged.
+ 1 more reference
Impaired Vasopressin-Dependent Water Reabsorption
Receptor activation in the collecting duct opposes vasopressin by driving down aquaporin-2. In a CaSR knock-in mouse modelling this disease the route was traced - less total AQP2, more AQP2 phosphorylated at the degradation site Ser261, higher phosphorylated p38MAPK and ATF1 upstream of it, and more of the AQP2-targeting miR-137 - and a calcilytic reversed it. This is the mechanism behind the urinary concentrating defect and the polyuria of the Bartter-type-V presentation. PROVISIONAL because the chain is established in the mouse and has not been demonstrated in patients.
AQP2 hgnc:634 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AQP2 (hgnc:634). hgnc:634 is a gene from the HUGO Gene Nomenclature Committee.
renal water homeostasis GO:0003091 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased renal water homeostasis (GO:0003091). GO:0003091 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (2 references)
PMID:38367250 SUPPORT Model Organism
"we provide evidence that, with respect to wild-type mice, CaSR knock-in (KI) mice mimicking autosomal dominant hypocalcaemia, display a significant decrease in the total content of AQP2 associated with significantly higher levels of AQP2 phosphorylation at Ser261, a phosphorylation site involved..."
The measured AQP2 defect in a knock-in mouse built to model this disease.
PMID:38367250 SUPPORT Model Organism
"In vivo treatment of KI mice with the calcilytic JTT-305, a CaSR antagonist, increased AQP2 expression and reduced AQP2-targeting miRNA137 levels in KI mice."
The pharmacological reversal, which is what attributes the AQP2 defect to receptor activity rather than to the hypocalcaemia it accompanies.
Hypocalcemia with Inappropriately Low PTH
The defining biochemical signature. The pairing matters more than either number: hypocalcaemia with a PTH that is merely low-normal is the finding that points at the receptor rather than at the gland.
Downstream
Neuromuscular Irritability
Ectopic Calcification Chronic hypocalcaemia with hyperphosphataemia is associated with intracranial calcification, but the step from the disturbed calcium-phosphate product to deposition at specific sites is not resolved.
Show evidence (1 reference)
PMID:31063613 SUPPORT Human Clinical
"Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria."
The three-part biochemical signature stated compactly in a clinical study of ADH1 patients.
Renal Calcium Wasting
Urinary calcium excretion is high relative to a serum calcium that is already low. Two independent inputs converge here - the absent PTH signal and the tubular receptor - which is why the hypercalciuria of ADH1 exceeds that of other hypoparathyroidisms and why it is hard to treat.
Downstream
Ectopic Calcification Sustained hypercalciuria supersaturates the tubular fluid, giving nephrocalcinosis and stones.
Show evidence (1 reference)
PMID:33112267 SUPPORT Human Clinical
"The combination of both loss of PTH and gain of CaSR activity provides a dual mechanism for hypercalciuria in ADH1"
Names the convergence of the two upstream limbs on this node, which is the reason this entry models them separately.
Hyperphosphatemia
Raised serum phosphate, the expected consequence of withdrawing a phosphaturic hormone.
Show evidence (1 reference)
PMID:37754292 SUPPORT Human Clinical
"Mean blood levels of intact PTH, magnesium, and 1,25-dihydroxy-vitamin D increased, whereas phosphorus levels and tubular reabsorption of phosphate decreased"
The phosphate response to restoring PTH, which demonstrates the phosphate elevation is PTH-dependent rather than incidental.
Neuromuscular Irritability
Reduced ionised calcium lowers the threshold for nerve and muscle depolarisation, giving paraesthesiae, carpopedal spasm, tetany and seizures. Severity is not simply a function of how low the calcium is: in one kindred four of seven affected members were symptomatic and the symptoms were explicitly unrelated to the degree of hypocalcaemia.
Show evidence (2 references)
PMID:22863393 SUPPORT Other
"Although hypocalcemic patients commonly present with symptoms of neuromuscular irritability with perioral numbers paresthesias, tingling, seizures and, bronchospasm; hypocalcemia may be identified on the biochemical profile of an asymptomatic patient."
Names the syndrome and its manifestations, and records that it may be absent altogether. The source's typo "numbers" for "numbness" is reproduced as published.
PMID:16128246 SUPPORT Human Clinical
"Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia."
The observation that symptom burden does not track calcium level, measured within a single kindred carrying one variant.
Ectopic Calcification
Deposition of calcium salts outside bone - in the renal medulla as nephrocalcinosis and stones, and intracranially in the basal ganglia and cerebral cortex. PROVISIONAL because the renal and intracranial deposits do not share a single established mechanism: the renal deposits follow directly from supersaturated tubular fluid, while the intracranial ones accompany chronic hypocalcaemia and hyperphosphataemia without a resolved pathway, and conventional treatment contributes to the renal component.
Animal models
Nuf mouse (Casr Leu723Gln) Mouse recapitulates The allele was originally found in a screen for eye mutants, and the mouse carries lens opacities and ectopic calcification alongside the mineral abnormalities - so it reproduces the entry's deposition node as well as its set-point node.
Show evidence (1 reference)
PMID:33112267 SUPPORT Human Clinical
"As a result, nephrocalcinosis and nephrolithiasis are more common in subjects with ADH1 than other forms of hypoparathyroidism"
Ties the renal deposits specifically to ADH1's extra renal limb rather than to hypoparathyroidism in general.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autosomal Dominant Hypocalcemia 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

14
Endocrine 1
Hypoparathyroidism OBLIGATE HP:0000829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoparathyroidism (HP:0000829). HP:0000829 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33112267 SUPPORT Human Clinical
"Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism."
Establishes the hypoparathyroid phenotype and ADH1's place among its genetic causes.
Eye 1
Cataract OCCASIONAL HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35818129 SUPPORT Human Clinical
"He was diagnosed with congenital cataracts at the age of 14 years."
An observed cataract in an ADH1 patient with long-standing poorly controlled hypocalcaemia.
Genitourinary 2
Nephrolithiasis OCCASIONAL HP:0000787 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrolithiasis (HP:0000787), qualified as course progressive. HP:0000787 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:33112267 SUPPORT Human Clinical
"he continued to have marked hypercalciuria, and he developed multiple, recurrent renal stones. He underwent lithotripsy at the age of 2 years"
Documents stones as a clinical course in an ADH1 patient, with the intervention they required.
PMID:33599907 SUPPORT Other
"The reported rate of nephrolithiasis was up to 36%, with the lowest rates in studies reporting shorter duration of disease."
PARTIAL for population - chronic hypoparathyroidism on conventional therapy rather than ADH1 specifically. The duration dependence in the same sentence is the reason this phenotype carries a PROGRESSIVE clinical_course.
Chronic Kidney Disease OCCASIONAL HP:0012622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic kidney disease (HP:0012622), qualified as course progressive. HP:0012622 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:8813042 SUPPORT Human Clinical
"treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment"
Renal impairment observed in the original ADH1 kindreds, and attributed there to the treatment rather than only to the disease.
PMID:33599907 SUPPORT Other
"A systematic literature review was performed to summarize the frequency and nature of renal complications in patients with chronic hypoparathyroidism managed with conventional therapy."
PARTIAL because the review's population is chronic hypoparathyroidism on conventional therapy rather than ADH1. It is cited to establish that renal complications are a recognised systematic burden of this management, not to supply an ADH1 rate.
Metabolism 3
Hypocalcemia OBLIGATE HP:0002901 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypocalcemia (HP:0002901). HP:0002901 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31063613 SUPPORT Human Clinical
"Individuals are hypocalcemic with inappropriately low parathyroid hormone (PTH) secretion and relative hypercalciuria."
States hypocalcaemia as a defining feature of the ADH1 cohort studied.
Hyperphosphatemia FREQUENT HP:0002905 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperphosphatemia (HP:0002905). HP:0002905 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35818129 SUPPORT Human Clinical
"Hypocalcemia, hyperphospheremia, and hypoparathyroidism were clearly evident, and brain computed tomography showed multiple intracranial calcifications"
The biochemical triad as measured in the reported patient. The source spells the finding "hyperphospheremia"; the quote is reproduced as published.
Hypokalemia OCCASIONAL HP:0002900 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypokalemia (HP:0002900). HP:0002900 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33112267 SUPPORT Human Clinical
"which accounted not only for his ADH1 but also type 5 Bartter syndrome with persistent hypokalemia, hypomagnesemia, and polyuria"
An observed Bartter-type-V presentation in a genetically confirmed ADH1 patient, which is why this phenotype is tagged to that subtype.
Musculoskeletal 1
Tetany FREQUENT HP:0001281 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tetany (HP:0001281), qualified as temporality recurrent. HP:0001281 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:33112267 SUPPORT Human Clinical
"She also experienced frequent episodes of tetany, manifesting as an inability to walk."
A directly observed clinical description of tetany and its functional impact.
Nervous System 2
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250), qualified as temporality recurrent. HP:0001250 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:35818129 SUPPORT Human Clinical
"Here, we describe a case who presented with symptoms of recurrent seizure caused by hypocalcemia with a novel CASR variant."
Seizure as the presenting manifestation, attributed to the hypocalcaemia.
Paresthesia FREQUENT HP:0003401 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paresthesia (HP:0003401). HP:0003401 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16128246 SUPPORT Human Clinical
"Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia."
Paraesthesia among the symptoms in a kindred, with a denominator.
Other 4
Hypercalciuria VERY_FREQUENT HP:0002150 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypercalciuria (HP:0002150). HP:0002150 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33112267 SUPPORT Human Clinical
"Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism."
States the phenotype and, importantly, that it exceeds that of other hypoparathyroidisms.
Nephrocalcinosis FREQUENT HP:0000121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrocalcinosis (HP:0000121). HP:0000121 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:33112267 SUPPORT Human Clinical
"Her renal ultrasound at two months of age demonstrated nephrocalcinosis."
A directly observed case finding, present in early infancy and therefore before prolonged treatment exposure.
PMID:16128246 SUPPORT Human Clinical
"Additional complications include nephrocalcinosis (n = 3) and basal ganglia calcification, identified by CT scanning in all five individuals."
A denominator rather than a single case - three of seven affected members of one kindred. This is what the FREQUENT grading rests on; the case observation above establishes only that the phenotype occurs.
PMID:33599907 SUPPORT Other
"The rate of nephrocalcinosis was up to 38%."
PARTIAL because the systematic review covers chronic hypoparathyroidism on conventional therapy generally, not ADH1 - so it bounds the rate in a population that includes but is broader than this disease.
Intracranial Calcification FREQUENT Basal ganglia calcification HP:0002135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Basal ganglia calcification (HP:0002135), qualified as course progressive. HP:0002135 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:35818129 SUPPORT Human Clinical
"Computed tomography of the brain revealed multiple intracranial calcifications, and electroencephalography showed extensive epileptic discharges."
Imaging documentation of the intracranial deposits in a genetically confirmed patient.
PMID:16128246 SUPPORT Human Clinical
"basal ganglia calcification, identified by CT scanning in all five individuals"
Present in every scanned member of the kindred, which is why this phenotype is graded FREQUENT rather than OCCASIONAL. Note the denominator is those who were imaged, not all affected members - so this is a yield in scanned patients, not a population frequency.
Hypomagnesemia FREQUENT HP:0002917 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypomagnesemia (HP:0002917). HP:0002917 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16128246 SUPPORT Human Clinical
"Affected members had hypocalcaemia (1.53-1.85 mmol/l), hypercalciuria, low but detectable parathyroid hormone (PTH) and hypomagnesaemia."
The full biochemical signature in a seven-member kindred, including magnesium and including the observation that PTH is low but detectable.
PMID:37754292 SUPPORT Human Clinical
"The CaSR primarily regulates parathyroid hormone (PTH) secretion and renal calcium and magnesium reabsorption."
The mechanistic basis - magnesium is handled by the same receptor, so its loss is expected rather than incidental.
🧬

Genetic Associations

1
CASR
Gene: CASR hgnc:1514 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CASR (hgnc:1514). hgnc:1514 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (5 references)
PMID:20374733 SUPPORT Other
"Heterozygous loss-of-function mutations cause familial (benign) hypocalciuric hypercalcemia (FHH) in which the lifelong mild hypercalcemia is generally asymptomatic. Homozygous inactivating mutations give rise to neonatal severe hyperparathyroidism (NSHPT) with extreme hypercalcemia and marked..."
The full allelic series in one passage, which is what places ADH1 at the gain-of-function end of a graded dosage relationship rather than treating it as an isolated phenotype.
PMID:8813042 SUPPORT Human Clinical
"Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease."
Establishes the allelic spectrum and its cosegregation across six kindreds.
PMID:31063613 SUPPORT Human Clinical
"There was significant variability in response clinically across genotypes."
PARTIAL because it supports only the second half of the note - variability across genotypes - and speaks to drug response rather than to disease severity.
+ 2 more references
💊

Medical Actions

5
Calcitriol and Calcium Supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: calcitriol CHEBI:17823 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcitriol (CHEBI:17823). CHEBI:17823 is a therapeutic agent from Chemical Entities of Biological Interest.
The conventional treatment, and the one whose limitation defines the field. It raises serum calcium without touching the receptor, so it drives more calcium through a tubule that is already wasting it. Guidelines still recommend it, and the practical aim is a low-normal serum calcium that relieves symptoms rather than a normal one.
Mechanism Target:
BYPASSES Hypocalcemia with Inappropriately Low PTH — Raises serum calcium by a route that does not involve PTH or the receptor, which is why it corrects the number without correcting the mechanism.
Show evidence (1 reference)
PMID:8813042 SUPPORT Human Clinical
"The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment."
PARTIAL because it documents the harm rather than the benefit - the observation that established why this treatment is a compromise.
Recombinant Human PTH(1-84)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: recombinant parathyroid hormone NCIT:C62555 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses recombinant parathyroid hormone (NCIT:C62555). NCIT:C62555 is a therapeutic agent from the NCI Thesaurus.
Replaces the hormone the receptor is suppressing, addressing one of the two limbs. Patients with CASR variants were excluded from the pivotal hypoparathyroidism trials on the reasoning that the extra renal limb would blunt the effect on urinary calcium; a later case series found that it nevertheless improved hypercalciuria relative to conventional therapy.
Mechanism Target:
RESTORES Suppressed Parathyroid Hormone Secretion — Supplies the hormone whose secretion is suppressed. It does not bind the renal receptor, so it addresses the tubular limb only through restoring PTH's own action on the distal tubule, not by correcting the receptor's sensitivity.
Show evidence (1 reference)
PMID:33112267 SUPPORT Human Clinical
"We have described three subjects with ADH1 who were treated effectively with rhPTH(1-84). In all cases, hypercalciuria improved by comparison to treatment with conventional therapy consisting of calcium supplementation and calcitriol."
The result, with its own scope stated - three subjects, compared against conventional therapy rather than against a control arm.
Palopegteriparatide
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
A long-acting PTH(1-34) prodrug giving continuous rather than pulsatile exposure. Reported in a paediatric ADH1 patient refractory to conventional therapy; the evidence base in this disease is a case report rather than a trial, and it is recorded at that strength.
Mechanism Target:
RESTORES Suppressed Parathyroid Hormone Secretion — Replaces the suppressed hormone, as rhPTH(1-84) does, but with a duration of action intended to hold calcium steady rather than to peak and fall.
Show evidence (1 reference)
PMID:42388864 SUPPORT Human Clinical
"Evidence on the use of long-acting PTH analogs in pediatric ADH1 remains scarce."
PARTIAL because the authors state the evidence base is scarce; this is a single case, and the entry does not present it as established practice.
Thiazide Diuretic
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: thiazide diuretic NCIT:C49185 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses thiazide diuretic (NCIT:C49185). NCIT:C49185 is a therapeutic agent from the NCI Thesaurus.
The adjunct that acts on the renal limb. Thiazides enhance distal tubular calcium reabsorption, which is precisely the process the over-sensitive receptor impairs, and they are singled out as being of particular benefit in activating calcium-sensing receptor mutations rather than in hypoparathyroidism generally. Its presence is the reason the calcilytic entry below is described as acting on the receptor itself rather than as the only thing reaching the kidney: a thiazide reaches the renal limb, but downstream of the lesion and without touching the set point.
Mechanism Target:
MODULATES Renal Calcium Wasting — Increases distal tubular calcium reabsorption, opposing the renal limb at its output rather than at its cause.
Show evidence (1 reference)
PMID:22863393 SUPPORT Other
"In the long-term management of hypoparathyroidism thiazide diuretics are of value as they enhance renal calcium reabsorption and increase serum calcium and are of particular benefit in those with activating mutations of the calcium-sensing receptor."
States both the mechanism and, in the same sentence, that the benefit is genotype-specific to this disease - which is why it belongs here rather than as generic hypoparathyroidism management.
Calcilytic (Negative Allosteric Modulator of the CaSR)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
The approach directed at the lesion itself: a negative allosteric modulator pushes the receptor's dose-response curve back towards normal, so it acts upstream of both limbs at once rather than on either output. The evidence has two generations and they say different things. NPSP795, in five adults over three days, raised PTH dose-dependently but did not significantly change fractional calcium excretion - proof of mechanism only. Encaleret, an oral calcilytic, was then given to 13 adults in an open-label phase 2b study and corrected hypocalcaemia and reduced hypercalciuria together, over 24 outpatient weeks. That second result is the one that matters for this entry's argument: it is the only intervention here that moves both sides of the trade-off in the same direction. It remains an open-label study of 13 patients, not a controlled trial.
Mechanism Target:
INHIBITS Left-Shifted Calcium Set Point — Acts on the shifted set point directly, which is the node no other treatment reaches.
Show evidence (5 references)
PMID:31063613 SUPPORT Human Clinical
"NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose-dependent manner, and thus, serves as proof-of-concept that calcilytics could be an effective treatment for ADH1."
PARTIAL because the authors themselves frame the result as proof of concept rather than as demonstrated efficacy.
PMID:31063613 SUPPORT Human Clinical
"Fractional excretion of calcium (FECa) trended down but not significantly so."
The negative result on the renal endpoint in the earlier compound, quoted separately so the limitation is recorded structurally rather than only in prose.
PMID:37754292 SUPPORT Human Clinical
"Encaleret corrected hypocalcemia and reduced hypercalciuria during the inpatient periods and the 24-week outpatient period."
Both endpoints moving together, which is the result no other treatment in this entry achieves and the reason the calcilytic class is described as acting upstream of both limbs.
+ 2 more references
🔬

Biochemical Markers

3
Serum ionised calcium (Decreased)
Context: The primary analyte. Ionised rather than total calcium is the meaningful measurement, since the receptor senses the ionised fraction.
Pathograph Readouts
Readout Of Hypocalcemia with Inappropriately Low PTH Negative Diagnostic
Reports the set-point shift as it appears in the circulation.
Show evidence (1 reference)
PMID:31063613 SUPPORT Human Clinical
"Blood ionized calcium levels remained stable during NPSP795 infusion despite fasting, no calcitriol supplementation, and little calcium supplementation."
Uses ionised calcium as the monitored analyte in an ADH1 study, which is the measurement this readout names.
Intact parathyroid hormone (Decreased)
Context: Interpreted only against the simultaneous calcium. A PTH within the reference range is abnormal here; the diagnosis rests on the pairing, not on either number crossing a threshold.
Pathograph Readouts
Readout Of Suppressed Parathyroid Hormone Secretion Negative Diagnostic
Reports the parathyroid limb of the receptor lesion.
Show evidence (1 reference)
PMID:31063613 SUPPORT Human Clinical
"NPSP795 increased plasma PTH levels in a concentration-dependent manner up to 129% above baseline (p = 0.013) at the highest exposure levels."
PTH used as the pharmacodynamic readout of receptor signalling in ADH1 patients, which is what makes it a readout of this node rather than only a diagnostic number.
Urinary calcium excretion (Increased)
Context: Measured as a 24-hour excretion or a calcium:creatinine ratio, and the variable that constrains treatment. It is why the therapeutic target in ADH1 is a low-normal serum calcium rather than a normal one.
Pathograph Readouts
Readout Of Renal Calcium Wasting Positive Monitoring
Reports the renal limb, and tracks whether treatment is aggravating it.
Show evidence (1 reference)
PMID:33112267 SUPPORT Human Clinical
"Case 1 was a 9.4-year-old female whose 24-h urinary calcium decreased from 7.5 to 3.9 mg/kg at 1 year."
Urinary calcium used as the monitored endpoint that determined whether the treatment change was working.
🔬

Diagnosis

2
Paired Serum Calcium and Intact PTH
The diagnostic step is not measuring either analyte but reading them together. Hypocalcaemia with a PTH that is low-normal rather than raised is the abnormality; a laboratory report that flags only out-of-range values will not flag it.
laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:8813042 SUPPORT Human Clinical
"We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor."
States the diagnostic inference explicitly - it is the combination, with a PTH inside the reference range, that points at the receptor.
CASR Sequencing
Confirms the diagnosis and distinguishes ADH1 from ADH2 (GNA11), which is biochemically similar and cannot be separated on the biochemistry alone.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35818129 SUPPORT Human Clinical
"It is caused by gain-of-function mutations in the calcium-sensing receptor gene (CASR) which affect PTH secretion from the parathyroid gland and calcium resorption in the kidney."
Identifies CASR as the gene to sequence and states both tissues in which the receptor acts.
📊

Prevalence

1
Worldwide
Point Prevalence 3.9 per 100,000 1–9 per 100,000
Reported as an estimated prevalence of 3.9 per 100,000. Best read as an estimate of diagnosed cases: mild carriers are asymptomatic and ADH1 is under-recognised because a low-normal PTH is easily read as normal.
Show evidence (1 reference)
PMID:33103030 SUPPORT Other
"ADH1 is the most common disease variant, with an estimated prevalence of 3.9 cases per 100,000"
The published prevalence estimate, stated in the paper's introduction rather than measured by the study, which is why it is graded OTHER.
🔬

Clinical Trials

1
NCT04581629 PHASE_II COMPLETED
Open-label dose-ranging study of the oral calcilytic encaleret (CLTX-305) in ADH1. This is the trial reported in the New England Journal of Medicine correspondence cited under treatments.
Target Phenotypes: Hypocalcemia HP:0002901 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Hypocalcemia (HP:0002901). HP:0002901 is a phenotype from the Human Phenotype Ontology. Hypercalciuria HP:0002150 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Hypercalciuria (HP:0002150). HP:0002150 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT04581629 SUPPORT Other
"The primary purpose of this study is to evaluate the safety, tolerability and effectiveness of encaleret in participants with Autosomal Dominant Hypocalcemia Type 1 (ADH1)."
The registry record establishing the trial's identity and its ADH1-specific population. Graded OTHER because a registration record is not itself study evidence.
🐁

Animal Models

1
Nuf mouse (Casr Leu723Gln)
A spontaneous activating Casr allele giving hypocalcaemia, used as the ADH1 model in which the calcilytic was tested alongside the human study.
Species
Mouse
Genotype
Casr Leu723Gln (Nuf), heterozygous and homozygous
Publication
PMID:33103030
Pathograph links
Left-Shifted Calcium Set Point recapitulates fidelity: high A germline activating Casr variant producing the same set-point lesion, in which pharmacological reversal of the shift can be tested directly.
Limitations: A single missense allele rather than the human allelic spectrum, so it cannot address the variability in clinical response between genotypes that the human study found. The mouse also corrected its plasma calcium on the calcilytic where the human study's calcium endpoints did not move, so the model is more responsive on that endpoint than the patients were.
Readouts
Plasma PTH response to calcilytic
Direction: RESTORED
Interpretation: A dose-dependent PTH rise on blocking the receptor shows that the suppressed secretion is actively driven by the mutant receptor rather than reflecting parathyroid failure.
Show evidence (1 reference)
PMID:33103030 SUPPORT Model Organism
"NPSP795 significantly increased plasma PTH concentrations in a dose-dependent manner with the 30 mg/kg dose causing a maximal (≥10-fold) rise in PTH."
The dose-response measurement behind this readout.
Plasma adjusted-calcium response to calcilytic
Direction: RESTORED
Interpretation: The calcium endpoint that moved in the mouse but not in the human study, which is the crux of the translational question for this compound.
Show evidence (1 reference)
PMID:33103030 SUPPORT Model Organism
"NPSP795 significantly increased plasma adjusted-calcium in Casr +/Nuf mice from 1.87 ± 0.03 mmol/L to 2.16 ± 0.06 mmol/L"
The measured calcium correction in the heterozygous mouse.
Ectopic Calcification recapitulates fidelity: moderate The allele was originally found in a screen for eye mutants, and the mouse carries lens opacities and ectopic calcification alongside the mineral abnormalities - so it reproduces the entry's deposition node as well as its set-point node.
Limitations: The mouse's ectopic calcification and cataracts were characterised as part of the strain description rather than in a study designed to ask where and why deposition occurs, so the model corroborates that the phenotype follows from receptor activation without illuminating the mechanism this entry grades PROVISIONAL.
Show evidence (1 reference)
PMID:15347804 SUPPORT Model Organism
"Nuf mice also display ectopic calcification, hypocalcemia, hyperphosphatemia, and inappropriately reduced levels of plasma parathyroid hormone."
The phenotype list establishing that this model carries the deposition phenotype and the full mineral signature.
Show evidence (1 reference)
PMID:33103030 SUPPORT Model Organism
"Nuf mice, which have hypocalcemia in association with a gain-of-function CaSR mutation, Leu723Gln"
Establishes the model's genotype and that it reproduces the hypocalcaemic phenotype.
{ }

Source YAML

click to show 
name: Autosomal Dominant Hypocalcemia 1
creation_date: "2026-08-28T16:30:00Z"
category: Mendelian
description: >-
  ADH1 is a disease of a moved set point rather than a missing protein. The
  calcium-sensing receptor is a class C G-protein-coupled receptor that reads
  extracellular ionised calcium and, when that concentration rises, both
  suppresses parathyroid hormone secretion and reduces calcium reabsorption in
  the renal tubule. A heterozygous activating variant leaves the receptor intact
  and correctly located but shifts its dose-response curve to the left, so
  calcium concentrations that a normal receptor would read as low are read as
  sufficient.

  The consequence is hypocalcaemia that the body does not defend. PTH is not
  absent - it is inappropriately low for the calcium level, which is what
  distinguishes this from parathyroid destruction or agenesis. And because the
  same over-sensitive receptor is present in the renal tubule, calcium is being
  excreted at the same time as it is being lost from the circulation. That
  second limb is what makes ADH1 clinically distinct from other
  hypoparathyroidisms: hypercalciuria is driven both by the low PTH and by the
  receptor acting directly on the tubule, so it is worse than PTH deficiency
  alone would explain.

  The therapeutic consequence follows directly and is the reason the mechanism
  is worth stating precisely. Conventional treatment - calcium plus activated
  vitamin D - raises serum calcium by pushing more calcium through a kidney that
  is already wasting it, so correcting the symptom aggravates the renal lesion
  and drives nephrocalcinosis and stones. Treatments that act on the mechanism
  rather than the number, PTH replacement and negative allosteric modulators of
  the receptor, are therefore not merely alternatives but are aimed at a
  different point in the causal chain.
disease_term:
  preferred_term: autosomal dominant hypocalcemia 1
  term:
    id: MONDO:0011013
    label: autosomal dominant hypocalcemia 1
synonyms:
- ADH1
- HYPOC1
- autosomal dominant hypocalcemia type 1
- CASR autosomal dominant hypocalcemia
- hypocalcemia, autosomal dominant 1, with Bartter syndrome
parents:
- Endocrine disorder
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single activating allele is sufficient, because the phenotype comes from
    the mutant receptor sensing calcium too well rather than from loss of the
    wild-type copy. De novo variants are common, so an absent family history
    does not argue against the diagnosis.
  evidence:
  - reference: PMID:7874174
    reference_title: Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor
      gene mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We conclude that this extracellular domain mutation increases the receptor's
      activity at low Ca2+ concentrations, causing hypocalcaemia in patients heterozygous
      for such a mutation.
    explanation: States both the dominant mechanism and that heterozygosity is sufficient.
has_subtypes:
- name: Isolated ADH1
  display_name: Isolated autosomal dominant hypocalcemia type 1
  description: >-
    The common presentation: hypocalcaemia with inappropriately low PTH and
    relative hypercalciuria, without a salt-wasting tubulopathy. Severity ranges
    from an incidental biochemical finding to seizures.
- name: Bartter type V
  display_name: ADH1 with Bartter syndrome type V
  description: >-
    A minority of activating CASR alleles additionally produce a salt-wasting
    tubulopathy with hypokalaemic metabolic alkalosis, hyperreninaemia and
    hyperaldosteronaemia. The extra limb is mechanistically explained: an
    activated receptor in the thick ascending limb inhibits the ROMK potassium
    channel, which is the channel mutated in Bartter syndrome type 2. This is
    curated as a subtype of ADH1 rather than as a separate Bartter entity,
    because the primary lesion is the same receptor.

    Nomenclature warning: the existing Bartter_Syndrome entry in this knowledge
    base carries an unrelated subtype also named Type 5, for transient antenatal
    Bartter syndrome caused by MAGED2. Both are called type 5 in the literature and
    they are different diseases with different genes. The name here is qualified as
    "ADH1 with Bartter syndrome type V" in display_name for that reason.
  evidence:
  - reference: PMID:12241879
    reference_title: Association between activating mutations of calcium-sensing receptor
      and Bartter's syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe two hypocalcaemic patients with deficient parathyroid hormone
      secretion who also showed characteristics of Bartter's syndrome. We found activating
      mutations of the gene for the calcium-sensing receptor (CASR) in both patients.
    explanation: The report establishing that activating CASR alleles can carry a Bartter
      phenotype alongside ADH1.
pathophysiology:
- name: Heterozygous CASR Gain-of-Function Variant
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    A missense variant, most often in the large extracellular domain, that makes
    the receptor easier to activate. The protein is expressed and trafficked
    normally; what changes is the calcium concentration at which it signals.
  genetic_context:
    gene:
      preferred_term: CASR
      term:
        id: hgnc:1514
        label: CASR
    functional_impact_category: GAIN_OF_FUNCTION
  molecular_functions:
  - preferred_term: calcium-sensing receptor activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0004930
      label: G protein-coupled receptor activity
  downstream:
  - target: Left-Shifted Calcium Set Point
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations
      in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Analysis of the functional expression of three of the mutant receptors in
      HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular
      calcium concentrations needed to produce half-maximal increases in total inositol
      phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required
      for the wild-type receptor.
    explanation: The direct measurement of the leftward shift in the dose-response curve,
      which is the molecular claim this node makes. Graded IN_VITRO because it is a
      heterologous expression experiment in HEK-293 cells.
- name: Left-Shifted Calcium Set Point
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The receptor now reaches half-maximal signalling at a lower extracellular
    calcium concentration than the wild-type receptor does. Every downstream
    consequence follows from this one quantitative change, in whichever tissue
    the receptor is expressed.
  biological_processes:
  - preferred_term: calcium-sensing receptor signalling
    modifier: INCREASED
    term:
      id: GO:0007186
      label: G protein-coupled receptor signaling pathway
  downstream:
  - target: Suppressed Parathyroid Hormone Secretion
    causal_link_type: DIRECT
    description: >-
      In the parathyroid chief cell, where receptor activation is the signal to
      stop secreting.
  - target: Impaired Renal Tubular Calcium Reabsorption
    causal_link_type: DIRECT
    description: >-
      In the renal tubule, where the same receptor independently reduces calcium
      reabsorption. This limb does not require the parathyroid limb.
  evidence:
  - reference: PMID:7874174
    reference_title: Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor
      gene mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Xenopus oocytes expressing the mutant receptor exhibit a larger increase in
      inositol 1,4,5-triphosphate in response to Ca2+ than oocytes expressing the wild-type
      receptor.
    explanation: The heterologous-expression measurement showing increased signalling
      output for the same calcium stimulus.
- name: Suppressed Parathyroid Hormone Secretion
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Parathyroid chief cells read the prevailing calcium as adequate and withhold
    PTH. Secretion is reduced, not abolished - measured PTH is typically
    low-normal rather than undetectable, which is precisely why the finding is
    described as inappropriate rather than absent.
  cell_types:
  - preferred_term: parathyroid chief cell
    term:
      id: CL:0000446
      label: chief cell of parathyroid gland
  biological_processes:
  - preferred_term: parathyroid hormone secretion
    modifier: DECREASED
    term:
      id: GO:0035898
      label: parathyroid hormone secretion
  downstream:
  - target: Hypocalcemia with Inappropriately Low PTH
    causal_link_type: DIRECT
  - target: Renal Calcium Wasting
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of PTH removes the hormone's own stimulus to distal tubular calcium
      reabsorption. This is the limb ADH1 shares with every other
      hypoparathyroidism.
  - target: Hyperphosphatemia
    causal_link_type: DIRECT
    description: >-
      PTH is phosphaturic, so withholding it raises serum phosphate.
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: which reduces PTH secretion from parathyroid cells despite low serum calcium
      levels
    explanation: States the parathyroid limb explicitly, including that it operates despite
      low serum calcium.
- name: Impaired Renal Tubular Calcium Reabsorption
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    The over-sensitive receptor in the renal tubule reduces calcium reabsorption
    directly. This is the limb that separates ADH1 from other causes of
    hypoparathyroidism, and it is why raising the filtered calcium load makes the
    renal picture worse rather than better.

    A route from the receptor to the transport defect has been traced.
    Claudin-14 is a negative regulator of the paracellular calcium pathway in the
    thick ascending limb, held in check by miR-9 and miR-374. ADH1 receptor
    variants repress transcription of those two microRNAs, which lifts the brake
    on claudin-14 and closes the paracellular route. The step is evidenced in
    cell and animal models rather than in patients, and is recorded here at that
    strength.
  biological_processes:
  - preferred_term: renal tubular calcium ion transport
    modifier: DECREASED
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
  genes:
  - preferred_term: CLDN14
    term:
      id: hgnc:2035
      label: CLDN14
  downstream:
  - target: Renal Calcium Wasting
    causal_link_type: DIRECT
  - target: Impaired Vasopressin-Dependent Water Reabsorption
    causal_link_type: DIRECT
    description: >-
      The same receptor is expressed in the collecting duct, where its activation
      opposes vasopressin action. This is a second renal consequence, parallel to
      the calcium one rather than downstream of it.
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the presence of CaSRs with increased sensitivity to calcium in the renal tubule
      also impairs reabsorption of calcium
    explanation: The renal limb stated as a mechanism independent of the parathyroid limb.
  - reference: PMID:37754292
    reference_title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia
      Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Gain-of-function CASR variants increase the sensitivity of the CaSR to extracellular
      calcium, reducing PTH secretion and renal calcium reabsorption and resulting in hypocalcemia,
      hyperphosphatemia, hypomagnesemia, and hypercalciuria.
    explanation: States both limbs and, importantly, names hypomagnesaemia among the
      cardinal biochemical consequences rather than as a Bartter-subtype feature.
  - reference: PMID:25071082
    reference_title: Epigenetic regulation of microRNAs controlling CLDN14 expression as
      a mechanism for renal calcium handling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The genetic mutations in the calcium-sensing receptor from patients with autosomal
      dominant hypocalcemia (ADH) repressed the transcription of miR-9 and miR-374 genes,
      and treatment with an HDAC inhibitor rescued the phenotypes of cell and animal models
      of ADH.
    explanation: The claudin-14 route stated for ADH variants specifically, with a
      pharmacological rescue in cell and animal models. This is the citation for the CLDN14
      descriptor on this node; the descriptor was previously carried on the strength of a
      deep-research lead alone, which PR review correctly flagged.
  - reference: PMID:25071082
    reference_title: Epigenetic regulation of microRNAs controlling CLDN14 expression as
      a mechanism for renal calcium handling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: miR-9 and miR-374 genes, which have been shown to repress the expression of
      claudin-14, the negative regulator of the paracellular pathway
    explanation: Establishes claudin-14's role as the brake on paracellular calcium
      reabsorption and the microRNAs that hold it, which is the intermediate step between
      the receptor and the transport defect.
- name: Impaired Vasopressin-Dependent Water Reabsorption
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Receptor activation in the collecting duct opposes vasopressin by driving down
    aquaporin-2. In a CaSR knock-in mouse modelling this disease the route was
    traced - less total AQP2, more AQP2 phosphorylated at the degradation site
    Ser261, higher phosphorylated p38MAPK and ATF1 upstream of it, and more of the
    AQP2-targeting miR-137 - and a calcilytic reversed it. This is the mechanism
    behind the urinary concentrating defect and the polyuria of the Bartter-type-V
    presentation. PROVISIONAL because the chain is established in the mouse and
    has not been demonstrated in patients.
  genes:
  - preferred_term: AQP2
    term:
      id: hgnc:634
      label: AQP2
  biological_processes:
  - preferred_term: renal water homeostasis
    modifier: DECREASED
    term:
      id: GO:0003091
      label: renal water homeostasis
  evidence:
  - reference: PMID:38367250
    reference_title: In vivo treatment with calcilytic of CaSR knock-in mice ameliorates
      renal phenotype reversing downregulation of the vasopressin-AQP2 pathway.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we provide evidence that, with respect to wild-type mice, CaSR knock-in (KI)
      mice mimicking autosomal dominant hypocalcaemia, display a significant decrease in
      the total content of AQP2 associated with significantly higher levels of AQP2 phosphorylation
      at Ser261, a phosphorylation site involved in AQP2 degradation.
    explanation: The measured AQP2 defect in a knock-in mouse built to model this disease.
  - reference: PMID:38367250
    reference_title: In vivo treatment with calcilytic of CaSR knock-in mice ameliorates
      renal phenotype reversing downregulation of the vasopressin-AQP2 pathway.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In vivo treatment of KI mice with the calcilytic JTT-305, a CaSR antagonist,
      increased AQP2 expression and reduced AQP2-targeting miRNA137 levels in KI mice.
    explanation: The pharmacological reversal, which is what attributes the AQP2 defect to
      receptor activity rather than to the hypocalcaemia it accompanies.
- name: Hypocalcemia with Inappropriately Low PTH
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The defining biochemical signature. The pairing matters more than either
    number: hypocalcaemia with a PTH that is merely low-normal is the finding
    that points at the receptor rather than at the gland.
  downstream:
  - target: Neuromuscular Irritability
    causal_link_type: DIRECT
  - target: Ectopic Calcification
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Chronic hypocalcaemia with hyperphosphataemia is associated with
      intracranial calcification, but the step from the disturbed
      calcium-phosphate product to deposition at specific sites is not resolved.
  evidence:
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic
      NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals are hypocalcemic with inappropriately low parathyroid hormone
      (PTH) secretion and relative hypercalciuria.
    explanation: The three-part biochemical signature stated compactly in a clinical study
      of ADH1 patients.
- name: Renal Calcium Wasting
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Urinary calcium excretion is high relative to a serum calcium that is already
    low. Two independent inputs converge here - the absent PTH signal and the
    tubular receptor - which is why the hypercalciuria of ADH1 exceeds that of
    other hypoparathyroidisms and why it is hard to treat.
  downstream:
  - target: Ectopic Calcification
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Sustained hypercalciuria supersaturates the tubular fluid, giving
      nephrocalcinosis and stones.
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The combination of both loss of PTH and gain of CaSR activity provides a dual
      mechanism for hypercalciuria in ADH1
    explanation: Names the convergence of the two upstream limbs on this node, which is
      the reason this entry models them separately.
- name: Hyperphosphatemia
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Raised serum phosphate, the expected consequence of withdrawing a phosphaturic
    hormone.
  evidence:
  - reference: PMID:37754292
    reference_title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia
      Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mean blood levels of intact PTH, magnesium, and 1,25-dihydroxy-vitamin D increased,
      whereas phosphorus levels and tubular reabsorption of phosphate decreased
    explanation: The phosphate response to restoring PTH, which demonstrates the phosphate
      elevation is PTH-dependent rather than incidental.
- name: Neuromuscular Irritability
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Reduced ionised calcium lowers the threshold for nerve and muscle
    depolarisation, giving paraesthesiae, carpopedal spasm, tetany and seizures.
    Severity is not simply a function of how low the calcium is: in one kindred
    four of seven affected members were symptomatic and the symptoms were
    explicitly unrelated to the degree of hypocalcaemia.
  evidence:
  - reference: PMID:22863393
    reference_title: Hypoparathyroidism.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Although hypocalcemic patients commonly present with symptoms of neuromuscular
      irritability with perioral numbers paresthesias, tingling, seizures and, bronchospasm;
      hypocalcemia may be identified on the biochemical profile of an asymptomatic patient.
    explanation: Names the syndrome and its manifestations, and records that it may be
      absent altogether. The source's typo "numbers" for "numbness" is reproduced as
      published.
  - reference: PMID:16128246
    reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria
      (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four of seven affected individuals were symptomatic (seizures, abdominal pains
      and paraesthesias), unrelated to severity of hypocalcaemia.
    explanation: The observation that symptom burden does not track calcium level, measured
      within a single kindred carrying one variant.
- name: Ectopic Calcification
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Deposition of calcium salts outside bone - in the renal medulla as
    nephrocalcinosis and stones, and intracranially in the basal ganglia and
    cerebral cortex. PROVISIONAL because the renal and intracranial deposits do
    not share a single established mechanism: the renal deposits follow directly
    from supersaturated tubular fluid, while the intracranial ones accompany
    chronic hypocalcaemia and hyperphosphataemia without a resolved pathway, and
    conventional treatment contributes to the renal component.
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: As a result, nephrocalcinosis and nephrolithiasis are more common in subjects
      with ADH1 than other forms of hypoparathyroidism
    explanation: Ties the renal deposits specifically to ADH1's extra renal limb rather
      than to hypoparathyroidism in general.
phenotypes:
- category: Biochemical
  name: Hypocalcemia
  frequency: OBLIGATE
  description: >-
    Low serum and ionised calcium, the finding that defines the disease. It may
    be an incidental result or may present with seizures.
  phenotype_term:
    preferred_term: Hypocalcemia
    term:
      id: HP:0002901
      label: Hypocalcemia
  evidence:
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic
      NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individuals are hypocalcemic with inappropriately low parathyroid hormone
      (PTH) secretion and relative hypercalciuria.
    explanation: States hypocalcaemia as a defining feature of the ADH1 cohort studied.
- category: Endocrine
  name: Hypoparathyroidism
  frequency: OBLIGATE
  description: >-
    PTH that is low or low-normal in the face of hypocalcaemia. ADH1 is described
    as the most common genetic cause of isolated hypoparathyroidism.
  phenotype_term:
    preferred_term: Hypoparathyroidism
    term:
      id: HP:0000829
      label: Hypoparathyroidism
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia
      Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism.
    explanation: Establishes the hypoparathyroid phenotype and ADH1's place among its
      genetic causes.
- category: Renal
  name: Hypercalciuria
  frequency: VERY_FREQUENT
  description: >-
    Urinary calcium excretion inappropriately high for the serum calcium. It is
    the phenotype that most distinguishes ADH1 from other hypoparathyroidisms and
    the one conventional treatment worsens.
  phenotype_term:
    preferred_term: Hypercalciuria
    term:
      id: HP:0002150
      label: Hypercalciuria
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Subjects have increased calcium sensitivity in the renal tubule, leading to
      increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared
      with other causes of hypoparathyroidism.
    explanation: States the phenotype and, importantly, that it exceeds that of other
      hypoparathyroidisms.
- category: Renal
  name: Nephrocalcinosis
  frequency: FREQUENT
  description: >-
    Medullary calcium deposition, which may be present before substantial
    treatment exposure and is typically stable rather than reversible once
    established.
  phenotype_term:
    preferred_term: Nephrocalcinosis
    term:
      id: HP:0000121
      label: Nephrocalcinosis
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Her renal ultrasound at two months of age demonstrated nephrocalcinosis.
    explanation: A directly observed case finding, present in early infancy and therefore
      before prolonged treatment exposure.
  - reference: PMID:16128246
    reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria
      (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additional complications include nephrocalcinosis (n = 3) and basal ganglia
      calcification, identified by CT scanning in all five individuals.
    explanation: A denominator rather than a single case - three of seven affected members
      of one kindred. This is what the FREQUENT grading rests on; the case observation above
      establishes only that the phenotype occurs.
  - reference: PMID:33599907
    reference_title: "Renal complications in patients with chronic hypoparathyroidism on conventional therapy: a systematic literature review : Renal disease in chronic hypoparathyroidism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The rate of nephrocalcinosis was up to 38%.
    explanation: PARTIAL because the systematic review covers chronic hypoparathyroidism on
      conventional therapy generally, not ADH1 - so it bounds the rate in a population that
      includes but is broader than this disease.
- category: Renal
  name: Nephrolithiasis
  frequency: OCCASIONAL
  description: >-
    Recurrent renal stones, reported in the more severely hypercalciuric patients
    and requiring intervention.
  phenotype_term:
    preferred_term: Nephrolithiasis
    term:
      id: HP:0000787
      label: Nephrolithiasis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: he continued to have marked hypercalciuria, and he developed multiple, recurrent
      renal stones. He underwent lithotripsy at the age of 2 years
    explanation: Documents stones as a clinical course in an ADH1 patient, with the
      intervention they required.
  - reference: PMID:33599907
    reference_title: "Renal complications in patients with chronic hypoparathyroidism on conventional therapy: a systematic literature review : Renal disease in chronic hypoparathyroidism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The reported rate of nephrolithiasis was up to 36%, with the lowest rates in
      studies reporting shorter duration of disease.
    explanation: PARTIAL for population - chronic hypoparathyroidism on conventional therapy
      rather than ADH1 specifically. The duration dependence in the same sentence is the
      reason this phenotype carries a PROGRESSIVE clinical_course.
- category: Neurologic
  name: Seizures
  frequency: FREQUENT
  description: >-
    Hypocalcaemic seizures, which may be the presenting event in infancy and can
    be mistaken for primary epilepsy when the calcium is not measured.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    temporality: RECURRENT
  evidence:
  - reference: PMID:35818129
    reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case
      study and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe a case who presented with symptoms of recurrent seizure
      caused by hypocalcemia with a novel CASR variant.
    explanation: Seizure as the presenting manifestation, attributed to the hypocalcaemia.
- category: Neurologic
  name: Tetany
  frequency: FREQUENT
  description: >-
    Carpopedal spasm and involuntary muscle contraction, reported as episodic and
    disabling in poorly controlled patients.
  phenotype_term:
    preferred_term: Tetany
    term:
      id: HP:0001281
      label: Tetany
    temporality: RECURRENT
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She also experienced frequent episodes of tetany, manifesting as an inability
      to walk.
    explanation: A directly observed clinical description of tetany and its functional
      impact.
- category: Neurologic
  name: Intracranial Calcification
  frequency: FREQUENT
  description: >-
    Calcification of the basal ganglia and cortex, described as progressive on
    serial imaging.
  phenotype_term:
    preferred_term: Basal ganglia calcification
    term:
      id: HP:0002135
      label: Basal ganglia calcification
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:35818129
    reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case
      study and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Computed tomography of the brain revealed multiple intracranial calcifications,
      and electroencephalography showed extensive epileptic discharges.
    explanation: Imaging documentation of the intracranial deposits in a genetically
      confirmed patient.
  - reference: PMID:16128246
    reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria
      (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: basal ganglia calcification, identified by CT scanning in all five individuals
    explanation: Present in every scanned member of the kindred, which is why this phenotype
      is graded FREQUENT rather than OCCASIONAL. Note the denominator is those who were
      imaged, not all affected members - so this is a yield in scanned patients, not a
      population frequency.
- category: Biochemical
  name: Hyperphosphatemia
  frequency: FREQUENT
  description: >-
    Raised serum phosphate accompanying the low PTH, part of the standard
    hypoparathyroid biochemistry.
  phenotype_term:
    preferred_term: Hyperphosphatemia
    term:
      id: HP:0002905
      label: Hyperphosphatemia
  evidence:
  - reference: PMID:35818129
    reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case
      study and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypocalcemia, hyperphospheremia, and hypoparathyroidism were clearly evident,
      and brain computed tomography showed multiple intracranial calcifications
    explanation: The biochemical triad as measured in the reported patient. The source
      spells the finding "hyperphospheremia"; the quote is reproduced as published.
- category: Biochemical
  name: Hypomagnesemia
  frequency: FREQUENT
  description: >-
    Low serum magnesium. This is cardinal ADH1 biochemistry rather than a
    Bartter-subtype feature - the receptor regulates renal magnesium as well as
    calcium reabsorption, and it is documented in an unselected kindred alongside
    the calcium and PTH findings.
  phenotype_term:
    preferred_term: Hypomagnesemia
    term:
      id: HP:0002917
      label: Hypomagnesemia
  evidence:
  - reference: PMID:16128246
    reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria
      (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Affected members had hypocalcaemia (1.53-1.85 mmol/l), hypercalciuria, low but
      detectable parathyroid hormone (PTH) and hypomagnesaemia.
    explanation: The full biochemical signature in a seven-member kindred, including
      magnesium and including the observation that PTH is low but detectable.
  - reference: PMID:37754292
    reference_title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia
      Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The CaSR primarily regulates parathyroid hormone (PTH) secretion and renal calcium
      and magnesium reabsorption.
    explanation: The mechanistic basis - magnesium is handled by the same receptor, so its
      loss is expected rather than incidental.
- category: Neurologic
  name: Paresthesia
  frequency: FREQUENT
  description: >-
    Perioral numbness, tingling and paraesthesiae, often the earliest symptom and
    the one that brings a patient to attention before a seizure does.
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
  evidence:
  - reference: PMID:16128246
    reference_title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria
      (ADHH): mutational analysis, phenotypic variability and treatment challenges.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four of seven affected individuals were symptomatic (seizures, abdominal pains
      and paraesthesias), unrelated to severity of hypocalcaemia.
    explanation: Paraesthesia among the symptoms in a kindred, with a denominator.
- category: Renal
  name: Chronic Kidney Disease
  frequency: OCCASIONAL
  description: >-
    Declining renal function, the dominant long-term morbidity and the endpoint the
    treatment trade-off is managed to avoid. It is the reason the target serum
    calcium in this disease is deliberately sub-normal.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations
      in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis,
      and renal impairment
    explanation: Renal impairment observed in the original ADH1 kindreds, and attributed
      there to the treatment rather than only to the disease.
  - reference: PMID:33599907
    reference_title: "Renal complications in patients with chronic hypoparathyroidism on conventional therapy: a systematic literature review : Renal disease in chronic hypoparathyroidism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A systematic literature review was performed to summarize the frequency and
      nature of renal complications in patients with chronic hypoparathyroidism managed with
      conventional therapy.
    explanation: PARTIAL because the review's population is chronic hypoparathyroidism on
      conventional therapy rather than ADH1. It is cited to establish that renal complications
      are a recognised systematic burden of this management, not to supply an ADH1 rate.
- category: Ophthalmologic
  name: Cataract
  frequency: OCCASIONAL
  description: >-
    Lens opacity, a recognised consequence of long-standing hypocalcaemia.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:35818129
    reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case
      study and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was diagnosed with congenital cataracts at the age of 14 years.
    explanation: An observed cataract in an ADH1 patient with long-standing poorly
      controlled hypocalcaemia.
- category: Renal
  name: Hypokalemia
  frequency: OCCASIONAL
  subtype: Bartter type V
  description: >-
    Part of the salt-wasting tubulopathy seen with the Bartter-type-V alleles,
    alongside hypomagnesaemia and polyuria.
  phenotype_term:
    preferred_term: Hypokalemia
    term:
      id: HP:0002900
      label: Hypokalemia
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: which accounted not only for his ADH1 but also type 5 Bartter syndrome with
      persistent hypokalemia, hypomagnesemia, and polyuria
    explanation: An observed Bartter-type-V presentation in a genetically confirmed ADH1
      patient, which is why this phenotype is tagged to that subtype.
genetic:
- name: CASR
  gene_term:
    preferred_term: CASR
    term:
      id: hgnc:1514
      label: CASR
  relationship_type: CAUSATIVE
  notes: >-
    The variants are typically heterozygous missense and clustered in the large
    extracellular domain, though transmembrane-domain variants also occur. Two
    things about the genotype-phenotype relationship are worth recording.
    Severity varies widely between carriers, so the variant does not by itself
    predict the clinical picture. And in the one study that tested it directly,
    the in vitro degree of receptor activation did not predict the clinical
    response to a calcilytic - so "activating" functions here as a qualitative
    classification, not a quantitative one that can be read off into a
    prediction.

    CASR is also one of the clearer allelic series in medicine, and reading ADH1
    against it is what makes "gain of function" mean something concrete here:
    heterozygous loss of function gives familial hypocalciuric hypercalcaemia,
    homozygous loss of function gives neonatal severe hyperparathyroidism, and
    heterozygous gain of function gives this disease. The same receptor, dosed in
    four directions.
  evidence:
  - reference: PMID:20374733
    reference_title: Calcium-sensing receptor and associated diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Heterozygous loss-of-function mutations cause familial (benign) hypocalciuric
      hypercalcemia (FHH) in which the lifelong mild hypercalcemia is generally asymptomatic.
      Homozygous inactivating mutations give rise to neonatal severe hyperparathyroidism
      (NSHPT) with extreme hypercalcemia and marked skeletal changes. Heterozygous activating
      mutations of the CASR cause autosomal dominant hypocalcemia (ADH) that may be asymptomatic
      or present with seizures in the neonatal period or childhood or later in life.
    explanation: The full allelic series in one passage, which is what places ADH1 at the
      gain-of-function end of a graded dosage relationship rather than treating it as an
      isolated phenotype.
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations
      in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys,
      and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor
      gene and shown to cosegregate with the disease.
    explanation: Establishes the allelic spectrum and its cosegregation across six kindreds.
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic
      NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There was significant variability in response clinically across genotypes.
    explanation: PARTIAL because it supports only the second half of the note - variability
      across genotypes - and speaks to drug response rather than to disease severity.
  - reference: PMID:11013439
    reference_title: 'Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric
      hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A common polymorphism in the intracellular tail of the CASR, Ala to Ser at position
      986, has a modest effect on the serum calcium concentration in healthy individuals.
    explanation: The A986S modifier polymorphism, which shifts calcium even in unaffected
      people and is therefore a plausible contributor to the variability this note records.
  - reference: PMID:27617113
    reference_title: Novel Mutation in the CASR Gene (p.Leu123Ser) in a Case of Autosomal
      Dominant Hypocalcemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sequencing analysis in the mother suggested mosaicism for the same variant, and
      she was clinically and biochemically unaffected.
    explanation: A clinically and biochemically normal parent mosaic for the proband's
      variant - the concrete case behind the inheritance block's claim that an absent family
      history does not argue against the diagnosis, and a warning that parental testing can
      mislead.
biochemical:
- name: Serum ionised calcium
  presence: Decreased
  context: >-
    The primary analyte. Ionised rather than total calcium is the meaningful
    measurement, since the receptor senses the ionised fraction.
  biomarker_term:
    preferred_term: calcium(2+)
    term:
      id: CHEBI:29108
      label: calcium(2+)
  readouts:
  - target: Hypocalcemia with Inappropriately Low PTH
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reports the set-point shift as it appears in the circulation.
    evidence:
    - reference: PMID:31063613
      reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic
        NPSP795 (SHP635).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Blood ionized calcium levels remained stable during NPSP795 infusion despite
        fasting, no calcitriol supplementation, and little calcium supplementation.
      explanation: Uses ionised calcium as the monitored analyte in an ADH1 study, which
        is the measurement this readout names.
- name: Intact parathyroid hormone
  presence: Decreased
  context: >-
    Interpreted only against the simultaneous calcium. A PTH within the reference
    range is abnormal here; the diagnosis rests on the pairing, not on either
    number crossing a threshold.
  biomarker_term:
    preferred_term: Parathyroid Hormone
    term:
      id: NCIT:C41027
      label: Parathyroid Hormone
  readouts:
  - target: Suppressed Parathyroid Hormone Secretion
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reports the parathyroid limb of the receptor lesion.
    evidence:
    - reference: PMID:31063613
      reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic
        NPSP795 (SHP635).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: NPSP795 increased plasma PTH levels in a concentration-dependent manner
        up to 129% above baseline (p = 0.013) at the highest exposure levels.
      explanation: PTH used as the pharmacodynamic readout of receptor signalling in ADH1
        patients, which is what makes it a readout of this node rather than only a
        diagnostic number.
- name: Urinary calcium excretion
  presence: Increased
  context: >-
    Measured as a 24-hour excretion or a calcium:creatinine ratio, and the
    variable that constrains treatment. It is why the therapeutic target in ADH1
    is a low-normal serum calcium rather than a normal one.
  biomarker_term:
    preferred_term: calcium(2+)
    term:
      id: CHEBI:29108
      label: calcium(2+)
  readouts:
  - target: Renal Calcium Wasting
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: Reports the renal limb, and tracks whether treatment is aggravating it.
    evidence:
    - reference: PMID:33112267
      reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
        hypoparathyroidism.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Case 1 was a 9.4-year-old female whose 24-h urinary calcium decreased from
        7.5 to 3.9 mg/kg at 1 year.
      explanation: Urinary calcium used as the monitored endpoint that determined whether
        the treatment change was working.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 3.9
  notes: >-
    Reported as an estimated prevalence of 3.9 per 100,000. Best read as an
    estimate of diagnosed cases: mild carriers are asymptomatic and ADH1 is
    under-recognised because a low-normal PTH is easily read as normal.
  evidence:
  - reference: PMID:33103030
    reference_title: Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal
      Dominant Hypocalcemia Type 1 Mouse Model.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ADH1 is the most common disease variant, with an estimated prevalence of 3.9
      cases per 100,000
    explanation: The published prevalence estimate, stated in the paper's introduction
      rather than measured by the study, which is why it is graded OTHER.
diagnosis:
- name: Paired Serum Calcium and Intact PTH
  description: >-
    The diagnostic step is not measuring either analyte but reading them
    together. Hypocalcaemia with a PTH that is low-normal rather than raised is
    the abnormality; a laboratory report that flags only out-of-range values will
    not flag it.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations
      in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism
      on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations,
      a combination that suggested a defect of the calcium-sensing receptor.
    explanation: States the diagnostic inference explicitly - it is the combination, with
      a PTH inside the reference range, that points at the receptor.
- name: CASR Sequencing
  description: >-
    Confirms the diagnosis and distinguishes ADH1 from ADH2 (GNA11), which is
    biochemically similar and cannot be separated on the biochemistry alone.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:35818129
    reference_title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case
      study and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It is caused by gain-of-function mutations in the calcium-sensing receptor
      gene (CASR) which affect PTH secretion from the parathyroid gland and calcium resorption
      in the kidney.
    explanation: Identifies CASR as the gene to sequence and states both tissues in which
      the receptor acts.
treatments:
- name: Calcitriol and Calcium Supplementation
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    The conventional treatment, and the one whose limitation defines the field.
    It raises serum calcium without touching the receptor, so it drives more
    calcium through a tubule that is already wasting it. Guidelines still
    recommend it, and the practical aim is a low-normal serum calcium that
    relieves symptoms rather than a normal one.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcitriol
      term:
        id: CHEBI:17823
        label: calcitriol
  target_mechanisms:
  - target: Hypocalcemia with Inappropriately Low PTH
    treatment_effect: BYPASSES
    description: >-
      Raises serum calcium by a route that does not involve PTH or the receptor,
      which is why it corrects the number without correcting the mechanism.
  evidence:
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations
      in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The hypocalcemia was associated with hypercalciuria, and treatment with vitamin
      D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment.
    explanation: PARTIAL because it documents the harm rather than the benefit - the
      observation that established why this treatment is a compromise.
- name: Recombinant Human PTH(1-84)
  therapeutic_modality: PEPTIDE
  description: >-
    Replaces the hormone the receptor is suppressing, addressing one of the two
    limbs. Patients with CASR variants were excluded from the pivotal
    hypoparathyroidism trials on the reasoning that the extra renal limb would
    blunt the effect on urinary calcium; a later case series found that it
    nevertheless improved hypercalciuria relative to conventional therapy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: recombinant parathyroid hormone
      term:
        id: NCIT:C62555
        label: Recombinant Parathyroid Hormone
  target_mechanisms:
  - target: Suppressed Parathyroid Hormone Secretion
    treatment_effect: RESTORES
    description: >-
      Supplies the hormone whose secretion is suppressed. It does not bind the
      renal receptor, so it addresses the tubular limb only through restoring PTH's
      own action on the distal tubule, not by correcting the receptor's
      sensitivity.
  evidence:
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We have described three subjects with ADH1 who were treated effectively with
      rhPTH(1-84). In all cases, hypercalciuria improved by comparison to treatment with
      conventional therapy consisting of calcium supplementation and calcitriol.
    explanation: The result, with its own scope stated - three subjects, compared against
      conventional therapy rather than against a control arm.
- name: Palopegteriparatide
  therapeutic_modality: PEPTIDE
  description: >-
    A long-acting PTH(1-34) prodrug giving continuous rather than pulsatile
    exposure. Reported in a paediatric ADH1 patient refractory to conventional
    therapy; the evidence base in this disease is a case report rather than a
    trial, and it is recorded at that strength.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Suppressed Parathyroid Hormone Secretion
    treatment_effect: RESTORES
    description: >-
      Replaces the suppressed hormone, as rhPTH(1-84) does, but with a duration of
      action intended to hold calcium steady rather than to peak and fall.
  evidence:
  - reference: PMID:42388864
    reference_title: 'Case Report: Palopegteriparatide as a novel therapeutic option in pediatric
      autosomal dominant hypocalcemia type 1.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Evidence on the use of long-acting PTH analogs in pediatric ADH1 remains scarce.
    explanation: PARTIAL because the authors state the evidence base is scarce; this is a
      single case, and the entry does not present it as established practice.
- name: Thiazide Diuretic
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    The adjunct that acts on the renal limb. Thiazides enhance distal tubular
    calcium reabsorption, which is precisely the process the over-sensitive
    receptor impairs, and they are singled out as being of particular benefit in
    activating calcium-sensing receptor mutations rather than in
    hypoparathyroidism generally.

    Its presence is the reason the calcilytic entry below is described as acting
    on the receptor itself rather than as the only thing reaching the kidney: a
    thiazide reaches the renal limb, but downstream of the lesion and without
    touching the set point.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: thiazide diuretic
      term:
        id: NCIT:C49185
        label: Thiazide Diuretic
  target_mechanisms:
  - target: Renal Calcium Wasting
    treatment_effect: MODULATES
    description: >-
      Increases distal tubular calcium reabsorption, opposing the renal limb at its
      output rather than at its cause.
  evidence:
  - reference: PMID:22863393
    reference_title: Hypoparathyroidism.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In the long-term management of hypoparathyroidism thiazide diuretics are of value
      as they enhance renal calcium reabsorption and increase serum calcium and are of particular
      benefit in those with activating mutations of the calcium-sensing receptor.
    explanation: States both the mechanism and, in the same sentence, that the benefit is
      genotype-specific to this disease - which is why it belongs here rather than as generic
      hypoparathyroidism management.
- name: Calcilytic (Negative Allosteric Modulator of the CaSR)
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    The approach directed at the lesion itself: a negative allosteric modulator
    pushes the receptor's dose-response curve back towards normal, so it acts
    upstream of both limbs at once rather than on either output.

    The evidence has two generations and they say different things. NPSP795, in
    five adults over three days, raised PTH dose-dependently but did not
    significantly change fractional calcium excretion - proof of mechanism only.
    Encaleret, an oral calcilytic, was then given to 13 adults in an open-label
    phase 2b study and corrected hypocalcaemia and reduced hypercalciuria
    together, over 24 outpatient weeks. That second result is the one that matters
    for this entry's argument: it is the only intervention here that moves both
    sides of the trade-off in the same direction. It remains an open-label study
    of 13 patients, not a controlled trial.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Left-Shifted Calcium Set Point
    treatment_effect: INHIBITS
    description: >-
      Acts on the shifted set point directly, which is the node no other
      treatment reaches.
  evidence:
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic
      NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: NPSP795 increased plasma PTH levels in subjects with ADH1 in a dose-dependent
      manner, and thus, serves as proof-of-concept that calcilytics could be an effective
      treatment for ADH1.
    explanation: PARTIAL because the authors themselves frame the result as proof of
      concept rather than as demonstrated efficacy.
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic
      NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fractional excretion of calcium (FECa) trended down but not significantly so.
    explanation: The negative result on the renal endpoint in the earlier compound, quoted
      separately so the limitation is recorded structurally rather than only in prose.
  - reference: PMID:37754292
    reference_title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia
      Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Encaleret corrected hypocalcemia and reduced hypercalciuria during the inpatient
      periods and the 24-week outpatient period.
    explanation: Both endpoints moving together, which is the result no other treatment in
      this entry achieves and the reason the calcilytic class is described as acting upstream
      of both limbs.
  - reference: PMID:37754292
    reference_title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia
      Type 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In our study, encaleret appeared to restore physiologic mineral homeostasis in
      13 participants with ADH1. This molecularly targeted approach, pending further studies,
      may establish calcilytics as a potential treatment for ADH1.
    explanation: PARTIAL because the authors' own conclusion is hedged to a 13-participant
      open-label study pending further work, and this entry does not upgrade it.
  - reference: PMID:40086735
    reference_title: Characterization of quinazolinone calcilytic therapy for autosomal
      dominant hypocalcemia type 1 (ADH1).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: were shown to bind at a common region within the CaSR transmembrane domain,
      which is also an ADH1 mutational hotspot
    explanation: Locates the drug-binding site on the receptor and notes it coincides with
      where ADH1 variants cluster - the structural reason this class acts on the lesion
      rather than around it.
clinical_trials:
- name: NCT04581629
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Open-label dose-ranging study of the oral calcilytic encaleret (CLTX-305) in
    ADH1. This is the trial reported in the New England Journal of Medicine
    correspondence cited under treatments.
  target_phenotypes:
  - preferred_term: Hypocalcemia
    term:
      id: HP:0002901
      label: Hypocalcemia
  - preferred_term: Hypercalciuria
    term:
      id: HP:0002150
      label: Hypercalciuria
  evidence:
  - reference: clinicaltrials:NCT04581629
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The primary purpose of this study is to evaluate the safety, tolerability and
      effectiveness of encaleret in participants with Autosomal Dominant Hypocalcemia Type
      1 (ADH1).
    explanation: The registry record establishing the trial's identity and its ADH1-specific
      population. Graded OTHER because a registration record is not itself study evidence.
animal_models:
- name: Nuf mouse (Casr Leu723Gln)
  species: Mouse
  genotype: Casr Leu723Gln (Nuf), heterozygous and homozygous
  publication: PMID:33103030
  description: >-
    A spontaneous activating Casr allele giving hypocalcaemia, used as the ADH1
    model in which the calcilytic was tested alongside the human study.
  modeled_mechanisms:
  - target: Left-Shifted Calcium Set Point
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      A germline activating Casr variant producing the same set-point lesion, in
      which pharmacological reversal of the shift can be tested directly.
    limitations: >-
      A single missense allele rather than the human allelic spectrum, so it
      cannot address the variability in clinical response between genotypes that
      the human study found. The mouse also corrected its plasma calcium on the
      calcilytic where the human study's calcium endpoints did not move, so the
      model is more responsive on that endpoint than the patients were.
    readouts:
    - name: Plasma PTH response to calcilytic
      target: Left-Shifted Calcium Set Point
      direction: RESTORED
      interpretation: >-
        A dose-dependent PTH rise on blocking the receptor shows that the
        suppressed secretion is actively driven by the mutant receptor rather
        than reflecting parathyroid failure.
      evidence:
      - reference: PMID:33103030
        reference_title: Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal
          Dominant Hypocalcemia Type 1 Mouse Model.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: NPSP795 significantly increased plasma PTH concentrations in a dose-dependent
          manner with the 30 mg/kg dose causing a maximal (≥10-fold) rise in PTH.
        explanation: The dose-response measurement behind this readout.
    - name: Plasma adjusted-calcium response to calcilytic
      target: Left-Shifted Calcium Set Point
      direction: RESTORED
      interpretation: >-
        The calcium endpoint that moved in the mouse but not in the human study,
        which is the crux of the translational question for this compound.
      evidence:
      - reference: PMID:33103030
        reference_title: Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal
          Dominant Hypocalcemia Type 1 Mouse Model.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: NPSP795 significantly increased plasma adjusted-calcium in Casr +/Nuf
          mice from 1.87 ± 0.03 mmol/L to 2.16 ± 0.06 mmol/L
        explanation: The measured calcium correction in the heterozygous mouse.
  - target: Ectopic Calcification
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The allele was originally found in a screen for eye mutants, and the mouse
      carries lens opacities and ectopic calcification alongside the mineral
      abnormalities - so it reproduces the entry's deposition node as well as its
      set-point node.
    limitations: >-
      The mouse's ectopic calcification and cataracts were characterised as part of
      the strain description rather than in a study designed to ask where and why
      deposition occurs, so the model corroborates that the phenotype follows from
      receptor activation without illuminating the mechanism this entry grades
      PROVISIONAL.
    evidence:
    - reference: PMID:15347804
      reference_title: Activating calcium-sensing receptor mutation in the mouse is associated
        with cataracts and ectopic calcification.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Nuf mice also display ectopic calcification, hypocalcemia, hyperphosphatemia,
        and inappropriately reduced levels of plasma parathyroid hormone.
      explanation: The phenotype list establishing that this model carries the deposition
        phenotype and the full mineral signature.
  evidence:
  - reference: PMID:33103030
    reference_title: Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal
      Dominant Hypocalcemia Type 1 Mouse Model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Nuf mice, which have hypocalcemia in association with a gain-of-function CaSR
      mutation, Leu723Gln
    explanation: Establishes the model's genotype and that it reproduces the hypocalcaemic
      phenotype.
discussions:
- discussion_id: adh1_calcium_target_is_a_tradeoff
  kind: INTERPRETATION
  attaches_to:
  - pathophysiology#Renal Calcium Wasting
  - treatments#Calcitriol and Calcium Supplementation
  prompt: Why is the treatment target in ADH1 a low-normal serum calcium rather than a
    normal one?
  rationale: >-
    In most hypoparathyroidism, hypercalciuria has one cause - no PTH to drive
    distal reabsorption - and PTH replacement addresses it. In ADH1 there are two
    causes, and only one of them responds to anything conventional therapy does.
    The renal receptor is over-sensitive whatever the PTH is doing, so every
    increment of serum calcium is filtered into a tubule that will not reabsorb
    it normally.

    That makes the usual therapeutic logic run backwards. Correcting serum
    calcium to the middle of the reference range does not restore normal
    physiology; it maximises the filtered load at the site of the second lesion,
    and the documented consequences are nephrocalcinosis, stones and declining
    renal function. So the accepted target is deliberately sub-normal - enough
    calcium to prevent tetany and seizures, not enough to normalise the number.

    This is why the mechanism is modelled here as two limbs converging on renal
    calcium wasting rather than as a single hypoparathyroid state. An entry that
    recorded only "hypoparathyroidism causes hypercalciuria" would make the
    conventional treatment look adequate.
  evidence:
  - reference: PMID:8813042
    reference_title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations
      in the calcium-sensing receptor.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis,
      and renal impairment
    explanation: The observed harm from raising calcium by the conventional route.
  - reference: PMID:33112267
    reference_title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated
      hypoparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The traditional approach to treatment includes activated vitamin D but this
      further increases urinary calcium excretion.
    explanation: States the trade-off directly as the motivation for seeking an alternative.
- discussion_id: adh1_in_vitro_activation_does_not_predict_response
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#CASR
  - treatments#Calcilytic (Negative Allosteric Modulator of the CaSR)
  prompt: Why does the degree of in vitro receptor activation not predict a patient's
    response to a calcilytic?
  rationale: >-
    The mechanistic argument for calcilytics in ADH1 is clean: the receptor is
    too easily activated, so shift it back. The clinical study tested that
    argument in five patients with four different CASR variants and measured, in
    parallel, what the drug did to each variant receptor in cells. Every variant
    behaved as activating in vitro and every one was shifted by the drug in vitro
    - and yet the in vitro numbers did not correlate with any clinical parameter,
    and the clinical responses varied substantially between patients.

    That is a gap rather than a negative result. It means the assay that
    classifies a variant as activating - a calcium dose-response curve in a
    heterologous cell line - is not measuring the quantity that determines what
    happens in a patient. Candidate explanations include signalling that is
    biased between pathways in ways the readout does not capture,
    tissue-specific differences between parathyroid and tubule, and expression or
    trafficking effects that a stable overexpression system removes.

    Of those, biased signalling has since acquired direct evidence rather than
    remaining a suggestion. A de novo p.Leu723Arg variant was shown to lower the
    EC50 for calcium activation of G11 while leaving Gi, Gq and Gs unchanged - so
    a variant can be activating along one coupling route and not others. A
    dose-response assay that reads a single downstream output cannot distinguish
    that from uniform activation, and the patient carrying it presented with
    short stature and inconsistent hypercalciuria rather than the usual ADH1
    picture. That does not close the gap, since the calcilytic study's variants
    were not profiled this way, but it shows the mechanism is real and that the
    standard assay would miss it.

    Recording this matters for how the genotype is used. A variant curated as
    "gain of function, confirmed functionally" carries less predictive
    information than that phrase suggests, and this entry deliberately does not
    let the functional classification stand in for a prognosis.
  evidence:
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic
      NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In vitro, all mutant CaRs were half-maximally activated (EC50 ) at lower
      concentrations of extracellular calcium (Ca2+o ) compared to wild-type (WT) CaR;
      NPSP795 exposure increased the EC50 for all CaR activity readouts. However, the in
      vitro responses to NPSP795 did not correlate with any clinical parameters.'
    explanation: The paired result - uniform in vitro behaviour, uncorrelated clinical
      behaviour - which is the gap itself.
  - reference: PMID:31063613
    reference_title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic
      NPSP795 (SHP635).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Albeit all mutations appear to be activating at the CaR, in vitro observations
      were not predictive of the in vivo phenotype or the response to calcilytics, suggesting
      that other parameters impact the response to the drug.
    explanation: The authors' own statement of the disconnect, quoted separately from the
      result that produced it.
  - reference: PMID:39658204
    reference_title: An activating calcium-sensing receptor variant with biased signaling
      reveals a critical residue for Gα11 coupling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Transient expression studies showed the Leu723Arg variant was normally expressed
      but resulted in a significantly lower EC50 for extracellular calcium activation of
      G11 but not other G proteins (ie, Gi, Gq, Gs).
    explanation: Direct evidence that a variant can be activating for one G-protein route
      and not others, which is one of the candidate explanations for the assay-to-clinic
      disconnect.
- discussion_id: adh1_vs_adh2_and_hypoparathyroidism
  kind: INTERPRETATION
  attaches_to:
  - diagnosis#CASR Sequencing
  prompt: What does ADH1 need to be distinguished from, and why does the distinction
    change management?
  rationale: >-
    Two differentials matter. The first is hypoparathyroidism from parathyroid
    destruction, surgery or agenesis. It looks similar - low calcium, low PTH,
    high phosphate - but has no renal limb, so calcium and vitamin D are
    appropriate treatment there and a compromise here. Distinguishing them is
    what the paired calcium/PTH plus a urinary calcium measurement is for, and it
    is why the original kindreds were relabelled from "autosomal dominant
    hypoparathyroidism".

    The second is ADH2, caused by activating variants of GNA11, the G-protein
    that transduces the receptor's signal. Because the lesion is one step
    downstream, the biochemistry is close to identical and sequencing is what
    separates them. The distinction is not academic for the calcilytic question:
    a drug that acts allosterically on the receptor has its target intact in
    ADH1, whereas in ADH2 the receptor is normal and the excess signalling begins
    beyond it - which is why the calcilytic effect in ADH2 was demonstrated in a
    mouse model rather than assumed to transfer.

    A third differential is acquired rather than inherited: activating
    autoantibodies against the receptor reproduce the ADH biochemistry with no
    CASR variant present. It is the differential a negative sequencing result
    should raise rather than close, and the mirror image of the inactivating
    autoantibodies that phenocopy familial hypocalciuric hypercalcaemia.
  evidence:
  - reference: PMID:28194447
    reference_title: Gα(11) mutation in mice causes hypocalcemia rectifiable by calcilytic
      therapy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Heterozygous germline gain-of-function mutations of G-protein subunit α11
      (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal
      dominant hypocalcemia type 2 (ADH2).
    explanation: Defines ADH2 and its relationship to the receptor, which is the basis of
      the differential.
  - reference: PMID:20374733
    reference_title: Calcium-sensing receptor and associated diseases.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Phenocopies of FHH or ADH are due to circulating CASR inactivating or activating
      autoantibodies, respectively.
    explanation: A third differential the genetic test settles - an acquired autoimmune
      phenocopy that reproduces the biochemistry with no CASR variant at all.
references:
- reference: PMID:7874174
  title: Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.
- reference: PMID:8813042
  title: A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the
    calcium-sensing receptor.
- reference: PMID:12241879
  title: Association between activating mutations of calcium-sensing receptor and Bartter's
    syndrome.
- reference: PMID:20374733
  title: Calcium-sensing receptor and associated diseases.
- reference: PMID:39658204
  title: An activating calcium-sensing receptor variant with biased signaling reveals a
    critical residue for Gα11 coupling.
- reference: PMID:40086735
  title: Characterization of quinazolinone calcilytic therapy for autosomal dominant hypocalcemia
    type 1 (ADH1).
- reference: PMID:28194447
  title: Gα(11) mutation in mice causes hypocalcemia rectifiable by calcilytic therapy.
- reference: PMID:31063613
  title: Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795
    (SHP635).
- reference: PMID:33103030
  title: Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia
    Type 1 Mouse Model.
- reference: PMID:33112267
  title: Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
- reference: PMID:11013439
  title: 'Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia,
    neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.'
- reference: PMID:15347804
  title: Activating calcium-sensing receptor mutation in the mouse is associated with cataracts
    and ectopic calcification.
- reference: PMID:16128246
  title: 'A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational
    analysis, phenotypic variability and treatment challenges.'
- reference: PMID:22863393
  title: Hypoparathyroidism.
- reference: PMID:25071082
  title: Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism
    for renal calcium handling.
- reference: PMID:27617113
  title: Novel Mutation in the CASR Gene (p.Leu123Ser) in a Case of Autosomal Dominant Hypocalcemia.
- reference: PMID:33599907
  title: 'Renal complications in patients with chronic hypoparathyroidism on conventional
    therapy: a systematic literature review : Renal disease in chronic hypoparathyroidism.'
- reference: PMID:35818129
  title: 'Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and
    literature review.'
- reference: PMID:37754292
  title: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1.
- reference: PMID:38367250
  title: In vivo treatment with calcilytic of CaSR knock-in mice ameliorates renal phenotype
    reversing downregulation of the vasopressin-AQP2 pathway.
- reference: PMID:42388864
  title: 'Case Report: Palopegteriparatide as a novel therapeutic option in pediatric autosomal
    dominant hypocalcemia type 1.'
- reference: clinicaltrials:NCT04581629
  title: A Phase 2b, Open-label Dose-ranging Study Evaluating the Safety, Tolerability, Pharmacodynamics
    and Pharmacokinetics, and Efficacy of CLTX-305 (Encaleret) in Autosomal Dominant Hypocalcemia
    (ADH) Type 1
notes: >-
  Scope. This entry covers ADH1 (CASR) only. ADH2 (GNA11) is a separate MONDO
  term with a different gene and is treated here as a differential, not as a
  subtype - the two share a biochemical phenotype but not a lesion. The
  Bartter-type-V presentation is curated as a has_subtypes entry rather than
  being folded into the existing Bartter_Syndrome entry, because its primary
  lesion is the same receptor as the rest of ADH1 and it appears among this MONDO
  term's own synonyms.

  Gain of function, in two senses. Both schema slots are used here and they make
  different claims. The variant node carries genetic_context with
  functional_impact_category GAIN_OF_FUNCTION, because that is the consequence of
  the variant. The descriptor modifiers are separate: the receptor node uses
  GAIN_OF_FUNCTION because the receptor is signalling outside its normal
  regulatory constraint, while the downstream signalling node uses the
  quantitative INCREASED, since what is claimed there is an amount of signalling
  for a given calcium concentration.

  evidence_source rule used here. CLAUDE.md says the slot classifies the cited
  publication, so that is the rule applied throughout: a case series is
  HUMAN_CLINICAL for every sentence quoted from it, including its background
  paragraphs, and a mouse study is MODEL_ORGANISM for the same reason. An earlier
  version of this entry graded background sentences from a case series as OTHER
  on a per-sentence reading; that was internally inconsistent with how a mouse
  paper's background sentence was graded in the same file, and PR review caught
  it. OTHER is now reserved for sources that are not primary studies at all -
  a review, a systematic literature review, a trial registration record.

  Molecular function term. GO has no "calcium-sensing receptor activity" term.
  The receptor node is bound to GO:0004930 (G protein-coupled receptor activity),
  which is accurate but less specific than the claim; preferred_term carries the
  specific reading. The same applies to GO:0006816 for the renal node, where GO
  has no term for renal tubular calcium reabsorption specifically.

  Nephrolithiasis label. HP:0000787 is carried here as "Nephrolithiasis", the
  label in this repository's HP cache. A live OLS lookup during curation returned
  "Kidney stone" for the same CURIE, so the two disagree; the cached label is what
  term validation checks against and is used.

  Prevalence. The 3.9 per 100,000 figure is quoted from a paper's introduction
  rather than from a primary epidemiological study, and the evidence item is
  graded OTHER for that reason.

  CLDN14. The descriptor on the renal node was added during the first review
  response on the strength of a deep-research lead, with no citation - which
  contradicted this entry's own rule that a report is a lead. Review flagged it
  as non-blocking; it is fixed rather than left, because an uncited gene
  assertion in a knowledge base is worse than an extra review cycle. PMID:25071082
  is ADH1-specific and supplies both the mechanism and a rescue.

  Reference consumption. The first version of this entry cited 11 of the 33
  references its deep-research run had fetched, and PR review established that
  several of the unused ones carried content the entry needed - the thiazide
  adjunct, ADH1-specific denominators for phenotype frequencies, hypomagnesaemia
  as cardinal rather than subtype-specific biochemistry, the AQP2 mechanism
  behind the concentrating defect, and the encaleret result. All were added from
  caches already committed, plus two new fetches for encaleret. The lesson is
  that a reference cache fetched during research is a reading list, not a
  by-product: leaving it uncited is a claim that it holds nothing, and here that
  claim was wrong.

  Deep research. An openscientist deep-research run was commissioned for this
  entry. The pathograph and the first eight references were built independently
  from PubMed before the report returned; the report was then read as a source of
  leads and contributed four further references (PMID:20374733, PMID:39658204,
  PMID:40086735 and the differentials they support). Every PMID was fetched with
  just fetch-reference and every snippet verified against the fetched cache
  rather than against the report's own quotation of it - which mattered, because
  three snippets initially taken from an abstract-metadata service did not match
  the fetched cache text word for word.

  What the report got wrong. Its term-validation section flagged one confabulated
  CL identifier (CL:1000456, named as a collecting-duct cell but actually a
  peritoneal mesothelial cell) among the terms it proposed; that term is not used
  here. It also gave MONDO:0008833 as this disease's identifier, where the
  curation stub and MONDO give MONDO:0011013 for "autosomal dominant hypocalcemia
  1"; the stub's identifier is used.
📚

References & Deep Research

References

22
PMID:7874174
Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.
No top-level findings curated for this source.
PMID:8813042
A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.
No top-level findings curated for this source.
PMID:12241879
Association between activating mutations of calcium-sensing receptor and Bartter's syndrome.
No top-level findings curated for this source.
PMID:20374733
Calcium-sensing receptor and associated diseases.
No top-level findings curated for this source.
PMID:39658204
An activating calcium-sensing receptor variant with biased signaling reveals a critical residue for Gα11 coupling.
No top-level findings curated for this source.
PMID:40086735
Characterization of quinazolinone calcilytic therapy for autosomal dominant hypocalcemia type 1 (ADH1).
No top-level findings curated for this source.
PMID:28194447
Gα(11) mutation in mice causes hypocalcemia rectifiable by calcilytic therapy.
No top-level findings curated for this source.
PMID:31063613
Treatment of Autosomal Dominant Hypocalcemia Type 1 With the Calcilytic NPSP795 (SHP635).
No top-level findings curated for this source.
PMID:33103030
Calcilytic NPSP795 Increases Plasma Calcium and PTH in an Autosomal Dominant Hypocalcemia Type 1 Mouse Model.
No top-level findings curated for this source.
PMID:33112267
Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.
No top-level findings curated for this source.
PMID:11013439
Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.
No top-level findings curated for this source.
PMID:15347804
Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification.
No top-level findings curated for this source.
PMID:16128246
A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH): mutational analysis, phenotypic variability and treatment challenges.
No top-level findings curated for this source.
PMID:22863393
Hypoparathyroidism.
No top-level findings curated for this source.
PMID:25071082
Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism for renal calcium handling.
No top-level findings curated for this source.
PMID:27617113
Novel Mutation in the CASR Gene (p.Leu123Ser) in a Case of Autosomal Dominant Hypocalcemia.
No top-level findings curated for this source.
PMID:33599907
Renal complications in patients with chronic hypoparathyroidism on conventional therapy: a systematic literature review : Renal disease in chronic hypoparathyroidism.
No top-level findings curated for this source.
PMID:35818129
Autosomal dominant hypocalcemia with a novel CASR mutation: a case study and literature review.
No top-level findings curated for this source.
PMID:37754292
Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1.
No top-level findings curated for this source.
PMID:38367250
In vivo treatment with calcilytic of CaSR knock-in mice ameliorates renal phenotype reversing downregulation of the vasopressin-AQP2 pathway.
No top-level findings curated for this source.
PMID:42388864
Case Report: Palopegteriparatide as a novel therapeutic option in pediatric autosomal dominant hypocalcemia type 1.
No top-level findings curated for this source.
clinicaltrials:NCT04581629
A Phase 2b, Open-label Dose-ranging Study Evaluating the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy of CLTX-305 (Encaleret) in Autosomal Dominant Hypocalcemia (ADH) Type 1
No top-level findings curated for this source.

Deep Research

1
OpenScientist ▸
Autosomal Dominant Hypocalcemia 1 (ADH1): Comprehensive Disease Characteristics Report
openscientist-autonomous 21 citations 2026-08-28T16:36:20.952107

Autosomal Dominant Hypocalcemia 1 (ADH1): Comprehensive Disease Characteristics Report

Disease: Autosomal Dominant Hypocalcemia 1 (ADH1) Gene: CASR (calcium-sensing receptor) OMIM: #601198 (phenotype), 601199 (gene) | Orphanet: ORPHA:428 | MONDO: 0008833 | HGNC: 1514 | UniProt: P41180 | Category:* Mendelian (autosomal dominant)

Evidence source note: This report is compiled from disease-level aggregated resources (OMIM, Orphanet, HGNC/UniProt) and primary literature (human clinical case series, in-vitro functional studies, and mouse-model studies), not from individual EHR data. Evidence type is indicated per claim.

Summary

Autosomal Dominant Hypocalcemia type 1 (ADH1; OMIM #601198) is a rare Mendelian endocrine disorder caused by heterozygous gain-of-function (activating) missense mutations in CASR, the gene encoding the calcium-sensing receptor (CaSR), a class C G-protein-coupled receptor on chromosome 3q13.33. The activating mutations "left-shift" the set-point for extracellular calcium sensing — the receptor is triggered at abnormally low calcium concentrations. This single molecular defect produces a dual-organ pathophysiology: in the parathyroid glands the over-active receptor inappropriately suppresses parathyroid hormone (PTH) secretion, producing hypocalcemia with inappropriately low/normal PTH; in the kidney the over-active receptor drives hypercalciuria and impairs urinary concentration. The result is a characteristic biochemical signature of low serum calcium, high phosphate, low-normal magnesium, low PTH, and relative-to-frank hypercalciuria.

Clinically, ADH1 spans a wide severity spectrum, from asymptomatic individuals detected on family screening to neonates and children presenting with seizures, tetany, carpopedal spasm, and paresthesias. Long-term complications are dominated by renal disease (nephrocalcinosis, nephrolithiasis, progressive chronic kidney disease), along with basal ganglia calcification, early cataracts, and cardiac QT prolongation. The central therapeutic dilemma is that conventional treatment (oral calcium plus active vitamin D) corrects hypocalcemia but worsens hypercalciuria and accelerates renal damage — so the guiding principle is to relieve symptoms while keeping serum calcium at the low end of normal, with thiazide diuretics as a useful adjunct.

The field is advancing toward mechanism-matched targeted therapy: calcilytics (negative allosteric CaSR modulators such as NPSP795/SHP635 and encaleret) have raised PTH and serum calcium in ADH1 patients and mouse models, and PTH-replacement approaches (palopegteriparatide) have rescued refractory pediatric cases. The Nuf mouse (Casr p.Leu723Gln) is the principal, faithful animal model. As an autosomal dominant disorder with 50% transmission risk (plus frequent de novo and mosaic events), prevention rests on genetic counseling, cascade testing, and reproductive genetic options. This report synthesizes 11 confirmed findings across 35 reviewed papers into a comprehensive knowledge-base entry.

Key Findings

Finding 1 — Genetic cause: heterozygous activating CASR mutations

ADH1 is caused by heterozygous gain-of-function (activating) missense variants in CASR. More than 400 germline CASR mutations (both loss- and gain-of-function) have been catalogued across the spectrum of calcium homeostasis disorders. In ADH1 specifically, the activating variants lower the EC50 for calcium-dependent G-protein activation, producing a left-shifted set-point so the receptor signals as if calcium is high even when it is low or normal. Inheritance is autosomal dominant, and de novo variants are common (e.g., p.Leu723Arg, p.Leu123Ser). ADH1 is molecularly distinct from ADH2, caused by gain-of-function variants in GNA11 (encoding Gα11, the CaSR's signaling partner).

"Autosomal dominant hypocalcemia (ADH) is due to enhanced calcium-dependent signaling caused by heterozygous gain-of-function (GOF) variants in the CASR gene (ADH1) or in the GNA11 gene, encoding Gα11 (ADH2)." — PMID: 39658204

"It is caused by the activating mutations of the calcium-sensing receptor gene (CASR), which produces a left-shift in the set point for extracellular calcium." — PMID: 34160437

"the identification of >400 different germline loss- and gain-of-function CaSR mutations that give rise to disorders of Ca2+ homeostasis" — PMID: 31189130

Finding 2 — Biochemical and clinical phenotype

The cardinal biochemistry of ADH1 is hypocalcemia (e.g., serum calcium 1.53–1.85 mmol/L), inappropriately low/normal PTH, hyperphosphatemia, hypomagnesemia, and relative-to-frank hypercalciuria. Clinical features include neuromuscular irritability (paresthesias, carpopedal spasm, tetany) and seizures, which are frequently the presenting feature in infancy and childhood. Complications include nephrocalcinosis/nephrolithiasis, basal ganglia calcification, and early cataracts. A key feature is variable expressivity: symptom severity is not tightly correlated with the degree of hypocalcemia. A severe subset manifests a Bartter-like (type V) salt-wasting phenotype.

"Affected members had hypocalcaemia (1.53-1.85 mmol/l), hypercalciuria, low but detectable parathyroid hormone (PTH) and hypomagnesaemia. Four of seven affected individuals were symptomatic (seizures, abdominal pains and paraesthesias), unrelated to severity of hypocalcaemia. Additional complications include nephrocalcinosis (n = 3) and basal ganglia calcification" — PMID: 16128246

"presented with hypocalcemia, recurrent tetany, seizures, hypercalciuria, nephrocalcinosis, basal ganglia calcifications, and early-onset cataracts" — PMID: 42388864

"Clinical manifestations of the index case started with seizures at 14 months of age; cognitive impairment and several neuropsychological disabilities were noted during childhood. Extrapyramidal signs and basal ganglia calcification developed later" — PMID: 27617113

Suggested HPO terms: Hypocalcemia (HP:0002901), Hypoparathyroidism (HP:0000829), Hyperphosphatemia (HP:0002905), Hypomagnesemia (HP:0002917), Hypercalciuria (HP:0002150), Seizure (HP:0001250), Tetany (HP:0001281), Paresthesia (HP:0003401), Nephrocalcinosis (HP:0000121), Nephrolithiasis (HP:0000787), Basal ganglia calcification (HP:0002135), Cataract (HP:0000518), Prolonged QT interval (HP:0001657).

Finding 3 — The therapeutic dilemma and emerging targeted therapies

Standard-of-care treatment (oral calcium plus active vitamin D — calcitriol or alfacalcidol) corrects hypocalcemia but exacerbates hypercalciuria, promoting nephrocalcinosis and renal impairment. Cautious ("judicious") dosing is therefore recommended. Targeted therapy is emerging on two fronts: calcilytics (negative allosteric CaSR modulators) — NPSP795/SHP635 raised PTH and serum calcium in five ADH1 adults, and JTT-305 reversed renal AQP2 downregulation in CaSR knock-in mice; encaleret is in clinical development. PTH-replacement approaches (palopegteriparatide) resolved symptoms and lowered the calcium-phosphate product in a refractory pediatric case.

"Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1. Five adults with ADH1 due to four distinct CAR mutations received escalating doses of the calcilytic compound NPSP795 (SHP635)" — PMID: 31063613

"In vivo treatment of KI mice with the calcilytic JTT-305, a CaSR antagonist, increased AQP2 expression and reduced AQP2-targeting miRNA137 levels in KI mice." — PMID: 38367250

"Optimal management of ADHH is difficult and we recommend judicious treatment to avoid an increased risk of nephrocalcinosis." — PMID: 16128246

Suggested NCIT terms: Calcium (C332), Calcitriol (C376), Vitamin D (C902), Thiazide Diuretic (C29713), Parathyroid Hormone (C2354).

Finding 4 — The Nuf mouse: the principal animal model

The Nuf mouse carries a germline gain-of-function Casr (Gprc2a) missense mutation Leu723Gln (chromosome 16), which lowers the receptor EC50. Both heterozygous and homozygous mice display hypocalcemia, hyperphosphatemia, inappropriately low PTH, ectopic/soft-tissue calcification, and nuclear cataracts — faithfully mirroring human ADH1. The model also revealed additional CaSR-dependent phenotypes, including impaired glucose tolerance and insulin secretion (hyperglycemia) that is rectified by calcilytics. Calcilytics (NPS 2143, NPSP795, and quinazolinones ATF936/AXT914) raise PTH and plasma calcium in Nuf mice; oral AXT914 raised PTH from 23±4 to 104±29 pmol/L (p<0.05).

"Nuf mice also display ectopic calcification, hypocalcemia, hyperphosphatemia, and inappropriately reduced levels of plasma parathyroid hormone. These features are similar to those observed in patients with autosomal dominant hypocalcemia." — PMID: 15347804

"Oral administration of 10 mg/kg AXT914 to Nuf mice increased parathyroid hormone to 104 ± 29 pmol/l compared with 23 ± 4 pmol/l for vehicle-treated mice, p < 0.05" — PMID: 40086735

"Heterozygous- (CasrNuf/+) and homozygous-affected (CasrNuf/Nuf) mice were shown to have hypocalcemia in association with impaired glucose tolerance and insulin secretion." — PMID: 28575322

Finding 5 — Dual-organ pathophysiology

Activated CaSR in parathyroid chief cells suppresses PTH secretion at a lowered set-point, producing hypocalcemia with inappropriately low PTH. In the kidney, CaSR overactivity in the thick ascending limb and distal nephron independently increases urinary calcium excretion (hypercalciuria) via Claudin-14 (Cldn14) upregulation, and in the collecting duct impairs the vasopressin–AQP2 axis. CaSR knock-in mice show reduced AQP2 with increased AQP2 phosphorylation at Ser261 through a p38MAPK–ATF1–miR137 pathway, contributing to a urinary concentrating/Bartter-like tendency. The calcilytic JTT-305 reversed this AQP2 downregulation, confirming the mechanism is receptor-driven.

"CaSR knock-in (KI) mice mimicking autosomal dominant hypocalcaemia, display a significant decrease in the total content of AQP2 associated with significantly higher levels of AQP2 phosphorylation at Ser261" — PMID: 38367250

"Our findings suggest that parathyroid CaSR overactivity can reduce plasma Ca" — PMID: 35313217

Suggested GO/CL/UBERON terms: GO:0007200 (phospholipase C-activating GPCR signaling), GO:0055074 (calcium ion homeostasis), GO:0038066 (p38 MAPK cascade), CL:0000446 (parathyroid chief cell), CL:1000456 (kidney collecting duct principal cell), UBERON:0001132 (parathyroid gland), UBERON:0002113 (kidney).

Finding 6 — Diagnostic approach

Diagnosis rests on biochemistry plus CASR sequencing. The workup includes serum calcium (low), phosphate (high), magnesium (often low), and PTH (inappropriately low/normal), plus a 24-hour urinary calcium showing relative/frank hypercalciuria. ADH1 is confirmed by identifying a heterozygous activating CASR variant (single-gene test or hypoparathyroidism/mineral gene panel; WES/WGS in undiagnosed cases). Monogenic causes account for only ~5–10% of hypoparathyroidism, so genetic testing is targeted to clinically suspicious cases. Thiazide diuretics enhance renal calcium reabsorption and are of particular benefit in patients with activating CaSR mutations. ADH1 must be distinguished from other hypoparathyroidism etiologies (postsurgical, autoimmune, DiGeorge/22q11 deletion).

"thiazide diuretics are of value as they enhance renal calcium reabsorption and increase serum calcium and are of particular benefit in those with activating mutations of the calcium-sensing receptor" — PMID: 22863393

"which have a monogenic aetiology in 5%-10% of cases" — PMID: 34935164

"Genetic testing forms an important tool in the investigation of PHPT and HP patients and is usually reserved for those deemed to be an increased risk of a monogenic disorder." — PMID: 34935164

Finding 7 — CaSR structure and biased signaling

CaSR (UniProt P41180) is a class C G-protein-coupled receptor functioning as a homodimer with a large Venus flytrap extracellular domain (ECD), a cysteine-rich domain, and a 7-transmembrane domain (TMD). Five cryo-EM structures of near-full-length CaSR show how Ca2+/agonist binding in the ECD is transmitted to the TMD to activate G proteins (Gq/11, Gi), and how allosteric modulators tune this. Activating ADH1 mutations map to regions important for structural integrity, dimerization, and ligand binding; a TMD "hotspot" (e.g., residue 723) is also the common calcilytic-binding pocket. Some variants produce biased signaling — the de novo p.Leu723Arg variant selectively lowers the EC50 for Gα11 activation without affecting Gi/Gq/Gs.

"five cryo-EM structures of the near full-length CaSR have been published, demonstrating how agonist-binding transmits changes in the CaSR extracellular domain to the transmembrane region to activate G proteins, and how allosteric modulators affect these structural dynamics" — PMID: 36707151

"the study of disease-causing mutations has demonstrated that CaSR signals in a biased manner" — PMID: 31189130

"the Leu723Arg variant was normally expressed but resulted in a significantly lower EC50 for extracellular calcium activation of G11 but not other G proteins" — PMID: 39658204

"bind at a common region within the CaSR transmembrane domain, which is also an ADH1 mutational hotspot" — PMID: 40086735

Finding 8 — Nosology, identifiers, and inheritance

ADH1 identifiers: OMIM #601198; gene CASR (601199, HGNC:1514, 3q13.33); Orphanet ORPHA:428 ("autosomal dominant hypocalcemia"); MONDO:0008833; MeSH via "Hypocalcemia"/"Receptors, Calcium-Sensing". Synonyms: hypocalcemia autosomal dominant; hypoparathyroidism, familial isolated, autosomal dominant; ADHH (autosomal dominant hypocalcemia with hypercalciuria); familial/sporadic isolated hypoparathyroidism; Bartter syndrome type V (severe subset). Inheritance: autosomal dominant with frequent de novo mutations; germline/gonadal mosaicism has been reported (asymptomatic transmitting parent), producing variable/incomplete expressivity within families. ADH accounts for the majority of genetic isolated hypoparathyroidism; ADH1 (CASR) is far more common than ADH2 (GNA11). ADH2 (OMIM #615361) is caused by gain-of-function GNA11 mutations and is associated with short stature in ~42%* and less consistent hypercalciuria — a key distinguishing feature.

"ADH1 patients typically manifest hypercalciuria, while ADH2 is associated with short stature in approximately 42% of cases." — PMID: 39658204

"autosomal dominant hypocalcemia type 2 (ADH2) are due to loss- and gain-of-function mutations, respectively, of the GNA11 gene that encodes the G protein subunit Gα11, a signaling partner of the calcium-sensing receptor (CaSR)" — PMID: 36970776

"Sequencing analysis in the mother suggested mosaicism for the same variant, and she was clinically and biochemically unaffected." — PMID: 27617113

Finding 9 — Variable onset, allelic spectrum, and phenocopies

Onset is highly variable: ADH may be asymptomatic (detected on family screening or incidental hypocalcemia) or present with seizures in the neonatal period, childhood, or adulthood; severe neonatal cases require IV calcium (e.g., de novo p.Glu228Lys). CASR is a single locus with a graded allelic spectrum: heterozygous loss-of-function → familial hypocalciuric hypercalcemia (FHH1); homozygous LOF → neonatal severe hyperparathyroidism (NSHPT); heterozygous gain-of-function → ADH1. A common polymorphism Ala986Ser (A986S) in the intracellular tail modestly influences serum calcium and can act as a modifier. Acquired activating anti-CaSR autoantibodies produce an autoimmune ADH phenocopy (an important differential). Drug interactions matter clinically: phenobarbital accelerates 1-alfacalcidol metabolism, causing swings between hypo- and hypercalcemia.

"Heterozygous activating mutations of the CASR cause autosomal dominant hypocalcemia (ADH) that may be asymptomatic or present with seizures in the neonatal period or childhood or later in life. Phenocopies of FHH or ADH are due to circulating CASR inactivating or activating autoantibodies, respectively." — PMID: 20374733

"A common polymorphism in the intracellular tail of the CASR, Ala to Ser at position 986, has a modest effect on the serum calcium concentration in healthy individuals." — PMID: 11013439

"The child presented in the neonatal period with clinical seizures associated with severe hypocalcaemia, hyperphosphataemia, low parathyroid hormone levels and elevated urine calcium:creatinine ratios." — PMID: 25227206

Finding 10 — Prognosis: normal life expectancy but chronic renal morbidity

ADH1 is a chronic, lifelong disorder with generally good survival, but morbidity is driven by renal complications, amplified by both the intrinsic hypercalciuria and by conventional calcium/active-vitamin-D therapy. A systematic review of chronic hypoparathyroidism on conventional therapy reports nephrolithiasis rates up to 36% and nephrocalcinosis up to 38%, with progression to renal insufficiency/CKD. Additional complications include hypocalcemic seizures, basal ganglia (and other ectopic) calcification, cataracts, and QT-prolongation risk. Postsurgical chronic hypoparathyroidism cohorts show elevated renal disease (moderate-to-severe 28.8% vs 5.6%), nephrocalcinosis (59.9% vs 0.6%), and higher mortality (HR ~2.75) versus controls — underscoring the renal/cardiovascular burden of the hypoparathyroid state that ADH1 shares and exacerbates.

"The reported rate of nephrolithiasis was up to 36%, with the lowest rates in studies reporting shorter duration of disease. The rate of nephrocalcinosis was up to 38%." — PMID: 33599907

"a higher prevalence of moderate-to-severe renal disease (28.8% vs. 5.6%), nephrocalcinosis (59.9% vs. 0.6%), and nephrolithiasis (8.3% vs. 1.0%). They also had significantly greater mortality (hazard ratio [HR] 2.75)" — PMID: 40531442

Finding 11 — Management principles and prevention

Because overtreatment drives renal damage, the guiding therapeutic principle is to relieve symptoms while keeping serum calcium at the low end of normal, using thiazides to blunt hypercalciuria. Human proof-of-concept for mechanism-matched therapy: the calcilytic NPSP795/SHP635 increased PTH in ADH1 patients, and in-vitro assays show variant-specific responsiveness (supporting genotype-guided calcilytic selection); PTH-based therapy (palopegteriparatide) rescued a refractory pediatric case. Prevention is exclusively at the reproductive/clinical level: as an autosomal dominant disorder, each child of an affected parent has a 50% risk; de novo and mosaic events mean absence of family history does not exclude risk. Preventive tools are genetic counseling, cascade testing of relatives, and prenatal/preimplantation genetic testing for a known familial CASR variant. No population-based primary prevention exists.

"Calcilytics are negative allosteric modulators of the extracellular calcium receptor (CaR) and therefore may have therapeutic benefits in ADH1." — PMID: 31063613

"also to allow the identification of other family members who may be at risk of disease" — PMID: 34935164

Mechanistic Model / Interpretation

ADH1 is fundamentally a single-gene, gain-of-function signalopathy with a two-organ output. The causal chain:

    Heterozygous activating CASR missense variant (e.g., L723Q, R205C, E228K)
              │
 Left-shifted Ca2+ set-point (↓ EC50 for Ca2+)
              │
  Receptor "reads" normal/low Ca2+ as if it were HIGH
 ┌────────────┴──────────────┐
 ▼                            ▼
       PARATHYROID GLAND                  KIDNEY
    (chief cells, CL:0000446)     (TAL + distal nephron + CD)
 │                            │
      ↓ PTH secretion            ↑ Cldn14 → ↑ urinary Ca2+ excretion
      (inappropriately low)      ↓ AQP2 (p38MAPK-ATF1-miR137)
 │                            │
 ▼                            ▼
      HYPOCALCEMIA               HYPERCALCIURIA + urine-concentration defect
      Hyperphosphatemia          (Bartter-like tendency in severe subset)
 │                            │
 └────────────┬───────────────┘
              ▼
       CLINICAL: seizures, tetany, paresthesias (acute);
       nephrocalcinosis, nephrolithiasis, CKD, basal ganglia
       calcification, cataracts, QT prolongation (chronic)

Upstream vs downstream: The upstream driver is the mutant receptor's shifted set-point. The parathyroid PTH suppression and renal calcium-wasting are parallel, independent downstream arms — a critical insight because it explains why simply raising serum calcium (which further activates the already over-sensitive renal receptor) worsens hypercalciuria. This is the mechanistic root of the treatment dilemma.

Why calcilytics work: By binding the TMD allosteric pocket (which coincides with the ADH1 mutational hotspot around residue 723), calcilytics raise the receptor's EC50 back toward normal, de-repressing PTH and reducing renal calcium wasting simultaneously — addressing both arms at their common origin rather than downstream.

Comparative nosology of CASR dosage:

Genotype Receptor activity Disorder Calcium phenotype
Heterozygous LOF ↓ FHH1 (familial hypocalciuric hypercalcemia) High Ca, low urine Ca
Homozygous LOF ↓↓ NSHPT (neonatal severe hyperparathyroidism) Severe high Ca
Heterozygous GOF ↑ ADH1 Low Ca, high urine Ca
— (GNA11 GOF) ↑ (via Gα11) ADH2 Low Ca, short stature ~42%

Report by Template Section

1. Disease Information

Rare AD form of hypoparathyroidism from activating CASR variants; hypocalcemia with inappropriately low PTH and hypercalciuria. Identifiers: OMIM #601198 (gene 601199), ORPHA:428, MONDO:0008833, HGNC:1514, UniProt P41180; ICD-10 E20.8 / ICD-11 5A50.0 (no ADH1-specific code); MeSH under Hypocalcemia / Receptors, Calcium-Sensing*. Synonyms: ADHH, familial isolated hypoparathyroidism (AD), Bartter syndrome type V (severe subset). Data are from aggregated disease-level resources plus published clinical case series/pedigrees.

2. Etiology

Primary cause is genetic/monogenic — heterozygous activating CASR missense variants (Finding 1). Genetic modifier: A986S (rs1801725) polymorphism. No environmental or infectious causation; environmental modifiers (dietary calcium/vitamin D, phenobarbital) alter severity only. Acquired activating anti-CaSR autoantibodies produce a phenocopy (differential, not etiology). No established protective alleles.

3. Phenotypes

See Finding 2 and the HPO list. Onset neonatal→adult; variable severity/expressivity; chronic lifelong course with episodic acute symptoms (seizures/tetany). QoL impacted by seizures, renal disease, and treatment burden; no ADH1-specific QoL instrument exists.

4. Genetic/Molecular Information

Causal gene CASR (3q13.33). Variant class predominantly heterozygous missense, gain-of-function; TMD hotspot (residue 723); some biased-signaling variants (Findings 1, 7). Classification: functionally validated activating variants are Pathogenic/Likely Pathogenic; novel variants often require in-vitro Ca2+-response assays. Allele frequency: private/rare, essentially absent in gnomAD; many de novo. Germline (with mosaicism reported). Modifier: A986S. No characteristic epigenetic or chromosomal abnormalities.

5. Environmental Information

Not causal. Modifiers of expression only: dietary calcium/vitamin D status; enzyme-inducing drugs (phenobarbital) that alter vitamin-D-analog metabolism. No infectious agents.

6. Mechanism/Pathophysiology

See Mechanistic Model and Finding 5. Pathways: Gq/11–PLC and Gi signaling, p38MAPK–ATF1–miR137 (renal AQP2), Cldn14-mediated renal calcium handling. Protein dysfunction: class C GPCR homodimer biased toward active state (Finding 7). CHEBI: calcium(2+) (CHEBI:29108), phosphate (CHEBI:43474). Immune involvement: none intrinsic.

7. Anatomical Structures Affected

Primary: parathyroid gland (UBERON:0001132), kidney/nephron (UBERON:0002113). Secondary: basal ganglia (UBERON:0002420), ocular lens (UBERON:0000965), soft tissue (ectopic calcification), heart (functional QT). Cells: parathyroid chief cell (CL:0000446), collecting-duct principal cell (CL:1000456), TAL epithelium. Subcellular: plasma membrane (GO:0005886), ER (trafficking). Lateralization: systemic/bilateral. Systems: endocrine, renal/urinary, nervous, cardiac electrophysiology.

8. Temporal Development

Onset congenital/neonatal → adult, or asymptomatic. Pattern chronic/insidious with acute symptomatic episodes. Course lifelong; renal complications slowly progressive. Critical periods: neonatal seizure risk; intercurrent illness, pregnancy, and medication changes; early diagnosis is the key intervention window to avoid overtreatment-related renal damage.

9. Inheritance and Population

Autosomal dominant; frequent de novo; germline/gonadal mosaicism reported (Finding 8). High biochemical penetrance, variable symptomatic expressivity; negative family history does not exclude ADH1. No anticipation, founder effect, or consanguinity role in the classic sense. Epidemiology: rare; precise prevalence not established; ADH is the most common genetic cause of isolated hypoparathyroidism; monogenic causes ~5–10% of all hypoparathyroidism; ADH1 >> ADH2. No strong sex or geographic predilection.

10. Diagnostics

Biochemistry: low Ca, high phosphate, low/normal PTH, often low Mg, high urine Ca (24-h or Ca:creatinine). Imaging: renal ultrasound, brain CT, ECG (QTc); slit-lamp for cataract. Genetic testing: single-gene CASR sequencing or hypoparathyroidism/mineral panel; WES/WGS if undiagnosed; functional assays for VUS. Diagnostic clue: hypoparathyroidism with hypercalciuria. Differential: postsurgical, autoimmune (incl. anti-CaSR autoantibody phenocopy), 22q11.2 deletion, hypomagnesemia-related, pseudohypoparathyroidism, vitamin D disorders, ADH2 (GNA11). Screening: cascade genetic testing; prenatal/PGT for a known variant; no population newborn screening.

11. Outcome/Prognosis

Near-normal life expectancy with treatment; dominant morbidity is renal (nephrocalcinosis up to ~38%, nephrolithiasis up to ~36%, progression to CKD), amplified by intrinsic hypercalciuria and overtreatment (Finding 10). Other complications: seizures, ectopic/basal ganglia calcification, cataracts, QT prolongation. Prognostic factors: cumulative urinary calcium load, treatment approach, disease duration. Established nephrocalcinosis/CKD is not fully reversible — prevention is key.

12. Treatment

Conventional: oral calcium + active vitamin D (calcitriol/alfacalcidol), targeting low-normal serum calcium with judicious dosing; thiazide diuretics (of particular benefit in activating-CaSR patients); magnesium repletion. Targeted: calcilytics (NPSP795/SHP635, NPS 2143, ATF936/AXT914, encaleret) and PTH-replacement (palopegteriparatide, recombinant PTH) (Finding 3). Pharmacogenomics: avoid enzyme inducers (phenobarbital). No approved gene/cell/RNA therapy; surgery not applicable. Personalized medicine: in-vitro variant response can guide calcilytic vs PTH-based choice. NCIT terms listed in Finding 3.

13. Prevention

Primary prevention not possible (germline). Genetic counseling (AD, 50% offspring risk; de novo/mosaicism caveats) and reproductive options (PGT/prenatal testing) are the main tools. Secondary: cascade testing and early biochemical surveillance of relatives. Tertiary (most important): avoid overtreatment, maintain low-normal calcium, monitor 24-h urine calcium and renal imaging, use thiazides/calcilytics/PTH to prevent nephrocalcinosis/CKD. Immunization/public-health/environmental interventions not applicable.

14. Other Species / Natural Disease

Taxonomy: Homo sapiens (NCBI:txid9606); modeled in Mus musculus (NCBI:txid10090). No notable naturally occurring ADH1 in companion animals/wildlife documented. Ortholog: mouse Casr (historically Gprc2a); receptor and its Ca2+-homeostasis role are evolutionarily conserved, so mechanisms translate well to mouse models. Zoonosis/transmission: not applicable.

15. Model Organisms

Principal model — the Nuf mouse (Casr p.Leu723Gln; Finding 4): AD gain-of-function; recapitulates hypocalcemia, hyperphosphatemia, low PTH, ectopic calcification, and cataracts; plus impaired glucose tolerance. CaSR knock-in mice dissect renal AQP2/vasopressin pathology. Cellular/in-vitro: HEK293 expressing WT vs mutant CaSR for intracellular-Ca2+/BRET assays and calcilytic docking. Applications: validating calcilytics, studying biased signaling, renal/pancreatic CaSR biology. Limitations: mouse mineral set-points/lifespan differ; neurological (basal ganglia calcification) features less emphasized. Resource: MGI (mouse Casr).

Evidence Base

PMID Title (abbreviated) Supports finding(s) Evidence type
39658204 Activating CaSR variant with biased signaling F1, F7, F8 Human genetics + in vitro
31189130 CaSR mutation review F1, F7 Review
34160437 p.Arg205Cys ADH1 pedigree F1 Human clinical
16128246 ADHH family, treatment challenges F2, F3, F10, F11 Human clinical
42388864 Palopegteriparatide pediatric ADH1 F2, F3 Human clinical case
27617113 Novel p.Leu123Ser + mosaicism F2, F8 Human clinical
31063613 Calcilytic NPSP795 in ADH1 patients F3, F11 Human clinical trial
38367250 Calcilytic reverses renal AQP2 defect F3, F5 Model organism (KI mouse)
15347804 Nuf mouse cataracts + calcification F4 Model organism
40086735 Quinazolinone calcilytic in Nuf mice F4, F7 Model organism
28575322 Nuf mice hyperglycemia F4 Model organism
35313217 Parathyroid vs kidney CaSR contributions F5 Model organism
22863393 Hypoparathyroidism review (thiazides) F6 Review
34935164 Genetics of calcium/bone disorders F6, F11 Review
36707151 CaSR cryo-EM structures F7 Structural/computational
36970776 GNA11 variants (ADH2) F8 Human genetics
20374733 CaSR-associated diseases + autoantibodies F9 Review
11013439 CASR mutation spectrum + A986S F9 Human genetics
25227206 Neonatal ADH1 + phenobarbital interaction F9 Human clinical
33599907 Renal complications systematic review F10 Systematic review
40531442 Postsurgical hypoparathyroidism outcomes F10 Retrospective cohort

The evidence base is coherent and mutually reinforcing across human clinical, human genetics, model organism, and structural/computational domains. Human genetic studies establish causation (activating CASR variants), the Nuf mouse and CaSR knock-in models provide mechanistic validation and pharmacological proof-of-concept, cryo-EM structures rationalize where mutations and calcilytics act, and clinical/registry studies define the phenotype, therapeutic dilemma, and prognosis. No paper in the reviewed set contradicts the central model.

Supported vs Refuted Hypotheses

Supported (evidence-backed): 1. ADH1 = heterozygous activating CASR variants, left-shifted Ca2+ set-point (gain of function) [PMID 39658204; 34160437]. 2. Phenotype = hypocalcemia + inappropriately low PTH + hypercalciuria + calcification complications [PMID 16128246]. 3. Dual parathyroid + renal CaSR overactivity explains hypocalcemia with hypercalciuria; renal AQP2 pathway involved [PMID 35313217; 38367250]. 4. Calcilytics are mechanism-matched therapy (human n=5 + mouse) [PMID 31063613; 40086735]. 5. Nuf mouse faithfully models the disease [PMID 15347804].

Refuted / not applicable: environmental or infectious causation; loss-of-function/misfolding mechanism (that is FHH/NSHPT); a role for population-based primary prevention.

Limitations and Knowledge Gaps

  1. Epidemiology is poorly quantified. No reliable population prevalence/incidence figures for ADH1 specifically; estimates are extrapolated from the broader hypoparathyroidism population (monogenic ~5–10%). Precise prevalence, incidence, sex ratio, and geographic/ethnic distribution remain gaps.
  2. Penetrance and expressivity are incompletely characterized. Variable expressivity and mosaicism are documented, but formal penetrance estimates by variant are lacking.
  3. Genotype–phenotype correlations are limited. Symptom severity is explicitly not tightly correlated with hypocalcemia degree; systematic variant-level correlation (including biased-signaling variants) is needed.
  4. Targeted therapy evidence is early-stage. Calcilytic human data are limited (n=5 for NPSP795) and PTH-replacement evidence is a single pediatric case. Long-term renal-protective outcomes are not yet established.
  5. Quality-of-life data are essentially absent — no EQ-5D/SF-36/PROMIS data specific to ADH1.
  6. Cross-species natural disease beyond engineered mouse models is not documented.

Proposed Follow-up Experiments / Actions

  1. Assemble a natural-history registry for ADH1 to quantify prevalence, penetrance, age-of-onset distribution, and long-term renal/neurological outcomes, stratified by variant.
  2. Systematic variant-function mapping: couple in-vitro Gq/11/Gi signaling assays with clinical severity to build a genotype–phenotype and calcilytic-responsiveness atlas guiding personalized therapy.
  3. Complete calcilytic clinical development (e.g., encaleret) with renal endpoints (24-h urine calcium, GFR trajectory, nephrocalcinosis imaging) as primary outcomes, not just PTH/serum calcium.
  4. Head-to-head comparison of thiazide + conventional therapy vs calcilytic vs PTH-replacement (palopegteriparatide) on renal protection in ADH1.
  5. Prospective QoL assessment using validated instruments to capture disease and treatment burden.
  6. Mechanistic follow-up on the renal AQP2/Cldn14 axis in patient-derived models (e.g., iPSC-derived kidney organoids carrying ADH1 variants) to validate the p38MAPK–ATF1–miR137 pathway in human cells.

Report compiled from 11 confirmed findings across 35 reviewed papers over 5 investigation iterations. Evidence spans human clinical, human genetics, model organism (Nuf/knock-in mouse), and structural/computational sources. PMIDs cited inline.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 21
Resolved 21
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 31
Quoted claims found in source 29
Quoted claims not found in source 2
References weighed for topical relevance 21
On topic 17
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:31189130 (abstract only): "the identification of >400 different germline loss- and gain-of-function CaSR mutations that give rise to disorders of Ca2+ homeostasis"
  • closest text in source: "The importance of the CaSR in the regulation of Ca2+ e has been highlighted by the identification of >400 different germline loss- and gain-of-function CaSR mutations that give rise to disorders of Ca2+ e homeostasis"
  • PMID:40531442 (abstract only): "a higher prevalence of moderate-to-severe renal disease (28.8% vs. 5.6%), nephrocalcinosis (59.9% vs. 0.6%), and nephrolithiasis (8.3% vs. 1.0%). They also had significantly greater mortality (hazard ratio [HR] 2.75)"
  • closest text in source: "a higher prevalence of moderate-to-severe renal disease (28.8% vs. 5.6%), nephrocalcinosis (59.9% vs. 0.6%), and nephrolithiasis (8.3% vs. 1.0%). They also had significantly greater mortality (hazard ratio [HR] 2.75)"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 28
Resolved 26
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 7
Terms named correctly 4
Terms named as a different term 1
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • CL:1000456 (2 mentions) - the report calls it "kidney collecting duct principal cell"; CL calls it mesothelial cell of parietal peritoneum

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0007200 (1 mention) - the report calls it "phospholipase C-activating GPCR signaling"; GO calls it phospholipase C-activating G protein-coupled receptor signaling pathway, and lists "PLC-activating GPCR signaling pathway" among its other names
  • CL:0000446 (3 mentions) - the report calls it "parathyroid chief cell"; CL calls it chief cell of parathyroid gland, and lists "parathyroid chief cell" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.