Familial Hypocalciuric Hypercalcemia 1

Mendelian MONDO:0007791 Pathograph 18 Show in embeddings browser Endocrine disorder

FHH1 is the loss-of-function half of the calcium-sensing receptor allelic series, and like its gain-of-function counterpart it is a disease of a moved set point rather than of 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 inactivating variant leaves that circuitry in place but shifts its dose-response curve to the right, so calcium concentrations a normal receptor would read as high are read as adequate. Two consequences follow from the one lesion, because the same receptor is doing two jobs in two organs. In the parathyroid, PTH is not suppressed at a calcium level that should suppress it, so hypercalcaemia is defended rather than corrected. In the thick ascending limb of the loop of Henle, the receptor normally restrains paracellular calcium reabsorption when calcium is high; with the receptor blunted, that brake is not applied and calcium is reabsorbed instead of excreted. The result is the combination the disease is named for: hypercalcaemia together with a urinary calcium that is low rather than the high value hypercalcaemia would otherwise produce. That second limb is also what makes the disease benign, and the contrast with primary hyperparathyroidism is the point. In PHPT the kidney is behaving normally and dutifully excretes the excess calcium, which is what generates stones and nephrocalcinosis; in FHH1 the kidney is part of the lesion and retains it, so the classic renal complications of hypercalcaemia largely do not occur, and bone density is not lost either. The hypercalcaemia is lifelong and non-progressive and most carriers never develop symptoms. The clinical stakes are therefore diagnostic rather than therapeutic. FHH1 produces a biochemical picture - raised calcium with a PTH that is normal or frankly elevated - that is nearly indistinguishable from mild primary hyperparathyroidism, and PHPT is treated surgically. A patient with FHH1 who is mistaken for one with PHPT undergoes a parathyroidectomy that cannot work, because the parathyroid glands are responding correctly to a receptor that is misreporting the calcium level. Distinguishing the two is what the urinary calcium measurement and CASR sequencing are for, and it is the reason this entry exists as a disease rather than as a laboratory curiosity.

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1
Inheritance
9
Pathophys.
7
Phenotypes
1
Gaps
18
Pathograph
1
Genes
3
Medical Actions
1
Subtypes
9
References
👪

Inheritance

1
Autosomal dominant HP:0000006
A single inactivating allele is sufficient. The receptor is a dimer and the phenotype in heterozygotes reflects roughly half-normal calcium sensing rather than complete loss, which is why heterozygous carriers have mild lifelong hypercalcaemia while biallelic loss produces the far more severe neonatal disease recorded as a subtype below.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:20374733 SUPPORT Other
"Heterozygous loss-of-function mutations cause familial (benign) hypocalciuric hypercalcemia (FHH) in which the lifelong mild hypercalcemia is generally asymptomatic."
States that a single inactivating allele is sufficient and that the resulting hypercalcaemia is lifelong and usually asymptomatic.
◆

Subtypes

1
Neonatal severe hyperparathyroidism (biallelic CASR loss of function)
Homozygous or compound heterozygous inactivating CASR variants remove calcium sensing almost entirely rather than blunting it, and the result is a different disease in severity and urgency: marked hypercalcaemia presenting in the first days of life with muscular weakness, respiratory distress, fractures and failure to thrive, carrying real mortality. It is curated here as a subtype rather than as a separate entry because the lesion is the same receptor at a higher dose, which is the relationship the entry's genetic block records. Management inverts the adult rule. Parathyroidectomy is generally inappropriate in FHH1 and is the definitive treatment in NSHPT, and subtotal resection is reported as ineffective. A neonate carrying a single paternally inherited or de novo variant may instead present with the milder neonatal hyperparathyroidism that resolves over the first months, so the biallelic and monoallelic neonatal presentations must be distinguished before committing to surgery.
Show evidence (2 references)
PMID:35566721 SUPPORT Other
"a clinically severe, ultra-rare disease associated with a high mortality usually caused by homozygous or compound heterozygous inactivating mutations in CaSR"
Establishes the biallelic genotype and the severity that separates this subtype from the heterozygous adult disease.
PMID:35566721 SUPPORT Other
"Infants with NSHPT develop significant and symptomatic hypercalcemia with muscular weakness, respiratory distress, fractures, and failure to thrive in the early days of life"
Source for the neonatal presentation described in this subtype.
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Discussions and Knowledge Gaps

1
Does the excess of cardiovascular and neurological diagnoses reported in CASR loss-of-function carriers reflect a consequence of the receptor defect, or ascertainment in a health-system cohort?
KNOWLEDGE GAP casr_lof_extracalcitropic_burden
Attached to
pathophysiology#Hypercalcemia with Non-Suppressed PTH
A rare-variant burden test in the DiscovEHR exomes associated aggregated CASR loss-of-function variants with cardiovascular, neurological and other diagnoses. That is a real signal against the long-standing description of FHH1 as entirely benign, and this entry deliberately does not fold it into the pathograph, because the study design cannot separate a mechanistic consequence of impaired calcium sensing from confounding in a healthcare-derived cohort. CASR is expressed well beyond parathyroid and kidney, so a genuine extra-calcitropic effect is biologically plausible rather than implausible - which is exactly why the question is worth recording rather than dismissing.
Proposed experiments
Independent replication in a population cohort not ascertained through care
replicate_casr_lof_burden_population_cohort
Test the same aggregated CASR loss-of-function burden against cardiovascular and neurological endpoints in a biobank recruited independently of healthcare contact, with serum calcium available so that carriers can be stratified by whether they are biochemically affected.
Would support
pathophysiology#Hypercalcemia with Non-Suppressed PTH
Supporting outcome
  • The association persists in carriers ascertained outside the health system and tracks biochemical severity, indicating a consequence of the receptor defect rather than of ascertainment.
Refuting outcome
  • The association is absent outside the healthcare-ascertained cohort, or is present in carriers with normal serum calcium as strongly as in those with hypercalcaemia, pointing to confounding.
⚙

Pathophysiology

9
Heterozygous CASR Loss-of-Function Variant
Mechanism confidence: Established
An inactivating variant, most often missense and frequently in the large extracellular calcium-binding domain, that raises the calcium concentration required to activate the receptor. Nonsense and frameshift alleles occur as well. Functional work on hypercalcaemia-associated missense alleles shows the defect is not confined to one step: expression, plasma-membrane targeting and signalling can each be impaired.
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: LOSS_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 loss of function. GO:0004930 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Right-Shifted Calcium Set Point A receptor that requires more calcium to activate is, at the level of the whole homeostatic loop, a receptor with a higher set point.
Show evidence (2 references)
PMID:32386559 SUPPORT In Vitro
"Functional studies showed that all hypercalcemia-associated missense variants impaired heterologous expression, plasma membrane targeting, and/or signaling"
Direct functional demonstration that the FHH1-associated alleles are loss of function, and that the impairment can act at expression, trafficking or signalling.
PMID:7916660 SUPPORT In Vitro
"The expressed wild-type receptor elicited large inward currents in response to perfused polyvalent cations; a markedly attenuated response was observed with the mutated protein."
The original oocyte expression experiment showing an FHH allele signals poorly compared with wild type.
Right-Shifted Calcium Set Point
Mechanism confidence: Established
The set point is the serum calcium concentration at which PTH secretion is half-maximal. Shifting it upward is the single mechanistic statement from which the rest of the disease follows: nothing downstream is broken, but every calcium-sensing tissue is now regulating toward a higher target.
G protein-coupled receptor signaling pathway GO:0007186 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased G protein-coupled receptor signaling pathway (GO:0007186). GO:0007186 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure to Suppress Parathyroid Hormone Secretion The parathyroid limb of the shifted set point.
Increased Renal Tubular Calcium Reabsorption The renal limb. It is a separate edge rather than a consequence of the parathyroid limb, because the receptor acts on the tubule directly.
Show evidence (1 reference)
PMID:35566721 SUPPORT Other
"LOF of CaSR (in FHH1) or its downstream partner signaling proteins (in FHH2 and FHH3) result in an elevation of the body's calcium set point, defined as the serum calcium concentration at which PTH secretion is half-maximal."
Defines the set point and states that CASR loss of function raises it, which is exactly this node.
Failure to Suppress Parathyroid Hormone Secretion
Mechanism confidence: Established
Parathyroid chief cells continue to secrete PTH at calcium concentrations that should silence them. The cells are not autonomous and the glands are not neoplastic, which is why removing them does not address the lesion - they are obeying a receptor that is under-reporting the calcium level.
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 increased parathyroid hormone secretion (GO:0035898). GO:0035898 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hypercalcemia with Non-Suppressed PTH Continued PTH secretion sustains bone resorption and renal calcium retention, holding serum calcium above the normal range.
Show evidence (1 reference)
PMID:35566721 SUPPORT Other
"The resulting disorders share a constellation of inappropriately high PTH concentrations despite elevated serum calcium levels"
States the defining parathyroid abnormality - PTH that is inappropriate for the prevailing calcium rather than absolutely raised.
Increased Renal Tubular Calcium Reabsorption
Mechanism confidence: Established
In the thick ascending limb the receptor normally responds to a rise in blood calcium by reducing paracellular calcium permeability, acting through the tight-junction protein claudin-14. A blunted receptor does not apply that brake, so calcium continues to be reabsorbed at concentrations where it should be shed. This is the limb that converts what would otherwise be ordinary hypercalcaemia into the hypocalciuric form.
paracellular calcium reabsorption in the thick ascending limb GO:0006816 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased paracellular calcium reabsorption in the thick ascending limb, annotated with calcium ion transport (GO:0006816). GO:0006816 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hypocalciuria Reabsorbed calcium is calcium that does not appear in the urine.
Hypercalcemia with Non-Suppressed PTH Renal retention contributes to the circulating excess independently of the parathyroid limb.
Reduced Renal Magnesium Excretion The same paracellular pathway carries magnesium, so the transport defect is not selective for calcium.
Show evidence (2 references)
PMID:42261748 SUPPORT Model Organism
"Functional studies demonstrate that hypercalcemia-induced increases in urinary calcium excretion depend on renal CASR signaling, primarily through reduced paracellular calcium permeability in the TAL. Loss of the renal Casr in mice impairs urinary calcium excretion in conditions of hypercalcemia."
Shows in mice that the calciuric response to hypercalcaemia requires renal CASR, which is the mechanism whose loss produces hypocalciuria here.
PMID:42261748 SUPPORT Model Organism
"CASR activation upregulates claudin-14 (CLDN14), a tight junction protein that selectively blocks paracellular divalent cation reabsorption."
Names the molecular effector through which the receptor restrains paracellular calcium reabsorption.
Hypocalciuria
Mechanism confidence: Established
Urinary calcium that is low in absolute terms or, more informatively, low relative to the prevailing serum calcium. It is simultaneously the diagnostic signature of the disease and the reason for its benign course, since the renal complications of chronic hypercalcaemia require calcium to be passing through the kidney.
Show evidence (1 reference)
PMID:32386559 SUPPORT Human Clinical
"80% of FHH-affected individuals are hypocalciuric (Ca creatinine clearance ratio [CCCR] < 0.01) versus <20% of PHPT individuals with CCCR < 0.01"
Quantifies how far hypocalciuria separates FHH from primary hyperparathyroidism, and by omission how often it does not.
Reduced Renal Magnesium Excretion
Mechanism confidence: Provisional
Magnesium shares the claudin-gated paracellular route that the receptor regulates, so a blunted receptor retains magnesium alongside calcium. The resulting serum magnesium is typically high-normal to mildly raised rather than overtly abnormal.
Downstream
Hypermagnesemia Retention raises circulating magnesium.
Show evidence (1 reference)
PMID:39810898 SUPPORT Human Clinical
"In the kidney, this defect leads to an increase in tubular calcium and magnesium reabsorption resulting in hypercalcemia, hypercalcaemia, and frequently high normal levels of serum magnesium"
States that the same renal reabsorptive defect retains magnesium alongside calcium, which is the claim this node makes.
Hypercalcemia with Non-Suppressed PTH
Mechanism confidence: Established
The biochemical core of the disease and the source of its entire clinical problem, which is that it looks like mild primary hyperparathyroidism. The hypercalcaemia is lifelong, non-progressive and usually mild, and the PTH accompanying it is normal or slightly raised rather than suppressed as it would be if the hypercalcaemia had a non-parathyroid cause.
Downstream
Preserved Bone Mineral Density Despite Chronic PTH Elevation Chronic exposure to a modestly raised PTH does not, in this disease, translate into the bone loss the same biochemistry causes in primary hyperparathyroidism.
Chondrocalcinosis Calcium pyrophosphate deposition follows the sustained calcium elevation rather than the receptor defect directly, and is reported at the moderate-to-severe end of the range rather than across carriers.
Pancreatitis Reported among the classical hypercalcaemic presentations at the moderate-to-severe end of the range. The attribution is contested rather than settled, which is why the phenotype records it as VERY_RARE.
Show evidence (1 reference)
PMID:35566721 SUPPORT Other
"Clinically, FHH is a benign, typically asymptomatic disease and usually presents with the biochemical triad: life-long, non-progressive hypercalcemia, normal or slightly increased serum PTH levels and hypocalciuria"
The biochemical triad this node names, together with the benign, non-progressive course.
Hypermagnesemia
Mechanism confidence: Provisional
Mildly raised serum magnesium, a supportive rather than a diagnostic finding. It is worth recording because it is a point of difference from primary hyperparathyroidism, where magnesium is typically normal or low.
Show evidence (1 reference)
PMID:39810898 SUPPORT Human Clinical
"Serum phosphate levels are often reduced, intact PTH levels are typically inappropriately normal in 80% of patients and mildly elevated in the remainder, and mild hypermagnesaemia may be present"
Names mild hypermagnesaemia as part of the expected FHH biochemistry, alongside the phosphate and PTH findings curated elsewhere in this entry.
Preserved Bone Mineral Density Despite Chronic PTH Elevation
Mechanism confidence: Established
A deliberately negative node. Patients carry raised PTH and alkaline phosphatase for decades without losing bone, and bone density does not track the severity of the CASR variant. This is a real dissociation rather than an absence of data, and it belongs in the pathograph because it is one of the things that makes FHH1 mechanistically unlike primary hyperparathyroidism despite the shared biochemistry.
Show evidence (2 references)
PMID:19250271 SUPPORT Human Clinical
"Familiar hypocalciuric hypercalcaemia is associated with increased PTH and AP compared to normal controls, but not with bone loss irrespective of the severity of the CASR mutations."
Directly states the dissociation between chronically raised PTH and bone loss, and that it holds across variant severity.
PMID:19250271 SUPPORT Human Clinical
"They had higher Z-scores in the hip and in the forearm."
The densitometric comparison against primary hyperparathyroidism underlying this node.
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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 Familial Hypocalciuric Hypercalcemia 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

7
Digestive 1
Pancreatitis VERY_RARE HP:0001733 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancreatitis (HP:0001733). HP:0001733 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35566721 SUPPORT Other
"Although typically asymptomatic, some patients with moderate-to-severe hypercalcemia may present with classical hypercalcemic symptoms (i.e., polyuria- polydipsia, fatigue, acute and chronic pancreatitis, gallstones and chondrocalcinosis, acute pancreatitis, chondrocalcinosis, and nephrolithiasis)"
Names acute and chronic pancreatitis among the classical hypercalcaemic presentations and scopes them to the moderate-to-severe end of the range rather than to FHH1 as a whole.
Endocrine 1
Elevated or Inappropriately Normal Parathyroid Hormone FREQUENT Elevated circulating parathyroid hormone level HP:0003165 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating parathyroid hormone level (HP:0003165). HP:0003165 is a phenotype from the Human Phenotype Ontology.
Sequelae: Failure to Suppress Parathyroid Hormone Secretion
Show evidence (1 reference)
PMID:32386559 SUPPORT Human Clinical
"FHH1 accounts for ∼65% of cases, and is an autosomal-dominant condition characterized by lifelong elevations of serum calcium concentrations and normal or elevated serum parathyroid hormone (PTH) concentrations."
States that PTH is normal or elevated rather than suppressed, which is the finding this phenotype records.
Genitourinary 1
Hypocalciuria VERY_FREQUENT HP:0003127 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypocalciuria (HP:0003127). HP:0003127 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32386559 SUPPORT Human Clinical
"80% of FHH-affected individuals are hypocalciuric (Ca creatinine clearance ratio [CCCR] < 0.01) versus <20% of PHPT individuals with CCCR < 0.01"
Gives the frequency of hypocalciuria in FHH, supporting VERY_FREQUENT rather than obligate.
Metabolism 2
Hypercalcemia OBLIGATE HP:0003072 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypercalcemia (HP:0003072), qualified as course stable. HP:0003072 is a phenotype from the Human Phenotype Ontology.
Course: STABLE
Sequelae: Hypercalcemia with Non-Suppressed PTH
Show evidence (1 reference)
PMID:35566721 SUPPORT Other
"Clinically, FHH is a benign, typically asymptomatic disease and usually presents with the biochemical triad: life-long, non-progressive hypercalcemia, normal or slightly increased serum PTH levels and hypocalciuria"
States the hypercalcaemia and that it is lifelong and non-progressive, which is what the STABLE clinical course records.
Hypermagnesemia OCCASIONAL HP:0002918 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypermagnesemia (HP:0002918). HP:0002918 is a phenotype from the Human Phenotype Ontology.
Sequelae: Hypermagnesemia
Show evidence (1 reference)
PMID:35566721 SUPPORT Other
"and mild hypermagnesemia may be present"
The review states mild hypermagnesaemia as an expected accompanying finding, which is the strength of claim this phenotype records.
Musculoskeletal 1
Chondrocalcinosis OCCASIONAL HP:0000934 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chondrocalcinosis (HP:0000934). HP:0000934 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35566721 SUPPORT Other
"Although typically asymptomatic, some patients with moderate-to-severe hypercalcemia may present with classical hypercalcemic symptoms (i.e., polyuria- polydipsia, fatigue, acute and chronic pancreatitis, gallstones and chondrocalcinosis, acute pancreatitis, chondrocalcinosis, and nephrolithiasis)"
Names chondrocalcinosis among the classical hypercalcaemic presentations and scopes them to the moderate-to-severe end of the range rather than to FHH1 as a whole.
Other 1
Absence of Nephrolithiasis and Nephrocalcinosis
Show evidence (3 references)
PMID:21986511 SUPPORT Other
"Similar to PHPT, FHH is characterized by hypercalcaemia, unsuppressed or elevated plasma parathyroid hormone, and typically normal renal function."
Renal-specific, and comparative in the right direction - FHH1 shares the biochemistry of primary hyperparathyroidism without the renal consequence.
PMID:21986511 SUPPORT Other
"The hallmark is a relatively low urine calcium excretion in contrast to PHPT, in which urine calcium excretion is increased."
The mechanism behind the low stone burden - the filtered calcium load that drives stone formation in primary hyperparathyroidism is not delivered here.
PMID:35566721 REFUTE Other
"Although typically asymptomatic, some patients with moderate-to-severe hypercalcemia may present with classical hypercalcemic symptoms (i.e., polyuria- polydipsia, fatigue, acute and chronic pancreatitis, gallstones and chondrocalcinosis, acute pancreatitis, chondrocalcinosis, and nephrolithiasis)"
Refutes an absolute reading of this absence - nephrolithiasis is named among the presentations seen with moderate-to-severe hypercalcaemia, so the defensible claim is comparative rather than categorical.
🧬

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 (3 references)
PMID:7916660 SUPPORT Human Clinical
"We demonstrate that mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), two inherited conditions characterized by altered calcium homeostasis."
The founding demonstration that CASR is the causative gene, and that the same gene accounts for the neonatal subtype.
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 dose-dependent allelic series in one passage, which is what the note above is describing.
PMID:32386559 SUPPORT Human Clinical
"FHH1 accounts for ∼65% of cases"
Source for the share of FHH attributable to CASR rather than to GNA11 or AP2S1, which is why a negative CASR result does not exclude FHH.
💊

Medical Actions

3
Observation Without Intervention
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Behavioral / lifestyle
The correct management for the great majority of carriers. The hypercalcaemia is stable, the renal and skeletal complications that would justify treating it do not develop, and there is no evidence that lowering the calcium improves any outcome. Recording this as a treatment rather than as an absence of one is deliberate: the intervention that matters in FHH1 is the decision not to operate.
Show evidence (1 reference)
PMID:32386559 SUPPORT Human Clinical
"FHH1 is usually asymptomatic and requires no intervention"
States directly that the usual management is no intervention.
Avoidance of Parathyroidectomy
Action: Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. NCIT:C15329
Platform: Surgery
The single most consequential management decision in the disease, and the reason the diagnosis matters. Parathyroidectomy is the treatment for primary hyperparathyroidism and is inappropriate here, because the glands are responding correctly to a receptor that under-reports calcium; removing them does not reset the set point. The exception is the neonatal biallelic subtype, where parathyroidectomy is the definitive treatment and subtotal resection is reported as ineffective.
Show evidence (2 references)
PMID:35566721 SUPPORT Other
"In children, adolescents and young adults with FHH the main challenge is to distinguish the condition from primary hyperparathyroidism and thereby to avoid unnecessary treatments including parathyroidectomy."
States avoidance of parathyroidectomy as the object of the diagnostic effort, which is what this entry records as a treatment decision.
PMID:35566721 SUPPORT Other
"In NSHPT, total parathyroidectomy is generally considered the definitive treatment."
The neonatal exception noted here, where the same operation is indicated rather than avoided.
Cinacalcet
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: cinacalcet CHEBI:48390 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cinacalcet (CHEBI:48390). CHEBI:48390 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A calcimimetic - a positive allosteric modulator that lowers the calcium concentration needed to activate the receptor - and therefore a drug aimed at the actual lesion rather than at the number. It is reserved for the minority with symptomatic or marked hypercalcaemia, since most carriers need nothing. Reported to lower serum calcium and improve calcium clearance, and used successfully in the neonatal forms as well.
Mechanism Target:
Right-Shifted Calcium Set Point — Allosteric sensitisation of the mutant receptor partially offsets the rightward shift, which is why the drug acts on the mechanism and not merely on the calcium level.
Show evidence (2 references)
PMID:35566721 SUPPORT Other
"In FHH, cinacalcet results in a significant reduction of serum calcium levels and improvement of calcium clearance after initiation of cinacalcet therapy"
Reports the biochemical effect of cinacalcet in FHH, which is the basis for its selective use here.
PMID:35566721 SUPPORT Other
"Calcimimetic drugs, such as cinacalcet, are allosteric agonists at the CaSR"
Establishes the pharmacological class and mode of action that the target_mechanisms link asserts.
🔬

Biochemical Markers

3
Serum total and ionised calcium (Increased)
Context: The presenting analyte, usually found incidentally. The elevation is mild and stable over decades, which is itself a point of difference from the progressive hypercalcaemia of some other causes.
Pathograph Readouts
Readout Of Hypercalcemia with Non-Suppressed PTH Positive Diagnostic
Reports the raised set point as it appears in the circulation.
Calcium/creatinine clearance ratio (Decreased)
Context: The discriminating measurement, computed from paired serum and urine calcium and creatinine. A ratio below 0.01 is the classic FHH figure; a two-step approach using a more permissive cut-off first and CASR sequencing second has been proposed because the distributions of FHH and primary hyperparathyroidism overlap.
Pathograph Readouts
Readout Of Hypocalciuria Negative Diagnostic
Expresses urinary calcium relative to the prevailing serum calcium and renal function, which is what makes it more informative than a raw 24-hour calcium.
Show evidence (1 reference)
PMID:18410554 SUPPORT Human Clinical
"Based on the ROC curve, the optimal cut-off point for diagnosing FHH using CCCR was < 0.0115, which yielded a diagnostic specificity of 0.88 and a sensitivity of 0.80."
Quantifies the performance of the ratio as a diagnostic readout, against genetically and surgically confirmed comparison groups.
Intact parathyroid hormone (Increased)
Context: Measured with calcium rather than alone. The value that matters is whether PTH is suppressed for the prevailing calcium, not whether it exceeds the reference interval.
Pathograph Readouts
Readout Of Failure to Suppress Parathyroid Hormone Secretion Positive Diagnostic
A PTH that is normal or raised alongside hypercalcaemia reports the parathyroid limb of the lesion.
🔬

Diagnosis

4
Paired Serum Calcium and Intact PTH
The entry point. Hypercalcaemia with a PTH that is not suppressed establishes a PTH-dependent hypercalcaemia and narrows the differential to primary hyperparathyroidism, FHH and a few rarer causes. It does not distinguish within that group.
Laboratory Procedure NCIT:C25294 NCI Thesaurus (NCIT)
Calcium/Creatinine Clearance Ratio
The discriminating test, from paired serum and 24-hour urine calcium and creatinine. It is a screening step and not a rule: roughly a fifth of FHH patients are not hypocalciuric by the strict cut-off, and a substantial minority of primary hyperparathyroidism patients fall below it, so the ratio stratifies who should be sequenced rather than settling the diagnosis. Recent thiazide use, lithium, low calcium intake and vitamin D deficiency all move it.
Laboratory Procedure NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:18410554 SUPPORT Human Clinical
"Our results support the use of the CCCR as an initial screening test for FHH. We suggest a two-step diagnostic procedure, where the first step is based on the CCCR with a cut-off at < 0.020, and the second step is CASR gene analysis in patients with FHH or PHPT."
Supports treating the ratio as a screening step followed by sequencing, which is how this entry describes it.
PMID:18410554 SUPPORT Human Clinical
"Overlap analysis revealed that a cut-off point for CCCR at < 0.020 would sample 98% (53/54) of all patients with FHH and include 35% (34/97) of the PHPT patients."
Quantifies the overlap that makes the ratio a stratifier rather than a decisive test.
Parathyroid Localization Imaging
Listed here to record what it does not do. Sestamibi scintigraphy, ultrasound and 4D-CT locate parathyroid tissue for a surgeon who has already decided to operate; they do not establish that the hypercalcaemia is parathyroid-driven in the first place, and a positive study does not exclude FHH1. A positive scan in a patient whose biochemistry has not resolved the differential is therefore not a reason to proceed, and this is a documented route to an operation that cannot work: in the case cited below, scintigraphy showed focal uptake beside the thyroid, that finding together with a mildly raised PTH settled a diagnosis of primary hyperparathyroidism, and the patient was still hypercalcaemic months after a total parathyroidectomy. Two further traps in the same case are worth recording. The uptake sat above the left thyroid lobe, which is also where a thyroid nodule sits, and the resected glands showed four-gland mild hyperplasia - a feature of FHH1 itself rather than evidence against it, so the operative histology did not correct the error either. The order of evidence that should have governed the decision is the reverse of the one followed: the differential rests on the biochemistry and on CASR genotype, not on where an isotope collects.
parathyroid localization imaging NCIT:C16502 NCI Thesaurus (NCIT)
Show evidence (5 references)
PMID:39810898 SUPPORT Human Clinical
"Parathyroid scintigraphy reported an ill-defined area of focal uptake above the left thyroid lobe."
A positive localization study in a patient subsequently shown to have FHH, which is the false-positive this entry warns about.
PMID:39810898 SUPPORT Human Clinical
"A diagnosis of PHPT was made likely secondary to parathyroid hyperplasia or a parathyroid adenoma. This was based on the elevated PTH concentration and scintigraphy results."
States that the scintigraphy result was part of what drove the incorrect diagnosis and the decision to operate.
PMID:39810898 SUPPORT Human Clinical
"Several months post-operatively the patient was noted to have persistent hypercalcaemia which is a strong indicator of FHH rather than PHPT"
The outcome that establishes the operation could not have worked, since the lesion was never in the glands that were removed.
+ 2 more references
CASR Sequencing
Confirmatory, and the step that should precede any decision about surgery in an ambiguous case. A negative result does not exclude FHH, since GNA11 and AP2S1 account for the remaining third.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
📊

Prevalence

1
DiscovEHR cohort, single US health system, whole-exome sequenced
Point Prevalence 74.1 per 100,000 1–9 per 10,000
Genetic rather than clinical ascertainment: predicted loss-of-function CASR variants identified in 51,289 exomes and triaged against serum calcium. The authors note this makes FHH1 about as common as primary hyperparathyroidism, which reframes it from a rarity to a routine differential. Clinically ascertained estimates are lower, since most carriers never come to attention.
Show evidence (2 references)
PMID:32386559 SUPPORT Human Clinical
"giving a prevalence in this population of 74.1 per 100,000 for FHH1 and 3.9 per 100,000 for ADH1"
The population prevalence figure recorded here, with its cohort stated.
PMID:32386559 SUPPORT Human Clinical
"In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence similar to that of primary hyperparathyroidism"
Supports the note's claim that FHH1 is comparably common to the disease it is mistaken for.
{ }

Source YAML

click to show 
name: Familial Hypocalciuric Hypercalcemia 1
creation_date: "2026-09-04T00:00:00Z"
category: Mendelian
description: >-
  FHH1 is the loss-of-function half of the calcium-sensing receptor allelic
  series, and like its gain-of-function counterpart it is a disease of a moved
  set point rather than of 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
  inactivating variant leaves that circuitry in place but shifts its
  dose-response curve to the right, so calcium concentrations a normal receptor
  would read as high are read as adequate.

  Two consequences follow from the one lesion, because the same receptor is
  doing two jobs in two organs. In the parathyroid, PTH is not suppressed at a
  calcium level that should suppress it, so hypercalcaemia is defended rather
  than corrected. In the thick ascending limb of the loop of Henle, the receptor
  normally restrains paracellular calcium reabsorption when calcium is high;
  with the receptor blunted, that brake is not applied and calcium is reabsorbed
  instead of excreted. The result is the combination the disease is named for:
  hypercalcaemia together with a urinary calcium that is low rather than the
  high value hypercalcaemia would otherwise produce.

  That second limb is also what makes the disease benign, and the contrast with
  primary hyperparathyroidism is the point. In PHPT the kidney is behaving
  normally and dutifully excretes the excess calcium, which is what generates
  stones and nephrocalcinosis; in FHH1 the kidney is part of the lesion and
  retains it, so the classic renal complications of hypercalcaemia largely do
  not occur, and bone density is not lost either. The hypercalcaemia is lifelong
  and non-progressive and most carriers never develop symptoms.

  The clinical stakes are therefore diagnostic rather than therapeutic. FHH1
  produces a biochemical picture - raised calcium with a PTH that is normal or
  frankly elevated - that is nearly indistinguishable from mild primary
  hyperparathyroidism, and PHPT is treated surgically. A patient with FHH1 who
  is mistaken for one with PHPT undergoes a parathyroidectomy that cannot work,
  because the parathyroid glands are responding correctly to a receptor that is
  misreporting the calcium level. Distinguishing the two is what the urinary
  calcium measurement and CASR sequencing are for, and it is the reason this
  entry exists as a disease rather than as a laboratory curiosity.
disease_term:
  preferred_term: familial hypocalciuric hypercalcemia 1
  term:
    id: MONDO:0007791
    label: familial hypocalciuric hypercalcemia 1
synonyms:
- FHH1
- FHH type 1
- familial hypocalciuric hypercalcemia type I
- hypocalciuric hypercalcemia type I
- familial benign hypercalcemia 1
- hypercalcemia, familial benign type 1
- HHC1
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 inactivating allele is sufficient. The receptor is a dimer and the
    phenotype in heterozygotes reflects roughly half-normal calcium sensing
    rather than complete loss, which is why heterozygous carriers have mild
    lifelong hypercalcaemia while biallelic loss produces the far more severe
    neonatal disease recorded as a subtype below.
  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.
    explanation: States that a single inactivating allele is sufficient and that the
      resulting hypercalcaemia is lifelong and usually asymptomatic.
has_subtypes:
- name: NSHPT
  display_name: Neonatal severe hyperparathyroidism (biallelic CASR loss of function)
  description: >-
    Homozygous or compound heterozygous inactivating CASR variants remove calcium
    sensing almost entirely rather than blunting it, and the result is a different
    disease in severity and urgency: marked hypercalcaemia presenting in the first
    days of life with muscular weakness, respiratory distress, fractures and
    failure to thrive, carrying real mortality. It is curated here as a subtype
    rather than as a separate entry because the lesion is the same receptor at a
    higher dose, which is the relationship the entry's genetic block records.

    Management inverts the adult rule. Parathyroidectomy is generally inappropriate
    in FHH1 and is the definitive treatment in NSHPT, and subtotal resection is
    reported as ineffective. A neonate carrying a single paternally inherited or
    de novo variant may instead present with the milder neonatal hyperparathyroidism
    that resolves over the first months, so the biallelic and monoallelic neonatal
    presentations must be distinguished before committing to surgery.
  evidence:
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: a clinically severe, ultra-rare disease associated with a high mortality
      usually caused by homozygous or compound heterozygous inactivating mutations
      in CaSR
    explanation: Establishes the biallelic genotype and the severity that separates
      this subtype from the heterozygous adult disease.
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Infants with NSHPT develop significant and symptomatic hypercalcemia with
      muscular weakness, respiratory distress, fractures, and failure to thrive in
      the early days of life
    explanation: Source for the neonatal presentation described in this subtype.
pathophysiology:
- name: Heterozygous CASR Loss-of-Function Variant
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    An inactivating variant, most often missense and frequently in the large
    extracellular calcium-binding domain, that raises the calcium concentration
    required to activate the receptor. Nonsense and frameshift alleles occur as
    well. Functional work on hypercalcaemia-associated missense alleles shows the
    defect is not confined to one step: expression, plasma-membrane targeting and
    signalling can each be impaired.
  genetic_context:
    gene:
      preferred_term: CASR
      term:
        id: hgnc:1514
        label: CASR
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: calcium-sensing receptor activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0004930
      label: G protein-coupled receptor activity
  evidence:
  - reference: PMID:32386559
    reference_title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant
      Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Functional studies showed that all hypercalcemia-associated missense variants
      impaired heterologous expression, plasma membrane targeting, and/or signaling
    explanation: Direct functional demonstration that the FHH1-associated alleles are
      loss of function, and that the impairment can act at expression, trafficking
      or signalling.
  - reference: PMID:7916660
    reference_title: Mutations in the human Ca(2+)-sensing receptor gene cause familial
      hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The expressed wild-type receptor elicited large inward currents in response
      to perfused polyvalent cations; a markedly attenuated response was observed with
      the mutated protein.
    explanation: The original oocyte expression experiment showing an FHH allele signals
      poorly compared with wild type.
  downstream:
  - target: Right-Shifted Calcium Set Point
    causal_link_type: DIRECT
    description: >-
      A receptor that requires more calcium to activate is, at the level of the
      whole homeostatic loop, a receptor with a higher set point.
- name: Right-Shifted Calcium Set Point
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The set point is the serum calcium concentration at which PTH secretion is
    half-maximal. Shifting it upward is the single mechanistic statement from
    which the rest of the disease follows: nothing downstream is broken, but
    every calcium-sensing tissue is now regulating toward a higher target.
  biological_processes:
  - preferred_term: G protein-coupled receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0007186
      label: G protein-coupled receptor signaling pathway
  evidence:
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: LOF of CaSR (in FHH1) or its downstream partner signaling proteins (in
      FHH2 and FHH3) result in an elevation of the body's calcium set point, defined
      as the serum calcium concentration at which PTH secretion is half-maximal.
    explanation: Defines the set point and states that CASR loss of function raises it,
      which is exactly this node.
  downstream:
  - target: Failure to Suppress Parathyroid Hormone Secretion
    causal_link_type: DIRECT
    description: The parathyroid limb of the shifted set point.
  - target: Increased Renal Tubular Calcium Reabsorption
    causal_link_type: DIRECT
    description: >-
      The renal limb. It is a separate edge rather than a consequence of the
      parathyroid limb, because the receptor acts on the tubule directly.
- name: Failure to Suppress Parathyroid Hormone Secretion
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Parathyroid chief cells continue to secrete PTH at calcium concentrations
    that should silence them. The cells are not autonomous and the glands are not
    neoplastic, which is why removing them does not address the lesion - they are
    obeying a receptor that is under-reporting the calcium level.
  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: INCREASED
    term:
      id: GO:0035898
      label: parathyroid hormone secretion
  evidence:
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The resulting disorders share a constellation of inappropriately high PTH
      concentrations despite elevated serum calcium levels
    explanation: States the defining parathyroid abnormality - PTH that is inappropriate
      for the prevailing calcium rather than absolutely raised.
  downstream:
  - target: Hypercalcemia with Non-Suppressed PTH
    causal_link_type: DIRECT
    description: >-
      Continued PTH secretion sustains bone resorption and renal calcium
      retention, holding serum calcium above the normal range.
- name: Increased Renal Tubular Calcium Reabsorption
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    In the thick ascending limb the receptor normally responds to a rise in blood
    calcium by reducing paracellular calcium permeability, acting through the
    tight-junction protein claudin-14. A blunted receptor does not apply that
    brake, so calcium continues to be reabsorbed at concentrations where it
    should be shed. This is the limb that converts what would otherwise be
    ordinary hypercalcaemia into the hypocalciuric form.
  biological_processes:
  - preferred_term: paracellular calcium reabsorption in the thick ascending limb
    modifier: INCREASED
    term:
      id: GO:0006816
      label: calcium ion transport
  evidence:
  - reference: PMID:42261748
    reference_title: Role of the calcium-sensing receptor in regulating calcium transport
      in the thick ascending limb.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Functional studies demonstrate that hypercalcemia-induced increases in urinary
      calcium excretion depend on renal CASR signaling, primarily through reduced paracellular
      calcium permeability in the TAL. Loss of the renal Casr in mice impairs urinary
      calcium excretion in conditions of hypercalcemia.
    explanation: Shows in mice that the calciuric response to hypercalcaemia requires
      renal CASR, which is the mechanism whose loss produces hypocalciuria here.
  - reference: PMID:42261748
    reference_title: Role of the calcium-sensing receptor in regulating calcium transport
      in the thick ascending limb.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: CASR activation upregulates claudin-14 (CLDN14), a tight junction protein
      that selectively blocks paracellular divalent cation reabsorption.
    explanation: Names the molecular effector through which the receptor restrains
      paracellular calcium reabsorption.
  downstream:
  - target: Hypocalciuria
    causal_link_type: DIRECT
    description: Reabsorbed calcium is calcium that does not appear in the urine.
  - target: Hypercalcemia with Non-Suppressed PTH
    causal_link_type: DIRECT
    description: >-
      Renal retention contributes to the circulating excess independently of the
      parathyroid limb.
  - target: Reduced Renal Magnesium Excretion
    causal_link_type: DIRECT
    description: >-
      The same paracellular pathway carries magnesium, so the transport defect is
      not selective for calcium.
- name: Hypocalciuria
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    Urinary calcium that is low in absolute terms or, more informatively, low
    relative to the prevailing serum calcium. It is simultaneously the diagnostic
    signature of the disease and the reason for its benign course, since the
    renal complications of chronic hypercalcaemia require calcium to be passing
    through the kidney.
  evidence:
  - reference: PMID:32386559
    reference_title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant
      Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 80% of FHH-affected individuals are hypocalciuric (Ca creatinine clearance
      ratio [CCCR] < 0.01) versus <20% of PHPT individuals with CCCR < 0.01
    explanation: Quantifies how far hypocalciuria separates FHH from primary
      hyperparathyroidism, and by omission how often it does not.
- name: Reduced Renal Magnesium Excretion
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Magnesium shares the claudin-gated paracellular route that the receptor
    regulates, so a blunted receptor retains magnesium alongside calcium. The
    resulting serum magnesium is typically high-normal to mildly raised rather
    than overtly abnormal.
  evidence:
  - reference: PMID:39810898
    reference_title: 'Retrospectively diagnosed familial hypocalciuric hypercalcaemia
      following total parathyroidectomy in an asymptomatic patient.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the kidney, this defect leads to an increase in tubular calcium and
      magnesium reabsorption resulting in hypercalcemia, hypercalcaemia, and frequently
      high normal levels of serum magnesium
    explanation: States that the same renal reabsorptive defect retains magnesium
      alongside calcium, which is the claim this node makes.
  downstream:
  - target: Hypermagnesemia
    causal_link_type: DIRECT
    description: Retention raises circulating magnesium.
- name: Hypercalcemia with Non-Suppressed PTH
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The biochemical core of the disease and the source of its entire clinical
    problem, which is that it looks like mild primary hyperparathyroidism. The
    hypercalcaemia is lifelong, non-progressive and usually mild, and the PTH
    accompanying it is normal or slightly raised rather than suppressed as it
    would be if the hypercalcaemia had a non-parathyroid cause.
  evidence:
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Clinically, FHH is a benign, typically asymptomatic disease and usually
      presents with the biochemical triad: life-long, non-progressive hypercalcemia,
      normal or slightly increased serum PTH levels and hypocalciuria'
    explanation: The biochemical triad this node names, together with the benign,
      non-progressive course.
  downstream:
  - target: Preserved Bone Mineral Density Despite Chronic PTH Elevation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Chronic exposure to a modestly raised PTH does not, in this disease,
      translate into the bone loss the same biochemistry causes in primary
      hyperparathyroidism.
  - target: Chondrocalcinosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Calcium pyrophosphate deposition follows the sustained calcium elevation
      rather than the receptor defect directly, and is reported at the
      moderate-to-severe end of the range rather than across carriers.
  - target: Pancreatitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reported among the classical hypercalcaemic presentations at the
      moderate-to-severe end of the range. The attribution is contested rather
      than settled, which is why the phenotype records it as VERY_RARE.
- name: Hypermagnesemia
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    Mildly raised serum magnesium, a supportive rather than a diagnostic finding.
    It is worth recording because it is a point of difference from primary
    hyperparathyroidism, where magnesium is typically normal or low.
  evidence:
  - reference: PMID:39810898
    reference_title: 'Retrospectively diagnosed familial hypocalciuric hypercalcaemia
      following total parathyroidectomy in an asymptomatic patient.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Serum phosphate levels are often reduced, intact PTH levels are typically
      inappropriately normal in 80% of patients and mildly elevated in the remainder,
      and mild hypermagnesaemia may be present
    explanation: Names mild hypermagnesaemia as part of the expected FHH biochemistry,
      alongside the phosphate and PTH findings curated elsewhere in this entry.
- name: Preserved Bone Mineral Density Despite Chronic PTH Elevation
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    A deliberately negative node. Patients carry raised PTH and alkaline
    phosphatase for decades without losing bone, and bone density does not track
    the severity of the CASR variant. This is a real dissociation rather than an
    absence of data, and it belongs in the pathograph because it is one of the
    things that makes FHH1 mechanistically unlike primary hyperparathyroidism
    despite the shared biochemistry.
  evidence:
  - reference: PMID:19250271
    reference_title: Skeletal consequences of familial hypocalciuric hypercalcaemia vs.
      primary hyperparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Familiar hypocalciuric hypercalcaemia is associated with increased PTH and
      AP compared to normal controls, but not with bone loss irrespective of the severity
      of the CASR mutations.
    explanation: Directly states the dissociation between chronically raised PTH and
      bone loss, and that it holds across variant severity.
  - reference: PMID:19250271
    reference_title: Skeletal consequences of familial hypocalciuric hypercalcaemia vs.
      primary hyperparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: They had higher Z-scores in the hip and in the forearm.
    explanation: The densitometric comparison against primary hyperparathyroidism
      underlying this node.
phenotypes:
- category: Biochemical
  name: Hypercalcemia
  frequency: OBLIGATE
  description: >-
    Lifelong, non-progressive and usually mild. Most often found incidentally on
    a routine calcium measurement rather than through symptoms.
  phenotype_term:
    preferred_term: Hypercalcemia
    term:
      id: HP:0003072
      label: Hypercalcemia
    clinical_course: STABLE
  evidence:
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Clinically, FHH is a benign, typically asymptomatic disease and usually
      presents with the biochemical triad: life-long, non-progressive hypercalcemia,
      normal or slightly increased serum PTH levels and hypocalciuria'
    explanation: States the hypercalcaemia and that it is lifelong and non-progressive,
      which is what the STABLE clinical course records.
  sequelae:
  - target: Hypercalcemia with Non-Suppressed PTH
    description: The clinical finding corresponding to the pathophysiology node.
- category: Biochemical
  name: Hypocalciuria
  frequency: VERY_FREQUENT
  description: >-
    Low urinary calcium excretion relative to serum calcium, conventionally
    expressed as a calcium/creatinine clearance ratio. It is the finding the
    disease is named for and the one that separates it from primary
    hyperparathyroidism, though the separation is imperfect.
  phenotype_term:
    preferred_term: Hypocalciuria
    term:
      id: HP:0003127
      label: Hypocalciuria
  evidence:
  - reference: PMID:32386559
    reference_title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant
      Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 80% of FHH-affected individuals are hypocalciuric (Ca creatinine clearance
      ratio [CCCR] < 0.01) versus <20% of PHPT individuals with CCCR < 0.01
    explanation: Gives the frequency of hypocalciuria in FHH, supporting VERY_FREQUENT
      rather than obligate.
- category: Biochemical
  name: Elevated or Inappropriately Normal Parathyroid Hormone
  frequency: FREQUENT
  description: >-
    PTH that is not suppressed in the face of hypercalcaemia. It may sit within
    the reference interval - which is itself abnormal at this calcium level - or
    be frankly raised. This is the finding that puts primary hyperparathyroidism
    on the differential and cannot be used to exclude it.
  phenotype_term:
    preferred_term: Elevated circulating parathyroid hormone level
    term:
      id: HP:0003165
      label: Elevated circulating parathyroid hormone level
  evidence:
  - reference: PMID:32386559
    reference_title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant
      Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FHH1 accounts for ∼65% of cases, and is an autosomal-dominant condition
      characterized by lifelong elevations of serum calcium concentrations and normal
      or elevated serum parathyroid hormone (PTH) concentrations.
    explanation: States that PTH is normal or elevated rather than suppressed, which is
      the finding this phenotype records.
  sequelae:
  - target: Failure to Suppress Parathyroid Hormone Secretion
    description: The circulating readout of the parathyroid limb of the lesion.
- category: Biochemical
  name: Hypermagnesemia
  frequency: OCCASIONAL
  description: >-
    Mildly raised serum magnesium, reflecting the same paracellular transport
    defect that retains calcium. Supportive rather than diagnostic, and mild
    enough that it is often reported as high-normal rather than frankly raised.
  phenotype_term:
    preferred_term: Hypermagnesemia
    term:
      id: HP:0002918
      label: Hypermagnesemia
  evidence:
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: and mild hypermagnesemia may be present
    explanation: The review states mild hypermagnesaemia as an expected accompanying
      finding, which is the strength of claim this phenotype records.
  sequelae:
  - target: Hypermagnesemia
    description: The clinical finding corresponding to the pathophysiology node.
- category: Musculoskeletal
  name: Chondrocalcinosis
  frequency: OCCASIONAL
  description: >-
    Calcium pyrophosphate deposition in cartilage, one of the few complications
    attributable to the chronic hypercalcaemia itself. Like the other symptomatic
    presentations of FHH1 it is reported in the moderate-to-severe end of the
    hypercalcaemic range rather than across carriers generally.
  phenotype_term:
    preferred_term: Chondrocalcinosis
    term:
      id: HP:0000934
      label: Chondrocalcinosis
  evidence:
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Although typically asymptomatic, some patients with moderate-to-severe
      hypercalcemia may present with classical hypercalcemic symptoms (i.e., polyuria-
      polydipsia, fatigue, acute and chronic pancreatitis, gallstones and chondrocalcinosis,
      acute pancreatitis, chondrocalcinosis, and nephrolithiasis)'
    explanation: Names chondrocalcinosis among the classical hypercalcaemic
      presentations and scopes them to the moderate-to-severe end of the range rather
      than to FHH1 as a whole.
- category: Gastrointestinal
  name: Pancreatitis
  frequency: VERY_RARE
  description: >-
    An uncommon association, and reported in the subset with moderate-to-severe
    hypercalcaemia rather than across FHH1 generally. Its causal attribution to
    FHH1 is contested rather than settled, and it should not be assumed in an
    individual patient without excluding the usual causes.
  phenotype_term:
    preferred_term: Pancreatitis
    term:
      id: HP:0001733
      label: Pancreatitis
  evidence:
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Although typically asymptomatic, some patients with moderate-to-severe
      hypercalcemia may present with classical hypercalcemic symptoms (i.e., polyuria-
      polydipsia, fatigue, acute and chronic pancreatitis, gallstones and chondrocalcinosis,
      acute pancreatitis, chondrocalcinosis, and nephrolithiasis)'
    explanation: Names acute and chronic pancreatitis among the classical
      hypercalcaemic presentations and scopes them to the moderate-to-severe end of the
      range rather than to FHH1 as a whole.
- category: Renal
  name: Absence of Nephrolithiasis and Nephrocalcinosis
  description: >-
    Recorded because the rarity of these complications is mechanistically
    informative rather than merely unremarkable. Chronic hypercalcaemia normally
    produces stones and nephrocalcinosis by way of hypercalciuria; the renal limb
    of the CASR lesion removes that intermediate step, so the renal burden that
    defines primary hyperparathyroidism is markedly lower here. The claim is
    comparative, not absolute: nephrolithiasis is reported in the
    moderate-to-severe end of the FHH1 range, which is why the REFUTE item below
    is carried alongside.

    Curated as a negative phenotype, and deliberately carrying NO phenotype_term
    and NO frequency. The schema has no negation slot and FrequencyEnum has no
    EXCLUDED value, so binding HP:0000787 with a frequency here would export as
    the assertion that FHH1 patients have nephrolithiasis - the inverse of the
    point, and it would invert this entry's own argument for distinguishing FHH1
    from primary hyperparathyroidism. The REFUTE grading on an evidence item is
    claim-relative and never reaches the phenotype assertion, so it cannot
    substitute. This follows the pattern in
    Autosomal_Dominant_Nonsyndromic_Hearing_Loss_11 ("Absence of Retinitis
    Pigmentosa") and Amyotrophic_Lateral_Sclerosis_27_Juvenile ("Absence of
    Sensory Neuropathy").
  evidence:
  - reference: PMID:21986511
    reference_title: 'Familial hypocalciuric hypercalcaemia: a review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Similar to PHPT, FHH is characterized by hypercalcaemia, unsuppressed or
      elevated plasma parathyroid hormone, and typically normal renal function.
    explanation: Renal-specific, and comparative in the right direction - FHH1 shares the
      biochemistry of primary hyperparathyroidism without the renal consequence.
  - reference: PMID:21986511
    reference_title: 'Familial hypocalciuric hypercalcaemia: a review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The hallmark is a relatively low urine calcium excretion in contrast to PHPT,
      in which urine calcium excretion is increased.
    explanation: The mechanism behind the low stone burden - the filtered calcium load
      that drives stone formation in primary hyperparathyroidism is not delivered here.
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: REFUTE
    evidence_source: OTHER
    snippet: 'Although typically asymptomatic, some patients with moderate-to-severe
      hypercalcemia may present with classical hypercalcemic symptoms (i.e., polyuria-
      polydipsia, fatigue, acute and chronic pancreatitis, gallstones and chondrocalcinosis,
      acute pancreatitis, chondrocalcinosis, and nephrolithiasis)'
    explanation: Refutes an absolute reading of this absence - nephrolithiasis is named
      among the presentations seen with moderate-to-severe hypercalcaemia, so the
      defensible claim is comparative rather than categorical.
genetic:
- name: CASR
  gene_term:
    preferred_term: CASR
    term:
      id: hgnc:1514
      label: CASR
  relationship_type: CAUSATIVE
  notes: >-
    CASR is one of the clearest allelic series in medicine, and FHH1 is best read
    against the rest of it: heterozygous loss of function gives this disease,
    biallelic loss of function gives neonatal severe hyperparathyroidism, and
    heterozygous gain of function gives autosomal dominant hypocalcaemia type 1,
    curated separately in this knowledge base. One receptor, dosed in both
    directions from normal.

    Two limits on genetic testing are worth recording. FHH1 accounts for roughly
    two-thirds of FHH; the remainder is FHH2 (GNA11) and FHH3 (AP2S1), which
    affect the receptor's downstream partners rather than the receptor itself and
    are clinically similar, so a negative CASR result does not exclude FHH. And
    within CASR, variant interpretation carries the usual difficulty that a rare
    missense change of uncertain significance is not by itself a diagnosis.
  evidence:
  - reference: PMID:7916660
    reference_title: Mutations in the human Ca(2+)-sensing receptor gene cause familial
      hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We demonstrate that mutations in the human Ca(2+)-sensing receptor gene
      cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism
      (NSHPT), two inherited conditions characterized by altered calcium homeostasis.
    explanation: The founding demonstration that CASR is the causative gene, and that
      the same gene accounts for the neonatal subtype.
  - 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.
    explanation: The dose-dependent allelic series in one passage, which is what the
      note above is describing.
  - reference: PMID:32386559
    reference_title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant
      Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FHH1 accounts for ∼65% of cases
    explanation: Source for the share of FHH attributable to CASR rather than to GNA11
      or AP2S1, which is why a negative CASR result does not exclude FHH.
  case_fractions:
  - population: Familial hypocalciuric hypercalcemia, all genetic subtypes
    case_fraction_percent: 65.0
    notes: Share of FHH attributable to CASR (FHH1) rather than GNA11 (FHH2) or AP2S1
      (FHH3).
    evidence:
    - reference: PMID:32386559
      reference_title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant
        Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: FHH1 accounts for ∼65% of cases
      explanation: States the CASR share of FHH directly.
biochemical:
- name: Serum total and ionised calcium
  presence: Increased
  context: >-
    The presenting analyte, usually found incidentally. The elevation is mild and
    stable over decades, which is itself a point of difference from the
    progressive hypercalcaemia of some other causes.
  biomarker_term:
    preferred_term: calcium(2+)
    term:
      id: CHEBI:29108
      label: calcium(2+)
  readouts:
  - target: Hypercalcemia with Non-Suppressed PTH
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Reports the raised set point as it appears in the circulation.
- name: Calcium/creatinine clearance ratio
  presence: Decreased
  context: >-
    The discriminating measurement, computed from paired serum and urine calcium
    and creatinine. A ratio below 0.01 is the classic FHH figure; a two-step
    approach using a more permissive cut-off first and CASR sequencing second has
    been proposed because the distributions of FHH and primary hyperparathyroidism
    overlap.
  biomarker_term:
    preferred_term: calcium(2+)
    term:
      id: CHEBI:29108
      label: calcium(2+)
  readouts:
  - target: Hypocalciuria
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Expresses urinary calcium relative to the prevailing serum calcium and renal
      function, which is what makes it more informative than a raw 24-hour calcium.
    evidence:
    - reference: PMID:18410554
      reference_title: 'Discriminative power of three indices of renal calcium excretion for
        the distinction between familial hypocalciuric hypercalcaemia and primary
        hyperparathyroidism: a follow-up study on methods.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Based on the ROC curve, the optimal cut-off point for diagnosing FHH using
        CCCR was < 0.0115, which yielded a diagnostic specificity of 0.88 and a sensitivity
        of 0.80.
      explanation: Quantifies the performance of the ratio as a diagnostic readout,
        against genetically and surgically confirmed comparison groups.
- name: Intact parathyroid hormone
  presence: Increased
  context: >-
    Measured with calcium rather than alone. The value that matters is whether
    PTH is suppressed for the prevailing calcium, not whether it exceeds the
    reference interval.
  biomarker_term:
    preferred_term: Parathyroid Hormone
    term:
      id: NCIT:C41027
      label: Parathyroid Hormone
  readouts:
  - target: Failure to Suppress Parathyroid Hormone Secretion
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: A PTH that is normal or raised alongside hypercalcaemia reports the
      parathyroid limb of the lesion.
prevalence:
- population: DiscovEHR cohort, single US health system, whole-exome sequenced
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 74.1
  notes: >-
    Genetic rather than clinical ascertainment: predicted loss-of-function CASR
    variants identified in 51,289 exomes and triaged against serum calcium. The
    authors note this makes FHH1 about as common as primary hyperparathyroidism,
    which reframes it from a rarity to a routine differential. Clinically
    ascertained estimates are lower, since most carriers never come to attention.
  evidence:
  - reference: PMID:32386559
    reference_title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant
      Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: giving a prevalence in this population of 74.1 per 100,000 for FHH1 and
      3.9 per 100,000 for ADH1
    explanation: The population prevalence figure recorded here, with its cohort stated.
  - reference: PMID:32386559
    reference_title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant
      Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In conclusion, FHH1 is a common cause of hypercalcemia, with prevalence
      similar to that of primary hyperparathyroidism'
    explanation: Supports the note's claim that FHH1 is comparably common to the disease
      it is mistaken for.
diagnosis:
- name: Paired Serum Calcium and Intact PTH
  description: >-
    The entry point. Hypercalcaemia with a PTH that is not suppressed establishes
    a PTH-dependent hypercalcaemia and narrows the differential to primary
    hyperparathyroidism, FHH and a few rarer causes. It does not distinguish
    within that group.
  diagnosis_term:
    preferred_term: Laboratory Procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
- name: Calcium/Creatinine Clearance Ratio
  description: >-
    The discriminating test, from paired serum and 24-hour urine calcium and
    creatinine. It is a screening step and not a rule: roughly a fifth of FHH
    patients are not hypocalciuric by the strict cut-off, and a substantial
    minority of primary hyperparathyroidism patients fall below it, so the ratio
    stratifies who should be sequenced rather than settling the diagnosis. Recent
    thiazide use, lithium, low calcium intake and vitamin D deficiency all move
    it.
  diagnosis_term:
    preferred_term: Laboratory Procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:18410554
    reference_title: 'Discriminative power of three indices of renal calcium excretion for
      the distinction between familial hypocalciuric hypercalcaemia and primary
      hyperparathyroidism: a follow-up study on methods.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Our results support the use of the CCCR as an initial screening test for
      FHH. We suggest a two-step diagnostic procedure, where the first step is based
      on the CCCR with a cut-off at < 0.020, and the second step is CASR gene analysis
      in patients with FHH or PHPT.'
    explanation: Supports treating the ratio as a screening step followed by sequencing,
      which is how this entry describes it.
  - reference: PMID:18410554
    reference_title: 'Discriminative power of three indices of renal calcium excretion for
      the distinction between familial hypocalciuric hypercalcaemia and primary
      hyperparathyroidism: a follow-up study on methods.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Overlap analysis revealed that a cut-off point for CCCR at < 0.020 would
      sample 98% (53/54) of all patients with FHH and include 35% (34/97) of the PHPT
      patients.
    explanation: Quantifies the overlap that makes the ratio a stratifier rather than a
      decisive test.
- name: Parathyroid Localization Imaging
  description: >-
    Listed here to record what it does not do. Sestamibi scintigraphy,
    ultrasound and 4D-CT locate parathyroid tissue for a surgeon who has
    already decided to operate; they do not establish that the hypercalcaemia
    is parathyroid-driven in the first place, and a positive study does not
    exclude FHH1. A positive scan in a patient whose biochemistry has not
    resolved the differential is therefore not a reason to proceed, and this is a
    documented route to an operation that cannot work: in the case cited
    below, scintigraphy showed focal uptake beside the thyroid, that finding
    together with a mildly raised PTH settled a diagnosis of primary
    hyperparathyroidism, and the patient was still hypercalcaemic months after
    a total parathyroidectomy.

    Two further traps in the same case are worth recording. The uptake sat
    above the left thyroid lobe, which is also where a thyroid nodule sits,
    and the resected glands showed four-gland mild hyperplasia - a feature of
    FHH1 itself rather than evidence against it, so the operative histology
    did not correct the error either. The order of evidence that should have
    governed the decision is the reverse of the one followed: the differential
    rests on the biochemistry and on CASR genotype, not on where an isotope
    collects.
  diagnosis_term:
    preferred_term: parathyroid localization imaging
    term:
      id: NCIT:C16502
      label: Diagnostic Imaging Testing
  evidence:
  - reference: PMID:39810898
    reference_title: 'Retrospectively diagnosed familial hypocalciuric hypercalcaemia
      following total parathyroidectomy in an asymptomatic patient.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Parathyroid scintigraphy reported an ill-defined area of focal uptake above
      the left thyroid lobe.
    explanation: A positive localization study in a patient subsequently shown to have
      FHH, which is the false-positive this entry warns about.
  - reference: PMID:39810898
    reference_title: 'Retrospectively diagnosed familial hypocalciuric hypercalcaemia
      following total parathyroidectomy in an asymptomatic patient.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A diagnosis of PHPT was made likely secondary to parathyroid hyperplasia
      or a parathyroid adenoma. This was based on the elevated PTH concentration and
      scintigraphy results.
    explanation: States that the scintigraphy result was part of what drove the incorrect
      diagnosis and the decision to operate.
  - reference: PMID:39810898
    reference_title: 'Retrospectively diagnosed familial hypocalciuric hypercalcaemia
      following total parathyroidectomy in an asymptomatic patient.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Several months post-operatively the patient was noted to have persistent
      hypercalcaemia which is a strong indicator of FHH rather than PHPT
    explanation: The outcome that establishes the operation could not have worked, since
      the lesion was never in the glands that were removed.
  - reference: PMID:39810898
    reference_title: 'Retrospectively diagnosed familial hypocalciuric hypercalcaemia
      following total parathyroidectomy in an asymptomatic patient.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient underwent a total parathyroidectomy and all four glands demonstrated
      mild hyperplasia but no evidence of adenoma. Mild parathyroid hyperplasia is a
      feature in keeping with FHH
    explanation: Source for the second trap recorded here - four-gland mild hyperplasia
      is consistent with FHH1, so the operative histology does not correct a
      mistaken preoperative diagnosis.
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: the differential diagnosis will be made based on molecular genetic findings
    explanation: States where the differential actually rests, which is the hierarchy
      this entry contrasts imaging against.
- name: CASR Sequencing
  description: >-
    Confirmatory, and the step that should precede any decision about surgery in
    an ambiguous case. A negative result does not exclude FHH, since GNA11 and
    AP2S1 account for the remaining third.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
treatments:
- name: Observation Without Intervention
  description: >-
    The correct management for the great majority of carriers. The hypercalcaemia
    is stable, the renal and skeletal complications that would justify treating it
    do not develop, and there is no evidence that lowering the calcium improves
    any outcome. Recording this as a treatment rather than as an absence of one is
    deliberate: the intervention that matters in FHH1 is the decision not to
    operate.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32386559
    reference_title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant
      Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FHH1 is usually asymptomatic and requires no intervention
    explanation: States directly that the usual management is no intervention.
- name: Avoidance of Parathyroidectomy
  description: >-
    The single most consequential management decision in the disease, and the
    reason the diagnosis matters. Parathyroidectomy is the treatment for primary
    hyperparathyroidism and is inappropriate here, because the glands are
    responding correctly to a receptor that under-reports calcium; removing them
    does not reset the set point. The exception is the neonatal biallelic subtype,
    where parathyroidectomy is the definitive treatment and subtotal resection is
    reported as ineffective.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In children, adolescents and young adults with FHH the main challenge is
      to distinguish the condition from primary hyperparathyroidism and thereby to avoid
      unnecessary treatments including parathyroidectomy.
    explanation: States avoidance of parathyroidectomy as the object of the diagnostic
      effort, which is what this entry records as a treatment decision.
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In NSHPT, total parathyroidectomy is generally considered the definitive
      treatment.
    explanation: The neonatal exception noted here, where the same operation is
      indicated rather than avoided.
- name: Cinacalcet
  description: >-
    A calcimimetic - a positive allosteric modulator that lowers the calcium
    concentration needed to activate the receptor - and therefore a drug aimed at
    the actual lesion rather than at the number. It is reserved for the minority
    with symptomatic or marked hypercalcaemia, since most carriers need nothing.
    Reported to lower serum calcium and improve calcium clearance, and used
    successfully in the neonatal forms as well.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cinacalcet
      term:
        id: CHEBI:48390
        label: cinacalcet
  target_mechanisms:
  - target: Right-Shifted Calcium Set Point
    description: >-
      Allosteric sensitisation of the mutant receptor partially offsets the
      rightward shift, which is why the drug acts on the mechanism and not merely
      on the calcium level.
  evidence:
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In FHH, cinacalcet results in a significant reduction of serum calcium levels
      and improvement of calcium clearance after initiation of cinacalcet therapy
    explanation: Reports the biochemical effect of cinacalcet in FHH, which is the basis
      for its selective use here.
  - reference: PMID:35566721
    reference_title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial
      Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Calcimimetic drugs, such as cinacalcet, are allosteric agonists at the CaSR
    explanation: Establishes the pharmacological class and mode of action that the
      target_mechanisms link asserts.
discussions:
- discussion_id: casr_lof_extracalcitropic_burden
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the excess of cardiovascular and neurological diagnoses reported in CASR
    loss-of-function carriers reflect a consequence of the receptor defect, or
    ascertainment in a health-system cohort?
  attaches_to:
  - pathophysiology#Hypercalcemia with Non-Suppressed PTH
  rationale: >-
    A rare-variant burden test in the DiscovEHR exomes associated aggregated CASR
    loss-of-function variants with cardiovascular, neurological and other
    diagnoses. That is a real signal against the long-standing description of FHH1
    as entirely benign, and this entry deliberately does not fold it into the
    pathograph, because the study design cannot separate a mechanistic
    consequence of impaired calcium sensing from confounding in a
    healthcare-derived cohort. CASR is expressed well beyond parathyroid and
    kidney, so a genuine extra-calcitropic effect is biologically plausible rather
    than implausible - which is exactly why the question is worth recording rather
    than dismissing.
  proposed_experiments:
  - experiment_id: replicate_casr_lof_burden_population_cohort
    name: Independent replication in a population cohort not ascertained through care
    description: >-
      Test the same aggregated CASR loss-of-function burden against cardiovascular
      and neurological endpoints in a biobank recruited independently of
      healthcare contact, with serum calcium available so that carriers can be
      stratified by whether they are biochemically affected.
    would_support:
    - pathophysiology#Hypercalcemia with Non-Suppressed PTH
    supporting_outcome:
    - >-
      The association persists in carriers ascertained outside the health system
      and tracks biochemical severity, indicating a consequence of the receptor
      defect rather than of ascertainment.
    refuting_outcome:
    - >-
      The association is absent outside the healthcare-ascertained cohort, or is
      present in carriers with normal serum calcium as strongly as in those with
      hypercalcaemia, pointing to confounding.
references:
- reference: PMID:7916660
  title: Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric
    hypercalcemia and neonatal severe hyperparathyroidism.
- reference: PMID:18410554
  title: 'Discriminative power of three indices of renal calcium excretion for the distinction
    between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a
    follow-up study on methods.'
- reference: PMID:19250271
  title: Skeletal consequences of familial hypocalciuric hypercalcaemia vs. primary hyperparathyroidism.
- reference: PMID:20374733
  title: Calcium-sensing receptor and associated diseases.
- reference: PMID:21986511
  title: 'Familial hypocalciuric hypercalcaemia: a review.'
- reference: PMID:32386559
  title: 'Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia
    Type 1: Prevalence in a Large Healthcare Population.'
- reference: PMID:35566721
  title: 'Disorders of the Calcium Sensing Signaling Pathway: From Familial Hypocalciuric
    Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.'
- reference: PMID:39810898
  title: Retrospectively diagnosed familial hypocalciuric hypercalcaemia following total
    parathyroidectomy in an asymptomatic patient.
- reference: PMID:42261748
  title: Role of the calcium-sensing receptor in regulating calcium transport in the thick
    ascending limb.
notes: >-
  Scope and lump/split. Curated as a disease rather than as a subtype of a
  parent FHH entry, and rather than as a grouping. MONDO records no descendants
  under MONDO:0007791, and FHH2 (GNA11) and FHH3 (AP2S1) are sibling terms with
  different genes rather than children of this one, so the term denotes the
  CASR-specific entity. Neonatal severe hyperparathyroidism is carried here as a
  subtype because it is the same receptor at a higher mutational dose; it was not
  curated separately elsewhere in this knowledge base at the time of writing.

  Relationship to the rest of the CASR series. Autosomal_Dominant_Hypocalcemia_1
  curates the gain-of-function mirror of this disease and was used as the
  structural template for this entry, so the two pathographs are deliberately
  parallel: the same set-point node, the same parathyroid and renal limbs, with
  the direction of every modifier reversed. Reading them together is what makes
  "loss of function" concrete here.

  Two negative findings are curated as pathophysiology nodes rather than left
  implicit, because in this disease the absences carry the mechanism. Preserved
  bone mineral density despite chronically raised PTH, and the near-absence of
  stones and nephrocalcinosis despite chronic hypercalcaemia, are both
  consequences of the renal limb of the lesion and are both points of
  differentiation from primary hyperparathyroidism.

  Ontology binding compromises. Two GO bindings here are deliberately broader
  than the claim they carry, for the same reason recorded in
  Autosomal_Dominant_Hypocalcemia_1. GO has no term for calcium-sensing receptor
  activity, so the receptor nodes bind GO:0004930 (G protein-coupled receptor
  activity) with the receptor identity carried in preferred_term. GO likewise has
  no term for renal tubular calcium reabsorption, so the thick ascending limb node
  binds the general GO:0006816 (calcium ion transport) rather than GO:0070588
  (calcium ion transmembrane transport), which denotes the transcellular route
  across a membrane and would mis-state a paracellular, claudin-gated mechanism.
  Binding the broader parent is the correct trade here: a wrong specific term is
  worse than a right general one.

  What is deliberately not claimed. The pancreatitis association is recorded as
  VERY_RARE with its attribution flagged as contested rather than asserted. The
  cardiovascular and neurological burden signal is held in a KNOWLEDGE_GAP
  discussion rather than in the pathograph, for the ascertainment reason given
  there. No comorbidity or environmental block is curated, since nothing in the
  sources supported one.
📚

References & Deep Research

References

9
PMID:7916660
Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
No top-level findings curated for this source.
PMID:18410554
Discriminative power of three indices of renal calcium excretion for the distinction between familial hypocalciuric hypercalcaemia and primary hyperparathyroidism: a follow-up study on methods.
No top-level findings curated for this source.
PMID:19250271
Skeletal consequences of familial hypocalciuric hypercalcaemia vs. primary hyperparathyroidism.
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:21986511
Familial hypocalciuric hypercalcaemia: a review.
No top-level findings curated for this source.
PMID:32386559
Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.
No top-level findings curated for this source.
PMID:35566721
Disorders of the Calcium Sensing Signaling Pathway: From Familial Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.
No top-level findings curated for this source.
PMID:39810898
Retrospectively diagnosed familial hypocalciuric hypercalcaemia following total parathyroidectomy in an asymptomatic patient.
No top-level findings curated for this source.
PMID:42261748
Role of the calcium-sensing receptor in regulating calcium transport in the thick ascending limb.
No top-level findings curated for this source.