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PubMed This is a summary of 19 peer-reviewed journal articles Updated
Endocrinology

The Genetics and Lab Markers of ADH1 and ADH2

At a Glance

Autosomal Dominant Hypocalcemia (ADH) is characterized by low blood calcium, low parathyroid hormone (PTH), and high urine calcium. ADH1 is caused by CASR gene mutations, while ADH2 stems from GNA11 mutations. Genetic testing is the gold standard to confirm your specific subtype.

Understanding the specific subtype of Autosomal Dominant Hypocalcemia (ADH) is more than just a medical label; it helps your doctors predict how the condition might affect your body and which treatments are safest. While both types result in low blood calcium, they stem from different genetic “typos” that influence your health in unique ways.

ADH Subtypes: ADH1 vs. ADH2

There are two primary forms of this condition, distinguished by the specific gene that is affected.

  • ADH Type 1 (ADH1): This is the most common form [1]. it is caused by gain-of-function mutations in the CASR gene [2][3]. This gene provides instructions for the calcium-sensing receptor itself. When this receptor is overactive, it acts like a thermostat stuck in the “too hot” position, even when the room is cold.
  • ADH Type 2 (ADH2): This form is rarer and involves the GNA11 gene [4]. Instead of the sensor being broken, the “wiring” (a protein called G$\alpha$11) that sends the signal from the sensor to the rest of the cell is overactive [5][6].
    • A Unique Feature: Patients with ADH2 are frequently found to have short stature—this occurs in roughly 42% of cases [4]. They may also develop early intracranial calcifications (small calcium deposits in the brain) [5].

The Biochemical Profile: Decoding Your Labs

When you look at your blood work, ADH typically creates a very specific pattern. Understanding these three key markers can help you engage with your medical team:

Lab Marker Typical ADH Result Why This Happens
Serum Calcium Low The body is tricked into thinking calcium is high, so it stops maintaining it [7].
PTH (Parathyroid Hormone) Low or “Inappropriately Normal” The sensor tells the glands to stop making PTH, even though your blood calcium is low [8][9].
Serum Phosphorus High or Normal Low PTH levels prevent the kidneys from flushing out phosphorus, causing it to build up [10][8].

The “Smoking Gun”: Urinary Calcium

The most distinctive feature of ADH—and the one that often helps doctors distinguish it from other types of hypoparathyroidism—is hypercalciuria (high calcium in the urine) [11][12].

In most people with low blood calcium, the body tries to save every bit of calcium it can. However, because the kidneys in ADH patients “think” blood calcium is too high, they continue to dump calcium into the urine [13][14]. Doctors often look at the calcium-to-creatinine clearance ratio (CCCR) or a 24-hour urine collection to see if the amount of calcium you are losing is “inappropriately high” for your blood level [15][16].

Confirming the Diagnosis

While lab patterns are helpful, genetic testing is the gold standard for diagnosis [17][18]. It is the only way to definitively tell the difference between ADH1, ADH2, and other conditions that look similar. It also allows for family screening, as there is a 50% chance of passing the mutation to children [19][9].

-1 | Symptoms and Complications

Common questions in this guide

What is the difference between ADH1 and ADH2?
ADH1 is the most common form and is caused by a mutation in the CASR gene, which makes the body's calcium sensor overactive. ADH2 is a rarer form caused by a mutation in the GNA11 gene and is uniquely associated with short stature in many patients.
Why does ADH cause high calcium in the urine?
In ADH, the kidneys' calcium sensors are overactive and mistakenly "think" your blood calcium levels are too high. To correct this perceived problem, the kidneys continually dump calcium into the urine, resulting in a condition called hypercalciuria.
Why is my PTH level low when my blood calcium is also low?
An overactive calcium sensor tricks your parathyroid glands into believing your body has plenty of calcium. Because of this false signal, the glands stop producing parathyroid hormone (PTH), causing your PTH levels to appear low or normal despite low actual blood calcium.
How is Autosomal Dominant Hypocalcemia officially diagnosed?
Doctors look for a distinct pattern of low blood calcium, inappropriately low or normal PTH, and high urinary calcium. However, the gold standard for officially diagnosing ADH and confirming whether you have type 1 or type 2 is genetic testing.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Is my genetic mutation in the CASR gene (ADH1) or the GNA11 gene (ADH2)?
  2. 2.How does my urinary calcium-to-creatinine ratio compare to the typical range for ADH?
  3. 3.Is my phosphorus level high enough to require dietary changes or specific management?
  4. 4.Since ADH2 is linked to short stature, should my height or my child's growth be tracked more closely?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (19)
  1. 1

    Differential parathyroid and kidney Ca2+-sensing receptor activation in autosomal dominant hypocalcemia 1.

    van Megen WH, Tan RSG, Alexander RT, Dimke H

    EBioMedicine 2022; (78()):103947 doi:10.1016/j.ebiom.2022.103947.

    PMID: 35313217
  2. 2

    A calcium-sensing receptor allelic series and underdiagnosis of genetically driven hypocalcemia.

    Chang JB, Barnhill CP, Apostolov AM, et al.

    American journal of human genetics 2025; (112(8)):1818-1832 doi:10.1016/j.ajhg.2025.06.013.

    PMID: 40664210
  3. 3

    Case Report: Calcium sensing receptor gene gain of function mutations: a case series and report of 2 novel mutations.

    Ali DS, Marini F, Alsarraf F, et al.

    Frontiers in endocrinology 2023; (14()):1215036 doi:10.3389/fendo.2023.1215036.

    PMID: 37654565
  4. 4

    An activating calcium-sensing receptor variant with biased signaling reveals a critical residue for Gα11 coupling.

    Benson MR, Wyatt RA, Levine MA, Gorvin CM

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2025; (40(2)):270-282 doi:10.1093/jbmr/zjae199.

    PMID: 39658204
  5. 5

    Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation.

    Tenhola S, Voutilainen R, Reyes M, et al.

    European journal of endocrinology 2016; (175(3)):211-8 doi:10.1530/EJE-16-0109.

    PMID: 27334330
  6. 6

    A pediatric case of autosomal dominant hypocalcemia type 2.

    Takahashi S, Fuchigami T, Suzuki J, Morioka I

    Journal of pediatric endocrinology & metabolism : JPEM 2023; (36(10)):974-977 doi:10.1515/jpem-2023-0097.

    PMID: 37579049
  7. 7

    Autosomal Dominant Hypocalcemia Type 1: A Systematic Review.

    Roszko KL, Stapleton Smith LM, Sridhar AV, et al.

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2022; (37(10)):1926-1935 doi:10.1002/jbmr.4659.

    PMID: 35879818
  8. 8

    Autosomal Dominant Hypocalcemia Type 1 (ADH1) Associated With Myoclonus and Intracerebral Calcifications.

    Elston MS, Elajnaf T, Hannan FM, Thakker RV

    Journal of the Endocrine Society 2022; (6(5)):bvac042 doi:10.1210/jendso/bvac042.

    PMID: 35402765
  9. 9

    An interesting case of coexistence of autosomal dominant hypocalcemia 1 with Bartter syndrome and chronic myelogenous leukemia.

    Chondrogianni ME, Diamantopoulos P, Papadopoulou A, et al.

    Hormones (Athens, Greece) 2026; (25(1)):283-288 doi:10.1007/s42000-025-00706-7.

    PMID: 40760326
  10. 10

    Autosomal Dominant Hypocalcemia Type 1 and Neonatal Focal Seizures.

    Teleanu RI, Sarman MA, Epure DA, et al.

    Children (Basel, Switzerland) 2023; (10(6)) doi:10.3390/children10061011.

    PMID: 37371242
  11. 11

    Recurrent hypocalcemic tetany presenting to the emergency room: Answers.

    Kakkar V, Pandit K, Yadav M, Saha A

    Pediatric nephrology (Berlin, Germany) 2022; (37(3)):581-584 doi:10.1007/s00467-021-05283-6.

    PMID: 34796387
  12. 12

    Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population.

    Dershem R, Gorvin CM, Metpally RPR, et al.

    American journal of human genetics 2020; (106(6)):734-747 doi:10.1016/j.ajhg.2020.04.006.

    PMID: 32386559
  13. 13

    Autosomal dominant hypocalcemia type 1: Status quo of tailored management and future perspectives.

    Harada D, Namba N

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2026; doi:10.1093/jbmr/zjag034.

    PMID: 41732805
  14. 14

    Recombinant human parathyroid hormone (1-84) is effective in CASR-associated hypoparathyroidism.

    Hawkes CP, Shulman DI, Levine MA

    European journal of endocrinology 2020; (183(6)):K13-K21.

    PMID: 33112267
  15. 15

    Efficacy of calcium excretion and calcium/creatinine clearance ratio in the differential diagnosis of familial hypocalciuric hypercalcemia and primary hyperparathyroidism.

    Bhangu JS, Selberherr A, Brammen L, et al.

    Head & neck 2019; (41(5)):1372-1378 doi:10.1002/hed.25568.

    PMID: 30554440
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    Factors influencing pre-operative urinary calcium excretion in primary hyperparathyroidism.

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    Clinical endocrinology 2017; (87(1)):97-102 doi:10.1111/cen.13348.

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    Familial hypocalciuric hypercalcemia in an index male: grey zones of the differential diagnosis from primary hyperparathyroidism in a 13-year clinical follow up.

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    Activating calcium-sensing receptor gene variants in China: a case report of hypocalcaemia and literature review.

    Guo S, Li X, Shan X

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    A novel CASR mutation (p.Glu757Lys) causing autosomal dominant hypocalcaemia type 1

    Kwan B, Champion B, Boyages S, et al.

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This page explains genetic and laboratory markers for Autosomal Dominant Hypocalcemia (ADH) for educational purposes. Always consult your endocrinologist or genetic counselor to accurately interpret your specific lab results and genetic tests.

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