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Familial Hypocalciuric Hypercalcemia

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Description: Familial hypocalciuric hypercalcemia is a genetic disorder characterized by elevated blood calcium levels and low calcium excretion in urine, often presenting with no symptoms or mild symptoms.
Type: Familial hypocalciuric hypercalcemia is transmitted in an autosomal dominant pattern.
Signs And Symptoms: Most cases of familial hypocalciuric hypercalcemia are asymptomatic. Laboratory signs of FHH include:
High blood levels of calcium (hypercalcemia)
A low amount of calcium excreted in the urine (Ca excretion rate < 0.02 mmol/L)
High blood levels of magnesium (hypermagnesemia)
High normal to mildly elevated parathyroid hormone
Prognosis: Familial hypocalciuric hypercalcemia (FHH) generally has a good prognosis. It is often a benign condition and many individuals remain asymptomatic throughout their lives. Serious complications are rare, and the hypercalcemia typically does not require treatment. Regular monitoring is recommended to ensure that calcium levels remain stable and to manage any potential symptoms or complications.
Onset: Familial hypocalciuric hypercalcemia (FHH) typically has an onset from birth. It is often asymptomatic and discovered incidentally during routine blood tests since individuals can remain largely unaffected by the condition throughout their life.
Prevalence: Prevalence of familial hypocalciuric hypercalcemia is estimated to be around 1 in 78,000 individuals.
Epidemiology: Familial hypocalciuric hypercalcemia (FHH) is a rare genetic disorder affecting calcium homeostasis. Its exact prevalence is not well-defined, but it is considered to be uncommon. The condition is typically inherited in an autosomal dominant manner, meaning a single copy of the mutated gene can cause the disorder. FHH is often asymptomatic and discovered incidentally through routine blood tests showing mild to moderate hypercalcemia with low urinary calcium excretion. The primary gene implicated in FHH is the calcium-sensing receptor (CASR) gene, with mutations in this gene causing the condition.
Intractability: Familial hypocalciuric hypercalcemia (FHH) is generally not considered intractable. It is a typically benign inherited condition characterized by asymptomatic mild to moderate hypercalcemia, hypocalciuria, and normal or mildly elevated parathyroid hormone levels. Management usually involves monitoring calcium levels rather than active treatment, as patients often do not require intervention and can have a normal life expectancy.
Disease Severity: Familial hypocalciuric hypercalcemia (FHH) is generally considered a benign condition. Most individuals with FHH are asymptomatic or have mild symptoms, and it typically does not require treatment. The primary concern is distinguishing FHH from primary hyperparathyroidism to avoid unnecessary surgical intervention.
Healthcare Professionals: Disease Ontology ID - DOID:0060699
Pathophysiology: Familial Hypocalciuric Hypercalcemia (FHH) is a genetic disorder characterized by elevated levels of calcium in the blood (hypercalcemia) with low levels of calcium in the urine (hypocalciuria). The pathophysiology of FHH primarily involves mutations in the calcium-sensing receptor (CaSR) gene.

CaSR is critical for maintaining calcium homeostasis. When functioning normally, it helps regulate parathyroid hormone (PTH) secretion and renal calcium reabsorption. Mutations in the CaSR gene reduce the sensitivity of the receptor to calcium levels. As a result, higher concentrations of calcium are required to suppress PTH secretion and decrease renal calcium reabsorption. This leads to mild to moderate hypercalcemia, low urinary calcium excretion, and, typically, normal to slightly elevated PTH levels.

FHH is usually benign and often requires no specific treatment, but it's important to differentiate it from primary hyperparathyroidism to avoid unnecessary surgical interventions.
Carrier Status: Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder. Carrier status typically isn't applicable, as individuals with one copy of the mutated gene usually exhibit the condition.
Mechanism: Familial hypocalciuric hypercalcemia (FHH) is a genetic disorder characterized by elevated levels of calcium in the blood (hypercalcemia) and low levels of calcium in the urine (hypocalciuria).

**Mechanism:**
FHH is primarily caused by mutations in the calcium-sensing receptor (CaSR) gene. The CaSR is responsible for regulating calcium homeostasis by sensing the level of calcium in the blood and adjusting parathyroid hormone (PTH) secretion accordingly. When the CaSR is mutated, its ability to detect calcium levels is impaired, leading to inappropriate regulation of calcium in the body.

**Molecular mechanisms:**
1. **CaSR Gene Mutations:** Mutations in the CaSR gene cause the receptor to have reduced sensitivity to calcium levels. This impairs the negative feedback mechanism that regulates PTH secretion.
2. **PTH Secretion:** Due to the reduced sensitivity of the CaSR, the parathyroid glands secrete normal or slightly elevated levels of PTH even when blood calcium levels are high. This inappropriate secretion of PTH leads to increased calcium reabsorption in the kidneys and increased calcium release from bones.
3. **Renal Calcium Handling:** The kidneys have a high reabsorption rate of calcium due to the altered signaling from the mutated CaSR, leading to low levels of calcium excretion in the urine.
4. **Clinical Presentation:** Patients typically exhibit mild hypercalcemia, low urinary calcium excretion, and normal to slightly elevated PTH levels. Because the condition is usually benign, most individuals remain asymptomatic or experience only mild symptoms.

Understanding these mechanisms is critical for diagnosis and management, distinguishing FHH from other conditions such as primary hyperparathyroidism.
Treatment: No treatment is generally required, as bone demineralisation and kidney stones are relatively uncommon in the condition.

== References ==
Compassionate Use Treatment: Familial hypocalciuric hypercalcemia (FHH) is generally a benign condition and often does not require treatment. However, in cases presenting with more severe symptoms or complications, potential approaches may include:

1. **Calcimimetics**: Drugs such as cinacalcet, which are typically used to manage secondary hyperparathyroidism or parathyroid carcinoma, might be considered off-label to reduce serum calcium levels.

2. **Parathyroidectomy**: Although not common, this surgical option might be considered in rare, severe cases where there is significant hypercalcemia leading to complications, and if the condition mimics primary hyperparathyroidism.

3. **Experimental Treatments**: Currently, no specific experimental treatments are well-established for FHH. Participation in clinical trials might be an option if they become available.

Management usually involves monitoring rather than active intervention, as the condition tends to cause fewer symptoms compared to primary hyperparathyroidism. It is important to distinguish FHH from primary hyperparathyroidism to avoid unnecessary treatments.
Lifestyle Recommendations: For familial hypocalciuric hypercalcemia (FHH), the following lifestyle recommendations may be helpful:

1. **Regular Monitoring:** Regular medical check-ups to monitor calcium levels and kidney function.
2. **Hydration:** Maintain proper hydration to support kidney function.
3. **Diet:** There is generally no need for special dietary restrictions concerning calcium or vitamin D unless advised by a healthcare provider.
4. **Physical Activity:** Engage in regular physical activity to promote overall health.
5. **Avoid Calcium Supplements:** Typically, avoid calcium supplementation unless specifically recommended by your physician.
6. **Awareness:** Be aware of symptoms of hypercalcemia such as muscle weakness, fatigue, and kidney stones, and consult a healthcare provider if these occur.

Always consult with a healthcare professional for personalized advice tailored to your specific condition.
Medication: Familial hypocalciuric hypercalcemia (FHH) usually does not require medication as most individuals are asymptomatic and manage well without treatment. However, careful monitoring of calcium levels is essential. In rare cases where symptoms are more severe, consultation with a healthcare provider for a personalized management plan is recommended.
Repurposable Drugs: There is currently no established drug repurposing specifically targeted for familial hypocalciuric hypercalcemia (FHH). FHH is generally a benign condition and often does not require treatment. However, accurate diagnosis is important to differentiate it from primary hyperparathyroidism, which may have different management strategies. Always consult with a healthcare provider for appropriate diagnosis and treatment options.
Metabolites: In familial hypocalciuric hypercalcemia (FHH), key metabolites affected include calcium and parathyroid hormone (PTH). Patients with FHH typically present with elevated serum calcium levels and normal or slightly elevated PTH levels. Additionally, they exhibit low urinary calcium excretion, which is a defining characteristic of the condition.
Nutraceuticals: For familial hypocalciuric hypercalcemia (FHH), there are no specific nutraceuticals recommended as part of the treatment or management of the condition. FHH is generally a benign genetic disorder related to calcium metabolism. Management typically focuses on monitoring rather than active intervention. Always consult with a healthcare provider for personalized advice.
Peptides: Familial hypocalciuric hypercalcemia (FHH) is primarily associated with mutations in the CASR gene, which encodes the calcium-sensing receptor. It is not directly related to peptides or nanoparticles (nan. refers to nanoparticles in this context). The condition leads to altered calcium homeostasis, but peptides and nanoparticles are not typically relevant to its pathophysiology or treatment.