What are the other Names for this Condition? (Also known as/Synonyms)

• FHHNC (Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis)
• Michellis-Castrillo Syndrome

What is Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis? (Definition/Background Information)

• Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC) is a form of familial primary hypomagnesemia, characterized by renal magnesium (Mg) and calcium (Ca) wasting, nephrocalcinosis, kidney failure and, in some cases, severe ocular impairment
• Two subtypes of Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis are described:
• FHHNC with severe ocular involvement (FHHNCOI)
• FHHNC without severe ocular involvement (FHHN)
• The median age of onset ranges from 1 to 8 years. The most common presenting features are recurrent urinary tract infections, nephrolithiasis, nephrocalcinosis, polyuria, polydipsia, enuresis, hematuria and pyuria. Additional manifestations include failure to thrive, seizures, abdominal pain, muscular tetany and, rarely, rickets
• Both forms share identical renal manifestations. By contrast, severe ocular involvement (macular coloboma, pigmentary retinitis, nystagmus, or visual loss) has been described in FHHNCOI, while mild nonspecific ocular involvement (myopia, astigmatism, hypermetropia, or strabismus) has been reported in some cases of FHHN
• Transmission is autosomal recessive. 

(Source: Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis? (Age and Sex Distribution)

• Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis is a rare congenital disorder with about 200 cases reported in the medical literature
• The presentation of symptoms generally occurs in childhood, before the child is 8 years old
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis? (Predisposing Factors)

• A positive family history may be an important risk factor, since Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis can be inherited
• Currently, no other risk factors have been clearly identified for the disorder

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis? (Etiology)

• Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis is caused by mutations in CLDN16 and CLDN19 genes, encoding claudin-16 and claudin-19 respectively
• Both proteins are expressed in the thick ascending limb of Henle's loop where they interact to form heteromultimers and play a role in the paracellular reabsorption of Mg and Ca
• Inactivating mutations in either gene results in urinary loss of Mg and Ca. Ocular involvement occurs in patients with the CLDN19 mutation as claudin-19 is expressed in retinal pigment epithelium
• The disorder is inherited in an autosomal recessive manner

(Source: Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

• It has been reported that among the affected individuals, those with CLDN19 mutations bear a higher risk of progression to chronic kidney disease than individuals with CLDN16 mutations

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis?

The signs and symptoms of Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis with or without ocular involvement may include the following:

• Recurrent urinary tract infections
• Nephrolithiasis
• Nephrocalcinosis
• Polyuria
• Polydipsia
• Enuresis
• Hematuria 
• Pyuria
• Failure to thrive
• Seizures 
• Abdominal pain
• Muscular tetany 
• Rickets (rare)
• Non-specific ocular symptoms such as:
• Myopia
• Astigmatism
• Hypermetropia
• Strabismus

Signs and symptoms of Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis with ocular involvement:

• Macular coloboma
• Pigmentary retinitis
• Nystagmus 

How is Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Diagnosed?

The diagnosis of Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis may involve the following:

• Tests to check for the triad of hypomagnesemia, hypercalciuria and nephrocalcinosis (Hypocalcemia, hyperuricemia, incomplete distal renal tubular acidosis and hypocitraturia are supportive findings) 
• Checking for elevated parathyroid hormone levels
• Test for high fractional urinary excretion of Mg with inappropriately low serum levels, particularly during the CKD phase
• Fundoscopy and optical coherence tomography (OCT) to detect ocular abnormalities
• Differential diagnosis to rule out Bartter syndrome, autosomal dominant hypocalcemia, Dent disease, hereditary hypophosphatemic rickets with hypercalciuria, distal renal tubular acidosis and other tubular disorders causing early nephrocalcinosis (like primary hyperoxaluria) 
• Genetic screening of CLDN16 and CLDN19 to confirm diagnosis

(Source: Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis?

The complications of Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis may include:

• Problems with movement
• Risk of falls and injuries due to seizures
• Chronic kidney disease, leading to end-stage kidney disease
• Loss of vision, if the condition occurs with ocular involvement

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Treated?

There is no cure for Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis, since it is a genetic condition. Treatment is generally tailored toward addressing symptoms, which may include the following:

• Administration of magnesium supplements in high doses and thiazide diuretics to reduce urinary calcium excretion and the progression of nephrocalcinosis
• Indomethacin to increase calcium reabsorption
• Therapies aimed at delaying progression of chronic kidney disease
• Conventional management strategies for kidney stones
• Renal transplantation for end-stage kidney disease
• Lens implantation for those suffering from severe ocular abnormalities

(Source: Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How can Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis be Prevented?

Currently, Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis? (Outcomes/Resolutions)

The prognosis of Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis is generally guarded, since the condition progresses to end-stage renal disease in about 50% of cases (at age 20 years).

Additional and Relevant Useful Information for Familial Primary Hypomagnesemia with Hypercalciuria and Nephrocalcinosis:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/