Nephrology · Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Understanding Your FHHNC Diagnosis: CLDN16 and CLDN19

At a Glance

FHHNC is a rare inherited kidney disorder caused by pathogenic variants in CLDN16 or CLDN19. The kidneys lose magnesium and calcium into the urine, causing low blood magnesium and nephrocalcinosis; CLDN19 can also cause eye problems, so lifelong monitoring is important.

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC) is a rare, inherited kidney disorder that affects how the body manages two vital minerals: magnesium and calcium ^[1]^[2]. Because it is so rare, you may find that many local doctors have never treated a patient with this condition before ^[2].

In a healthy kidney, minerals are filtered out of the blood and then most are reabsorbed (reclaimed) back into the body. In FHHNC, the kidney’s ability to reclaim these minerals is impaired ^[3]. This leads to:

Hypomagnesemia: Low levels of magnesium in the blood because too much is lost in the urine ^[1].
Hypercalciuria: Excessive amounts of calcium in the urine ^[1].
Nephrocalcinosis: The buildup of calcium deposits in the kidney tissue, which can lead to scarring and reduced kidney function over time ^[1]^[2].

The Reabsorption Problem

Your kidneys contain millions of tiny tubes that process waste. One specific section, called the thick ascending limb, is responsible for pulling magnesium and calcium back into your bloodstream ^[4]. To do this, the kidney uses “gatekeeper” proteins called claudins ^[5].

Two specific proteins, claudin-16 and claudin-19, must work together to form a seal and a specialized pathway that allows minerals to pass back into the body ^[4]^[6].

Claudin-16 creates the path for the minerals to move ^[5].
Claudin-19 helps guide claudin-16 to the right spot and ensures the channel is selective ^[6].

When the genes that provide instructions for these proteins (CLDN16 or CLDN19) have pathogenic variants (mutations), the proteins cannot function correctly ^[3]. The kidney fails to reclaim magnesium and calcium from the filtered fluid, allowing them to slip away into the urine instead of being saved ^[5]. Note that genetic testing can sometimes return a “variant of uncertain significance,” which requires a specialist to interpret whether it actually causes the disease.

How FHHNC is Inherited

FHHNC is an autosomal recessive condition ^[7]. This means:

A child must inherit two changed (mutated) copies of the gene—one from each parent—to have the condition ^[7]^[8].
The parents are typically “carriers.” They have one mutated copy and one healthy copy, so they usually do not have any symptoms of the disease themselves ^[9]^[8].
If both parents are carriers, there is a 25% (1 in 4) chance with each pregnancy that the child will have FHHNC, a 50% chance the child will be a carrier like the parents, and a 25% chance the child will not have the mutation at all ^[7]. Targeted testing of relatives should be arranged through genetic counseling ^[10].

CLDN16 vs. CLDN19: What is the Difference?

While both mutations cause the same kidney problems, they differ in how they affect the rest of the body.

Feature	CLDN16 Mutation	CLDN19 Mutation
Kidney Effects	High urine calcium, low blood magnesium, kidney scarring ^[1].	High urine calcium, low blood magnesium, kidney scarring ^[2].
Eye Effects	Generally not affected ^[11].	Frequently affected (up to 60% of cases in some cohorts) ^[12].
Ocular Symptoms	None typical.	May include severe nearsightedness (myopia), involuntary eye movement (nystagmus), or retinal abnormalities ^[12]^[13].

If a CLDN19 mutation is identified, it is essential to have regular check-ups with an ophthalmologist (eye doctor) to monitor for vision changes or structural issues in the eye ^[14].

What to Expect

FHHNC is a chronic, progressive condition. It often appears in childhood or adolescence, though some people are diagnosed later ^[2]^[15]. Over time, the constant calcium deposits can cause the kidneys to work less effectively, sometimes leading to kidney failure in early adulthood ^[2]^[12].

There is currently no cure that “fixes” the genetic mutation, but knowing which gene is involved helps your care team tailor your monitoring ^[14]. Management typically focuses on:

Replacing magnesium through oral supplements ^[2].
Reducing the amount of calcium in the urine using medications like thiazide diuretics ^[16].
Drinking tailored fluids to help prevent stones and further calcium buildup ^[2].
Monitoring PTH (parathyroid hormone) alongside eGFR, as trends can reflect kidney function ^[12]^[17].

While the diagnosis can feel overwhelming, your medical team will work to protect your kidney function and manage symptoms safely as they arise. Genetic counseling is highly recommended for families to understand the risks for future children and other family members ^[10].

Common questions in this guide

What is FHHNC, and what do CLDN16 and CLDN19 have to do with it?

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare inherited kidney disorder. Disease-causing changes in CLDN16 or CLDN19 disrupt proteins in a kidney segment called the thick ascending limb, allowing too much magnesium and calcium to be lost in the urine and causing calcium deposits to build up in the kidneys.

How are CLDN16-related and CLDN19-related FHHNC different?

Both gene-related forms can cause high urine calcium, low blood magnesium, nephrocalcinosis, and kidney scarring. CLDN19-related FHHNC can also affect the eyes, causing severe nearsightedness, involuntary eye movements, or retinal abnormalities, while eye problems are not typical with CLDN16-related FHHNC.

What are the chances of passing FHHNC to a child if both parents are carriers?

FHHNC follows an autosomal recessive inheritance pattern, so a child needs a changed copy of the gene from each parent to have the condition. When both parents are carriers, each pregnancy has a 25% chance of FHHNC, a 50% chance of being a carrier, and a 25% chance of inheriting neither changed copy.

What does a variant of uncertain significance mean in an FHHNC genetic test?

A variant of uncertain significance is a genetic change whose connection to FHHNC is not yet clear. A genetics specialist must review the result with the clinical and family information to determine whether it is disease-causing; it is not the same as a confirmed diagnosis by itself.

How is FHHNC treated and monitored?

Management may include oral magnesium supplements, thiazide diuretics to lower calcium loss in the urine, and a tailored fluid plan to help prevent stones and further calcium buildup. Clinicians may monitor magnesium, calcium, PTH, and eGFR over time, with targets and treatment adjusted to the individual.

When are eye exams needed for someone with a CLDN19 variant?

CLDN19-related FHHNC can affect vision, so regular appointments with an ophthalmologist are important after the variant is identified. The eye doctor can monitor for nearsightedness, involuntary eye movements, retinal changes, and other structural or vision problems; children may be referred to a pediatric ophthalmologist.

Can FHHNC lead to kidney failure?

FHHNC is chronic and progressive, and ongoing calcium deposits can scar the kidneys and reduce their function. Some people develop kidney failure in early adulthood, so regular monitoring of kidney function and mineral levels is important.

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This page explains how CLDN16 and CLDN19 relate to FHHNC for informational purposes only and does not constitute medical advice. Your nephrologist, genetic counselor, and ophthalmologist should interpret your results and create a monitoring plan for you or your child.