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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
Orpha Number: 306516
Familial primary hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a form of familial primary hypomagnesemia (FPH, see this term), characterized by renal magnesium (Mg) and calcium (Ca) wasting, nephrocalcinosis, kidney failure and, in some cases, severe ocular impairment. Two subtypes of FHHNC are described: FHHNC with severe ocular involvement (FHHNCOI) and without severe ocular involvement (FHHN) (see these terms).
To date, approximately 200 cases have been reported in the literature.
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. Patients develop chronic kidney disease (CKD) that progresses to end-stage renal disease (ESRD). Two subtypes of FHHNC have been described: FHHNCOI and FHHN. 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.
The disease is caused by mutations in the genes CLDN16 (3q28) and CLDN19 (1p34.2), 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.
Diagnosis is based on the triad of hypomagnesemia, hypercalciuria and nephrocalcinosis. Hypocalcemia, hyperuricemia, incomplete distal renal tubular acidosis and hypocitraturia are supportive findings. Parathyroid hormone levels are high before onset of CKD. High fractional urinary excretion of Mg is found while serum level is inappropriately low. Ocular abnormalities are detected by fundoscopy and optical coherence tomography (OCT). Diagnosis is confirmed by genetic screening of CLDN16 and CLDN19.
Differential diagnosis includes 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) (see these terms).
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% chance of having an affected child.
Management and treatment
Management is mainly supportive and includes administration of Mg supplements in high doses and thiazide diuretics to reduce urinary Ca excretion and the progression of nephrocalcinosis. Indomethacin may be used to increase Ca reabsorption. Therapies aimed at delaying progression of CKD should be provided as well as conventional management strategies for kidney stones. Renal transplantation is the optimal treatment for ESRD. Lens implantation can be proposed to patients suffering from severe ocular abnormalities.
Progression to ESRD is frequent (50% of patients at 20 years). Follow-up data in one of the described cohorts suggested that patients harboring CLDN19 mutations have a higher risk of progression to CKD than patients with CLDN16 mutations.
Visit the Orphanet disease page for more resources.
Source: GARD Last updated on 05-01-20
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