Idiopathic Infantile Hypercalcaemia Types 1 and 2 (CYP24A1 and SLC34A1)

1,25-Dihydroxyvitamin D-dependent, parathyroid hormone-independent hypercalcaemia: 24-hydroxylase deficiency (type 1, CYP24A1) and primary renal phosphate wasting due to deficiency of the NaPi-IIa cotransporter (type 2, SLC34A1), with the adult forms, heterozygotes and the class of vitamin D hypersensitivity

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1 A disease described before it had a gene

Idiopathic infantile hypercalcaemia (IIH) was recognised in the United Kingdom in the early 1950s. Lightwood then described a wave of infants with hypercalcaemia, faltering growth and vomiting that coincided with the increase in vitamin D in infant formulas and in fortified foods intended to prevent rickets [11, 13]. Metabolic studies in the same decade showed that the hypercalcaemia resulted from excessive vitamin D-mediated intestinal calcium absorption and was accompanied by hypercalciuria [11]. Because the great majority of children exposed to the same doses did not become ill, the hypothesis of an intrinsic hypersensitivity to vitamin D was formulated, which would only be clarified six decades later [1].

The first familial observations reinforced the idea of a hereditary predisposition. Smith and colleagues (1959), and later Kenny and colleagues (1963), described two affected sisters, suggested a defect in vitamin D inactivation and observed that the normocalcaemic mother became hypercalcaemic with small supplementary doses of vitamin D, unlike the father [1]. Hooft and colleagues (1961) reported an infant with idiopathic hypercalcaemia whose father had sarcoidosis with hypercalcaemia, and Mehes and colleagues (1975) a family with an affected father and two children, interpreted at the time as dominant [1]. Weisman and colleagues (1979) proposed a defect in the esterification of 1,25-dihydroxyvitamin D as the mechanism, a hypothesis that was not confirmed [1]. Pronicka and colleagues later postulated two alternative mechanisms, reduced catabolism or increased synthesis of the active metabolites, and both were eventually demonstrated [13].

The severe form described by Joseph and Parrott in 1958, with a particular facies, was later incorporated into Williams-Beuren syndrome, in which infantile hypercalcaemia is a possible manifestation [21, 22]. This historical overlap explains why nephrologists and endocrinologists spoke of "idiopathic infantile hypercalcaemia" while cardiologists described "supravalvular aortic stenosis syndrome" in the same patients [22]. Today, the term IIH is reserved for hypercalcaemia of monogenic cause in the vitamin D and phosphate pathway, and Williams-Beuren syndrome is a differential diagnosis.

There was a second endemic wave in the 1980s in Poland and in the former East Germany, associated with rickets prophylaxis using high doses of vitamin D, including oral boluses of 600,000 IU [1, 13]. Patients from those cohorts would prove essential for gene identification and for knowledge of long-term outcome.

1.2 Milestones of the molecular discovery

In 2011, Schlingmann and colleagues studied four infants from four unrelated families, one of them Turkish and consanguineous, who presented between 6 and 8 months of age with symptomatic hypercalcaemia on daily prophylaxis with 500 IU of vitamin D, and two asymptomatic siblings [1, 23]. Analysis of four candidate genes of vitamin D metabolism revealed homozygous or compound heterozygous CYP24A1 variants, all with complete or near-complete loss of 24-hydroxylase activity in vitro [4]. In the same work, three of four German patients who had developed hypercalcaemia after one or more boluses of 600,000 IU of vitamin D2 also had biallelic variants [1]. The entity came to be called infantile hypercalcaemia type 1 (HCINF1, OMIM #143880). Also in 2011, Streeten and colleagues described a 47-year-old man, with nephrolithiasis at 19 years and asymptomatic hypercalcaemia discovered at 39, homozygous for the same p.(Glu143del) deletion found in infants, which extended the spectrum to adulthood [1, 24].

In 2016, the same group identified a second mechanism. In four patients from three consanguineous Turkish families without CYP24A1 variants, homozygosity mapping located the locus at 5q35, with a multipoint LOD score of 6.79, and sequencing of the candidate gene SLC34A1 showed homozygous variants in all four [8]. Screening of 126 sporadic IIH patients without CYP24A1 variants found biallelic variants in a further 11 [8]. The entity became infantile hypercalcaemia type 2 (HCINF2, OMIM #616963), in which primary renal phosphate wasting suppresses fibroblast growth factor 23 (FGF23) and releases calcitriol synthesis [3, 8]. One of the patients, with hyperechogenic kidneys on fetal ultrasound and extensive nephrocalcinosis at 2 months, had been published in 2010 by Lameris and colleagues [3, 25].

The unifying concept of vitamin D hypersensitivity was consolidated by the French cohort of Molin and colleagues (2021), which studied 185 patients with low PTH and hypercalcaemia or hypercalciuria and showed the phenotypic overlap between CYP24A1, SLC34A1 and SLC34A3 [15]. In 2026 the first national diagnosis and care protocol dedicated to IIH was published, prepared by the French reference centre for rare diseases of calcium and phosphate metabolism and the OSCAR network, following the Haute Autorité de Santé method [11].

1.3 Nomenclature and classification

OMIM numbers the phenotypic series as infantile hypercalcaemia 1 (CYP24A1) and 2 (SLC34A1) [1, 3]. Orphanet groups the two types in a single entity, ORPHA:300547, "autosomal recessive infantile hypercalcemia", classified as a rare disorder of calcium and phosphate metabolism and defined by early-onset hypercalcaemia, hypophosphataemia, hypercalciuria, decreased intact PTH and medullary nephrocalcinosis [10]. The term "idiopathic" is historical and is retained by usage, although most severe patients now have an identified genetic cause [11]. A Toronto group proposed the designation "HCINF3" for patients with an IIH phenotype without pathogenic variants in the two genes and with variants of uncertain significance in other genes; this is the authors' proposal, without an OMIM number or established mechanism [26].

In a broader sense, IIH belongs to the class of 1,25-dihydroxyvitamin D-mediated, PTH-independent hypercalcaemias and hypercalciurias. This class includes hereditary hypophosphataemic rickets with hypercalciuria due to SLC34A3 (HHRH, OMIM #241530), in which renal phosphate wasting produces the same hormonal profile but serum calcium is usually normal [11, 15]. It also includes the transient forms of the newborn, which the PNDS calls "vitamin D hypersensitivity" and attributes to enzymatic immaturity, without a genetic cause [11].

1.4 Definition of the entities in this article

HCINF1 is the autosomal recessive disease caused by biallelic loss-of-function variants in CYP24A1, which prevent the degradation of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and cause vitamin D-dependent hypercalcaemia, hypercalciuria and nephrocalcinosis, with maximal expression in infancy and young adulthood [1, 7]. HCINF2 is the autosomal recessive disease caused by biallelic loss-of-function variants in SLC34A1, in which renal phosphate wasting is the primary defect and hypercalcaemia is a consequence of inappropriate vitamin D activation [8]. This article also covers heterozygotes for both genes, the adult forms due to CYP24A1, the autosomal dominant form associated with SLC34A1 (hypophosphataemic nephrolithiasis/osteoporosis type 1, OMIM #612286) and the relationship with renal Fanconi syndrome type 2 (OMIM #613388) [2, 6].

2. Molecular Genetics and Pathophysiology

2.1 The balance between activation and inactivation of vitamin D

1,25-Dihydroxyvitamin D (calcitriol) results from renal 1α-hydroxylation of 25-hydroxyvitamin D by CYP27B1, stimulated by PTH and inhibited by FGF23. Its inactivation begins with mitochondrial 24-hydroxylation by CYP24A1, which calcitriol itself induces through two vitamin D response elements in the gene promoter and which PTH suppresses in hypocalcaemia [4]. FGF23, for its part, inhibits CYP27B1 and activates CYP24A1, while internalising the renal phosphate cotransporters [8]. Normal homeostasis therefore depends on a balance between production and inactivation, in which CYP24A1 is the main defence against excess calcitriol [17]. A secondary inactivation pathway is hepatic and intestinal CYP3A4, which oxidises 25(OH)D to 4β,25(OH)2D and 1,25(OH)2D to 1,23,25-trihydroxyvitamin D; its pharmacological induction is the basis of the experimental use of rifampicin [17].

In both types of IIH the end result is the same: PTH-independent excess of 1,25(OH)2D, increased intestinal calcium absorption, hypercalcaemia with suppressed PTH, hypercalciuria and calcium deposition in the renal parenchyma [2, 11]. The hypercalciuria has absorptive and bone-resorptive components, because calcitriol stimulates both [11]. The upstream mechanism differs, and this difference determines treatment.

2.2 CYP24A1 and infantile hypercalcaemia type 1

CYP24A1 is located at 20q13.2 (GRCh38 20:54,143,538–54,173,986) and encodes 1,25-dihydroxyvitamin D3 24-hydroxylase, a mitochondrial cytochrome P450 monooxygenase [4]. The initial mapping to 20q13.1 and to 20q13.2–q13.3, in the 1990s, reflected the cytogenetic techniques of the time [4]. The enzyme degrades 25(OH)D and 1,25(OH)2D by oxidation at C24 and C23, producing 24,25(OH)2D and 1,24,25(OH)3D and, at the end of the pathway, calcitroic acid [2, 11]. The MANE transcript is NM_000782.5 (protein NP_000773.2) [5].

Biallelic loss of function prevents clearance of 1,25(OH)2D and 25(OH)D, which accumulate mainly when there is exogenous or cutaneous vitamin D supply [2]. The biochemical signature is a markedly raised 25(OH)D3:24,25(OH)2D3 ratio, a direct reflection of the deficiency of the enzyme's product [15]. All variants studied in the initial series showed complete or near-complete loss of catabolic activity in cell lines [4]. Molecular models suggest that p.(Arg159Gln) and p.(Arg396Trp) disrupt hydrogen bonds between the haem propionate group and arginine, and that p.(Leu409Ser) weakens substrate binding [4]. The p.(Leu148Pro) variant reduces activity by 30 to 50% [17].

The Cyp24-deficient mouse has defective mineralisation of intramembranous bone, and it is thought that chronically high 1,25(OH)2D may mobilise calcium from the skeleton and sustain hypercalcaemia [26]. In the Molin series, 27 to 28% of patients with biallelic CYP24A1 variants had hypophosphataemia; the authors propose that reduced calcitriol clearance stimulates FGF23 and causes secondary renal phosphate wasting, which lowers the ability of serum phosphate to discriminate between the two types [15].

2.3 SLC34A1 and infantile hypercalcaemia type 2

SLC34A1 (formerly NPT2 or SLC17A2) is located at 5q35.3 (GRCh38 5:177,384,434–177,398,848), spans about 16 kb and has 13 exons, with translation starting in exon 2 [6]. The MANE transcript is NM_003052.5 (protein NP_003043.3) [5]. It encodes NaPi-IIa, an electrogenic sodium-phosphate cotransporter with 3:1 stoichiometry, located in the brush border of the proximal tubule and the main determinant of renal phosphate reabsorption [2]. In mouse studies, NaPi-IIa accounts for about 70% of renal phosphate reabsorption and NaPi-IIc (SLC34A3) for less than 30%; NaPi-IIc is more highly expressed in the growing kidney and loses importance in adults [27].

The pathogenic chain has been demonstrated in patients and in mice. Loss of NaPi-IIa function causes renal phosphate wasting and phosphate depletion; hypophosphataemia suppresses FGF23; without the FGF23 brake, CYP27B1 increases and CYP24A1 decreases; 1,25(OH)2D rises inappropriately, increases intestinal absorption of calcium and phosphate and produces hypercalcaemia with suppressed PTH and hypercalciuria [8, 11]. In Slc34a1-/- mice fed a low-phosphate, high-vitamin D diet, simulating breast milk with 500 IU/day prophylaxis, CYP27B1 mRNA was 0.110 versus 0.005 in the wild type (p = 0.001), CYP24A1 mRNA 0.34 versus 7.78 (p < 0.001), 1,25(OH)2D3 16.5 versus 7.4 ng/mL (p = 0.01) and FGF23 14 versus 571 pg/mL (p < 0.05) [8]. Restricting vitamin D attenuated these changes only slightly, whereas a high-phosphate diet normalised phosphate, FGF23, 1,25(OH)2D3 and calcium [8]. This finding underpins phosphate treatment and explains why simple withdrawal of vitamin D is not sufficient in type 2 [2, 8]. The first model, the Npt2-/- mouse generated by targeted mutagenesis by Beck and colleagues (1998), already combined urinary phosphate loss, hypophosphataemia, raised 1,25(OH)2D with hypercalcaemia, hypercalciuria, decreased PTH and increased alkaline phosphatase, that is, the biochemistry that would come to define HCINF2 [9]. At weaning, these mice had poorly developed trabecular bone and delayed secondary ossification, but with age the skeletal phenotype reversed and even exceeded that of the wild type; unlike patients with HHRH, they never had rickets or osteomalacia [9, 28].

The missense variants studied cause complete intracellular retention of the protein in opossum kidney cells and absence of phosphate uptake in Xenopus oocytes, which points to a defect in trafficking to the membrane [8]. The in-frame deletion p.(Val91_Ala97del) is different: in oocytes uptake is similar to wild type, but in kidney cells the protein is partially retained [8]. In the Turkish series of Turan, variants cluster in the cotransport domain, mainly between residues 109–205 and 375–487, and codons Gly153 and Gly194 emerge as possible hotspots [14].

2.4 Inheritance patterns

Both diseases are autosomal recessive in their severe forms, caused by homozygous or compound heterozygous variants [1, 3, 11]. The dominant inheritance suggested in early families is now explained by expression in heterozygotes with triggering factors, by pseudodominance in families with frequent carriers or by an undetected second variant [1, 15]. Heterozygotes do not usually have hypercalcaemia, but may have hypercalciuria and renal phosphate wasting, and some patients with a mild form have a single identified variant [11].

For CYP24A1, the evidence on heterozygotes is conflicting. In the systematic review of 221 carriers, monoallelic carriers had nephrolithiasis in 19.4%, nephrocalcinosis in 4.9% and symptomatic hypercalcaemia in 5.6% [7]. By contrast, French studies showed normal 24-hydroxylase activity in heterozygotes, assessed by the metabolite ratio, and in a large family heterozygotes had slightly higher calcium and 25(OH)D than relatives without the variant, with no difference in the frequency of lithiasis [2, 15, 29, 30]. ClinGen dosage curation assigns the gene the score "associated with autosomal recessive phenotype", which means that an isolated heterozygous deletion is not, by itself, pathogenic for a dominant disease [2]. A prospective study by the Hospices Civils de Lyon (NCT07201701) was designed to measure the prevalence of nephrolithiasis in heterozygotes and homozygotes [31].

For SLC34A1, inheritance has two faces. Biallelic variants cause HCINF2, an association classified as definitive [2]. Heterozygous variants were associated by Prié and colleagues (2002) with nephrolithiasis or bone demineralisation with hypophosphataemia and decreased maximal phosphate reabsorption, found in 2 of 20 patients studied, which gave rise to the OMIM entity hypophosphataemic nephrolithiasis/osteoporosis type 1 (NPHLOP1, #612286, autosomal dominant) [6, 32]. The first proband was a 34-year-old man with recurrent urolithiasis and a tubular maximum for phosphate reabsorption normalised to glomerular filtration rate (TmP/GFR) of 0.47 mmol/L; the second was a 64-year-old woman with bone demineralisation, whose only daughter had a spinal deformity and forearm fractures, with TmP/GFR of 0.58 and 0.67 mmol/L, respectively, and the mother-to-daughter transmission supported dominant inheritance [9]. OMIM distinguishes a second form, NPHLOP2 (#612287), due to variants in SLC9A3R1, which encodes the scaffolding protein NHERF1 [9]. Initial functional studies suggested a dominant-negative effect, but later work did not confirm it, ClinGen has issued no validity assertion and two GenCC submitters classify the association as limited [2, 8]. In the 2016 series, 3 of 26 heterozygous first-degree relatives had nephrolithiasis, which suggests a predisposition dependent on additional factors [8].

2.5 Variant spectrum

The following table presents variants with a historical or recurrent role, normalised in VariantValidator to the MANE transcripts; the nomenclature in brackets is that used in the original literature.

The recurrent deletion p.(Val91_Ala97del) deserves attention. In the French cohort its allele frequency (2.7%) did not differ from the general population, and the authors considered it probably benign or hypomorphic [15]. In the 2016 series, three compound heterozygous patients with a non-functional allele had a phenotype indistinguishable from the others, and one homozygous patient had a mild form, with borderline hypercalcaemia and hypercalciuria [8]. An infant with Sotos syndrome, due to a 5q35 deletion that included SLC34A1, and this deletion on the other allele had clinical IIH [8]. The most coherent interpretation is that of a hypomorphic allele, pathogenic only in trans with a null allele, whose classification should be made in the context of the complete genotype.

For CYP24A1, the systematic review by Cappellani and colleagues brings together in a supplementary table the genotypes of carriers published up to the end of 2020, in protein nomenclature: 58 homozygotes (three with unspecified variants), 76 compound heterozygotes and 85 monoallelic carriers [7]. The most frequent homozygous genotypes were p.(Glu143del) (21 patients), p.(Arg396Trp) (16) and p.(Leu409Ser) (5); among compound heterozygotes, p.(Glu143del)/p.(Arg396Trp) (13), p.(Leu148Pro)/p.(Arg396Trp) (6), p.(Arg396Trp)/p.(Leu409Ser) (6) and p.(Glu143del)/p.(Leu409Ser) (5) predominated; among monoallelic carriers, p.(Arg396Trp) (22), p.(Glu143del) (18) and NM_000782.5:c.667A>T p.(Arg223Ter) (8) [7, 33]. The same table records two homozygotes for a deletion of exons 9 to 11 and one homozygote for a large deletion, copy number variations that sequencing alone does not detect [7].

2.6 Genotype-phenotype correlations, penetrance and modifiers

There is no established genotype-phenotype correlation for CYP24A1. The same variant, p.(Glu143del), occurs in infants with severe hypercalcaemia and in adults with lithiasis or mild hypercalcaemia, and the same genotype may be expressed differently within a family [1, 11, 24]. Penetrance depends strongly on external factors: vitamin D prophylaxis, sun exposure and sunbeds, fortified milk and pregnancy [7, 17, 34]. The monozygotic twins of the 2011 series both had biochemical abnormalities and nephrocalcinosis, and the sibling who did not receive prophylaxis had, at 18 months, normal calcium with suppressed PTH and medullary hyperechogenicity [1]. Hawkes and colleagues suggest that fast-metabolising CYP3A4 alleles may attenuate severity by strengthening the alternative inactivation pathway [17].

For SLC34A1, patients with biallelic variants present earlier than heterozygotes, with a median age at diagnosis of 4 months versus 16 months in the Turan series [14]. Digenic mechanisms have been proposed: two siblings with symptomatic neonatal hypercalcaemia inherited a variant of uncertain significance in SLC34A3 from the father and the p.(Leu409Ser) variant of CYP24A1 from the mother, both parents having a mild vitamin D hypersensitivity profile [15]. An infant homozygous for p.(Thr454Met) in SLC34A1 also had a heterozygous 101 bp deletion in SLC34A3, which the authors consider may have worsened the renal calcifications [27].

2.7 Allelic disorders and entities of the same class

Renal Fanconi syndrome type 2 rests on a single family, described by Tieder and colleagues in 1988 and resolved by Magen and colleagues in 2010, with two siblings homozygous for a 21 bp in-frame duplication that prevents NaPi-IIa from reaching the membrane [6, 35]. OMIM lists it with a question mark and ClinGen classifies the association as disputed; the panel separates it from infantile hypercalcaemia type 2, which is a definitive association of the same gene [2]. In adults, heterozygous variants in SLC34A3, SLC9A3R1 and SLC34A1 cause primary renal phosphate wasting with raised calcitriol and hypercalciuria, without hypercalcaemia [11]. In the French cohort no SLC9A3R1 variants were found in patients with PTH below 20 pg/mL, which is consistent with the higher PTH described in these patients [15].

3. Clinical Spectrum and Manifestations by System

3.1 A phenotype dependent on age and triggers

The clinical expression of IIH depends on age, vitamin D intake and factors that increase calcitriol production. The systematic review by Cappellani and colleagues, which brought together 221 carriers of CYP24A1 variants from 50 studies published up to the end of 2020, showed that acute hypercalcaemia is the typical presentation in the first year of life (76%, p = 0.0005) and that nephrocalcinosis is more frequent in childhood (p < 0.0001) [7]. The Russian literature describes two peaks of manifestations, the first in infancy and the second at around 20 years [12]. The French PNDS summarises the pattern: acute presentation in infants and young children, renal disease predominating from adolescence onwards [11].

The supplementary table of the same review compares, by age group, biallelic with monoallelic carriers. In biallelic adults (median age 31 years), there was nephrolithiasis in 52 of 61 (85.3%), nephrocalcinosis in 26 of 60 (43.3%) and symptomatic hypercalcaemia in 22 of 70 (31.4%), with a median total calcium of 10.9 mg/dL, median PTH of 6.3 pg/mL and a median 25(OH)D:24,25(OH)2D ratio of 152.4 [7]. In biallelic carriers under 18 years (median age 0.8 years), there was nephrolithiasis in 44 of 47 (93.6%), nephrocalcinosis in 42 of 47 (89.4%) and symptomatic hypercalcaemia in 28 of 49 (57.1%), with a median total calcium of 13.5 mg/dL and a median ratio of 134.4 [7]. The denominators vary because published reports do not describe all outcomes, and a sample made of published cases over-represents symptomatic forms; these proportions are not estimates of penetrance.

Patients may alternate between chronic phases, with normal calcium, inappropriately high 1,25(OH)2D and low PTH, and acute phases with hypercalcaemia and suppressed PTH, triggered by vitamin D supplements or sun exposure [15]. Susceptibility is lifelong [15].

3.2 The infant: symptomatic hypercalcaemia

In the newborn and infant the signs of hypercalcaemia are non-specific: fatigue, faltering growth, irritability, constipation, weight loss, anorexia, vomiting, abdominal pain and hypotonia [11]. In severe forms there is polyuria, due to renal sodium and water loss, dehydration with acute kidney injury, altered consciousness and cardiac rhythm disturbances, with QT interval shortening and PR segment prolongation [11]. Other reports add arterial hypertension, unexplained fever and a picture suggestive of urinary tract infection with leucocyturia and erythrocyturia [13]. Nephrocalcinosis may already be present in the prenatal period and be asymptomatic [11].

In the 2011 series, the four probands with CYP24A1 variants presented between 6 and 8 months with weight loss or faltering growth, polyuria or dehydration and hypotonia or lethargy; all had been receiving 500 IU/day of vitamin D since birth; they had profound hypercalcaemia, suppressed PTH, hypercalciuria and medullary nephrocalcinosis [1]. Even after vitamin D was stopped and a low-calcium diet instituted, serum calcium remained slightly raised and PTH suppressed during follow-up [1].

In the Russian cohort of 44 patients with 24-hydroxylase deficiency (3 months to 32 years; 41 children), the main complaints were poor appetite, delayed physical and psychomotor growth, signs of acute pyelonephritis or persistent abacterial leucocyturia and nephrocalcinosis; 70.5% of the children were taking prophylactic colecalciferol at disease onset, for a median of 6 months; there was hypercalcaemia in 88.6% (median total calcium 2.9 mmol/L, range 2.65–4.03), hypercalciuria in 45.5% and nephrocalcinosis or nephrolithiasis in 95% [12]. The 16 infants under 1 year had the most marked manifestations [12].

In HCINF2, the 16 patients of the 2016 series received vitamin D from birth according to national recommendations (200 to 2000 IU/day), presented between 20 days and 10 months, mainly with faltering growth and polyuria, and all had medullary nephrocalcinosis [8]. There was hypercalcaemia and suppressed PTH at presentation; 1,25(OH)2D, measured in 11 patients during hypercalcaemia, was raised in 6 (median 82 pg/mL); median serum phosphate was 1.1 mmol/L, −5.0 standard deviations for age, and renal phosphate wasting was demonstrated in 4 of 7 patients with data [8]. There were no signs of rickets, despite hypophosphataemia, and the calcium abnormalities overshadowed the primary phosphate defect [8]. In the Turkish series of Turan (11 patients with SLC34A1 variants), the most frequent presentation was faltering growth, followed by nephrocalcinosis found on ultrasound requested for another reason, irritability, hypercalcaemia detected during admission for pneumonia and, in a 14-year-old boy, genu valgum; none had radiological rickets and all had hypercalciuria and/or nephrocalcinosis [14].

3.3 Prenatal presentation

Increased renal echogenicity on fetal ultrasound is a form of presentation described mainly in HCINF2. Lameris's patient had bilateral hyperechogenic kidneys in the fetal period, presented at 2 months with faltering growth and extensive nephrocalcinosis, raised total and ionised calcium, a urinary calcium/creatinine ratio four times above normal and low PTH; calcium fell with increased fluid intake and growth normalised, but she had recurrent urinary tract infections from 2 years of age and, at 8 years, a slightly reduced creatinine clearance [3]. Verjans and colleagues described a newborn with echogenic kidneys of normal size at 23 weeks, hypercalcaemic in the first week, treated with phosphate and vitamin D avoidance, with biochemical normalisation and nephrocalcinosis as the only sequela [2, 36]. In the French cohort, two patients with biallelic SLC34A1 variants had hyperechogenic kidneys in utero, and the authors consider this finding a clue to type 2 [15].

3.4 The child and adolescent

After the first year, hypercalcaemia tends to attenuate and renal disease comes to dominate. About half of children normalise their urinary calcium by 6 months of age [11]. A Polish patient homozygous for the SLC34A1 p.(Val91_Ala97del) deletion had only polyuria and nephrocalcinosis discovered incidentally at 18 months, with high-normal calcium and PTH at the lower limit [8]. An 11-year-old patient with hypertension, hypercalciuria and nephrocalcinosis with normal calcium has been described [2]. In adolescents, hypercalcaemia may manifest as mood changes, psychotic symptoms, confusion and hallucinatory episodes [11].

3.5 The adult: lithiasis, nephrocalcinosis and mild hypercalcaemia

In adults, renal colic due to stones and nephrocalcinosis secondary to hypercalciuria predominate, with hypercalcaemia of variable degree [11]. Hypercalcaemia may be seasonal, worsened by summer sun exposure, and patients may have 25(OH)D that is high for the estimated intake [13, 34]. In the French cohort, biallelic variants were more frequent in adults (45 to 51% of the 35 adults) than in children (8 to 12% of the 150 children); among patients with lithiasis, 21% had biallelic CYP24A1 variants, mostly adults, and four adults with biallelic variants had only hypercalcaemia, without nephrocalcinosis or lithiasis [15]. In a genetic screen of 256 patients with lithiasis, one (0.4%) had a homozygous CYP24A1 variant [34].

Reports of adults illustrate the spectrum. An English man with renal colic at 10 years and recurrent lithiasis presented at 45 years with symptomatic hypercalcaemia (corrected calcium 3.27 mmol/L), acute kidney injury and, subsequently, chronic kidney disease with an estimated glomerular filtration rate (eGFR) of about 33 mL/min/1.73 m² [34]. A 53-year-old man with recurrent calcium phosphate stones since the age of 24, 12 lithotripsies and one percutaneous nephrolithotomy developed hypercalcaemia of 2.84 mmol/L on hydrochlorothiazide, a sign of inability to compensate for the increase in tubular calcium reabsorption [37]. Two Croatian women aged 46 and 49 years with lithiasis since adolescence had severe nephrocalcinosis, secondary incomplete distal tubular acidosis with calcium phosphate stones and, in one of them, an eGFR of 35 mL/min/1.73 m² [38]. In patients with CYP24A1 variants, parenchymal renal cysts have been described, attributed to obstruction of small collecting ducts by microcalcifications [17]. Other reports describe nephrogenic diabetes insipidus, microalbuminuria, mild hypertension, corneal calcium deposits and osteoporosis [13].

3.6 Pregnancy

Pregnancy is the main trigger in adult women, because of the physiological increase in placental and renal production of 1,25(OH)2D [11]. In the systematic review, pregnancy was associated with symptomatic hypercalcaemia in 81.8% of carriers of CYP24A1 variants and with high rates of obstetric complications [7]. A woman who was asymptomatic until pregnancy may thus have the first manifestation of the disease in the third trimester or the puerperium.

3.7 Long-term renal manifestations and treated disease

Follow-up data distinguish treated disease from natural history only partially, because almost all published patients received avoidance measures. In the Warsaw cohort, 18 IIH survivors with variants in CYP24A1 (16) or SLC34A1 (4), diagnosed between 2 and 14 months of life with eGFR between 23 and 100 mL/min/1.73 m² at that time, followed to a mean age of 23.8 years (2 to 34) under advice to avoid sun, vitamin D and calcium, had a mean eGFR of 72 mL/min/1.73 m² (15 to 105); 14 (77%) had an eGFR below 90 and 5 (28%) below 60; two patients with CYP24A1 progressed to end-stage kidney disease at 27 and 34 years and were transplanted; 16 (88%) had nephrocalcinosis; 3 still had calcium above 2.6 mmol/L and 10 (55%) low PTH, but only one had mild hypercalciuria [13]. eGFR at diagnosis did not predict final renal function (r = 0.419, p = 0.09), and the ultrasound severity of nephrocalcinosis was not directly related to loss of function: the two patients who reached transplantation had hyperechogenic pyramids and, from puberty, loss of corticomedullary differentiation [13]. The authors attribute progression to tubulointerstitial inflammation and fibrosis; one biopsy showed diffuse tubulointerstitial fibrosis with foci of microlithiasis [13].

This cohort has limitations that should be stated. Fourteen of the 18 patients had been exposed to the very high-dose prophylaxis of the 1970s and 1980s, which may explain part of the renal disease; but two of the four exposed to less than 2000 IU/day also had chronic kidney disease in adolescence [13]. In the French cohort, four adults with biallelic CYP24A1 variants had a GFR below 60 mL/min/1.73 m² [15]. The PNDS considers progression of nephrocalcinosis to be the main long-term risk, sometimes already in childhood, and the other risks almost non-existent [11].

3.8 Heterozygotes

Most SLC34A1 heterozygotes have no renal disease; in the 2016 series both parents of one patient had lithiasis, the mother of another had undergone nephrectomy in adolescence for recurrent pyelonephritis and a staghorn calculus, one father had hypophosphataemia (0.6 mmol/L) with suppressed PTH and four of six carriers had TmP/GFR at the lower limit [8]. In the French cohort, heterozygous relatives for SLC34A3 had hypercalciuria in 8 of 11, low PTH in 6 of 11 and high 1,25(OH)2D in 9 of 11, and two of four relatives with SLC34A1 variants had hypercalciuria or hypophosphataemia [15]. In CYP24A1 heterozygotes, the systematic review found nephrolithiasis in 19.4%, nephrocalcinosis in 4.9% and symptomatic hypercalcaemia in 5.6%, in a sample made up of published patients and relatives [7]. Stratified by age, monoallelic adults (median age 45 years) had nephrolithiasis in 7 of 37, no nephrocalcinosis (0 of 37) and symptomatic hypercalcaemia in 1 of 39, with a median PTH of 31.6 pg/mL and a median 25(OH)D:24,25(OH)2D ratio of 15.2; monoallelic carriers under 18 years had nephrolithiasis in 3 of 16, nephrocalcinosis in 3 of 15 and symptomatic hypercalcaemia in 3 of 16 [7]. In all these comparisons, monoallelic carriers had lower calcium and 25(OH)D and higher PTH than biallelic carriers of the same age group [7].

4. Clinical Recognition and Warning Signs

4.1 When to suspect, by age and context

In the fetal period, suspicion arises from hyperechogenic kidneys of normal size, especially in families with a history of IIH or early lithiasis [2, 15]. In the newborn and infant, IIH should be considered in the presence of faltering growth, vomiting, constipation, irritability, hypotonia, polyuria or dehydration, particularly when these appear weeks or months after starting vitamin D prophylaxis [1, 11]. Likewise in the presence of medullary nephrocalcinosis found on ultrasound requested for urinary tract infection or for another reason, or hypercalcaemia detected incidentally during an admission [14]. The combination of hypercalcaemia with suppressed PTH and normal or high alkaline phosphatase, without drugs or granulomatous disease, is the starting point of the reasoning [11].

In the older child and adolescent, suspicion arises in the presence of nephrocalcinosis, early lithiasis, persistent hypercalciuria with low PTH, polyuria, hypertension or unexplained neuropsychiatric symptoms with hypercalcaemia [2, 11]. In adults, IIH should be considered in recurrent calcium lithiasis since adolescence, especially calcium phosphate, in nephrocalcinosis, in mild or seasonal hypercalcaemia with suppressed PTH and inappropriately normal or high 1,25(OH)2D, and in disproportionate hypercalcaemia on thiazides, vitamin D supplements, sunbeds or intense sun exposure [34, 37, 38]. In pregnant women, hypercalcaemia with suppressed PTH in the second or third trimester should prompt consideration of 24-hydroxylase deficiency [7, 11].

4.2 Clues that point to the type

Presentation in the first days or weeks of life, prenatal nephrocalcinosis, marked hypophosphataemia with low TmP/GFR and persistence of hypercalcaemia after vitamin D withdrawal point to SLC34A1 [8, 15]. 25(OH)D that is high for intake, low or undetectable 24,25(OH)2D and presentation in adulthood or pregnancy point to CYP24A1 [15, 17]. These clues are a guide and do not replace genetic testing: one third of patients with SLC34A1 variants in the 2016 series did not have hypophosphataemia, and 27 to 28% of patients with CYP24A1 in the French cohort did [15].

4.3 Warning and emergency signs

Any symptomatic hypercalcaemia requires urgent treatment [11]. Hypercalcaemia is considered severe from 3.4 mmol/L, a threshold at which almost all patients have symptoms [11]. Signs of severity are dehydration with acute kidney injury, altered consciousness, seizures, hypertension and electrocardiographic changes, with QT interval shortening, flat or absent T waves, atrioventricular conduction disturbances and ventricular arrhythmias [11, 39]. An infant with a serum calcium of 5.98 mmol/L at 5 months has been described [38]. During follow-up, alarm signs are a fall in eGFR, loss of corticomedullary differentiation on ultrasound, recurrence of hypercalcaemia on stopping a treatment and hypercalcaemia in pregnancy [7, 13, 17].

There are also iatrogenic circumstances that should raise concern: severe hypercalcaemia after fluconazole was prescribed to an infant with biallelic CYP24A1 variants, which normalised on stopping the drug, and marked hypercalcaemia on hydrochlorothiazide in an adult with lithiasis [17, 37].

4.4 Newborn screening and family screening

There is no newborn screening for IIH. The PNDS recommends biochemical screening of children born into affected families and, in the neonatal period, accepts that the biochemical study may also be carried out in the parents [11].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Biochemical definitions

There are no formal validated diagnostic criteria. Diagnosis rests on three steps: demonstrating 1,25(OH)2D-dependent, PTH-independent hypercalcaemia or hypercalciuria, excluding acquired causes and other diseases of the same class, and confirming biallelic variants [11, 15].

Hypercalcaemia can only be diagnosed with an accurate measurement of ionised calcium, collected, transported and analysed immediately [11]. Studies use thresholds of 2.8 mmol/L total calcium in the first year of life, 2.7 mmol/L up to 17 years and 2.6 mmol/L after 17 [11]. Age-specific reference values are given in the following table.

Source: French PNDS [11].

In children, hypercalciuria is defined as urinary calcium excretion above 0.1 mmol/kg/day; in adults, as more than 6.25 mmol/24 h in women and more than 7.5 mmol/24 h in men [11]. In young children the calcium/creatinine ratio in a morning urine sample is used, with reference values of 1.5–2.2 mmol/mmol before 2 years, 0.7–1.4 from 2 to 4 years, 0.2–0.8 from 5 to 10, 0.1–0.7 from 10 to 18 and 0.05–0.5 in adults [11]. The French cohort used upper limits of 2.4 before 6 months, 1.7 from 7 to 12 months, 1.1 from 1 to 5 years, 0.7 after 5 years and 0.33 in adults [15]. The difference between the two tables reflects different methods and reference populations and should be taken into account in interpretation. Urinary calcium is interpreted in the light of sodium and animal protein intake, urinary creatinine confirms the adequacy of the 24-hour collection and, in renal failure, urinary calcium may be normal or low despite the disease [11].

5.2 Initial work-up

The PNDS recommends, preferably fasting in the morning, total and ionised calcium, phosphate, magnesium, alkaline phosphatase, creatinine, intact PTH, 25(OH)D and 1,25(OH)2D; in urine, a spot sample in young children (calcium, phosphate, creatinine, to calculate the calcium/creatinine ratio and TmP/GFR) and a 24-hour collection in adolescents and adults (calcium, sodium, creatinine, urea and phosphate) [11]. TmP/GFR is calculated as plasma phosphate minus the product of urinary phosphate and the plasma creatinine/urinary creatinine ratio, and tubular reabsorption of phosphate (TRP) as 1 minus the ratio of phosphate to creatinine clearances [8, 14]. Alkaline phosphatase should be requested in all paediatric hypercalcaemias, so as not to miss hypophosphatasia [11]. The electrocardiogram assesses cardiac repercussions [11].

Renal ultrasound is the reference modality in children to look for nephrocalcinosis and stones; in adults, renal computed tomography complements the assessment because it is more sensitive [11].

The typical profile is hypercalcaemia and hypercalciuria with suppressed PTH and high or inappropriately normal 1,25(OH)2D [11]. A merely "normal" 1,25(OH)2D does not exclude the disease: in Hawkes's second case it was 49 pg/mL with corrected calcium of 12.8 mg/dL and PTH of 4 pg/mL [17]. In the 2016 series, only 6 of 11 patients with HCINF2 had raised 1,25(OH)2D during hypercalcaemia [8]. In the French cohort, patients with biallelic CYP24A1 variants had, on average, calcium of 2.95 mmol/L, PTH of 6.8 pg/mL, 25(OH)D of 114 nmol/L and 1,25(OH)2D of 195 pmol/L, and patients with SLC34A3 had lower calcium (2.43 mmol/L; p = 0.0123) and lower 25(OH)D (52 nmol/L; p = 0.0139) [15]. The 1,25(OH)2D/PTH ratio has been proposed as an index of PTH-independent calcitriol production, raised in all forms of IIH [26].

5.3 The vitamin D metabolite profile

Measurement of 24,25(OH)2D by liquid chromatography-tandem mass spectrometry allows calculation of the 25(OH)D3:24,25(OH)2D3 ratio, whose elevation suggests CYP24A1 variants [11]. In the 2015 French cohort, the ratio was generally above 80 in patients with biallelic variants and below 25 in non-carriers and heterozygotes [2, 16]. In the Russian cohort, the median ratio was 340.65 (132.2–630.75) in 10 patients, and 132 in Davidson Peiris's adult [12, 37]. In the systematic review of published cases, the median ratio was 152.4 (interquartile range 88.6–208.6) in biallelic adults versus 15.2 (12.7–22.9) in monoallelic adults, and 134.4 (89.8–195.7) versus 22 (18.2–132.1) in those under 18 years [7]. In patients with biallelic SLC34A1 variants the ratio is normal, which readily separates the two types [15]. A broader profile, with 23,25,26-(OH)3D3, 25-OH-D3-26,23-lactone and 1,24,25-(OH)3D3, accentuates the difference from other vitamin D-mediated hypercalcaemias [15]. These assays are only performed in specialised laboratories [11].

5.4 Genetic testing

Genetic testing should cover the coding regions and intron-exon junctions of CYP24A1 and SLC34A1, by Sanger sequencing, panel, exome or genome, depending on the context [11]. Because no biochemical pattern reliably separates CYP24A1, SLC34A1 and SLC34A3, the French cohort recommends that a patient with suspected CYP24A1 deficiency also be tested for SLC34A1 and SLC34A3 [2, 15]. In lithiasis and nephrocalcinosis series, inherited kidney disease panels usually include these genes, together with CLDN16, CLDN19, CLCN5, CASR, ALPL, SLC9A3R1, VDR and others [38].

The yield depends on the inclusion criteria. In the French cohort of 185 patients with PTH below 20 pg/mL, biallelic variants were found in 15 to 19% (14% in CYP24A1), monoallelic variants in 8 to 14% and no variant in 66 to 77%; the yield was 45 to 51% in adults and only 8 to 12% in children, most of them under 2 years [15]. In the earlier French cohort of 72 hypercalcaemic patients with low PTH, 20 (28%) had biallelic CYP24A1 variants and 19 of these had nephrocalcinosis or lithiasis [2, 16]. In the 2016 series, 11 of 126 sporadic IIH patients without CYP24A1 variants (8.7%) had biallelic SLC34A1 variants [8]. The low yield in young children reflects, according to the authors, admixture with transient hypersensitivity of the newborn, attributed to renal immaturity of 24-hydroxylase [15].

5.5 Limitations of testing

A negative result does not exclude the disease. Panels that analyse only coding regions do not detect deep intronic or regulatory variants, and methods without copy number analysis miss deletions such as the deletion of exons 10–12 of CYP24A1 described in France [15]. In a newborn with HCINF2, the pathogenic 21 bp SLC34A1 deletion was filtered out of the exome analysis because of its high population frequency and was found only on targeted reanalysis [2, 36]. Automatic filters that exclude variants with a frequency above 1% remove p.(Val91_Ala97del), which has a frequency of 1.7 to 2.7% depending on the population [13, 15]. In the Warsaw cohort, three patients with a typical clinical picture had only one variant, and only the coding region of one of the genes had been analysed [13]. In a patient with a heterozygous CYP24A1 variant and a raised 25(OH)D3:24,25(OH)2D3 ratio, a second non-coding variant or a rearrangement should be sought [15].

5.6 Reporting and interpretation of variants

The report should state the gene, the versioned transcript (NM_000782.5 or NM_003052.5), the variant in HGVS nomenclature at DNA and protein level, zygosity, the class according to ACMG/AMP criteria and, whenever possible, the phase of the variants confirmed by segregation [5, 14]. Variants of uncertain significance are frequent in SLC34A1 and SLC34A3: in the French cohort, 17 of 24 variants in these genes were of uncertain significance, and gnomAD records more than 700 heterozygous SLC34A3 variants [15]. Functional studies are not feasible in routine diagnosis, and the metabolite ratio and renal phosphate wasting act as indirect functional evidence [15]. After variants have been identified in a patient, family segregation studies are essential [11].

5.7 Algorithm

The algorithm summarises the guidance of the PNDS and the French cohort [11, 15]. In children without a variant, reassessment of PTH after vitamin D withdrawal helps to distinguish a transient form (normalisation of PTH) from a genetic defect (persistently low PTH) [15].

5.8 Prenatal and preimplantation diagnosis

The PNDS considers that there is no indication for prenatal diagnosis and recommends instead biochemical screening of children born into affected families; the same document describes the disease as relatively benign with a favourable course in most cases, and genetic counselling supports pregnancy plans [11]. The literature consulted does not describe cases of preimplantation diagnosis for this disease.

6. Differential Diagnosis

6.1 Comparative table

6.2 Transient hypersensitivity of the newborn

This is the main differential in the neonatal period. The PNDS describes it as a transient physiological condition rather than a disease, often found on tests performed in the maternity unit or in the first weeks for non-specific signs; it shares the hormonal profile and management with IIH, but has no genetic cause, the mean calcium at diagnosis is below 3.4 mmol/L and clinical tolerance is good [11]. The proposed explanation is a transient immaturity of renal CYP24A1, which delays the adaptation of mineral metabolism from the prenatal to the postnatal period [11, 15]. In the French cohort, 78% of the 150 children were under 2 years and the genetic yield was low in that group, which is consistent with a high proportion of transient forms [15]. The distinction is made by the course: PTH normalises after vitamin D withdrawal in transient forms and remains low in genetic defects [15].

6.3 Hereditary hypophosphataemic rickets with hypercalciuria and other phosphate-wasting disorders

HHRH, due to biallelic SLC34A3 variants, has the same functional consequences as HCINF2 on FGF23 and 1,25(OH)2D, but manifests mainly as hypophosphataemia with rickets or osteomalacia and hypercalciuria, with normal serum calcium [2, 11]. The overlap is real: in the French cohort, two patients with biallelic pathogenic SLC34A3 variants had normal phosphate, and a homozygous boy was referred at 5 years for hypercalciuria and nephrocalcinosis and only at 10 years developed bowing of the lower limbs [15]. Treatment of HHRH with phosphate alone and the contraindication of active vitamin D analogues, which worsen hypercalciuria, are shared with HCINF2 [2]. Renal Fanconi syndrome type 2 associated with SLC34A1 is distinguished by generalised proximal tubulopathy, with glycosuria and aminoaciduria [2, 6].

The history of HHRH sheds light on that of IIH. Tieder and colleagues (1985) described a consanguineous Bedouin family with six affected members (five male), rickets with onset in early childhood, short stature, TmP/GFR 2 to 4 standard deviations below the mean for age, urinary calcium of 8.6 mg/kg/24 h (upper limit 4.0), normal serum calcium, increased intestinal absorption of calcium and phosphorus, 1,25(OH)2D about four times above normal and decreased PTH; prolonged phosphate supplementation corrected all abnormalities except the low TmP/GFR, which identified renal phosphate leak as the primary defect [28]. In 1987, the same group studied 50 asymptomatic members of the tribe and found in about 40% "idiopathic" hypercalciuria with the same profile, to an intermediate degree: urinary calcium/creatinine ratio of 0.43 mg/mg in patients, 0.34 in those with hypercalciuria and 0.14 in normal relatives, serum phosphate and tubular reabsorption of phosphate 1.1 standard deviations below the mean (versus 4.3 and 3.0 in HHRH) and mean 1,25(OH)2D of 303 pg/mL (upper limit 110); the authors concluded that the severity of hypophosphataemia determines whether the presumed carrier has only hypercalciuria or also bone disease, a model parallel to that of SLC34A1 heterozygotes [28]. Proesmans and colleagues (1987) described a family with the same picture and dominant transmission [28]. In a Turkish boy with severe rickets from 2 years and osteomalacia on biopsy, high-dose phosphate treatment combined with vitamin D was followed by symptomatic nephrolithiasis at 10 years, and in a Yemenite Jewish family with two mildly symptomatic members Tieder and colleagues (1992) emphasised that phosphate alone is effective and that active vitamin D metabolites may worsen the disease [28]. The entity probably corresponds to the hypercalciuric rickets described by Royer and colleagues in 1962, also with parental consanguinity [28]. The locus was mapped to 9q34 in 2006, by homozygosity mapping in the Bedouin family (1.6 Mb region) and in two consanguineous Arab families, and two groups simultaneously identified biallelic loss-of-function variants in SLC34A3, the first of which was a homozygous single-nucleotide deletion; before that, Jones and colleagues (2001) had excluded SLC34A1 (NPT2) in that family [28].

6.4 Vitamin D intoxication

Intoxication may result from prescribing errors, accidental ingestion or food supplements containing vitamin D that are not regulated as medicines [11]. The profile includes hypercalcaemia, hypercalciuria, suppressed PTH and very high 25(OH)D [11]. In IIH type 1, 25(OH)D may also be high, because CYP24A1 is the clearance pathway of this metabolite; the history of intake, the 25(OH)D3:24,25(OH)2D3 ratio and genetic testing separate the two situations [15, 17]. In the historical episodes of "intoxication" from high-dose prophylaxis, some of the infants had CYP24A1 variants [1, 13].

6.5 Williams-Beuren syndrome

Williams-Beuren syndrome, caused by a recurrent 1.5 to 1.8 Mb deletion at 7q11.23, has a prevalence of about 1/7500 in Norway [22]. Hypercalcaemia occurs in 20 to 40% of patients, is clinically significant mainly before 2 years and is associated with dehydration, hypercalciuria (30%) and nephrocalcinosis (5%) [22]. The PNDS cites a frequency of hypercalcaemia with nephrocalcinosis of 5 to 50% and a prevalence of the syndrome of 1/7500 to 1/10,000, and the Oxford Desk Reference reports hypercalcaemia in about 15% of infants [11, 51]. The difference between these proportions reflects different definitions, ages of observation and data collection methods. Its aetiology has not been clarified; abnormalities of 1,25(OH)2D metabolism, reduced calcitonin production and the BAZ1B gene, which interacts with the vitamin D receptor, have been implicated [11, 22]. Management of hypercalcaemia is similar: avoid paediatric multivitamins, which always contain vitamin D, keep calcium intake at no more than 100% of requirements, use oral corticosteroids in refractory hypercalcaemia and intravenous pamidronate in infants with severe symptomatic hypercalcaemia [22]. The facies, supravalvular aortic stenosis, cognitive and behavioural profile and microarray allow the diagnosis [21, 22, 41].

6.6 Subcutaneous fat necrosis, hypophosphatasia and Jansen chondrodysplasia

Subcutaneous fat necrosis of the newborn arises in the context of anoxia-ischaemia, sepsis or therapeutic hypothermia, up to 6 weeks of life, with hard plaques and nodules that may calcify; hypercalcaemia appears after the skin lesions, is proportional to their extent and probably results from macrophage activation of 1α-hydroxylase, with management comparable to that of IIH [11]. Hypophosphatasia may present in the neonatal period with hypercalcaemia, hypercalciuria and low PTH, and the infantile form runs a course with faltering growth, vomiting and nephrocalcinosis; it is distinguished by low or absent alkaline phosphatase and raised pyridoxal 5'-phosphate, and vitamin D and mineral supplements increase the risk of hypercalcaemia and should be avoided [11, 42]. In the neonatal form serum calcium may be raised and vomiting has been attributed to hypercalcaemia, with proteinuria and impaired renal function frequent in the youngest infants; in survivors of the perinatal form, faltering growth, hypotonia, irritability and, at times, hypercalcaemia and nephrocalcinosis are common [43, 44]. Jansen metaphyseal chondrodysplasia, due to activating variants of the PTH/PTHrP receptor, causes asymptomatic hypercalcaemia in the first months with normal or low PTH and low phosphate, and nephrocalcinosis in adults; the rachitic-like metaphyseal changes and short-limbed short stature make it recognisable [48].

6.7 Neonatal hyperparathyroidisms

In neonatal severe hyperparathyroidism due to CASR, marked hypercalcaemia is accompanied by raised PTH, high alkaline phosphatase, multiple fractures and subperiosteal resorption; unlike other hyperparathyroidisms, it is not associated with nephrocalcinosis or lithiasis [39]. The heterozygous parents may have familial hypocalciuric hypercalcaemia [39]. In transient neonatal hyperparathyroidism due to TRPV6, calcium is normal or low and the abnormalities regress in 6 to 12 months, and hereditary self-limiting neonatal hyperparathyroidism (MIM 239199) combines hypercalciuria, nephrocalcinosis and renal tubular acidosis [39]. Raised PTH distinguishes all these forms from IIH.

6.8 Syndromes with hypercalcaemia, hypercalciuria or nephrocalcinosis

Some malformation syndromes and tubulopathies enter the differential of the infant with hypercalcaemia or nephrocalcinosis. In IMAGE syndrome (intrauterine growth restriction, metaphyseal dysplasia, congenital adrenal hypoplasia and genital anomalies), caused by maternally inherited heterozygous CDKN1C variants, hypercalcaemia and hypercalciuria may lead to nephrocalcinosis and to prenatal hepatic and splenic calcifications; the metaphyseal changes only appear in childhood, so early diagnosis rests on clinical and endocrine findings, and unrecognised adrenal insufficiency may be fatal [45]. In SHORT syndrome, due to dominant PIK3R1 variants, nephrocalcinosis with hypercalcaemia and hypercalciuria, with normal vitamin D and PTH, has been described from 2 months of age, in a context of growth restriction, faltering growth with frequent admissions in the first 2 years, facial lipoatrophy and Rieger anomaly [46]. In Bartter syndrome, which is genetically heterogeneous (SLC12A1, KCNJ1, SLC12A3), hypercalciuria is accompanied by hypokalaemic alkalosis, a history of polyhydramnios and preterm birth and severe faltering growth, and plasma potassium may be normal [47]. In all three, dysmorphological examination, adrenal assessment and electrolytes with blood gases guide the diagnosis before molecular testing.

6.9 In adults: lithiasis and hypercalcaemia with suppressed PTH

In adults with hypercalcaemia and suppressed PTH, the differential includes sarcoidosis and other granulomatous diseases, malignancies and vitamin D intoxication; general lists of the differential diagnosis of hypercalcaemia add acute renal failure, thyrotoxicosis, adrenal insufficiency, phaeochromocytoma, vasoactive intestinal peptide-producing tumours, immobilisation, milk-alkali syndrome, lithium therapy and vitamin A intoxication, together with the forms of primary, familial and tertiary hyperparathyroidism and familial hypocalciuric hypercalcaemia [52]; in reports of CYP24A1 deficiency in adults, angiotensin-converting enzyme, chest imaging, protein electrophoresis, tumour markers and PTHrP were normal [34, 37]. Coexisting parathyroid disease requires care: in one of the Croatian patients, neck ultrasound, sestamibi scintigraphy and choline positron emission tomography excluded an adenoma, and the minimally raised PTH was interpreted as secondary to chronic kidney disease [38]. In paediatric lithiasis in other populations, the most frequent monogenic causes may be different: in a Saudi series of 54 children with genetic testing, the most frequent causal variants were in CLDN16, SLC2A2, AGXT and SLC12A1 [50]. Tables of inherited metabolic diseases with lithiasis or nephrocalcinosis include hereditary hyperparathyroidism, the primary hyperoxalurias, cystinuria, xanthinuria, adenine phosphoribosyltransferase deficiency and renal tubular acidosis, and do not include disorders of the vitamin D pathway [53].

7. Treatments and Risk Management Strategies

7.1 Framework and level of evidence

There is no approved treatment for IIH in any jurisdiction consulted, nor any completed randomised trial. The only specific normative guidance is the French PNDS, which is based on a critical review of the literature and a multidisciplinary expert consensus and describes the 2024 standard of care [11]. The systematic review of 221 carriers of CYP24A1 variants concluded that the variability of the treatments tested does not allow a preferred regimen to be recommended [7]. The therapeutic evidence therefore consists of case reports, retrospective series and two small open-label studies with rifampicin [17, 26]. All drugs used in IIH are used off-label, and the PNDS doses are the reference, with label doses cited only for comparison.

The strategy depends on the mechanism. In type 1, the aim is to reduce the production or accelerate the inactivation of 1,25(OH)2D; in type 2, it is to correct the phosphate loss that underlies the excessive calcitriol production [8, 11]. In both, the long-term aim is to limit hypercalciuria, which leads to nephrocalcinosis and loss of renal function [11, 14].

7.2 Treatment of acute hypercalcaemia

The indication for urgent treatment depends on severity and above all on the clinical repercussions; not all hypercalcaemias require it, but any symptomatic hypercalcaemia does [11]. The PNDS sets out the following lines of action, without imposing a rigid protocol [11]:

Pamidronate acts through osteoclast apoptosis and inhibition of bone resorption [11]. The US label for pamidronate covers only malignancy-associated hypercalcaemia in adults, with 60 to 90 mg as a single dose infused over 2 to 24 hours in moderate hypercalcaemia, vigorous saline hydration with a urine output of about 2 L/day and longer infusions to reduce renal toxicity; it has no paediatric indication nor any indication in hypercalcaemia of other causes [54]. The PNDS per-kilogram dose is therefore an off-label use. In Portugal, pamidronate disodium is available as Pamidran® (concentrate for solution for infusion, 3 mg/ml and 9 mg/ml) [55]. In Williams-Beuren syndrome, the same strategy with pamidronate has been used successfully in infants with severe symptomatic hypercalcaemia [22].

Glucocorticoids are a documented option, but with limitations. In Sayers's adult, intravenous hydration and oral prednisolone corrected calcium only partially, and the authors note that the hypercalcaemia of some patients with CYP24A1 deficiency is resistant to corticosteroids, which are not a targeted treatment [34]. In the 2016 series, acute measures included intravenous hydration, furosemide, corticosteroids and ketoconazole, and calcium fell but remained raised during follow-up in 6 of 16 patients [8].

The PNDS does not give doses for furosemide or calcitonin, and the labels of these drugs serve as a reference, with the caveat that this is an extrapolation [11]. The US label for injectable furosemide, approved for oedema and not for hypercalcaemia, gives in children 1 mg/kg by slow intravenous or intramuscular injection, with increments of 1 mg/kg no sooner than 2 hours after the previous dose, not exceeding 6 mg/kg; in preterm infants, the dose should not exceed 1 mg/kg/day, because of the risk of ototoxicity [56]. The US label for injectable salmon calcitonin, which includes hypercalcaemia among the adult indications, provides for 4 IU/kg every 12 hours subcutaneously or intramuscularly, 8 IU/kg every 12 hours if the response is insufficient after one to two days and, at most, 8 IU/kg every 6 hours; safety and efficacy in children have not been established [57]. For prednisone, the US label includes malignancy-associated hypercalcaemia and gives initial doses of 5 to 60 mg/day in adults, adjusted to the disease; the PNDS dose of 0.5 to 2 mg/kg/day is the reference [11, 58]. For pamidronate, the PNDS does not set a maximum dose; the adult label goes up to 90 mg per infusion [11, 54].

The systematic review by Cappellani compiled, from published cases, the percentage reduction in total serum calcium between the last value before and the first value after each intervention: azoles 5 to 31.3%, bisphosphonates 12.8 to 20%, calcitonin 14.3 to 47.7%, glucocorticoids 20.2 to 38.1%, furosemide 22.4%, hydrochlorothiazide 6.4%, rifampicin 6.5 to 8.6%, cinacalcet 10.3 to 18.2% and denosumab 14.7 to 24.1%; combinations of three or four drugs (furosemide, glucocorticoids or calcitonin with bisphosphonates and potassium phosphate) reached 40 to 46.5% [7]. These are values from isolated reports, without direct comparison or control for time course, and in one case the combination of furosemide and glucocorticoids was followed by a rise in calcium; the authors conclude that these data do not allow a preferred regimen to be chosen [7]. Cinacalcet and denosumab do not appear in the PNDS [11].

7.3 Non-specific long-term measures

Long-term treatment begins after the acute phase or, without an acute phase, when hypercalcaemia is well tolerated but there are severity criteria capable of leading to renal complications [11]. Nephrocalcinosis on ultrasound and persistently raised urinary calcium are the severity criteria that justify specific treatment; in mild forms, without symptoms or severity criteria, non-specific measures and surveillance suffice [11].

Non-specific measures aim to reduce vitamin D and calcium intake and to limit hypercalciuria: stop native vitamin D, ensure oral hydration appropriate for age, use calcium-free milk (for example, LOCASOL) only in severe forms under acute treatment, for a limited time and under close supervision, and maintain a diet normal in protein and sodium [11]. In formula-fed infants, a low-calcium, vitamin D-free formula (Calcilo-XD) makes restriction practicable; in older children and adults, restrictions are difficult to maintain [26]. Patients followed in Warsaw were advised to avoid sun exposure, vitamin D and calcium supplements and to drink plenty of fluids [13]. In adults, avoidance of sunbeds and of drinks or supplements containing vitamin D is part of the instructions [34].

Restriction has a cost that should be known. Restriction of vitamin D and calcium may increase 1α-hydroxylase activity and maintain or worsen 1,25(OH)2D, and does not correct the underlying defect; this is one of the reasons put forward for seeking pharmacological therapies [26]. In Williams-Beuren syndrome, the recommendation is not to restrict calcium without medical supervision and to keep intake at no more than 100% of daily requirements [22]. The PNDS limits the calcium-free diet to severe forms and for a short time [11].

7.4 Specific treatment of type 1: azole antifungals

Azoles non-specifically inhibit mitochondrial cytochrome P450 enzymes, including 1α-hydroxylase and 25-hydroxylase, and reduce the production of 1,25(OH)2D [11, 34]. The PNDS emphasises that they can cause serious adverse effects, hepatic and renal, that they are not approved for this indication and that large studies are lacking; it recommends that the indication be discussed and validated within the network of reference centres, with close clinical and laboratory monitoring, the shortest possible duration and explanation of adverse effects to the parents [11].

Published clinical experience consists of cases. In the English adult homozygous for p.(Glu143del), fluconazole 50 mg once daily allowed prednisolone to be stopped, lowered 1,25(OH)2D from 118 to 69 pmol/L in 98 days and urinary calcium from 8.8 to 5.2 mmol/24 h, without adverse effects [34]. In the three Croatian patients, the same dose of 50 mg/day normalised calcium and urinary calcium within one to four months, with stability up to 18 months; one patient reported hair loss [38]. In Davidson Peiris's adult, ketoconazole lowered 1,25(OH)2D from 88 to 40 pg/mL and normalised urinary calcium within two months, but caused fatigue with low testosterone, which required replacement [37]. Tebben and colleagues used ketoconazole 200 mg three times daily in an adult, and Nesterova and colleagues up to 800 mg/day, with reduction of serum and urinary calcium [34, 38]. In infants, Nguyen and colleagues treated 10 of 20 infants with IIH with ketoconazole 3–9 mg/kg/day: calcium normalised earlier in those treated, with no difference in time to normalisation of urinary calcium, and one infant had a marked fall in cortisol that required discontinuation [17].

There is a paradox that should be known. In an infant with biallelic CYP24A1 variants, fluconazole prescribed for an infection triggered severe hypercalcaemia, which normalised after withdrawal; the authors explain this by inhibition of CYP3A4, the alternative vitamin D inactivation pathway, which azoles also block [17]. The net effect of an azole thus depends on the balance between inhibition of CYP27B1 and inhibition of CYP3A4, which reinforces the need for close biochemical monitoring at the start of treatment.

7.5 Investigational treatment of type 1: rifampicin

Rifampicin is a potent CYP3A4 inducer and has been proposed to create an alternative vitamin D inactivation pathway in patients without functional CYP24A1 [17]. Hawkes and colleagues treated two patients on a compassionate-use basis, with the standard antituberculous dose of 10 mg/kg/day up to 600 mg/day, for up to 13 months [17]. In an 18-year-old man with extensive nephrocalcinosis, renal cysts and creatinine of 1.4 mg/dL, 600 mg/day lowered 1,25(OH)2D3 and calcium, normalised PTH and reduced creatinine to 1.1 mg/dL within one month [17]. In an 8-year-old girl previously treated with pamidronate, calcitonin and diet, 300 mg/day lowered corrected calcium from 10.7 to 9.8 mg/dL, raised PTH from 3 to 31 pg/mL and resolved the polyuria; when it was stopped at 11 months, hypercalcaemia and hypercalciuria recurred within a month, with 1,25(OH)2D3 rising from 58 to 90 pg/mL [17]. In the Toronto pilot study, a control patient with HCINF1 received 5 mg/kg/day (up to 300 mg) and then 10 mg/kg/day (up to 600 mg), two months each, with reductions in 1,25(OH)2D of 60.6% and 32.8% and in the 1,25(OH)2D/PTH ratio, without change in serum calcium; there was no statistical significance, given the sample size [26].

The US label and the Portuguese SmPC for rifampicin give, in tuberculosis, 10 to 20 mg/kg/day in children up to 600 mg/day, as a single dose on an empty stomach, and the SmPC adds that data are insufficient to establish the long-term dose below 5 years and that, in hepatic impairment, the dose should be reduced, with a maximum of 8 mg/kg [62, 63]. In Portugal, single-agent rifampicin is available as Rifadin® in 300 mg capsules and as a 20 mg/ml oral suspension [63]. The Philadelphia patients had no hepatic dysfunction or adrenal insufficiency, with normal morning ACTH and cortisol; in a series of 157 adolescents treated with similar doses, 2.5% stopped because of ALT above twice the upper limit, and there are reports of adrenal crisis with higher doses in patients with pre-existing adrenal insufficiency [17]. In the Toronto study, tolerance was good, without hepatic or adrenal changes [26]. Rifampicin does not appear in the PNDS, and the safety of its prolonged use has not been studied [13]. An open-label phase 2 trial (NCT03301038) is evaluating this regimen in patients with at least one inactivating CYP24A1 variant [18].

7.6 Specific treatment of type 2: phosphate supplementation

In HCINF2 the primary defect is renal phosphate wasting, and correcting it normalises FGF23, 1,25(OH)2D and calcium, as was demonstrated in the Slc34a1-/- mouse [8]. In children, the PNDS recommends as the main treatment phosphate supplementation of 40 to 60 mg/kg/day in four doses, each separated from bottle feeds, together with the non-specific measures [11]. In the 2016 series, the patient diagnosed in the midst of the acute phase did not respond to oral hydration or to a low-calcium, vitamin D-free diet, and oral phosphate at a dose of 0.5 to 1 mmol/kg/day rapidly corrected the hypophosphataemia, normalised calcium metabolism, reduced urinary calcium and allowed rapid weight gain; FGF23 rose from low-normal to high-normal [3, 8]. Six of the 16 patients in that series received sodium phosphate or sodium glycerophosphate [8]. The central claim of the study is that, in HCINF2, the abnormalities persist despite withdrawal of vitamin D prophylaxis and respond rapidly to phosphate, which makes early distinction between the two types essential [2, 8].

In the Turkish series, oral phosphate at doses of 5 to 20 mg/kg/day normalised urinary calcium in 10 of 11 patients, regardless of baseline serum phosphate, improved growth in all but one and was accompanied by resolution of nephrocalcinosis in three; in several patients, interruption of treatment by the family led to recurrence of hypercalciuria, which normalised again on reintroduction [14]. The prenatally diagnosed newborn described by Verjans was treated with phosphate and vitamin D avoidance, with biochemical normalisation [2, 36]. Published doses thus range between 5 and 60 mg/kg/day, expressed in different units; the reference dose is that of the PNDS. The PNDS does not set a maximum dose [11]. In X-linked hypophosphataemia, a disease with renal phosphate wasting treated with the same salts, the 2019 European recommendation gives an initial dose of 20 to 60 mg/kg/day of elemental phosphorus (0.7 to 2.0 mmol/kg/day) in infants and pre-school children, divided into 4 to 6 daily doses in young children, and advises against doses above 80 mg/kg/day because of the risk of gastrointestinal complaints and hyperparathyroidism [64]. This limit is an extrapolation from an analogous condition, with one important difference: in X-linked hypophosphataemia phosphate is combined with calcitriol or alfacalcidol, which are contraindicated in HCINF2 [2, 64].

The long-term safety of phosphate has not been established [26]. In the Npt2a-/- mouse the degree of renal mineralisation correlates with serum phosphate, and phosphate may raise PTH, increase renal phosphate wasting, stimulate 1,25(OH)2D synthesis and raise the calcium-phosphorus product in the tubule; this course was not observed in the Turkish series, and in another recent study the rise in PTH was not significant [14]. An Israeli patient with the same genotype as one of the Turkish patients progressed to chronic renal failure at 12 years [14]. Efficacy relative to baseline serum phosphate is also debated: the Toronto group suggests it mainly when phosphate is low or borderline, whereas the Turkish series documents benefit also with normal phosphate [14, 26].

In adults, the PNDS considers phosphate supplementation infrequent and decided case by case, mainly in the presence of a severe and progressive bone phenotype, and only after hypercalciuria has been controlled with a thiazide diuretic, so as not to worsen lithiasis or nephrocalcinosis [11]. Dipyridamole (Persantine®) has been proposed to increase apical expression of NaPi-IIa, but tolerance is often poor and efficacy inconsistent [11]. In HHRH, the same logic applies: oral phosphate alone, in divided doses, normalises phosphate in more than half of patients in a pooled analysis of 304 individuals from 145 families, and active vitamin D analogues are contraindicated [2].

In Portugal, Infomed does not list any oral phosphate medicine authorised for supplementation in hypophosphataemia; sodium phosphate solutions for bowel preparation (Phospho-Soda®, Preclint®) and concentrates for infusion of monopotassium phosphate and sodium glycerophosphate (Glycophos®) are authorised, but are not intended for this use [65]. Oral supplementation is therefore given with compounded or imported preparations. The sources consulted did not allow the situation in Brazil to be verified.

7.7 Thiazide diuretics: an indication with reservations

Thiazides reduce urinary calcium and are among the personalised treatments described in vitamin D hypersensitivity, and the PNDS uses them in adults with HCINF2 before starting phosphate [11, 15]. Their use requires caution in type 1: an adult with CYP24A1 variants developed hypercalcaemia of 2.84 mmol/L on hydrochlorothiazide, interpreted as an inability to compensate for the increase in tubular calcium reabsorption [37].

7.8 Agents and circumstances to avoid

7.9 When and how to resume vitamin D

Criteria vary widely between teams, and long-term studies are lacking [11]. The PNDS recommends resuming vitamin D when signs of deficiency appear in bone metabolism, that is, an unfavourable calcium balance with stimulation of bone resorption; the indicators are a rise in PTH and undetectable or very low urinary calcium, and vitamin D should be resumed as soon as PTH reaches the top of the normal range, without waiting for it to exceed it [11]. Because the range depends on the technique, the PNDS lists the limits for each assay: Roche Cobas 15–65 ng/L, DiaSorin Liaison 1–84 6.5–36.8, Liaison XL 5–40, Beckman Coulter Access Intact 10–50 and Siemens Centaur 17–84 [11]. Resumption follows the age-specific recommendations: 400 to 800 IU/day in children, for example two drops daily (600 to 660 IU, depending on the formulation) from 0 to 18 years or, from 2 years, one 50,000 IU ampoule every three months; in adults daily doses are preferred to reduce the risk of hypercalciuric episodes; reassessment takes place about one month after resumption [11].

7.10 Pregnancy and lactation

Pregnancy is a high-risk period for women with biallelic CYP24A1 variants, with symptomatic hypercalcaemia in 81.8% of the pregnancies described and frequent obstetric complications [7]. The PNDS attributes this to the physiological increase in 1,25(OH)2D production and recommends that genetic counselling support pregnancy plans [11]. The sources consulted do not establish an obstetric surveillance protocol, nor safety data for azoles or rifampicin in pregnancy or lactation in this disease.

7.11 Intercurrent illness, perioperative care and transition

The sources consulted do not describe perioperative risks specific to IIH beyond those of hypercalcaemia and renal dysfunction. Polyuria and dehydration are part of the acute picture, and rehydration is the first therapeutic measure [11]. Transition to adult medicine should ensure continuous nephrological follow-up, because loss of renal function may become manifest in the third and fourth decades, and the authors of the Warsaw cohort recommend that all IIH survivors remain under permanent renal care [13]. The PNDS recommends, at the same time, avoiding excessive medicalisation, with unnecessary tests, admissions or therapies, given the relatively benign nature of the disease in most cases [11].

7.12 Chronic kidney disease, lithiasis and transplantation

Nephrocalcinosis and lithiasis are treated with all the non-specific and mechanism-targeted specific measures, which limit hypercalcaemia and hypercalciuria [11]. Obstructing stones may require extracorporeal lithotripsy, percutaneous nephrolithotomy or a ureteral stent [37, 38]. Secondary incomplete distal tubular acidosis, with hypocitraturia and high urinary pH, favours calcium phosphate stones [38]. Two patients from the Polish cohort reached end-stage kidney disease and were transplanted at 27 and 34 years; at the last assessment, after transplantation, they had eGFRs of 50 and 55 mL/min/1.73 m² and calcium of 2.49 and 2.59 mmol/L [13]. The sources consulted do not describe recurrence of nephrocalcinosis in the graft.

7.13 Regulatory status

There are no initial authorisations, paediatric extensions or regulatory applications directed at IIH in the sources consulted.

7.14 Clinical studies and registries

These studies do not allow comparisons between them. The two studies with results have one and two patients with HCINF1, without a control group, with short durations and biochemical measures as outcomes; the relative reduction in 1,25(OH)2D did not translate into a change in serum calcium in the Toronto patient [26]. The ClinicalTrials.gov search did not identify trials of oral phosphate, azoles or other therapies, nor any terminated or negative trials.

7.15 Developments in the last 12 months

Between November 2025 and October 2026 the following were published: the French PNDS, the first specific normative guidance (expert consensus, 2026) [11]; the Turkish series of 11 children with SLC34A1 variants treated with oral phosphate (retrospective series, 2026) [14]; the Croatian series of three adults with HCINF1 controlled with fluconazole 50 mg/day (case reports, 2026) [38]; and the Russian study of 44 patients with 24-hydroxylase deficiency, with the first population estimate of disease frequency in Russia (retrospective cohort and calculation from exome databases, late 2025) [12]. The Lyon study on CYP24A1 heterozygosity was registered in November 2025 and the Philadelphia rifampicin trial was still recruiting in October 2026 [18, 31]. No applications for authorisation, regulatory opinions or trials of targeted therapies, including gene therapy, were identified.

7.16 Recommendations and divergences

The PNDS reserves specific treatment for forms with nephrocalcinosis or persistently raised urinary calcium and insists on avoiding excessive medicalisation [11]. The Warsaw cohort argues for a more active position: since renal disease progressed despite avoidance, it proposes early consideration, in all survivors, of inhibitors of the synthesis or inducers of the degradation of active metabolites, recognising that the long-term safety of these drugs has not been studied [13]. The Toronto group points out that dietary restriction may stimulate 1α-hydroxylase and does not correct the mechanism [26]. As for phosphate, the PNDS limits it in adults and requires prior control of urinary calcium, whereas the Turkish series documents benefit in children even with normal phosphate [11, 14]. As for rifampicin, the data are promising but preliminary, and the drug does not appear in the PNDS [11, 17, 26].

8. Reproductive Options and Family Counselling

8.1 Recurrence risks

Both severe forms are autosomal recessive [1, 3]. When both parents are heterozygous, each child has a 25% chance of inheriting both variants, 50% of being heterozygous and 25% of inheriting neither; the children of a patient with a non-carrier partner are obligate heterozygotes. Because the recurrent variants are frequent in some populations, the probability that a patient's partner is a carrier is not negligible: the estimated carrier frequency is 1 in 90 in Poland and 1 in 53 in Russia, for the most common CYP24A1 variants [12]. The SLC34A1 p.(Val91_Ala97del) deletion has an allele frequency of 1.7 to 2.7% depending on the population [15]. In these circumstances, a patient may have affected children, and families with patients in two generations may appear dominant [1].

The risks for heterozygotes are different from the recurrence risks of the disease. CYP24A1 heterozygotes have, in the pooled literature, nephrolithiasis in 19.4% and symptomatic hypercalcaemia in 5.6%, but normal enzyme activity in the French studies [7, 15]. SLC34A1 heterozygotes are predisposed to lithiasis, with nephrolithiasis in 3 of 26 relatives in one series [8]. The PNDS considers that heterozygotes may have a mild or asymptomatic form [11].

8.2 Cascade testing and family screening

Once variants have been identified in a patient, family segregation studies are essential to confirm phase and to identify heterozygotes with a mild or asymptomatic form [11]. Siblings should be studied, even if asymptomatic: in the 2011 series, an asymptomatic monozygotic twin had raised calcium, suppressed PTH, hypercalciuria and nephrocalcinosis, and a sibling who did not receive prophylaxis had, at 18 months, suppressed PTH and medullary hyperechogenicity [1]. Children born into affected families are screened biochemically, and in the neonatal period it may be useful to study the parents as well [11]. Identification of a newborn with biallelic variants allows vitamin D prophylaxis to be avoided from birth and calcium and urinary calcium to be monitored, which in the historical series was associated with absence of symptomatic hypercalcaemia in the unexposed sibling [1].

8.3 Prenatal and preimplantation diagnosis

The PNDS states that there is no indication for prenatal diagnosis [11]. The literature consulted does not describe cases of preimplantation diagnosis in this disease. Specialised genetic counselling provides information on the disease and its transmission, organises screening of relatives and supports pregnancy plans, including the obstetric risk of women with biallelic CYP24A1 variants [7, 11].

8.4 Counselling of minors and adult relatives

Testing of children at risk has direct benefit, because it allows vitamin D prophylaxis to be adjusted, urinary calcium to be monitored and hypercalcaemia to be prevented [1, 11]. In adult relatives, identification of a biallelic or heterozygous variant has practical consequences: avoiding vitamin D supplements and sunbeds, and providing information about the risk in pregnancy and the risk of hypercalcaemia with thiazides or CYP3A4-inhibiting drugs [7, 17, 34, 37].

9. Special Considerations: Population Diversity and Epidemiology

9.1 What the available estimates measure

Estimates of the frequency of IIH differ by several orders of magnitude, because they measure different things. Orphanet records for the entity ORPHA:300547 a worldwide point prevalence class below 1/1,000,000, with 12 validated cases; this is a class based on published cases, covering both types, and is certainly an underestimate [2, 10]. The French PNDS estimates the prevalence at 1/33,000, acknowledging underdiagnosis of mild forms [11]. The Russian literature cites an estimated frequency of 1/60,000 newborns, and the registration of the Lyon study gives 1 in 80,000 births [12, 31]. The Warsaw cohort cites a frequency of CYP24A1 variants of 420 per 100,000 people and a contribution of 4 to 20% to renal lithiasis, figures from an earlier study cited by the authors [13]. For HCINF2 there is no separate estimate; the authors of the long-term follow-up study emphasise that the incidence of IIH in children remains unknown [13].

Genetic estimates are based on the frequency of the recurrent variants. In Poland, the allele frequency of p.(Arg396Trp) leads to a calculated incidence of 1/32,465 newborns and a carrier frequency of 1/90 [12]. In Russia, from p.(Arg396Trp) (66% of patients' alleles) and p.(Glu143del) (27%) and from Russian exome and genome databases, the calculated disease frequency is 1/10,900 newborns and the carrier frequency 1/53 [12]. These figures estimate the frequency of biallelic genotypes, not of clinical disease, because penetrance depends on vitamin D intake and other triggers.

9.2 Europe and founder populations

The CYP24A1 p.(Arg396Trp) variant is the most frequent in Central and Eastern Europe: it accounted for 15 of 29 mutated alleles in the Polish cohort, with 12 of the 18 patients carrying it, and 66% of alleles in the Russian cohort [12, 13]. In gnomAD, its maximum frequency is 0.14% in Finns; that of p.(Glu143del) is 0.11% in non-Finnish Europeans and that of p.(Leu148Pro) 0.18% in Ashkenazi Jews [15]. In the French cohort, biallelic CYP24A1 variants explained 14% of the 185 patients with vitamin D hypersensitivity, those in SLC34A3 2% and those in SLC34A1 none with a pathogenic class [15]. HCINF2 was first described in consanguineous Turkish families, and the 2026 Turkish series brought together 11 patients from independent families [8, 14]. The SLC34A1 p.(Val91_Ala97del) deletion is frequent in Europeans, with an allele frequency of 2.5% in non-Finns and 2.7% in Finns [15].

The history of the epidemics illustrates the interaction between genetics and environment: infantile hypercalcaemia became frequent in the United Kingdom in the 1950s with food fortification and in Poland and the former East Germany in the 1980s with high-dose prophylaxis [11, 13].

9.3 Other populations

In the USA, data come from case reports and from the Mayo Clinic registry, open to 600 participants [17, 68]. In a paediatric series of lithiasis and nephrocalcinosis from Saudi Arabia, with 64.8% genetic diagnoses in 54 children tested, CYP24A1 and SLC34A1 were not among the most frequent causes, which were dominated by CLDN16, SLC2A2, AGXT and SLC12A1 [50]. The sources consulted do not include data from Portugal or Brazil; the Brazilian book on genetic syndromes deals with hypercalcaemia only in the context of Williams syndrome [41]. The lack of data in these sources does not demonstrate the absence of patients in those countries.

9.4 Special populations

The infant on vitamin D prophylaxis, the pregnant woman with CYP24A1 variants and the adult with recurrent lithiasis are the populations in which the disease reveals itself [7, 11, 15]. In patients with chronic kidney disease, urinary calcium loses diagnostic value, because it may be normal or low [11].

9.5 European networks and patient resources

IIH falls within the calcium and phosphate disorders thematic group of Endo-ERN, the European Reference Network for rare endocrine conditions, with more than 100 centres in 27 Member States and Norway [19]. ERKNet, the European Reference Network for rare kidney diseases, has working groups for tubulopathies and for metabolic diseases and lithiasis [20]. In France, the CRMR CAP reference centre and the OSCAR network coordinate follow-up and published the PNDS, also available on the Haute Autorité de Santé website [11]. The Mayo Clinic international registry (NCT03478761) accepts patients with suspected or confirmed 24-hydroxylase deficiency [68]. The sources consulted did not identify patient associations dedicated specifically to IIH.

10. Illustrative Clinical Case

10.1 From infantile hypercalcaemia to adult lithiasis: CYP24A1 deficiency

Vucenovic Basic and colleagues described in 2026, at a Croatian university hospital, three patients with HCINF1 treated with fluconazole [38]. The third patient sums up the natural history of the disease. He was admitted at 5 months with severe hypercalcaemia, with a serum calcium of 5.98 mmol/L, faltering growth and osteopenia, and during childhood had several admissions for renal and ureteral lithiasis [38]. Tests repeatedly showed hypercalcaemia, hypophosphataemia, markedly raised 25(OH)D (157 nmol/L) with inappropriately normal to high 1,25(OH)2D (78 pmol/L), raised alkaline phosphatase, low urinary citrate, raised oxaluria and marked hypercalciuria (13.3 mmol/24 h); ultrasound confirmed persistent lithiasis and densitometry osteopenia [38]. At 8 years he underwent extracorporeal lithotripsy for obstructing stones on the left [38].

A hereditary lithiasis gene panel identified the CYP24A1 variant NM_000782.5:c.1186C>T p.(Arg396Trp) in the homozygous state, and both parents were heterozygous [5, 38]. Despite avoidance of vitamin D supplements and sun exposure and increased hydration, he maintained biochemical activity and intermittent episodes of hypercalcaemia in adolescence [38]. At 18 years he started fluconazole 50 mg/day; calcium normalised after four months and remained at 2.52 mmol/L at 16 months of follow-up (reference 2.14–2.53 mmol/L), without adverse effects [38].

The first patient in the same series shows the adult form. A 46-year-old woman with lithiasis and colic since adolescence was referred for recurrent lithiasis; low-dose computed tomography showed severe bilateral nephrocalcinosis (Figure 1 of the article, https://pmc.ncbi.nlm.nih.gov/articles/PMC13574611/figure/fig1/), and tests revealed an eGFR of 35 mL/min/1.73 m², hypercalcaemia up to 2.74 mmol/L, hypercalciuria and inappropriately suppressed PTH [38]. Parathyroid imaging was negative, and borderline hypokalaemia, hypocitraturia and persistently high urinary pH with normal bicarbonate indicated incomplete distal tubular acidosis, consistent with calcium phosphate stones [38]. The panel found p.(Leu148Pro) and p.(Leu409Ser) in CYP24A1, and a brother heterozygous for p.(Leu409Ser) confirmed segregation; with avoidance, hydration and fluconazole 50 mg/day, calcium and urinary calcium normalised within one month and remained stable for 18 months [38].

These cases illustrate several points of this article: the severe presentation in infancy, the persistence of biochemical activity despite avoidance, the progression to lithiasis and nephrocalcinosis with loss of renal function, secondary distal tubular acidosis and the response to a low dose of fluconazole. The 50 mg/day dose used in adults is lower than the PNDS range of 3 to 12 mg/kg/day, and fluconazole remains an off-label treatment, decided case by case in reference centres with hepatic monitoring [11, 38].

10.2 Hypercalcaemia that does not yield to vitamin D withdrawal: NaPi-IIa deficiency

In the 2016 series, patient F9.1 was diagnosed while still in the acute phase, with hypercalcaemia and hypophosphataemia [8]. Oral hydration and a low-calcium diet without vitamin D supplements did not correct the hypercalcaemia or allow clinical recovery; after the genetic diagnosis of biallelic SLC34A1 variants, oral phosphate (0.5–1 mmol/kg/day) normalised phosphataemia and calcium metabolism, reduced urinary calcium and allowed rapid clinical recovery with weight gain [8]. Ultrasound showed severe medullary nephrocalcinosis (Figure 3 of the article, https://pmc.ncbi.nlm.nih.gov/articles/PMC4731111/figure/fig3/) [8]. This child's mother had undergone nephrectomy in adolescence for recurrent pyelonephritis and a staghorn calculus [8]. The case documents the mechanism of type 2 and the reason why withdrawal of vitamin D alone is not sufficient treatment in this form, in agreement with the PNDS [11].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

Hypercalcaemia usually resolves in the first months to years of life, and about half of children normalise their urinary calcium by 6 months [11]. Susceptibility to hypercalcaemia persists throughout life and becomes manifest with new triggers, mainly sun exposure, vitamin D supplements and pregnancy [7, 15]. Prognosis is determined by the kidney. In the Warsaw cohort, at a mean age of 23.8 years, 88% of survivors had nephrocalcinosis, 77% an eGFR below 90 and 28% below 60 mL/min/1.73 m², and two reached kidney transplantation in the third and fourth decades [13]. The ultrasound severity of nephrocalcinosis and eGFR at diagnosis did not predict the course, which points to progressive tubulointerstitial injury [13]. In the French and Croatian cohorts, adults with biallelic CYP24A1 variants had a GFR below 60 mL/min/1.73 m² [15, 38].

For HCINF2, most patients in the 2016 series normalised their PTH during a median follow-up of 3.5 years, and FGF23 was normal with normophosphataemia; its long-term effect on nephrocalcinosis and lithiasis has not yet been determined [8]. In the Turkish series, nephrocalcinosis resolved in three patients on phosphate, but a patient with the same genotype described in Israel had chronic renal failure at 12 years [14]. Other risks, outside the kidney, are considered almost non-existent by the PNDS, although isolated reports describe osteopenia, osteoporosis and corneal calcium deposits [11, 13, 38].

The prognostic data have clear limitations. The published cohorts are small, retrospective and exposed to prophylaxis at very different doses, and measurements were generally made at a single time point [13]. Information on disease treated with azoles, rifampicin or phosphate comes from short series, without a comparison group [14, 17, 26].

11.2 Surveillance table

The PNDS warns against excessive medicalisation in mild forms, with unnecessary tests, admissions or therapies [11]. The Warsaw authors, in view of the renal course of their cohort, advocate permanent renal care for all survivors [13].

12. Summary and Final Considerations

Idiopathic infantile hypercalcaemia is an autosomal recessive disorder of vitamin D regulation with two distinct mechanisms and a common outcome. In type 1, biallelic CYP24A1 variants abolish 24-hydroxylase and prevent the inactivation of 25(OH)D and 1,25(OH)2D; in type 2, biallelic SLC34A1 variants cause renal phosphate wasting, suppress FGF23 and release calcitriol synthesis. In both, excessive PTH-independent 1,25(OH)2D increases intestinal calcium absorption and produces hypercalcaemia, hypercalciuria and nephrocalcinosis. The disease was recognised in epidemics triggered by vitamin D, in the United Kingdom in the 1950s and in Eastern Europe in the 1980s, and the genes were identified in 2011 and 2016.

The infant presents with faltering growth, vomiting, polyuria and dehydration, often on vitamin D prophylaxis; the adult with recurrent lithiasis, nephrocalcinosis and mild or seasonal hypercalcaemia; the pregnant woman with symptomatic hypercalcaemia. Diagnosis rests on ionised calcium, suppressed PTH, high or inappropriately normal 1,25(OH)2D, the 25(OH)D3:24,25(OH)2D3 ratio (raised in type 1), assessment of phosphate and TmP/GFR (low in type 2) and a panel including CYP24A1, SLC34A1 and SLC34A3 with copy number analysis. The frequent SLC34A1 p.(Val91_Ala97del) deletion and frequency filtering in exomes are known pitfalls. The differential includes transient hypersensitivity of the newborn, vitamin D intoxication, HHRH, Williams-Beuren syndrome, subcutaneous fat necrosis, hypophosphatasia, Jansen chondrodysplasia, the neonatal hyperparathyroidisms and syndromes such as IMAGE, SHORT and Bartter.

Acute treatment follows the general principles of hypercalcaemia, with hydration, furosemide and pamidronate. In the long term, withdrawal of vitamin D and calcium supplements and hydration suffice in mild forms; in forms with nephrocalcinosis or persistent hypercalciuria, the French PNDS recommends azoles in type 1 and oral phosphate in type 2, always off-label and with monitoring. Rifampicin, a CYP3A4 inducer, is an investigational option in type 1. Prognosis depends on the kidney: nephrocalcinosis is almost universal in survivors and some progress to chronic kidney disease, sometimes end-stage. Follow-up should be proportionate to severity, extend into adulthood and include counselling of the family, study of siblings and preparation for pregnancy.

13. References

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