Hereditary Hypercalcemia Caused by a Homozygous Pathogenic Variant in the CYP24A1 Gene: A Case Report and Review of the Literature

Introduction. Loss of function mutations of CYP24A1 gene, which is involved in vitamin D catabolism, cause vitamin D-mediated PTH-independent hypercalcemia. The phenotype varies from life-threatening forms in the infancy to milder forms in the adulthood. Case Presentation. We report a case of a 17-year-old woman with a history of nephrolithiasis, mild PTH-independent hypercalcemia (10,5mg/dL), and high serum 1,25(OH)2D concentrations (107pg/mL). Other causes of hypercalcemia associated with the above biochemical signature were excluded. Family history revealed nephrolithiasis in the sister. Blood testing in first-degree relatives showed serum PTH in the low-normal range and 1,25(OH)2D at the upper normal limit or slightly elevated. The CYP24A1 gene analysis revealed a known homozygous loss-of-function pathogenic variant (c.428_430delAAG, rs777676129, p.Glu143del). The panel of vitamin D metabolites evaluated by liquid chromatography showed the typical profile of CYP24A1 mutations, namely, low 24,25(OH)2D3, elevated 25(OH)D3:24,25(OH)2D3 ratio, and undetectable 1,24,25(OH)3D3. The parents and both the siblings harbored the same variant in heterozygosis. We decided for a watchful waiting approach and the patient remained clinically and biochemically stable over a 24-month followup. Conclusion. CYP24A1 gene mutations should be considered in cases of PTH-independent hypercalcemia, once that more common causes (hypercalcemia of malignancy, granulomatous diseases, and vitamin D intoxication) have been ruled out.

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Coexistent CYP24A1 and PHEX Gene Mutations With Hypervitaminosis D Plus Hypercalcemia Treated With Fluconazole

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.382 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A188-A189

Author(s):

David Bawden ◽

William Fraser ◽

Darrell Green ◽

Shoib Ur Rehman

Keyword(s):

Vitamin D ◽

Gene Mutations ◽

Pathogenic Variant ◽

Full Blood Count ◽

Vitamin D Metabolites ◽

Dihydroxyvitamin D ◽

Hypervitaminosis D ◽

Vitamin D Levels ◽

Phex Gene ◽

25 Oh Vitamin D

Abstract Background: CYP24A1 and PHEX gene mutations are rare and can cause hypercalcemia, hypervitaminosis D and elevated FGF23 levels. Fluconazole, an antifungal medication, has shown therapeutic benefit in achieving normocalcemia plus normalisation of vitamin D levels in this case report. Clinical Case: A 42 year old man was referred to the endocrine clinic with a history of severe nephrocalcinosis and recurrent nephrolithiasis requiring surgical intervention and gradual decline in kidney function over 20 years. Biochemical investigations revealed hypercalcaemia with adjusted calcium levels of 2.83 mmol/L (R 2.2–2.6 nmol/L) and suppressed PTH 1.1 pmol/L(R 1.6–6.9 pmol/L). Twenty-four hour urine calcium/creatinine clearance ratio was above 0.0578 mmol/mmol indicating hypercalciuria. Vitamin D metabolites 25 OH Vitamin D was elevated at 201 nmol/L, (R 50–120 nmol/L) along with intermittently elevated 1,25 OH Vitamin D 147 pmol/L(R 55–139 pml/L). 24,25 Vitamin D was low at 2.0 nmol/L producing a 25:24,25 dihydroxyvitamin D ratio of 80 (n<25). This biochemical data was highly suggestive of a loss of function mutation in the CYP24A1 gene that codes for the enzyme 24-hydroxylase, which is responsible for conversion of 1,25 vitamin D to 24,25 vitamin D. A pathogenic variant (heterozygous c.756G>A) was confirmed on genetic testing. Plasma FGF23 (immutopics) was raised (with a peak of 596 RU/mL, n<100 RU/mL) but a full body octreotide scan did not reveal malignancy or other paraneoplastic syndromes such as oncogenic osteomalacia. A pathogenic variant in his PHEX gene (homozygous c.1874A>T) was also identified that has been associated with increased levels of FGF23 plus hypophosphataemia. Fluconazole at 50 mg once daily was initiated. Azoles inhibit cytochrome P450 enzymes and have been used in sarcoidosis to block vitamin D-synthesizing enzymes such as 25-hydroxylases and 1-α-hydroxylase that are P450 dependent. Few cases of CYP24A1 gene defects have been treated with fluconazole, which has a favourable side effect profile and yields good results. Adjusted calcium reduced to 2.62 nmol/L, 25 OH Vitamin D normalised to 111 nmol/L and 24:24,25 dihydroxyvitamin D ratio is now 17. Patient’s liver functions and full blood count has been monitored regularly during the course of treatment and the drug was well tolerated. Conclusion: Genetic causes of hypercalcemia can be left undiagnosed for long periods and there is a lack of proven or definitive therapeutic agents for correction of elevated calcium. Here fluconazole has been shown to reduce the hypercalcaemic burden and effectively lowered the Vitamin D levels in this case of a CYP24A1 mutation. This study augments fluconazole use in these cases but further studies are needed to elucidate the long term safe usage.

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Do the Heterozygous Carriers of a CYP24A1 Mutation Display a Different Biochemical Phenotype than Wild Types?

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa876 ◽

2020 ◽

Author(s):

Alessandro Brancatella ◽

Daniele Cappellani ◽

Martin Kaufmann ◽

Simona Borsari ◽

Paolo Piaggi ◽

...

Keyword(s):

Vitamin D ◽

Fibroblast Growth Factor 23 ◽

Clinical Manifestations ◽

Pathogenic Variant ◽

Complete Analysis ◽

Vitamin D Metabolites ◽

Loss Of Function ◽

Wild Type ◽

Biochemical Phenotype ◽

Heterozygous Carriers

Abstract Context Human cytochrome P450 24 subfamily A member 1 (CYP24A1) loss-of-function mutations result in impaired activity of the 24-hydroxylase involved in vitamin D catabolism, thus inducing a vitamin D-dependent hypercalcemia. Homozygotes often present an overt clinical phenotype named idiopathic infantile hypercalcemia (IIH), whereas it is debated whether heterozygotes display an abnormal phenotype. Objective To compare the clinical and biochemical features of heterozygous carriers of CYP24A1 variant and healthy wild-type controls sharing the same genetic and environmental exposure. Methods A large family harboring the nonsense c.667A>T, p.Arg223* pathogenic variant in the CYP24A1 gene was evaluated. All subjects underwent clinical and biochemical evaluation and complete analysis of vitamin D metabolites using mass spectroscopy including 1,24,25(OH)3D3. Subjects were divided into 2 groups according to their genotype: heterozygotes and wild-type for the CYP24A1 variant. Results The proband, a 40-year-old man, homozygous for p.Arg223* pathogenic variant, had a history of mild hypercalcemia with a seasonal trend, recurrent nephrolithiasis, and no episodes of acute hypercalcemia. He showed the highest serum levels of fibroblast growth factor 23, the highest 25(OH)D3/24,25(OH)2D3 ratio and undetectable levels of 1,24,25(OH)3D3, which represent indicators of a loss-of-function CYP24A1. Compared with the wild-types, heterozygotes had higher serum calcium and 25(OH)D3 concentrations (P = .017 and P = .025, respectively), without any difference in the other biochemical parameters and in the rate of nephrolithiasis. Conclusion Heterozygotes exhibit a biochemical phenotype different from that of wild-type subjects. In clinical practice, these individuals might require surveillance because of the potential risk of developing hypercalcemia and related clinical manifestations if exposed to triggering factors.

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Vitamin D Intoxication in An Elderly: A Case Report

International Healthcare Research Journal ◽

10.26440/ihrj/0304.07257 ◽

2019 ◽

Vol 3 (4) ◽

pp. 147-149

Author(s):

Sahil Singh ◽

Prernika Mittal ◽

Ajay Sharma

Keyword(s):

Vitamin D ◽

Serum Vitamin ◽

High Serum ◽

Intravenous Fluids ◽

Serum Vitamin D ◽

Replacement Surgery ◽

Vitamin D Intoxication ◽

History Of ◽

Very High

Vitamin D is a very common prescribed drug for numerous indications. Due to scarce knowledge and poor awareness of the various formulations, preparations and dosages of Vitamin D, there are many chances of prescription errors, medication errors, product use issue and undesirable adverse drug reactions. We hereby detail case of 70-year-old ex-army gentleman reported to us with a history of lethargy, confusion, reduced appetite and gait imbalance since few days with a history of knee replacement surgery 2 years back. Medical history was not of much relevance before it was revealed that he was getting cholecalciferol injection with a strength of 600000 IU once a week for few months. He was detected to have very high serum vitamin D level and hypercalcemia. He was started on intravenous fluids, diuretics and glucocorticoids. In a few days, after effective treatment, the patient was discharged in a recovering stage and advised to stop intake calcium and vitamin D in any form. At his last follow up, after a few months of discharge, he had totally recovered.

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Hypercalcemia: A Metabolic Complication of an AIDS-Defining Illness

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.403 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A198-A199

Author(s):

Dorothy E Bennett ◽

Ruba Riachy ◽

Lucas S Blanton ◽

L Maria Belalcazar

Keyword(s):

Vitamin D ◽

Immune Reconstitution ◽

Kidney Injury ◽

Thyroid Stimulating Hormone ◽

High Serum ◽

Hiv Viral Load ◽

Dihydroxyvitamin D ◽

Metabolic Complication ◽

Granulomatous Diseases ◽

Hiv 1

Abstract Background: Hypercalcemia may result from the activation of macrophages in granulomatous diseases with increased production of 1,25 dihydroxyvitamin D/calcitriol. Its occurrence in patients with human immunodeficiency virus-1 (HIV-1) infection may be atypical and signal major changes in immune status. We report on a patient with acquired immunodeficiency syndrome (AIDS) presenting with new-onset hypercalcemia after months of treatment for mycobacterium avium complex (MAC) infection and normal calcitriol levels. Clinical Case: A 37-year-old man on treatment for HIV-1 and disseminated MAC infection presented to the hospital 6 months after initial diagnosis with worsening headache, cough, and abdominal pain. On arrival he was afebrile and without palpable lymphadenopathy. He was found to have a high serum calcium (13.4 mg/dL, n 8.6–10.6 mg/dL) and acute kidney injury (AKI) (creatinine 4 mg/dL, n 0.6–1.25 mg/dL). His CD4 count had increased from 24 at time of diagnosis to 162 cells/μL (n 410–1,590 cells/μL); his HIV viral load was undetectable. Workup for hypercalcemia revealed an elevated phosphorus (5.2 mg/dL, n 2.5–5.0 mg/dL), low 25-OH vitamin D level (<13 ng/mL, n 25–80 ng/dL), low PTH (4.8 pg/mL, n 12–88 pg/mL), and calcitriol level of 31.4 pg/mL, n 19.9–73.3 pg/mL). Additional tests, including serum electrophoresis, thyroid stimulating hormone, and parathyroid hormone-related peptide levels, were unremarkable. The patient was diagnosed with hypercalcemia secondary to dysregulated calcitriol production in the setting of disseminated MAC and possible immune reconstitution. Hypercalcemia resolved with hydration and prednisone 20 mg daily. Patient was discharged with an 8-day prednisone taper, but readmitted to the hospital 3 weeks later with recurrent hypercalcemia (13.8 mg/dL) and AKI. Urine calcium was found to be elevated (484 mg/24 hours, n100-300 mg/24 hours) and repeat calcitriol was 53.6 pg/ml. Patient was restarted on prednisone 40 mg daily with normalization of calcium within 5 days (calcium 10.3 mg/dL). Conclusion: Hypercalcemia due to increased calcitriol production in the setting of MAC infection, an AIDS-defining illness, may occur months after initiation of effective antibiotic and antiviral therapy and could represent a manifestation of immune reconstitution. The deleterious effects of excess calcitriol may be present even in patients with chronic vitamin D deficiency and a calcitriol level that inappropriately remains within the normal range.

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Association of parathyroid adenoma and familial hypocalciuric hypercalcaemia in a teenager

Acta Endocrinologica ◽

10.1530/eje-09-0257 ◽

2009 ◽

Vol 161 (1) ◽

pp. 207-210 ◽

Cited By ~ 28

Author(s):

C Brachet ◽

E Boros ◽

S Tenoutasse ◽

W Lissens ◽

G Andry ◽

...

Keyword(s):

Parathyroid Adenoma ◽

Serum Calcium ◽

Receptor Gene ◽

Causal Link ◽

Urinary Calcium ◽

High Serum ◽

Calcium Excretion ◽

Loss Of Function ◽

Mixed Family ◽

History Of

ObjectiveFamilial hypocalciuric hypercalcaemia (FHH) is clinically characterized by mild to moderate parathyroid hormone (PTH)-dependent hypercalcaemia, autosomal dominant pattern of inheritance, and normal to frankly reduced urinary calcium excretion in spite of a high serum calcium (clearance (Ca)/clearance (Cr)<0.01). FHH has a benign course and should be differentiated from primary hyperparathyroidism. It is usually caused by a heterozygous loss-of-function mutation in the calcium-sensing receptor gene (CASR).DesignWe report the case of a 16-year-old patient with hypercalcaemia and a mixed family history of parathyroid adenoma and mild hypercalcaemia. Serum calcium was 14 mg/dl with a serum iPTH of 253 pg/ml.ResultsA neck 99mTc-sesta MIBI tomoscintigraphy showed a definite hyperactivity in the left upper quadrant. A surgical four-gland exploration confirmed a single parathyroid adenoma. After surgical resection of a left superior parathyroid adenoma, the patient's hypercalcemia improved but did not normalize, returning to a level typical of FHH. An inactivating mutation in exon 4 of the CASR gene, predicting a p.Glu297Lys amino acid substitution was found.ConclusionsThus, this 16-year old patient presented with the association of FHH and a single parathyroid adenoma. The young age of the patient and the association of parathyroid adenoma and FHH in his grandmother argue for a causal link between CASR mutation and parathyroid adenoma in this family. This case contributes to illustrate the expanding clinical spectrum of CASR loss-of-function mutations.

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Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0169 ◽

2020 ◽

Vol 33 (10) ◽

pp. 1353-1358

Author(s):

Ayla Güven ◽

Martin Konrad ◽

Karl P. Schlingmann

Keyword(s):

Vitamin D ◽

Stop Codon ◽

Gene Mutations ◽

Splice Site Mutation ◽

Heterozygous Mutation ◽

High Dose ◽

Loss Of Function ◽

Site Mutation ◽

Medullary Nephrocalcinosis ◽

Idiopathic Infantile Hypercalcemia

AbstractObjectivesBoth CYP24A1 and SLC34A1 gene mutations are responsible for idiopathic infantile hypercalcemia, whereas loss-of-function mutations in CYP24A1 (25-OH-vitamin D-24-hydroxylase) lead to a defect in the inactivation of active 1.25(OH)2D; mutations in SLC34A1 encoding renal sodium phosphate cotransporter NaPi-IIa lead to primary renal phosphate wasting combined with an inappropriate activation of vitamin D. The presence of mutations in both genes has not been reported in the same patient until today.Case presentationHypercalcemia was incidentally detected when a 13-month-old boy was being examined for urinary tract infection. After 21 months, hypercalcemia was detected in his six-month-old sister. High dose of vitamin D was not given to both siblings. Both of them also had hypophosphatemia and decreased tubular phosphate reabsorption. Intensive hydration, furosemide and oral phosphorus treatment were given. Bilateral medullary nephrocalcinosis was detected in both siblings and their father. Serum Ca and P levels were within normal limits at follow-up in both siblings. Siblings and their parents all carry a homozygous stop codon mutation (p.R466*) in CYP24A1. Interestingly, both siblings and the father also have a heterozygous splice-site mutation (IVS6(+1)G>A) in SLC34A1. The father has nephrocalcinosis.ConclusionsA biallelic loss-of-function mutation in the CYP24A1 gene was identified as responsible for hypercalcemia, hypercalciuria and nephrocalcinosis. In addition, a heterozygous mutation in the SLC34A1 gene, although not being the main pathogenic factor, might contribute to the severe phenotype of both patients.

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Importance of Extra-Renal CYP24A1 Expression for Maintaining Mineral Homeostasis

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.476 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A234-A234

Author(s):

Melody Shi ◽

Alexander Grabner ◽

Myles Wolf

Keyword(s):

Vitamin D ◽

Mrna Expression ◽

Calcium Absorption ◽

Clinical Importance ◽

P Value ◽

Loss Of Function ◽

Vitamin D Metabolism ◽

Severe Hypercalcemia ◽

Functional Measure ◽

Serum Pth

Abstract Calcium homeostasis involves a complex interplay between kidneys, parathyroid glands, intestine and bone. Specifically, 1,25(OH)2D3 is a key calciotropic hormone which stimulates intestinal calcium absorption. A growing body of evidence suggests that circulating levels of 1,25(OH)2D3 depend not only on its synthesis under the action of PTH in the kidneys, but also its catabolism by 24-hydroxylase, herein referred to as CYP24A1. The clinical importance of CYP24A1 has been demonstrated by human loss-of-function mutations, which lead to severe hypercalcemia due to exaggerated levels of 1,25(OH)2D3. Despite its growing importance, little is known about its tissue-specific contributions to normal vitamin D metabolism. To explore the physiology of CYP24A1 and delineate renal-specific effects of CYP24A1 in calcium metabolism, we generated a mouse with constitutive kidney-specific deletion of Cyp24a1 (Six2Cre-Cyp24flox). Six2 marks the nephron progenitor population throughout nephrogenesis. We hypothesized that hypercalcemia as seen in CYP24A1 inactivating mutations is related to lack of both renal and extrarenal expression, and that renal deletion does not lead to severe hypercalcemia. To confirm Cyp24a1 deletion, we measured mRNA expression in the kidney using qPCR and RNA in situ hybridization. All mice were fed a standard commercial rodent diet and followed longitudinally for five months with interval calcium measurements. At time of termination, serum PTH levels were measured along with vitamin D-dependent calcium transporters as a functional measure of 1,25(OH)2D3 action. Cyp24a1 expression was significantly knocked down in total kidneys from Six2Cre-Cyp24flox mice as compared to intestinal expression suggesting successful gene deletion. Compared to age-matched wildtype controls, Six2Cre-Cyp24flox mice were mildly but persistently hypercalcemic (diff between means= 0.46 mg/dL, p-value: 0.03, n=8 per group). As expected, 1,25D-dependent calcium transporters in the kidney (Calb1, Trpv5, Slc8a1, Atp2b1) and intestine (Trpv6, s100g) were all increased, consistent with increased systemic 1,25(OH)2D3 activity. PTH levels were appropriately suppressed in the Six2Cre-Cyp24flox mice (diff between means=83 pg/mL, p-value 0.2, n=9 control, n=3 exp) as were renal cyp27b1 mRNA expression. These data suggest that renal CYP24A1 is important for systemic 1,25(OH)2D3 regulation, but the lack of severe hypercalcemia supports critical contributions of extra-renal CYP24A1.

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SAT-368 CYP24A1 Mutation Masking Malignancy Mediated Hypercalcemia

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.353 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Cheng Cheng ◽

Chienying Liu ◽

Daniel D Bikle ◽

Dolores M Shoback

Keyword(s):

Vitamin D ◽

Obstructive Uropathy ◽

Urinary Calcium ◽

High Dose ◽

Low Grade ◽

Loss Of Function ◽

Non Hodgkin Lymphoma ◽

Ckd Stage ◽

History Of ◽

Biallelic Mutations

Abstract Background: Mutations in CYP24A1, resulting in reduced conversion of 1,25(OH)2D to its inactive metabolite 24,25-(OH)2D3,are rare causes of parathyroid hormone (PTH)-independent hypercalcemia. While manifestations may range from the severe idiopathic infantile hypercalcemia due to biallelic mutations, heterozygous loss-of-function mutations causing milder phenotypes are increasingly reported in adults. Elevated 1,25(OH)2D and hypercalciuria often accompanied by a history of nephrolithiasis are characteristic. Worsening hypercalcemia, under conditions such as pregnancy or sunlight exposure that enhance 1,25(OH)2D and 25(OH)D production, respectively, has been described in CYP24A1 mutations. We describe a patient with hypercalcemia and a history of lymphoma who was found to have elevated 25-OH-D3 and low 24,25-(OH)2D3 levels, suggesting a mutation in CYP24A1. Clinical Case: An 80 year-old Caucasian male with history of indolent non-Hodgkin lymphoma diagnosed in 2016,well controlled after several courses of chemotherapy,was referred for recurrent hypercalcemia. Laboratory studies showed levels of 1,25(OH)2D of 78 (18–72 pg/mL) and PTH 22 (10–65 pg/mL) with calcium ranging from 10.3 to 12.6 (8.5–10.1mg/dL), an undetectable PTHrP, 25(OH)D level of 32.9 (30–100 ng/mL), and 24-hour urinary calcium of 378mg. He was treated with high dose prednisone for presumed 1,25(OH)2D-mediated hypercalcemia. Despite initial good response, hypercalcemia became progressively difficult to control requiring escalating doses of steroids. Repeat 1,25(OH)2D levels improved to 30–40 pg/mL, but subsequently rebounded to >150. Oncologic re-evaluation found low-grade follicular lymphoma in inguinal lymph nodes,which were thought to be the source of 1,25(OH)2D overproduction. Detailed history and records review, however, revealed that onset of hypercalcemia dated back to 2006, concurrent with the development of several episodes obstructive uropathy due to stones. These events preceded the diagnosis of lymphoma by a decade, and resulted in CKD stage 4. Family history is notable for nephrolithiasis in his fatherand son. We suspected CYP 24A1 mutation. Vitamin D metabolite analysis demonstrated a 25-OH-D3 of 27 (20-50ng/mL) and 24,25-(OH)2D3 of 0.56 ng/mL with a ratio elevated to 48.21 (<25), indicative of a defect in vitamin D degradation that potentially exacerbates oversupply of 1,25(OH)2D, mediated via its reduced metabolism. Genetic evaluation is in progress. After initiation of treatment with Rituximab, his serum calcium levels declined along with regression of his lymphoma. Conclusion: Although mutations in CYP24A1 are an uncommon cause of hypercalcemia, they should be considered in the differential diagnosis of elevated 1,25(OH)2D levels without a clear source, as confirming this diagnosis strongly impacts treatment decisions and clinical outcome.

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Novel CYP24A1 Mutation in a Young Male Patient with Nephrolithiasis: Case Report

Kidney & Blood Pressure Research ◽

10.1159/000500922 ◽

2019 ◽

Vol 44 (4) ◽

pp. 870-877 ◽

Cited By ~ 2

Author(s):

Jana Jiráčková ◽

Radomir Hyšpler ◽

Sumaya Alkanderi ◽

Ladislava Pavlíková ◽

Vladimir Palicka ◽

...

Keyword(s):

Vitamin D ◽

Male Patient ◽

Young Male ◽

Renal Stones ◽

Compound Heterozygous ◽

Vitamin D Metabolites ◽

Vitamin D Levels ◽

History Of ◽

Biochemical Analyses ◽

Biallelic Mutations

Background/Aims: The CYP24A1 gene encodes the vitamin D 24-hydroxylase enzyme, which hydroxylates active forms of vitamin D into inactive forms. Biallelic mutations in the CYP24A1 gene can lead to elevated levels of active vitamin D metabolites and, consequently, to hypercalcemia, hypercalciuria, nephrocalcinosis, and nephrolithiasis; however, monoallelic mutations have been associated only with milder phenotypes. In the present manuscript, we report the case of a young male patient who presented hypercalcemia and nephrolithiasis, suppressed parathormone, and elevated 1,25 dihydroxy vitamin D levels. Methods: Biochemical analyses were performed on Cobas 8000, F. Hoffmann-La Roche AG, Basel, Switzerland. The proband was initially evaluated for occult malignancies by body imaging, serum electrophoresis, and tumor markers, which did not reveal any pathology. DNA samples of the proband and his sibling were then examined using Sanger sequencing. Results: Genetic analysis revealed 2 compound heterozygous CYP24A1 mutations (p.L148P and p.R223*). The novel nonsense CYP24A1 mutation, p.R223*, was also found heterozygously in other family members with a medical history of nephrolithiasis. Conclusions: The identification of this gene mutation causing hypercalcemia, hypercalciuria, and renal stones allows the specific management of endogenous vitamin D production.

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Genetic causes of neonatal and infantile hypercalcaemia

Pediatric Nephrology ◽

10.1007/s00467-021-05082-z ◽

2021 ◽

Author(s):

Caroline M. Gorvin

Keyword(s):

Serum Calcium ◽

Subcutaneous Fat ◽

High Serum ◽

Dietary Factors ◽

Endocrine Disorders ◽

Vitamin D Metabolites ◽

Genetic Causes ◽

Young Infants ◽

Fat Deposits ◽

Serum Pth

AbstractThe causes of hypercalcaemia in the neonate and infant are varied, and often distinct from those in older children and adults. Hypercalcaemia presents clinically with a range of symptoms including failure to thrive, poor feeding, constipation, polyuria, irritability, lethargy, seizures and hypotonia. When hypercalcaemia is suspected, an accurate diagnosis will require an evaluation of potential causes (e.g. family history) and assessment for physical features (such as dysmorphology, or subcutaneous fat deposits), as well as biochemical measurements, including total and ionised serum calcium, serum phosphate, creatinine and albumin, intact parathyroid hormone (PTH), vitamin D metabolites and urinary calcium, phosphate and creatinine. The causes of neonatal hypercalcaemia can be classified into high or low PTH disorders. Disorders associated with high serum PTH include neonatal severe hyperparathyroidism, familial hypocalciuric hypercalcaemia and Jansen’s metaphyseal chondrodysplasia. Conditions associated with low serum PTH include idiopathic infantile hypercalcaemia, Williams-Beuren syndrome and inborn errors of metabolism, including hypophosphatasia. Maternal hypocalcaemia and dietary factors and several rare endocrine disorders can also influence neonatal serum calcium levels. This review will focus on the common causes of hypercalcaemia in neonates and young infants, considering maternal, dietary, and genetic causes of calcium dysregulation. The clinical presentation and treatment of patients with these disorders will be discussed.

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