Inherited Calcium and Magnesium Disorders

Transcription

1 Inherited Calcium and Magnesium Disorders Martin Konrad University Children s Hospital Münster, Germany IPNA / ESPN Master Class, Leuven, Sep 2nd 2015

2 Outline Hypercalcemia Hypomagnesemia

3 Outline Hypercalcemia Hypomagnesemia

4 Case report: Emilia, age 4 weeks, failure to thrive Past med history: inadaequate weight gain since birth (born at term, 3410 g) Status: poor overall clinical condition, dystrophia, dehydration, 2780 g! workup: labs: no infection, normal echocardiography & iontophoresis hypercalcemia (3,8 mmol/l), suppr PTH (< 3 ng/ml) Renal ultrasound: Excessive hypercalciuria, normal renal function

5 Pediatric Hypercalcemia Hypercalcemia (3.8 mmol/l) high PTH low (< 3 pg/ml) Primary or Secondary hyperparathyroidism high Vitamin D metabolites hereditary: CaSR-related, FHH NSHPT Vitamin D intoxication Subcutanous fat necrosis Granulomatous diseases Hypophosphatemia

6 Pediatric Hypercalcemia Hypercalcemia (3.8 mmol/l) high PTH low (<3 pg/ml) Primary or econdary Hyperparathyroidism high Vitamin D metabolites hereditary: CaSR-related, FHH NSHPT Vitamin D intoxication Subcutanous fat necrosis Granulomatous diseases Hypophosphatemia Williams-Beuren-Sy. Idiopathic infantile Hypercalcemia normal 25OHD 31 ng/ml 1,25OHD??

7 Williams Beuren Syndrome Peculiar face, elfin - like Cardiovascular anomalies Developmental delay Hyperacusis Overfriendliness, empathetic Many other signs 15 % have hypercalcemia Hemizygous submicroscopic deletion 7q11.23 (FISH)

8 Pediatric Hypercalcemia Hypercalcemia (3.8 mmol/l) high PTH low (<3 pg/ml) Primary or econdary Hyperparathyroidism high Vitamin D metabolites hereditary: CaSR-related, FHH NSHPT Vitamin D intoxication Subcutanous fat necrosis Granulomatous diseases Hypophosphatemia normal? Williams-Beuren-Sy. Idiopathic infantile Hypercalcemia

9 Idiopathic Infantile Hypercalcemia Diagnostic Criteria: hypercalcemia / low PTH hypercalciuria / nephrocalcinosis failure to thrieve polyuria / dehydration muscular hypotonia Inheritance: autosomal recessive, CYP24A1

10 CYP24A1 mutations in IIH, pathophysiolgy

11 Relation between IIH and Vit D prophylaxis? After the diagnosis of IIH in P3.1, the parents decided not to give Vit D prophylaxis to the younger siblings. P3.2 has the same pathogenic mutations but never showed any symptoms. Last follow-up P3.1 P3.2 age 7 years 18 months S-Ca (mmol/l) PTH (pg/l) Nephrocalcinosis yes no

12 Pediatric Hypercalcemia, CYP24A1 defects Hypercalcemia high PTH low Primary or secondary Hyperparathyroidism high Vitamin D metabolites hereditary: CaSR-related, FHH NSHPT Vitamin D intoxication Subcutanous fat necrosis Granulomatous diseases Hypophosphatemia normal? Williams-Beuren-Sy. Idiopathic infantile Hypercalcemia

13 Ca ++ Serum [mmol L -1 ] Phenotypic characterization IIH, > 40 patients -> laboratory findings: -> hypercalcemia at manifestation at follow-up -> low PTH -> high normal or slightly increased vit D levels -> low 24/25- vit D metabolites -> hypercalciuria -> nephrocalcinosis

14 PTH [pg/ml] Phenotypic characterization IIH, > 40 patients -> laboratory findings: -> hypercalcemia -> low PTH -> high normal or slightly increased vit D levels -> low 24/25- vit D metabolites at manifestation at follow-up -> hypercalciuria -> nephrocalcinosis

15 Pediatric Hypercalcemia Hypercalcemia (3.8 mmol/l) high PTH low (<3 pg/ml) Primary or econdary Hyperparathyroidism Vitamin D metabolites high low (1,25OHD < 5pg/ml ) hereditary: CaSR-related, FHH NSHPT Vitamin D intoxication Subcutanous fat necrosis Granulomatous diseases Hypophosphatemia normal? Williams-Beuren-Sy. Idiopathic infantile Hypercalcemia Malignancy Vitamin A intoxication hereditary: Jansen`s Chondrodysplasia Hypophosphatasia

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17 Pediatric Hypercalcemia Hypercalcemia (3.8 mmol/l) high PTH low (<3 pg/ml) Primary or secondary Hyperparathyroidism Vitamin D metabolites high low (1,25OHD < 5pg/ml ) hereditary: CaSR-related, FHH NSHPT Vitamin D intoxication Subcutanous fat necrosis Granulomatous diseases Hypophosphatemia normal? Williams-Beuren-Sy. Idiopathic infantile Hypercalcemia Malignancy Vitamin A intoxication hereditary: Jansen`s Chondrodysplasia Hypophosphatasia

18 Case report: Emilia, alkaline phosphatase Datum Emilia Labor MS NW LM :39 60 L U/l :20 71 L U/l :16 59 L U/l :18 56 L U/l :22 52 L U/l :53 53 L U/l :55 56 L U/l

19 Case report: Emilia, 4 weeks, failure to thrive

20 Case report: Emilia, 4 weeks, failure to thrive

21 Case report: Emilia, 4 weeks, failure to thrive {

22 Definite diagnosis Emilia: Hypophosphatasia Mutations in TNSALP (AR/AD) AP enzyme activity Impaired bone mineralisation, rickets or osteomalacia-like picture { Accumulation of substrates anorganic pyrophophosphate (blocks mineralisation) pyridoxalphosphate (Vit B6) Broad phenotypic variability!

23 Hypophosphatasia: clinical variants Infantile form (biallelic, residual function) Onset first 6 months of life - respiratory distress { - rickets - failure to thrive - muscular hypotonia, myopathy - hypercalcemia, nephrocalcinosis - functional craniosynostosis - epilepsy (VitB6 sensitive) Whyte MP et al N 2012

24 Hypophosphatasia: clinical variants { Whyte MP et al N 2012

25 Hypophosphatasia: clinical variants Infantile form (biallelic, residual function) Onset first 6 months of life - respiratory distress { - rickets - failure to thrive - muscular hypotonia, myopathy - hypercalcemia, nephrocalcinosis - functional craniosynostosis - epilepsy (VitB6 sensitive) Whyte MP et al N 2012

26 Hypophosphatasia: enzyme replacement therapy Baseline 7 months old 6 Months of Treatment 13 months old 21 Months of Treatment 28 months old Whyte MP et al N Engl J Med 2012

27 Summary Pediatric Hypercalcemia Hypercalcemia high PTH low Primary or secondary Hyperparathyroidism high Vitamin D metabolites low hereditary: CaSR-related, FHH NSHPT Vitamin D intoxication Subcutanous fat necrosis Granulomatous diseases Hypophosphatemia normal? Williams-Beuren-Sy. Idiopathic infantile Hypercalcemia Malignancy Vitamin A intoxication hereditary: Jansen`s Chondrodysplasia Hypophosphatasia

28 Outline Hypercalcemia Hypomagnesemia

29 Magnesium Deficiency days: decreased urinary excretion weeks: nausea, vomiting, weakness months: paraesthesia, muscle weakness, seizures, QT prolongation arrhythmia, cardiac arrest

30 Magnesium Loss Ethanol ingestion Calcineurin inhibitors Proton pump inhibitors Aminoglycosides SIADH Diuretics Acute tubular necrosis Cisplatin Cetuximab (anti-egfr) Idiopathic, inherited

31 Renal Tubular Magnesium Reabsorption mmol/d

32 Renal Magnesium Loss: Etiology Urinary magnesium Urinary calcium nephrocalcinosis Urinary calcium normal kidneys Urinary calcium abnormal kidneys TAL defect DCT defect DCT defect FHHNC Bartter s Gitelman s primary hypomagnesemia Renal cysts/diabetes sy HNF1B

33 Hereditary Magnesium-losing Diseases Disease Inheritance Gene TAL Hypomagnesemia/Hypercalciuria/ AR CLDN16 Nephrocalcinosis (FHHNC) AR CLDN19 Bartter syndrome variants AR various? HNF1B nephropathy (RCAD) AD HNF1B DCT Gitelman syndrome AR NCCT Hypomagnesemia/Hypocalcemia AR TRPM6 Isolated renal hypomagnesemia AD FXYD2 Isolated renal hypomagnesemia AD KCNA1 Isolated renal hypomagnesemia AD CNNM2 Isolated renal hypomagnesemia AR EGF EAST / SeSAME AR KCNJ10

34 Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC) Inheritance: autosomal recessive Diagnostic Criteria: hypomagnesemia hypercalciuria nephrocalcinosis progressive renal failure possible eye affection

35 Macular Coloboma in FHHNC Dr. Almeida, Brazil

36 Paracellular Magnesium Transport in TAL Ca 2+ Na + Mg 2+ Na + 2Cl - K + Na + K + K + 2Cl 2Cl - Ca 2+ Na + Mg

37 Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC) PCLN Tight Junctions of TAL NH 2 Paracellin-1 (Claudin-16) Simon et al, Science 1999

38 Missense mutations in the tight junction gene CLDN19 G123R G123R Am J Hum Genet 2006

39 Phenotypic Characterization CLDN16 CLDN19 (n=107) (n=23) Hypomagnesemia 100% 100% Hypercalciura 100% 100% Nephrocalcinosis 100% 100% Polyuria / Polydipsia 80% 67% Urinary tract infections 50% 67% Increased PTH prior to CRF 82% 50% Chronic renal failure 80% 75% Ocular abnormalities 17% 95% Myopia 78% 91% Nystagm 0% 100% Macular colobomata 0% 50%

40 Pathophysiology of FHHNC Ca 2+ Mg 2+ Ca 2+ Mg 2+

41 Pathophysiology of FHHNC Ca 2+ Mg 2+ High risk for CRF Claudin-19 Claudin-16 Ca 2+ Mg 2+

42 Hereditary Magnesium-losing Diseases Disease Inheritance Gene TAL Hypomagnesemia/Hypercalciuria/ AR CLDN16 Nephrocalcinosis (FHHNC) AR CLDN19 Bartter syndrome variants AR various? HNF1B nephropathy (RCAD) AD HNF1B DCT Gitelman syndrome AR NCCT Hypomagnesemia/Hypocalcemia AR TRPM6 Isolated renal hypomagnesemia AD FXYD2 Isolated renal hypomagnesemia AD KCNA1 Isolated renal hypomagnesemia AD CNNM2 Isolated renal hypomagnesemia AR EGF EAST / SeSAME AR KCNJ10

43 Primary Hypomagnesemia with Secondary Hypocalcemia (HSH) Inheritance: autosomal recessive Symptoms at onset: generalized seizures first months of life, muscle spasms, tetany, dizziness vomiting, failure to thrive Laboratory findings: profound hypomagnesemia ( mmol/l), hypocalcemia, hypoparathyroidism

44 Primary Hypomagnesemia with Secondary Hypocalcemia (HSH) Therapy: high oral Mg supplementation (up to 20x of normal intake) low-normal serum Mg levels ( mmol/l) normocalcemia, normal PTH Pathophysiology: defective intestinal Mg absorption additional renal reabsorption defect (DCT)

45 TRPM6 mutations in HSH encodes a molecule with a covalently bound ion channel and kinase domain. member of the TRP ( transient receptor potential ) family. high similarity to TRPM7, a Ca 2+ - and Mg 2+ -permeable ion channel regulated by Mg 2+ -ATP. expressed in intestine and DCT

46 Renal leak of magnesium in HSH patients Schlingmann et al, JASN 2005

47 Reabsorption of Salt and Magnesium in the distal convoluted tubule (DCT) urine blood HSH TRPM6

48 Mg 2+ absorption intestinal Mg 2+ absorption Mg 2+ Kinetics Mg 2+ TRPM6 K + ATPase Na + Mg 2+? Na + transcellular Mg 2+ Mg 2+ intake

49 Mg 2+ absorption intestinal Mg 2+ absorption Mg 2+ Kinetics Mg 2+ TRPM6 K + ATPase Na + Mg 2+? Na + Mg 2+ Mg 2+ intake

50 Hereditary Magnesium-losing Diseases Disease Inheritance Gene TAL Hypomagnesemia/Hypercalciuria/ AR CLDN16 Nephrocalcinosis (FHHNC) AR CLDN19 Bartter syndrome variants AR various? HNF1B nephropathy (RCAD) AD HNF1B DCT Gitelman syndrome AR NCCT Hypomagnesemia/Hypocalcemia AR TRPM6 Isolated renal hypomagnesemia AD FXYD2 Isolated renal hypomagnesemia AD KCNA1 Isolated renal hypomagnesemia AD CNNM2 Isolated renal hypomagnesemia AR EGF EAST / SeSAME AR KCNJ10

51 Figure 2. Plasma total magnesium, calcium, and GFR values in mut+ and mut- patients assessed at stages 1 through 3 CKD HNF1B mutations and hypomagnesemia HNF1B encodes a transcription factor expressed in pancreas, liver, and kidney. Mutations result in MODY5 and renal develomental defects. Hypomagnesemia and hypocalciuria are frequent in HNF1B mutation carriers and may be symptomatic. Adalat, S. et al. JASN 2009

52 HNF1B mutations associated with hypomagnesemia and renal magnesium wasting. Adalat et al, J Am Soc Nephrol May;20(5): Hypocalciuria Hypokalemia? Study cohort: children with renal malformations studied for HNF1B

53 Renal Magnesium Loss: Etiology Urinary magnesium Urinary calcium Nephrocalcinosis Urinary calcium normal kidneys Urinary calcium abnormal kidneys TAL defect DCT defect DCT defect FHHNC Bartter s Gitelman s primary hypomagnesemia Renal cysts/diabetes sy HNF1B

54 Thank you!