METABOLISM, INCLUDING CALCIUM/PHOSPHATE METABOLISM

Transcription

1 Wit JM, Ranke MB, Kelnar CJH (eds): ESPE classification of paediatric endocrine diagnosis. 12. Disorders of bone metabolism, including calcium/phosphate metabolism. Horm Res 2007;68(suppl 2):87 90 ESPE Code Diagnosis OMIM ICD10 12 DISORDERS OF BONE METABOLISM, INCLUDING CALCIUM/PHOSPHATE METABOLISM 12A TRANSIENT HYPOCALCAEMIA (NEONATAL) E A.1 Early neonatal 1 P A.1a Prematurity 2 12A.1b Asphyxia 12A.1c Infant of diabetic mother 12A.1d Perinatal stress or trauma 12A.2 Late neonatal 3 P A.2a Disorders classified elsewhere: Conditions classified under permanent hypocalcaemia, hypomagnesaemia 12A.2b High milk phosphate load P71.0, P A.2c Parenteral nutrition 12A.2d Exchange transfusions 12A.2e Chronic alkalosis or bicarbonate treatment 12A.2f Maternal hypercalcaemia 12A.2g Maternal vitamin D deficiency 12A.2h Transient hypoparathyroidism P B PERMANENT HYPOCALCAEMIA 12B.1 Genetic disorders of the calcium-sensing receptor 12B.1a Autosomal-dominant hypocalcaemia # B.1b Autosomal-dominant hypocalcaemia with Bartter-like features B.2 Hypoparathyroidism E B.2a Disorders classified elsewhere: E20.8 DiGeorge syndrome types 1 and 2 (14B.10) Autoimmune polyglandular syndrome type 1 (APECED syndrome) (14C.4a) 12B.2b X-linked hypoparathyroidism % E20.8 Disorders of Bone Metabolism, Including Calcium/Phosphate Metabolism 87

2 ESPE Code Diagnosis OMIM ICD10 12B.2c Mitochondrial disorders 12B.2c.1 Kearns-Sayre # B.2c.2 MELAS # B.2c.3 Pearson marrow-pancreas syndrome # B.2c.4 trna-leu mutation * B.2c.9 Other 12B.2d Hypoparathyroidism, deafness and renal anomalies (Barakat # syndrome) 12B.2e Long-chain hydroxyacyl-coa dehydrogenase deficiency (LCHAD deficiency) [primary 11B.5d] * B.2f Other familial syndromes E B.2f.1 Kenny-Caffey syndrome type 1 # B.2f.2 Sanjad-Sakati # B.2f.9 Other specified syndromes 12B.2g Acquired hypoparathyroidism 12B.2g.1 Parathyroid surgery 12B.2g.2 Isolated autoimmune hypoparathyroidism 12B.2g.3 Iron overload 12B.2g.4 Other specified acquired forms 12B.2z Idiopathic E B.3 PTH defects (autosomal-dominant or autosomal-recessive familial isolated hypoparathyroidism) # E B.4 PTH/PTHrP receptor defects 4 12B.4a Pseudohypoparathyroidism type 1b # B.4z Other PTH/PTHrP receptor defects, unspecified 12B.5 Post-receptor defects 12B.5a Classified elsewhere: Pseudohypoparathyroidism type Ia (Albright s hereditary osteodystrophy, 14B.2) 12B.5b Pseudohypoparathyroidism type Ic # E B.5c Pseudohypoparathyroidism type II % E B.5d Pseudohypoparathyroidism with testotoxicosis # E B.6 Magnesium deficiency 5 E B.6a Familial primary hypomagnesaemia # B.6b Familial hypomagnesaemia with hypercalciuria, # nephrocalcinosis, and severe ocular involvement 12B.6c Isolated renal magnesium wasting # B.6d Hypomagnesaemia with secondary hypocalcemia # E20.1 ESPE Classification of Paediatric Endocrine Diagnoses 88

3 ESPE Code Diagnosis OMIM ICD10 12B.6e Gitelman syndrome [primary 14B.15] # B.7 Calciopenic rickets (see 12C.1) 12B.8 Systemic conditions associated with hypocalcaemia 12B.8a Tumour lysis syndrome 12B.8b Renal osteodystrophy 6 N B.8c AIDS 12B.8y Other specified conditions 12B.8z Other conditions, unspecified 12C RICKETS 12C.1 Calciopenic rickets E C.1a Nutritional (vitamin D deficiency) 12C.1a.1 Malabsorption 12C.1a.2 Liver disease 12C.1a.3 Anticonvulsant treatment (phenobarbital, phenytoin) 12C.1a.4 Renal osteodystrophy 6 N C.1a.5 Calcium deficiency rickets 7 12C.1b Genetic 12C.1b.1 Vitamin D 1 -hydroxylase deficiency (formerly known as # E83.3 pseudo-vitamin D-deficiency rickets, vitamin D-dependent rickets type I) 12C.1b.2 Hereditary 1,25(OH) 2 D-resistant rickets (formerly known as pseudo-vitamin D-deficiency rickets type II, vitamin D-dependent rickets type II, calcitriol-resistant rickets) # E C.2 Phosphopenic rickets E C.2a Classified elsewhere: McCune-Albright syndrome (14B.22) Renal tubular disorders Fanconi renotubular syndrome (14B.13) 12C.2b Familial hypophosphataemic rickets 12C.2b.1 X-linked hypophosphataemic rickets 8 # C.2b.2 Autosomal-dominant hypophosphataemic rickets 9 # C.2b.3 Hereditary hypophosphataemic rickets with hypercalciuria 10 # C.2b.4 Hypophosphataemic nonrachitic bone disease % C.2c Tumour-induced osteomalacia 11 12C.2d Decreased phosphate intake 12 12C.3 Hypopophosphatasia (if not associated with rickets, classify under 12E.5l) # # E83.3 Disorders of Bone Metabolism, Including Calcium/Phosphate Metabolism 89

4 ESPE Code Diagnosis OMIM ICD10 12D OSTEOPOROSIS M D.1 Genetic defects 12D.1a Classified elsewhere: Ehlers-Danlos syndrome (14B.11) Marfan syndrome [primary 14B.20, other secondary 2A.2a] 12D.1b Osteogenesis imperfecta (types I VII) # # # # # D.1c Homocystinuria [if tall, classify also as 2A.2c] D.1d Other genetic defects 12D.2 Chromosomal defects M D.3 Endocrine disorders M D.4 Iatrogenic causes M D.5 Nutritional disorders M D.6 Chronic diseases M D.7 Malignancies M D.8 Disuse M D.9 Other specified disorders, e.g. muscle and neuromuscular disorders M D.10 Idiopathic juvenile osteoporosis 13 M E HYPERCALCAEMIA E E.1 Disorders of the calcium-sensing receptor 12E.1a Familial benign hypercalcaemia (familial hypocalciuric # hypercalcaemia) 12E.1b Neonatal severe primary hyperparathyroidism # E.1c Calcium-sensing receptor blocking antibodies ESPE Classification of Paediatric Endocrine Diagnoses 90

5 ESPE Code Diagnosis OMIM ICD10 12E.2 Disorders of the parathyroid glands/pth oversecretion E21 12E.2a Disorders classified elsewhere: Multiple endocrine neoplasia type 1 (14C.5a) Multiple endocrine neoplasia type 2a (14C.5b) Multiple endocrine neoplasia type 2b (14C.5c) 12E.2b Familial isolated hyperparathyroidism, type 1 # E E.2c Familial isolated hyperparathyroidism, type 2 (jaw tumour) # E E.2d Sporadic parathyroid adenomas E E.2e Parathyroid carcinomas E E.2f Tertiary hyperparathyroidism E E.2y Other PTH abnormalities (specified) E E.3 PTH/PTHrP Receptor abnormalities 12E.3a Metaphyseal chondrodysplasia, Jansen type # Q E.4y Other PTH/PTHrP receptor abnormalities (specified) 12E.4 Abnormal vitamin D metabolism 12E.4a Disorders classified elsewhere: Williams-Beuren syndrome (14B.37) 12E.4b Idiopathic infantile hypercalcaemia 14 # E.5 Miscellaneous causes of hypercalcaemia in childhood E E.5a Vitamin D (or vitamin D metabolite) intoxication 15 E E.5b Sarcoidosis, other granulomatous diseases D E.5c Immobilisation 16 E E.5d Hypercalcaemia of malignancy E E.5e Subcutaneous fat necrosis 12E.5f Excessive calcium supplementation 12E.5g Congenital lactase deficiency # E.5h Disaccharidase deficiency # E.5i Endocrine forms (adrenal insufficiency, severe congenital hypothyroidism, thyrotoxicosis) (primarily classified elsewhere) 12E.5j Down syndrome # Q90 12E.5k AIDS B24 12E.5l IMAGe syndrome E.5m Hypophosphatasia # E E.5y Other specified disorders 12E.5z Other disorders (unspecified) Disorders of Bone Metabolism, Including Calcium/Phosphate Metabolism 91

6 1 Early neonatal hypocalcemia (ENH) (<72 h) Phenotype: Specific signs: tetany, generalised or focal clonic seizures, frequent twitches or jerking of limbs, hyperacusis, laringospasm, jitteriness, irritability; nonspecific signs: apnoea, tachycardia, tachypnoea, cyanosis, oedema; may be asymptomatic. Serum-Ca ( ), P (+), Mg ( ), PTH (+), CT (+), 25-OHD ( ), 1,25(OH) 2 D ( ). Comments: The mechanism(s) of ENH is uncertain; possible pathogenetic factors are exaggerated postnatal depression of circulating Ca levels, transient pseudohypoparathyroid-like state probably due to an immaturity of renal and bone response to PTH, and exaggerated rise in CT levels. Reduced 25-OHD and 1,25(OH) 2 D levels may be contributing factors. Conditions at risk to develop ENH: diabetes in the mother, pre-eclampsia, perinatal asphyxia, and prematurity. 2 Metabolic bone disease (MBD) of prematurity Synonym: Rickets of prematurity, osteopenia of prematurity. Phenotype: Asymptomatic, or hypotonia, signs of rickets and/or osteopenia, fractures of the ribs or long bones, skeletal deformities (rib cage softening, altered head shape), respiratory distress syndrome, growth delay. Serum-Ca ( /N), P ( /N), alkaline phosphatase (+/N), PTH (+/N), 25-OHD ( /N), 1,25(OH) 2 D (+ if Ca and P are reduced, in case of substrate deficiency), urine-ca (+ in phosphate depletion syndrome), urine-p (+ in secondary hyperparathyroidism, in phosphate depletion syndrome or normal). Hormonal findings may vary on the basis of the amount of Ca and P supplied by the preterm formula, fortified human milk, or parenteral nutrition, the degree of vitamin D deficiency, and the adaptative mechanisms in response to the dietary mineral insufficiency. Comments: MBD of prematurity mainly arises from insufficient dietary minerals (Ca and P). Copper deficiency, as a result of abnormal collagen metabolism, has also been implicated in this condition. Phosphate depletion syndrome mainly occurs in preterm neonates who are fed unfortified human milk or during parenteral nutrition. 3 Late neonatal hypocalcemia (> 72 h) Phenotype: Asymptomatic, or symptoms similar to those of early neonatal hypocalcaemia. Serum- Ca ( ), P (+), Mg ( ), PTH ( /+), CT (N), 25-OHD ( ), 1,25(OH) 2 D ( ). Comments: Possible pathogenetic factors seem to be excessive dietary P load in neonates fed cow s milk or cow s milk based formula with Ca/P molar ratio 3 4 times that of human milk, inability of the immature kidney to excrete P efficiently, insufficient PTH response to hypocalcaemia, and materno-foetal vitamin D deficiency. Late neonatal hypocalcaemia is less frequent than early neonatal hypocalcaemia. The incidence of late neonatal hypocalcaemia is greater in full term than in preterm infants. Infants of diabetic mother and infants with transient hypoparathyroidism due to maternal hypercalcaemia secondary to primary hyperparathyroidism may be at risk for late neonatal hypocalcaemia. 4 PTH/PTHrP receptor defects Comment: A congenital defect of the PTH/PTHrP receptor is Blomstrand chondrodysplasia, a perinatally lethal condition, that does not present with hypocalcaemia. 5 Magnesium deficiency Comment: Only some conditions, such as familial primary hypomagnesaemia and hypomagnesaemia with secondary hypocalcaemia, show hypocalcaemia. ESPE Classification of Paediatric Endocrine Diagnoses 92

7 6 Renal osteodystrophy (ROD) Phenotype: Growth failure, bone pain, muscle weakness, skeletal deformities (scoliosis, kyphosis, genu valgum, distorsion of the thoracic cage), bone fractures (ribs, hips, vertebral bodies), extraskeletal calcifications (periarticular, vascular, subcutaneous, and visceral). Serum-P (+), Ca ( ), Mg (+), alkaline phosphatase (+), PTH (+), 25-OHD ( /N), 1,25(OH) 2 D ( ). Osteitis fibrosa (subperiosteal erosions, osteosclerosis, slipped epiphyses), rickets-like lesions. Comments: ROD is determined by the skeletal effect of secondary hyperparathyroidism associated with a reduced 1,25(OH) 2 D production. Reduced GFR ] decreased urinary loss of P ] mild hyperphosphataemia ] hypocalcaemia ] secondary hyperparathyroidism. As renal function continues to decline, hypocalcaemia is further aggravated by a resistance to the action of PTH on bone. In addition, the set-point for the inhibition of PTH secretion by extracellular calcium is raised in chronic renal failure, making it more difficult to turn off the secondary hyperparathyroidism. Reduced 1,25(OH) 2 D production derives from a decline in the functioning renal mass available to perform 1 -hydroxylation of 25-OHD, hyperphosphataemia suppressing renal 1 -hydroxylase activity, and metabolic acidosis. The signs and symptoms of ROD are rather nonspecific, and laboratory and radiological abnormalities often do not correspond to the severity of the clinical manifestations. 7 Calcium deficiency rickets Phenotype: Clinical features are identical to those observed in patients with vitamin D deficiency rickets. Calcium deficiency rickets usually occurs after the age of 18 months. Serum-Ca ( /N), P ( /N), alkaline phosphatase (+), PTH (N/+), 25-OHD (N/ ), 1,25(OH) 2 D (+). Comments: Low dietary calcium intake, often exacerbated by a high oxalate and phytate content in the diet that impairs intestinal calcium absorption, is not able to ensure calcium demand for growth plate mineralisation. Reduced calcium intake ] hypocalcaemia ] secondary hyperparathyroidism ] increased 1,25(OH) 2 D production. Reduced 25-OH-D levels due to increased catabolism. 8 X-linked hypophosphataemic rickets (XLH) Synonyms: Hypophosphataemic vitamin D-resistant rickets. Phenotype: Growth failure with disproportionate short stature, lower limbs deformities, dental and periodontal lesions. Serum-P ( ), alkaline phosphatase (+), PTH (N), 25-OHD (N), 1,25(OH) 2 D ( or inappropriately normal relative to hypophosphataemia), TmP/GFR ( ), urine-p (+), urine-ca (N). Osteomalacia in both cortical and trabecular bone, increase in osteoid volume, areas of hypomineralisation around osteocytes in the lamellar cortical bone. Comment: Defective tubular reabsorption of P associated with abnormal renal vitamin D metabolism caused by mutations in the PHEX (phosphate-regulating gene with homology to endopeptidases) gene, which is located on Xp Autosomal-dominant hypophosphataemic rickets (ADHR) Synonym: Vitamin D-resistant rickets. Phenotype: Clinical features are similar to those observed in patients with XLH. In contrast to XLH, ADHR shows incomplete penetrance, variable age at onset (childhood to adult), and resolution of the phosphate-wasting defect in rare cases. Comments: Autosomal dominant. It is caused by mutation in a gene encoding a member of the fibroblast growth factor family (FGF23). Disorders of Bone Metabolism, Including Calcium/Phosphate Metabolism 93

8 10 Hereditary hypophosphataemic rickets with hypercalciuria (HHRH) Synonym: Hypercalciuric hypophosphataemic rickets. Phenotype: Stunted growth, lower limbs deformities. Serum-P ( ), PTH (N), 25-OHD (N), 1,25(OH) 2 D (+), TmP/GFR ( ), urine-p (+), urine-ca (+). Comments: Defective tubular reabsorption of P ] hypophosphataemia ] increased 1,25(OH) 2 D production ] increased intestinal calcium absorption ] hypercalcaemia ] increased calcium filtered load and PTH suppression ] hypercalciuria. A significant number of asymptomatic family members showed idiopathic hypercalciuria alone without associated bone disease. Complete remission of the disease on P therapy alone. 11 Tumour rickets and osteomalacia Synonyms: Tumour-associated rickets and osteomalacia, tumour-induced rickets, oncogenic hypophosphataemic osteomalacia (OHO), oncogenic rickets and osteomalacia. Phenotype: Stunted growth, bone and muscle pain, muscle weakness, fatigue, gait disturbances, skeletal abnormalities (bowing of the lower limbs), recurrent fractures of long bones (occasionally). The majority of patients have benign or malignant tumours of mesenchymal origin of either soft tissues or bone, carcinomas of epidermal or endodermal origin; occasionally, epidermal naevus, von Recklinghausen neurofibromatosis. Serum-P ( ), 25-OHD (N), 1,25(OH) 2 D ( or inappropriately normal relative to hypophosphatemia), TmP/GFR ( ), urine-p (+). Occasionally glycinuria, glucosuria, and hyperaminoaciduria. Comments: Production of a humoral factor(s) known as phosphatonin (FGF-23, matrix extracellular phosphoglycoprotein, frizzled-related protein 4), that may affect multiple functions of the proximal renal tubule, including P reabsorption. Complete resection of the tumour restores normophosphataemia. 12 Decreased phosphate intake Synonyms: Dietary phosphate deficiency, nutritional phosphate deficiency. Phenotype: Severe serum-p ( ): red cell dysfunction (haemolytic anaemia), leukocyte dysfunction [chemotaxis ( ), phagocytosis ( ), bacterial killing ( )]; platelet dysfunction (thrombocytopenia); musculo-skeletal: rhabdomyolysis, reversible cardiomyopathy and myopathy; CNS: metabolic encephalopathy; metabolic acidosis, rickets/osteomalacia/osteopenia. Serum-P ( ). Comments: The signs and symptoms of severe hypophosphataemia may be related to a decrease in 2,3-diphosphoglycerate and/or ATP content in tissues. Main causes: total parenteral nutrition (nutritional recovery syndrome) in which aluminium loading may be a complicating factor, low-phosphate feedings in low-birthweight infants (phosphate depletion syndrome), malabsorption. 13 Idiopathic juvenile osteoporosis Phenotype: Diffuse bone pain, mainly in the back, hips, and feet, and a characteristic gait with difficulty in walking, associated with radiological evidence of osteoporosis and fractures of the vertebrae and long bones, mostly at metaphyseal sites. Idiopathic juvenile osteoporosis may have a spontaneous recovery, usually within 3 5 years. Comments: The diagnosis of idiopathic juvenile osteoporosis is based on the exclusion of the other known causes of osteoporosis. It may be difficult to distinguish from mild forms of osteogenesis imperfecta. Bone biopsy may be useful for the correct diagnosis. ESPE Classification of Paediatric Endocrine Diagnoses 94

9 14 Idiopathic infantile hypercalcaemia Synonyms: Lightwood type (mild form) and Fanconi-Schlesinger type (severe forms). Phenotype: Similar to patients with Williams-Beuren syndrome; the distinction between the two syndromes remains problematic. Comment: A disorder in vitamin D metabolism with increased vitamin D sensitivity with respect to gastrointestinal transport of Ca has been postulated in some cases. Elevated serum PTHrP levels at the time of hypercalcaemia have been reported. 15 Vitamin D intoxication Synonym: Hypervitaminosis D. Phenotype: Asymptomatic or symptoms of hypercalcaemia/hypercalciuria. Excessive storage of vitamin D in adipose tissue and voluntary muscle. Serum-Ca (+), P (N/+), PTH ( ), 25-OHD (+ if vitamin D or 25-OHD is ingested), 1,25(OH) 2 D (N), urine-ca (+). Comment: Increased action of vitamin D metabolites on intestinal Ca absorption and Ca mobilisation from bone. 16 Immobilisation Synonyms: Immobilisation-induced hypercalciuria, immobilisation-induced hypercalcaemia and osteopenia. Phenotype: Asymptomatic or symptoms related to hypercalcaemia/hypercalciuria. Osteopenia. Serum-Ca (N/+), alkaline phosphatase (N/+), PTH (N), 1,25(OH) 2 D ( ), urine-ca (+), urine-p (+), GFR ( ), metabolic alkalosis. Comment: Uncoupling of bone cells activity for increased osteoclastic bone resorption and decreased osteoblastic bone formation. Disorders of Bone Metabolism, Including Calcium/Phosphate Metabolism 95