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Context: Childhood hyperphosphatasemia is usually transient and may be associated with infections. It remains less well known how hyperphosphatasemia is related to growth and bone mineralization. Objective: We explored alkaline phosphatase (ALP) concentrations and prevalence of hyperphosphatasemia, and their association with vitamin D, growth, infections, and bone parameters in healthy children. Methods: The study was a secondary analysis of a vitamin D intervention trial. Participants received vitamin D3 10 or 30 µg daily from age 2 weeks to 2 years. Children with data on ALP at 12 and/or 24 months (n = 813, girls 51.9%) were included. Anthropometrics and bone parameters were measured at 12 and 24 months. Infections were recorded prospectively by the parents. Results: Boys had higher ALP than girls at 12 months (median [IQR] 287 [241-345] U/L vs 266 [218-341] U/L; P = .02). At 24 months concentrations were lower than at 12 months (240 [202-284]; P < .001) but without sex difference. The prevalence of hyperphosphatasemia (ALP > 1000 U/L) at 12 months was 5.3% and at 24 months 0.6%. Body size, growth rate, and bone mineral content associated positively with ALP, while vitamin D intervention had no effect. Infants with hyperphosphatasemia were smaller than infants with ALP ≤ 1000 U/L. Hyperphosphatasemia was not associated with previous infections. Conclusion: Approximately 5% of infants had hyperphosphatasemia at 12 months, but <1% at 24 months. ALP concentrations and hyperphosphatasemia were associated with sex, anthropometry, and bone mineralization. Infections did not contribute to hyperphosphatasemia. [ABSTRACT FROM AUTHOR]

Alkaline phosphatase (AP) is a membrane bound enzyme and when it is elevated in blood, it is mostly due to either hepatobiliary or bone diseases. We report isolated intestinal hyperphosphatasemia (IAP) in two sisters. Both sisters presented with identical trends of isolated AP elevation. Both underwent extensive workup for liver diseases including cholangiograms, and none was identified. Subsequent isoenzyme electrophoresis showed that 45%–56% of the elevated AP was due to IAP. This elevation of the intestinal AP is consistent with a rare hereditary biochemical abnormality, benign familial intestinal hyperphosphatemia. This condition should be considered in the differential diagnosis of otherwise isolated serum AP levels to avoid unnecessary investigations. [ABSTRACT FROM AUTHOR]

Alkaline phosphatase (ALP) is detected in most human tissues. However, ALP activity is routinely assayed using high concentrations of artificial colorimetric substrates in phosphate-free laboratory buffers at lethal pH. Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) of the ALPL gene that encodes the ALP isoenzyme expressed in bone, liver, kidney, and elsewhere and is therefore designated "tissue-nonspecific" ALP (TNSALP). Consequently, HPP harbors clues concerning the biological function of this phosphohydrolase that is anchored onto the surface of cells. The biochemical signature of HPP features low serum ALP activity (hypophosphat asemia) together with elevated plasma levels of three natural substrates of TNSALP: i) phosphoethanolamine (PEA), a component of the linkage apparatus that binds ALPs and other proteins to the plasma membrane surface; ii) inorganic pyrophosphate (PPi), an inhibitor of bone and tooth mineralization; and iii) pyridoxal 5′-phosphate (PLP), the principal circulating vitameric form of vitamin B 6 (B 6). Autosomal dominant and autosomal recessive inheritance involving several hundred ALPL mutations underlies the remarkably broad-ranging expressivity of HPP featuring tooth loss often with muscle weakness and rickets or osteomalacia. Thus, HPP associates the "bone" isoform of TNSALP with biomineralization, whereas the physiological role of the "liver", "kidney", and other isoforms of TNSALP remains uncertain. Herein, to examine HPP's broad-ranging severity and the function of TNSALP, we administered an oral challenge of pyridoxine (PN) hydrochloride to 116 children with HPP. We assayed both pre- and post-challenge serum ALP activity and plasma levels of PLP, the B 6 degradation product pyridoxic acid (PA), and the B 6 vitamer pyridoxal (PL) that can enter cells. Responses were validated by PN challenge of 14 healthy adults and 19 children with metabolic bone diseases other than HPP. HPP severity was assessed using our HPP clinical nosology and patient height Z -scores. PN challenge of all study groups did not alter serum ALP activity in our clinical laboratory. In HPP, both the post-challenge PLP level and the PLP increment correlated (Ps < 0.0001) with the clinical nosology and height Z-scores (Rs = +0.6009 and + 0.4886, and Rs = −0.4846 and − 0.5002, respectively). In contrast, the plasma levels and increments of PA and PL from the PN challenge became less pronounced with HPP severity. We discuss how our findings suggest extraskeletal TNSALP primarily conditioned the PN challenge responses, and explain why they caution against overzealous B 6 supplementation of HPP. • Hypophosphatasia (HPP) denotes heritable deficiency of alkaline phosphatase (ALP) • In HPP the ALP substrate pyridoxal 5′-phosphate (PLP) accumulates extracellularly • High pre- and post-PN challenge plasma PLP levels reflect pediatric HPP severity • The PN challenge responses seem mediated largely elsewhere than the skeleton • The PN-augmented plasma PLP might inhibit some metabolic/transport processes [ABSTRACT FROM AUTHOR]

Abstract Background Several genetic defects have been identified in the glycosylphosphatidylinositol (GPI) anchor synthesis, including mutations in PIGO encoding phosphatidylinositol glycan anchor biosynthesis class O protein. These defects constitute a subgroup of the congenital disorders of glycosylation (CDG). Seven patients from five families have been reported carrying variants in PIGO that cause an autosomal recessive syndrome characterised by dysmorphism, psychomotor disability, epilepsy and hyperphosphatasemia. Methods Whole exome sequencing was performed in a boy with dysmorphism, psychomotor disability, epilepsy, palmoplantar keratoderma, hyperphosphatasemia and platelet dysfunction without a clinical bleeding phenotype. Results Two novel variants in PIGO were detected. The missense variant encoding p. His871Pro was inherited from the boy’s father while the frameshift variant encoding p. Arg604ProfsTer40 was maternally inherited. Conclusion A boy with two novel PIGO variants is reported. The skin phenotype and platelet dysfunction in this patient have not been described in previously reported patients with PIGO deficiency but it is of course uncertain whether these are caused by this disorder. The literature on PIGO deficiency is reviewed.

• Alkaline Phosphatase levels rise in liver damage or in bone remodelling disorders. • Benign Transient Hiperphosphatasemia has marked elevation in Alkaline phosphatase. • Alkaline phosphatase isoenzymes measurement can help in the diagnosis. • Importance of the communication between laboratory personnel and clinicians. [ABSTRACT FROM AUTHOR]

Abstract Sclerosteosis (SOST) refers to two extremely rare yet similar skeletal dysplasias featuring a diffusely radiodense skeleton together with congenital syndactyly. SOST1 is transmitted as an autosomal recessive (AR) trait and to date caused by ten homozygous loss-of-function mutations within the gene SOST that encodes the inhibitor of Wnt-mediated bone formation, sclerostin. SOST2 is transmitted as an autosomal dominant (AD) or AR trait and to date caused by one heterozygous or two homozygous loss-of-function mutation(s), respectively, within the gene LRP4 that encodes the sclerostin interaction protein, low-density lipoprotein receptor-related protein 4 (LRP4). Herein, we investigated two teenagers and one middle-aged man with SOST in three families living in the state of Tamil Nadu in southern India. Next generation sequencing of their genomic DNA using our high bone density gene panel revealed SOST1 in the teenagers caused by a unique homozygous nonsense SOST mutation (c.129C > G, p.Tyr43X) and SOST2 in the man caused by homozygosity for one of the two known homozygous missense LRP4 mutations (c.3508C > T, p.Arg1170Trp). He becomes the fourth individual and the first non-European recognized with SOST2. His clinical course was milder than the life-threatening SOST1 demonstrated by the teenagers who suffered blindness, deafness, and raised intracranial pressure, yet his congenital syndactyly was more striking by featuring bony fusion of digits. All three patients were from consanguineous families and heterozygosity for the SOST mutation was documented in the mothers of both teenagers. Thus, on the endogamous genetic background of Indian Tamils, SOST1 from sclerostin deficiency compared to SOST2 from LRP4 deactivation is a more severe and life-threatening disorder featuring complications due to osteosclerosis of especially the skull. In contrast, the syndactyly of SOST2 is particularly striking by involving bony fusion of some digits. Both the SOST and LRP4 mutations in this ethnic population likely reflect genetic founders. Highlights • Sclerosteosis (SOST) denotes diffusely dense bones and congenital syndactyly. • SOST1 and 2 are due to loss-of-function mutations in SOST and LRP4 , respectively. • In Indian Tamils, SOST1 and 2 reflect homozygous founder mutations in SOST and LRP4. • Congenital syndactyly is more striking in SOST2, and uniquely features fused bones. • SOST1 is a more severe and life-threatening disorder compared to SOST2. [ABSTRACT FROM AUTHOR]

Background: Several genetic defects have been identified in the glycosylphosphatidylinositol (GPI) anchor synthesis, including mutations in PIGO encoding phosphatidylinositol glycan anchor biosynthesis class O protein. These defects constitute a subgroup of the congenital disorders of glycosylation (CDG). Seven patients from five families have been reported carrying variants in PIGO that cause an autosomal recessive syndrome characterised by dysmorphism, psychomotor disability, epilepsy and hyperphosphatasemia.Methods: Whole exome sequencing was performed in a boy with dysmorphism, psychomotor disability, epilepsy, palmoplantar keratoderma, hyperphosphatasemia and platelet dysfunction without a clinical bleeding phenotype.Results: Two novel variants in PIGO were detected. The missense variant encoding p. His871Pro was inherited from the boy's father while the frameshift variant encoding p. Arg604ProfsTer40 was maternally inherited.Conclusion: A boy with two novel PIGO variants is reported. The skin phenotype and platelet dysfunction in this patient have not been described in previously reported patients with PIGO deficiency but it is of course uncertain whether these are caused by this disorder. The literature on PIGO deficiency is reviewed. [ABSTRACT FROM AUTHOR]

Transient Hyperphosphatemia of Childhood (HTI), is a benign and self-limiting entity, defined as the serum elevation of alkaline phosphatase (FA), with no evidence of hepatic or bone pathology being of a transient nature and presenting no subsequent sequelae. Classically, a specific entity has been considered according to Kraut's diagnostic criteria: patient less than 5 years old, variable symptomatology, absence of clinical and biological symptoms of liver and / or bone disease, isoenzyme analysis showing a joint elevation of bone and liver fractions Of AF, and subsequent normalization in less than 4 months. [ABSTRACT FROM AUTHOR]

Benign transient hyperphosphatasemia of infancy and early childhood is a self-limiting condition characterized by transiently increased serum alkaline phosphatase in the absence of liver, kidney or metabolic bone diseases. It is often accidentally found in children under five years old and it might be associated with a variety of underlying clinical disorders. Its pathophysiology remains unclear. Herein, we report a case of a 4-year-old girl with a 1-year history of persistent oligoarticular Juvenile Idiopathic Arthritis, who was found to have transient hyperphosphatasemia during a periodic check-up. This clinical case underlines the importance of promptly recognizing this benign condition, which avoids unnecessary extensive investigations. [ABSTRACT FROM AUTHOR]

Introduction: Respiratory syncytial virus (RSV) infection is the most common cause of hospitalization in infants and small children. The aim was to present a 13-months old boy diagnosed with acute airway infection, acute otitis media (AOM) and hepatitis during the RSV-infection. Material and methods: Serum catalytic activities of alkaline phosphatase (ALP), aspartate aminotranspherase (AST), alanine aminotranspherase (ALT), gamma glutamyl transpherase (GGT), lactate dehydrogenase (LD), and concentrations of bilirubin were monitored during hospitalization and at control examination. Results: The child had clinical signs and symptoms of respiratory failure, AOM, and laboratory findings of virus infection and liver disease. On admission, catalytic activities of enzymes were markedly increased, especially the activity of ALP (10333 U/L, i.e. 24-fold increase in comparison with the upper reference limit). The highest increased in AST (339 U/L, 4.5-fold), ALT (475 U/L, 10.3-fold) and LD (545 U/L, 1.5-fold) were registered on the 3rd day, and the highest increase in GGT (68 U/L, 3.1-fold) occurred on the 11th day. Seven weeks after discharge AST, ALT, GGT and LD decreased into reference range, and ALP remain mildly increased (478 U/L, 1.1 fold increase). RSV was confirmed in nasal lavage fluid. Conclusion: Laboratory results in patient with RSV infection needs to be interpreted in the light of both, respiratory and extrapulmonary manifestations of the infection, respectively. [ABSTRACT FROM AUTHOR]

Due to the possibility of underlying hepatobiliaryor bone diseases, the diagnostic work up of a child with elevated alkaline phosphatase (AP) levels can be quite costly. In a significant proportion of these patients, elevated AP is benign, requiring no intervention: hence, known as transient hyperphosphatasemia (THP) of infants and children. A 27-month old previously healthy Caucasian female was found to have isolated elevation of AP four weeks after the initial symptoms of acute gastroenteritis. One month later, when seen in hepatobiliary clinic, signs and symptoms of gastrointestinal, hepatobiliary, or bone disease were absent and physical examination was normal. The diagnosis of THP was made, and, as anticipated, AP levels normalized after four months. Using this case as an example, we suggest an algorithm that can be utilized as a guide in a primary care setting to arrive at the diagnosis of THP and avoid further tests or referrals. [ABSTRACT FROM AUTHOR]

The article discusses four cases of healthy patients with an elevated serum alkaline phosphatase (SAP). A review of the related literature on benign transient hyperphosphatasemia (BTH) of infancy is offered. Data collection included complete blood count (CBC), erythrosedimentation rate and hepatogram, among others. A discussion on SAP is detailed.

Introduction: A case of transient hyperphosphatasemia in a 21-month-old boy diagnosed with recurrent wheezing during acute respiratory infection is described. Materials and methods: Determination of alkaline phosphatase catalytic activity was performed by the recommended photometric method, and elec-trophoretic separation of alkaline phosphatase isoenzymes on agarose gel by serum processing with lectin. Results: During hospital treatment, increased catalytic activity of alkaline phosphatase was recorded (4109 U/L on day 1 and 2156 U/L on day 6). On control examination on day 27 of hospital admission, the value decreased to 505 U/L. Electrophoretic separation of alkaline phosphatase isoenzymes demonstrated a band faster than the hepatic-osseous isoenzyme, a fast anodal form. Conclusion: A marked increase in the alkaline phosphatase catalytic activity with typical electrophoretic isoenzyme pattern persisting for several weeks points to transient hyperphosphatasemia. Additional unnecessary diagnostic work-up can be obviated by timely recognition of the phenomenon. [ABSTRACT FROM AUTHOR]

Aim: To present the electrophoretic pattern of alkaline phosphatase (ALP) isoenzymes in serum of infants and children exhibiting increased total ALP catalytic activity in the course of acute respiratory disease. Subjects and methods: Results obtained in 21 children (17 of them infants), including 13 male and eight female children aged 2 months to 8 years, hospitalized for respiratory diseases are presented. Total ALP catalytic activity was determined and electrophoretic separation of ALP isoenzymes was performed in children's sera. Results: Increased total ALP catalytic activity(range, 528-5622 U/L) during hospital stay was recorded in eight (38.1%) children. Atypical picture of benign transient hyperphosphatasemia TH), which implies the occurrence of fast anodal fraction (faster than hepatic fraction) and near-cathode fraction (faster than bone fraction), was recorded in five children. The placental-like isoenzyme was detected in two children. Expression of bone fraction and placental-like fraction was recorded in a rachitic child. Prehepatic ALP was expressed in two children, and hepatic ALP isoenzyme in one child. Conclusion: Acute respiratory disease in infants and children may entail transient increase in the ALP catalytic activity with the occurrence of various isoenzyme bands such as fast anodal and near-cathode fraction (in TH), prehepatic fraction and placental-like fraction. TH is verified when total ALP activity has decreased and returned to reference intervals. In this case, no additional testing is required. [ABSTRACT FROM AUTHOR]

A clinical, radiological and biochemical study of 300 Cape coloured out-patients in order to clarify the diagnosis of rickets and to establish its incidence in the specific ethnic group selected, is presented. 95 Cases (31.6%) were diagnosed as suffering from rickets. Analysis of the results indicates that radiological examination is necessary to confirm or exclude the clinical diagnosis. The most useful biochemical parameter is the serum level of alkaline phosphatase. [ABSTRACT FROM AUTHOR]

Transient hyperphosphatasemia (TH) is characterized by isolated elevation of serum alkaline phosphatase (ALP). This condition was first recognized in children but only few cases reported this problem in adult population. There is no evidence of liver or bone disease and no signs of infection and usually levels of ALP return to normal levels within few months. Here we report a case of benign TH in a 60-year-old male renal transplant recipient. [ABSTRACT FROM AUTHOR]

Juvenile Paget's disease (JPD) became in 1974 the commonly used name for ultra-rare heritable occurrences of rapid bone remodeling throughout of the skeleton that present in infancy or early childhood as fractures and deformity hallmarked biochemically by marked elevation of serum alkaline phosphatase (ALP) activity (hyperphosphat asemia). Untreated, JPD can kill during childhood or young adult life. In 2002, we reported that homozygous deletion of the gene called tumor necrosis factor receptor superfamily, member 11B (TNFRSF11B) encoding osteoprotegerin (OPG) explained JPD in Navajos. Soon after, other bi-allelic loss-of-function TNFRSF11B defects were identified in JPD worldwide. OPG inhibits osteoclastogenesis and osteoclast activity by decoying receptor activator of nuclear factor κ-B (RANK) ligand (RANKL) away from its receptor RANK. Then, in 2014, we reported JPD in a Bolivian girl caused by a heterozygous activating duplication within TNFRSF11A encoding RANK. Herein, we identify mutation of a third gene underlying JPD. An infant girl began atraumatic fracturing of her lower extremity long-bones. Skull deformity and mild hearing loss followed. Our single investigation of the patient, when she was 15 years-of-age, showed generalized osteosclerosis and hyperostosis. DXA revealed a Z -score of +5.1 at her lumbar spine and T-score of +3.3 at her non-dominant wrist. Biochemical studies were consistent with positive mineral balance and several markers of bone turnover were elevated and included striking hyperphosphatasemia. Iliac crest histopathology was consistent with rapid skeletal remodeling. Measles virus transcripts, common in classic Paget's disease of bone, were not detected in circulating mononuclear cells. Then, reportedly, she responded to several months of alendronate therapy with less skeletal pain and correction of hyperphosphatasemia but had been lost to our follow-up. After we detected no defect in TNFRSF11A or B , trio exome sequencing revealed a de novo heterozygous missense mutation (c.926C>G; p.S309W) within SP7 encoding the osteoblast transcription factor osterix (specificity protein 7, transcription factor SP7). Thus, mutation of SP7 represents a third genetic cause of JPD. • Juvenile Paget's disease (JPD) features heritable, remarkably fast, bone turnover. • Onset is typically early childhood with skeletal pain, fracture, and deformity. • Deactivation or activation of TNFRSF11B (OPG) or A (RANK), respectively, causes JPD. • We identify altered SP7 encoding osterix as the third genetic basis for JPD. [ABSTRACT FROM AUTHOR]

Four heterozygous in-frame tandem duplications of different lengths in TNFRSF11A , the gene that encodes receptor activator of nuclear factor κB (RANK), constitutively activate RANK and lead to high turnover skeletal disease. Each duplication elongates the signal peptide of RANK. The 18-base pair (bp) duplication at position 84 (84dup18) causes familial expansile osteolysis (FEO), the 15-bp duplication at position 84 (84dup15) causes expansile skeletal hyperphosphatasia (ESH), the 12-bp duplication at position 90 (90dup12) causes panostotic expansile bone disease (PEBD), and the 27-bp duplication causes early-onset Paget's disease of bone (PDB2). The severity of the associated skeletal disease seems inversely related to the duplication's length. Additional 15- and 18-bp duplications of TNFRSF11A fit this pattern. Herein, we delineate the skeletal disease of a middle-aged man of Mexican descent who we found to harbor a novel 27-bp tandem duplication at position 77 (77dup27) of TNFRSF11A. His disorder shares features, particularly hand involvement, with the single Japanese (75dup27) and Chinese (78dup27) kindreds with PDB2 (PDB2 Jpn and PDB2 Chn , respectively). However, his distinct hearing loss developed later in adulthood compared to the other 27-bp families. He reported no morbidities during childhood, but in his late 20s developed unexplained tooth loss, low-trauma fractures, post-operative hypercalcemia, and painless enlargement of his fingers. Biochemical studies showed elevated serum alkaline phosphatase (ALP), bone-specific ALP, C-telopeptide, and osteocalcin consistent with rapid bone remodeling. Radiologic imaging revealed remarkably lucent bones with vertebral compression fractures, calvarial lucencies, and thinned long bone cortices. DXA showed extremely low bone mineral density. His disorder genetically and phenotypically fits best with PDB2 and can be called PDB2 Mex. Unlabelled Image • 77dup27 is a novel tandem duplication in TNFRSF11A , the gene that encodes RANK. • The associated phenotype resembles early-onset Paget's disease of bone (PDB2). • PDB2 Mex has later onset of hearing loss than PDB2 Jpn and PDB2 Chn (OMIM # 602080). [ABSTRACT FROM AUTHOR]

Some tumors are known to produce alkaline phosphatase (ALP). Seven cases of uterine leiomyosarcoma were identified from the clinical records of Sakai City Medical Center from January 2006 to December 2014. Patients' ages ranged from 47 to 75 years (median: 58). Clinical stages were IB, IIB, IIIA, and IVB in four, one, one, and one cases, respectively. Of these, two were found to have hyperphosphatasemia before surgery, and the elevated ALP level decreased after surgery, and increased with disease recurrence. In the cases of hyperphosphatasemia, leiomyosarcoma cells showed positive staining for ALP. There was no correlation between serum ALP and lactate dehydrogenase, or ALP and cancer antigen 125. The combination of ALP, lactate dehydrogenase, and cancer antigen 125 may be more useful for diagnosis and follow-up of leiomyosarcoma. [ABSTRACT FROM AUTHOR]