Approximately 80% of all cases of primary hyperoxaluria (PH) is PH type 1, which is also the most severe type [1] [2] [3]. The clinical presentation, although being diverse depending on the extent of the genetic defect, is more frequently described in children with an early onset of life-threatening symptoms [1] [2]. Hematuria, pain and recurrent urinary tract infections are typical signs in this patient population and the term "infantile oxalosis" represents a triad of acidosis, anemia, and failure to thrive that develops from the deposition of oxalate crystals in various tissues [1] [2] [4] [5]. Nephrolithiasis, urolithiasis, and nephrocalcinosis are three cardinal features of PH and are one of the most important findings in these patients [1] [3] [6] [7]. In addition, oxalate eventually deposits in the heart, the joints, the retina, and the central nervous system, causing complications in the form of cardiomyopathy, disturbances in the cardiac conduction system, retinopathy, severe myalgia, bone pain, and even death in the absence of early therapy [5] [7]. On the other hand, a missed diagnosis in early childhood or a milder clinical presentation that is misinterpreted as another clinical entity is observed in a small proportion of cases and patients frequently present with kidney failure as the first symptom [1] [7]. PH type 2 is a somewhat milder variant with lower incidence rates of ESRD, whereas virtually no cases of PH type 3 suffering from terminal renal failure have been reported to date [1] [3] [7].

• Splenomegaly

  Increased bone density Bone fractures; bone pain Anemia that is resistant to treatment Damage to cranial nerve and optic nerve Damage to the retina Inflammation of heart membrane (myocarditis) Irregular heartbeat Stroke (cardioembolic) Enlarged spleen (splenomegaly [dovemed.com]

• Pain

  Symptoms of kidney or urinary tract stones include: Blood in the urine Pain when you pee Need to pee often Belly pain Many urinary tract infections Blocked urinary tract Sudden, serious back pain Chills Fever Babies and young children with PH1 may also [webmd.com]

  Kidney stones are often the first sign of hyperoxaluria, with symptoms including sudden back pain, persistent flank or abdominal pain, a frequent urge to urinate and blood or pain when urinating. [medthority.com]

  CASE 3: A 2.5-year-old girl had attacks of dark urine without any pain; renal stones were imaged on sonography. She was diagnosed with PH1 and operated on several times due to obstruction. [ncbi.nlm.nih.gov]

  Other symptoms of primary hyperoxaluria may include: severe or sudden back pain chills fever painful urination (dysuria) chronic pain below the ribs on the back hematuria (blood in urine) high levels of calcium in the kidneys (except with primary hyperoxaluria [healthline.com]

• Anemia

  This can include bone disease, anemia, skin ulcers, heart and eye problems, and, in children, a failure to develop and grow normally. [ohf.org]

  Erythropoietin-resistant anemia and hypothyroidism were thought to be due to accumulation of oxalate in the bone marrow and thyroid gland, respectively. [ncbi.nlm.nih.gov]

  Symptoms of kidney failure can include decreased or no urine output; feeling ill or tired; loss of appetite; nausea and vomiting; and pale skin due to anemia. [checkorphan.org]

  The term "infantile oxalosis" is used to describe the triad of anemia, failure to thrive, and acidosis in infants with this condition. [symptoma.com]

  Biological check-up showed only a normochromic and normocytic regenerative anemia resistant to treatment and a bone marrow biopsy was performed. [bmcclinpathol.biomedcentral.com]

• Gangrene

  Arteriole occlusive disease may lead to gangrene, Raynaud phenomena, acrocyanosis and intermittent claudication. Renal failure is common. [disorders.eyes.arizona.edu]

  The ongoing systemic oxalosis also may lead to other clinical manifestations such as cardiac conduction defects, vascular calcification with distal gangrene, disturbed vision, specific brown colored retinal deposits, skin nodules, joint involvement and [orpha.net]

  skin (livedo reticularis, calcinosis cutis metastatica, gangrene), bone (pain, joint immobility, anemia, fractures) and central nervous system (Curr Rheumatol Rep 2013;15:340, N Eng J Med 2013;369) Essential features Birefringent oxalate crystals are [pathologyoutlines.com]

  Peripheral neuropathy, a painful nerve condition Irregular heartbeat Heart block, in which your heart beats too slowly Inflammation of your heart tissue Stroke Narrowed blood vessels Joint pain Swollen liver or spleen Purple spots on the skin Skin rashes Gangrene [webmd.com]

• Recurrent Urinary Tract Infection

  Deposits in the urinary tract can lead to difficulty with urination, blood in the urine, and recurrent urinary tract infections. [myriadwomenshealth.com]

  Two patients were compound heterozygous for the c.731 T > C, c.32C > T, c.1020A > G and c.33_34insC and presented clinically with recurrent urinary tract infection, multiple urolithiasis and nephrocalcinosis under the age of 1 year and a persistent hyperoxaluria [ncbi.nlm.nih.gov]

  [Full text - PDF] ABSTRACT A young patient of African origin is presented, with previous history of urinary calcull observed at the age of 10 years and recurrent urinary tract infections and severe acute pyelonephritis; seven years later he arrived at [new.medigraphic.com]

• Enuresis

  […] urination 0100518 Failure to thrive Faltering weight Weight faltering [ more ] 0001508 Hematuria Blood in urine 0000790 5%-29% of people have these symptoms Abnormality of the skeletal system Skeletal abnormalities Skeletal anomalies [ more ] 0000924 Enuresis [rarediseases.info.nih.gov]

• Failure to Thrive

  Family history of kidney or bladder stones A single pediatric kidney stone Recurring kidney stones in adults Chronic kidney disease (CKD) with unknown etiology Nephrocalcinosis Systemic oxalosis Failure to thrive, ESRD, severe retinal abnormalities or [uncoveringph.com]

  […] to Thrive 11 Nephrocalcinosis 40 Urolithiasis 78 Hematuria 44 Abdominal Pain 60 Asymptomatic 10 Of the 454 patients in the registry as of July 2015: 11% of the patients had failure to thrive (low height and weight) at diagnosis 40% of the patients had [rarediseasesnetwork.org]

  Failure to thrive can be a presenting sign in infants. Most patients have glycolic aciduria and hyperoxaluria as the result of failure to transaminate glyoxylate to form glycine. [disorders.eyes.arizona.edu]

  The term "infantile oxalosis" is used to describe the triad of anemia, failure to thrive, and acidosis in infants with this condition. [symptoma.com]

  The severe infantile form is characterized by a failure to thrive, nephrocalcinosis with or without nephrolithiasis and early end-stage renal failure. [orpha.net]

• Nausea

  Symptoms of kidney failure may include: Decrease in urine amount or not being able to urinate at all Feeling generally ill or tired, or having heavy fatigue Loss of appetite, nausea, and vomiting Pale skin color related to anemia Oxalosis in its late [ohf.org]

  If these symptoms are left untreated, more severe complications can arise which include feeling ill and tired, loss of appetite, nausea, vomiting, swelling of hands and feet and decreased or no urine output. [rapidaccesstomedicalspecialists.ca]

  Symptoms of oxalosis include: Blood in Urine Kidney Stones Nausea Vomiting Abdominal Pain Tetany Protein in Urine Urinary Tract Obstruction Kidney Fibrosis Haematuria In advanced stages, the accumulation of oxalate crystals in the bones and joints will [stlouischildrens.org]

  Its symptoms include: Making little or no urine Fatigue Feeling ill overall No appetite Nausea Vomiting Pale skin Swollen hands or feet Oxalate can also build up in other parts of your body, like your: Bones Eyes Heart Skin Blood vessels Central nervous [webmd.com]

• Abdominal Pain

  Pain 60 Asymptomatic 10 Of the 454 patients in the registry as of July 2015: 11% of the patients had failure to thrive (low height and weight) at diagnosis 40% of the patients had a history of nephrocalcinosis (when the kidneys are extensively filled [rarediseasesnetwork.org]

  We present a 39-year-old patient with end-stage renal failure due to PH1, who was admitted with symptoms of feeling bloated, vomiting, diarrhea, and abdominal pain related to encapsulating peritoneal sclerosis (EPS). [ncbi.nlm.nih.gov]

  A 3-year-old boy presented to the pediatric urology clinic with a 6-month history of gross hematuria and intermittent abdominal pain. Urinalysis revealed red cells, white cells, and 3+ protein. [nejm.org]

  Kidney stones are often the first sign of hyperoxaluria, with symptoms including sudden back pain, persistent flank or abdominal pain, a frequent urge to urinate and blood or pain when urinating. [medthority.com]

  The most common side effects are injection site reactions and abdominal pain. [ema.europa.eu]

• Loss of Appetite

  In cases that have progressed to renal failure, symptoms include low urine output, fatigue, loss of appetite and anaemia. [medthority.com]

  Symptoms of kidney failure may include: Decrease in urine amount or not being able to urinate at all Feeling generally ill or tired, or having heavy fatigue Loss of appetite, nausea, and vomiting Pale skin color related to anemia Oxalosis in its late [ohf.org]

  If these symptoms are left untreated, more severe complications can arise which include feeling ill and tired, loss of appetite, nausea, vomiting, swelling of hands and feet and decreased or no urine output. [rapidaccesstomedicalspecialists.ca]

  The symptoms of hyperoxaluria include: Abdominal pain Loss of appetite Frequent urge to urinate Blood in the urine Severe back pain Fever or chills Flank pain (pain below the ribs) Pale coloured skin Risk factors of Hyperoxaluria: The following are the [medlife.com]

  Symptoms of kidney failure can include decreased or no urine output; feeling ill or tired; loss of appetite; nausea and vomiting; and pale skin due to anemia. [checkorphan.org]

• Diarrhea

  A 5-month-old female infant who had chronic diarrhea and acute renal failure was referred to Chulalongkorn Hospital for further investigation and management. [ncbi.nlm.nih.gov]

  Demodicosis 355 Dermatophilosis 362 Dermatoses Exfoliative 369 Dermatoses Sterile NodularGranulomatous 375 Destructive and Scratching BehaviorCats 381 Destructive BehaviorDogs 382 Diabetes Mellitus without ComplicationCats 388 Diaphragmatic Hernia 394 Diarrhea [books.google.es]

  In children who suffer from infections or other disorders that induce diarrhea and vomiting that cause fluid loss, intravenous administration must be considered. [symptoma.com]

  We also informed her about the necessity of intravenous fluid treatment in case of fever, vomiting, or diarrhea. Her 18-year follow-up data are shown in Table 1. [thepermanentejournal.org]

• Hepatosplenomegaly

  He had painless hepatosplenomegaly. Both knees were swollen and the right shoulder was visibly swollen. [revistanefrologia.com]

  GAUCHER's DISEASE Type 1 Gaucher's disease, the most common lysosomal storage disorder, typically presents with hepatosplenomegaly, pancytopenia, and destructive bone disease. [aafp.org]

  […] block, irregular heartbeats (arrhythmias), inflammation of the myocardium (myocarditis), and cardioembolic stroke; narrowing of a blood vessel due to spasms of the vessel (vasospasm); joint disease (arthropathy); enlargement of the liver and/or spleen (hepatosplenomegaly [rarediseases.org]

• Hepatomegaly

  He presented with fatigue, anorexia, weight loss, and was found to have cachexia, diffuse edema, hepatomegaly, ascites, hypercalcemia, hyperphosphatemia, hypoalbuminemia, low parathyroid hormone levels, lytic and resorptive areas in the vertebrae, diffusely [ncbi.nlm.nih.gov]

  bone pain Anemia that is resistant to treatment Damage to cranial nerve and optic nerve Damage to the retina Inflammation of heart membrane (myocarditis) Irregular heartbeat Stroke (cardioembolic) Enlarged spleen (splenomegaly) and enlarged liver (hepatomegaly [dovemed.com]

  GSD is classified according to the type of genetically defective enzymes and induces hepatomegaly, hypoglycemia and/or muscular symptoms. [ojrd.biomedcentral.com]

• Hypertension

  […] and Hypertension, Department of Biochemistry and Molecular Biology, and [email protected] [ncbi.nlm.nih.gov]

  Food & Drug Administration (FDA) for the treatment of pulmonary arterial hypertension (PAH). [bio-medicine.org]

  Department of Nephrology and Hypertension, Mayo Clinic, Rochester, MN. Abstract OBJECTIVE: To present our experience with surgical management of nephrolithiasis in patients with primary hyperoxaluria (PH). [storzmedical.com]

  […] on admission Serum creatinine (mg/dl) 8.42 24 h Urine oxalate level (mg) 80 Characteristics Sex Male Age (year) 51 BMI (kg/m 2 ) 42 Renal function Normal Diabetes mellitus Yes Hypertension No Hyperlipidemia No Chronic obstructive pulmonary disease No [academic.oup.com]

  High level of circulating oxalate in end-stage renal failure leads to the deposition of oxalate in tissues causing cardiac conduction defects, hypertension, distal gangrene, and reduced joint mobility and pain. [cags.org.ae]

• Heart Block

  One developed complete heart block, a novel finding, as a result of severe cardiac oxalosis. [medcraveonline.com]

  This can lead to bone pain; vision loss; tingling, numbness, or pain in the extremities; enlargement of the liver and spleen; and problems with the electrical system of the heart (heart block). [counsyl.com]

  Insoluble calcium deposits in other body tissues can lead to bone pain; vision loss; tingling, numbness, or pain in the extremities; enlargement of the liver and spleen; and problems with the electrical system of the heart (heart block). [myriadwomenshealth.com]

  block Retinopathy and visual impairment Failure to thrive, ESRD, severe retinal abnormalities or vision loss in infants Infantile onset occurs in 18% of patients with PH1. [uncoveringph.com]

• Heart Failure

  We report a 38-year-old male with cardiac oxalosis, a severe complication of PHI, presenting with an infiltrative cardiomyopathy, secondary heart failure and severe mitral regurgitation, necessitating surgical repair to allow combined liver-kidney transplantation [ncbi.nlm.nih.gov]

  Oxalosis involving the myocardium or conduction system can potentially lead to heart failure and fatal arrhythmias. [mayoclinic.pure.elsevier.com]

  Consequently, the build-up of oxalate can lead to the deposition of oxalate crystals in the eyes, bones, skin, heart, and central nervous system, causing diminished vision, bone fractures, ulcers, heart failure, and other complications. [raredisorders.imedpub.com]

  A 41-year-old man with right-sided dominant heart failure, dialysis-dependent renal insufficiency, and severe neuropathy of unknown cause was sent to our institution for cardiac examination. [circ.ahajournals.org]

• Visual Impairment

  impairment Failure to thrive, ESRD, severe retinal abnormalities or vision loss in infants Infantile onset occurs in 18% of patients with PH1. [uncoveringph.com]

• Skin Ulcer

  This can include bone disease, anemia, skin ulcers, heart and eye problems, and, in children, a failure to develop and grow normally. [ohf.org]

  The excess build-up of these crystals can lead to multiple complications elsewhere in the body, including skin ulcers, anemia, heart and eye problems, and in children it may lead to a failure in natural growth. [rapidaccesstomedicalspecialists.ca]

  It may also cause anemia and skin ulcers. [stlouischildrens.org]

  Systemic oxalosis involves a build-up of oxalate in other regions of the body causing a variety of complications including: Bone disease leading to fractures Anemia (lack of red blood cells causing tiredness, weakness and other symptoms) Skin ulcers or [dicerna.com]

• Calcinosis Cutis

  cutis metastatica, gangrene), bone (pain, joint immobility, anemia, fractures) and central nervous system (Curr Rheumatol Rep 2013;15:340, N Eng J Med 2013;369) Essential features Birefringent oxalate crystals are noted in vessel walls and connective [pathologyoutlines.com]

  Retinal epithelium and the macula  diminished visual acuity Hypothyroidism, peripheral neuropathy, dental problems Skin manifestations Livedo reticularis, peripheral gangrene, and calcinosis cutis metastatica 6. [slideshare.net]

  cutis 0025520 Calcium oxalate nephrolithiasis 0008672 Choroidal neovascularization 0011506 Cutis marmorata 0000965 Gangrene Death of body tissue due to lack of blood flow or infection 0100758 Increased bone mineral density Increased bone density 0011001 [rarediseases.info.nih.gov]

• Fracture

  In the current case, we present a 3-year-old boy with a pathological fracture of his right femur, 2 years after liver-kidney transplantation. We opted for a conservative regime, leading to good fracture healing. [ncbi.nlm.nih.gov]

  Among the possible consequences there are optic atrophy, arrhythmias, neuropathy, fractures. Diagnosis usually occurs by means of urinalysis, which show high levels of calcium oxalate. [testprenataleaurora.it]

  Oxalosis in bones can cause fractures. There are three types of primary hyperoxaluria that differ in their severity and genetic cause. [rarediseases.oscar.ncsu.edu]

  […] oxalosis also may lead to other clinical manifestations such as cardiac conduction defects, vascular calcification with distal gangrene, disturbed vision, specific brown colored retinal deposits, skin nodules, joint involvement and bone disease leading to fractures [orpha.net]

• Bone Pain

  This can lead to bone pain; vision loss; tingling, numbness, or pain in the extremities; enlargement of the liver and spleen; and problems with the electrical system of the heart (heart block). [counsyl.com]

  Insoluble calcium deposits in other body tissues can lead to bone pain; vision loss; tingling, numbness, or pain in the extremities; enlargement of the liver and spleen; and problems with the electrical system of the heart (heart block). [myriadwomenshealth.com]

  Severe bone pain Skin nodules and ulcers Cardiomyopathy Cardiac conduction disturbances and heart block Retinopathy and visual impairment Failure to thrive, ESRD, severe retinal abnormalities or vision loss in infants Infantile onset occurs in 18% of [uncoveringph.com]

  Oxalosis may cause serious symptoms like: Bone pain Broken bones Abnormally hard, dense bones Dental problems like tooth pain or loose teeth, and exposure of the tooth roots and pulp Anemia that’s hard to treat Damage to a nerve that affects eyesight, [webmd.com]

• Arthralgia

  Associated symptoms included arthralgias and episodic acral cyanosis. [jaad.org]

  When oxalate deposits in the synovium of joints, excessive inflammation can procure, often resembling arthralgias (joint pain). [physio-pedia.com]

• Myalgia

  In addition, oxalate eventually deposits in the heart, the joints, the retina, and the central nervous system, causing complications in the form of cardiomyopathy, disturbances in the cardiac conduction system, retinopathy, severe myalgia, bone pain, [symptoma.com]

• Kidney Failure

  This oxalate leads to a buildup of insoluble calcium salts in the kidneys and other organs. If untreated, it results in life-threatening kidney failure. People with PH1 are prone to recurrent kidney stones that can lead to kidney failure. [counsyl.com]

  While individuals with PH2 are less likely to develop kidney failure than those with PH1, organ transplantation remains an option if kidney failure does occur. [mysupport360.com]

  But as many as half of adults with PH1 get kidney disease or kidney failure. Complications of PH1 People with primary PH1 can have serious complications if they don't get treated. As their disease gets worse, they can get kidney failure. [webmd.com]

• Hematuria

  The most common presenting symptom was hematuria, while 14% of patients were asymptomatic and detected by family screening after the diagnosis of an index case. [ncbi.nlm.nih.gov]

  […] the 1990's 164 patients (36%) have been diagnosed since the year 2000 179 patients (39%) have been diagnosed since the year 2010 SYMPTOMS AND FINDINGS Symptoms and Findings Percent at Diagnosis Failure to Thrive 11 Nephrocalcinosis 40 Urolithiasis 78 Hematuria [rarediseasesnetwork.org]

  Initially, all patients presented with UL, which was accompanied by microscopic hematuria (83%) or / and sterile leukocyturia (67%). [mp.pl]

  A 3-year-old boy presented to the pediatric urology clinic with a 6-month history of gross hematuria and intermittent abdominal pain. Urinalysis revealed red cells, white cells, and 3+ protein. [nejm.org]

• Dysuria

  Other manifestations include urinary tract infections, dysuria and hematuria. [orpha.net]

  She presented for follow-up 1 month later with persistent flank pain, dysuria, subjective fever and chills, and decreased urine output. [karger.com]

• Flank Pain

  She presented for follow-up 1 month later with persistent flank pain, dysuria, subjective fever and chills, and decreased urine output. [karger.com]

  Within 5 years he experienced flank pain, hematuria attacks, and anuric phases due to obstruction and received hemodialysis (HD) when ESRD appeared. CLKT was performed from his full-match sister at the age of 9.5. He is doing well at 5.5 years. [ncbi.nlm.nih.gov]

  Adults with recurrent kidney stones also should be evaluated for oxalate in the urine.Symptoms of a kidney stone can include the following:Severe or sudden abdominal or flank pain,Blood in the urine,Frequent urge to urinate,Pain when urinating,Fever and [omicsonline.org]

  When a person with PH1 has a kidney stone, symptoms can include: • Flank pain • Urinary tract infections • Painful urination • Blood in the urine People with PH1 often experience the formation of oxalate stones throughout the urinary tract and kidneys [ohf.org]

• Anuria

  要約・抄録 A 3-month-old female infant was admitted to our hospital because of convulsions and anuria. [iss.ndl.go.jp]

  In our case serum oxalate was very high and the urinary sediment could not be performed given the anuria. [bmcclinpathol.biomedcentral.com]

  He suffered from shortness of breath and anuria. While his growth was appropriate for his age, he was found to be pale, irritable, hypertensive and edematous. [cags.org.ae]

  The patient has history of recurrent renal stones since early childhood when he presented to 1 hospital at the age of 2 years old with hypertension, severe metabolic acidosis, hyperkalemia, anuria, high serum creatinine (s.Cr) and high urinary calcium [journals.lww.com]

  For patients in whom urinary oxalate could not be measured because of anuria, highly elevated plasma oxalate levels of more than 20 times the upper limit of the reference range were considered to be caused by PH1 and not by renal insufficiency itself [academic.oup.com]

• Stroke

  stroke in patients with primary oxalosis. [ncbi.nlm.nih.gov]

  Di Pasquale G, Ribani M, Andreoli A et al (1989) Cardioembolic stroke in primary oxalosis with cardiac involvement. Stroke 20:1403–1406 Article PubMed Google Scholar 19. [link.springer.com]

  […] a nerve that affects eyesight, called optic atrophy Retinopathy, a disease of your eye’s retina Peripheral neuropathy, a painful nerve condition Irregular heartbeat Heart block, in which your heart beats too slowly Inflammation of your heart tissue Stroke [webmd.com]

  The following are some of the complications of Primary Hyperoxaluria: Chronic kidney disease End-stage kidney disease Cardiac arrhythmia and stroke Peripheral gangrene Note: The end-stage kidney disease can occur early in type 1 disease, and later in [dovemed.com]

  In the same year he had a thalamic stroke and right perimesencephalic haemorrhage. [revistanefrologia.com]

• Peripheral Neuropathy

  neuropathy, a painful nerve condition Irregular heartbeat Heart block, in which your heart beats too slowly Inflammation of your heart tissue Stroke Narrowed blood vessels Joint pain Swollen liver or spleen Purple spots on the skin Skin rashes Gangrene [webmd.com]

  Case of the Month First published: 31 October 2014 Citations: 6 Disclosure:: P.J.D. receives financial support directed to research activity in the Peripheral Neuropathy Laboratory at the Mayo Clinic, Rochester, MN, from Pfizer, Inc.; Pfizer Japan, Inc [onlinelibrary.wiley.com]

  There is also a progressive peripheral neuropathy. The normal clinical course is of recurrent stones leading inevitably to renal failure. [patient.info]

  Retinal epithelium and the macula  diminished visual acuity Hypothyroidism, peripheral neuropathy, dental problems Skin manifestations Livedo reticularis, peripheral gangrene, and calcinosis cutis metastatica 6. [slideshare.net]

  Damaged optic nerve 0001138 Pathologic fracture Spontaneous fracture 0002756 Peripheral arterial stenosis 0004950 Peripheral neuropathy 0009830 Raynaud phenomenon 0030880 Renal insufficiency Renal failure Renal failure in adulthood [ more ] 0000083 Retinal [rarediseases.info.nih.gov]

• Lethargy

  Clinical manifestations of galactosemia include lethargy, hypotonia, jaundice, hypoglycemia, elevated liver enzymes, and coagulopathy. [aafp.org]

Up to 30% of patients with PH are diagnosed when ESRD has already ensued, meaning that clinical suspicion must be raised early on [1]. The workup of patients in whom primary hyperoxaluria is suspected starts with a detailed patient history that covers the onset of symptoms, as well as their course and progression. It is imperative to obtain all relevant information about the duration of symptoms, as a misdiagnosis is made in up to 30% of cases [8]. Having in mind the autosomal recessive pattern of inheritance seen across all types of PH [8], the importance of a complete family history should not be underestimated. After a thorough physical examination, imaging and laboratory studies are the next steps. Abdominal ultrasonography is an essential procedure in the evaluation of patients with PH, showing stones both in the kidneys and the ureters, along with nephrocalcinosis [1] [3]. The presence of calcium oxalate stones and salts in urine after a proper urinalysis are one of the first clues toward this rare entity [1] [3]. In order solidify suspicion, however, urinary excretion of oxalate is recommended. Excretion of > 1.0 mmol/1.73 m2 per 24h (< 0.45 is considered to be normal) is considered to be diagnostic for hyperoxaluria [1] [2]. Oxalate levels are usually much higher in PH1 compared to PH2 [9], whereas urinary glycerate levels are markedly elevated in PH2 patients [1] [2]. To discriminate between primary and secondary hyperoxaluria, evaluation of specific enzymatic activity or genetic testing for AGXT, GRHRP, and HOGA1 genes are regarded as definite steps to confirm primary hyperoxaluria [1].

• Nephrolithiasis

  The diagnosis of PH1 must be considered in the differential diagnosis of patients presenting with ESRD with a history of recurrent nephrolithiasis. [ncbi.nlm.nih.gov]

  In our patient, earlier diagnosis and treatment – particularly before the development of severe and extensive nephrolithiasis – may have prevented the development of severe nephrolithiasis, her accelerated loss of kidney function, and the need for native [karger.com]

• Enlargement of the Liver

  This can lead to bone pain; vision loss; tingling, numbness, or pain in the extremities; enlargement of the liver and spleen; and problems with the electrical system of the heart (heart block). [counsyl.com]

  Insoluble calcium deposits in other body tissues can lead to bone pain; vision loss; tingling, numbness, or pain in the extremities; enlargement of the liver and spleen; and problems with the electrical system of the heart (heart block). [myriadwomenshealth.com]

  Dialysis or kidney and liver transplants If primary hyperoxaluria develops into advanced kidney disease or end stage renal disease, you may need more aggressive treatment, which may include: dialysis kidney transplant liver transplant combined liver-kidney [healthline.com]

• Glomerular Filtration Rate Decreased

  Although serum oxalate levels have not been measured, they would certainly be high, since oxalate content increases as glomerular filtration rate decreases. [jped.com.br]

  As glomerular filtration rate decreases due to progressive renal damage, oxalate accumulates leading to systemic oxalosis. [hindawi.com]

The optimal treatment strategy depends on the state of the kidneys at the time of diagnosis. If patients are recognized in the early stages of the disorder, some of the most efficient methods to reduce the deleterious effects of hyperoxaluria are increased fluid intake to 3-4 liters every day [1] [7]. If necessary, a gastrostomy or feeding tube may be indicated in order to achieve the desired fluid intake [1] [12]. In children who suffer from infections or other disorders that induce diarrhea and vomiting that cause fluid loss, intravenous administration must be considered [12]. Supplementation with pyridoxine (B6) in very high doses has shown improvement in patients with PH1, as the deficient enzyme is B6- dependent for its activity [1]. Another non-invasive method that can be useful in early stages of PH is alkalinization of urine through administration of potassium citrate, which binds to calcium and thus limits the capacity for oxalate binding with calcium [1]. In the presence of stones, endoscopy and extracorporeal shock wave lithotripsy (ESWL) is the optimal procedure [1]. For severe cases with advanced stages of renal failure and ESRD, hemodialysis (favored over peritoneal dialysis) is indicated [1] [11]. As a last resort, transplatation of either the liver, the kidney, or both, and GFR levels of 15-30 mL/min/1.73 m2 are the threshold for this procedure [1].

The prognosis of primary hyperoxalurias depends on the type (type 1 is by far the most severe form), but more importantly, on a timely diagnosis and initiation of proper therapy [1]. Renal failure and ESRD are known complications of this condition and ESRD develops in virtually all patients by the time they reach the period between the third and fifth decade of life, indicating a substantial reduction in life expectancy [1]. For this reason, early recognition is imperative.

Unlike "secondary" hyperoxaluria, in which excessive dietary intake of oxalate or disorders that promote oxalate absorption from the gastrointestinal tract produce an abnormal amount of oxalate in urine, the term "primary hyperoxaluria" denotes the occurrence of elevated oxalate in urine due to inborn errors and genetic mutations [2]. Three distinct types of primary hyperoxaluria have been described in the literature, each developing from different genetic defects through autosomal recessive patterns of inheritance [1] [6] [7] [8] [10] [11]:

• Primary hyperoxaluria type 1 (PH1) - Mutations of the alanine glyoxalate aminotransferase (AGXT) gene located on chromosome 2 leads to insufficient activity of alanine glyoxalate aminotransferase (AGT), a hepatic vitamin B6-dependent enzyme [1] [5] [10] [11].
• Primary hyperoxaluria type 2 (PH2) - Mutations of the Glyoxalate/hydroxypuruvate reductase gene (GRHPR) located on chromosome 10 produces a defect in the ability of the respective enzyme to perform its function [1] [10].
• Primary hyperoxaluria type 3 (PH3) - The exact cause remains to be solidified, but mutations of the HOGA1 gene on chromosome 9 and DHDPSL gene mutations on chromosome 10 are assumed to be the key event for PH3 [3] [8] [12] [13]. A mitochondrial enzyme 4-hydroxy 2-oxoglutarate aldolase, another important constituent of oxalate metabolism, is allegedly affected in PH3 [3] [8] [13] [14].

Primary hyperoxalurias are rare entities in clinical practice, with established prevalence rates of approximately 1-3 cases per 1 million individuals [1]. In Europe, rough incidence rates are around 1 in 100,000 newborns [3]. Some studies have established a higher rate of the disorder in countries where consanguineous marriages are more frequent [1] [3]. Notable examples are Kuwait and Tunisia, where prevalence rates of up to 13% are reported [3]. In Europe and certain parts of Asia (Japan), PH represents around 1% of all end-stage renal diseases in the pediatric population, indicating that this disorder should be included in the differential diagnosis of undisclosed kidney stones in childhood, but also adulthood [1] [3] [5].

Oxalate is derived from oxalic acid, which is abundantly present in many foods of both animal and plant origin [1]. As mammals cannot fully metabolize oxalate, it is largely eliminated by the kidneys through the activity of various enzymes that play a key role in its degradation and excretion [2]. The end-result in all primary hyperoxalurias is the same - as oxalate reaches the urine, its increased amounts in the renal tubular system and the glomeruli promotes calcium oxalate salt deposition and creation of kidney stones, while simultaneously accumulating in the interstitium, causing nephrocalcinosis [1] [2] [3]. In PH1, the deficiency of alanine glyoxylate aminotransferase impairs the conversion of L-alanine and glyoxalate to pyruvate and glycine, whereas GRHRP is unable to reduce glyoxylate to glycolate in PH2 [1] [2] [3]. In both forms, failure of these processes eventually leads to the formation of oxalate through the activity of lactate dehydrogenase (LDH) [1] [2]. PH3 still has an undisclosed pathogenic model.

Little can be done to prevent mutations that occur and cause deficient enzymatic activity, but screening procedures for children with renal stones and adults with recurrent oxalate stones are an efficient way to make an early diagnosis. Furthermore, family histories of such patients and genetic testing of close relatives of confirmed patients are powerful tools for recognizing primary hyperoxalurias in clinical practice [1].

Primary hyperoxaluria (PH) is defined as a condition in which inborn genetic defects are the cause of improper metabolism of glyoxylate and oxalate, two compounds arising from oxalic acid that is found in many animal and food sources [1] [3]. So far, three distinct phenotypes have been described in the literature: type 1 (PH1), known as the most common and most severe form, stems from autosomal recessive mutations in the vitamin B6-dependent alanine glyoxylate amino transferase (AGT) located in the liver; type 2 (PH2) occurs as a result of reduced glyoxylate/hydroxypyruvate reductase (GRHPR) activity; and type 3 (PH3), although being incompletely understood, is assumed to arise from deficiencies in the mitochondrial enzyme 4-hydroxy 2-oxoglutarate aldolase [1] [3] [10] [11] [8] [7]. In all three types of primary hyperoxaluria, respective enzyme defects lead to increased concentrations of oxalate in the renal tubular system and promote the formation of calcium oxalate stones (nephrolithiasis) and nephrocalcinosis, most prominently in PH1 [1] [2] [3]. Failure to thrive is a major sign and together with anemia and acidosis, the term "infantile oxalosis" is often used to describe the clinical presentation of these patients, particularly in PH1, whereas progressive decline in renal function, the development of renal failure and eventually end-stage renal disease (ESRD) that may significantly reduce life expectancy is the usual course [1] [2] [9]. The initial diagnosis can be made after a thorough biochemical workup that reveals calcium oxalate crystals in serum, increased levels of oxalate in urine (> 40-45 mg per 24 h) and evaluation of glomerular filtration rate (GFR) that determines the stage of renal insufficiency [1] [3] [7]. Imaging studies are useful as well, but in order to confirm the underlying cause, more advanced studies need to be employed, such as genetic and enzymatic activity testing [1] [2] [3]. Treatment principles vary depending on the extent of kidney damage, ranging from higher intake of fluids and alkalinization of urine, to dialysis and transplantation of both the kidneys and the liver [1] [2]. Screening of families in whom known cases are reported is crucial in order to provide proper genetic counselling [1] [7].

Hyperoxaluria is a medical term for increased levels of oxalate in urine. Oxalate is formed from oxalic acid, a constituent of many food and animal products that we ingest on a daily basis. Because we are unable to fully process and metabolize oxalate and its similar molecular forms (mainly glyoxylate), it is rapidly excreted in urine after being absorbed from the gastrointestinal tract. Under various circumstances, levels of oxalate in urine and consequently in the kidneys can increase, which poses a risk for the formation of stones in the kidneys (nephrolithiasis) and the ureters (urolithiasis), as oxalate binds with calcium and forms the most common type of stones - calcium oxalate stone. Primary hyperoxaluria is a term representing three specific disorders that develop due to inborn errors of metabolism. This means that genetic mutations in the enzymes responsible for the degradation and elimination of oxalate from the body are not fully capable to perform their function. Symptoms usually develop in early childhood, with blood in urine (hematuria) accompanied by pain, as well as urinary tract infections being the first signs of primary hyperoxaluria. The term "infantile oxalosis" is used to describe the triad of anemia, failure to thrive, and acidosis in infants with this condition. In a smaller number of cases, symptoms might be missed or misdiagnosed, with a diagnosis being made in late adulthood. Unfortunately, up to a third of cases are confirmed when severe kidney damage has already occurred, the most feared and most important complication of primary hyperoxalurias. Renal failure can significantly impact the quality of life and life expectancy, which is why physicians must pay close attention when examining children (and adults) with blood in urine and calcium oxalate stones. Urinalysis for oxalate crystals and determination of oxalate in 24h urine is crucial to make an initial diagnosis, together with abdominal ultrasonography that identifies stones in the renal system. To confirm the exact subtype of primary hyperoxaluria, genetic studies that detect specific mutations must be employed. Treatment principles depend on the severity of kidney damage. Higher fluid intake, increasing pH of urine (in order to prevent stone formation) supplementation with pyridoxine (vitamin B6) in patients who suffer from primary hyperoxaluria type 1 (the most common and most severe form), dialysis, and kidney/liver transplantation are viable therapeutic options. Screening of families with known cases is recommended, as all mutations are transferred from a parent to a child without being aware of it.

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