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

  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]

  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]

  pain while passing urine, and progressive kidney malfunction The type 1 Primary Hyperoxaluria onset in late childhood, adolescence, or adulthood may present with kidney stones and kidney failure. [dovemed.com]

• Anemia

  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]

  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]

  Resulting organ system dysfunction including ischemic ulcers of the skin, metabolic bone disease, refractory anemia, cardiomyopathy, and cardiac conduction system abnormalities are the cause of severe morbidity and mortality. [mayo.edu]

  This may lead to kidney dysfunction and failure, which can lead to oxalate starting to accumulate in other organs, blood vessels and bones, causing further symptoms These include anemia, abnormally dense bones, bone fractures, enlarged liver and spleen [dovemed.com]

• Recurrent Urinary Tract Infection

  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]

  The natural history of PH is such that this problem presents early in childhood as calcium oxalate stones and nephrocalcinosis with recurrent urinary tract infection and progresses with increase in time to full blown renal failure and death. [austinpublishinggroup.com]

  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 [symptoma.com]

  [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]

  She had a past medical history of bilateral nephrolithiasis and recurrent urinary tract infections since the age of 4 years. [docplayer.net]

• Failure to Thrive

  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]

  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]

• Abdominal Pain

  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]

  pain, pain while passing urine, and progressive kidney malfunction The type 1 Primary Hyperoxaluria onset in late childhood, adolescence, or adulthood may present with kidney stones and kidney failure. [dovemed.com]

  Urinary tract infection, abdominal pain and hematuria were relatively common. None of the patients included in the study presented with the infantile form of PHI. [cags.org.ae]

  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]

• Nausea

  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]

  Six months later, she came to the Emergency Room presenting nausea, vomiting and asthenia and blood tests revealed scr 17.3mg/dL, blood urea nitrogen (BUN) 157mg/dL and haemoglobin (Hb) 6.6 g/dl. [docplayer.net]

• Periodontitis

  Dental complications include periodontal disease. Hypothyroidism is also reported. [ncbi.nlm.nih.gov]

• 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]

• Hepatosplenomegaly

  angiokeratomas in Fabry's disease), or hepatosplenomegaly (with various storage diseases; Table 2 1 – 3 ). [aafp.org]

  Partial adrenal insufficiency has been reported in type B, a non-neurologic, visceral form with hepatosplenomegaly, pulmonary disease and survival into adolescence and/or adulthood [ 110 ]. [ojrd.biomedcentral.com]

• Heart Block

  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]

  block, left ventricular hypertrophy, systolic and diastolic dysfunction ECG, echocardiography CT: calcifications Thyroid d Hypothyroidism US Thyroid function tests Skin e (Painful) skin nodules, skin necrosis, gangrene, calciphylaxis-like skin lesions [academic.oup.com]

  Additional clinical manifestations of oxalosis may include visual disturbance due to retinopathy and/or maculopathy, cardiac conduction disturbances such as heart block, cardiomyopathy, and synovitis secondary to oxalate deposition in the joints. [ncbi.nlm.nih.gov]

• 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]

• 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]

  He presented bone pain with worsening of his general state. On physical examination, no organomegaly was detected. [bmcclinpathol.biomedcentral.com]

  […] kidneys and systemically (systemic oxalosis), including in the retina (diminished visual acuity), myocardium (conduction defects), blood vessel walls (vascular occlusion and gangrene), skin (livedo reticularis, calcinosis cutis metastatica, gangrene), bone [pathologyoutlines.com]

  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]

  Organ involvement in PH patients with renal failure a Organ Symptoms Diagnosis Kidney b Stones, medullary or diffuse nephrocalcinosis, cortical nephrocalcinosis US CT (cortical nephrocalcinosis may be missed on US) Bone c Fractures, bone pain, growth [academic.oup.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]

• Stroke

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

  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]

  lipoamide dehydrogenase deficiency [rare]) Myoadenylate deaminase deficiency (1:100,000) Familial myocardial infarct/stroke 5,10-methylenetetrahydrofolate reductase deficiency (common) Familial hypercholesterolemia (1:500) Fabry's disease (1:80,000 [aafp.org]

  PubMed Google Scholar Hopkins SE, Somoza A, Gilbert DL: Rare autosomal dominant POLG1 mutation in a family with metabolic strokes, posterior column spinal degeneration, and multi-endocrine disease. [ojrd.biomedcentral.com]

• Peripheral Neuropathy

  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]

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

  A young patient with end-stage renal disease, dyspnoea, weakness, peripheral neuropathy and an unsuspected underlying disease. Nephrol Dial Transplant. 2003; 18 :1670–2. [ PubMed : 12897114 ] Yamanouchi M, Ubara Y, Takayama T, Kuhara T, Takaichi K. [ncbi.nlm.nih.gov]

  holocarboxylase synthetase [rare]) and biotinidase deficiencies (1:60,000) Metachromatic leukodystrophy (1:100,000) HHH syndrome (rare) Peripheral neuropathy Mitochondrial disorders (1:30,000) Peroxisomal disorders (1:50,000; e.g., Zellweger syndrome [aafp.org]

• Kidney Failure

  If untreated, it results in life-threatening kidney failure. People with PH1 are prone to recurrent kidney stones that can lead to kidney failure. Among people with PH1, 50% experience kidney failure by the age of 15, 80% by the age of 30. [counsyl.com]

  About 50 percent of patients will have kidney failure by age 15, and about 80 percent will have end stage renal disease by age 30. [alnylam.microartswpdev.com]

  We report the case of a 57-year-old woman with history of chronic kidney failure presenting with paraplegia due to spinal cord compression by thoracic mass-like lesions. [ncbi.nlm.nih.gov]

• 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]

  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]

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

  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. [symptoma.com]

• Dysuria

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

  Destructive and Scratching BehaviorCats 381 Destructive BehaviorDogs 382 Diabetes Mellitus without ComplicationCats 388 Diaphragmatic Hernia 394 Diarrhea ChronicDogs 400 Digoxin Toxicity 402 Discolored ToothTeeth 406 Drowning Near Drowning 412 Dysphagia 419 Dysuria [books.google.es]

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]

• 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]

• 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]

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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