Presentation
The clinical presentation was characterized by a severe early-onset of hypertension refractory to multiple therapy. [ncbi.nlm.nih.gov]
Early-onset disease presents variably with fetal distress, heart failure, polyhydramnios, hypertension, respiratory distress, hydrops fetalis, edema, visceral effusions, cyanosis, cardiomegaly, and ascites. [orpha.net]
Entire Body System
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Congestive Heart Failure
Affected infants are usually diagnosed before birth or in the neonatal period with symptoms of congestive heart failure. Therapy with bisphosphonate has been used to treat the condition, but with inconsistent results. [ncbi.nlm.nih.gov]
More on Hypophosphatemic rickets » Congestive heart failure : Congestive Heart Failure occurs when the heart cannot pump adequately to send the blood around the body. [familydiagnosis.com]
Three new patients are reported who presented with congestive heart failure. The visualization of faint vascular calcifications in the extra-thoracic soft tissues presented an opportunity to establish the diagnosis radiologically. [doi.org]
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Pain
He was receiving EHDP, 200 mg/day orally, and had odynodysphagia, diffuse opioid-controlled pain, plagiocephaly, facial dysmorphism, joint calcifications, contractures, and was wheelchair bound. [ncbi.nlm.nih.gov]
[…] bone pain, bowed femora, and short stature. [symptoma.com]
Beyond six months, the mortality rate significantly decreases among survivors, who may later develop ARHR2, characterized clinically by short stature, bone deformities and pain. [bone-abstracts.org]
[…] the child uses for pain, e.g., ouch, hurt. • Ask the child to give examples of pain (to identify the child’s understanding and use of words Chest Wall Pain: Costochondritis. [apotechsrl.it]
At first, she began having pain in her hands and was initially diagnosed with arthritis. However, test results were negative. She was sent home with no answers. Over the years, the pain intensified and traveled to her lower extremities. [medicalbag.com]
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Short Stature
As a consequence, GACI patients develop severe rachitic complications such as short stature and skeletal deformities. [ncbi.nlm.nih.gov]
Phenotype Short stature, deafness, conductive (in some patients), angioid retinal streaks (in some patients), coronary and generalized artery calcification, cardiac dysfunction, periarticular calcification, hypophosphatemic rickets, and pseudoxanthoma [iofbonehealth.org]
[jultrasoundmed.org] Short Stature As a consequence, GACI patients develop severe rachitic complications such as short stature and skeletal deformities. [symptoma.com]
Beyond six months, the mortality rate significantly decreases among survivors, who may later develop ARHR2, characterized clinically by short stature, bone deformities and pain. [bone-abstracts.org]
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Feeding Difficulties
Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension, and edema. [orpha.net]
[symptoma.com] Feeding Difficulties Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension, and edema. [symptoma.com]
Newborns with GACI may also present with feeding difficulties, irritability or failure to thrive. In nearly 50% of cases, babies are diagnosed soon after birth due to these symptoms. [gaciglobal.org]
In infants, common manifestations include: irritability, feeding difficulties and poor growth [ 1 ]. Coronary artery calcification was the worst prognostic indicator and majority of infants expired due to myocardial infarction [ 1, 16 ]. [bmcpediatr.biomedcentral.com]
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Plethora
Chest radiography showed cardiomegaly and pulmonary plethora. Electrocardiography showed left ventricular hypertrophy and strain pattern. [doi.org]
[bmcpediatr.biomedcentral.com] Plethora Chest radiography showed cardiomegaly and pulmonary plethora. Electrocardiography showed left ventricular hypertrophy and strain pattern. [symptoma.com]
[…] hematopoiesis of liver [19] Hypertrophy of myocardium Bright and hyper-reflective myocardium [20] Periarticular calcifications in the wrists, ears, shoulders, ankles and hip [21] [22] Heart usually looks structurally normal Cardiomegaly and pulmonary plethora [en.wikipedia.org]
Respiratoric
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Respiratory Distress
Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with sudden onset of fever, vomiting, irritability, or respiratory [ncbi.nlm.nih.gov]
Early-onset disease presents variably with fetal distress, heart failure, polyhydramnios, hypertension, respiratory distress, hydrops fetalis, edema, visceral effusions, cyanosis, cardiomegaly, and ascites. [orpha.net]
Abstract BACKGROUND A baby girl developed respiratory distress immediately after birth and required supplemental oxygen. She was born at term via lower-segment cesarean section. [unboundmedicine.com]
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Dyspnea
[unboundmedicine.com] Dyspnea In GACI probands, initial symptoms included dyspnea (62%) and cyanosis (16%); 73% were ventilated. [symptoma.com]
In GACI probands, initial symptoms included dyspnea (62%) and cyanosis (16%); 73% were ventilated. [bone-abstracts.org]
Color compare parasternal short axis view demonstrating origin of the right coronary artery from the left sinus of Valsalva in a 16-year-old female presenting with exertional chest pain and dyspnea. [acc.org]
Note: there is a “thoracic” set of questions you can ask for chest pain, cough, dyspnea. Note the similarities. 1. ... Chest pain does not necessarily suggest a heart issue. [apotechsrl.it]
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Tachypnea
[symptoma.com] Tachypnea [bone-abstracts.org] Tachypnea […] months of life or in utero. [2] Decreased fetal activity Gestation with an antenatal diagnosis of hydrops fetalis [6] [7] Polyhydramnios Low biophysical profile Marked cyanosis Edema [8] Severe [symptoma.com]
[…] months of life or in utero. [2] Decreased fetal activity Gestation with an antenatal diagnosis of hydrops fetalis [6] [7] Polyhydramnios Low biophysical profile Marked cyanosis Edema [8] Severe hypertension [9] No or fade pulses Refusal of feeds [10] Tachypnea [en.wikipedia.org]
Gastrointestinal
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Failure to Thrive
Idiopathic infantile arterial calcification was diagnosed in a 2 week old infant with failure to thrive associated with neurological, renal and cardiac signs. Therapy with diphosphonate resulted in a complete resolution of vascular calcifications. [ncbi.nlm.nih.gov]
Abstract Idiopathic infantile arterial calcification was diagnosed in a 2 week old infant with failure to thrive associated with neurological, renal and cardiac signs. [doi.org]
The features associated with ACI typically include heart failure, high blood pressure (hypertension), and failure to thrive. These features vary, with each infant being differently affected by the severity of their symptoms. [checkorphan.org]
Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension, and edema. [orpha.net]
[…] to Thrive Idiopathic infantile arterial calcification was diagnosed in a 2 week old infant with failure to thrive associated with neurological, renal and cardiac signs. [symptoma.com]
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Vomiting
Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with sudden onset of fever, vomiting, irritability, or respiratory [ncbi.nlm.nih.gov]
Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension, and edema. [orpha.net]
[orpha.net] [orpha.net] Vomiting Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with sudden onset of fever, vomiting [symptoma.com]
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Abdominal Distension
[en.wikipedia.org] [en.wikipedia.org] The infant’s subsequent course in NICU was complicated by recurrent abdominal distension, feeding intolerance, irritability, pyrexia and systemic hypertension. [symptoma.com]
distension General arterial rigidity [11] Cardiac failure (most common clinical finding) Strain pattern Cause [ edit ] GACI is inherited in an autosomal recessive pattern. [en.wikipedia.org]
The infant’s subsequent course in NICU was complicated by recurrent abdominal distension, feeding intolerance, irritability, pyrexia and systemic hypertension. Oral Editronate Sodium (10 mg/kg/day, twice a day) was started on day 40. [bmcpediatr.biomedcentral.com]
Liver, Gall & Pancreas
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Hepatosplenomegaly
[bmcpediatr.biomedcentral.com] Liver, Gall & Pancreas Hepatosplenomegaly […] clinical features including microcephaly, intracranial calcifications, rash, intrauterine growth restriction, jaundice, hepatosplenomegaly [hindawi.com] The absence of jugular [symptoma.com]
[…] calcification involving aorta, carotid, cerebral, renal, mesenteric and cardiac arteries Echo-dense aortic annulus, ascending aorta, transverse arch, descending aorta, main pulmonary artery, and coronary arteries unusually. [23] Abdominal ultrasound can reveal hepatosplenomegaly [en.wikipedia.org]
Although each of the congenital intrauterine infections has distinct clinical manifestations and sequelae, some of them do share certain clinical features including microcephaly, intracranial calcifications, rash, intrauterine growth restriction, jaundice, hepatosplenomegaly [hindawi.com]
The absence of jugular turgor and hepatosplenomegaly were evaluated and fluids were administered through intraosseous tibial as anti-shock rescue; however, the non-invasive blood pressure remains invaluable. [pediatrics.imedpub.com]
Cardiovascular
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Hypertension
The clinical presentation was characterized by a severe early-onset of hypertension refractory to multiple therapy. [ncbi.nlm.nih.gov]
Standard anti-hypertensive therapy is warranted for hypertension. Aspirin therapy is warranted in those with severe coronary stenosis who are at increased risk for coronary thrombosis. Anti-hypertensive therapy is warranted for hypertension. [orpha.net]
At the age of 2 years the child is doing well but requires medical treatment for arterial hypertension. [doi.org]
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Heart Failure
We report the case of a 32-week-old infant with hydrops fetalis and heart failure who died at 4 days of age. [ncbi.nlm.nih.gov]
Early-onset disease presents variably with fetal distress, heart failure, polyhydramnios, hypertension, respiratory distress, hydrops fetalis, edema, visceral effusions, cyanosis, cardiomegaly, and ascites. [orpha.net]
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Cardiomegaly
At autopsy the infant was found to have cardiomegaly, myocardial infarctions and multifocal calcifications of the aorta and arteries in the lungs, heart, thyroid, spleen, and testis. [ncbi.nlm.nih.gov]
Chest radiography showed cardiomegaly and pulmonary plethora. Electrocardiography showed left ventricular hypertrophy and strain pattern. [doi.org]
Early-onset disease presents variably with fetal distress, heart failure, polyhydramnios, hypertension, respiratory distress, hydrops fetalis, edema, visceral effusions, cyanosis, cardiomegaly, and ascites. [orpha.net]
Striking cardiomegaly with calcifications of the great vessels were noted. Radiological examination showed global and bilateral calcifications of the brachial and femoral arterial network. [ashg.org]
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Cyanosis
Early-onset disease presents variably with fetal distress, heart failure, polyhydramnios, hypertension, respiratory distress, hydrops fetalis, edema, visceral effusions, cyanosis, cardiomegaly, and ascites. [orpha.net]
There are 2 types: Central cyanosis and Acrocyanosis. [nicklauschildrens.org] There are 2 types: Central cyanosis and Acrocyanosis. [symptoma.com]
Reviewed by: Jack Wolfsdorf, MD, FAAP This page was last updated on: December 18, 2020 05:03 PM Learn more about Cyanosis A bluish tinge of the lips, tongue, nail beds or skin is called cyanosis. There are 2 types: Central cyanosis and Acrocyanosis. [nicklauschildrens.org]
In other babies, GACI is recognized later, within the first three to six months of life, with symptoms ranging from respiratory distress and cyanosis to heart failure and hypertension. [chop.edu]
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Weak Pulse
At one hour of age, he was noted to be pale, hypoperfused, with weak pulses, a hyperdynamic precordium and a grade IV/VI pansystolic murmur. The rest of his examination was normal. A chest X-ray showed massive cardiomegaly and pulmonary oedema. [bmcpediatr.biomedcentral.com]
[chop.edu] Weak Pulse At one hour of age, he was noted to be pale, hypoperfused, with weak pulses, a hyperdynamic precordium and a grade IV/VI pansystolic murmur. The rest of his examination was normal. [symptoma.com]
Musculoskeletal
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Bone Pain
Rickets leads to severe skeletal deformities, short stature, severe bone pain, and an increased risk of bone fractures. [inozyme.com]
bone pain, bowed femora, and short stature. [symptoma.com]
Five patients (cases 8, 15, 16, 43, and 45) were supplemented with phosphate and calcitriol for signs of hypophosphatemic rickets becoming apparent between 8 months and 11 years of age, including bone pain, bowed femora, and short stature. [doi.org]
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Skeletal Dysplasia
• Skeletal dysplasias. The specific symptoms and physical findings associated with OI vary greatly from case to case. Nearly ninety percent are X-ray features. [shop.inmobiliariasands.com]
Fetus
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Hydrops Fetalis
We report the case of a 32-week-old infant with hydrops fetalis and heart failure who died at 4 days of age. [ncbi.nlm.nih.gov]
Antenatal detection of idiopathic arterial calcification with hydrops fetalis. J Ultrasound Med 2003;22:653-659. Nasrallah MK.Prenatal diagnosis of idiopathic infantile arterial calcification with hydrops fetalis. [ojhas.org]
Ears
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Hearing Impairment
[ojhas.org] Ears Hearing Impairment [doi.org] Ears Hearing Impairment Fishman G, Miller-Hansen D, Jacobsen C, Singhal V, Alon U: Hearing impairment in familial X-linked hypophosphatemic rickets. Eur J Pediatr 2004;163:622-623. [symptoma.com]
Fishman G, Miller-Hansen D, Jacobsen C, Singhal V, Alon U: Hearing impairment in familial X-linked hypophosphatemic rickets. Eur J Pediatr 2004;163:622-623. [karger.com]
Urogenital
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Kidney Failure
The initial indication of GACI is high blood pressure or kidney failure. Physicians may order X-rays for newborns with these conditions to look for calcification in arteries. [chop.edu]
[karger.com] Urogenital Kidney Failure The initial indication of GACI is high blood pressure or kidney failure. Physicians may order X-rays for newborns with these conditions to look for calcification in arteries. [symptoma.com]
Neurologic
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Irritability
Of these, 48% of cases presented in utero or at birth with hydrops fetalis, maternal hydramnios, heart failure, or respiratory distress and 52% present later, at a median age of 3 months, with sudden onset of fever, vomiting, irritability, or respiratory [ncbi.nlm.nih.gov]
Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension, and edema. [orpha.net]
vomiting, irritability, or respiratory [ncbi.nlm.nih.gov] Presentation of late-onset disease variably includes respiratory distress, cyanosis, feeding difficulties, congestive heart failure, vomiting, irritability, failure to thrive, fever, hypertension [symptoma.com]
The drug was given for a total of 65 days and then stopped after the appearance of severe thrombocytopenia; other side effects included sporadic hyperthermia and irritability. [doi.org]
Workup
The infant died at the age of 7 weeks of cardiac failure and the parents were referred to Molecular Biology and Cytogenetic lab for further workup. [jcdronline.org]
[doi.org] Workup The infant died at the age of 7 weeks of cardiac failure and the parents were referred to Molecular Biology and Cytogenetic lab for further workup. [symptoma.com]
X-Ray
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Pericardial Effusion
The fetal and postnatal echocardiographic features were a large pericardial effusion, thickened pulmonary and aortic valves, poor pulsation of the descending aorta, and calcification of the great vessels. [doi.org]
The sonographic findings were fetal hydrops (hydrothorax, skin edema, ascites, pericardial effusion and polyhydramnion), echogenic great arteries and pathological Doppler findings. [ncbi.nlm.nih.gov]
Internal examination revealed pleural and pericardial effusions and moderate splenomegaly. Striking cardiomegaly with calcifications of the great vessels were noted. [ashg.org]
The sonographic examination performed at 28 weeks' gestation revealed scalp edema, severe skin edema, bilateral hydrocele, ascites, and pleural and pericardial effusion. [avesis.istanbul.edu.tr]
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Cervical Spine X-Ray
Where endotracheal intubation is required, lateral cervical spine x-ray is recommended to evaluate for cervical spine fusion, and thereby avoid secondary complications. [orpha.net]
Hypertrophy
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Ventricular Hypertrophy
Electrocardiography showed left ventricular hypertrophy and strain pattern. Echocardiography showed a dilated and hypertrophied left ventricle, with bright and hyper-reflective myocardium (fig 1). Fractional shortening was 12.5%. [doi.org]
[austinpublishinggroup.com] Hypertrophy Ventricular Hypertrophy Electrocardiography showed left ventricular hypertrophy and strain pattern. [symptoma.com]
Echocardiography demonstrated left ventricular hypertrophy with good function (fractional shortening 40%). He was normotensive. X-radiographs of chest and abdomen were normal. [documents.tips]
hypertrophy and multiple intracardiac as well as vascular calcifications [6] Idiopathic arterial calcification of infancy should be suspected when there is hyperechogenicity of vessel walls, evidence of polyhydramnios or a past history of early neonatal [en.wikipedia.org]
Repeated ECHO examinations showed normal systemic and pulmonary venous drainage, thickened semilunar and tricuspid valve leaflets, and concentric left ventricular hypertrophy. An ECG was negative for ischaemic changes. [bmcpediatr.biomedcentral.com]
Treatment
Despite treatment with disodium etidronate both children died. [doi.org]
"Generalized arterial calcification of infancy: Treatment with bisphosphonates". [en.wikipedia.org]
Treatment with bisphosphonates, which are synthetic PP(i) analogues, has been proposed as a means of reducing arterial calcifications in GACI patients, but no formalized treatment approach exists. [ncbi.nlm.nih.gov]
Treatment of hypophosphatemic rickets involves calcitriol and oral phosphate supplements. It seems prudent to avoid the use of warfarin if possible. [orpha.net]
Prognosis
Prognosis Prognosis is poor; most infants die from myocardial infarction within the first year of life, with the greatest number of deaths occurring within the first six months. [orpha.net]
The prognosis is extremely poor, with 85% of affected infants dying within the first 6 months of life. [ncbi.nlm.nih.gov]
Prognosis - Generalized arterial calcification of infancy-1 (GACI1) Not supplied. Treatment - Generalized arterial calcification of infancy-1 (GACI1) Not supplied. Resources - Generalized arterial calcification of infancy-1 (GACI1) Not supplied. [checkorphan.org]
Etiology
Idiopathic infantile arterial calcification is a disorder of unknown etiology manifested by widespread arterial calcification. This usually leads to early death from coronary artery occlusion. [ncbi.nlm.nih.gov]
Abstract Idiopathic infantile arterial calcification (IIAC) is a rare disease of unknown etiology, which causes wide-spread arterial calcification and usually leads to early death from coronary arterial occlusion. [doi.org]
Epidemiology
Summary Epidemiology Approximately 300 cases have been reported worldwide in the medical literature. The prevalence is unknown; however, based on carrier frequency of the recognized pathogenic variants, the frequency of 1/566,000 has been suggested. [orpha.net]
[doi.org] Epidemiology Summary Epidemiology Approximately 300 cases have been reported worldwide in the medical literature. [symptoma.com]
[…] electron-beam CT–measured CAC was quantified12 for validation of their findings, and the risk allele was associated with both CAC and premature atherosclerosis.9 In the more recent multi-ethnic Atherosclerotic Disease, Vascular Function and Genetic Epidemiology [ahajournals.org]
Pathophysiology
[…] biochemistry of nutrition 180 Nutritional disorders and their management 200 Clinical biochemistry of the gastrointestinal tract 214 Assessment of hepatic function and investigation of jaundice 231 Acute and chronic liver disease 250 Glucose metabolism and the pathophysiology [books.google.com]
[symptoma.com] It can therefore be hypothesized that the pathophysiology of ENPP1 and ABCC6 related disorders is based on common downstream mechanisms. [symptoma.com]
It can therefore be hypothesized that the pathophysiology of ENPP1 and ABCC6 related disorders is based on common downstream mechanisms. [frontiersin.org]
Monogenic ENPP1, CD73, and ABCC6 deficiencies each drive a molecular pathophysiology of closely related but phenotypically different diseases (GACI, ACDC, and PXE, respectively), in which premature onset arterial calcification is a prominent but not sole [circresearch.com]
Purpose of Review This review summarizes current understanding of generalized arterial calcification of infancy (GACI), emphasizing pathophysiology, clinical presentation, and approaches and controversies in management. [x-mol.com]
Prevention
Here we demonstrate that subcutaneous administration of an ENPP1-Fc fusion protein prevents the mortality, vascular calcifications and sequela of disease in animal models of GACI, and is accompanied by a complete clinical and biomarker response. [ncbi.nlm.nih.gov]
Prevention - Generalized arterial calcification of infancy-1 (GACI1) Not supplied. [checkorphan.org]
Recently, a study on animal model has described that bisphosphonate treatment may be beneficial by a dual effect for preventing ectopic soft tissue mineralization while correcting decreased bone mineralization in GACI caused by ENPP1 mutations. [iofbonehealth.org]
Alternatively, a lack of functioning MRP6 may impair the transport of a substance that would normally prevent mineralization, leading to the abnormal accumulation of calcium characteristic of GACI. [ghr.nlm.nih.gov]
Citing Literature Number of times cited according to CrossRef: 24 Yvonne Nitschke, Yan Yan, Insa Buers, Kristina Kintziger, Kim Askew and Frank Rutsch, ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the [doi.org]