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| ID | Type | Description | Link |
|---|---|---|---|
| FD-R-0003903 | Other Grant/Funding Number | FDA OOPD |
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The purpose of this study is to evaluate the effectiveness of magnesium oxide supplements on the reversal of calcium deposits in the skin, and the yellow bumps and folds of skin in subjects with pseudoxanthoma elasticum (PXE). Magnesium oxide is a dietary supplement that has been shown in some research to reduce these calcium deposits. This study consists of two parts. The first part is a year-long, double-blind, placebo-controlled study. Part two is an open-label, year-long study. In Part 1, qualified subjects will be randomized to receive either magnesium oxide supplements or placebo, in a 1:1 ratio for the first 12 months. The starting dose will be 1000 mg daily, and depending on tolerability, doses may be decreased. Baseline evaluations will be comprised of: blood tests; clinical evaluations; skin biopsy; eye examination; bone density test; and photography of skin lesions. Subjects will be evaluated at week 2, week 6, month 3, and then every 3 months during the first year. Upon completion of the first year, barring any safety concerns, all subjects will be administered magnesium oxide supplements for up to one additional year. Subjects will undergo the same evaluations/ procedures every 3 months. We hypothesize that the magnesium oxide will cause a reduction in calcifications in the subject's soft tissue/skin. Funding Source - FDA OOPD.
Pseudoxanthoma elasticum (PXE) is a systemic connective tissue disorder involving elastic fiber calcification and fragmentation with major clinical manifestations occurring in the cutaneous, ocular and cardiovascular systems.
Calcification of the elastic fibers leads to cracks in Bruch's membrane, an elastic tissue-containing membrane that separates the vascular choroid from the retinal pigment epithelium. These are known as angioid streaks and may be the only sign of the disease for years. Retinal hemorrhage and loss of vision are common. Calcification of the internal elastic lamina of arteries results in gastrointestinal bleeding, sometimes fatal in nature. Accelerated heart disease is an additional complication.
Cutaneous manifestations are characterized by the presence of yellow papules in a cobblestone pattern or plaques resembling "plucked chicken-skin" in flexural regions. Redundant folds of skin may develop in more advanced cases. The most frequent sites of cutaneous involvement include the neck, axillae, inguinal region, antecubital and popliteal fossae and the periumbilical area. Skin lesions provide an easy way of grading degree of calcification of elastic tissue.
A clinical study of 80 subjects with a variety of cutaneous soft tissue mineralization disorders had the affected areas injected locally with magnesium sulfate while also receiving oral magnesium lactate for 4 to 6 months. About 75% of these subjects showed a significant decrease or complete disappearance of calcification.
More recently, a knockout mouse model for PXE has linked a reversal in calcification to a diet high in magnesium. Mice were placed on diets that were either high or low in phosphate, high or low in magnesium, or on a controlled diet. The mice placed on the high magnesium diet did not show any evidence of connective tissue mineralization, while those on the other diets did show mineralization as characterized by calcification of the connective tissue capsule surrounding the vibrissae.
Based on this information and the research linking increased magnesium levels to decreased calcification, we plan to supplement the diets of PXE patients with magnesium oxide in order to show a reduction in elastic fiber calcification in the skin and to slow the progression of the disease.
Randomized subjects will be instructed to take study drug (active or placebo) for 12 months, then all subjects will receive active study drug for the following 12 months.
When ingested through foods, magnesium has not demonstrated any adverse effects. When obtained through supplements, however, excessive magnesium intake has been known to result in diarrhea as well as other gastrointestinal effects such as nausea, and abdominal cramping. Large pharmacological doses of magnesium have been associated with more serious side effects, such as metabolic alkalosis and hypokalemia with the repeated daily ingestion of 30g of magnesium oxide. Hypermagnesemia may result with excessive magnesium supplement ingestion, however, it has rarely been reported in individuals with normal renal function.
Study data will be analyzed using the Wilcoxon Rank Sum Test to compare changes in physician global assessment of skin lesions, evaluation of target lesions and assessment of biopsies between treatment and placebo groups. Assuming a negligible placebo response, we believe power analyses can be performed on our primary measure in 40 completed subjects as proposed in this study. Analyses will be based on intent-to-treat, with the last observation carried forward. Patients who withdraw for safety, lack of efficacy, and generally those without other documentation will in the absence of the requested 'final-visit evaluation' be assigned the highest (worst) score. A finding of significance based on the intent-to-treat analysis would be supplemented with an analysis of patients completing the trial without any protocol deviations.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Magnesium oxide | Active Comparator | Part 1: 1000 mg elemental magnesium (given as one 800 mg capsule of magnesium oxide two times daily). Part 2: 1500 mg elemental magnesium (given as two 500 mg capsules of magnesium oxide in the morning and three 500 mg capsules of magnesium oxide in the evening). |
|
| Placebo | Placebo Comparator | Part 1: 1000 mg (one 500 mg capsule two times daily) of placebo. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Magnesium Oxide | Drug | Part 1: 1000 mg elemental magnesium (given as one 800 mg capsule of magnesium oxide two times daily). Part 2: 1500 mg elemental magnesium (given as two 500 mg capsules of magnesium oxide in the morning and three 500 mg capsules of magnesium oxide in the evening). |
| Measure | Description | Time Frame |
|---|---|---|
| Von Kossa Staining Per Unit Area of Dermis | A blinded dermatopathologist graded skin biopsies on the density of Von Kossa staining, assessed changes in the amount of calcification of elastic fibers by assessing von Kossa staining per unit area of dermis | up to 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With a 1-point Decrease of Target Lesions | Changes in skin skin lesions observed through investigator evaluations and clinical photographs. The number of patients with a 1-point decrease of target lesions | up to 2 years |
| LogMar |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mark Lebwohl, MD | Icahn School of Medicine at Mount Sinai | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Icahn School of Medicine at Mount Sinai | New York | New York | 10029 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8277008 | Background | Lebwohl M, Neldner K, Pope FM, De Paepe A, Christiano AM, Boyd CD, Uitto J, McKusick VA. Classification of pseudoxanthoma elasticum: report of a consensus conference. J Am Acad Dermatol. 1994 Jan;30(1):103-7. doi: 10.1016/s0190-9622(08)81894-4. No abstract available. | |
| 3359381 | Background | Neldner KH. Pseudoxanthoma elasticum. Clin Dermatol. 1988 Jan-Mar;6(1):1-159. doi: 10.1016/0738-081x(88)90003-x. No abstract available. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Magnesium Oxide | Magnesium oxide capsules 800mg twice daily (total of 1000mg of elemental magnesium) for year 1. Upon completion of the first year, barring any safety concerns, all subjects were administered 2500 mg magnesium oxide (total of 1500 mg elemental magnesium) daily for up to one additional year. Subjects received 600 mg elemental magnesium oxide in the morning (taken as two 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium) and 900 mg elemental magnesium oxide in the evening (taken as three 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium). |
| FG001 | Placebo | Placebo year 1. Upon completion of the first year, barring any safety concerns, all subjects were administered 2500 mg magnesium oxide (total of 1500 mg elemental magnesium) daily for up to one additional year. Subjects received 600 mg elemental magnesium oxide in the morning (taken as two 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium) and 900 mg elemental magnesium oxide in the evening (taken as three 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Placebo-controlled Period |
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| ||||||||||||||||||
| Open-label Period |
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| ID | Title | Description |
|---|---|---|
| BG000 | Magnesium Oxide | Magnesium oxide capsules 800mg twice daily (total of 1000mg of elemental magnesium) for year 1. Upon completion of the first year, barring any safety concerns, all subjects were administered 2500 mg magnesium oxide (total of 1500 mg elemental magnesium) daily for up to one additional year. Subjects received 600 mg elemental magnesium oxide in the morning (taken as two 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium) and 900 mg elemental magnesium oxide in the evening (taken as three 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Von Kossa Staining Per Unit Area of Dermis | A blinded dermatopathologist graded skin biopsies on the density of Von Kossa staining, assessed changes in the amount of calcification of elastic fibers by assessing von Kossa staining per unit area of dermis | Estimate: Estimated change from baseline and its standard error (SEM). After 1 year=M12-Baseline, After 2 year=M24-Baseline; during 2nd year =M24-M12. | Posted | Mean | Standard Error | microns | up to 2 years |
|
2 years
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Magnesium Oxide | Magnesium oxide capsules 800mg twice daily (total of 1000mg of elemental magnesium) for year 1. Upon completion of the first year, barring any safety concerns, all subjects were administered 2500 mg magnesium oxide (total of 1500 mg elemental magnesium) daily for up to one additional year. Subjects received 600 mg elemental magnesium oxide in the morning (taken as two 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium) and 900 mg elemental magnesium oxide in the evening (taken as three 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment | diarrhea |
Small study of a rare disease with tremendous patient variation.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Mark Lebwohl | Icahn School of Medicine at Mount Sinai | 212-241-9728 | mark.lebwohl@mountsinai.org |
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| ID | Term |
|---|---|
| D011561 | Pseudoxanthoma Elasticum |
| D002114 | Calcinosis |
| ID | Term |
|---|---|
| D020141 | Hemostatic Disorders |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006474 | Hemorrhagic Disorders |
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| ID | Term |
|---|---|
| D008277 | Magnesium Oxide |
| ID | Term |
|---|---|
| D017616 | Magnesium Compounds |
| D007287 | Inorganic Chemicals |
| D010087 | Oxides |
| D017601 | Oxygen Compounds |
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|
|
| Placebo | Drug | 1000 mg (one 500 mg capsule two times daily) of placebo. |
|
|
Rate of disease progression - Changes observed through ophthalmologic examinations. (+) a decrease in this score indicates improvement of the disease (-) an increase in this score indicates worsening of the disease. LogMAR: logarithm of the minimum angle of resolution. The LogMAR scale converts the geometric sequence of a traditional chart to a linear scale. It measures visual acuity loss: positive values indicate vision loss, while negative values denote normal or better visual acuity.
| 2 years |
| VAS - Visual Acuity Score | Rate of disease progression observed through ophthalmologic examinations.(+) an increase in this score indicates improvement of the disease (-) a decrease in this score indicates worsening of the disease. VAS ranges from 10 to 200, with higher score indicating poorer visual acuity. | 2 years |
| Central Retinal Thickness | Rate of disease progression observed through ophthalmologic examinations. (+) a decrease in this scores indicates improvement of the disease; (-) an increase in this scores indicates improvement of the disease. | 2 years |
| 7046115 | Background | Clarkson JG, Altman RD. Angioid streaks. Surv Ophthalmol. 1982 Mar-Apr;26(5):235-46. doi: 10.1016/0039-6257(82)90158-8. |
| 6507474 | Background | Renie WA, Pyeritz RE, Combs J, Fine SL. Pseudoxanthoma elasticum: high calcium intake in early life correlates with severity. Am J Med Genet. 1984 Oct;19(2):235-44. doi: 10.1002/ajmg.1320190205. |
| 580723 | Background | Martinez-Hernandez A, Huffer WE, Neldner K, Gordon S, Reeve EB. Resolution and repair of elastic tissue calcification in pseudoxanthoma elasticum. Arch Pathol Lab Med. 1978 Jun;102(6):303-5. |
| 9703148 | Background | Sapadin AN, Lebwohl MG, Teich SA, Phelps RG, DiCostanzo D, Cohen SR. Periumbilical pseudoxanthoma elasticum associated with chronic renal failure and angioid streaks--apparent regression with hemodialysis. J Am Acad Dermatol. 1998 Aug;39(2 Pt 2):338-44. doi: 10.1016/s0190-9622(98)70385-8. |
| 16198780 | Background | Sherer DW, Singer G, Uribarri J, Phelps RG, Sapadin AN, Freund KB, Yanuzzi L, Fuchs W, Lebwohl M. Oral phosphate binders in the treatment of pseudoxanthoma elasticum. J Am Acad Dermatol. 2005 Oct;53(4):610-5. doi: 10.1016/j.jaad.2004.11.066. |
| Background | Blum R, Phelps R, Fuchs W, Lebwohl M. Oral Phosphate Binders in the Treatment of Pseudoxanthoma Elasticum. 64th Annual Meeting American Academy of Dermatology March 3-7, 2006, San Francisco, CA. Manuscript in press J Amer Acad Dermatol 2011 |
| 1838878 | Background | Steidl L, Ditmar R. Treatment of soft tissue calcifications with magnesium. Acta Univ Palacki Olomuc Fac Med. 1991;130:273-87. |
| 19122649 | Background | LaRusso J, Li Q, Jiang Q, Uitto J. Elevated dietary magnesium prevents connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(-/-)). J Invest Dermatol. 2009 Jun;129(6):1388-94. doi: 10.1038/jid.2008.391. Epub 2009 Jan 1. |
| 6375330 | Background | Iseri LT, French JH. Magnesium: nature's physiologic calcium blocker. Am Heart J. 1984 Jul;108(1):188-93. doi: 10.1016/0002-8703(84)90572-6. No abstract available. |
| 3812346 | Background | Joffres MR, Reed DM, Yano K. Relationship of magnesium intake and other dietary factors to blood pressure: the Honolulu heart study. Am J Clin Nutr. 1987 Feb;45(2):469-75. doi: 10.1093/ajcn/45.2.469. |
| 2662695 | Background | Paolisso G, Passariello N, Pizza G, Marrazzo G, Giunta R, Sgambato S, Varricchio M, D'Onofrio F. Dietary magnesium supplements improve B-cell response to glucose and arginine in elderly non-insulin dependent diabetic subjects. Acta Endocrinol (Copenh). 1989 Jul;121(1):16-20. doi: 10.1530/acta.0.1210016. |
| 7013665 | Background | Rude RK, Singer FR. Magnesium deficiency and excess. Annu Rev Med. 1981;32:245-59. doi: 10.1146/annurev.me.32.020181.001333. No abstract available. |
| Background | Dietary Reference Intakes for Calcium, Magnesium, Vitamin D and Flouride. IOM Institute of Medicine. 1997 Washington, DC: National Academy Press. |
| 8237806 | Background | Bashir Y, Sneddon JF, Staunton HA, Haywood GA, Simpson IA, McKenna WJ, Camm AJ. Effects of long-term oral magnesium chloride replacement in congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1993 Nov 15;72(15):1156-62. doi: 10.1016/0002-9149(93)90986-m. |
| 1195509 | Background | Urakabe S, Nakata K, Ando A, Orita Y, Abe H. Hypokalemia and metabolic alkalosis resulting from overuse of magnesium oxide. Jpn Circ J. 1975 Oct;39(10):1135-7. doi: 10.1253/jcj.39.1135. |
| NOT COMPLETED |
|
|
| BG001 | Placebo | Placebo year 1. Upon completion of the first year, barring any safety concerns, all subjects were administered 2500 mg magnesium oxide (total of 1500 mg elemental magnesium) daily for up to one additional year. Subjects received 600 mg elemental magnesium oxide in the morning (taken as two 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium) and 900 mg elemental magnesium oxide in the evening (taken as three 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium). |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Bone Mineral Density (BMD) | Number of participants with low t-score < -1. The T-score is a radiographic diagnosis that compares bone mineral density (BMD) to that of a "normal, healthy, 30-year-old female". The lower the T-score, the lower the BMD. A T-score of +1 to -1 is normal. A T-score decrease of -1 indicates a 10%-15% decrease in BMD. | Count of Participants | Participants |
|
| Peau D'Orange right eye | 0 - No evidence of PXE, 1 - Poorly defined, barely visible macules, 2 - Well defined, easily identified macules, 3 - Mostly macules with <5 papules, 4 - >= 5 papules, 5- Patches consisting of confluent macules with <50% of target area covered by papules, 6 - Patches consisting of confluent macules with >=50% of target area covered by papules, 7 - Plaques, 8 - Plaques with mild folds of skin, 9 - Plaques with redundant folds of skin | Count of Participants | Participants |
|
| Peau D'Orange left eye | 0 - No evidence of PXE, 1 - Poorly defined, barely visible macules, 2 - Well defined, easily identified macules, 3 - Mostly macules with <5 papules, 4 - >= 5 papules, 5- Patches consisting of confluent macules with <50% of target area covered by papules, 6 - Patches consisting of confluent macules with >=50% of target area covered by papules, 7 - Plaques, 8 - Plaques with mild folds of skin, 9 - Plaques with redundant folds of skin | Count of Participants | Participants |
|
| Angioid Streaks right eye | 2- Streaks may be found in association with cardiovascular disease, most commonly of the arterio-sclerotic, hypertensive type 3- Associated with Paget's disease 4- Streaks caused by pigment accumulations and may be termed "secondary" | Count of Participants | Participants |
|
| Angioid Streaks left eye | Count of Participants | Participants |
|
| Subretinal fluid right eye | Count of Participants | Participants |
|
| Subretinal fluid left eye | Count of Participants | Participants |
|
| OG001 | Placebo | Placebo year 1. Upon completion of the first year, barring any safety concerns, all subjects were administered 2500 mg magnesium oxide (total of 1500 mg elemental magnesium) daily for up to one additional year. Subjects received 600 mg elemental magnesium oxide in the morning (taken as two 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium) and 900 mg elemental magnesium oxide in the evening (taken as three 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium). |
|
|
| Secondary | Number of Participants With a 1-point Decrease of Target Lesions | Changes in skin skin lesions observed through investigator evaluations and clinical photographs. The number of patients with a 1-point decrease of target lesions | Posted | Count of Participants | Participants | up to 2 years |
|
|
|
| Secondary | LogMar | Rate of disease progression - Changes observed through ophthalmologic examinations. (+) a decrease in this score indicates improvement of the disease (-) an increase in this score indicates worsening of the disease. LogMAR: logarithm of the minimum angle of resolution. The LogMAR scale converts the geometric sequence of a traditional chart to a linear scale. It measures visual acuity loss: positive values indicate vision loss, while negative values denote normal or better visual acuity. | Posted | Mean | Standard Error | LogMar | 2 years |
|
|
|
| Secondary | VAS - Visual Acuity Score | Rate of disease progression observed through ophthalmologic examinations.(+) an increase in this score indicates improvement of the disease (-) a decrease in this score indicates worsening of the disease. VAS ranges from 10 to 200, with higher score indicating poorer visual acuity. | Posted | Mean | Standard Error | units on a scale | 2 years |
|
|
|
| Secondary | Central Retinal Thickness | Rate of disease progression observed through ophthalmologic examinations. (+) a decrease in this scores indicates improvement of the disease; (-) an increase in this scores indicates improvement of the disease. | Posted | Mean | Standard Error | µm | 2 years |
|
|
|
| 0 |
| 22 |
| 0 |
| 22 |
| 11 |
| 22 |
| EG001 | Placebo | Placebo year 1. Upon completion of the first year, barring any safety concerns, all subjects were administered 2500 mg magnesium oxide (total of 1500 mg elemental magnesium) daily for up to one additional year. Subjects received 600 mg elemental magnesium oxide in the morning (taken as two 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium) and 900 mg elemental magnesium oxide in the evening (taken as three 500 mg magnesium oxide capsules, each containing 300 mg elemental magnesium). | 0 | 22 | 0 | 22 | 11 | 22 |
| Loose Stool | Gastrointestinal disorders | Non-systematic Assessment |
|
| Abdominal Cramps | Gastrointestinal disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Flatulance | Gastrointestinal disorders | Non-systematic Assessment |
|
| Bloating | Gastrointestinal disorders | Non-systematic Assessment |
|
| Increased bowel movements | Gastrointestinal disorders | Non-systematic Assessment |
|
| Loss of Appetite | Gastrointestinal disorders | Non-systematic Assessment |
|
| Gastroenteritis | Gastrointestinal disorders | Non-systematic Assessment |
|
| Upper Respiratory Infection | Infections and infestations | Non-systematic Assessment |
|
| Infections | Infections and infestations | Non-systematic Assessment | Sinus, Dental, urinary |
|
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| D006402 |
| Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D012868 | Skin Abnormalities |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D012873 | Skin Diseases, Genetic |
| D030342 | Genetic Diseases, Inborn |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D012871 | Skin Diseases |
| D002128 | Calcium Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| After 2 years |
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| After 2 years |
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| After 2 years |
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| After 2 years |
|