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With this study we want to investigate the pharmacokinetic (PK) effect of a single injection of rhIGF-1 in patients with PAPP-A2 mutations compared to heterozygous carriers and healthy controls. This will be followed by treatment of PAPP-A2 deficient patients with IGF-1 for a period of one-year to assess growth velocity. Additionally, we want to further describe the phenotypic characteristics of patients with PAPP-A2 deficiency.
The 24-hour pharmacokinetic response of free and total IGF-1 and IGF binding protein-3 (IGFBP-3) to a single dose of rhIGF-1 (120 mcg/kg) in three patients with PAPP-A2 mutation compared to up to four unaffected heterozygous relatives and 2 healthy adult controls.
One-year trial of rhIGF-1 at standard dose given to the two youngest males with PAPP-A2 mutation. The primary end point of this trial will be first year height velocity. Secondary outcomes will include height standard deviation score (SDS), height velocity, and whole body and lumbar spine bone mineral density assessment. The study was amended to extend the treatment period to continue until the subject has stopped growing (or elects to withdraw). All study procedures remain the same. Important note: the treatment phase continues to follow the youngest affected male. The older affected male developed an adverse event that resulted in discontinuation of treatment.
A post-treatment follow up visit (either in-person or remote) will be completed for the study participant who remained on Increlex approximately one-year after their discontinuation of therapy.
Description of additional phenotypic characteristics of patients with PAPP-A2 mutation will be studied by collecting information on glucose and insulin metabolism, body composition, bone geometry and bone density before and after treatment with rhIGF-1. These measures will be collected at the 12-month time period, and every year thereafter until the completion of the study. All three affected siblings will take part in the phenotyping activities.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PAPP-A2 deficient patients | Experimental | Patients deficient in PAPP-A2 with short stature will be treated with Increlex (rhIGF-1) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Increlex | Drug | Treat PAPP-A2 deficient patients with Increlex |
|
| Measure | Description | Time Frame |
|---|---|---|
| Height Velocity | Height velocity in a patient with PAPP-A2 deficiency treated with rhIGF-1 for five years (when the patient elected to discontinue treatment after reviewing growth velocity and skeletal maturation). Ultimately only one patient was treated for the study duration with results reported, as the other recruited participant (sibling of the treated patient) experienced pseudotumor cerebri and discontinued treatment after 51 days. He nevertheless was followed, with height velocity also reported. | Yearly until participant on treatment stops growing, or discontinues treatment (up to 6 years) |
| Measure | Description | Time Frame |
|---|---|---|
| Height Standard Deviation Score | Height Standard Deviation Score is the standard deviation above or below the mean the height is for age and gender. Values were obtained by plotting heights on Centers for Disease Control and Prevention growth charts. An increase in Height Standard Deviation Score correlates with increase in height. Results are reported for the participant with PAPP-A2 deficiency treated with rhIGF-1, as well as sibling who did not continue treatment with rhIGF-1. |
| Measure | Description | Time Frame |
|---|---|---|
| Glucose Pre- and Post-treatment With Recombinant Human IGF-I | Observe nonparametric measures of glucose pre and post ongoing treatment with rhIGF-1. Oral glucose tolerance tests (OGTT) were performed annually during the five-year treatment period at pre-treatment (baseline) and post-initiation of treatment (after 12 months, 24 months, 36 months, 48 months, and 60 months). | Yearly until completion of the study, up to 6 years |
PAPP-A2 deficient
Inclusion Criteria:
Exclusion Criteria:
Healthy Volunteers
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Philippe Backeljauw, MD | Cincinnati Childrens Hospital | Principal Investigator |
| Gajanathan Muthuvel, MD | Cincinnati Childrens Hospital Medical Center | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36646053 | Result | Muthuvel G, Dauber A, Alexandrou E, Tyzinski L, Andrew M, Hwa V, Backeljauw P. Five-Year Therapy with Recombinant Human Insulin-Like Growth Factor-1 in a Patient with PAPP-A2 Deficiency. Horm Res Paediatr. 2023;96(5):449-457. doi: 10.1159/000529071. Epub 2023 Jan 16. | |
| 29029190 | Result | Cabrera-Salcedo C, Mizuno T, Tyzinski L, Andrew M, Vinks AA, Frystyk J, Wasserman H, Gordon CM, Hwa V, Backeljauw P, Dauber A. Pharmacokinetics of IGF-1 in PAPP-A2-Deficient Patients, Growth Response, and Effects on Glucose and Bone Density. J Clin Endocrinol Metab. 2017 Dec 1;102(12):4568-4577. doi: 10.1210/jc.2017-01411. |
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De-identifiable data may be shared with physician that is treating the only other two patients in the world with this genetic mutation.
The participant data will be available when the treatment trial is actively ongoing. Per study protocol, the study will provide clinical updates to the participants primary Endocrinologist. Should the family request any further information be shared once the study is closed, it can be given to a physician specified by the family.
De-identifiable data may be shared with physician that is treating the only other two patients in the world with this genetic mutation.
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Not applicable to this research study. All participants that were eligible for the study and agreed to participate were enrolled.
This is an n=7 study. A total of seven individuals will be recruited to participate in this study. Among the participants, we will have the three affected siblings with Pappalysin-2 (PAPP-A2) mutation (two males and one female), their heterozygous relatives (2 parents) and 2 healthy adult controls.
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| ID | Title | Description |
|---|---|---|
| FG000 | PAPP-A2 Deficient Patients | Patients deficient in PAPP-A2 will participate in the 24-hour pharmacokinetic study, and those who have not completed growth will be treated with Increlex (recombinant human IGF-1). |
| FG001 | Healthy Control Participants | Healthy controls between the ages of 18-30 will be included in the 24-hour pharmacokinetic study. |
| FG002 | PAPP-A2 Heterozygous Relatives | Unaffected heterozygous PAPP-A2 deficient relatives will be included in the 24-hour pharmacokinetic study. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | PAPP-A2 Deficient Patients | Three siblings with PAPP-A2 deficiency due to homozygous PAPP-A2 mutation. The two younger siblings were recruited for extension trial treatment with recombinant human Insulin-like Growth Factor 1 (IGF-1). |
| BG001 | PAPP-A2 Heterozygous Relatives |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Height Velocity | Height velocity in a patient with PAPP-A2 deficiency treated with rhIGF-1 for five years (when the patient elected to discontinue treatment after reviewing growth velocity and skeletal maturation). Ultimately only one patient was treated for the study duration with results reported, as the other recruited participant (sibling of the treated patient) experienced pseudotumor cerebri and discontinued treatment after 51 days. He nevertheless was followed, with height velocity also reported. | The untreated comparison sibling was not evaluated at year 5 past completion of growth. | Posted | Number | cm/y | Yearly until participant on treatment stops growing, or discontinues treatment (up to 6 years) |
|
The study adverse event data was collected over a period of 6 years (from baseline visit to one year post-treatment phone follow up).
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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 | PAPP-A2 Deficient Patients | Patients deficient in PAPP-A2 will participate in the 24-hour pharmacokinetic study, and those who have not completed growth will be treated with Increlex (recombinant human IGF-1). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pseudotumor cerebri in subject | Nervous system disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Walking pneumonia | Respiratory, thoracic and mediastinal disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Philippe Backeljauw | Cincinnati Childrens Hospital Medical Center | 513-636-8444 | philippe.backeljauw@cchmc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 26, 2020 | Oct 13, 2023 | Prot_SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | Mar 15, 2021 | Feb 9, 2022 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D004392 | Dwarfism |
| ID | Term |
|---|---|
| D001848 | Bone Diseases, Developmental |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
| D030342 | Genetic Diseases, Inborn |
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| ID | Term |
|---|---|
| C000604197 | mecasermin |
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| Annually until completion of study, up to 6 years |
| Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Assess the PK/PD relationship (PD marker being IGFBP-3) annually while on treatment with rhIGF-1 | Yearly until completion of the study, up to 6 years |
| Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | Observe nonparametric measures of insulin metabolism in each individual pre (baseline) and post ongoing treatment with rhIGF-1. Oral glucose tolerance testing (OGTT) was performed pre-treatment (baseline) and post-treatment (after 12 months, 24 months, 36 months, 48 months, and 60 months). | Annually through completion of the study, up to 6 years |
| Body Mass Index at Baseline and on Treatment With rhIGF-I | Observe nonparametric measures of body composition pre (baseline) and post ongoing treatment with rhIGF-1 (assessed after 12 months, 24 months, 36 months, 48 months, and 60 months of rhIGF-1 treatment). BMI percentiles were determined utilizing Centers for Disease Control and Prevention growth charts. | Annually until completion of the study, up to 6 years |
| Body Composition at Baseline and on Treatment With rhIGF-I | Observe nonparametric measures of body composition pre (baseline) and post ongoing treatment with rhIGF-1 (assessed after 12 months, 24 months, 36 months, 48 months, and 60 months of rhIGF-1 treatment). Body fat content and lean body mass were evaluated with dual energy x-ray absorptiometry. | Annually until completion of the study, up to 6 years |
| Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I | Observe nonparametric measures of body composition pre (baseline) and post ongoing treatment with rhIGF-1 (assessed after 12 months, 24 months, 36 months, 48 months, and 60 months of rhIGF-1 treatment). Body fat content and lean body mass were evaluated with dual energy x-ray absorptiometry. | Annually until completion of the study, up to 6 years |
| C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Observe nonparametric measures of bone turnover pre-treatment (baseline) and post initiation of ongoing treatment (at 12 months, 24 months, 36 months, 48 months, and 60 months) while on rhIGF-1 | Yearly until completion of the study, up to 6 years |
| Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Observe nonparametric measures of bone density at baseline (pre-treatment) and post initiation of ongoing treatment with rhIGF-1. Dual energy x-ray absorptiometry (DXA) was performed of total body less head, lumbar spine, hip, and forearm. Results are reported as height adjusted z-scores for age and gender, commonly done for bone density. A z-score of 0 is equivalent to population mean, positive above the mean, and negative below the mean. Z-scores within 2 standard deviations of the mean (Z-score 2 to -2) are generally considered normal, however are not sufficient to comment on presence or absence of osteoporosis in the pediatric population. | Annually until completion of therapy, up to 6 years |
| Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Maximum Corrected Total IGF-I and Free IGF-I | This was a pharmacokinetic assessment in regards to rhIGF-1 completed in siblings with PAPP-A2 deficiency, Participants received a 120 mcg/kg dose of rhIGF-1 (Increlex). Pharmacokinetic measurements were obtained over 24 hours. To isolate the effect of injected rhIGF-1, baseline-corrected concentrations were included by subtracting baseline concentration from measured concentrations. Results reported include maximum corrected total IGF-I and free IGF-I. Due to constraints of reporting platform, time to maximum values and area under the curve (AUC) 12 hours after the dose are reported as separate outcomes. | At baseline, prior to the ongoing treatment phase with rhIGF-1 |
| Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Time to Maximum Corrected Total IGF-I and Free IGF-I | This was a pharmacokinetic assessment in regards to rhIGF-1 completed in siblings with PAPP-A2 deficiency, Participants received a 120 mcg/kg dose of rhIGF-1 (Increlex). Pharmacokinetic measurements were obtained over 24 hours. To isolate the effect of injected rhIGF-1, baseline-corrected concentrations were included by subtracting baseline concentration from measured concentrations. Results reported include time to maximum corrected total IGF-I and free IGF-I. Due to constraints of reporting platform, maximum corrected total IGF-I and free IGF-I values and area under the curve (AUC) 12 hours after the dose are reported as separate outcomes. | At baseline, prior to the ongoing treatment phase with rhIGF-1 |
| Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Area Under the Curve | This was a pharmacokinetic assessment in regards to rhIGF-1 completed in siblings with PAPP-A2 deficiency, Participants received a 120 mcg/kg dose of rhIGF-1 (Increlex). Pharmacokinetic measurements were obtained over 24 hours. To isolate the effect of injected rhIGF-1, baseline-corrected concentrations were included by subtracting baseline concentration from measured concentrations. Results reported include area under the curve (AUC) 12 hours after the dose. Due to constraints of reporting platform, maximum corrected total IGF-I and free IGF-I, as well as time to maximum values separate outcomes. | At baseline, prior to the ongoing treatment phase with rhIGF-1 |
Unaffected heterozygous PAPP-A2 deficient relatives (2 parents). |
| BG002 | Health Control Participants | Healthy adult controls with no known variants in PAPP-A2. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| OG001 | Untreated Comparison | Patient deficient in PAPP-A2 with short stature who was not treated with rhIGF-1 due to development of pseudotumor cerebri (sibling of treated patient) |
|
|
| Secondary | Height Standard Deviation Score | Height Standard Deviation Score is the standard deviation above or below the mean the height is for age and gender. Values were obtained by plotting heights on Centers for Disease Control and Prevention growth charts. An increase in Height Standard Deviation Score correlates with increase in height. Results are reported for the participant with PAPP-A2 deficiency treated with rhIGF-1, as well as sibling who did not continue treatment with rhIGF-1. | The participant treated with rhIGF-1 continued on treatment for five years, when he elected to discontinue treatment after reviewing current growth trajectory and skeletal maturation. His untreated sibling was followed for four years through completion of growth. | Posted | Number | standard deviation score | Annually until completion of study, up to 6 years |
|
|
|
| Secondary | Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | Assess the PK/PD relationship (PD marker being IGFBP-3) annually while on treatment with rhIGF-1 | Biochemical measurements in patient treated with rhIGF-1 over five years. | Posted | Number | ng/mL | Yearly until completion of the study, up to 6 years |
|
|
|
| Other Pre-specified | Glucose Pre- and Post-treatment With Recombinant Human IGF-I | Observe nonparametric measures of glucose pre and post ongoing treatment with rhIGF-1. Oral glucose tolerance tests (OGTT) were performed annually during the five-year treatment period at pre-treatment (baseline) and post-initiation of treatment (after 12 months, 24 months, 36 months, 48 months, and 60 months). | OGTT results at baseline, 12 months, 24 months, 36 months, 48 months, 60 months | Posted | Number | mg/dL | Yearly until completion of the study, up to 6 years |
|
|
|
| Other Pre-specified | Insulin Metabolism Pre- and Post-treatment With Recombinant Human IGF-I | Observe nonparametric measures of insulin metabolism in each individual pre (baseline) and post ongoing treatment with rhIGF-1. Oral glucose tolerance testing (OGTT) was performed pre-treatment (baseline) and post-treatment (after 12 months, 24 months, 36 months, 48 months, and 60 months). | insulin levels measured with OGTT | Posted | Number | mcIU/mL | Annually through completion of the study, up to 6 years |
|
|
|
| Other Pre-specified | Body Mass Index at Baseline and on Treatment With rhIGF-I | Observe nonparametric measures of body composition pre (baseline) and post ongoing treatment with rhIGF-1 (assessed after 12 months, 24 months, 36 months, 48 months, and 60 months of rhIGF-1 treatment). BMI percentiles were determined utilizing Centers for Disease Control and Prevention growth charts. | Posted | Number | percentile | Annually until completion of the study, up to 6 years |
|
|
|
| Other Pre-specified | Body Composition at Baseline and on Treatment With rhIGF-I | Observe nonparametric measures of body composition pre (baseline) and post ongoing treatment with rhIGF-1 (assessed after 12 months, 24 months, 36 months, 48 months, and 60 months of rhIGF-1 treatment). Body fat content and lean body mass were evaluated with dual energy x-ray absorptiometry. | Posted | Number | g | Annually until completion of the study, up to 6 years |
|
|
|
| Other Pre-specified | Total Body Fat Percentage at Baseline and on Treatment With rhIGF-I | Observe nonparametric measures of body composition pre (baseline) and post ongoing treatment with rhIGF-1 (assessed after 12 months, 24 months, 36 months, 48 months, and 60 months of rhIGF-1 treatment). Body fat content and lean body mass were evaluated with dual energy x-ray absorptiometry. | Posted | Number | percentage of total body fat | Annually until completion of the study, up to 6 years |
|
|
|
| Other Pre-specified | C-telopeptide and Osteocalcin Concentrations at Baseline (Pre-treatment) and While on rhIGF-1. | Observe nonparametric measures of bone turnover pre-treatment (baseline) and post initiation of ongoing treatment (at 12 months, 24 months, 36 months, 48 months, and 60 months) while on rhIGF-1 | Posted | Number | ng/mL | Yearly until completion of the study, up to 6 years |
|
|
|
| Other Pre-specified | Bone Density Pre-treatment (Baseline) and on Treatment With rhIGF-1 | Observe nonparametric measures of bone density at baseline (pre-treatment) and post initiation of ongoing treatment with rhIGF-1. Dual energy x-ray absorptiometry (DXA) was performed of total body less head, lumbar spine, hip, and forearm. Results are reported as height adjusted z-scores for age and gender, commonly done for bone density. A z-score of 0 is equivalent to population mean, positive above the mean, and negative below the mean. Z-scores within 2 standard deviations of the mean (Z-score 2 to -2) are generally considered normal, however are not sufficient to comment on presence or absence of osteoporosis in the pediatric population. | Posted | Number | z-score | Annually until completion of therapy, up to 6 years |
|
|
|
| Other Pre-specified | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Maximum Corrected Total IGF-I and Free IGF-I | This was a pharmacokinetic assessment in regards to rhIGF-1 completed in siblings with PAPP-A2 deficiency, Participants received a 120 mcg/kg dose of rhIGF-1 (Increlex). Pharmacokinetic measurements were obtained over 24 hours. To isolate the effect of injected rhIGF-1, baseline-corrected concentrations were included by subtracting baseline concentration from measured concentrations. Results reported include maximum corrected total IGF-I and free IGF-I. Due to constraints of reporting platform, time to maximum values and area under the curve (AUC) 12 hours after the dose are reported as separate outcomes. | Posted | Mean | Full Range | mcg/L | At baseline, prior to the ongoing treatment phase with rhIGF-1 |
|
|
|
| Other Pre-specified | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Time to Maximum Corrected Total IGF-I and Free IGF-I | This was a pharmacokinetic assessment in regards to rhIGF-1 completed in siblings with PAPP-A2 deficiency, Participants received a 120 mcg/kg dose of rhIGF-1 (Increlex). Pharmacokinetic measurements were obtained over 24 hours. To isolate the effect of injected rhIGF-1, baseline-corrected concentrations were included by subtracting baseline concentration from measured concentrations. Results reported include time to maximum corrected total IGF-I and free IGF-I. Due to constraints of reporting platform, maximum corrected total IGF-I and free IGF-I values and area under the curve (AUC) 12 hours after the dose are reported as separate outcomes. | Posted | Mean | Full Range | h | At baseline, prior to the ongoing treatment phase with rhIGF-1 |
|
|
|
| Other Pre-specified | Pharmacokinetic Description After Receiving Recombinant Human Insulin Like Growth Factor 1 (rhIGF-1): Area Under the Curve | This was a pharmacokinetic assessment in regards to rhIGF-1 completed in siblings with PAPP-A2 deficiency, Participants received a 120 mcg/kg dose of rhIGF-1 (Increlex). Pharmacokinetic measurements were obtained over 24 hours. To isolate the effect of injected rhIGF-1, baseline-corrected concentrations were included by subtracting baseline concentration from measured concentrations. Results reported include area under the curve (AUC) 12 hours after the dose. Due to constraints of reporting platform, maximum corrected total IGF-I and free IGF-I, as well as time to maximum values separate outcomes. | Posted | Mean | Full Range | mcg*h/L | At baseline, prior to the ongoing treatment phase with rhIGF-1 |
|
|
|
| 0 |
| 3 |
| 1 |
| 3 |
| 2 |
| 3 |
| EG001 | PAPP-A2 Heterozygous Relatives | Unaffected heterozygous PAPP-A2 deficient relatives (2 parents). | 0 | 2 | 0 | 2 | 0 | 2 |
| EG002 | Healthy Control Participants | Healthy controls between the ages of 18-30. | 0 | 2 | 0 | 2 | 0 | 2 |
| Headaches | Nervous system disorders | Non-systematic Assessment |
|
| Hair loss | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Fever | Infections and infestations | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | Non-systematic Assessment |
|
| Body aches and chills | Infections and infestations | Non-systematic Assessment |
|
| Mild lipohypertrophy | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Flu type A | Infections and infestations | Non-systematic Assessment |
|
| Viral strep throat | Infections and infestations | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Leg pain with walking | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Vitamin D deficiency | Metabolism and nutrition disorders | Non-systematic Assessment |
|
| Thrush on tongue | Ear and labyrinth disorders | Non-systematic Assessment |
|
| Otitis externia | Ear and labyrinth disorders | Non-systematic Assessment |
|
| Priaprism | Reproductive system and breast disorders | Non-systematic Assessment |
|
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| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D004700 | Endocrine System Diseases |
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