Genetic Disorders Flashcards

Question

What gene causes Anderson-Tawill syndrome and what is the inheritance?

Answer 1

KCNJ2 Autosomal dominant with variability

Answer 2

Significant cardiac manifestations * may need a pace maker * Can have sudden cardiac death Myotonia (delayed muscle relaxation

Answer 3

Channelopathy Abnormal long exercise test normal short exercise test

Answer 4

Loss of functioning maternal UBE3A gene * deletion most common * paternal UPD 15 * imprinting center defect (ICD) * UBE3A mutation (will have normal methylation) Could be inherited from normal mother if mom inherited a deletion, ICD, or mutation from her father

Answer 5

Methylation study * If abnormal, can do deletion analysis and/or UPD study to find out mechanism * If normal but still suspicion, sequence & del/dup UBE3A

Answer 6

Features * Severe developmental and speech delay * Receptive communication \> expressive * Hypotonia and feeding difficulties in infancy, tongue thrust or suck/swallowing disorders * Gait ataxia, wide based gait with hands raised while walking * Happy demeanor, happy puppet hands * Fascination with water * Seizures * Abnormal sleep cycles * Absolute or relative microcephaly by age 2 * Prominent chin, wide mouth and wide spaced teeth, hyperpigmented skin, light hair/eyes, scoliosis, constipation

Answer 7

ATM Autosomal recessive Carriers at increased risk for breast cancer

Answer 8

Features * Progressive cerebellar ataxia b/w 1-4 years * Oculomotor apraxia (eyes don’t work in symmetry) * Frequent infections, immunodeficiency * Choreoathetosis (dancing type movements that can’t be controlled) * Telangiectasias of the conjunctivae (lots of vessels in the sclera) * Increased risk for malignancy * Leukemia & lymphoma (1/3) * Sensitive to ionizing radiation

Answer 9

**Uveal melanoma** cutaneous melanoma renal cell carcinoma mesothelioma lung adenocarcinoma meningioma peritoneal serous adenocarcinoma

Answer 10

BAP1 BRCA2 CDKN2A

Answer 11

Dystrophin gene Majority large deletions In-frame deletions usually

Answer 12

X-linked recessive

Answer 13

Loss of ambulation \>12 years Looks like Duchenne Muscular dystrophy, but they do better Isolated cardiomyopathy Myalgias (muscle aches)

Answer 14

Imprinting on chromosome 11 * Same region as Russel-Silver syndrome Mom's copy is missing/mutated or dad's copy is overexpressed * 50% hypomethylation of imprinting center 2 (IC2) on maternal copy * 20% paternal UPD * can be from gain of methylation of maternal CDKN1C, a microdeletion/duplication, or a translocation/inversion * Rarely autosomal dominant

Answer 15

Features * Big baby * **Omphalocele** * **Prematurity** * **Macroglossia** * Asymmetry * Hypoglycemia * Umbilical hernia * Neonatal hypoglycemia * Ear creases/pits * Renal abnormalities * Overgrowth Tumor risk * Wilms tumor * Hepatoblastoma

Answer 16

Wilms tumors Hepatoblastoma

Answer 17

B+/B+ or B+/B0 Mild anemia later presentation at risk for iron overload

Answer 18

B/B+ or B/B0 A Elevated A2 Fetal may or may not be elevated

Answer 19

B+/B+ or B+/B0 Elevated A2 Elevated Fetal A present

Answer 20

B0/B0 Elevated A2 Elevated fetal NO A

Answer 21

B0/B0 Features * Severe microcytic anemia * FTT, feeding difficulties, diarrhea * Frontal bossing, limb shortening, compression fractures of the spine * Hepatosplenomegaly * Jaundice * Iron overload * Extramedullary hematopoiesis * Endorine and liver issues

Answer 22

Autosomal recessive

Answer 23

No features if treated with biotin supplement

Answer 24

If untreated * Sensorineural hearing loss * Seizures * vision loss * hair loss * Hypertonic * Developmental delay/intellectual disability * Ataxia

Answer 25

BLM gene autosomal recessive AJ founder mutation

Answer 26

Chromosome breakage syndrome

Answer 27

1 in 100 AJ carrier frequency

Answer 28

Features * Pre- and postnatal growth deficiency * Microcephaly, dolichocephaly * malar hypoplasia * loss of lower lashes * Little subcutaneous fat * Facial telangiectatic erythemia & sun sensitive skin * Areas of hyper- and hypopigmentation * Possible learning disability, but normal intelligence * Males infertile, early menopause for women * More infections due to GER * Increased risk for DM, cancer, and COPD

Answer 29

Autosomal dominant

Answer 30

Hearing loss * conductive, sensorineural, or mixed External ear abnormalities (pits or severely deformed) Branchial cleft cysts or fistulae (lump in the neck or collarbone) Kidney abnormalities

Answer 31

SOX9 cartilage gene Autosomal dominant

Answer 32

Features * bent long bones (campomelia) * short stature * hearing loss * scolosis * Pierre-Robin sequence * sex reversal in males * club feet * problems with cartilage in the trachea * leads to severe air trapping

Answer 33

Multifactorial Increased risk wit HLA-DQA1 adn HLA-DQB1 alleles (3% with one or both of these alleles develops celiac, but 30% of the general population have one of the alleles)

Answer 34

5-10% risk if you have an affected FDR 40% risk if you have the same HLA profile as the affected FDR

Answer 35

Autoimmune disorder to ingestion of gluten * Leads to inflammation of the small intestine and damage of villi, which can impair nutrient absorption Signs/symptoms * Diarrhea, bowel irritability * Abdominal pain and distention * Weight loss * Vitamin deficiency, FTT, short stature, dental/enamel defects * Chronic fatigue * Joint pain/inflammation, osteoporosis/osteopenia * Depression, ADD * Infertility, fetal loss * Delayed puberty * Migraines

Answer 36

CDH7 gene Autosomal dominant majority de novo

Answer 37

**C**oloboma * Looks like a break in the iris and pupil is coming out Congenital **h**eart defect * ASD, VSD, mitral valve defects Choanal **a**tresia * Respiratory and feeding problems **R**etardation of Growth and mental development * May mimic autism * Facial asymmetry, unilateral facial palsy from cranial nerve dysfunction **G**enital defects * Genital hypoplasia, delayed puberty from hypogonadotropic hypogonadism **E**ar malformations * May be deaf * External and internal malformations

Answer 38

CHM gene X-linked Females have milder signs

Answer 39

Progressive choroido-retinal degeneration

Answer 40

Males present with * early night blindness (not muc peripheral vision loss) * Central vision is preserved until later in life Gene therapy trials

Answer 41

PIK3CA heterozygous somatic mutations test skin, saliva, or affected tissue de novo

Answer 42

Lipomatous overgrowth syndrome

Answer 43

Features * **C**ongenital **l**ipomatous asymmetric **o**vergrowth * Of the trunk, lymphatic, capillary, and venous * Typically of the thoracic and abdominal wall * Combined-type **v**ascular malformations * Low-flow and high-flow vascular and lymphatic malformations * **E**pidermal nevi * **S**keletal and **s**pinal anomalies * Can have various degrees of intellectual disability because of it * Renal anomalies * Tumors

Answer 44

Autosomal dominant

Answer 45

Autosomal dominant

Answer 46

Demyelinating * slow nerve conduction velocity * pathology of nerves has an onion appearance

Answer 47

Axonal * nerve conduction velocity near normal * decreased number of nerves

Answer 48

Autosomal recessive Axonal (decreased number of nerves)

Answer 49

X-linked dominant

Answer 50

PMP22 Duplications (have 3 copies of PMP22) * 4 copies of PMP22 is severe CMT1 * (A deletion of PMP22 causes hereditary neuropathy with liability to pressure palsy)

Answer 51

Onset 1st-2nd decade Slow progression to orthotics Foot deformities foot drop distal muscle weakness distal muscle atrophy sensory loss slow nerve conduction

Answer 52

ERCC6 and ERCC2 autosomal recessive

Answer 53

Premature aging syndrome

Answer 54

Features * Progressive neurological and cognitive dysfunction (demyelination) * Microcephaly with developmental delay, spasticity, ataxia * Low birth weight and postnatal growth failure (Cahectic dwarfism) * Muscle atrophy, weight loss * Skin photsensitivity * Dental decay * Pigmentary retinopathy, optic atrophy, cataracts * Sensorineural hearing loss * vision loss, cataracts * Skeletal abnormalaties (kyphosis, scoliosis) * Prematurely aged face with deep set eyes and pinched nose

Answer 55

PHOX2B Caused by a decrease in a triplett repeat Autosomal dominant mostly de novo and/or mosaic

Answer 56

Features * Apnea * Stop breathing when go to sleep * Absent respiratory response to hypoxia and hypercapnia, no change in respiratory effort during CO2 inhalation, illness, or exercise * Profound in sleep, especially non-REM sleep * Cyanosis * Cardiorespiratory arrest * Ophthalmologic abnormalities due to cranial nerves * Some have hirschprung (specific mutation) * Neural crest tumors * Arrhythmias * Some have seizures & cognitive disability

Answer 57

X-linked Autosomal dominant Autosomal recessive

Answer 58

Night blindness Contrast sensitivity Nystagmus

Answer 59

NIPBL gene mostly Autosomal dominant 99% de novo

Answer 60

Features * Growth retardation * Facial * Long eyelashes * Thick eyebrows/synophorus, arched eyebrows * Upturned nose * Small widely spaced teeth * Microcephaly * Cognitive delay * Autistic and self-destructive tendencies * Shortened limbs * Missing digits * Genital abnormalities * GI dysfunction * Hearing loss * myopia * Cardia septal defects (VSD)

Answer 61

5p- loss of CTNND2, SEMA5A, possibly TERT 90% de novo, 80% from deletion of paternal copy

Answer 62

4:3 females:males

Answer 63

Features * Cat cry * Heart defects (VSD, ASD, PDA, Tetralogy of fallot) * Significant intellectual disability * Self-injury * Abnormal sleep patterns * Microcephaly * Hypotonia, poor feeding, Cleft lip/palate * Thymic dysplasia * Intestinal malrotation, megacolon, inguinal hernia * Dislocated hips * Rare renal malformations * Cryptorchidism, hypospadias * Hyperextensible joints * Scoliosis * Face * Hypoplastic nasal bridge * Hypertelorism, down-slanting palpebral fissures, Deep set eyes, prominent supraorbital ridges * Myopia, cataracts * Low-set ears with tags and/or fistulas * Micrognathia, cleft lip/palate * Short fingers * 2,3 syndactyly of hands and/or feet * Club feet, flat feet

Answer 64

Multifactorial 29 genes, SNPS, and HLA status important Environment, lifestyle, diet important

Answer 65

Signs and symptoms * Weight loss, loss of appetite * Fever * Fatigue, night sweats * Loss of normal menstrual cycle * Mouth ulcers * Abdominal pain, diarrhea, bowel obstruction, rectal bleeding Crohn’s disease * Mostly affects the ileum and entire thickness of the bowel wall * Can affect GI system anywhere from mouth to anus, and can “skip” areas Ulcerative colitis * Affects the innermost lining of the colon/large intestine with no skipping

Answer 66

Lung disease from increased mucus * Poor genotype/phenotype correlation * Infection Pancreatic insufficiency * Severe, classic mutations lead to pancreatic insufficiency * Milder, nonclassic mutations lead to pancreatic sufficiency Infertility in males (\>97%) * May be only feature

Answer 67

Features/signs * Affects the whole body * Night blindness * Can’t digest fat, so vitamins don’t get absorbed * Sterility in males due to CBAVD & decreased fertility in females * Digital clubbing * Osteoporosis * Diabetes * Cirrhosis * Dry, salty skin * Chronic pain * Liver disease * Can be associated with diabetes

Answer 68

First line testing is sweath chloride test Then do a panel of common mutations * can reduce carrier risk to 1 in 240 Can also do sequencing and del/dup * Can reduce carrier risk to 1 in 2500 * Is this worth it for the family?

Answer 69

CFTR autosomal recessive

Answer 70

Reduced or absetn transcription and protein Read through therapy

Answer 71

Protein is made, but it isn't processed correctly and gets destroyed immediately. Never makes it to the cell surface Gets destroyed becuase of protein misfolding, incomplete/incorrect post-translational modifications, or error in protein trafficking Therapy would be correctors to help the protein fold properly and get to the cell surface DeltaF508

Answer 72

Protein is made and it gets to the cell surface, but it doesn't function properly Treat with Kalydeco

Answer 73

Protein is made and gets to the cell surface, but it doesn't work as well as it should. It is a little functional, though R117H * If cis poly-T tract is 5T, it is disease causing because affects folding & gives alternate splicing * Having a higher TG tract with 5T makes it more likely to be disease causing because it leads to skipping of exon 9

Answer 74

There is reduced synthesis/protein production because of alternative splicing

Answer 75

Protein gets to the cell surface, but it is unstable and quickly get degraded Rescued DeltaF508

Answer 76

Class II Protein is made, but isn't processed quickly and quickly gets destroyed Once it has been treated with a corrector (helps fold the protein), it becomes a Class VI mutations (protein gets to the cell surface, but then gets quickly degraded)

Answer 77

Class III (protein is made and gets to the cell surface, but it doesn't function properly) Treat with Kalydeco Accounts for 4% of CF mutations

Answer 78

Poly T tract: * The lower the poly T tract (5T), the more likely it is to be pathogenic * 5T, and potentially 7T can be pathogenic when in cis with R117H * Homozygous 5T can be at risk for male infertility * Lower T-tract is pathogenic because it can cause skipping of exon 9 TG-tract * Only pathogenic when in combination with 5T poly-T tract * The higher the TG-tract is (12 or 13), the more likely it is to be pathogenic when combined with 5T * 5T with 12 or 13 TG tract without R117H mutation can cause nonclassic disease * A higher TG tract can lead to skipping of exon 9

Answer 79

GJB2 Autosomal recessive

Answer 80

Non-syndromic congenital sensorineural hearing loss (DFNB1) Milder presentation for compound heterozygotes

Answer 81

10-15% of all hearing loss 50% of autosomal recessive hearing loss

Answer 82

1 in 31-35 for Caucasians 1 in 21-25 for AJ

Answer 83

Multifactorial * Genetics (stronger for Type II) * diet, exercise, weight (74% of risk for Type II) * HLA status

Answer 84

Autosomal dominant

Answer 85

1-2% of diabetes is MODY

Answer 86

MODY has an effective treatment (sulfonylureas), which does not work for other types of diabetes

Answer 87

Autosomal dominant

Answer 88

**Pleuropulmonary blastoma (PPB)** **Cystic nephroma** **Ovarian Sertoli-Leydig tumor** Other sex-cord stromal tumors Wilms tumor (rare) Intraocular medulloepithelioma Nasal chondromesenchymal hamaroma (present with stuffy nose) Thyroid (nodular thyroid hyperplasia, differentiated thyroid carcinoma) Embryonal rhabdomyosarcoma Intestinal hamartomatous polyps

Answer 89

The cancer risk is greatest when young

Answer 90

PPB may present as a spontaneous pneumothorax Test for DICER1 60-70% of these cases are from DICER1 mutations

Answer 91

DICER1 90-100% are due to DICER1 mutations 2/3 of cystic nephroma cases without a family history of PPB have a DICER1 mutation

Answer 92

Dystrophin gene Out of frame deletions X-linked recessive

Answer 93

Features/presentation * Inability to run/keep up around age 3 * Gower maneuver * Difficulty climbing stairs * Gait abnormalities/toe walking * Calf hypertrophy (pseudohypertrophy from fatty infiltration) * Proximal leg weakness, progressing to arms * Wheelchair confined by age 12 * Can’t life arms very high * Scoliosis because muscles can’t hold them up * Squishes lungs and leads to respiratory issues * Sleep disorders due to extra shallow breathing * Can’t take deep breaths or cough properly * Dilated cardiomyopathy * Mild obesity (because of steroids) * Mild mental retardation * CK levels 50-100x normal * Death due to pneumonia or congestive heart failure (DCM) in 20s

Answer 94

Muscle aches May have elevated CK levels May be more severely effective due to mosaicism (10%) or skewed X-inactiation

Answer 95

2/3 (1/3 of cases are de novo)

Answer 96

Stop codon readthrough Exon skipping therapies * Make an out of frame deletion and in-frame to give BMD phenotype * Restores reading frame in ~13% * Gives some expression of dystrophin Gene transfer therapy * Myostatin inhibitor to get hypertrophy * Decreases severity of disease Gene replacement * Mini-dystrophin in vector Surrogate gene transfer of Galgt2 * Restores CK levels * Doesn’t induce immunity because the gene is already expressed

Answer 97

COL5A1 gene, autosomal dominant Features * Skin hyperextensibility * fish mouth or cigarette paper scars * joint hypermobility

Answer 98

Major criteria * Smooth, velvety skin * Joint hypermobility Minor criteria * Chronic joint/limb pain * Recurrent joint dislocations * Positive family hx Other features * Narrow, high arched palate * Scoliosis * Flat feet * Valgus deformity * Marfanoid habitus, but don’t meet Marfan criteria * Pectus excavatum (carinatum more rare) * Constipation, IBS, GER * Family hx of fibromyalgia

Answer 99

Autosomal dominant Clinical dx only, no known gene

Answer 100

COL3A1 Autosomal dominant

Answer 101

Features * Arterial, bowel, and uterine ruptures * Pneumothorax * Postpartum bleeding * Lobeless ears * Acrogeria (premature aging, hands may look really old) * Translucent skin (seen veins) * A little bit of joint hypermobility

Answer 102

Lysosomal storage disorder

Answer 103

GLA gene X-linked recessive with varied symptoms in females

Answer 104

Features * Pain in distal extremities * Heat intolerance * Angiokeratomas on trunk * GI dysfunction * Renal disease * Cardiomyopathy * Stroke

Answer 105

ERT available, but not 100% effective * Decreases vascular lesions * Increases renal and myocardial function * Decreases pain * Increases heat/cold tolerance by improving nerve conduction * Improve exercise intolerance * Improves quality of life

Answer 106

4q35 regions Need to do southern blot to detect D4Z4 repeat encodes DUX4 * Causes myopathy via a p53 dependent pathway Get disease when have reduce repeats (1-10) and 4QA allele (makes poly-A tail) Not a trinucleotide repeat where size varies between generations 1:20,000-435,000

Answer 107

Facial weakness * Tapered lip, can’t smile well, can’t squeeze eyes shut, chiseled cheek bones, can’t pucker lips, many can’t drink through a straw Scapula stick out Peroneal and hip girdle weakness later Weakness in pectoral muscles and biceps * Atrophic biceps with maintained deltoids Can’t lift arms very high Hypertrophy of forearms Sensorineural deafness Retinal vascular tortuosity possible Absent brachio-radialis Bulbar, extraocular, and respiratory muscles spared asymetric onset and progression Relatively normal CK

Answer 108

F5 gene p.Arg506Gln, 1691G\>A

Answer 109

Venous thromboembolism (VTE) (deep vein thrombosis) * Heterozygous: 3-8x increased risk for VTE (\<10%) * Homozygous 50-80x increased risk for VTE (\<10%) * Risk increases with age * No impact on risk for a recurrent VTE Pulmonary emboism Small increased risk (2-7 fold increased risk) for pregnancy loss and pregnancy complications Other risk factors include pregnancy, oral contraceptives/HRT, cancer, age, obesity, surgery, injury

Answer 110

APC (many mutations not detected) Autosomal dominant

Answer 111

Colon cancer * 100s-1000s of polyps * risk 100% if untreated Extracolonic tumors * Upper GI * Desmoid * Osteoma * Thryoid * Brain * Soft tissues tumors * hepatoblastoma * 2% risk * CHRPE * Dental anomalies

Answer 112

MEFV gene (sequence only) Autosomal recessive High carrier frequency in Turkey & North African Jewish (1:5), and Armenian (1:7)

Answer 113

Features * Recurrent fevers in childhood may be only manifestation * Abdominal attacks (90%) * Recurrent, acute fevers with intense abdominal pain * Articular attacks (75%) * High fever and joint pain, can lead to chronic joint pain * Pleural attacks (45%) * High fever with chest pain & painful breathing * Erysipelas-like erythema * Lesion on lower limb often accompanied by a fever or arthritis * Amyloidosis (Build up of AA amyloids in kidneys) * can lead to end stage renal disease (presents with proteinuria)

Answer 114

Mostly autosomal recessive FANCB is X-linked Homozygous BRCA2 and PALB2 cause Fanconi anemia FANCC gene has a common AJ mutation 15 genes

Answer 115

Chromosome breakage syndrome

Answer 116

Features * Progressive bone marrow failure (usually in 1st decade, 90% by 4th-5th decade) * Short stature * Abnormal skin pigmentation, Café-au-lait spots * Skeletal, thumb, forearm malformation, radial ray anomalies * Ocular issues * Kidney/urinary disease, GI abnormalities * Hearing loss * Heart defects (VSD) * Developmental delay * Underdeveloped pituitary, hypogonadism * Cancer * Hemotolagic (10-30%) * Head and neck, GI, genital tract (25-30%)

Answer 117

PIK3CA heterozygous **somatic** mutations (test skin, saliva, or affected tissue) De novo

Answer 118

Lipomatous overgrowth syndrome

Answer 119

Features * Cutaneous capillary vascular malformations * Testicular or epidymal abnormalities * Epidermal nevi * Polydactyly

Answer 120

25% have an autism spectrum disorder

Answer 121

Genetically male (XY) ambiguous genitalia kidney problems (focal segmental glomerulosclerosis) gonadoblastoma Wilms tumor

Answer 122

GALT gene autosomal recessive

Answer 123

Disorder of carbohydrate metabolism Treat by eliminating galactose from the diet

Answer 124

Features * Failure to thrive * Hepatomegaly * Cataracts * Speech and developmental problems when not treated * Vomiting, diarrhea, dehydration

Answer 125

GBA gene autosomal recessive

Answer 126

Lysosomal storage disorder

Answer 127

Features * Hepatosplenomegaly * Cytopenia * Gaucher cells (pathoneumonic) * Erlenmeyer flask shape to bones * Vascular necrosis

Answer 128

Enzyme replacement therapy available * Decreases hepatosplenomegaly * Improves liver and spleen function * Improves bone manifestations * Helps with growth

Answer 129

HFE gene (C282Y adn H63D) Autosomal recessive

Answer 130

Increased iron accumulation * can lead to diabetes * hyperpigmentation of skin (bronze) * arthritis * CV issues Treat with phlebotomy

Answer 131

F8 gene, Factor VIII deficiency, Hemophilia A, most common F9 gene, Factor IX deficiency, Hemophilia B X-linked

Answer 132

Symptoms * Mild hemophilia * menorrhagia * bleeding with tooth extraction, trauma, etc * easy bruising Obligate carrier is father is affected, 2 sons affected or 1 affected sone and 1 affected maternal relative If son is a simplex case * 30% chance the son is a de novo case * Mom could have a de novo mutation * common with inversion 22, which occurs during spermatogenesis 90% of the time * Mom could have inherited it from her mom

Answer 133

Hemorrhage (spontaneous or with incidental injury) Joint or deep muscle bleeds (severe) bleeding after mild trauma, minor procedures, surgery Severe \<1% factor Modertae 1-5% factor Mild 6-35% factor

Answer 134

Carrier screening, prenatal testing, or confirming a diagnosis To figure out inhibitor risk * Genotype/phenotype correlation with this * inversion22 has a high risk for inhibitors

Answer 135

Deletion of PMP22 (only have 1 copy of PMP22) Can also be PMP22 point mutations (Duplication of PMP22 causes CMT1A)

Answer 136

* Young adult onset * mild axonal peripheral neuropathy * tomauli are a pathological hallmark (looks like sausages)

Answer 137

CFTR PRSS1 SPINK-1

Answer 138

May appear like albinism normal or decreased vision Many die from bleeding diathesis 2 founder mutations in Puerto Rico

Answer 139

IDS gene x-linked

Answer 140

Mucopolysaccharidosis

Answer 141

Features * Coarse facial features (gets worse over time) * Hepatosplenomegaly * Joint contractures * Developmental delay/intellectual disorders * Limited range of motion

Answer 142

ERT available * Decreases GAGS * Improves hepatosplenomegaly * Improves airway problems (often have storage in their airway) * Improves sleep apnea * Improves motor function * Improves myocardial function * Improves range of motion in joints * Give better growth rate

Answer 143

HTT gene Autosomal dominant with anticipation CAG trinucleotide repeat * 10-27 repeats normal * 28-35 repeats normal, but risk for expansion * 36-39 reduced penetrance, risk for expansion * 40+ repeats=disease

Answer 144

Features * Progressive neurodegeneration * Unseteady gait and involuntary movements * Personality changes, mood swings, outbursts, depression, OCD * Forgetfulness, impaired judgement, decreased memory, reasoning, and concentration * Slurred speech and difficulty swallowing * Onset 30s-40s, live 15-20 years after onset

Answer 145

IDUA autosomal recessive

Answer 146

Mucopolysaccharidosis

Answer 147

Features * Coarse facial features * Hepatosplenomegaly * Corneal clouding * Joint contractures & limitations * Developmental delay/intellectual disorders * Macroglossia * Dysostosis multiplex (bone involvement) * Deafness * Valvular heart disease

Answer 148

Bone marrow transplant ERT available * Decreases GAGS * Improves hepatosplenomegaly * Improves airway problems (often have storage in their airway) * Improves sleep apnea * Improves motor function * Improves myocardial function * Improves range of motion in joints * Give better growth rate

Answer 149

Hunter syndrome is X-linked Hurler syndrome has corneal clouding

Answer 150

SCN4A gene Autosomal dominant

Answer 151

* Periodic paralysis * triggers include exercise, fasting, or cold exposure * myotonia * Problems with anesthesia * Inconsistently high serum potassium levels

Answer 152

Channelopathy Abnormal long exercise test, normal short exercise test

Answer 153

EDA, X-linked, most common EDAR, autosomal recessive EDARADD, autosomal dominant IKKG, NEMO, X-linked (immune deficiency)

Answer 154

Features * Thin, peely skin * Fine, dry hair, doesn’t grow well, abnormal pattern (**HYPERTRICHOSIS**) * Don’t sweat (**HYPOHIDROSIS**) * Hypoplastic or absent mucous glands * Hypodontia or anodontia with conical shaped teeth (**HYPODONTIA**) * May have low immune system with recurrent infections

Answer 155

CACNA1S and SCN4A Autosomal dominant

Answer 156

Channelopathy abnormal long exercise test, normal short exercise test

Answer 157

* Hours to days of muscle weakness * Can awak with paralysis * usually hours after exertion or a carbohydrate rich meal * Low potassium levels * can have problems with anesthesia * NO myotonia present

Answer 158

IKBKG gene X-linked dominant lethal in males

Answer 159

Skin lesions * Progress from herpes appearing lesions, to severe burn appearing lesions, to hyperpigmentation, to hypopigmented lesions CNS Problems * developmental delay (including cognitive) * seizures * microcephaly * spasticity * paralysis Dental manifestations * Late dentition, hypodontia, conical teeth Ocular manifestations * Strabismus, neovascularization, microphthalmos, optic nerve atrophy, cataracts, glaucoma

Answer 160

11q terminal deletion slightly more common in females

Answer 161

Features * Heart defects (VSD, hypoplastic left heart) * Kidney defects * FTT, feeding difficulties, pyloric stenosis * Recurrent infections (ear, respiratory) * Short stature, skeletal abnormalities * **High bleeding risk (Paris-Trousseau)** * ****20% die by age 2 from heart and bleeding problems * Developmental delay with mild to severe mental retardation * OCD, ADHD, short attention span * Facial * Macrocephaly, trigonalcephaly * Low set ears * Hypertelorism, ptosis, epicanthal folds, strabismus, coloboma * Broad nasal bridge, thin philtrum, micorgnathia, downturned mouth

Answer 162

KCNQ1 and KCNE1 Autosomal recessive Homozygous form of long QT syndrome

Answer 163

Risk of sudden death Congenital sensorineural hearing loss Fainting Both parents have long QT syndrome

Answer 164

Congenial severe vision loss nystagmus Group of disease, lots of genes

Answer 165

Mitochondrial inheritance heteroplasmy may affect phenotype 5:1 male:females affected

Answer 166

* Bilateral, painless, subacute visual failure * First color vision profoundly affected (especially red/green) * Then develops to blurred central vision, loss of central vision (peripheral vision spared) * Most have isolated optic neuropathy, some have systemic neuropathy * Tremors, myopathy, ovement disorders * Cardiac arrhythmias * Rapid optic nerve death * Onset late teens to early 30s, women develop later and may have an MS-like phenotype

Answer 167

SPRED1 gene autosomal dominant

Answer 168

* Isolated cafe-au-lait spots * important to differentiate from NF1 because screening is not needed * freckling * macrocephaly * intellectual disability

Answer 169

Cancers * Early onset bone sarcoma (except Ewing) * Early onset soft tissue sarcoma * Osteosarcoma * Early onset breast cancer * Adrenocortical carcinoma (50-80% of these are TP53) * Choroid plexus carcinoma (36-100% of these are TP53) * Rhabdomyosarcoma \<3 years (~25% of these are TP53) * Brain tumors * Multiple primary tumors, especially with radiation * 70% risk for males, 100% for females

Answer 170

TP53/Li-Fraumeni 50-80% of these are due to TP53 mutations

Answer 171

TP53/Li-Fraumeni 36-100% of these are due to TP53 mutations

Answer 172

TP53/Li-Fraumeni ~25% of these are due to a TP53 mutation

Answer 173

* Proband \<45 with sarcoma AND * FDR \<45 with any cancer AND * 3rd family member who is FDR or SDR \<45 with cancer, or sarcoma at any age

Answer 174

* Proband with any childhood cancer, or sarcoma, brain tumor, or adrenocortical tumor \<45 AND * FDR or SDR with LFS cancer at any age AND * another FDR or SDR with any cancer \<60 20% chance of having a TP53 mutation if meet this criteria

Answer 175

Autosomal Dominant

Answer 176

Autosomal recessive

Answer 177

* Affect the voluntary proximal muscles of the shoulder, hips, thighs, and top part of the arm * Waddling gait * Difficulty running, standing, climbing stairs. Fall frequently * Trouble raising and holding arms above head and carrying objects * Scapular winging, lordosis, scoliosis, contractures, calf hypertrophy * Cardiomyopathy or arrhythmia * Difficulty breathing

Answer 178

CK levels are elevated Muscle biopsy EMG Genetic testing with a panel

Answer 179

FBN1 gene (gain-of function mutation leads to decreased myofibrils, nonsense mutations lead to haploinsufficiency) Autosomal dominant

Answer 180

Features * Tall stature * Decreased upper segment/lower segment ratio * Arm span exceeds height * Dolichocephaly (long back of head) * Long, slender, curved fingers * Pectus carinatum/excavatum * Malar hypoplasia (flat cheeks) * Retinal detachment * Lens sublaxation or dislocation (ectopia lentis) * High myopia * Megalocornia * Long, spider fingers * Scoliosis * Flat feet * Pneumothorax * Striae not associated with marked weight change * Family hx of sudden death * Heart defects * Aortic aneurysm, aortic root dilation--\>sudden death

Answer 181

Microcephaly mental retardation congenital heart disease light colored hair

Answer 182

GNAS gene (activating mutation) Always somatic mosaicism, never inherited (don't do genetic testing)

Answer 183

Features * Polyostotic fibrous dysplasia (scar-like tissue in bones leading to uneven growth & fractures) * Age 3-10 * Facial-painless lumps, asymmetry, loss of vision/hearing rare * Skeletal-limping, pain, fractures * scoliosis * Café-au-lait like spots * Irregular borders (coast of Maine), not smooth, defined borders * First sign * Early puberty in girls * Thyroid lesions/disease (hyperthyroid) * Hypophosphatemia (severe skeletal involvement, fractures, bone pain) * Excess growth hormone * Neonatal Cushings syndrome-rare * Can also have malignancies, polyps, and cardiac involvement

Answer 184

PIK3CA gene Heterozygous somatic mutations * test skin, saliva, or affected tissue De novo

Answer 185

Brain overgrowth syndrome

Answer 186

Features * **Congenital or early post-natal megalencephaly** * Can have ventriculomegaly and hydrocephaly, cortical brain malformation and polymicrogyria * **Segmental or generalized overgrowhth** * **Midline facial capillary malformation** * **Hypotonia** * Intellectual disability * Autistic features * Epilepsy * Cutaneous syndactyly * Coarse facial features with frontal bossing * Heart defects (VSD, ASD) * GI problems * Tumors

Answer 187

ATP7A gene X-linked recessive

Answer 188

Copper deficiency * copper doesn't get absorbed correctly from the intestine * Copper builds up in some tissues (small intestine & kidneys) * Low copper levels in brain and other tissues

Answer 189

Features * Hypotonia * Kinky, brittle hair * Fragile skin, skin laxity * Hypopigmented skin * Umbilical or inguinal hernia * Pectus excavatum * Temperatures instability * hypoglycemia * Occipital horn in skull * Seizures * Failure to thrive * Neurodevelopmental delay & neurologic issues * Gastric polyps * Wormian bone * osteoporosis

Answer 190

Treat with copper injections Usually die around 9 months

Answer 191

CLCN1 gene Can be dominant (Thomsen myotonia congenita) Can be recessive (Becker myotonia congenita)

Answer 192

* Warm-up phenomenon * onset childhood to young adulthood * Myotonia (delayed muscle relaxation)

Answer 193

Channelopathy Abnormal short exercise test (repeated drops and rises because of warm-up phenomenon) Normal long exercise test

Answer 194

DMPK gene Autosomal dominant with anticipation CTG Triplett repeat expansion * 35-49 repeats-asymptomatic premutation * 50-~150 repeats-mild presentation * ~100-~1000 repeats-classic presentation * \>1000 repeats-congenital myotonic dystrophy Expands through the mother

Answer 195

* Myotonia * gait disturbance, weakness * Cataracts with Christmas tree appearance * Frontal balding, Ptosis and myotonic mouth * Arrhythmia, cardiomyopathy (cause of death) * Anxiety/depression, Hypersomnia, sleep apnea * Minor cognitive delay * Thyroid dysfunction * Diabetes * Testicular atrophy, gynecomastia, infertility * Constipation * Difficulty swallowing, dysphagia * Onset typically 20s-30s, * Death typically 48-55 years * Due to respiratory difficulty and/or cardiac disease

Answer 196

Autosomal dominant and autosomal recessive de novo 9 genes one gene common in Amish communities

Answer 197

Severe congenital, congenital, and childhood-onset forms * Severe congenital form is often lethal, severe hypotonia, GER, respiratory insufficiency * Amish form is lethal in early childhood, hypotonia, contractures, tremors, pectus carinatum, muscle atrtophy * Intermediate congenital form has contractures, weakness, need for wheelchair & ventilator support by 11 * Typical congenital has hypotonia, feeding difficulties, delayed motor milestones, waddling gait, bulbar and proximal weakness, nocturnal hypoventilation, recurrent infections, slow/static progressive weakness * Childhood onset 1st-2nd decade onset, foot drop, muscle slowness, slowly progressive * Adult onset 20-50 years, myalgia, cardiomyopathy, head drop, rapid progression * CK levels normal to mildly elevated * Muscle biopsy shows nemaline rods with Gomori tricome stain

Answer 198

NF1 gene Autosomal dominant 50% de novo

Answer 199

Diagnosis (2 of the the following) is highly specific (~50% meet by age 1 without family hx) * Skin lesions * Café-au-lait spots * ≥6 lesions over 5 mm when pre-pubertal, over 15mm if post-pubertal * Tend to grow and get bigger with the child * Plexiform neurofibromas * Tend to be invasive * Can be hard or soft * Earlier onset * ≥2 neurofibromas * Can be internal and never seen * Post-pubertal onset * Axilla and/or inguinal skin freckling * Eye findings * Lisch nodules * In 90% of patients over age of 6 * Iris hamartomas, don’t affect vision * Optic nerve glioma * Develop before age 6 * 3% become malignant, but can also spontaneously regress * May not affect vision, but can lead to blindness * Family history of NF1 * Skeletal Features * Sphenoid wing dysplasia (bone pushes eye out) * Usually unilateral * Pseudo-arthrosis bowing * Almost like a second joint that causes bowing in the leg or arm * These bones tend to be fragile and fracture

Answer 200

Plexiform neurofibroma tibial dysplasia cafe-au-lait developmental delay (mainly speech)

Answer 201

Optic glioma (by age 6) lisch nodules short stature hypertension cafe-au-lait

Answer 202

Dermal neurofibroma scoliosis hypertensin cafe-au-lait

Answer 203

Neurofibromas Cafe-au-lait Breast, thyroid, colon cancer (low risk) Hypertension

Answer 204

NF2 gene Autosomal dominant * 1/3 somatic mosaicism

Answer 205

Hearing loss * from bilateral vestibular schwannoma * can be presenting feature High risk for tumors * bilateral vestibular schwannoma * schwannomas of other cranial and peripheral nerves (60%) * meningiomas (50%) * Ependymomas (rare) * Astrocytomas (rare) Facial nerve palsy or other single nerve disorder compromise

Answer 206

Cafe-au-lait spots congenital heart defects (PVS, PDA, hypertrophic cardiomyopathy) Mild intellectual disability coarse facial features short stature webbing of the neck with low hairline

Answer 207

Autosomal recessive 4 genes (TYR, OCA2, TYRP1, SLC45A2)

Answer 208

General features * Hypopigmentation of hair, skin, iris (blue) * can see choroidal blood vessels in eyes * Infantile nystagmus, strabismus * Reduced visual acuity (from foveal hypoplasia) * With sun exposure * Rough/thickened skin (pachydermia) * Premalignant lesions (solar keratosis) and skin cancer * 4 different types with varying severity

Answer 209

Collagen gene Autosomal dominant

Answer 210

* Fractures * Conductive hearing loss in adulthood * because the middle ear bones break * Norma to short stature * joint hypermobility * dentinogenesis imperfecta (yellow, translucent teeth)

Answer 211

SCN4A gene Autosomal dominant

Answer 212

Myotonia worse in the cold, stiff in the cold

Answer 213

Channelopathy Abnormal short exercise test * immediate drop that stays low Normal long exercise test

Answer 214

Idiopathic Autosomal dominant Autosomal recessive X-linked

Answer 215

Resting tremor muscle rigidity Bradykinesia (slow movement) shuffling gait and/or postural instability depression, halluciations, dementia Can lose sense of smell

Answer 216

Mostly SCL26A4 gene, but can be FOX11 or KCNJ10 * can be digenic * 48% have no mutation found Autosomal recessive

Answer 217

Congenital sensorineural hearing loss * enlarged or dilated vestibular aqueduct * Think Pendred if you see this * Mondini malformation possible Thyroid goiters in early pubery to adulthood

Answer 218

Mandibular hypoplasia U-Shaped cleft palate big tongue obstructive apnea (from tongue) feeding difficulties

Answer 219

Stickler 22q11 deletion Treacher-Collins Compomelic dysplasia

Answer 220

Dizziness trouble standing up (because of blood vessel problems) Tachyarrhythmias (Treat with fluids and salts)

Answer 221

Loss/alteration to the paternal copy of 15q11.2-q13 * 70% from paternal deletion * Maternal UPD * Imprinting center defect (recurrence 50%) Do methylation testing of SNRPN

Answer 222

Features * Severe hypotonia and feeding difficulties, FTT as an infant * Excessive eating & morbid obesity in early childhood * Global developmental delay, most need lifetime support and supervision * Temper tantrums, manipulative behavior, stubborn, OCD * Infertility, hypogonadism * Short stature, small feet and hands * Hypopigmentation of skin, eyes, and hair * Sleep abnormalities (daytime sleepiness) * Scoliosis, strabismus * Almond shaped eyes, thin upper lip, down-turned mouth, narrow nasal bridge

Answer 223

Liver problems * cholestasis (high direct bilirubin) * liver cancer * liver disease and failure * May been liver transplant Itching Growth failure Pancrease, intestine, and lung problems

Answer 224

MECP2 gene X-linked

Answer 225

Males * severe but not lethal * intellectual disability * resting tremor * ataxia * enlarged testes Carrier females have milder symptoms

Answer 226

* Cowden syndrome-increased cancer risk * Thyroid cancer * Even in kids, get baseline ultrasound at age 5 * Breast cancer * Uterine cancer * Other cancers * GI polyps, bleeding risk * Begin cancer screening at age 18

Answer 227

BRRS * Macrocephaly * Big baby at birth, normal height as adult * hypotonia * Mild intellectual developmental delay * Hamartomas * Speckled penis * Autism * 5-10% of children with macrocephaly and an autism spectrum disorder have a PTEN mutation * Intestinal polyposis (hamartomas) * Lipomas, hemangiomas * May have same cancer risks as Cowden syndrome * Screen for thyroid nodules

Answer 228

Autosomal recessive

Answer 229

Severe progressive sensorineural hearing loss retinitis pigmentosa anosmia

Answer 230

Dietary restriction of phytanic acid high calorie diet plasmaphoresis for cardiac arrhythmias or extremem weakness

Answer 231

RB1 gene Autosomal dominant * 80% de novo, usually no family history * still test sibs in case germline mosaicism * If unilateral and no family history, 1 in 7 have a mutation Test tumor tissue first if possible in case it is due to somatic mosaicism

Answer 232

Retinoblastoma osteosarcoma soft tissue sarcoma brain tumors nasal cavity tumors

Answer 233

MECP2 gene (loss of function mutation) do deletin analysis X-linked dominant De novo mostly lethal in males

Answer 234

Eye exam every 3-4 weeks until age 1, then less frequently until age 3 Be aware of and evaluate bone pain or lumps for sarcoma risk Unsure if this extra screening needs to be done for somatic mosaicism

Answer 235

Features * Regression around 6 mos-1.5 years * Mental retardation * Language and learning disabilitys * Hand wringing * Lose the ability to walk * Parkinsonian-like symptoms Neurodegenerative disorder

Answer 236

Later regression than Rett Similar to unconfirmed Angelman but with regression Females can ahve few or no symptoms due to skewed X-inactivation Can have just mild learning disabilities and neurological manifestations MECP2 gene

Answer 237

**R**apid onset **o**besity **H**ypothalmic dysfunction **H**ypoventilation and respiratory manifestations **A**utonomic **d**ysregulation Behavior disorders (very rare)

Answer 238

HbS variant (on beta-globin gene HBB) + another beta-globin gene mutation (SS, SC, SB+, SB0) Autosomal recessive

Answer 239

HBB gene Glu6Val 1 in 12 African Americans are carriers 1 in 625 Caucasians are carriers

Answer 240

Features * anemia * Pallor * Delayed growth and puberty * Pain crises * Jaundice * Hand-foot syndrome (can’t bend hands & feet b/c of trapped RBCs) * Stroke * Acute chest syndrome (like pneumonia) * Fever, chest pain, hypoxia, and other respiratory symptoms * More common in kids, but can occur at any age * Most common cause of acute death in adults * Often follow vaso-occlusive crisis * General weakness * Priapism (erection won’t go away b/c of trapped RBCs) * Gallstones * Pulmonary hypertension * Chronic sores/ulcers on legs * Spleen dysfunction (splenomegaly) from sequestration and infarction * Infections (spleen fights infections) * Neurologic * Stroke, silent cerebral infarcts, cerebral hemorrhage, Moyamoya disease

Answer 241

* Prophylactic penicillin in children * illness can lead to an anemic crisis * prompt follow-up with fevers * risk for anemia * hydration * avoidance of climate extremes and extreme fatigue * Hydroxyurea * upregulates gamma chain production and fetal hemoglobin * bone marrow translplant for severe cases

Answer 242

In children * Infection * Splenic sequestration crises In adults * Chronic end-organ dysfunction * Thrombosis * Treatment-related complications Average lifespan 42y for males, 48 y for females

Answer 243

GPC3 gene X-linked

Answer 244

Overgrowth mental retardation dysmorphic features hepatoblastoma risk

Answer 245

Atypical/Tertoid rhabdoid tumor (AT/RT) (CNS rhabdoid) Rhabdoid (can be in kidney or soft tissue Schwanomatosis (multiple schwanomas)

Answer 246

Gonadal mosaicism common Can be deleted with 22q11 deletion syndrome

Answer 247

SMARCB1 ~35% of AT/RT are due to SMARCB1 mutations

Answer 248

SMARCB1 ~25% of rhabdoid tumors are due to SMARCB1

Answer 249

Baseline CNS MRI renal ultrasound

Answer 250

DHCR7 gene autosomal recessive Cholesterol biosynthesis problem (high 7-DHC levels because it can't be converted to cholesterol)

Answer 251

Features * 2,3 toe syndactyly * Cleft palate * Cataracts * Intellectual disability * Hearing loss * Renal anomalies * Liver disease * GI problems (Pyloric stenosis, Hirschprungs) * Sex reversal in males * Microcephaly & midline defects (Dandy-Walker malformation, Holoprosencephaly) * Facial * Ptosis, Epicanthal folds, Downward slanting palpebral fissures * Small upturned nose * Micrognathia & High arches palate * Congenital heart defects (AVSD, ASD) * Abnormal Behavior * Sleep cycle disturbance * Self-injury * Autism behaviors (50% risk for autism spectrum disorder) * Depression * Hyperreactivity and temper dysregulation

Answer 252

Low uE3, HCG, and AFP

Answer 253

Treat with cholesterol supplementation Not super effective

Answer 254

17p11.2 deletion RAI1 is the critical gene can also be RAI1 mutations De novo

Answer 255

Features * Hypotonia, FTT, feeding difficulties * Infrequent crying as babies * **Disrupted sleep pattern from abnormal circadian rhythm** * Mild-moderate intellectual disability and developmental delay, significant expressive language deficit * Ocular abnormalities * Abnormal gait * **Hearing loss or issues** * Constipation * **Hoarse voice and laryngeal anomalies** * **Self-injurious behavior and other behavioral problems** * **“Self hug”** * scoliosis * short stature * small hands and feet * Facial * tent shaped upper lip * upslanting palpebral fissures * hypopigmentation with rosy cheeks * synophrys

Answer 256

Channelopathy

Answer 257

Grip myotonia electrical myotonia episodic weakness muscle pain symptomatic eyelid myotonia normal short and long exercise tests

Answer 258

SMN1 gene * majority due to a homozygous deletion of exon 7 * some compound heterozygotes of an exon 7 deletion and an intragenic mutation SMN2 can provide a better outcome * the more copies of SMN2 you have, the milder the phenotype

Answer 259

Severe muscle weakness * In the severe form (Type 1-most common), they may never sit on their own * In the least severe forms (Type 3 and Type 4), they may be able to walk or just have mild proximal muscle weakness Respiratory and bulbar muscle weakness with swallow dysfunction * may need a G-tube * leads to aspiration and pneumonia * Usually die \<2 years due to respiratory and swallowing issues Develop REM sleep disordered breathing and eventually NREM sleep disordered breathing With the less severe forms, may have tremors, contractures, kyphoscoliosis, obesity, scoliosis

Answer 260

ATXN gene Autosomal dominant with anticipation Trinucleotide repeat * CAG repeats with effect from interrupting CAT repeats * 6-44 CAG repeats is normal * 36-44 repeat pathogenicity depends on CAT size * If no CAT interruptions, you are asymptomatic but can expand into pathogenic range for children * 39-44 repeats without CAT interruptions can be symptomatic, but if interrupted may be asymptomatic * \>44 repeats is pathogenic

Answer 261

Features * Progressive cerebellar ataxia * Chorea, distal muscle weakness, peripheral neuropathy, gait disturbance * Deterioration of bulbar functions * Dysarthria, dysphagia * Other * Nystagmus, optic atrophy, brisk deep tendon reflexes, hypotonia Supportive care only * Onset to death 10-30 years

Answer 262

ABCA4 gene, autosomal recessive EVOLVL4 gene, autosomal dominant

Answer 263

Eye problems with a heterogeneous presentation (60% present \<40 years) * Hereditary macular dystrophy * progressive worsening of visual acuity * retinitis pigmentosa

Answer 264

COL2A1 gene Autosomal dominant

Answer 265

Features * **Myopia from birth--\>thick glasses** * Retinal detachment * Mitral valve prolapse * Hypermobile joints * **Progressive sensorioneural hearing loss** * Later develop spondyloepiphyseal dysplasia * Leads to arthritis * Mild short stature * Narrowed joint spaces on x-ray * **Abnormalities of the vitreous gel architecture (ocular finding)** * **Pathognomonic** * Facial features * Flat midface * Depressed nasal bridge with short nose * Anteverted nares * Micrognathia * **U-shaped cleft palate from Pierre Robin sequence** **Can be confused with Marfan**

Answer 266

Early arthritis (from spondyloepiphyseal dysplasia) Retinal detachment Cleft palate Hearing loss

Answer 267

Multifactorial and complex Mendelian genetics Strong familial component for syndromic and non-syndromic forms

Answer 268

20-30% if the parents are not affected 30-50% if a parent is affected

Answer 269

16-50% recurrence risk for FDR ~8% risk for SDR

Answer 270

GNAQ gene (548G\>A) * Activation of the ERK pathway Not seen familialy! * 1-18% are somatic mosaics

Answer 271

Vascular problems * Port-wine stains on face * seizures * mental retardation Glaucoma Calcifications to the cortex

Answer 272

Interstitial Lung Disease * misfolded surfactant protein C accumulates in the alveolar type II cells and results in cell injury and apoptosis

Answer 273

3-5% of Caucasians are heterozygous 1 in 400 caucuasians are homozygous 12-20% of unselected venous thrombosis patients have a Factor V Leiden mutation

Answer 274

Virchow's Triad * Changes in the vessel wall * Changes in blood composition * Changes in blood flow Environment * oral contraceptives, hormone replacement therapy * pregnancy * weight, diet Genetics

Answer 275

Pain, tender to the touch tight swelling redness

Answer 276

It's not really recommended * Knowing about a genetic mutation will not change management But testing might increase awareness Do an individual assessment to decide to test or not

Answer 277

2-3 fold increased risk for thrombotic event slightly increased risk for arterial clots (stroke, heart attack) Associated wtih pregnancy loss and pregnancy complications

Answer 278

Prothrombin G20210A

Answer 279

Neonatal purpura fulminans Severe

Answer 280

2-10 fold increased risk for thrombosis (5-10% lifetime risk) * Rate of recurrence slightly increased Mild assosication with stroke and heart attack, especially in young Associated with pregnancy loss (especially late) Treat with human plasma-derived protein C concentrate

Answer 281

50% lifetime risk to clot * VTE risk is 10-17% per year Weak association with MI/stroke Slightly higher risk of fetal loss Homozygous is lethal Heterozygous is rare

Answer 282

TCOF1 gene Autosomal dominant 60% de novo

Answer 283

Underdevelopment of bone in the face and jaw * very dysmorphic * downslanting palpebral fissures Conductive hearing loss because of external ear abnormalities Coloboma of the lower eyelid Pierre-Robin sequence

Answer 284

TSC1 and TSC2 Autosomal dominant 2/3 de novo

Answer 285

Very variable, may not be affected at all Skin * Ash leaf spots/hypopigmented spots * Shagreen patch (looks like rash) * Facial angiofibroma (looks like acne) * Ungual fibroma (fibroma under the nail) Kidney issues * Can be associated with polycystic kidney disease (TSC2) * Benign angiomyolipoma (huge mass on kidney, cysts) Brain issues * Subependymal glial nodules * Cortical/subcortical tubers * 70% * Correlated with seizures Cardiac rhabdomyoma * Infants and fetuses only * Typically goes away and is benign Dental pits Lymphangioleiomyomatosis (large growth in the lung) * Famales only Seizures Developmental delays Headaches

Answer 286

Tuberous sclerosis

Answer 287

Management * MRI 1-3 years * Seizure management with meds, removal of tubers, electroencephalography * Electrocardiogram & ECG if heart problesm * Renal u/s * Ophthalmology exam * Neurodevelopmental & behavioral evaluation * Chest CT for adult females (for LAMs)

Answer 288

XO genotype * 50% mosaic * If are mosaic XY, have a 12% risk for gonadoblastoma

Answer 289

Features * Short stature * Phenotypic female * Infertility/don’t undergo puberty/premature ovarian failure * Webbed neck * Low posterior hairline * Lymphedema of hands and feet * Skeletal abnormalities * Kidney issues * Heart defects (aortic coarctation) * Variable developmental delay and behavior problems

Answer 290

Glycogen storage disorder (Type II) and a lysosomal storage disorder

Answer 291

GAA gene Autosomal recessive

Answer 292

Features * Muscle weakness * Cardiomyopathy * Delays * Failure to thrive * Respiratory distress * Early death (if infantile presentation)

Answer 293

ERT available * Increases lifespan * Improves myocardial function * Improves skeletal muscle function * Improves motor abilities & walking abilities (from improving muscle function) * Helps with sleep disordered breathing and lung function * Improves quality of life

Answer 294

Autosomale recessive

Answer 295

Sensorineural hearing loss * Mostly congenital * May not develop speech without cochlear implant Retinitis Pigmentosa * Progressive vision loss * Onset usually in 1st to 2nd decade of life

Answer 296

Loss of night vision Loss of peripheral vision --\>tunnel vision

Answer 297

Inheritance unknown Multigene and environement association Associated with maternal diabetes

Answer 298

Features (at least 3+ of the following) * **V**ertebral abnormalities * hypoplastic/malformed vertebrae & ribs, scoliosis, sacral agenesis * **A**nal atresia * can’t poop, passageway not there * **C**ardiac defect * VSD mostly, can be ASD, tetralogy of fallot, CHF, hypoplastic left heart, truncus arteriosus * **T**racheo-**E**sophageal fistula and/or esophageal atresia * leads to aspiriation, respiratory infections, FTT * **R**enal abnormalities * renal aplasia, dysplasia, hydronephrosis etc * **L**imb anomalies * radial aplasia/hypoplasia, absent/displaced thumb, poly/syndactyly, clubfoot

Answer 299

VHL gene Autosomal dominant

Answer 300

* Retinal hemangioblastoma * CNS hemangioblastoma * Clear cell renal cell carcinoma * Pancreatic neoplasms & cysts * Deletion/truncating mutation

Answer 301

Type 2A * **Pheo** * Retinal hemangioblastomas * CNS hemangioblastomas Type 2B * **Pheo** * Retinal hemangioblastomas * Clear cell renal cell carcinoma * Pancreatic neoplasm cysts Type 2C * Pheos only

Answer 302

Bleeding tendency (milder than hemophilia) Symptoms * Menorrhagia * Epistaxis * Bleeding at dental extraction or with minor injury * Ecchymoses * Post-operative hemorrhage

Answer 303

Type 1 (75%)

Answer 304

Quantitative defect of Von Willebrand factor (not enough factor made)

Answer 305

Mostly autosomal dominant except for Type 2N and Type 3 (autosomal recessive)

Answer 306

Mild to moderate mucocutaneous bleeding reduced Factor VIII (because they bind togeher)

Answer 307

Qualitative problem of Von Willebrand factor (can't function or bind as it should)

Answer 308

Von Willebrand disease Type 2N autosomal recessive Excessive bleeding with surgery

Answer 309

Hemophilia phenotype * severe, recurrent, spontaneous mucocutaneous and musculoskeletal bleeing Autosomal recessive * homozygous form of Type 1 Von Willebrand disease * No Von WIllebrand factor is made May develop Von Willebrand Factor inhibitors

Answer 310

Autosomal dominant mostly some autosomal recessive

Answer 311

Sensorineural hearing loss (variable degree) White forelock Heterochromia irides Dystopia canthorum (wide spaced eyes) Hirschprung disease

Answer 312

Deletion of WT1 and PAX6

Answer 313

**W**ilms tumor **A**niridia **G**enitourinary abnormality mental **R**etardation

Answer 314

ATP7B gene Autosomal recessive

Answer 315

Copper accumulation in the eyes, brain, and kidneys Low serum copper, higher urine copper

Answer 316

* Acute or chronic liver failure * Neurologic disease * due to copper accumulation in the brain * change in school performance or behavior * Kayser-Fleischer rings * due to copper accumulation in the eyes

Answer 317

Screen all FDR for Wilson's disease (urine and serum test, look for Kaiser-Fleischer rings)

Answer 318

Chelation to try to prevent the accumulation of copper

Answer 319

4p16.3 deletion 85-90% de novo

Answer 320

2:1 female:male

Answer 321

Features * “Greek warrior helmet” face, hypertelorism, microcephaly, asymmetry * Poorly formed ears * Hearing loss * Pits or skin tags * Intellectual disability mild to severe * Developmental delays * Poor motor and verbal skills * Hypotonia, feeding difficulties * IUGR and postnatal growth retardation * Febrile seizures * Hemangiomas (red spots) * Marble/dry skin * Skeletal anomalies * Scoliosis, short stature * Congenital heart defect * Antibody deficiency

Answer 322

May be stillborn 35% die within first 2 years Can live into 20s-40s

Answer 323

Genes that make up the peroxisome Autosomal recessive

Answer 324

Defect with perosisomal metabolism * Leads to the accumulation of very long fatty acids and branched chain fatty acids, and a deficiency of plasmoalogens

Answer 325

Features * Hypotonia, poor feeding * Seizures * Apnea * Hepatomegaly and/or renal cysts * Vision problems * Chondrodysplasis punctata * Brain issues * Impaired neuronal migration and positioning * Demyelination of CNS (cerebral neurons) * Reduced brain development * Progressive vision and hearing loss * Profound developmental delay/intellectual disability * Facial * High forehead * Hypoplastic supraorbital ridges * Epicanthal folds * Midface hypoplasia * Heart defects (VSD, ASD) * Eventually respiratory distress, GI bleeding, and liver failure

Answer 326

Start with a biochemical test for very long chain fatty acids, branched chain fatty acids, and plasmalogens

Answer 327

Survival usually \<1 year

Genetic Disorders Flashcards

(363 cards)