GET IN YOUR BRAIN Flashcards
1
Q
Increased Leucine on PAA
A
MSUD
2
Q
Defects in biotin metabolism cause
A
biotinidase deficiency and propionic acidemia
3
Q
Primary lactic acidosis
A
Electron Transport Chain (ETC) - mito defects.
Pyruvate dehydrogenase deficiency
4
Q
Hiccuping and apnea
A
Nonketotic hyperglycinemia
5
Q
Hyperammonemia
A
Urea cycle disorders
6
Q
Severe acidosis
A
Organic acidemias
7
Q
Lethargy and seizures
A
MSUD
8
Q
Jaundice, hypoglycemia, liver failure, hepatomegaly, vomiting
A
Galactosemia
9
Q
Hypoglycemia, weakness, cardiac
A
FAOD
10
Q
Hypoglycemia and circulatory collapse
A
CAH
11
Q
Respiratory alkalosis (Tacypnea), vomiting and lethargy, NOT ACIDOTIC
A
Urea cycle disorders
12
Q
Elevated C3 acylcarnitine measured in NBS
A
Propionic acidemia and methylmalonic acidemia
13
Q
Elevated C5 acylcarnitine measured on NBS
A
Isovaleric acidemia
14
Q
Liver failure, E. coli sepsis
A
Galactosemia
15
Q
Dysostosis Multiplex
A
LSD’s - typically MPS
16
Q
Erlenmeyer flask defomity
A
Gaucher
17
Q
Sphingomyelinase deficiency
A
Types A and B of Niemann Pick
18
Q
Cholesterol trafficking defect
A
Type C of Niemann Pick
19
Q
Palsy of upward gaze
A
Type C of Niemann Pick
20
Q
Spinal “gibbus” - kink in spine
A
MPS
21
Q
Earliest onset and most severe MPS
A
MPS I - Hurler Scheie
22
Q
No corneal clouding and X-linked MPS
A
Hunter
23
Q
More neurologic symptoms (frequently have behavioral problems with progression to severe neurologic disease) - mildest somatic symptoms of the MPS
A
MPS III - Sanfilippo
24
Q
Most severe skeletal disease, normal intelligence (MPS)
A
MPS IV - Morquio
25
Usually normal intelligence, Arylsulfatase B deficiency (MPS)
MPS VI - Maroteaux-Lamy
26
Most severe cases characterized by hydrops fetalis (MPS)
MPS VII - Sly
27
Glycogen debrancher deficiency; progressive hypertrophic cardiomyopathy
GSD III: Forbes, Cori disease
28
Phosphorylase kinase deficiency (GSD IX) inheritance
X-LINKED
29
Hepatosplenomegaly, FTT, progressive cirrhosis, liver failure, myopathy/cardiomyopathy
Anderson disease (GSD IV): different phenotype from other hepatic glycogenoses
30
Hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, poor growth, +/- myopathy
Clinical presentation of Hepatic GSD
31
Vitamin B6 therapy
Homocystinuria
32
Vitamin B12 therapy
Methylmalonic aciduria
33
Thiamin therapy
MSUD
34
Tetrahydrobiopterin therapy
PKU and tetrahydrobiopterin deficiency (also provide DOPA for this one - not for PKU)
35
Fragile X inheritance
FMR1 - X-Linked Dominant
CGG repeats in 5' untranslated region
200+ repeats = disorder (at this number FMR1 gene becomes methylated and fails to produce Fragile X MR protein [FMRP])
36
Normal number of repeats in FMR1
<45 = unaffected, make all the protein needed
37
Chance that a premutation 69 or lower would expand to a full mutation
<6%
38
Chance that a premutation 100 or higher would expand to a full mutation
94-100%
39
Lack of CFTR leads to
abnormal epithelial ion and fluid transport
40
Class I CFTR mutation
Null production - frame shifts, premature term (G542X, R553X, W1282X) [Worst]
41
Class II CFTR mutations
Trafficking - missense deltaF508, N1303K
42
Class III CFTR mutations
Regulation - Missense G551D
43
Class IV CFTR mutations
Conduction - Conservative Missense R117H [Best]
44
Chronic respiratory infections, exocrine pancreatic insufficiency, Intestinal obstruction/meconium ileus, male sterility, diabetes, progressive obstructive liver disease
Cystic fibrosis
45
Class I, II, and III mutations vs. Class IV and V mutations
Class I, II, and III mutations have essentially absent CFTR function and are associated with a more severe phenotype with pancreatic insufficiency
Class IV and V mutations retain partial CFTR function and are associated with a more mild phenotype with pancreatic sufficiency
46
CBAVD (Congenital bilateral absence of the vas deferens)
Otherwise healthy male presents for evaluation of infertility
Normally have normal lung function, BMI, negative sweat test
Male with CBAVD should be screened for CFTR mutations, especially uncommon mutations
47
Mannose binding lectin and TGFB
modifiers of pulmonary disease in CF
48
Increased incidence of CFTR mutations in general population with
- Asthma
- Chronic Rhinosinusitis
- Idiopathic pancreatitis
- Primary sclerosing cholangitis
49
Basic tenets of taking care of a patient with CF
- CF is a nutritional disease (before enzymes, most kids with CF died of malnutrition)
- CF is a disease of airway clearance
- CF is a disease of epithelial ion transplant (too much salt in sweat, respiratory glandular obstruction, intestinal obstruction, biliary cholestasis, exocrine pancreatic insufficiency)
- CF is a disease of inflammation
- CF-related diabetes
50
Neonatal hypoparathyroidism and immunodeficiency
22q
51
Immunodeficiency, CHD, palate defects, hypocalcemia, GU anomalies, GI problems, DD, psychiatric illness
22q
52
Conotruncal heart defects
22q (TOF, VSD, IAA typeB)
53
In frame deletions of FBN1 usually have a _
more severe phenotype
54
Brushfield spots
T21
55
hypertonia, prenatal growth deficiency, fists clenched, rocker-bottom feet, severe heart malformations, feeding difficulties
T18
56
Microcephaly, sloping forhead, fist clenching, rocker-bottom feet, severe CNS malformations, CHD
T13
57
Repeat expansion in Huntington
CAG in HTT; Coding region in exon 1
26 or less is normal
27-35 is intermediate
36-39 repeats is reduced penetrance
40+ is full mutation
58
Anticipation seen in HD
more commonly when paternally inherited
59
Agents to avoid in HD
L-dopa-containing compounds, alcohol consumption, and smoking
60
Sickle cell disease = homozygous
HbSS
61
Anterior horn cells
SMA - loss of anterior horn cells in the spinal cord
62
SMN1 deletions
cause SMA (usually deletion of exon 7)
63
SMN2 determines
prognosis (dosage: # copies 0-5; 3+ = milder)
64
Why should you avoid prolonged fasting in SMA
unexplained metabolic acidosis is a potential complication of SMA
65
Why is the lifespan shortened in SMA
progressive ventilatory insufficiency resulting from chest muscle involvment
66
UBA1
gene associated with X-linked SMA
67
Female heterozygote carriers for DMD at an increased risk for
DCM
68
In frame deletions of DMD
Becker
69
Out of frame deletions of DMD
Duchenne
70
Testing used for immunohistochemistry of dystrophin
Western blot
71
DMD associated DCM is characterized by
left ventricular dilation and congestive heart failure
72
_ complications are common causes of death in DMD and BMD
Respiratory and cardiomyopathy complications
73
Myxomas
Carney Complex
74
Psammamatous, melanotic schwannomas, thyroid cancer, skin tags, lipomas, blue nevi, cafe au lait spots, thyroid nodules, cardiomyopathy, primary pigmented nodular adrenocortical disease, spotty skin pigmentation
Carney Complex
75
Used when only first degree female relatives had breast cancer
Gail
76
Used when first and second degree relatives had breast cancer
Claus
77
Takes into account current age, age at first menses, and age a first live birth
Gail
78
Considers previous biopsy and if atypical cells were seen
Gail
79
For breast cancer risk AND mutation risk
BRCAPro, Tyrer-Cuzick, BOADICEA
80
Considers risk for "lower penetrance" gene in addition to BRCA
Tyrer-Cuzick
81
FAP plus osteomas and soft tissue tumors (desmoids, epidermoids, fibromas)
Gardner syndrome
82
FAP plus CNS tumors, specifically medulloblastoma
Turcot syndrome
83
Cancers that Amsterdam II takes into consideration
CRC, uterine, small bowel, ureter, renal pelvis
84
Absence of MLH1 and PMS2 could be
MLH1 germline mutation
MLH1 promoter hypermethylation (rule out through BRAF testing)
85
Absence of just PMS2 could be
MLH1 or PMS2 germline mutations
86
Most Lynch CRC tumors are _ on microsatellite testing
MSI-high (high instability)
87
Absence of MSH2 and MSH6 could be
MSH2 germline mutation
EPCAM germline mutation (EPCAM is just upstream of MSH2, 3' EPCAM deletions can lead to absence of MSH2 expression)
88
Absence of just MSH6 could be
MSH6 germline mutation
89
Adrenocortical carcinoma
Li-Fraumeni
90
Choroid plexus carcinoma
Li-Fraumeni
91
Cancer syndrome may manifest as primary hyperparathyroidism
MEN1
92
MEN2A and 2B associated with _ mutations
gain of function
93
RET associated Hirschsprung's disease
Associated with LOF mutations
Megacolon
Constipation
94
Bilateral vestibular schwannomas
NF2
Conductive HL by age 30
Tinnitus
Balance dysfunction "death by drowning" is key pedigree note
Decreased visual acuity
95
Cardiac rhabdomyoma
Tuberous Sclerosis Complex (TSC)
96
Angiofibromas, cortical dysplasias, hypomelanotic macules, lymphangioleiomyomatosis, multiple retinal nodular hamartomas, renal angiomyolipoma, subependymal giant cell astrocytoma, subependymal nodules, ungual fibromas, neuroendocrine tumors
Tuberous Sclerosis Complex
97
Shagreen Patches
Tuberous Sclerosis Complex
98
Neuroendocrine tumors seen in TSC
Pituitary adenoma, parathyroid adenoma, pancreatic adenoma, gastrinoma, pheochromocytoma, carcinoids
99
Penile freckline
PTEN
100
Subependymal nodules
Tuberous Sclerosis Complex
101
Subependymal giant cell astrocytoma (brain tumor)
Tuberous Sclerosis Complex
102
"confetti" hypopigmented skin lesinos, dental pits, intraoral fibromas, multiple renal cysts, retinal achromic patch
Tuberous Sclerosis Complex
103
Cancer syndrome with seizures, ASD, ADHD, DD/ID
Tuberous Sclerosis Complex
104
Endolymphatic sac tumors
VHL
105
Clear cell renal carcinoma, spinal or cerebellar hemangioblastoma, pancreatic neuroendocrine tumors, pheochromocytoma, paraganglioma, retinal angioma, multiple renal and pancreatic cysts
VHL
106
Spinal or cerebellar hemangioblastoma
VHL
107
Coved type ST segment
Brugada
108
SCN5A is the main gene in
Brugada
109
Sudden death, negative T wave, Coved type ST segment, V fib, self-terminating polymorphic ventricular tachycardia, episodes of syncope, nocturnal agonal respiration (gasping)
Brugada
110
Type of arrhythmia associated wtih normal baseline/resting ECG and abnormal ECG only after andrenergic event. Suden death or syncope with exercise/excitement, major cause of sudden death in childhoos
Catecholaminergic Polymorphic entricular Tachycardia (CPVT)
111
Migraines with aura, strokes, mood disturbances, progression to subcortical dementia, pseudobulbar palsy, leukoencephalopathy
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)
Gene: NOTCH3
112
Xanthomas, elevated cholesterol, premature atherosclerosis, coronary artery disease, increased risk for MI
Familial Hypercholesterolemia
Genes: LDLR, APOB, PCSK9, LDLRAP1
113
Telangiectasias, nose bleeds, AVMs (occur in large organs)
HHT
Genes: ACVRL (ALK1), ENG, SMAD4, GDF2
114
Torsades de pointes
Long QT
115
LQTS with congenital deafness
Jervell and Lange-Nielsen Syndrome (Autosomal Recessive)
Genes: KCNE1 and KCNQ1
116
LQTS with autism
Timothy syndrome
117
Timothy syndrome
- Autosomal dominant
- LQTS, type 8
- syndactyly
- autism
- structural cardiac malformations
- ID
- dental anomalies
118
Thickening, usually of the left ventricle which leads to reduced cardiac output
Hypertrophic Cardiomyopathy (HCM)
119
Caused by mutations in sarcomere genes
HCM
120
HCM is seen in
Noonan syndrome and Fabry
121
Stretching of muscle fibers, often in the left ventricle, leads to dilation of the chamber and reduced cardiac output
Dilated Cardiomyopathy (DCM)
122
Caused by mutations in cytoskeletal genes
DCM
123
DCM is seen in
DMD, mito disease, Bardet-Biedl Syndrome, Alstrom sydnrome
124
Caused by fibrofatty replacement of the right ventricular heart tissue (myocardium)
Arrhythmogenic right-ventricular Dysplasia/Cardiomyopathy (ARVD/ARVC)
125
Associated arrhythmia generated from the right ventricle
ARVD/ARVC
126
Naxos/Carvajal disease
Recessive ARVD/ARVC with palmoplantar keratoderma and "wooly hair"
127
Caused by mutations in desmosomal genes
ARVD/ARVC
128
During embryogenesis, the heart is made up of spongy layers of blood vessels, which should normally compact. Failure to compact leads to
Left-Ventricular Non-compaction (LVNC)
129
Excessive, prominent, persistent trabeculations are major feature (congenital but typically manifests later in life)
LVNC
130
Heart walls become rigid, reducing ability to pump blood/cardiac output
LVNC
131
Most cardiac arrhythmias are
Channelopathies
132
NBS for CF uses
Immunoreactive trypsinogen (IRT) - will be elevated in CF, then check common mutations
133
CF and Brugada are
Channelopathies
134
Chromosomal Breakage Disorders
Ataxia-Telangiectasia
Bloom
Cockayne
Fanconi Anemia
Nijmegen Breakage syndrome
Werner Syndrome
Xeroderma Pigmentosum
135
Dysarthria (slurred speech)
Ataxia-Telangiectasia
136
Ataxia, oculomotor apraxia, involuntary movements, recurrent infections, delayed puberty, premature menopause, growth delay, drooling, dysarthria, premature aging, type 2 diabetes at young age, increased risk for lymphomas and leukemias
Ataxia-Telangiectasia
137
Extreme growth deficiency and characteristic high-pitched voice
Bloom syndrome
138
IUGR, short stature, feeding dificulties, immune deficiency, premature menopause, azoospermia/oligospermia, learning problems (most intellectually normal), butterfly shaped skin lesion/rashes after sun exposure
Bloom syndrome
139
Biggest cancer risk for bloom syndrome
Colon followed by breast, liver, respiratory tract, lymphatic, sarcoma, germ cell, CNS, retinoblastoma
140
Postnatal growth failure, progressive microcephaly, leukodystrophy, neurologic dysfunction, DD, behavior problems, Intellectual deterioration, photosensitivity, Demyelinating peripheral neuropathy, pigmentary retinopathy, cataracts, SNHL, dental anomalies, premature aging
Cockayne Syndrome
141
Cachectic dwarfism
Cockayne syndrome
142
Worst type of Cockayne Syndrome
Type 2
143
Chromosome breakage syndrome not predisposed to cancer or infection
Cockayne Syndrome
144
Nucleotide excision repair
Cockayne Syndrome and Xeroderma Pigmentosum
145
Pancytopenia/bone marrow failure
Fanconi Anemia
146
FANCB inheritance pattern
X-linked recessive
147
Short stature, skeletal anomalies (abnormal limbs and digits, dysplastic, hypoplastic, or absent), microcephaly, skin lesions, DD/ID, conductive HL due to middle ear skeletal anomalies, CHD, GI issues, kidney problems, pituitary/CNS hypoplasia
Fanconi Anemia
148
Cross-link repair, homologous recombination repair
Fanconi Anemia
149
Double stranded break repair
Ataxia-Telangiectasia and Werner Syndrome
150
Increased sister chromatid exchanges/double-stranded break repair
Bloom syndrome
151
Homologous recombination repair
Nijmegen Breakage Syndrome
152
Microcephaly, growth delay, recurrent sinopulmonary infections, progressive decline in intellectual ability leading to borderline/moderate ID, dysmorphic features, T and B-cell lymphomas are common
Nijmegen Breakage Syndrome
153
Premature aging and early onset of disease normally associated with aging (osteoporosis, diabetes, atherosclerosis, calcinosis)
Werner Syndrome
154
Short stature, premature again, skin atrophy with sclerodermic lesions (can lead to gangrene/amputation), lipodystrophy, change in voice (weak and high-pitched), gonadal atrophy with associated infertility, telangiectasias, increased risk for cancer (melanoma, sarcoma, thyroid, liver, myelodysplastic syndrome, malignant fibrous histiocytoma)
Werner Syndrome
155
Extreme sun sensitivity, multiple freckles at an early age, solar keratoses, extreme ocular sunsensitivity, skin blistering with sun exposure, spider veins, dry skin, corneal ulcerations, SNHL, neuropathy, BCC and SCC risks, cutaneous melanoma, gliomas, increased risk for any internal neoplasm
Werner Syndrome
156
Ciliopathies
Alstrom syndrome, Bardet-Biedl Syndrome, Joubert syndrome, Meckel-Gruber Syndrome, Orofaciodigital Syndrome 1, Polycystic Kidney Disease, Primary Ciliary Dyskinesia
157
Visual pathology (nystagmus, blindness, other), obesity, DCM with CHF, hearing loss, hepatic and renal dysfunction, advanced bone age, ABSENCE OF POLYDACTYLY
Alstrom syndrome (ALMS1) - autosomal recessive
158
Alstrom syndrome is similar to
Bardet-Biedl Syndrome (but ABSENCE OF POLYDACTYLY)
159
Retinitis pigmentosa, postaxial polydactyly, syndactyly, renal anomalies, ID, DD, GU abnormalities (TWO UTERUS), speech disorders, DCM, left ventricular hypertrophy, GI problems and feeding difficulties, truncal obesity
Bardet-Biedl Syndrome (Autosomal recessive, digenic recessive)
Genes: BBS1-BBS12, CCDC28B, CEP290, TMEM67, MKS1, MKKS
160
Hypotonia in infancy with later development of ataxia, moderate ID, DD, episodic tachypnea or apnea, atypical eye movements (nystagmus, oculomotor apraxia, seizures, speech apraxia, autism, behavior problems, MRI findings
Can also see: retinal dystrophy, cystic kidney disease, coloboma, congenital hepatic fibrosis, polydactyly, CL/P and orofacial anomalies
Joubert syndrome (AR and X-linked)
161
Embryonic lethal, renal cystic dysplasia
Meckel-Gruber Syndrome (AR)
162
Renal cystic dysplasia, CNS malformations, polydactyly, hepatic malformations, oligohydramnios, pulmonary hypoplasia
Meckel-Gruber Syndrome (AR)
163
Typically embryonic male lethal, oral anomalies (hamartomas/lipomas of tongue, CP, hypodontia, dental anomalies), facial anomalies, digital anomalies, brain anomalies, polycystic kidney disease, mild ID
Orofaciodigital Syndrome 1 (X-linked dominant)
164
OFD1
Orofaciodigital Syndrome 1
165
Renal cysts develop in utero but grow over time; bilateral renal cysts, cysts also on (liver, pancreas, seminal vesicles, arachnoid membrain), intracranial aneurysm, aortic root dilation/dissection, MVP
Polycystic Kidney Disease - can be AD or AR, AR more severe (30% death rate in newborns)
166
heterotaxy (situs inversus), impaired ciliary motility, frequent upper and lower respiratory infections due to poor clearance of mucus from thelungs
Primary Ciliary Dyskinesia (AR)
167
F8 gene
Hemophilia A (X-linked recessive)
168
Excessive bleeding, renewed bleeding, deep-muscle and intracranial or GI tract bleeds without obvious trauma, poor wound healing, menorrhagia, excessive bruising
Hemophilia A (X-linked recessive)
F8 gene!
169
F9 gene
Hemophilia B (X-linked recessive)
170
Acute treatment with DDAVP
Hemophilias
171
Increased risk for venous thromboembolism
Factor V (Autosomal dominant and recessive)
Gene: F5
172
Long-term oral anticoagulants is necessary, particularly in homozygotes
Factor V (Autosomal dominant and recessive)
Gene: F5
173
Factor V "Leiden" refers to
The common allele, c.1691G>A in F5
174
Mild to moderate mucocutaneous bleeding. Easy bruising, nosebleeds, heavy periods
von Willebrand Disease (most AD, occasional AR)
VWF gene
175
von Willebrand Disease type 2B and 2N may have
thrombocytopenia
176
von Willebrand Disease type 2N has more
severe bleeding and mimics hemophilia
177
Congenital Contractural Arachnodactyly
Beals Syndrome
AD - FBN2 gene
178
Marfanoid habitus, flexion contractures of elbows, hips, knees, and/or fingers, kyphoscoliosis, muscular hypoplasia, crumpled ear outer helices
Beals Syndrome (Congenital Contractural Arachnodactyly)
179
Rare severe/lethal form of Beals Syndrome (Congenital Contractural Arachnodactyly)
Marfanoid habitus, flexion contractures of elbows, hips, knees, and/or fingers, kyphoscoliosis, muscular hypoplasia, crumpled ear outer helices
PLUS
```
CV anomales (ASD, VSD, interrupted aortic arch, arotic root dilation)
Duodenal and/or esophageal atresia, intestinal malrotation
```
180
Loose, inelastic skin that hangs/looks wrinkled, joint hypermobility, hernia, blue sclera, cardiopulmonary complications
Cutis Laxa (AD, AR, XL)
ELN gene usually, are others
181
Most severe type of EDS
Vascular type - Type IV
182
Vascular/arterial dissection or rupture, Gi rupture, bowel rupture, organ rupture, club foot, spontaneous pneumothorax, hip dysplasia, inguinal hernia
Vascular type EDS - Type IV
183
Hyperelastic skin, atrophic scarring, joint hypermobility, smooth and velvety skin, pseudotumors over elbows and knees, dislocations and sprains and flat feet, joint pain, easy bruising, increased risk for postoperative hernia
Classic type of EDS - EDS 1 and 2
184
Vessel tortuosity
Loeys-Dietz (AD)
Genes: TGFBR1, TGFBR2, SMAD3, TGFB2
185
Aortic dilation/dissection, bicuspid aortic valve, arterial aneurysms, pectus, scoliosis, joint laxity/contracture, arachnodactyly, C-spine instability, bifid uvula/CP, translucent skin, dystrophic scars
Loeys-Dietz (AD)
186
Connective tissue disorder with cleft palate/bifid uvula
Loeys-Dietz
187
Types of OI with blue sclera
Type I, III
188
Woods lamp for skin diagnoses
Tuberous Sclerosis
189
"mesh-like" bone appearance
OI Type V
190
"Fish scale" bone appearance
OI type VI
191
Type II Loeys-Dietz has no
craniofacial findings
192
Very similar to Loeys-Dietz including dysmorphic features/craniosynostosis with multiple abdominal hernias, ID, brain anomalies
Sphrintzen-Goldberg Syndrome (AD)
Gene: SKI
193
Type 1 Stickler syndrome is "_"
"Membranous" - most common type
Persistent vestigial vitreous gel in the retrolental space of the eye
194
Type 2 Stickler syndrome is "_"
"Beaded"
Sparse and irregularly thickened bundles throughout the vitreous cavity of the eye
195
Midface hypoplasia, telecanthus and epicanthal folds, Pierre-Robin sequence, progressive SNHL, high myopia, short stature, early-onset arthritis, kyphoscoliosis, platyspondylia, MVP
Stickler Syndrome (AD)
Genes: COL2A1, COL11A1, COL11A2, COL9A1
196
Severe microcytic hypochromic anemia, splenomegaly, severe bone deformities, death before age 20 if untreated
Beta Thal (AR)
HBB gene
197
Treatment:
Periodic blood infusions
Splenectomy
Chelation of transfusion-induced iron overload
Beta Thal Major
198
Vaso-occlusive events
Sickle cell
199
Dactylitis
Sickle cell
200
Pulmonary hypertension, acute chest syndrome (chest pain, fever, pulmonary infiltrate, respiratory problems, hypoxia), splenic dysfunction, chronic hemolysis, stroke
Sickle Cell anemia (HbSS genotype)
201
Normal blood genotype
Hb AA
202
Sickle cell trait genotype
Hb AS
203
Sickle cell trait may experience symptoms with
Extreme exertion, high altitude, or dehydration
May have higher risk for venous thromboembolism
Protective advantage against malaria
More often due to point mutations
204
Poor growth, exercise intolerance, muscle weakness, vision/hearing loss, LD, seizures and strokes
Common features of mito disorders
205
Cardiomyopathy (left ventricular non-compaction), neutropenia, underdeveloped muscles and muscle weakness, growth delay, exercise intolerance, normal intelligence or mild-moderate LD, growth problems resolve after puberty
Barth syndrome (X-linked recessive)
TAZ gene
206
Major cause of death in Barth syndrome
cardiomyopathy and neutropenia
207
Rapid developmental regression, onset in first months/years of life, FTT, onset after an energetically taxing event, diarrhea, vomiting, dysphagia, seizures, lactic acidosis, muscular deterioration, hypotonia, dystonia, ataxia, ophthalmoparesis, nystagmus, cardiac and respiratory failure, VSDs, peripheral neuropathy, lifespan in 6-7 years
Leigh syndrome
X-linked, AR, or can be mito
MANY genes
208
Major cause of death in Leigh syndrome
Respiratory failure
209
Psychiatric illness (depression, psychosis, dementia), seizure disorders/epilepsy, extrapyramidal movement disorders (parkinsonianism, chorea), cerebrovascular involvement, SNHL, retinopathy, myopathy, exercise intolerance, peripheral neuropathy, endocrine/gonadal failure, GI problems, liver failure, cardiomyopathy, cataracts, early death may occur
POLG-related disorders (AR and AD)
210
Metabolic form:
lactic acidosis/elevated blood lactate
Hyperventilation secondary to metabolic acidosis
Pyruvate Dehydrogenase Deficiency (X-linked)
211
Neurologic form:
```
Onset in first year of life
Hypotonia
Poor feeding
Lethargy
Brain MRI abnormalities
DD/ID
Seizures
Microcephaly
Blindness
Spasticity
Progressive disorder
```
Pyruvate Dehydrogenase Deficiency (X-linked)
212
Treatment of sodium bicarbonate for acute metabolic episodes and ketogenic diet
Pyruvate Dehydrogenase Deficiency (X-linked)
213
NORMAL cognition, DD, muscle weakness, congenital cataracts, HCM, lactic acidosis, high risk of death in infancy due to cardiac failure
Senger's syndrome (AR)
214
Myopathy, encephalopathy, stroke, lactic acidosis
MELAS (mito) - onset between 5-15 years
215
Myoclonic epilepsy, hearing loss, symmetrical lipomatosis around neck, ragged red fibers (clumps of disease mitochondria that accumulate in the muscle fibers)
MERRF (mito)
216
Neuropathy, ataxia, retinitis pigmentosa
NARP (mito); moderate heteroplasmy at T8993G
217
High heteroplasmy at T8993G
causes Leigh syndrome (moderate causes NARP)
218
Fatal in infancy, FTT, sideroblastic anemia, exocrine pancreas dysfunction
Pearson syndrome (mito)
219
Chronic PEO, pigmentary retinopathy, cardiac conduction abnormalities, onset before 20 years, cerebellar ataxia may be seen
Kearns-Sayre Syndrome (mito)
220
Due to nondisjunction in paternal meiosis
Turner syndrome
221
Due to nondisjunction in maternal OR paternal meiosis I
Klinefelter Syndrome
222
Usually maternal meiosis I (can be paternal meiosis I)
Trisomy 21
223
Due to nondisjunction in maternal meiosis II
Trisomy 18
224
Due to nondisjunction in maternal meiosis I
T13
225
```
Caused by motor neuron death
Muscle weakness/atrophy
Stiffness/cramping of muscles
Difficulty swallowing
Foot drop
Progressive bulbar palsy
Difficulty talking
Progressive motor deterioration/muscle atrophy
Loss of ability to walk/use hands and arms
Loss of ability to speak/swallow
Ventilator dependence
Average survival from onset of symptoms is 4 years
```
ALS (mostly multifactorial)
226
Duplication of PMP22
Charcot Marie tooth (CMT) - 70-80% of cases; AD versions
227
Foot drop - forefoot drops due to muscle weakness; can cause hammer toe
CMT (AD, AR, X-linked)
228
Onset of symptoms in early childhood/early adulthood, musclewasting and weakness, neuropathy and loss of feeling in feet, ankles, legs, hands, and arms; painful, spasmodic muscular contractions, damage of sensory nerves while pain nerves are left intact, bruxism, scoliosis, pregnancy and emotional stress can exacerbate disease progression, vocal tremor from muscle wasting, neuropathic pain, eventual wheelchair dependence
CMT
229
Positive Gower's sign
BMD and DMD
230
Preservation of neck flexor muscle strength
Differentiates BMD from DMD
231
Muscle wasting and weakness, toe walking, joint contractures, arrhythmia, wheelchair dependency/respiratory insufficiency, may have ID
Emery-Dreifuss Muscular Dystrophy
ID when X-linked, AD, AR
232
EMD, LMNA, SYNE1, SYNE2, FHL1
Emery-Dreifuss MD
233
Normal lifespan, slowly progressive weakness of teh facial muscles, scapular muscles, and humeral muscles, no weakness in bulbar or ocular muscles, winged scapula, onset by 20 years
Facio-Scapulo-Humeral MD
234
Deletion of 4q35 which causes deletions of microsatellite repeat D4Z4
Facio-Scapulo-Humeral MD
This deletion that causes 10 or FEWER repeats (REPEAT CONTRACTION) which leads to FSHD
235
Normal repeat number for Facio-Scapulo-Humeral MD
11 - 100 repeats. Deletions lead to 10 or fewer repeats which lead to FSHD
236
Winged scapula
Facio-Scapulo-Humeral MD
237
Symmetric proximal slowly progressive muscle weakness, difficulty walking and using stairs, difficulty bending over, frequent falls, difficulty holding arms above head, pseudohypertrophy, respiratory difficulties, lwer back pain, heart palpitations, facial muscle weakness, distal muscle weakness, should weakness, age of onset (10-30 years), not typically fatal but can weaken heart or lungs and lead to death
Limb-Girdle MD (AD or AR)
Lots of genes
238
Muscle weakness, most severe in the face, neck flexors, and proximal limbs; hypotonia, depressed/absent deep tendon reflexes
Nemaline Myopathy
239
Forms of Nemaline Myopathy (NM)
AD or AR
Severe congenital
Amish NM
Intermediate
Typical (mild) congenital NM
Childhood-onset NM
Adult-onset NM
240
May present with "head drop"
Nemaline Myopathy
241
Hypotonia with muscle weakness, absence of motor development, involuntary twitching of the tongue, mild joint contractures, absent tendon reflexes, normal brain function and intellect; lethal by age 2 years
SMA type I (AR)
242
Can sit independently once placed in a seated position, onset after 6 months, hypotonia, absent tendon reflexes, normal intellect, may live past age 4 years
SMA type II
243
Onset after 10 months, most motor milestones achieved, muscle weakness manifesting as frequent falls and trouble with stairs, proximal limb weakness (legs worse than arms
SMA type III
244
SMA IV
Adult onset muscle weakness
245
The more copies of SMN2 the _ severe the phenotype
less
246
Hypotonia, muscle weakness, DD, absence of motor skill development, severe ID, seizures, brain defects (lissencephaly, hydrocephalus, cerebellar malformations), encephalocele (gap in skull that won't seal and meninges of brain can protrude through this gap), microphthalmia, retinal abnormalities
Walker Warburg Syndrome (AR)
Genes: POMT1, POMT2
247
Muscle disease with encephalocele
Walker Warburg Syndrome (AR)
Genes: POMT1, POMT2
248
Port wine stain
Klippel-Trenaunay-Weber Syndrome (KTW Syndrome)
SPORADIC INHERITANCE: may be due to somatic changes in early development
Unknown gene
249
Hyperplasia of bone and soft tissues, often in one limb.
Varicose Veins
Lymphatic malformations
Vascular malformations
Port-wine stain
Klippel-Trenaunay-Weber Syndrome (KTW Syndrome)
250
Inheritance of KTW syndrome
SPORADIC
251
Overgrowth of skin, bones, muscles, fatty tissues, blood vessels, and lymphatic vessel. Overgrowth is non-congenital and disproportionate. Cerebriform connective tissue nevi.
Proteus syndrome: Due to SOMATIC MOSAIC AKT1 mutation c.49G>A in all cases (there is a PTEN related Proteus syndrome)
252
Macrosomia, macroglossia, macrocephaly, mild to severe ID, coarse facies, diastasis recti, CHD, diaphragmatic hernia, GU anomalies, GI anomalies, polydactyly, pectus deformities, scoliosis, vertebral fusion, rib anomalies
Simpson-Golabi-Behmel syndrome (X-linked recessive)
Genes: GPC3, GXORF5
253
"Bulldog syndrome"
Simpson-Golabi-Behmel syndrome (X-linked recessive)
Genes: GPC3, GXORF5
254
Macrocephaly, tall stature, mild to severe ID, flushed cheeks, monotone voice with stuttering, DD, cardiac anomalies, behavior problems, flat feet, joint hyperlaxity, renal anomalies, scoliosis, seizures, advanced bone age, maternal preeclampsia
Sotos syndrome (AD; 95% de novo)
NSD1 = gene
255
Flushed cheeks
Sotos syndrome (AD; 95% de novo)
NSD1 = gene
256
Overgrowth syndrome causes maternal preeclampsia
Sotos syndrome (AD; 95% de novo)
NSD1 = gene
257
Tall stature, rapid and continuous growth, intellect can range from normal to severe ID, macrocephaly, coarse facies, advanced bone age, poor coordination, soft and doughy skin, camptodactyly, umbilical hernia, hoarse and low cry in infancy
Weaver syndrome (AD)
EZH2 = gene
258
Sparse, brittle, curly scalp hair. Skin abnormalities (dermatitis, ichthyosis). CHDs (pulomonic stenosis), Craniofacial malformations. Growth delays. Foot abnormalities. Dysmorphic features.
Cardiofaciocutaneous syndrome (AD)
Genes: KRAS, BRAF, MEK1, MEK2
259
ID, DD, joint hypermobility, loose folds of extra skin, HCM, pulmonic stenosis, short stature, arrhythmia, rhabdomyosarcoma and neuroblastoma
Costello syndrome (AD)
Gene: HRAS (proto-oncogene)
260
RASopathy caused by a proto-oncogene
Costello syndrome (AD)
Gene: HRAS (proto-oncogene)
261
How is Legius syndrome different from NF1
DOES NOT HAVE LISCH NODULES OR NEUROFIBROMAS
Legius is caused by SPRED1 (AD)
262
How is Legius syndrome similar to NF1
CAL macules, optic gliomas, learning problems, etc.
263
Genes to think about in Noonan
PTPN11 and KRAS (many others) - AD
264
Short stature, webbed neck, HCM, ASDs/VSDs, pulmonic stenosis, GI issues, cryptorchidism, pectus, joint contractures or hypermobility, scoliosis, hypertelorism, DD, ID/LD, autism, clotting disorders/factor deficiencies, recurrent illness, chronic pain, SNHL
Noonan syndrome (AD)
Genes: PTPN11, KRAS, others
265
Noonan plus multiple lentienes (liver spots)
LEOPARD syndrome (AD)
Genes: PTPN11, RAF1, BRAF, MAP2K1
266
LEOPARD mnemonic
```
Lentigines
Electrocardioraphic abnormalities
Ocular hypertelorism
Pulmonic stenosis
Abnormal genitalia
Retarded growth
Deafness
```
267
Only AR repeat expansion disorder
Friedrich's Ataxia
FXN gene
Trinucleotide repeat: GAA (intronic region)
268
Slowly progressive, disabling ataxia, vision impairment, hearing impairment, slurred speech, scoliosis, pes cavus, diabetes, pyramidal signs, nystagmus, cardiac involvment (cardiomegaly, DCM, heart murmur, conduction defects), average lifespan is 35 years
Friedrich's Ataxia (AR)
FXN gene
Trinucleotide repeat: GAA (intronic region)
269
Muscle weakness, myotonia, cataracts, balding, cardiac arrythmia, average lifespan 45-55 years
Myotonic Dystrophy Type I; AD
DMPK gene; CTG repeats
270
Infantile hypotonia, respiratory deficits, ID, muscle weakness, myotonia, cataracts, balding, cardiac arrhythmia, average lifespan 45 years
Congenital Myotonic Dystrophy Type I; AD
DMPK gene; CTG repeats
3'UTR region
271
Type of expansion you can see (anticipation) in Myotonic dystrophy type I
MATERNAL
272
Muscle weakness and pain, myotonia (begins with neck and finger flexors), cataracts, cardiac arrhythmia, cardiomyopathy, type 2 diabetes, testicular failure/male infertility, sleep disturbances, white matter changes, GI problems, doesn't exhibit anticipation
Myotonic Dystrophy Type II; AD
ZNF9 gene; CCTG repeats
Intronic region
273
Muscular atrophy, difficulty walking/clumsiness, bulbar signs (speech difficulties, swallowing difficulties), endocrine dysfunction (gynecomastia, erectile dysfunction, testicular atrophy) - androgen insensitivity
Spinal and Bulbar Muscular Atrophy (Kennedy Disease)
X-linked recessive
Gene: AR
Trinucleotide repeat CAG
274
Slowly progressive ataxia, poor hand-eye coordination, poor speech coordination, irregular eye movements, chorea, pyramidal signs, tremors, peripheral neuropathy, cognitive impairment (rare, only some types), seizures, cerebellar atrophy
Spinocerebellar ataxia (AD)
Trinucleotide repeats: CAG or CTG
Over 60 types
275
Inability to utilize androgen for virilization due to defective androgen receptor. 46, XY karyotype with 'biologically female' appearance
Androgen Insensitivity
Inheritance: X-linked
Gene: AR
276
Complete androgen insensitivity
Appear phenotypically female, but are lacking a uterus (Mullerian regression)
- blind ending vagina (no cervix)
277
Partial Andregen Insensitivity
May exhibit ambiguous genitalia and/or undervirilization at puberty
278
Why do undescended testes in androgen insensitivity need to be removed?
Increased risk for germ-cell tumors
279
Normal sex differentiation, failure to start or complete puberty, small testicles, primary amenorrhea, poorly defined secondary sexual characteristics, infertility, SNHL, imrror movement of hands (synkinesis), renal agenesis/aplasia, CP, craniofacial defects, micropenis, cryptorchidism, dental defects
Kallman syndrome (also have anosmia and hypogonadotropic hypogonadism)
X-linked, AD, or AR
Genes: KAL1, KAL2 (FGFR1), KAL3
280
Acute adrenal insufficiency
X-linked Adrenal hypoplasia congenita
Gene: NROB1
281
Adrenal failure, acute adrenal insufficiency, hypogonadotropic hypogonadism, DD
X-linked Adrenal hypoplasia congenita
282
Treatment: HRT
Kallman syndrome
283
Treatment: Glucocorticoid and mineralcorticoid replacement therapy
X-linked Adrenal Hypoplasia Congenita
284
Treatment: Glucocorticoid replacement therapy and Florinef
21-Hydroxylase Deficiency
285
Trident hands
Achondroplasia
286
c.1138G>A in FGFR3
Common mutation for Achondroplasia
287
Normal intellect, rhizomelic shortening, trident hands, brachydactyly, frontal bossing, kyphosis or lordosis, bow-leg or knock knee leg deformities, sleep apnea, hydrocephalus, higher risk for obesity, delayed motor milestones
Achondroplasia (AD)
Gene: FGFR3
288
Brachycephaly, bulging eyes, arachnodactyly, craniosynostosis, facial hypoplasia, bowed ulna and femur, radial synostosis, humeral synostosis, trapezoidal synostosis, camptodactyly, nasal/anal/vaginal atresia, cryptorchidism, renal malformations, ID, hydrocephalus, upper airway obstruction
Antley-Bixler (AR)
Genes: FGFR2, POR
289
Cause of death in Antley-Bixler
Respiratory concerns
290
Absence of clavicles
Cleidocranial dysplasia (AD)
Gene: RUNX2 (CBFA1)
291
Respiratory insufficiency in newborns, "unusual" clubfoot, scoliosis, hitchhiker thumbs, CP, restricted joint mobility, severe lumbar lordosis, valgus deformities, toe walking, phalangeal synostosis with disability, short stature, normal intellect, spinal cord compression
Diastrophic Dysplasia (AR)
Gene: SLC26A2
292
Craniosynostosis, radially deviated short thumb, syndactyly, omphalocele
Apert syndrome (AD)
Gene: FGFR2
293
Cloverleaf skull
Pfeiffer and thanatophoric dysplasia
294
Craniosynostosis, bulging eyes, high and prominent forehead, hearing loss, dental malocclusion, wide thumbs/large toes which bend outward from other digits, brachydactyly and/or syndactyly
Pfeiffer Syndrome (AD)
Gene: FGFR2
295
FGFR2 related disorders
Apert, Pfeiffer, Crouzon (all AD)
FGFR2 is APPLE PEPPER CROUTONS
296
"Branchial arch syndrome"
Crouzon syndrome (AD)
Gene: FGFR2
297
"beak-like" nose
Crouzon syndrome (AD)
Gene: FGFR2
298
Craniosyostosis, bracycephaly, bulging eyes, strabismus, prognathic profile, CHD's (PDA and aortic coarctation), lifespan is normal if treated for cranial vault symptoms
Crouzon syndrome (AD)
Gene: FGFR2
299
Skeletal dysplasia with "normal appearance at birth"
Hypochondroplasia (AD)
FGFR3
300
Similar but milder skeletal features as achondroplasia
Hypochondroplasia (AD)
FGFR3
301
Coast of Maine CAL (Distribution along the midline)
McCune Albright (somatic, post-zygotic mutations)
GENE: GNAS1
302
CAL, fibrous dysplasia, endocrine dysfuncition
McCune Albright (somatic, post-zygotic mutations)
GENE: GNAS1
303
Craniosynostosis, hypertelorism, hearing loss, DD, LD in some; abnormally shaped head (even if craniosynostosis is not present as other parts of the skull may be malformed)
Muenke syndrome
304
Craniosynostosis, acrocephaly (cone-shaped head), lop-sided face, syndactyly, brachydactyly, valgus deformity, optic atrophy, vision problems, small and low-set ears, CP/high-arched palate, malocclusion, peg teeth, ptosis, short stature, CHDs
Saethre-Chotzen Syndrome (AD)
Gene: TWIST
305
Shawl scrotum and short stature (mild to moderate in childhood)
Aarskog Syndrome (X-linked recessive)
Gene: FGD1
306
Immune deficiency, recurrent bacterial infections, absence of circulating B cells, low serum immunoglobulins
X-linked Agammaglobulinemia
Gene: BTK
307
Gammaglobulin supplementation and prophylactic antibiotics to treat
X-linked Agammaglobulinemia
Gene: BTK
308
Complete or partial ACC, seizures (infantile spasms), retinal lacunae, increased tumor risk, lifespan 8-9 years
Aicardi syndrome (X-liked dominant)
Unknown gene
309
Bile duct paucity
Alagille syndrome (AD)
Genes: JAG1, NOTCH2
310
cholestasis, cardiac defects (stenosis of the pulmonary artery and its branches is the most common) - can manifest from TOF, butterfly vertebrae and other skeletal anomalies, posterior embryotoxon on ophtho exam, inverted triangle face
Alagille syndrome (AD)
Genes: JAG1, NOTCH2
311
Hematuria and proteinuria, glomerulonephritis, end-stage kidney disease, progressive HL, leiomyomatosis of the esophagus, eye changes (cataracts, kerataconus, retinal flecks in the macula)
Alport syndrome (AD, AR, or XL)
Genes: COL4A3, COL4A4, COL4A5
312
Treatment: ACE inhibitors slow progression of kidney disease, dialysis, kidney transplant
Alport syndrome (AD, AR, or XL)
Genes: COL4A3, COL4A4, COL4A5
313
Alzheimers genes
APP, PSEN1, PSEN2
314
Coffin-Lowry Syndrome
X-linked
Gene: RPS6KA3
short stature, severe ID, cardiac anomalies, auditory problems, dysmorphic features
Female carriers can have intellect ranging from normal to severe ID
315
Mild to severe ID, short thumbs with hypoplastic/absent nails, frequent respiratory infections, low birth weight/feeding difficulties, hypotonia, joint laxity, delayed bone age, microcephaly, coarse facies
Coffin-Siris Syndrome (AR, AD)
Genes: ARID1B, SOX11
316
Retinal dystrophy, acquired microcephaly, progressive high myopia, ID, GDD, hypotonia, joint hypermobility, short stature, truncal obesity, slender extremities, sociable disposition, neutropenia
Cohen syndrome (AR)
Gene: VPS13B
317
Growth retardation, hirsutism, limb reduction defects, seizures, autistic/self-destructive behaviors, SNHL, GERD, cryptorchidism, CHD, ID/DD
Cornelia De Lange Syndrome (AD/XL)
Genes: NIPBL, RAD21, SMC3, HDAC8, SMC1A
318
Normocytic or macrocytic anemia with normal platelets and leukocytes. Increased risk for hematological malignancies and osteogenic sarcoma, Klippel-Feil anomaly, upper limb and hand deformities, GU abnormalities, CHDs, growth delays
Diamond-Blackfan Anemia (AD/XL)
Genes: GATA1, RPLs and RPSs, TSR2
319
Inability to produce tears, usually normal intellect, progressive neuronal deterioration, delayed speech, delayed motor milestones, unstead gait, corneal abrasion, decreased pain and temperature perception, poor growth, dysphagia, skin picking/self mutilation, unstable blood pressure, red and puffy hands, crises
Familial Dysautonomia (AR)
Gene: IKBKAP
AJ common mutation, c.2204+6T>C
320
Autoinflammatory disease, AA Amyloidosis, recurrent febrile episodes recurrent erythema, elevated serum fibrinogen, kidney failure
Familial Mediterranean Fever (AR)
Gene: MEFV
321
Treatment: Preventative oral colchecine
Familial Mediterranean Fever (AR)
Gene: MEFV
322
Lissencephaly
Miller Dieker
323
Rickets
Tyrosinemia
324
Tall stature, feminization at puberty
Klinefelter
325
Cataracts
Galactosemias
326
LSD/GSD that mimics Limb Girdle
Pompe
327
Oculomotor apraxia
Gaucher type 3
328
Cherry red spot
Tay Sachs and Niemann pick type A
329
Only urea cycle defect where hyperammonemia is rarely present
Arginase deficiency
330
Protein aversion, hyperammonemia, respiratory alkalosis
Urea cycle disorders
331
Triad of hypotonia, head lag, macrocephaly
Canavan disease
332
Chromosomal breakage syndrome without sensitivity to ionizing radiation
Cockayne Sydnrome
333
Polydactyly, retinitis pigmentosa, renal problems
Bardet-Biedl
334
DCM and neutropenia
Barth sndrome
335
Rapid and lethal lactic acidosis and cardiopulmonary failure
Leigh syndrome
336
Psych issues, parkinsonism/chorea, standard mito symptoms
POLG
337
Standard mito symptoms, ketogenic diet helps treat
Pyruvate dehydrogenase
338
Foot drop, muscle wasting
CMT
339
Most severe congenital MD; death by age 3
Walker-Warburg
340
Sparse hair, pointed chin, overgrowth, flushed cheeks
Sotos syndrome
341
Rapid continuous growth, coarse facies, hoarse cry as babies
Weaver syndrome
342
ID, HCM/pulmonic stenosis, rhabdomyosarcoma/neuroblastoma
Costello syndrome
343
AR dwarfism, unusual clubfoot, hitchhiker thumb
Diastrophic Dysplasia
344
Craniosynostosis, hearing loss, FGFR3
Muenke
345
Severe immune deficiency
XL Agammaglobulinemia
346
Diaphragmatic hernia, death in neonatal
Fryns
347
Hemifacial microsomia with visceral organ underdevelopment, unilateral hearing/vision loss
Goldenhar
348
Macrocephaly, poly/syndactyly
Greig Cephalopolysyndactyly
349
Ectodermal dysplasia, fusion of eyelids
Hay-Wells (AD)
350
Limb reduction defects, thalidomide phenocopy
Holt-Oram (AD)
Gene: TBX5
351
Childhood diabetes, vision/hearing loss
Wolfram (AR)
352
Mutations in different genes can cause the same disorder/phenotype
Locus heterogeneity
Ex. Autism, retinitis pigmentosa
353
Different mutations in the same gene can cause the same disorder
Allergic heterogeneity
354
Different mutations in the same gene can cause different phenotypes
Phenotypic heterogeneity
355
Stellar irises
Williams syndrome (deletion of 7q)
356
Supravalvular aortic stenosis
Williams syndrome (deletion of 7q)
357
Aniridia
Absence of the colored part of the eye (seen in WAGR - deletion of 11p)
358
WAGR
Wilms tumor
Aniridia
GU anomalies
Retardation (ID)
359
Anterior lenticonus
Virtually pathognomonic for Alport Syndrome
