Increased Leucine on PAA
MSUD
Defects in biotin metabolism cause
biotinidase deficiency and propionic acidemia
Primary lactic acidosis
Electron Transport Chain (ETC) - mito defects.
Pyruvate dehydrogenase deficiency
Hiccuping and apnea
Nonketotic hyperglycinemia
Hyperammonemia
Urea cycle disorders
Severe acidosis
Organic acidemias
Lethargy and seizures
MSUD
Jaundice, hypoglycemia, liver failure, hepatomegaly, vomiting
Galactosemia
Hypoglycemia, weakness, cardiac
FAOD
Hypoglycemia and circulatory collapse
CAH
Respiratory alkalosis (Tacypnea), vomiting and lethargy, NOT ACIDOTIC
Urea cycle disorders
Elevated C3 acylcarnitine measured in NBS
Propionic acidemia and methylmalonic acidemia
Elevated C5 acylcarnitine measured on NBS
Isovaleric acidemia
Liver failure, E. coli sepsis
Galactosemia
Dysostosis Multiplex
LSD’s - typically MPS
Erlenmeyer flask defomity
Gaucher
Sphingomyelinase deficiency
Types A and B of Niemann Pick
Cholesterol trafficking defect
Type C of Niemann Pick
Palsy of upward gaze
Type C of Niemann Pick
Spinal “gibbus” - kink in spine
MPS
Earliest onset and most severe MPS
MPS I - Hurler Scheie
No corneal clouding and X-linked MPS
Hunter
More neurologic symptoms (frequently have behavioral problems with progression to severe neurologic disease) - mildest somatic symptoms of the MPS
MPS III - Sanfilippo
Most severe skeletal disease, normal intelligence (MPS)
MPS IV - Morquio
Usually normal intelligence, Arylsulfatase B deficiency (MPS)
MPS VI - Maroteaux-Lamy
Most severe cases characterized by hydrops fetalis (MPS)
MPS VII - Sly
Glycogen debrancher deficiency; progressive hypertrophic cardiomyopathy
GSD III: Forbes, Cori disease
Phosphorylase kinase deficiency (GSD IX) inheritance
X-LINKED
Hepatosplenomegaly, FTT, progressive cirrhosis, liver failure, myopathy/cardiomyopathy
Anderson disease (GSD IV): different phenotype from other hepatic glycogenoses
Hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, poor growth, +/- myopathy
Clinical presentation of Hepatic GSD
Vitamin B6 therapy
Homocystinuria
Vitamin B12 therapy
Methylmalonic aciduria
Thiamin therapy
MSUD
Tetrahydrobiopterin therapy
PKU and tetrahydrobiopterin deficiency (also provide DOPA for this one - not for PKU)
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])
Normal number of repeats in FMR1
<45 = unaffected, make all the protein needed
Chance that a premutation 69 or lower would expand to a full mutation
<6%
Chance that a premutation 100 or higher would expand to a full mutation
94-100%
Lack of CFTR leads to
abnormal epithelial ion and fluid transport
Class I CFTR mutation
Null production - frame shifts, premature term (G542X, R553X, W1282X) [Worst]
Class II CFTR mutations
Trafficking - missense deltaF508, N1303K
Class III CFTR mutations
Regulation - Missense G551D
Class IV CFTR mutations
Conduction - Conservative Missense R117H [Best]
Chronic respiratory infections, exocrine pancreatic insufficiency, Intestinal obstruction/meconium ileus, male sterility, diabetes, progressive obstructive liver disease
Cystic fibrosis
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
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
Mannose binding lectin and TGFB
modifiers of pulmonary disease in CF
Increased incidence of CFTR mutations in general population with
- Asthma
- Chronic Rhinosinusitis
- Idiopathic pancreatitis
- Primary sclerosing cholangitis
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
Neonatal hypoparathyroidism and immunodeficiency
22q
Immunodeficiency, CHD, palate defects, hypocalcemia, GU anomalies, GI problems, DD, psychiatric illness
22q
Conotruncal heart defects
22q (TOF, VSD, IAA typeB)
In frame deletions of FBN1 usually have a _
more severe phenotype
Brushfield spots
T21
hypertonia, prenatal growth deficiency, fists clenched, rocker-bottom feet, severe heart malformations, feeding difficulties
T18
Microcephaly, sloping forhead, fist clenching, rocker-bottom feet, severe CNS malformations, CHD
T13
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
Anticipation seen in HD
more commonly when paternally inherited
Agents to avoid in HD
L-dopa-containing compounds, alcohol consumption, and smoking
Sickle cell disease = homozygous
HbSS
Anterior horn cells
SMA - loss of anterior horn cells in the spinal cord
SMN1 deletions
cause SMA (usually deletion of exon 7)
SMN2 determines
prognosis (dosage: # copies 0-5; 3+ = milder)
Why should you avoid prolonged fasting in SMA
unexplained metabolic acidosis is a potential complication of SMA
Why is the lifespan shortened in SMA
progressive ventilatory insufficiency resulting from chest muscle involvment
UBA1
gene associated with X-linked SMA
Female heterozygote carriers for DMD at an increased risk for
DCM
In frame deletions of DMD
Becker
Out of frame deletions of DMD
Duchenne
Testing used for immunohistochemistry of dystrophin
Western blot
DMD associated DCM is characterized by
left ventricular dilation and congestive heart failure
_ complications are common causes of death in DMD and BMD
Respiratory and cardiomyopathy complications
Myxomas
Carney Complex
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
Used when only first degree female relatives had breast cancer
Gail
Used when first and second degree relatives had breast cancer
Claus
Takes into account current age, age at first menses, and age a first live birth
Gail
Considers previous biopsy and if atypical cells were seen
Gail
For breast cancer risk AND mutation risk
BRCAPro, Tyrer-Cuzick, BOADICEA
Considers risk for “lower penetrance” gene in addition to BRCA
Tyrer-Cuzick
FAP plus osteomas and soft tissue tumors (desmoids, epidermoids, fibromas)
Gardner syndrome
FAP plus CNS tumors, specifically medulloblastoma
Turcot syndrome
Cancers that Amsterdam II takes into consideration
CRC, uterine, small bowel, ureter, renal pelvis
Absence of MLH1 and PMS2 could be
MLH1 germline mutation
MLH1 promoter hypermethylation (rule out through BRAF testing)
Absence of just PMS2 could be
MLH1 or PMS2 germline mutations
Most Lynch CRC tumors are _ on microsatellite testing
MSI-high (high instability)
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)
Absence of just MSH6 could be
MSH6 germline mutation
Adrenocortical carcinoma
Li-Fraumeni
Choroid plexus carcinoma
Li-Fraumeni
Cancer syndrome may manifest as primary hyperparathyroidism
MEN1
MEN2A and 2B associated with _ mutations
gain of function
RET associated Hirschsprung’s disease
Associated with LOF mutations
Megacolon
Constipation
Bilateral vestibular schwannomas
NF2
Conductive HL by age 30
Tinnitus
Balance dysfunction “death by drowning” is key pedigree note
Decreased visual acuity
Cardiac rhabdomyoma
Tuberous Sclerosis Complex (TSC)
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
Shagreen Patches
Tuberous Sclerosis Complex
Neuroendocrine tumors seen in TSC
Pituitary adenoma, parathyroid adenoma, pancreatic adenoma, gastrinoma, pheochromocytoma, carcinoids
Penile freckline
PTEN
Subependymal nodules
Tuberous Sclerosis Complex
Subependymal giant cell astrocytoma (brain tumor)
Tuberous Sclerosis Complex
“confetti” hypopigmented skin lesinos, dental pits, intraoral fibromas, multiple renal cysts, retinal achromic patch
Tuberous Sclerosis Complex
Cancer syndrome with seizures, ASD, ADHD, DD/ID
Tuberous Sclerosis Complex
Endolymphatic sac tumors
VHL
Clear cell renal carcinoma, spinal or cerebellar hemangioblastoma, pancreatic neuroendocrine tumors, pheochromocytoma, paraganglioma, retinal angioma, multiple renal and pancreatic cysts
VHL
Spinal or cerebellar hemangioblastoma
VHL
Coved type ST segment
Brugada
SCN5A is the main gene in
Brugada
Sudden death, negative T wave, Coved type ST segment, V fib, self-terminating polymorphic ventricular tachycardia, episodes of syncope, nocturnal agonal respiration (gasping)
Brugada
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)
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
Xanthomas, elevated cholesterol, premature atherosclerosis, coronary artery disease, increased risk for MI
Familial Hypercholesterolemia
Genes: LDLR, APOB, PCSK9, LDLRAP1
Telangiectasias, nose bleeds, AVMs (occur in large organs)
HHT
Genes: ACVRL (ALK1), ENG, SMAD4, GDF2
Torsades de pointes
Long QT
LQTS with congenital deafness
Jervell and Lange-Nielsen Syndrome (Autosomal Recessive)
Genes: KCNE1 and KCNQ1
LQTS with autism
Timothy syndrome
Timothy syndrome
- Autosomal dominant
- LQTS, type 8
- syndactyly
- autism
- structural cardiac malformations
- ID
- dental anomalies
Thickening, usually of the left ventricle which leads to reduced cardiac output
Hypertrophic Cardiomyopathy (HCM)
Caused by mutations in sarcomere genes
HCM
HCM is seen in
Noonan syndrome and Fabry
Stretching of muscle fibers, often in the left ventricle, leads to dilation of the chamber and reduced cardiac output
Dilated Cardiomyopathy (DCM)
Caused by mutations in cytoskeletal genes
DCM
DCM is seen in
DMD, mito disease, Bardet-Biedl Syndrome, Alstrom sydnrome
Caused by fibrofatty replacement of the right ventricular heart tissue (myocardium)
Arrhythmogenic right-ventricular Dysplasia/Cardiomyopathy (ARVD/ARVC)
Associated arrhythmia generated from the right ventricle
ARVD/ARVC
Naxos/Carvajal disease
Recessive ARVD/ARVC with palmoplantar keratoderma and “wooly hair”
Caused by mutations in desmosomal genes
ARVD/ARVC
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)
Excessive, prominent, persistent trabeculations are major feature (congenital but typically manifests later in life)
LVNC
Heart walls become rigid, reducing ability to pump blood/cardiac output
LVNC
Most cardiac arrhythmias are
Channelopathies
NBS for CF uses
Immunoreactive trypsinogen (IRT) - will be elevated in CF, then check common mutations
CF and Brugada are
Channelopathies
Chromosomal Breakage Disorders
Ataxia-Telangiectasia
Bloom
Cockayne
Fanconi Anemia
Nijmegen Breakage syndrome
Werner Syndrome
Xeroderma Pigmentosum
Dysarthria (slurred speech)
Ataxia-Telangiectasia
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
Extreme growth deficiency and characteristic high-pitched voice
Bloom syndrome
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
Biggest cancer risk for bloom syndrome
Colon followed by breast, liver, respiratory tract, lymphatic, sarcoma, germ cell, CNS, retinoblastoma
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
Cachectic dwarfism
Cockayne syndrome
Worst type of Cockayne Syndrome
Type 2
Chromosome breakage syndrome not predisposed to cancer or infection
Cockayne Syndrome
Nucleotide excision repair
Cockayne Syndrome and Xeroderma Pigmentosum
Pancytopenia/bone marrow failure
Fanconi Anemia
FANCB inheritance pattern
X-linked recessive
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
Cross-link repair, homologous recombination repair
Fanconi Anemia
Double stranded break repair
Ataxia-Telangiectasia and Werner Syndrome
Increased sister chromatid exchanges/double-stranded break repair
Bloom syndrome
Homologous recombination repair
Nijmegen Breakage Syndrome
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
Premature aging and early onset of disease normally associated with aging (osteoporosis, diabetes, atherosclerosis, calcinosis)
Werner Syndrome
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
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
Ciliopathies
Alstrom syndrome, Bardet-Biedl Syndrome, Joubert syndrome, Meckel-Gruber Syndrome, Orofaciodigital Syndrome 1, Polycystic Kidney Disease, Primary Ciliary Dyskinesia
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
Alstrom syndrome is similar to
Bardet-Biedl Syndrome (but ABSENCE OF POLYDACTYLY)
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
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)
Embryonic lethal, renal cystic dysplasia
Meckel-Gruber Syndrome (AR)
Renal cystic dysplasia, CNS malformations, polydactyly, hepatic malformations, oligohydramnios, pulmonary hypoplasia
Meckel-Gruber Syndrome (AR)
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)
OFD1
Orofaciodigital Syndrome 1
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)
heterotaxy (situs inversus), impaired ciliary motility, frequent upper and lower respiratory infections due to poor clearance of mucus from thelungs
Primary Ciliary Dyskinesia (AR)
F8 gene
Hemophilia A (X-linked recessive)
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!
F9 gene
Hemophilia B (X-linked recessive)
Acute treatment with DDAVP
Hemophilias
Increased risk for venous thromboembolism
Factor V (Autosomal dominant and recessive)
Gene: F5
Long-term oral anticoagulants is necessary, particularly in homozygotes
Factor V (Autosomal dominant and recessive)
Gene: F5
Factor V “Leiden” refers to
The common allele, c.1691G>A in F5
Mild to moderate mucocutaneous bleeding. Easy bruising, nosebleeds, heavy periods
von Willebrand Disease (most AD, occasional AR)
VWF gene
von Willebrand Disease type 2B and 2N may have
thrombocytopenia
von Willebrand Disease type 2N has more
severe bleeding and mimics hemophilia
Congenital Contractural Arachnodactyly
Beals Syndrome
AD - FBN2 gene
Marfanoid habitus, flexion contractures of elbows, hips, knees, and/or fingers, kyphoscoliosis, muscular hypoplasia, crumpled ear outer helices
Beals Syndrome (Congenital Contractural Arachnodactyly)
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
Loose, inelastic skin that hangs/looks wrinkled, joint hypermobility, hernia, blue sclera, cardiopulmonary complications
Cutis Laxa (AD, AR, XL)
ELN gene usually, are others
Most severe type of EDS
Vascular type - Type IV
Vascular/arterial dissection or rupture, Gi rupture, bowel rupture, organ rupture, club foot, spontaneous pneumothorax, hip dysplasia, inguinal hernia
Vascular type EDS - Type IV
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
Vessel tortuosity
Loeys-Dietz (AD)
Genes: TGFBR1, TGFBR2, SMAD3, TGFB2
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)
Connective tissue disorder with cleft palate/bifid uvula
Loeys-Dietz
Types of OI with blue sclera
Type I, III
Woods lamp for skin diagnoses
Tuberous Sclerosis
“mesh-like” bone appearance
OI Type V
“Fish scale” bone appearance
OI type VI
Type II Loeys-Dietz has no
craniofacial findings
Very similar to Loeys-Dietz including dysmorphic features/craniosynostosis with multiple abdominal hernias, ID, brain anomalies
Sphrintzen-Goldberg Syndrome (AD)
Gene: SKI
Type 1 Stickler syndrome is “_”
“Membranous” - most common type
Persistent vestigial vitreous gel in the retrolental space of the eye
Type 2 Stickler syndrome is “_”
“Beaded”
Sparse and irregularly thickened bundles throughout the vitreous cavity of the eye
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
Severe microcytic hypochromic anemia, splenomegaly, severe bone deformities, death before age 20 if untreated
Beta Thal (AR)
HBB gene
Treatment:
Periodic blood infusions
Splenectomy
Chelation of transfusion-induced iron overload
Beta Thal Major
Vaso-occlusive events
Sickle cell
Dactylitis
Sickle cell
Pulmonary hypertension, acute chest syndrome (chest pain, fever, pulmonary infiltrate, respiratory problems, hypoxia), splenic dysfunction, chronic hemolysis, stroke
Sickle Cell anemia (HbSS genotype)
Normal blood genotype
Hb AA
Sickle cell trait genotype
Hb AS
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
Poor growth, exercise intolerance, muscle weakness, vision/hearing loss, LD, seizures and strokes
Common features of mito disorders
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
Major cause of death in Barth syndrome
cardiomyopathy and neutropenia
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
Major cause of death in Leigh syndrome
Respiratory failure
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)
Metabolic form:
lactic acidosis/elevated blood lactate
Hyperventilation secondary to metabolic acidosis
Pyruvate Dehydrogenase Deficiency (X-linked)
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)
Treatment of sodium bicarbonate for acute metabolic episodes and ketogenic diet
Pyruvate Dehydrogenase Deficiency (X-linked)
NORMAL cognition, DD, muscle weakness, congenital cataracts, HCM, lactic acidosis, high risk of death in infancy due to cardiac failure
Senger’s syndrome (AR)
Myopathy, encephalopathy, stroke, lactic acidosis
MELAS (mito) - onset between 5-15 years
Myoclonic epilepsy, hearing loss, symmetrical lipomatosis around neck, ragged red fibers (clumps of disease mitochondria that accumulate in the muscle fibers)
MERRF (mito)
Neuropathy, ataxia, retinitis pigmentosa
NARP (mito); moderate heteroplasmy at T8993G
High heteroplasmy at T8993G
causes Leigh syndrome (moderate causes NARP)
Fatal in infancy, FTT, sideroblastic anemia, exocrine pancreas dysfunction
Pearson syndrome (mito)
Chronic PEO, pigmentary retinopathy, cardiac conduction abnormalities, onset before 20 years, cerebellar ataxia may be seen
Kearns-Sayre Syndrome (mito)
Due to nondisjunction in paternal meiosis
Turner syndrome
Due to nondisjunction in maternal OR paternal meiosis I
Klinefelter Syndrome
Usually maternal meiosis I (can be paternal meiosis I)
Trisomy 21
Due to nondisjunction in maternal meiosis II
Trisomy 18
Due to nondisjunction in maternal meiosis I
T13
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)
Duplication of PMP22
Charcot Marie tooth (CMT) - 70-80% of cases; AD versions
Foot drop - forefoot drops due to muscle weakness; can cause hammer toe
CMT (AD, AR, X-linked)
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
Positive Gower’s sign
BMD and DMD
Preservation of neck flexor muscle strength
Differentiates BMD from DMD
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
EMD, LMNA, SYNE1, SYNE2, FHL1
Emery-Dreifuss MD
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
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
Normal repeat number for Facio-Scapulo-Humeral MD
11 - 100 repeats. Deletions lead to 10 or fewer repeats which lead to FSHD
Winged scapula
Facio-Scapulo-Humeral MD
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
Muscle weakness, most severe in the face, neck flexors, and proximal limbs; hypotonia, depressed/absent deep tendon reflexes
Nemaline Myopathy
Forms of Nemaline Myopathy (NM)
AD or AR
Severe congenital
Amish NM
Intermediate
Typical (mild) congenital NM
Childhood-onset NM
Adult-onset NM
May present with “head drop”
Nemaline Myopathy
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)
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
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
SMA IV
Adult onset muscle weakness
The more copies of SMN2 the _ severe the phenotype
less
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
Muscle disease with encephalocele
Walker Warburg Syndrome (AR)
Genes: POMT1, POMT2
Port wine stain
Klippel-Trenaunay-Weber Syndrome (KTW Syndrome)
SPORADIC INHERITANCE: may be due to somatic changes in early development
Unknown gene
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)
Inheritance of KTW syndrome
SPORADIC
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)
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
“Bulldog syndrome”
Simpson-Golabi-Behmel syndrome (X-linked recessive)
Genes: GPC3, GXORF5
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
Flushed cheeks
Sotos syndrome (AD; 95% de novo)
NSD1 = gene
Overgrowth syndrome causes maternal preeclampsia
Sotos syndrome (AD; 95% de novo)
NSD1 = gene
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
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
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)
RASopathy caused by a proto-oncogene
Costello syndrome (AD)
Gene: HRAS (proto-oncogene)
How is Legius syndrome different from NF1
DOES NOT HAVE LISCH NODULES OR NEUROFIBROMAS
Legius is caused by SPRED1 (AD)
How is Legius syndrome similar to NF1
CAL macules, optic gliomas, learning problems, etc.
Genes to think about in Noonan
PTPN11 and KRAS (many others) - AD
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
Noonan plus multiple lentienes (liver spots)
LEOPARD syndrome (AD)
Genes: PTPN11, RAF1, BRAF, MAP2K1
LEOPARD mnemonic
Lentigines Electrocardioraphic abnormalities Ocular hypertelorism Pulmonic stenosis Abnormal genitalia Retarded growth Deafness
Only AR repeat expansion disorder
Friedrich’s Ataxia
FXN gene
Trinucleotide repeat: GAA (intronic region)
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)
Muscle weakness, myotonia, cataracts, balding, cardiac arrythmia, average lifespan 45-55 years
Myotonic Dystrophy Type I; AD
DMPK gene; CTG repeats
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
Type of expansion you can see (anticipation) in Myotonic dystrophy type I
MATERNAL
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
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
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
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
Complete androgen insensitivity
Appear phenotypically female, but are lacking a uterus (Mullerian regression)
- blind ending vagina (no cervix)
Partial Andregen Insensitivity
May exhibit ambiguous genitalia and/or undervirilization at puberty
Why do undescended testes in androgen insensitivity need to be removed?
Increased risk for germ-cell tumors
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
Acute adrenal insufficiency
X-linked Adrenal hypoplasia congenita
Gene: NROB1
Adrenal failure, acute adrenal insufficiency, hypogonadotropic hypogonadism, DD
X-linked Adrenal hypoplasia congenita
Treatment: HRT
Kallman syndrome
Treatment: Glucocorticoid and mineralcorticoid replacement therapy
X-linked Adrenal Hypoplasia Congenita
Treatment: Glucocorticoid replacement therapy and Florinef
21-Hydroxylase Deficiency
Trident hands
Achondroplasia
c.1138G>A in FGFR3
Common mutation for Achondroplasia
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
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
Cause of death in Antley-Bixler
Respiratory concerns
Absence of clavicles
Cleidocranial dysplasia (AD)
Gene: RUNX2 (CBFA1)
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
Craniosynostosis, radially deviated short thumb, syndactyly, omphalocele
Apert syndrome (AD)
Gene: FGFR2
Cloverleaf skull
Pfeiffer and thanatophoric dysplasia
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
FGFR2 related disorders
Apert, Pfeiffer, Crouzon (all AD)
FGFR2 is APPLE PEPPER CROUTONS
“Branchial arch syndrome”
Crouzon syndrome (AD)
Gene: FGFR2
“beak-like” nose
Crouzon syndrome (AD)
Gene: FGFR2
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
Skeletal dysplasia with “normal appearance at birth”
Hypochondroplasia (AD)
FGFR3
Similar but milder skeletal features as achondroplasia
Hypochondroplasia (AD)
FGFR3
Coast of Maine CAL (Distribution along the midline)
McCune Albright (somatic, post-zygotic mutations)
GENE: GNAS1
CAL, fibrous dysplasia, endocrine dysfuncition
McCune Albright (somatic, post-zygotic mutations)
GENE: GNAS1
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
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
Shawl scrotum and short stature (mild to moderate in childhood)
Aarskog Syndrome (X-linked recessive)
Gene: FGD1
Immune deficiency, recurrent bacterial infections, absence of circulating B cells, low serum immunoglobulins
X-linked Agammaglobulinemia
Gene: BTK
Gammaglobulin supplementation and prophylactic antibiotics to treat
X-linked Agammaglobulinemia
Gene: BTK
Complete or partial ACC, seizures (infantile spasms), retinal lacunae, increased tumor risk, lifespan 8-9 years
Aicardi syndrome (X-liked dominant)
Unknown gene
Bile duct paucity
Alagille syndrome (AD)
Genes: JAG1, NOTCH2
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
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
Treatment: ACE inhibitors slow progression of kidney disease, dialysis, kidney transplant
Alport syndrome (AD, AR, or XL)
Genes: COL4A3, COL4A4, COL4A5
Alzheimers genes
APP, PSEN1, PSEN2
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
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
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
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
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
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
Autoinflammatory disease, AA Amyloidosis, recurrent febrile episodes recurrent erythema, elevated serum fibrinogen, kidney failure
Familial Mediterranean Fever (AR)
Gene: MEFV
Treatment: Preventative oral colchecine
Familial Mediterranean Fever (AR)
Gene: MEFV
Lissencephaly
Miller Dieker
Rickets
Tyrosinemia
Tall stature, feminization at puberty
Klinefelter
Cataracts
Galactosemias
LSD/GSD that mimics Limb Girdle
Pompe
Oculomotor apraxia
Gaucher type 3
Cherry red spot
Tay Sachs and Niemann pick type A
Only urea cycle defect where hyperammonemia is rarely present
Arginase deficiency
Protein aversion, hyperammonemia, respiratory alkalosis
Urea cycle disorders
Triad of hypotonia, head lag, macrocephaly
Canavan disease
Chromosomal breakage syndrome without sensitivity to ionizing radiation
Cockayne Sydnrome
Polydactyly, retinitis pigmentosa, renal problems
Bardet-Biedl
DCM and neutropenia
Barth sndrome
Rapid and lethal lactic acidosis and cardiopulmonary failure
Leigh syndrome
Psych issues, parkinsonism/chorea, standard mito symptoms
POLG
Standard mito symptoms, ketogenic diet helps treat
Pyruvate dehydrogenase
Foot drop, muscle wasting
CMT
Most severe congenital MD; death by age 3
Walker-Warburg
Sparse hair, pointed chin, overgrowth, flushed cheeks
Sotos syndrome
Rapid continuous growth, coarse facies, hoarse cry as babies
Weaver syndrome
ID, HCM/pulmonic stenosis, rhabdomyosarcoma/neuroblastoma
Costello syndrome
AR dwarfism, unusual clubfoot, hitchhiker thumb
Diastrophic Dysplasia
Craniosynostosis, hearing loss, FGFR3
Muenke
Severe immune deficiency
XL Agammaglobulinemia
Diaphragmatic hernia, death in neonatal
Fryns
Hemifacial microsomia with visceral organ underdevelopment, unilateral hearing/vision loss
Goldenhar
Macrocephaly, poly/syndactyly
Greig Cephalopolysyndactyly
Ectodermal dysplasia, fusion of eyelids
Hay-Wells (AD)
Limb reduction defects, thalidomide phenocopy
Holt-Oram (AD)
Gene: TBX5
Childhood diabetes, vision/hearing loss
Wolfram (AR)
Mutations in different genes can cause the same disorder/phenotype
Locus heterogeneity
Ex. Autism, retinitis pigmentosa
Different mutations in the same gene can cause the same disorder
Allergic heterogeneity
Different mutations in the same gene can cause different phenotypes
Phenotypic heterogeneity
Stellar irises
Williams syndrome (deletion of 7q)
Supravalvular aortic stenosis
Williams syndrome (deletion of 7q)
Aniridia
Absence of the colored part of the eye (seen in WAGR - deletion of 11p)
WAGR
Wilms tumor
Aniridia
GU anomalies
Retardation (ID)
Anterior lenticonus
Virtually pathognomonic for Alport Syndrome