High Yield Flashcards - Final

Neurofibromatosis 1 Genetic Cause

AD: germline pathogenic variants in NF1 (17q11.2), 30-50% de novo

Neurofibromatosis 1 Molecular Mechanism

• Loss of function - neurofibromin is a negative RAS regulator, with pathogenic variant RAS will be more active

• 2-hit hypothesis: somatic mutation of NF1 needed for tumor progression

Neurofibromatosis 1 Symptoms/Presentation

• cutaneous findings

• skeletal abnormalities

• cardiovascular involvement

• cancer predisposition

• learning difficulties, seizures, sleep disturbances

Neurofibromatosis 1 Cutaneous Findings

• cafe-au-lait macules

• neurofibromas (benign cutaneous or subcutaneous lesions)

• plexiform neurofibromas

• axillary/inguinal freckling

• iris Lisch nodules

• optic glioma

Neurofibromatosis 1 Skeletal Abnormalities

• antero-lateral bowing of tibia and fibula

• pseudoarthrosis of tibia and fibula

• sphenoid bone dysplasia w/ orbital plexiform neurofibroma (facial hemihyperplasia)

Neurofibromatosis 1 Diagnostic Criteria

2+ following manifestations:

• optic pathway glioma

• 2+ Lisch nodules/choroidal abnormalities

• axillary/inguinal freckling

• 6+ cafe au lait macules 

• 2+ neurofibroma tumors

• distinctive osseous lesion

• Pathogenic variant alone is not sufficient for diagnosis

Mosaic Neurofibromatosis 1 Clinical Presentation

• Clinical features of NF1 can be seen, but only some tissues present with these manifestations

Mosaic Neurofibromatosis Type 1 Diagnostic Criteria

If any of the following present:

• pathogenic heterozygous NF1 variant w/ allele fraction less than 50% AND one other NF1 criterion

• identical pathogenic heterozygous NF1 variant in two anatomically independent tissues

• segmental distribution of cafe-au-lait macules or neurofibromas

Neurofibromatosis 1 Cancer Risks

Female breast cancer, brain tumors, and malignant peripheral nerve sheath tumors (MPNSTs)

Neurofibromatosis 1 Cardiovascular Symptoms

• arterial hypertension (15-20%)

• pulmonary hypertension

• higher frequency of cardiac issues (pulmonic valve and mitral valve)

• blood pressure check every visit!

Legius Syndrome Genetic Cause

AD: pathogenic variants in SPRED1

Legius Syndrome Molecular Mechanism

Loss-of-function in SPRED1 causes hyperactivation of RAS pathway (SPRED1 typically acts to inhibit the protein cascade)

Legius Syndrome Symptoms/Presentation

• cafe-au-lait macules

• skin freckling

• neurobehavioral/developmental issues

• macrocephaly

• short stature

• multiple lipomas

• pectus deformity

• Noonan facies

Legius Syndrome Diagnostic Criteria

Following criteria present:

• 6+ cafe-au-lait macules bilaterally distributed

• no other NF1 diagnostic criteria (aside from freckling)

• heterozygous pathogenic variant in SPRED1

Neurofibromatosis 2 Genetic Cause

AD: heterozygous pathogenic variants in NF2

Neurofibromatosis 2 Molecular Mechanism

Loss-of-function variants in NF2 - Merlin is a negative RAS regulator, involved in PI3K and other pathways that increase cell growth, LOF causes hyperactivation

Neurofibromatosis 2 Tumor Types

• CNS tumors (gliomas, meningiomas, cranial schwannomas)

• spinal cord tumors (astrocytomas, ependymomas, meningiomas)

• skin (cafe-au-lait, subcutaneous schwannoma)

• auditory system (bilateral vestibular schwannoma)

• visual system (optic nerve sheath meningiomas, orbital tumors)

Neurofibromatosis 2 Symptoms/Presentation

• multi-system tumors

• symptoms from tumor compression:

  • tinnitus

  • seizures

  • mono/polyneuropathy

  • muscle wasting

  • pain

  • diplopia (double vision)

Neurofibromatosis 2 Management

• surgery for bilateral vestibular schwannomas

• audiology referral and hearing aids

• annual MRIs (starting age 12 - 40s)

• annual hearing and eye examinations

Schwannomatosis Genetic Cause

AD: pathogenic variants in LZTR1 and SMARCB1

Schwannomatosis Symptoms/Presentation

Schwannoma

Benign tumor that forms from schwann cells (that create the myelin sheath around nerves)

Schwannomatosis Symptoms/Presentation

• predisposition to develop multiple non-intradermal schwannomas

• localized or diffuse pain or asymptomatic mass

• most often present in peripheral and spinal nerves

Specific Changes in SMARCB1 Related Schwannomatosis

• meningiomas reported only in these individuals

• malignant transformation is a risk

Schwannomatosis Molecular Mechanism

• Two hit hypothesis (present on Chromosome 22)

• Loss of NF2 can results from genetic changes present on the same allele

Schwannomatosis Diagnostic Criteria

• 2+ non-intradermal tumors

• absence of bilateral vestibular schwannomas

• AD family history

• identification of heterozygous germline pathogenic variant in LZTR1 or SMARCB1

Tuberous Sclerosis Genetic Cause

AD: pathogenic variants in TSC1 and TSC2, 2/3 are de novo mutations (mostly found in TSC2)

Tuberous Sclerosis Pathophysiology

• TSC1 and TSC2 encode for proteins hamartin and tuberin which compose TSC complex

• TSC acts as a negative regulator for mTOR signaling

• overactivation of mTOR signaling pathway leads to cellular hyperplasia and tissue dysplasia

Tuberous Sclerosis Molecular Mechanism

• TSC1 mutations mostly nonsense/frameshift - lead to protein truncation

• TSC2 mutations more often missense, large deletions, rearrangements

• may be missed on exome testing and may require del/dup analysis

• 10-25% have negative genetic testing, does not rule out clinical diagnosis

Tuberous Sclerosis Symptoms/Presentation

• CNS manifestations

• Neuropsychiatric disorders

• Cutaneous findings

• ocular findings

• renal findings

• lung and cardiac findings

Tuberous Sclerosis CNS Manifestations

• 80-90% have seizures

• subependymal nodules

• cortical tubers

• subependymal giant cell astrocytomas

Tuberous Sclerosis Neuropsychiatric Findings

• TSC-associated neuropsychiatric disorders (TAND)

• Different behavioral, psychiatric, intellectual, academic, and psychosocial differences

• may be very functional but present with ADHD, autistic traits, behavioral abnormalities like self-injury, mild ID

Tuberous Sclerosis Cutaneous Findings

• hypomelanotic macules (ash leaf spots)

• confetti skin

• facial angiofibroma

• shagreen patch (leathery skin)

• fibrous cephalic plaques

• ungual fibroma

• gingival fibromas and enamel pitting

Tuberous Sclerosis Ocular Findings

• retinal astrocytic hamartomas

• retinal hypopigmentation

• usually benign unless optic disc is compressed

Tuberous Sclerosis Renal Findings

• single or multiple simple cysts

• angiolipomas can be found by age 10

• TSC2 gene located next to PKD1 - presence of early onset polycystic kidney disease can be considered

Tuberous Sclerosis Lung and Cardiac Findings

• multifocal pulmonary cysts

• lympangiomyomatosis (estrogen driven)

• cardiac rhabdomyomas (found in infancy, resolve with age)

Tuberous Sclerosis Management

• symptoms potentially treatable with mTOR inhibitors

• surgery for significant CNS tumors

• treatment of seizures

• echocardiogram and abdominal MRIs

Tuberous Sclerosis Diagnostic Criteria

• no mutation is found in 10-25% of cases (somatic mosaicism)

2+ major features OR 1 major and 2+ minor features

Major features:

• angiofibromas

• cardaic rhabdomyoma

• cortical tubers

• LAM

• shagreen patch

• renal angiomyolipoma (2+)

• subependymal giant cell astrocytoma

• subependymal nodules

• ungual fibromas (2+)

Minor features:

• sclerotic bone lesions

• confetti skin lesions

• dental enamel pits (3+)

• intraoral fibromas (2+)

• multiple renal cysts

Noonan Syndrome Genetic Cause

AD: PTPN11, SOS1, SOS2, KRAS, NRAS, RIT1, RAF1
AR: LZTR1

Gain-of-function, may occur de novo but FHx reported in 50% of cases

Noonan Syndrome Prenatal Features

• nuchal thickening/cystic hygroma

• pleural effusion

• polyhydramnios

• normal/increased birth weight (edema)

Noonan Syndrome Craniofacial Features

• broad forehead

• hypertelorism

• down-slanting palpebral fissures

• ptosis

• high-arched palate

• low-set and posteriorly rotated ears

Noonan Syndrome Dysmorphology

• short stature

• developmental delay

• broad/webbed neck

• unusual chest shape (pectus carinatum and inferior pectus excavatum)

• widely spaced nipples

Noonan Symptoms/Presentation

• heart findings (pulmonary valve stenosis, hypertrophic cardiomyopathy)

• lymphatic dysplasia (edema)

• bleeding disorders

• cryptorchidism

• potentially mild cognitive impairment

Noonan Syndrome Cancer Predispositions

• juvenile myelomonocytic leukemia (JMML)

• neuroblastoma

• rhabdomyosarcoma

• acute lymphoblastic leukemia

Noonan Syndrome Management

• echocardiogram and EKG

• early intervention programs

• manage bleeding disorders

• growth hormone treatment

• treat heart conditions

Noonan Syndrome with Multiple Lentigines (NSML) Genetic Cause

AD: pathogenic variants in PTPN11, RAF1, BRAF, MAP2K1
Missense gain-of-function; allelic heterogeneity

NSML Syndrome Symptoms/Presentation

Clinical manifestations of Noonan Syndrome BUT:

• hearing loss more common

• lentigines

• hypertrophic cardiomyopathy

• milder facial features

Costello Syndrome Genetic Cause

AD: pathogenic variants in HRAS

Almost exclusively de novo, missense GOF

Costello Syndrome Prenatal Features

• increased nuchal thickness

• polyhydramnios

• ulnar deviation of wrist

• short humeri and femurs

• fetal tachycardia

• preterm

Costello Syndrome Craniofacial Features

• most severe craniofacial features

• full lips

• large mouth

• full nasal tip

Costello Syndrome Symptoms/Presentation

• cardiac issues (cardiac hypertrophy, PVS, arrhythmia

• soft redundant skin, joint laxity

• deep palmar/plantar creases

• FTT and GI dysfunction

• papillomata

Costello Syndrome Cancer Risk

• highest cancer risk among RASopathies

• rhabdomyosarcoma, neuroblastoma, bladder cancer

Cardio-facio-cutaneous (CFC) Syndrome Genetic Cause

AD: pathogenic variants in BRAF, MAP2K1, MAP2K2, and KRAS
Mostly de novo; missense GOF variants

CFC Syndrome Prenatal Features

• polyhydramnios

• may be large for gestational age

CFC Syndrome Symptoms/Presentation

• Cardiac features

• Craniofacial (like Noonan but coarser)

• Cutaneous findings

• Feeding issues, DD

• Seizures

• Ocular abnormalities

• lymphedema and chylothorax

CFC Syndrome Cutaneous Findings

• extremely dry skin (xerosis)

• hyperkeratosis/ichthyosis

• eczema

• hemangioma

• cafe-au-lait macules

• hair and nail involvement

CFC Cardiac Features

• PVS, ASD, VSD, HCM

• HCM can be progressive

• pulmonic stenosis in 50% of CFC (with PV in BRAF)

Noonan Syndrome Buzz Words

short stature and pulmonary valve stenosis

Costello Syndrome Buzz Words

papillomata and deep plantar creases

Cardio-facio-cutaneous (CFC) Syndrome Buzz Words

eczema + heart + coarse features

CMMRD Buzz Words

Cafe-au-lait macules + cancer + FHx cancer

Levels of Dysmorphic Features RASopathies

CS > CFC > NS > NF1

Metachondromatosis Genetic Cause

PTPN11 Loss-of-function pathogenic variants; not RASopathy, allelic variant

Potential Treatment for RASopathies

MEK inhibitor therapy

CHD buzzwords: trisomy 21

atrial septal defect, arterioventricular canal defect (ASD, AVCD)

CHD buzzwords: Monosomy X (Turner Syndrome)

coarctation of the aorta

CHD buzzwords: 22q11.2 deletion syndrome

aortic arch anomalies, truncus arteriosis, tetralogy of fallot

CHD buzzwords: 7q11.23 deletion

supravalvular aortic stenosis

CHD buzzwords: Noonan Syndrome

pulmonary valve stenosis with dysplastic pulmonary valve

CHD buzzwords: Costello Syndrome

hypertrophic cardiomyopathy

CHD buzzwords: NSML Syndrome

cardiac conduction abnormalities

CHD buzzwords: Alagille Syndrome

peripheral pulmonary stenosis

CHD buzzwords: Marfan Syndrome

aortic root dilation and dissection, mitral valve prolapse

CHD buzzwords: Heterotaxy Syndrome

dextrocardia and double inlet left ventricle

Cardiomyopathy Definition

Disease of the heart muscle that makes it more challenging to pump blood throughout the body

Ischemic cardiomyopathy

Cardiomyopathy resulting from damage to the heart related to lack of blood flow - usually coronary artery disease (less suspicious for genetic cause)

Non-ischemic cardiomyopathy

Unrelated to coronary artery disease, more likely to be genetic

Hypertrophic Cardiomyopathy (HCM) Prevalence

~1 in 500

HCM Pathophysiology

• (Typically) left ventricular hypertrophy, asymmetric septal hypertrophy

• Left ventricular outflow tract is obstructed with mitral valve regurgitation

• Diastolic dysfunction as LV can’t relac

HCM Manifestations

Variable expression (asymptomatic LVH to mild or severe arrhythmias to heart failure)

• Risk for sudden death, resuscitated cardiac arrest or ICD shock

Acquired HCM

Caused by systemic hypertension, aortic stenosis, or rigorous athletic training (“athlete’s heart”)

Fabry Disease Genetic Cause

X-linked inheritance: hemizygous pathogenic variants in GLA gene 

Fabry Disease Symptoms

• hypertrophic cardiomyopathy

• periodic pain crises

• angiokeratomas

• hypohydrosis

• ocular abnormalities

• kidney disease

Pompe Disease Genetic Cause

AR: pathogenic variants in GAA

Pompe Disease Symptoms

• hypertrophic cardiomyopathy

• poor feeding

• macroglossia

• motor delay

• muscle weakness

• respiratory difficulty

Syndromic Hypertrophic Cardiomyopathy

• Fabry Disease

• Pompe Disease

• RASopathies

Non-Syndromic Hypertrophic Cardiomyopathy Genetic Cause

Typically AD: pathogenic variants in sarcomeric genes - most commonly MYBPC3 and MYH7; potential for multiple genetic variants

Cardiac Amyloidosis

Build-up of misfolded amyloid proteins within the heart (and peripheral nerves), may be mistaken for left ventricular hypertrophy related to HCM

• Immunoglobulin light-chain (AL): not thought to be hereditary

• Transthyretin (ATTR): recommend genetic testing

Hereditary TTR Amyloidosis Genetic Cause

AD: pathogenic variants in TTR (chromosome 18q12.1) causing transthyretin amyloidoses - predominantly affects peripheral nerves and heart

TTR p.Val50Met

• most widely studied TTR variant

• usually causes neuropathy (less cardiac involvement)

• expected disease risk depends on ancestry (ex. higher in Portugal)

• some asymptomatic heterozygotes

TTR p.Val142Ile

• High prevalence in Black populations (3-3.9%)

• Development of late-onset cardiac amyloidosis

  • other amyloid symptoms such as carpal tunnel

Hereditary TTR Amyloidosis Genotypes

• Can help characterize clinical presentation, age of onset, organ involvement, and prognosis

• Homozygous TTR variants may cause more severe/early onset

• BUT considered adult onset generally

Hereditary TTR Amyloidosis Symptoms

• heart disease

• sensory/motor neuropathy

• autonomic dysfunction

• carpal tunnel syndrome

• spinal stenosis

• renal abnormalities

• ocular changes

Hereditary TTR Amyloidosis Treatments

• TTR tetramer stabilizer

• Gene-silencing therapies

Dilated Cardiomyopathy Prevalence

~1 in 250-400

Dilated Cardiomyopathy Pathophysiology

• left ventricular enlargement

• systolic dysfunction (EF < 50%)

DCM Manifestations

Usually between age 40-60, increased risk for:

• heart failure

• arrhythmias

• conduction system disease

• thromboembolism

Acquired DCM

• ischemic injury

• valvular or congenital heart disease

• chemotheray

• thyroid disease

• inflammatory or infectious disease

• severe hypertension

• radiation

Duchenne and Becker Muscular Dystrophy Genetic Cause

X-linked recessive: pathogenic variants in DMD gene

Duchenne and Becker Muscular Dystrophy Symptoms

• dilated cardiomyopathy

• muscle weakness

• elevated serum CK

• loss of ambulation in males

• risk for isolated DCM in heterozygous females