RASopathies, Neurocutaneous, Connective Tissue Disorders

Ras/MAPK Pathway

• important for growth

• lead to activation of cytosolic and nuclear effectors

• overactivated in RASopathies

Neurofibromatosis 1 (NF1) - Gene

AD: pathogenic variants in NF1

• loss of function

Neurofibromatosis 1 (NF1) - Mechanism

• neurofibromin is a negative regulator of Ras/MAPK pathway

• LOF neurofibromin = overactivation

• 2-hit hypothesis

Neurofibromatosis 1 (NF1) - De Novo Rate

about 50%

Neurofibromatosis 1 (NF1) - Clinical Diagnostic Criteria

Pathogenic variant NOT sufficient for diagnosis

• 2+ optic glioma

• 2+ Lisch nodules

• freckling (inguinal)

• 6+ CALMs

• 2+ neurofibromas

• osseous lesion

• choroidal findings

• parent with NF1

Neurofibromatosis 1 (NF1) - Symptoms

• cafe au lait macules

• neurofibromas, plexiform neurofibromas

• optic glioma

• proptosis

• freckling

• iris Lisch nodules

• skeletal findings

• arterial hypertension

Neurofibromatosis 1 (NF1) - Skeletal Findings

• anterolateral tibia and fibula bowing

• pseudoarthrosis of tibia and fibula

• sphenoid bone dysplasia (facial asymmetry)

Neurofibromatosis 1 (NF1) - Cancer Predisposition

• female breast cancer

• malignant peripheral sheath tumors (from transformation of internal plexiform neurofibromas)

Mosaic NF1

• VAF of less than 50% + 1 NF1 Criterion

• segmental distribution of neurocutaneous findings

Other conditions with Cafe-au-lait Macules

• Fanconi Anemia

• Legius

• NF2

• McCune Albright

• Noonan

• Silver-Russel

• CMMRD

• Carney Complex

Legius Syndrome - Gene

AD: pathogenic variants in SPRED1

• loss of function

• mostly inherited

Legius Syndrome - Symptoms

• cafe-au-lait macules

• freckling (inguinal, intertriginous)

• neurobehavioral/developmental

• macrocephaly

• multiple lipomas

• facies

• pectus abnormalities

Legius Syndrome - Clinical Diagnostic Criteria

• 6+ Cafe-au-lait macules

• no other NF1 criteria except freckling

Neurofibromatosis 2 (NF2) - Gene

AD: pathogenic variants in NF2

• loss of function Merlin protein (negative regulator)

Neurofibromatosis 2 (NF2) - Tumor Risk

• schwannomas (vestibular, cranial, subcutaneous, peripheral nervous system)

• spinal cord tumors

• visual tumors

Neurofibromatosis 2 (NF2) - Symptoms

• hearing loss

• seizures

• neuropathy

• pain

• muscle wasting

Neurofibromatosis 2 (NF2) - Treatment

• surgery

• audiology referral

• hearing aids

• annual MRIs (start at 12y)

• hearing and eye exams

Schwannomatosis - Genes

AD: pathogenic variants in SMARCB1 and LZTR1

• loss of function (2-hit hypothesis)

Schwannomatosis - Symptoms

• multiple non-intradermal schwannoma (peripheral and spinal)

• 2nd-4th decade onset

• localized/diffuse pain

• can also be asymptomatic

• NO vestibular schwannoma

SMARCB1 Schwannomatosis

• meningioma risk

• risk of malignant transformation

Tuberous Sclerosis (TSC) - Genes

AD: pathogenic variants in TSC1 and TSC2

• variants in mTOR signaling pathway

• TSC1 = mostly nonsense/truncating

• TSC2 = missense

TSC2 and PKD1

contiguous gene deletion = TSC symptoms + polycystic kidneys

Tuberous Sclerosis (TSC) - De Novo Rate

2/3 de novo (66%)

Tuberous Sclerosis (TSC) - Treatment

• mTOR inhibitors

• surgery

Tuberous Sclerosis (TSC) - Pneumonic

H - hamartomas

A - angiofibromas

M - mental

A - ash leaf spots

R - rhabdomyoma

T - tubers in the brain

O - Optic hamartoma

M - mitral regurgitation

A - astrocytomas

S - seizures

Tuberous Sclerosis (TSC) - Clinical Diagnostic Criteria

• 2+ major criteria (or 1 major, 2 minor)

• 10-25% test negative

Tuberous Sclerosis (TSC) - Symptoms

• cortical tubers

• hamartomas

• astrocytomas

• skin findings (confetti skin, ungual fibromas, shagreen patch, ash leaf spots)

• TAND

• cardiac rhabdomyomas (resolves by adulthood)

• mortality from lung and renal problems

TSC-Associated Neuropsychiatric Disorders (TAND)

• behavior

• psychiatric

• intellect

• academic

• psychosocial

Noonan Syndrome - Genes

AD: pathogenic variants in PTPN11, SOS1

AR: biallelic pathogenic variants in LZTR1

• gain of function

Noonan Syndrome - De Novo Rate

50%

Noonan Syndrome - Prenatal Findings

• nuchal thickening

• cystic hygroma

• pleural effusion

• polyhydramnios

Noonan Syndrome - Penetrance

100%, but variable expressivity

Noonan Syndrome - Dysmorphology

• hypertelorism

• ptosis

• broad forehead

• low set ears

• short stature

• broad/webbed neck

• pectus abnormality

• cryptorchidism

Noonan Syndrome - Symptoms

• Facies

• DD, cognitive issues

• Cardiac (50-80%)

  • pulmonic valve stenosis, HCM

• lymphatic dysplasia

• bleeding disorders

• hearing loss

Noonan Syndrome - Cancer Risk

• juvenile myelomonocytic leukemia (JMML)

• neuroblastoma

Noonan Syndrome - Treatment

• echocardiogram

• EKG

• dev peds

• growth hormone

• bleeding treatments

Noonan Syndrome w/ Multiple Lentigines (NSML) - Genes

AD: pathogenic variants in PTPN11, RAF1

• missense, gain of function

Noonan Syndrome w/ Multiple Lentigines (NSML) - Symptoms

• lentigines (brown spots on face and trunk)

• hearing loss

• HCM > PVS

• milder facies

Costello Syndrome - Gene

AD: pathogenic variants in HRAS

• missense, GOF, typically de novo

Costello Syndrome - Prenatal Findings

• polyhydramnios

• increased NT

• ulnar deviations of wrists

• short humeri and femurs

• fetal tachycardia

Costello Syndrome - Symptoms

• coarse facies

• HCM > PVS

• cancer risk

• deep palmar and plantar creases

• papillomata

• GI dysfunction

• joint laxity

Costello Syndrome - Cancer Risk

• rhabdomyosarcoma

• neuroblastoma

• bladder cancer

Costello Syndrome - Facies

• large lips and mouth

• full nasal tip

• macrocephaly

Cardio-facio-cutaneous (CFC) Syndrome - Genes

AD: pathogenic variants in BRAF, MAP2K1/2

• missense, GOF, mostly de novo

Cardio-facio-cutaneous (CFC) Syndrome - Prenatal Findings

• polyhydramnios

• large for gestational age

Cardio-facio-cutaneous (CFC) Syndrome - Symptoms

• cardiac: PVS, septal defects, HCM

• coarse facies

• skin: severe xerosis, eczema, hyperkeratosis, hemangiomas, hair, nails

• feeding issues

• DD

• seizures

• ocular abnormalities

RASopathies - Memory Tricks

• All AD except LZTR1-Noonan

• NF1 and Legius = loss of function

• all others gain of function (missense SNVs)

RASopathies - Level of Dysmorphic Facies

Costello > CFC > Noonan > NF1

Noonan Syndrome - Key Words

short stature + pulmonic valve stenosis

Costello Syndrome - Key Words

papillomata + deep plantar creases + HCM

Cardio-Facio-Cutaneous (CFC) Syndrome - Key Words

heart + coarse features + eczema

CMMRD - Key Words

cafe-au-lait macules + cancer (both sides of family)

Clinical Heterogeneity - PTPN11

loss of function = metachondromatosis

Ras variants in cancer

• variants in 20% of cancers (tumor and germline)

• germline variants are less activating (otherwise embryonic lethality)

Marfan Syndrome - Gene

AD: pathogenic variants in FBN1

• missense changes w/ cysteine residues

Marfan Syndrome - De Novo Rate

20-30% de novo, 75% inherited

Marfan Syndrome - Craniofacial Features

• enophthalmos

• long narrow face

• malar hypoplasia

• micro-retrognathia

• high narrow palate

Marfan Syndrome - Musculoskeletal Features

• taller than predicted

• arachnodactyly

• pectus deformity

• scoliosis

• joint laxity

• flat feet

• arm span/height

• thumb and wrist sign

Marfan Syndrome - Ocular Findings

• ectopia lentis (upward)

• myopia

• flat cornea

Marfan Syndrome - Symptoms

• aortic root enlargement

• mitral valve prolapse

• craniofacial

• musculoskeletal

• ectopia lentis

• pneumothorax

• inguinal hernias

Marfan Syndrome - Key Findings

• ectopia lentis

• aortic root enlargement

• mitral valve prolapse

• arachnodactyly

• pectus deformity

Marfan Syndrome - Diagnosis Criteria (w/o FHx)

• aortic dilation and ectopia lentis

• aorta dilation and FBN1 mutation

• aorta dilation and systemic score (7+)

Marfan Syndrome - Diagnosis Criteria (w/ FHx)

• ectopia lentis

• systemic score (7+)

• aortic dilation

Marfan Syndrome - Treatment

• annual echocardiogram for heart and aorta

• Beta-blocker/angiotensin receptor blocker

• annual eye, ortho, dental

Marfanoid Habitus - Differential

• MEN2B (FHx cancer)

  • pheos, MTC, mucosal neuromas

• Homocystinuria

  • high homocysteine, ID/DD, thromboembolism

Loeys-Dietz Syndrome - Genes

AD: pathogenic variants in TGFBR2, TGFBR1, SMAD3

Loeys-Dietz Syndrome - De Novo Rate

75% de novo, 25% inherited

Loeys-Dietz Syndrome - Symptoms

• skeletal (club foot, laxity)

• craniofacial (bifid uvulum. cleft palate)

• cardiac (aortic aneurysm and dissection)

• skin and soft tissue (similar to vEDS)

• eosinophilic esophagitis

• asthma

Loeys-Dietz Syndrome - Skeletal Findings

• club foot

• joint laxity

• contractures

• pectus scoliosis

Loeys-Dietz Syndrome - Craniofacial Findings

• bifid uvulum

• cleft palate

• hypertelorism

• craniosynostosis

Loeys-Dietz Syndrome - Cardiac/Vascular Findings

• severe

• aortic aneurysm and dissection

• arterial tortuosity

• small diameter vessels

Loeys-Dietz Syndrome - Skin and Soft Tissue Findings

• velvety/soft skin

• atrophic scars

• bruising

• hernias

Loeys-Dietz Syndrome - Treatment

• annual echocardiogram

• surgical repair

• full body CTA/MRA

• x-rays (risk of cervical spine instability)

Loeys Dietz vs. Marfan

• more severe (more de novo)

• no ectopia lentis

• vEDS-like soft tissue findings

• possible craniosynostosis and clubfoot

Beals Syndrome (Congenital Contractural Arachnodactyly) - Gene

AD: pathogenic variants in FBN2

• 75% found on sequencing

Beals Syndrome (Congenital Contractural Arachnodactyly) - Symptoms

• major joint contractures

• kyphosis/scoliosis

• pectus deformities

• craniofacial (crumpled ears, dolichocephaly)

Beals Syndrome (Congenital Contractural Arachnodactyly) - Dysmorphic Findings

• marfanoid habitus

• crumpled ears

• dolichocephaly

• enophthalmia

• flat midface

• micrognathia

Ehlers-Danlos Syndrome - General Symptoms

• joint hypermobility

• skin hyperextensibility

• skin and tissue fragility

Classic EDS (Type I and II) - Genes

AD: pathogenic variants in COL5A1, COL5A2

Classic EDS (Type I and II) - Symptoms

• atrophic scars

• skin hyperextensibility

• hypermobility

• bruising

• soft skin/fragility

• hernia

• epicanthal folds

• heel papules

Vascular EDS - Gene

AD: pathogenic variants in COL3A1

Vascular EDS - Symptoms

• arterial/intestinal/uterine fragility

  • dissection without enlargement

• velvety/soft skin, atrophic scars, bruising

• inguinal hernia

• pneumothorax

• subluxation and dislocations

• clubfeet

• median age of death = 50y

Vascular EDS - Treatment

• echo every 1-2 years

• head to pelvis MRA/CTA

• aggressively treat hypertension

• avoid elective surgical procedures

Kyphoscoliotic EDS (Type VI) - Genes

AR: biallelic pathogenic variants in PLOD1, FKBP14

Kyphoscoliotic EDS (Type VI) - Symptoms

• hypotonia

• progressive kyphoscoliosis

• osteopenia

• joint hypermobility

Kyphoscoliotic EDS (Type VI) - Gene Associations

• PLOD1 = ocular rupture

• FKBP14 = congenital hearing loss

Spondylodysplastic EDS - Genes

AR: biallelic pathogenic variants in B4GALT6, B4GALT7, SLC39A13

Spondylodysplastic EDS - Symptoms

• short stature

• bowed limbs

• hypotonia

• cognitive development issues

• kyphoscoliosis

Hypermobile EDS - Genetic Cause

AD: no known genes

Hypermobile EDS - Symptoms

• hypermobility

• subluxations/dislocations

• skin issues (w/o atrophic scars)

• chronic pain/fatigue

• dysautonomia, POTS, syncope

• GI issues

• TMJ, dental issues

• spinal issues

• MCAS

Hypermobile EDS - Diagnostic Criteria

• generalized joint hypermobility

• syndromic features/FHx

• exclude alternate diagnoses

Beighton Score

Out of 9

• pinkies (>90 degrees)

• thumb to forearm

• elbow extension (>190 degrees)

• knee extension (>190 degrees)

• hands flat to floor

• Positive result: Child score 6+, 18-50yrs score 5+, >50yrs score 4+

Stickler Syndrome - Genes

AD: pathogenic variants in COL2A1, COL11A1

Stickler Syndrome - Symptoms

• connective tissue disorder

• ocular (myopia, cataracts, retinal detachment)

• hearing loss

• Pierre-Robin sequence

Hereditary Hemorrhagic Telangiectasia (HHT) - Genes

AD: pathogenic variants in ACVRL1, ENG

Hereditary Hemorrhagic Telangiectasia (HHT) - Symptoms

• multiple arteriovenous malformations (lungs, liver, brain)

• recurrent nosebleeds (epistaxis)

• telangiectasias (lip, tongue, mucsoa, GI)

Hereditary Hemorrhagic Telangiectasia (HHT) - Diagnosis

At least 3 criteria

• recurrent epistaxis

• mucocutaneous telangiectasia

• visceral AVMs

• affected 1st degree relative

Things to Avoid for Connective Tissue Disorders

• contact sports

• agents that stimulate cardiac system

• joint injury

• breathing against resistance (ex. woodwind instruments)

• positive pressure ventilation