THE FINAL BOARDS SUPER SET BOSS

Cafe-Au-Lait Spots: Differential Diagnosis

The RAS-opathies

• Neurofibromatosis Type 1 (NF1)

• Legius Syndrome (SPRED1)

• Noonan Syndrome (PTPN11, SOS1, RAF1, KRAS, etc.)

• Costello Syndrome (HRAS)

• LEOPARD Syndrome (Noonan with multiple lentigenies)

The NON-Ras-opathies

• ******Neurofibromatosis Type 2 (NF2)*****

  • ***NOT A RAS-OPATHY***

• McCune-Albright Syndrome

• Proteus Syndrome

• Russell-Silver Syndrome

Neurofibromatosis Type 1: Overview

Gene: NF1 (important for turning OFF RAS/MAPK pathway)

• A RASopathy

• Loss of ‘brakes’ for RAS signaling → abnormal cell growth and tumor formation

Inheritance

• Autosomal Dominant

  • De Novo 50%

  • Inherited 50%

• COMPLETE PENETRANCE (by adulthood)

  • 50% meet criteria at age 1

  • 95 % meet criteria by adulthood

• ****HIGHLY variable expressivity****

Clinical Features

• Skin

  • Cafe-Au-Lait (at Least 6)

  • Neurofibromas (at Least 2)

    • Sub-cutaneous (small)

    • Plexiform (large) → painful, large, can become malignant nerve sheath tumors

  • Axillary or Inguinal Freckling (many freckles where there is NO SUNLIGHT)

• Eye

  • Optic Glioma (tumors along the optic nerve)

  • Iris Hamartoma (at least 2) → also call LISHC NODULES

• Bone

  • Osseous Lesions

    • Sphenoid Dysplasia

    • Tibial Pseudarthrosis

• Neurologic

  • Learning disabilities, ADHD

• Cancer Risk

  • Malignant peripheral nerve sheath tumor (MPNST)

  • Breast Cancer

  • Pheochromocytoma

  • Gastrointestinal stromal tumor (GIST)

Neurofibromatosis Type 1 Clinical Diagnostic Criteria

(CRITERIA MODIFER: IF a PARENT is affected → ONLY 1 FEATURE needs to be present)

Must have two of the following

• CAFE-AU-LAIT: AT LEAST 6 Cafe-Au-Lait Spots:

  • pre-pubescent: more than 5mm in size

  • post-pubescent: more than 15mm in size

• NEUROFIBROMAS: AT LEAST

  • 2 Neurofibromas: (external) Cutaneous or Subcutaneous

  • 1 PLEXIFORM Neurofibroma: (internal) form along nerves → Painful and MALIGANT potential (pathognomonic)

• Axillary (Armpit) and Inguinal (Groin) Freckling → Early childhood

• OPTIC GLIOMA: Optic Nerve tumor

• LISCH NODULES (Iris Hamartomas): AT LEAST 2

• OSSEUS LESION

  • Sphenoid wing dysplasia (eye socket/ skull bone)

  • Tibial bowing (curving out of the shin bone)

  • Tibial pseudarthrosis (endstage tibial bowing: broken tibia never heals but remains sperate)

• CONFIRMED PATHOGENIC NF1 VARIANT

Neurofibromatosis Type 2:

Gene: NF2 (controls the proliferation of nerve cells via NONE RAS/MAPK PATHWAYS)

• NOT a RAS-opathy

• Loss of control → uncontrolled proliferation of SCHWANN CELLS and other nervous system cells

Inheritance

• Autosomal Dominant

  • De Novo 50%

  • Inherited 50%

• COMPLETE PENETRANCE (100% by 60yo)

  • but still AGE DEPENDENT

• Variable Expressivity

• ***MOSASCISM COMMON**** → reduced tumors + later onset

  • 20-30% of all cases

  • 50-60% of apparently DE NOVO cases

Clinical Features

***AN ADULT-ONSET CONDITION***

NO SKIN FINDINGS

• Ear

  • ****BILATERAL Vestibular Schwannomas**** (late teens - early 30s yo) → Leads too :

    • progressive sensorineural hearing loss

    • Tinnitus

    • Balance issues

• Eye

  • Cataracts (subcapsular or cortical wedge)

• Central Nervous system

  • Cranial/Spinal Nerve Schwannomas

  • Meningiomas

  • Glioma (not just optic nerve → can be any nerve/brain cell)

  • Ependymomas

  • Neurofibroma

Neurofibromatosis Type 2 Diagnostic Criteria

To meet Clinical Diagnostic Criteria, must have:

• 1 PRIME feature

• 2 MAJOR features

• 1 Major + 2 Minor features

PRIME Features

• Bilateral Vestibular Schwannomas

• Identical NF2 pathogenic variant *in two separate types* of NF2-related tumors

  • *****NOTE: if Variant allele frequency is <50% → MOSAIAC NF2*****

Major Features (Need 2 or 1 + 2 minor)

• UNILATERAL vestibular schwannoma

• One 1st-degree relative with NF2→ ****CANNOT BE A SIBLING****

• At Least Two Meningiomas

• NF2 Pathogenic Variant found in UNAFFECTED TISSUE (i.e. blood sample rather than tumor tissue)

Minor Features

• One Meningiomas (two = 1 major)

• One Ependymoma or Schwannoma (two = 2 minors, not 1 major)***

• Cataracts (the special ones) BEFORE the age of 40yo

LEGIUS syndrome

Gene: SPRED1 (enables NF1 protein to regulate RAS/MAPK pathway effectively)

• RASopathy

• Loss of SPRED→ Longer for RAS pathway to be turned off (but not fully lost) → “On” signal = Skin findings but NOT the Neurofibromas/Nerve tumors/Eye

Inheritance

• Autosomal Dominant

  • De Novo 50%

  • Inherited 50%

• High Penetrance

• Variable Expressivity

Clinical Features

ONLY NF1 Skin findings, NO CNS

No PROVEN increased Cancer Risk

• Skin

  • Cafe-Au-Lait

  • Axillary/Inguinal Freckling

  • Lipomas (occasional)

• Neurology

  • Relative Macrocephaly

  • Learning Disabilities /ADHD

  • Mild Speech/Motor delays

[ NF1 without Tumors ]

Non-NF2 Schwannomatosis

Genes: SMARCB1, LZTR1 (Both tumor-suppressor genes → loss of function = schwannoma formation)

• s

Inheritance

• Autosomal dominant

  • Mostly De Novo

• Reduced Penetrance

• Variable Expressivity

Clinical Features

Onset Adolescence to Adulthood

• Multiple Schwannomas (mainly peripheral or spinal)

  • Painful → chronic pain common

  • nerve compress → weakness/ numbness

  • ****Vestibular uncommon → ONLY UNILATERAL ; bilateral suggest bilateral)

• Meningiomas (less common)

Tuberous Sclerosis

Gene: TSC1, TSC2 ( control mTOR pathway → loss of function = cell proliferation)

Inheritance

• Autosomal Dominant

  • ****DE NOVO 80%****

  • Inherited 20%

Clinical Features

Intelligence affect and Shortened life expectancy

• Skin

  • ****Ash Leaf Spots****

  • Facial Angiofibroma

  • Shagreen Patches

• CNS tumors

  • Cortical Tubers (90%)

  • Subendymal nodules

• Cardiac tumors

  • Congenital Rhabdomyoma→ will REGRESS with age

• Renal

  • Angiomyolipoma

• Ocular

  • Retinal Hamartomas

Management

• “Full Body” imaging (working with each organ system specialist to monitor)

Tuberous Sclerosis Diagnostic Criteria

Require:

• 2 Major Features

• 1 Major Feature + AT LEAST 2 Minor Features

• TSC1 or TSC2 Pathogenic Variant

MAJOR CRITERIA:

Skin

• AT LEAST (3) Hypomelanotic Macules (Piebald patches)

• AT LEAST (3) Angiofibromas (found on face usually)

• AT LEAST (2) Ungual Fibromas (found on edge of nail-beds)

• (1) Shagreen Patch (large, pebbly, dimpled ‘organ peel’ → Lower Back, Neck, Buttocks, Thighs)

CNS

• AT LEAST (2) Subependymal Nodules (SEN)

• *****MULTIPLE Cortical Tubers***** (ITS IN THE DAMN NAME)

• (1) Subepdenymal Giant Cell Astrocytoma (SEGA)

Cardiac

• (1) CONGENTIAL Rhabdomyoma

Renal

• AT LEAST (2) Angiomyolipomas

Eye

• AT LEAST (2) Retinal Nodular Hamartomas

MINOR

Skin

• “Confetti” Skin Lesions (smaller, scattered hypopigmented macules)

Bone

• Sclerotic Bone Lesions

Teeth

• AT LEAST 3 Dental Enamel Pits

• AT LEAST 2 Intraoral Fibromas

Renal

• AT LEAST 2 Renal Cysts

Waardenburg Syndrome

Gene: PAX3 (important for neural crest cell migration)

• Neural cells particularly for: Melanocytes, Inner Ear, GI nervous systems (Hirschsprung disease for Type IV)

  • Type I: Dystopia Canthorum

  • Type II: No Dystopia Canthorum

  • Type III: Type 1 + Upper limb abnormalities (Recessive)

  • Type IV: Hirschsprung Disease

Inheritance

• Autosomal Dominant (most forms)

Clinical Features

Normal intelligence and life expectancy

• Ear

  • *****CONGENITAL sensorineural hearing loss*****

  • Complete or Segmental Heterochromia (one blue one brown eye)

  • ***Dystopia Canthorum (displacment of the canothroum makes eyes seem hypertelmoric)*** → Type I + III

• Hair

  • ****White Forelock****

  • Premature graying

• Skin

  • ****Piebald spots (areas of HYPOPIGMENTATION)****

Hermansky - Pudlak Syndrome (HPS)

Gene: HPS1, HPS3, HPS4, HPS5, HPS6 (important for organ specific- Lysosomes)

• Melanosomes → Pigmentation (skin + eyes)

• Platelet dense granules → Platelet production (blood clotting)

• Lamellar Bodies → SURFACANT production

Inheritance

• Autosomal Recessive

• VERY HIGH in PUERTO RICO

Clinical Features

• Skin/Hair

  • ****Oculocutaneous albinism****

  • White hair

• Eyes

  • Decreased visual acuity

  • Photophobia (Sensitive to Light)

  • Strabismus (Misalignment of the eyes)

• Bleeding

  • Excessive bleeding

  • *****EASY BRUISING****

• Pulmonary

  • Progressive Pulmonary Fibrosis (loss of lung function over time)

Incontinentia Pigmenti

Gene: NEMO (important for controlling apoptosis of ectodermal cells → loss of function = abnormal apoptosis of skin, hair teeth, eyes, CNS)

• “Whirled & Swirled” Skin pattern on Lines of Blaschko

Inheritance

• X LINKED DOMIANT

  • De Novo 80%

  • FEMALE ONLY (Male Lethal)

Clinical Features

Intelligence CAN be affect but with a NORMAL life expectancy

***PROGRESSIVE development of ECTODERMAL DYSPLASIA***

• Skin (progressive development)

  • Hyperpigmentation in a “Swirling” pattern → starts as blisters in infancy

  • Hair loss (in affected areas)

• Eyes

  • Hypodontia (missing teeth)

  • “Peg” Teeth

• Eyes

  • Retinal Vascular Diease: Ischemia (lack of blood), Detachment → VISION LOSS if untreated

• CNS (20-30%) → VARIABLE, can range from absent to severe

  • Intellectual Disability

  • Seizures

  • Stroke-Like Episodes

Hypomelanosis of Ito

Gene: Somatic Mosaic Point Mutation or Chromosomal Abnormality

• “Whirled & Swirled” Skin pattern on Lines of Blaschko

• WIDE range of features

Inheritance

• SPORADIC Post-Meiotic Mosaicism

• MALES and FEMALEs equally (vs Females only for IP)

Clinical features

• Skin

  • Hypopigmented Streaks “Whirled & Swirled” Skin pattern on ****Lines of Blaschko****

• CNS

  • Epilepsy

  • Developmental delay

  • OTHER CONGENTIAL ANOMLAIES

Management

• TEST AFFECTED TISSUE → The Skin in the Pattern

Hypohidrotic Ectodermal Dysplasia

Gene: EDA (Most Common), EDAR, EDARADD, WNT10A (important for development of ectodermal structures)

• a

Inheritance

• X-Linked Recessive (EDA)

Clinical Features

Normal Intelligence

• *****Teeth***** (Hypodontia)

  • Missing teeth

  • Peg/Conical Shaped teeth

• ***Hair*** (Hypotrichosis)

  • Sparse scalp hair (Hypotrichosis)

• *****Sweat Glands***** (Hypohidrosis)

  • Reduced Ability to Sweat

  • Heat Intolerance/ hyperthermia

• Facial

  • Flat Nasal Bridge

Epidermolysis Bullosa

Gene: COL7A1 + Many Genes (associated with important structural proteins for the skin)

• Non-functional structural proteins → Abnormally fragile skin = BLISTERING

• Large group of disorders grouped into three

  • Simplex: blisters at surface of skin; (MILDEST)

  • Junctional: slightly deeper → some scars, hair

  • Dystrophic: Blisters at deepest level → severe scarring (COL7A1)

Inheritance

• Simplex: AR and AD

• Junctional: AR

• Dystrophic: AR and AD

Clinical Features

Increased Risk for

• Simplex: Mildest form, Normal Life Exp.,

  • Blisters on hands and feet, minimal scarring, nails preserved

• Junctional: Range of severity, some life-threatening in infancy

  • Blistering all over body, Scarring, Growth failure, Enamel Hypoplasia

• Dystrophic:

  • SEVERE Scarring, Nail Loss, Pseudosyndactyly (“Mitten Deformities”)

  • ****Cutaneous squamous cell carcinoma****

Hearing Loss / Deafness Differential Diagnosis

• Post-Infections:

  • TORCH

  • Measles, Mumps, Rubella

  • Meningitis

• Environmental:

  • Noise Pollution

  • Trauma

  • ***Hyperbilirubinemia****

• UNKNOWN → 30-40%

Hearing Loss Genetic Etiology

MORE for COGENTIAL HL rather than later in life → Genetic Awnser

• Genetic Cause

  • 50% of Congenital Cases

    • 2/3 Isolated

    • 1/3 Syndromic

• Genetically Heterogenous

  • GKB/Connexin genes often associated (GJB2 Gene → Connexin 26 most often)

• Inheritance

  • Autosomal Recessive: 80%

  • Autosomal Dominant: 15%

  • X-Linked Recessive: 1%

  • Mitochondrial: 1%

GJB2-related hearing loss

Gene: GJB2, GJB6 (a deletion - less common) (coeds for CONNEXIN 26→ important for potassium ion recycling in cochlea after sound stimulation)

• NON-SYNDROMIC Hearing Loss

• 21% of all Congenital Hearing Loss

• Loss of function GJB2 → cochlear hairs become dysfunctional

Inheritance

• Autosomal Recessive

  • ALWAYS INHERITED (from a Carrier Parent)

Clinical Features

• Congenital Sensorineural Hearing Loss

  • Bilateral

  • Usually PROFOUND

  • Normal vestibular function (BALANCE NORMAL)

*****Some Infants Pass New Born Audiology Screening*****

Pendred Syndrome

Gene: SLC26A4 (codes for pendrin: a anion transporter that moves chloride, iodide and bicarbonate)

• 5% of Inherited Hearing loss

• Expressed in

  • Inner ear → maintains ions needed for normal hearing and balance

  • Thyroid → moves iodide into thyroid follicle for hormone synthesis

  • Kidney → maintain acid-base balance (NO KIDNEY DIEASE USUALLY)

• Loss of Pendrin → cochlear development and iodine transport disrupted → hearing loss and thyroid abnormalities

Inheritance

• Autosomal Recessive

  • ALWAYS Inherited (from a carrier parent)

Clinical Features

• Congenital/Early childhood Hearing Loss

  • Progressive

  • Bilateral

  • ***FLUCTUATING***(sudden drops and recovery) - unlike GBJ2 → can be triggered by minor head trauma or infections

• Vestibular Issues (33%)

  • Balance problems

  • shows ***ENLARGED VESTIBULAR AQUEDUCT**** (hallmark sign)

• Thyroid

  • ***GOITER***

  • Usually normal thyroid function is normal → can get mild hypothyrpidsm

Managment

• Hearing aids/Implants

• Life style:

  • avoid contact sports (making HL worse)

  • Avoid activities with PRESSURE CHANGES (life flying or Suba diving)

• 
  

Usher Syndrome

Gene: MYO7A (Type I), USH2A (Type II - Most Common), CLRN1 (Type III) (codes proteins important for sensory cells: cochlear, vestibular and photoreceptors)

• HEARING, BALANCE, VISION

• Accounts for 50% of inherited Deaf-Blindness

• Three Types

  • Type I: Balance+ DEAF

  • Type II: Moderate HL w/ normal balance

  • Type III: Progressive (vision, hearing, blance)

Inheritance

• Autosomal Recessive

  • ALWAYS INHERITED (from carrier parents)

Clinical Features

• Vision (ALL TYPES LOSS VISION)

  • ****RETINITIS PIGMENTOSA**** (all types) progression to vision loss

• Type I (most severe)

  • Profound congenital Deafness

  • Absent vestibular function → ***DELAYED WALKING***

  • RP is early onset

• Type II (MOST COMMON)

  • Moderate-to-severe SNHL

  • NORMAL BLANCE***

  • RP in adolescence

Stickler Syndrome

Gene: COL2A1 (90%), COL11A1 (10%) (codes for collagens that are important for the Eye and the Ear)

• Connective Tissue disorder causing retinal detachment

Inheritance

• Autosomal Dominant

  • DE NOVO 50%

  • Inherited 50%

Clinical Features

Vary with age of onset

• Eyes

  • Myopia: congenital, severe, progressive

  • ***Retinal Detachment***

  • ***Cataracts: JUVENLIE ONSET****

• Hearing

  • Sensorineural hearing loss (can also be Conductive and Mixed)

  • Progressive

• Craniofacial

  • Pierre Robin Sequence (micrognathia, glosspostis, CLEFT PALATE)

• Skeletal

  • Joint Hypermobility + Degeneration

  • ****EARLY ARTHRITIS***** (by 20-30s yo)

  • Chronic Pain

Jervell and Lange-Nielsen syndrome

Gene: KCNQ1 (90%), KCNE1 (10%) (important for potassium channel function)

• Loss of function → unable to cardiac repolarize and recycle potassium in the inner ear

• Long QT syndrome + Profound Congenial Hearing Loss

Inheritance

• Autosomal Recessive

  • Always Inherited (from carrier parents)

  • Carrier Parents usually normal ECG or have ***Mild QT Prolongation***

Clinical Features

• Congenital Bilateral Profound Sensorineural Hearing Loss

  • Present at Birth

  • Profound

  • No progression or Fluctuation

• Congenital Long QT Syndrome

  • ****Torsades de pointes****

  • Syncope

  • Seizures (from cerebral hypoperfusion)

  • Ventricular fibrillation

  • Sudden cardiac death

Management

• DIAGNOSIS → ****PROLONGED QT INTERVAL****

Leber Congenital Amaurosis

Gene: Many genes (important for rods and cones of the eye) - RPE65

• Loss of function → early degeneration or dysfunction of rods/cones→ severe visual impairment in infancy

• RETINAL DYSTROPHY

Inheritance

• Autosomal Recessive (usually)

  • ALWAYS INHERTIED (from carrier parents)

Clinical Features

• Vision Impairment (at birth)

• Nystagmus (rapid, involuntary eye movement)

• ****Oculodigital Sign****: Children rub, poke or press on their eye

Management

• Testing

  • Electroretinography → VERY ABNORMAL: ABSENT or SEVERLY REDUCED

• Treatment: RPE65 has gene-therapy

Congenital Cataracts (Crystallin-Related Congenital Cataracts)

Gene: Many Genes (important for crystallin which maintain the transparency of the lens)

• Loss of function → Lens opacification (cataract)

• ISOLATED congenital cataracts

Inheritance

• Autosomal Dominant (usually)

  • ***DE NOVO 70%***

  • Inherited 30%

Clinical Features

• Congenital Cataracts

  • present at birth

  • Unilateral or Bilateral

  • leukocoria (abnormal white refelection from retina seen through the pupil)

Management

• Diagnosis → need to rule out potential metabolic conditions (due to how early the eye-sight loss is)

  • ****GALACTOSEMIA****

  • Congenital Rubella

  • Peroxisomal Disorders (Zellweger Spectrum)

Retinitis Pigmentosa

Gene: Many Genes

• Groupe of conditions that have the same retinal deteriorating: From ***Night blindness***→ Peripheral vision loss → central vision loss

Inheritance

• Autosomal Dominant (25%)

• Autosomal Recessive (40%)

• X-linked (15%)

Clinical Features

• Progressive vision loss:

  • Night Blindness First

  • Peripheral Vision Loss

  • Central Vision Loss

Management

• Imagining: very specific → Using Eye Exam

  • Bone-Spicule Pigmentation: clumping of pigment on retina

  • Attenuated (narrowed) Retinal Vessels

  • Waxy Optic Disc Pallor

Retinoblastoma

Gene: RB1 (a tumor suppressor → loss of function = uncontrolled retinal cell proliferation)

• Two-Hit Hypothesis

• Cancer Predisposition Syndrome with HIGH PENETRANCE

Inheritance

• Autosomal Dominant

  • HIGH PENETRANCE (90%)

  • De Novo 80%

  • 1/3 of ALL RETINOBLASTOMA cases are from DE NOVO VARIANTS

Clinical Features

• Eyes

  • Retinoblastoma (before age 5)

    • Germline: Bilateral - <1 yo

    • Sporadic: Unilateral - 1-3 yo

  • Leukocoria (abnormal white reflection from retina seen through the pupil)

• Cancer Risk

  • Pineoblastoma (trilater retinblasotoma) - Childhood

  • ******Osteosarcoma****** - Adulthood

  • Melanoma - Adulthood

  • Leiomyosarcoma - Adulthood

Bardet-Diel Syndrome

Genes: Many genes - BBS1 (25%), BBS10 (20%) (encode for primary cilium → critical for retina, kidney, limb development, gonads)

• Loss of function → impaired intracellular signaling (WNT +SHH) = multisystem dysregulation

• CILIOPATHY

• Tri-Allelic Inheritaince (possibly)

Inheritance

• Autosomal Recessive

  • ALWAYS INHERITED 9from carrier parents)

Clinical Features

• Eyes

  • ****Retinitis Pigmentosa**** (starts after 10yo)

• Growth

  • Truncal Obesity (infancy/early childhood)

• Limbs

  • ***Postaxial Polydactyly***(extra digit is after the 5th toe/finger)

• Neurologic

  • Mild Intellecualt/learning disalbity

  • Autism

• Kidney (leading cause of death)

  • Structural Renal Anomalies

  • Chronic kideny diease → End-Stae renal deiase

• Genetial

  • Hypogondaism

  • Reduced fertility (inferltiy common in men, women usually not full infertile)

Managment

• Needs disalysiss

• 
  

Alport Syndrome

Gene: COL4A5

Inheritance

• **** X-Linked RECESSIVE *****

  • HETEROZYGOTE FEMALES can still develope some disease (are not just unaffected carrier)

Clinical Features

Childhood Onset

Renal

• ***HEMATURIA****(blood in urine)

• End Stage Kidney Disease

Ear

• ****Bilateral PROGRESSIVE sensorineural hearing loss****

Eye

• Eye abnormalities BUT NOT VISION LOSSS!!!

• *****Anterior lenticonus*****

Management

• ACE inhibtors

1 Primary Pulmonary hypolpasia

• extremely rare

• "Defective Genetic ‘toolkit’

Secondary Pumonary Hypolasia

• way more common than primary

• caused by

  • inadequate ammonitic fluid (oligohydramnios)

    • Decreased fetal amniotic fluid production

    • Increased amniotic fluid loss

  • inadequate respiratory excursion

    • Neuromuscular disease with diaphragmic weakness

    • CNS brainstem defects reducing respitroy drive

  • Inadequate thoracic volume (ribcage to small or another space occupying lesion: large mass, herniation of the bowl into chest cavity)

Oligiohydraminos

Abnormally low Amniotic Fluid

• Fetal pulmonary hypoplasia (lungs can’t develop properly)

• Limb contractures (due to restricted movement)

• Umbilical cord compression → distress

If a result of RENAL AGENSIS → CALLED POTTERS SYNDROME

Obstructive Uropathy Sequence

Prune belly syndrome

• Obstructive uropathy: the urethra is obstructed, kidneys are working—> Bladder obstrution—> bladder deistnetion

• Potters sequence also often present

Spinal Muscualr Atrophay (SMA)

Gene: SMN1

• SMN2 “backup” gene →

  • GENE CONVERSION SMN1→ SMN2 COMMON; SMN2 lacks Exon 7

• Degeneration of anterior horn cells → lower moto neuron weakness

Inheritance

• Autosomal Recessive

  • 95% BIALLEIC Absence of EXON 7 (either deletion or GENE CONVERISON - common)

  • 5% SMN1 del + intragenic pathogenic variant

• Babies with NO SMN1 or SMN2 copies

• Parents have SMN1 or SMN2 deletions

Clinical Features

Normal intelligence, Normal SENSATION

• LETHAL AT BIRTH OR SHORTLY THEREAFTER

Muscle

• Hypotonia

• Muscle atrophy/weakness

• ****DECREASE/ABSENT deep tendon reflexes****

• *****PULMONARY HYPOPLSIA****

• ****RESPIRATORY WEAKNESS****

  • repisortr failure leading cause of death

• polyhydramnios,

• pulmonary hypoplasia,

• arm/leg deformities

Management

• NBS screening detects absence of EXON 7

Treatment:

• Nusinersen (Spinraza) Antisense oligonucleotide targeting SMN2 splicing

→ promotes inclusion of exon 7
→ increases functional SMN protein

Congential Diagrammatic Hernia

Bowel herniation through a diaphragmatic defect

• Lungs have no space to develop, the bowel physical limits

Often part of larger, lethal syndrome

• Mostly chromosomal aneuploidy, microdeletion/duplication

• Often lethal, 50-80% survival rate but with stunted lungs (Pulmonary HTN/Insufficney)

Can be corrected with Tracheal Blocking

Isoalted throaci Dystrophies

• Jarcho-Levin Syndrome: “short” ribcage

  • Autosomal recessive DLL3

• Jeune’s Asphyxiating Thoracic Dystrophy” “skinny” ribcage

  • Autosomal recessive Multigenic, Lethal

Generalized Skeletal Dysplasias

Thanatophoric Dysplasia

• narrow thorax: severe Pulmonary hypoplasia (early death)

• type 1: short, curved limbs (telephone receiver)

• type 2: shore straight limbs; large clover-leaf head

Autosomal Dominant FGFR-3 Gene mutation

• Almost always DE NOVO MUTATION (no reproductive fitness, early death)

• Recurrence risk <5% (high rate of germline mosiacsm in mothers)—> recommend future testing in pregnancies for parents with a child

Congenital Alveolar Capillary Dysplasia

Vascularization Disorder

• Persistent hypoxemia in normal appearing newborn (Clear lungs, normal heart, normal hemoglobin): Capillaries are not ‘hooked up” to Aveolar sacs—> cannot oxygenate

• ALWAYS LETHAL: only diagnosed at autopsy

DE NOVO: FOXF1 mutation/deletion

• recurrence very rare

Surfactant Metabolism Disorder

Lack of functional surfactant: does not maintain the integrity of the alveolar

• in utero fine:

• at birth, alveoli collapse

  • '“honeycombing” fibrosis pattern in lungs

• Lung transplant

Autosomal Recessive Surfactant Protein (SFTP, ABCA3 genes)

Primary Ciliary Dyskinesia

The failure of cilia to move properly:

• Chronic Sino-pulmonary infection leading to Bronchiectasis

• Infertility, Hearing impairment (sperm flagella, inner ear cilia)

• Situs-Inversus ~50% (Kartagener’s Syndrome)

Autosomal Recessive Mutation of Ciliary genes (over 30 known)

Cystic Fibrosis

Classical clinical triad:

• chronic sinopulmonary infection

• Exocrine pancreatic insufficiency

• Elevated Sweat chloride and Sodium levels

Sodium-Chloride transport issues, mutations in CF Transmembrane conductor Regulator (CFTR) → Causes High thick sodium secretions

• Autosomal Recessive: most common mutation DelatF508 (Caucasian)

• PAN ETHNIC (Caucasian 1:25)

Diagnosis: (immuno-testing) for screening, then DNA sequencing + Sweat test for diagnosis

Alpha-1 Antitrypsin (AAT)

AAT Deficiency is the major genetic cause of Chronic Obstructive Pulmonary Disease (COPD)→ An Expiratory Issue, irreversible.

AAT normally protects lung tissue from inflammation caused by enzymes like neutrophil elastase

• Low AAT → uncontrolled enzyme activity of neutrophils→ destruction of alveoli (air sacs) → early-onset emphysema (even in non-smokers

• Abnormal AAT proteins (due to mutations) can accumulate in liver cells → inflammation → scarring (cirrhosis) → liver failure (in severe cases)

Autosomal Recessive inheritance (CODOMINANT): SERPINA1 gene mutation

• Higher incidence in Caucasian

CF Newborn Screening

• Primary: immunoreactive trypsinogen (IRTE

  • Normal: produced in pancreas → released into GI

  • CF: pancreatic ducts blocked → leaks into bloodstream → HIGH IRT LEVELS

• Secondary: DNA Screen

  • Expanded screening: 97 CFTR genes

  • A bit mute now: WGS allows for total picture and sequencing

• Confirmatory Testing: DNA sequencing and Sweat testing

Recurrence Risks for an effected child

• 25% for 2 carrier parents

• 50% 1 affected, 1 carrier parent

CF Clinical issues

• Lungs: colonization by abnormal bacterial P Aerugionas, etc

  • Obstructive, restrictive pulmonary diease

• GI Manfiastions (Pacnrease): Pancrease is blocked up

  • Pancreatic insufficney: Malabsorption

  • Hepatic Dysfunction

• Salt loss syndrome: Chronic Metaolic Alkalosis

• Male Infertility: CFTR deficney = blocked vas deferens → sperm is fine but it cannot get into the semen

  • congenital bilateral absence of the vas deferens (CBAVD) in Males (XY)

CF Treatment

• Nutrition

• Mechanical therapy

• Medication: Mucolytics, Bronchodilators

  • Kalydeco (Ivacaftor) : CFTER Potentiator, Protein present but ‘locked’, get ‘opened’ (38 genotypes)

  • Lumacaftor (Orkambi) : CFTR Modulator, Protein stuck in ER, increases transport to cell membrane (DeltaF508)

AAT Deficeiny Diagnosis

• Alpha 1 Antitrypsin Serum Levels: Normal is >80mg/dl (false negative if measured during acute illness/stress)

AAT Protease Inhibitor (Pi) phenotyping: eltroperhsis bands (M medium migration, S slow migration, Z very slow)

• Pi ZZ: most common diease phenotype: misfolded→ major protien dysfunction

• Pi MZ: most common carier phenotype: mild dysfunction

• Null: no bands present on eltropahis

  
  

SERPNA1 GENE

AAT Deficeny Cardinal Features

• COPD: 30-45yo, very early on

• Hepatitis/Cirrohis: 40-50yo ZZ Pi phenotype, protiens misfolded and gets stuck in the liver causing issues (need lvier transplant)

Empahsema in a non smoker

Liver Diease in a young person

Who to Test for AAT?

• All moderate/severe COPD diagnosed by age 50

• COPD in non-smokers at any age

• Unexplained bronchiectasis

• Unexplained basilar emphysema

• Unexplained severe asthma

• Unexplained cirrhosis

• Unexplained panniculitis

• Family history known/suggests AAT deficiency

AAT Deficiency Treatments

• COPD Monitoring and Treatment

• Liver transplant

Therapeutics have not really been developed

Intravenous infusion of purified pooled human serum AAT:

Hereditary Hemochromatosis (HH)

• Very common

  Clinical features

  • Increased Iorn uptake and Accumulation of iron: it tends to deposit in certain tissues, skin, heart, glands liver

  • Classic Triad of symptoms:

    • Glycosuria (excess glucose in urine)

    • Liver Cirrhosis

    • Bronzing of the skin

• Autosomal Inheritance:

  • Mutation in HFE gene:

• Seen more in CAUCASIANS

• AGE OF ONSET VARIABLE (majority remain asymptomatic)

  • Male: 40-60yo,

  • FemaleL Post-Menopausal (menstruation protects against iron overload)

Untreated HPE

• Artheritis

• Gladular dysfunction

• Liver Dysfunction

• Cardiac Dysfunction

• Progressively increased skin pigmenation

Diagonsis Hereditary haemochromatosis

Confirmatory Testing

AUTOSOMAL RECESSIVE

HFE gene Mutation Analysis

• C282y/C282Y in >80% if Causcasins

• C282Y/H63D in 3-8% (not as severe)

• H63d/H63D: Carriers, not typtically clincally affected

But there are MANT other forms

NON-HFE HH

• Type 2: HH: Juvenlie HH

  • aurosomal recssive:

    • type2A (HJV gene, in 90%)

    • type2B (HAMP gene, in 10%)

• Type 3 HH: ( ss )

• 
  

Treating HFE-HH

• Chelating

• Plhemobolating (bleeding)

• Avoid Iorn, Vitamin C, raw shellfish

Wilsons Disease

• inheritance: Autosomal recessive (ATP7B gene loss of function, transports copper)

• Pathophysiology:

  • Loss of ATP7B → impaired copper transport

  • ↓ Ceruloplasmin-bound copper

  • ↓ Biliary copper excretion → toxic buildup

• Key Effects:

  • ↑ Free copper in blood

  • Copper deposits in liver, brain (basal ganglia), eyes (Kayser-Fleischer rings → BOARDS QUESTION)

• Clinical:

  • Liver disease (cirrhosis, hepatitis)

  • Neurologic (tremors, dysarthria, psychosis)

  
  

Wilsons Diease Presentation

• Liver Disease: unexplained liver dysfunction,

• Neurologic disease: Movement disorder (unusual movements)

• Psychiatric symptoms: depression, neurotic behavior

• Kayser-Fleischer rings: copper deposits in the Cornea (A BOARDS QUESTION!!!!!) 50-90%

• Age of Onset: 3 to 60 years old (Kids or adults)

Wilsons Disease Treaments

• Copper chelation (increase urinary copper excretion)

• Blocking Copper absorption

• Decrease copper intake

Hereditary Pancreatitis

Inflammation of the Pancreas

Can be acute or chronic

can be genetic and non-genetic

• PRSS1 Gene Most common genetic cause: Autosomal Dominant

• SPINK1 Autosomal recessive

• CFTR Gene: Autosomal recessive, can present with recurrent pancreatitis

Hereditary Pancreatitis

• Prevention: low fat diet, small meals, good hydration, no alchol

• 
  

Proper Lung Development

Requires 4 elements:

1. Intact Genetic ‘toolkit’: proper genes→ Defect resuit in 1’ pulmonary hypoplasia, Malformaiton, Vasculrization defect

2. Adequate Aminotic fluid: "Breahting” aminotic fluid drives lung growht→ Defects reuslt in 2’Pulmonary Hypoplasia

3. Adeaute Respiroty Excurison → 2’Pulmonary Hypolplasia

4. Adeaute Throaic Volume: ribcage cannot rescrit space for lungs to gorw →2’Pulmonary Hypoplasia

Potters Sequence

• Caused by severe oligohydramnios (too little amniotic fluid).

• Key effects:

  • Pulmonary hypoplasia (underdeveloped lungs → often fatal).

  • Flattened facial features (Potter’s facies: flat nose, recessed chin, wide-set eyes).

  • Limb deformities (twisted limbs, joint contractures).

• Most common cause: Bilateral renal agenesis (no kidneys → no urine → no amniotic fluid).

• Outcome: Usually lethal due to lung failure.

Inadequate Thoracic Volume

• Internal Compression

  • Congenital Diaphragmatic Hernia (most common)

  • Intra-Thoracic Mass/Cyst

  • Severe Abdominal Distention (Pushes diaphragm up, but not a herniation)

• External Compression

  • Generalized Skeletal Dysplasias (thanatophoric dysplasia)

  • Isolated thoracic dystrophies (asphyxiating thoracic dystrophy)

  • Uterine Malformations (constrictive uterine anatomy)

lSpondylocostal Dysostosis (Jarcho-Levin Syndrome)

Extreme shortening of thorax & trunk

Dysplastic/absent ribs & vertebrae

Pulmonary Hypoplasia

AR DLL3 Gene Mutation, Lethal

Jeune’s Asphyxiating Thoracic Dystrophy

Extreme narrowing of thorax

Short ribs/long chest

Pulmonary Hypoplasia

AR, Multigenic, Lethal

Disorder of Pulmonary Maintenace

• Primary Ciliary Dyskinesia

• Cystic Fibrosis

• Alpha-1-Antityrpsin Deficiency

Type 2 Hereditary haemochromatosis (Juvenile Hemochromatosis)

What are the key features of Type 2 (Juvenile) Hemochromatosis?
Back:

• Onset: Earliest and most severe (symptoms by age 10–30).

• Genetics: Autosomal recessive.

  • Type 2A (90%): HJV (hemojuvelin) gene mutation.

  • Type 2B (10%): HAMP (hepcidin) gene mutation.

• Clinical: Rapid iron overload → heart/liver failure, endocrine disorders.

Type 3 Hereditary haemochromatosis (TFR2-Related)

• Onset: Earlier than HFE-HH but milder than Juvenile HH.

• Genetics: Autosomal recessive (TFR2 gene mutation).

• Epidemiology: Very rare (Italian/European isolates).

• Clinical: Similar progression to HFE-HH (liver/heart damage).

Type 4 HH (Ferroportin Disease)

• Onset: Adult, slower progression.

• Genetics: Autosomal dominant (unique among HH types). SLC40A1

• Iron Storage: Macrophages (not liver initially) → high ferritin but normal/low transferrin saturation.

• Clinical: Milder organ damage; may mimic anemia.

Neonatal Hemochromatosis

• Onset: In utero → liver failure at birth.

• Etiology: Unknown (maternal alloimmunity suspected).

• Inheritance: Unclear (possibly AR or mitochondrial).

• Outcome: Often fatal without liver transplant.

Alagille Syndrome

Gene: JAG1 (Majority), NOTCH2

Inheritance

• Autosomal Dominant

  • HIGH DE NOVO RATE

• VARIABLE EXPRESSIVITY

Clinical Features

Onsent: Infancy

Liver

• ***FEWER BILE DUCTS***

  • causes Jaundice, hepatomegaly

Heart

• Pulmonary Artery Stenosis

Skeletal

• Butterfly Vertebrae

Eye

• Posterior Embryotoxon

Hemoglobinopathies

Different pathogenic variants in the HBB gene result in different types of hemoglobinopathies

The single alleles are listed as:

• HbS: Sickle Cell

  • ( a a / s s)

• HbC:

• HbD

• HbE

Hemoglobinopathy: CBC

Complete Blood count: measures the number and characteristics of blood cells

Measures

• Red Blood Cells (RBC)

• Hemoglobin (Hb)

• Mean Corpuscular Hemoglobin (MCH): amount of hemoglobin in each RBC

• ****Mean Corpuscular Volume (MCV)****: average size of red blood cells

A MCV BELOW 80% IS SUGGESTIVE OF A HEMOGLOBINTOPYH OR IORN DEFIENCEY

Test allows you to know something is abnormal: but not what → need Hemoglobin Electrophoresis

Hemoglobin

Hemoglobin is composed of 4 chains (a a / b b )

There are 4 types of chains:

• Alpha (a) Gene HBA1/HBA2 : Fetal + Adult

• Beta (b) - Gene HBB : Adult

• Gamma (g) - Gene HBG1/HBG2 : Fetal

• Delta (d) - Gene HBD : Adult (small amount)

Come together to form diffrent forms of HEMOGLOBIN PROTIen

• Adult Major Hemoglobin (HbA): (a a / b b)

  • 95-98% of adult hemoglobin

• Adult Minor hemoglobin (HbA₂): (a a / d d)

  • 2% of Adult hemoglbin (normally)

  • ****elevated in BETA-THAL****

• Fetal Hemoglobin (HbF): (a a / g g)

  • binds O2 better than HbA → ‘outcompete’ the maternal RBCs

At 6months, Gama-chain decreases and Beta-chain increases (where all the pathogenic blood issue variants come form)

Hemoglobinopathy: Hemoglobin Electrophoresis

Tells you WHICH HEMOGLOBINS are present in the RBCs → pull protines through the gel see how they seperate

• Normal Audlt:

  • HbA: 98%

  • HbA2: 3%

  • HbF: <1%

• Sickle Cell Trait (HbA/S): still a normal HBB allele to produce some normal ( b ) to make HbA

  • HbA: ~60%

  • HbS: ~40% (BELOW 50%)

  • HbA2: Low

  • HbF: Low

• “Classic” Sickle Cell DIEASE (HbS/S): Both HBB alleles only make abnormal ( b ) = all HbS

  • HbA: 0%*****

  • HbS: 95%

  • HbF: INCREASED (2-20%)***

  • HbA2: low

Sickle Cell Anemia: Etiology

Gene: HBB (codes for the Beta-globin chain)

• A Hemoglobinopathy

• Hemoglobin in red blood cells polymerizes in low o2→ causes RB cell to form sickle shape = clots

• Represented as HbS: can combine with other Hb_ alleles to cause different ‘levels’ of sickle cell disease

  • ex:HbS/S = ‘classic’ Sickle Cell vs. HbS/C = more mild

Inheritance

• Autosomal Recessive

• Classic variant: c20A>T (p.Glu6Val)

Pathophysiology

Onset 4-6 months: fetal hemoglobin (HbF) prevents HbS polymerization → decline after birth

• Chronic Hemolytic Anemia: RB cells las 10-20days (vs 120 for normal)

• Vaso-Occlusive Pain Crisises: sickle cell RB cells block small blood vessles (ischemia)

Sickle Cell Anemia: Clinical Features

Chronic Anemia Related

• Hemolytic Anemia (Hallmark)

  • Fatigue

  • Pallor/Jaundice

  • Dark Urine

Vaso-Occlusive related (usually triggered by infection, dehydration, stress etc.)

• Limbs

  • Dactylitis (Hand-Foot syndrome): painful swelling of feet/hands - -

    • Onset 6months-2years

• Lungs

  • ****Acute chest Syndrome (Medical Emergency)*****: blocks in lungs triggered by infection

• Brain

  • Stroke: 10% risk - childhood

• Spleen:

  • Functional Asplenia: spleen fails to filter blood → infections increas (encapsualted bacteria)

    • Onset by 5yo

Sickle Cell Anemia: Screening

Both NBS and carrier screening are extremely important for sickle cell

CBC

Parent Carrier

• ******CBC NORMAL!*****

Affected Child

• Hemoglobin/Hematocrit: Decreased

• ****MCV: NORMAL!!!*****

• ****RBC: Low****

• WBC/Platelets: often elevated

Hb Electrophoresis

Parent Carrier (sickle-cell TRAIT)

• HbA: 60%

• HbS: 35%

• HbA2: 3%

Affected Child (sickle-cell DIEASE)

• ****HbA: 0%****

• HbS: 95%

Sickle Cell Disease: All Hb variants

• HbSS: Classic sickle Cell Anemia

• HbSC: Milder form (Proliferative retinopathy common) 2nd most common form

  • HbS 50%

  • HbC 50%

• HbS/β⁰: Similar to HbSS in severity

  • HbS Domiant

  • HbA₂ increased

  • HbF increased

• HbSD-Punjab: Similar to HbSS in severity

  • HbD by itself is benign

  • But HbD + Hbs : promotes polymerization → sickle cell RBCs

• HbS/β⁺: Mild to moderate

  • HbA PRESENT but REDUCED

  • HbS Dominant

  • Normal HbF/HbA2

• HbSE: Less severe than HbSS

  • More frequent in South-East Asian populations

Common Hemoglobin Alleles

• HbA - Normal Hemoglobin

• HbS - Causes sickling when

  • Homozygote

  • combined iwth certain variants

• HbC: Causes ***mild hemolytic anemia*** as homozygote

  • BUT does not cause sickle by itself

• HbD: Usually clincially silent

  • UNLESS combined with HbS : will promote sickling of HbS and cause SSD

• HbE: Mild B-Thalassemia-like phenotype

Beta-Thalessemia: Overview

Gene: HBB (beta chain globin that makes up part of hemoglobin in RBCs)

• A QUANATATIVE hemoglobinopathy: not abnormal structure but lack of proper amount causes disease

• Either complete absent or reduced B-globin production

  • β⁰ : No production

  • β⁺ : Reduced production

Inheritance

• Autosomal Recessive

  • ****POINT MUTATIONS****

Two forms:

• B-Thalassemia Major

  • β⁰/β⁰ or severe β⁺/β⁰

  • Small RBCs + Marrow expansion + Transfusions

• B-Thalassemia Intermedia

  • β⁺/β⁺ or mild Mild β⁺/β⁰

  • Less severe: occasional transfusion

• B-Thalassemia Trait

  • β/β⁰ or β/β⁺

  • Asymptomatic or very mild Anemia

Beta-Thalassemia Major: Clinical features

Age of onset 4-6 months

Chronic infusions + increased intestinal iorn absorption (body’s response to anemia) = Iron Overload

Skeletal

• Bone Marrow Expansion

  • Frontal Bossing + Prominent Cheek bones+ Maxillary over growth (“Chipmunk facies”)

  • Osteopenia

  • Fractures

  • Long bone deformities

Liver/Spleen

• Hepatosplenomegaly (RBC breakdown)

• Liver cirrhosis (transfusion Iron overload)

Heart

• ***Cardiomyopathy (transfusion Iron overload)***

  • *** Leading cause of death ***

B-Thal Intermdia:

• similar but less sever

• Varialbe age of presenation

B-thal Minor (trait)

• asymptomatic or mild anemia

Beta-Thalassemia: Screening

B-Thalassemia Major

• CBC

  • MCV: very low

  • RBC: Low

• Electro

  • HbA: ****ABSENT***

  • HbF: **** 98% ***

  • HbA2: 2-5%

β-Thalassemia Intermedia

• CBC

  • MCV: very low

  • RBC: variable

• Electro

  • HbA: 40% (SOME HbA still being made)

  • HbF: **** 40% Elevated ****

  • HbA2: 4-8%

B-Thalassemia Minor (Trait)

• CBC

  • Hemoglobin: lower

  • **** MCV: Very Low ****

  • RBC: NORMAL

• Electro

  • HbA: 95%

  • ****HbA2: 4-8% ELEVATED****

Beta-Thalassemia: Management

B-Thal Major

• Blood Transfusions

  • Every 3-5 weeks

• Iron Chelation

  • Prevent iron buildup (Cardiomyopathy, chrisosis)

• Hematopoietic Stem Cell Transplantation (HSCT)

  • Only curative option

  • Best for

    • young patients,

    • matched siblings,

    • before severe iron overload

B-Thal-Intermedia

• Avoid chronic transfusions if possible

  • Only do them occasionally when needed

    • infection

    • pregnancy

    • surgery

Alpha-Thalassemia: overview

Gene: HBA1, HBA2 (codes for the a-globin chain that is a part of all hemoglobin forms - ex. HbA ( a a / b b)

• Because there are two genes for a- globin, normal people have 4 WORKING COPIES of a-globin producing genes

• Lack of a-globin + normal b-globin = excess b-globin forms abnormal tetramers (HbH-β₄) → poor 02 delivery

Inheritance

• Autosomal Recessive

  • ****GENE DELETIONS****

4 Clinical Forms

• Silent Carrier

  • - a / a a

  • 3 working copies

  • Asymptomatic

• α-Thalassemia Trait

  • - a / - a (trans) or - - / a a (cis)

    • Cis deletion common in SE Asian populations

  • 2 working copies

  • Mild microcytic anemia

• Hemoglobin H Disease

  • - - / a -

  • 1 working copy

  • Moderate hemolytic anemia

• Hb Bart Hydrops Fetalis

  • - - / - -

  • No working copies

    • No (a) = No (b) produced

    • Only (g) produced → forms Hb Bart’s : o2 binding EXTRMELY tight

  • Severe Anemia, Hydrops Fetalis, Edema, Heart Failure (FATAL if untreated)

Alpha-Thalassemia: Screening

Silent Carrier (- a / a a)

• CBC: normal

• Electro: normal

A-Thal Trait: Trans ( - a / a a) or Cis ( - - / a a)

• CBC: low MCV, normal RBC

• Electro: ***NORMAL***

*****DNA TESTING THE ONLY WAY TO DIAGONSIS SILENT AND A-THAL TRAIT*****

HbH Disease: ( - - / - a)

• CBC: very low MCV, low RBC

• Electro: HbH present (β₄), HbA low

Hb Bart Hydrops Fatalis: (- - / - -)

• CBC: ****ALL VALUES LOW: Hemoglbin, Hemocrit, MCV****

• Electro: ONLY Hb Bart’s (γ₄) PRESENT ***

Alpha Thalassemia: Clinical Features

Silent Carrier: Asymptomatic

A-Thal Trait: Asymptomatic → may be mis diagnosed with iron deficiency

Hemoglobin H Disease:

• Chronic Hemolytic Anemia

  • Fatigue, pallor, weakness, exercise intolerance

• Splenomegaly

• Infusions only when needed (infection, surgery, pregancy)

Hb Bart Hydrops Fetalis

• Severe Fetal Anemia

• Hydrops Fetalis

• Heart Failure

• Intrauterine transfusions + Chronic infusions after birth

  • ****MOTHER AT RISK FOR COMPLICAITONS****

• Fetus cannot surive without treatment

jaundice + splenomegaly + chronic hemolytic anemia + No dramatic skeletal changes = HbH Deiase

Gluclose-6-Phosphate Dehydrogenase (G6PD) Deficiency

Gene: G6PD (with out RBC cannot neutralize oxidative stress)

Inheritance

• ****X-Linked Recessive****

Clinical Features

• Acute Hemolytic Episodes

  • ****TRIGGERED by Oxidative Stress***

    • Infections

    • Medications: Sulfa-drugs

    • Food: ***FLAVA BEANS***

Diagnosis

• G6PD Enzyme Assay of RBCs

  • DONT test during acute hemolytic crisis

Diamond-Blackfan Anemia (DBA)

Gene: RPS19 (Most common) (ribosomal protein)

• Defective ribosomes lead to apoptosis of RBC -precursor cells → severe anemia

• Failure to make RBC, but WBC and Platelets normal

  • Pure red cell aplasia

Inheritance

• Autosomal Dominant

  • DE NOVO 70%

Clinical Features

Onset before 1yo

Blood

• Severe Anemia: very LOW RBCs produce

• Macrocytic Anemia; RBCs that re produced, are way to big

  • MCV: very high

  • Hemoglobin/Hemocrit: LOW

  • Reticulocyte: VERY LOW

Congenital Anomalies

• Upper Limbs

  • ****ABSENT THUMB****

• Craniofacial

  • Cleft Palate

• Cardiac

• Renal

Management

• Steroids: first line treatment

• Chronic transfusions: if steroids fail

• Iron Chelation

• Stem Cell Transplant

Hemophilia A

Gene: F8 (coagulation factor VIII)

• More common than Hemophilia B

• Hemophilia A + B are essentially indistinguishable

• DEEP TISSUE BLEEDING

Inheritance

• ****X-Linked Recessive*****

  • Inherited 70%

  • DE NOVO 30%

• Intron 22 Inversion: most severe

• Females protected

Clinical Features

Severe and Moderate forms

Severe:

• Presents in Infancy

  • Spontaneous + prolonged bleeding

  • Recurrent hemarthroses (joint bleeding)

  • Easy Bruising

Moderate

• bleeding after minor trauma

Mild

• Bleeding after surgery and major trauma

Hemophilia B

Gene: F9 (coagulation factor IXa)

• Hemophilia A + B are essentially indistinguishable

• DEEP TISSUE BLEEDING

Inheritance

• ****X-Linked Recessive*****

  • Inherited 70%

  • DE NOVO 30%

• Intron 22 Inversion: most severe

• Females protected

Clinical Features

Severe and Moderate forms

Severe:

• Presents in Infancy

  • Spontaneous + prolonged bleeding

  • Recurrent hemarthroses (joint bleeding)

  • Easy Bruising

Moderate

• bleeding after minor trauma

Mild

• Bleeding after surgery and major trauma

von Willebrand disease

Gene: VWF

• Platlets affected

• MUSCOSAL BLEEDING

Inheritance

• Autosomal Dominant or Recessive

Clinical Features

• Prolonged bleeding (especially after dental work - mucosal bleeding)

• Easy Bruising

• Heavy mensuration

Unlike Hemophilia

• NO JOINT BLEEING

• Mucosal Bleeding is primary bleeding

Thrombocytopenia-Absent Radius (TAR) Syndrome

Gene: RBM8A

• Abnormal development of platelet precursors and upper limbs

• Weird feature: cow milk intolerance

Inheritance

• Autosomal Recessive

Clinical Features

Presents by 2yo

• Thrombocytopenia: low platelets (but get better with age)

  • ***Intracranial Hemorrhage in INFANCY****

• Limb Abnormalities

  • Bilateral Absent Radius

  • ****BUT THUMBS ARE PRESENT**** (unliked Fanconi anemia, Holt-Oram, VACTERL)

Factor V Leiden Thrombophilia

Gene: F5 (coagulation factor V)

• A BLOOD CLOTTING disorder → NOT a bleeding disorder

• too much CLOTTING

Inheritance

• Autosomal Dominant

• INCOMEPLTLE PENETRANCE

• Homozygotes have higher risk than Heterozygotes

Clinical Features

• Deep Vein Thrombosis: a blood clot

  • Usually forms in Calf or Femoral Artery

• Pulmonary Embolism: when clot breaks off and gets sucked into the lungs

  • can be life threatening

****Many Heterozygotes never develop a clot***

• ESTROGEN increased Embolism Risk

Severe combined immunodeficiency (SCID)

• SCID presents in early infancy with recurrent severe and opportunistic infections.

• Persistent thrush + failure to thrive + absent tonsils = think SCID.

• Newborn screening detects SCID using TRECs.

• The most common cause is X-linked IL2RG deficiency (T− B+ NK−).

• Early hematopoietic stem cell transplantation is the standard curative treatment and has the best outcomes when performed before serious infections occur.

Chronic Granulomatous Disease (CGD)

Gene: CYBB (important for neutrophils to kill pathogens once they eat them) but many genes

• Unable to effectively kill bacteria/pathogens = RECURRENT INFECTIONS

Inheritance

• X-Linked Recessive

Clinical Features

Onset in infancy or early childhood

Recurrent infections including

• Recurrent Pneumonia

• Skin Abscesses (from Staph. infections)

• Liver Abscesses (from Staphylococcus aureus)

  • Aspergillus especially

Wiskott-Aldrich Syndrome (WAS)

Gene: WAS (important for functioning in hematopoietic cells)

• Immune cells and Platelets cannot function properly

Inheritance

• ****X-Linked Recessive****

  • 1/3 DE NOVO

Clinical Features

Presents in infancy

• Thrombocytopenia (low Platelets)

• Eczema

• Recurrent infections

  • Otitis media (ear)

  • Sinusitis

  • Pneumonia

Chediak-Higashi Syndrome (CHS)

Gene: LYST (important for lysosome formation)

• s

Inheritance

• Autosomal Recessive

Clinical Features

Onset infancy or early childhood

• Partial Oculocutaneous Albinism: pigment reduced but NOT ABSENT

  • Light skin w Silver/light-colored hair

  • Vision issues

• Recurrent Infections: specially staphylococcal

  • Skin infections

  • Pneumonia

  • Otisis media

• *****Hemophagocytic lymphohistiocytosis (HLH)-like phase*****:

  • Immune system become hyperactivated → massive inflammation

  • = bone marrow failure + organ failure

• Progressive Neurologic Disease

Diagnosis

• Peripheral smear showing giant cytoplasmic granules in neutrophils

Holoprosencephaly

Incomplete division of embryonic forebrain (prosencephalon) into lateral hemispheres

• - 1:250 conceptions/1:10,00 live births —> one of the most common embryonic abnormalities, but most are lethal in utero

• - Assoacted with dysmoprphic features related to laterality: cylopia, probisoicus, hypertelorism, SCMI (a tooth thing?)

• “Face preditcs the brain” : mental retardaiton, seixures, pituitary insufficney, FTT

Holoprosencephaly Eitology

- 90% genetic

• Half are Chrsome Abnormalities: OVERWHELMINGLY Trisomy 13 (Patau)

• Half are Monogenic disorders: Mutations in SHH (Non-syndromic) autosomal domaint

HPE and Patau syndrome

***MOST COMMON CAUSE OF HPE ACROSS ALL GENETIC CAUSES***

• HPE occurs with:

  • Facial clefting

  • ****POLYDACTYLY***

  • CHD

  • PKD

  • Omphalocele

• Severe mental retardation

• 3% Survival at 1 Year

• Recurrence risk: 1%