Inheritance of Disorders😊

Autosomal Dominant Disorders (AD)

• Her husband is Very Dominant hunter.

• He hunts adipoli bra in new hypermarket.

• He faps for Pearley mani

• He had good muscle (). Make her nude (). Maar (beat) her. Then take a tube () → insert intermittently () into her ootta () → Aakki () aakki sugipikkum ()

• He has heart disease

• AIP

• Lisch epithelial dystrophy

• Her husband is Very Dominant hunter.
• Her: Everything hereditary
• Hereditary spherocytosis
• Hereditary hemorrhagic telangiectasia
• Hereditary nonpolyposis colon cancer (HNPCC) / Lynch syndrome
• Comprises: Colon cancer, Endometrial cancer, Ovarian cancer
• Mnemonic: "CEO has gone for lunch"
• Very: (Two V's)
• Von Willebrand disease (bleeding disorder)
• Von Hippel-Lindau (VHL) syndrome
• Defect:
• Chromosome 3p deletion (from VHL's three alphabets)
• VHL gene.
• Activate Hypoxemia Inducible Factors (HIF)
• Clear cell RCC
• SmaLL CELL lung cancer (L myc, 3p)
• Pheochromocytoma
• Cerebellar Hemangioblastoma
• Retinal hemangioblastoma
• may bleed causing vision loss
• Spinal cord hemangioblastoma
• Vascular tumour of spinal cord
• Cutaneous: Café-au-lait macules.
• Hemangioendothelioma
• Hemangioendothelioma + RCC ⇒ Paraneoplastic Polycythemia



• Hunter
• Brain: Huntington disease

• He hunts adipoli bra in new hypermarket.
• Adipoli
• Autosomal dominant polycystic kidney disease (ADPKD)
• Bra → BRCA 1
• New → NF 1 and 2
• Hypermarket → Hypercholesterolemia

• He faps for Pearley mani
• Fap → Familial adenomatous polyposus
• Pearly mani → Li fraumeni (p53)

• He had good muscle (). Make her nude (). Maar () her. Then take a tube () → insert intermittently () into her ootta () → Aakki () aakki sugipikkum ()
• Muscular dystrophy
• Noonan
• Marfan
• Tuberous sclerosis
• intermittent porphyria
• Osteogenisis imperfecta
• Achondroplasia
• Pseudohyperparathyroidism

• He has heart disease ()
• Heart: Hypertrophic cardiomyopathy (banana-shaped appearance)

Autosomal Recessive Disorders (AR)

• Mnemonic:
• Wilson (wilson ds) told albin (), come(cah) here (Hemochromatosis) sit (sickle cell, Cystic fibrosis) in thara (thalassemia)
• Wilsons disease
• Albinism
• CAH
• Hemochromatosis
• Sickle cell, CF
• Thalassemia
• Store () il fry () eduth avanu koduth, fan () itt koduth
• Storage disease → LSD, GSD
• Friedrich ataxia
• Fanconi
• Homo → Stood up and peed on him → Black color, bad smell
• Homocystenuria
• Alkaptonuria
• Phenylketonuria
• To see (C) blood (Hemo) → marker X on his skin
• Blood → Hemo →
• Hemophilia C
• Xeroderma Pigmentosa
• Fucked him with a broom ()
• Bloom syndrome
• Atlast he was ataxic
• Ataxia telangiectasia
• Ennitt orumich (as one) tryp () poi
• Alpha 1 antitrypsin

X-linked Recessive Disorders (XLR)

• General Inheritance: Males are diseased; females are carriers.

• Agammaglobulinemia

• Mnemonic:
• Her name was Fabry, she was very fragile
• Put her in a cage
• Put a leash on her
• Brutal HaRD BJ →
• Tie her eyes → Drink whisky → then hunt her

• Her name was Fabry(), she was very fragile()
• Fabrys ds
• Fragile X (more common as XLR)

• Put her in a cage ()
• CGD

• Put a leash () on her
• Lesch Neyhan (biochemistry enzyme disorder, self-mutilation)

• Brutal (Bruton) HaRD (Haemophilia, Red green color blindness, Dmd) BJ (BMD, G6PDD)

• Tie her eyes (color blind, ocular albinism) → Drink whisky (wiskott)→ then hunt her (Hunter)

Corneal Dystrophies

• Leash on Fragile fabry (XLR)

• AR → Gay → he was congenitally gay → do posteriorly (Conegnital posterior endothelial dystrophy)

Lisch epithelial dystrophy

• Leish vachitt Adi (AD)

Feature	Classic View	Latest Update (IC3D 3rd Ed, 2024)
Inheritance	X-Linked Dominant	Autosomal Dominant
Chromosome	Xp22.3	Chromosome 19
Gene	ㅤ	MCOLN1

Lyonization

• Applied
• Hemophilia A in Heterozygous Females
• Unfavourable lyonization
• Inactivated X chromosome → normal Factor VIII gene
• Active X chromosome → defective gene.
• Leads to reduced Factor VIII levels → Symptoms of Hemophilia A.
• Barr bodies







• Used for sex determination

• Inactivation / Lyonisation of X chromosome

• Mechanism: DNA Methylation

• Gene: XIST gene

• Time: 6th day of gestation

• Facultative Heterochromatin
• “Heterochromatin” → highly condensed and stains densely
• "facultative" → because random.

• Appear as Davidson bodies in WBCs

X-linked Dominant Disorders (XLD)

• General Inheritance: DDD (Dad gives the Disease only to all the Daughters).

• Mnemonic: "Ex (x linked) is very dominant (dominant)→ Ravi"
• R: Rett syndrome
• A: Alport syndrome
• V: Vitamin D resistant rickets
• I: Incontinentia pigmenti

Type	Cause
Posterior	• Lowe syndrome ↳ Oculo Cerebro Renal syndrome • Opacity at posterior capsule center
Anterior	SAW Spina bifida Alport syndrome Waardenburg syndrome

Y-linked Inheritance (Holandric Inheritance)

• General Inheritance: Dad to all sons.

• Example: Hypertriosis (Hairy ear).

• Every 10th patient is Y-linked

Introduction to Genetics

• Mendelian Disorders

• Non-Mendelian Disorders

• Chromosomal Disorders

• Diagnosis Techniques for genetic disorders

Mitochondrial Inheritance

 

• Mnemonic:
• Mighty (Mitochondria) Loan (LHON) eduth oru Pears (Pears) soap nte Large (Leigh) mela (Melas) nadathi
• Pottiyapo Nari (NARP)→ Fits vannu (MERFF → epilepsy)
• last Kayar (Kearn Sayre) eduth

Mitochondrial diseases

• Caused by failure in oxidative phosphorylation (ETC).

• High-energy demanding tissues (e.g., CNS, skeletal muscle) are preferentially affected.

• Key Rule: Mother to all, father to none (Maternal inheritance).

• Most Common Mitochondrial Disorder: 
• MELAS
• Mitochondrial Encephalopathy, 
• Lactic Acidosis, 
• Stroke-like episode

• Most Common Mitochondrial Myopathy: 
• CPEO (Chronic Progressive External Ophthalmoplegia)

• Light Microscopy:
• Shows ragged red fibers
• due to compensatory mitochondrial proliferation

• Electron Microscopy:
• Reveals mitochondrial crystalline inclusions.

Other Mitochondrial Diseases (often with eye involvement):

• LHON
• Leber's Hereditary Optic Neuropathy
• Caused by mutations in complex I of the electron transport chain.
• Leads to neuronal death in the retina and optic nerve.
• Presents as:
• Subacute bilateral vision loss
• young adults (more common in males).
• Usually permanent.
• May also show neurologic symptoms (e.g., tremors, MS-like illness).

• NARP (Neurogenic Ataxia with Retinitis Pigmentosa)

• Leigh syndrome
• Pyruvate dehydrogenase deficiency
• Recurrent lactic acidosis
• developmental delay, and hypotonia
• Bilateral cystic lesions in the basal ganglia

• Pearson syndrome

• Kearns-Sayre syndrome

• Optic neuropathy

• Barth syndrome (Cardioskeletal myopathy)
• Cardiomegaly + myopathy
• Cardiolipin involved
• Mitochondrial disease
• Bar → Alcohol → Dont drive car (Cardiolipin)
• DCM → cardiomegaly
• get beaten → Myopathy

MERRF (Myoclonic Epilepsy with Ragged Red Fibers):

• MERRF: (Myoclonic Epilepsy) with (Ragged Red Fibers)

• Features: 
• Myoclonus; 
• Epilepsy

• Microscopy:
• Red Ragged Fibers (RRF) on muscle biopsy (Gomori Trichrome stain)
• Parking lot appearance (abnormal mitochondria on EM)
• Phonographic record appearance (abnormal mitochondria on EM)

• Death occurs by 3rd decade

• Mnemonic: Jomon 3 color (Gomon Trichrome) shirt itt parking lotil (Parking lot appearance → EM) irunnu phone (Phonographic record appearance → EM) vilichapo fits () vannu marichu

Features of Mitochondrial DNA

Trinucleotide Repeat Disorders

• Location of repeats: Mostly in intronic (non-coding) region.
• Exception: Huntington disease (in exonic (coding) region).

Disease	Repeat	ㅤ	Mnemonic / Key Fact
Huntington disease	CAG CHromosome 4	Exon Extrovert → talks/codes	Hunting in a CAGE CAG+E Exon; CAG repeat cage has 4 corners
Fragile X syndrome	CGG	Intron (Introvert → Non coding)	Jiji fragile
Myotonic Dystrophy	CTG Chromosome 19	Intron	myoTonic dysTrophy has a T
Friedreich's Ataxia	GAA Chromosome 9	Intron	Friend → sings → Gana → GAA Awesom heart (HOCM) and big toes (Hallux Valgus)

Mnemonic:

• CAG → CGG → CTG → GAA

• Hunting () fragile () muscle () to Fry ()

Fragile X Syndrome (Detailed)

FMR → Face Mandible Really long/ Fragile with Mental Retardation

CGG → Characteristic Giant Gonads

Chromosome affected: 

• X chromosome (XQ)

• Gene affected: FMR1 gene (Fragile X Mental Retardation 1)

• Repeat: CGG repeats

Repeat Numbers:

• Normal:
• < 55 repeats ("fit and fine")

• Premutation: 
• 55 to 200 repeats (patient has Fragile X tremor-ataxia)

• Mutation:
• > 200 repeats (patient has Fragile X syndrome)

Sherman's paradox / Anticipation:

• Repeats increase with each generation.

Clinical Features:

• Mental retardation (IQ 20-60)

• Large head, Long face, large mandible, large ears (Amir Khan PK character)

• Macroorchidism (large testicles) - most characteristic feature
• Mnemonic: Small X → SO large Y → Large Testis

• Female carriers risk: 
• 10% females
• Premature Ovarian Failure (POF) before 40 years.
• intellectual disability

Diagnosis of choice: 

• PCR

• Southern blotting
• If PCR fails

Blotting techniques:

• Mnemonic: Dosa (Southern - DNA), Roti (Northern - RNA), Pizza (Western - Protein)

• Eastern: Post-translational modifications

Myotonic Dystrophy

• Clinical Features:
• Cannot terminate grip 
• muscle spasms
• Christmas tree cataract
• Hatchet faces (sharp jawline)
 

• Repeat: 
• CTG repeats

• Chromosome 19

• Myotone → muscle tone ↑↑ → cannot terminate grip → while holding christmas tree and a hatchet (hatchet facies)

Genomic Imprinting (Gene Silencing)

• Epigenetic process → gene expression depends on parent of origin

• One allele is imprinted/marked during gamete formation
• Not expressed / Silenced

• Expression from either maternal or paternal allele only.

 

• Mechanism: DNA methylation (M for Mute).

• Normal Imprinting: One parental gene is silenced.

Syndrome	Chromosome	Clinical Features
Prader-Willi	Chr 15 → SNORP (P) Paternal deletion,  + Maternal imprinting ("PRADE") OR Maternal disomy of Chr 15	Mental retardation; Chubby, short, obese (↑ ghrelin) During Neonatal period ➔ Hypotonia (Floppy baby) / Difficult to feed (thin upper lip and downturned mouth) / short extremities / almond-shaped eyes. During Childhood Excessive eating (hyperphagia) / Obese and Short / learning difficulties / growth abnormalities / self-injurious behaviour. GORE (GHERLIN) → SNORT (SNORP)
Angelman	Chr 15 → UB3A (A) Maternal deletion,  Paternal imprinting OR Paternal disomy of Chr 15	Happy puppets, microcephaly Mental retardation;  Seizures;  Inappropriate laughter Ubekuttan → Ubequitin ligase 3A

• Prader Willi
• Mnemonic:
• Proud william - he is a prince with blue eyes.. he is just 15... but he is obese and arrogant
• Arrogant → Father → paternal deletion → also maternal disomy
• He is obese → so snores → SNORP gene
• Ghur nnu purath povilla (Gherlin)

• Angelman
• Mnemonic:
• Happy puppey → chirich chirich seizure avum (seizures)
• Angel 5 → Pathinanj (15)
• She is Happy → tell “you be you” → UB3A

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Beckwith-Wiedemann syndrome.

• BWS = 11p15 imprinting defect → Overgrowth + Macroglossia + Omphalocele + Tumor risk (Wilms, Hepatoblastoma).

• Cause: ↑ copies of imprinted genes (placental overgrowth).

• LGA baby with hemihypertrophy.

• Macroglossia / Protruding tongue

• Omphalocele.

• Organomegaly (liver/spleen).

• Horseshoe kidney

• Double → Ear lobe creases.

• Increased risk of embryonal Tumors:
• Wilms tumor (nephroblastoma)
• Hepatoblastoma
• Neuroblastoma, rhabdomyosarcoma (less common)

---

William Syndrome

• Chromosome 7 micromutation

• Elastin Mutation
• Results in Williams syndrome

• Overfriendly

• HyperCalcemia

• Elfian facies

• Leads to Supravalvular aortic stenosis
• Differential BP
• Right arm BP > Left arm Bp > Lower Limb

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ㅤ	Williams syndrome	Marfan syndrome
Mutations	Elastin Mutation	Fibrillin Mutation
Leads to	Supravalvular aortic stenosis	Dilatation of aortic root ↳ Rupture → Death

ㅤ	ㅤ
Supravalvular AS	• Vitamin D toxicity • William syndrome
Supravalvular PS	• Noonan syndrome

ㅤ	Seen in
GNAS	• Mccune Albright • Cardiac Myxoma
GNAS 1	• Pseudohypoparathyroid/ Albright Hereditary Osteodystrophy
GNAQ	• Sturge Weber (Sporadic)

Gonadal Mosaicism (Germline Mosaicism)

• "Pop-up disease":
• Mutation occurs post-zygotically.

• Inheritance:
• Parents/family normal
• one child "pops up" with the disease.

• Examples: (AD diseases potentially via this if no family history).
• Osteogenesis imperfecta; 
• Tuberous sclerosis 

Types of Genetic disorders

• Chromosomal

• Single gene

• Multifactorial
• Examples:
• Diabetes,
• Hypertension,
• Neural tube defects

• Mendelian

Chromosomal/Numerical Disorders

Trisomies

• Most common trisomy overall:
• Trisomy 16 (not compatible with life, causes intrauterine death).

Trisomy 21 (Down Syndrome):

Karyotype

• Male: 47 XY

• Most common trisomy compatible with life.

• Mechanism: Meiotic non-disjunction (most common), associated with maternal age.

• Extra copy come from maternal ova

Genetic Basis

• NO DELETION

• Maternal meiotic nondisjunction (M/C)

• Robertsonian Translocation:
• Chromosome 21
• Acrocentric chromosomes
• 13/14/15
• 21/22/y

• Mosaicism:
• > 1 cell line in same individual
• e.g., Trisomy 21 + monosomy 21
• Clinical features less severe

What does the division of a chromosome perpendicular to the normal axis of division lead to?

1. Ring chromosome

2. Isochromosome

3. Acrocentric chromosome

4. Subtelocentric chromosome
ANS

Clinical Features (Head to Toe):

• A:
• Atlantoaxial subluxation
• Griesel syndrome
• Check before contact sports / GA surgeries
• Acute leukemia
• < 3 yrs → ALL
• > 3 yrs → AML-M7
• Early Onset Alzheimers
• A/w with APP gene in chromosome 21
• (Amyloid Precursor Protein)
• Absent Moro reflex (due to hypotonia)

• C:
• Congenital heart disease
• Congenital hypothyroidism
• Congenital diaphragmatic hernia

• Mental retardation (most common cause)

• Clinodactyly → Incurved little finger

• Mongoloid facies: Oblique palpebral fissures; flat nasal bridge (nasal bone hypoplasia)

• Brushfield spots in iris

• Miscellaneous
• Simean crease (single palmar crease)
• Single crease on little finger
• Sandal toe (gap between great toe and other toes)
• Open mouth (due to macroglossia and micrognathia)

Complications:

• EAR
• Conductive hearing loss → Serous Otitis media
• NOT SNHL → In turners

• Most common hematological abnormality:
• TAM (Transient Abnormal Myelopoiesis)

• Leukemias:
• Overall most common → ALL;
• <3 years → AML M7.

• CNS: 
• Premature Alzheimer's (<30 yrs)

• GIT: 
• Hirschsprung's disease / Mega colon

• Bone:
• Grisel syndrome:
• Seen in Downs
• Non-traumatic inflammatory atlanto-axial subluxation
• Neck stiffness
• Torticollis
• Severe neck pain
• Due to paraspinal spasm from inflammation

• Cardiac: 
• Endocardial cushion defect (most common)

Screening (during pregnancy):

• Ultrasound: 
• 1st trimester:
• ↑ Nuchal thickness (>3 mm)
• Absent nasal bone
• Scan done at 11 weeks gestation
• 2nd trimester:
• Soft markers:
• Short femur,
• absent/hypoplastic nasal bones
• Duodenal atresia
• Cardiac anomalies

• Combines:
1. Maternal age
2. 1st trimester:
• Double marker:
• β-HCG ↑
• PAPP-A ↓
3. 2nd trimester:
• Triple Marker:
• β-HCG ↑↑
• Unconjugated estriol,
• α-Fetoprotein
• Quadruple Marker:
• β-HCG ↑↑
• Unconjugated estriol,
• α-Fetoprotein,
• Inhibin A ↑

• Mnemonic: Only 2 are elevated → both in Downs → High has ‘H’ in it
• b Hcg
• inHibin

Best Screening Test

• NIPS / NIPT (Non-Invasive Prenatal Screening/Test)
• Detects cell-free fetal DNA in maternal blood
• Screens for aneuploidies
• Pick-up rate >95%
• Limiting factor earlier:
• Cost, now routinely available

Confirmation: 

• Fetal Karyotype (invasive)
• 11–13 weeks: Chorionic villus sampling
• Mnemonic: viLLus → 11 weeks
• 14–16 weeks: Amniocentesis
• Mnemonic: Amnio → 6 → 16
• 17–20 weeks: Cordocentesis
• Risk of abortion
• Indicated for high-risk mothers

Triads

• Gradenigo's Syndrome:
• Petrous apicitis
1. Persistence of ear discharge (after cortical mastoidectomy)
2. Deep seated retro-orbital pain → D/t CN 5
3. Diplegia - Lateral rectus palsy due to CSOM → D/t CN 6
• Mnemonic: Pettennu (Petrositis) Granede (Gradenigo) 5,6 thavana itt → Kannilum cheviyilum kond → Eye pain + ↓ movement - case eduth(CSOM)

• Sampter's triad
• (Mnemonic: AAP): SAM → MAS → AS, AS, NAS
• AS - Asthma
• AS - Aspirin intolerance (& other NSAIDS that block COX1)
• NAS - Nasal polyp (Ethmoidal)

• Trotter's Triad
• Diagnostic of Nasopharyngeal Carcinoma
• NPC
• Temporoparietal neuralgia.
• Palatal paralysis.
• CN 10
• Tensor and Levator Veli Palatini involvement
• Unilateral conductive hearing loss.

---

• CSOM → Lateral sinus thrombophlebitis signs



• Hectic picket fence type
• Intermittent septic emboli enter bloodstream
• Fever + rigors
• Fever does not touch baseline
• Tobey-Ayre's test:
• Compression of IJV on healthy side raises CSF pressure.
• Mnemonic: Tobey has lot of pressure in his head
• Crowe-Beck test:
• Pressure on IJV on healthy side causes engorgement of retinal veins.
• Mnemonic: Crow with red eyes
• Griesinger sign
• Mastoid emissary veins cannot drain
• Edema and bluish discoloration of the mastoid
• Similar to battle sign
• Mnemonic: Blue color grease

---

• Grisel syndrome:
• Seen in Downs
• Non-traumatic inflammatory atlanto-axial subluxation
• Neck stiffness
• Torticollis
• Severe neck pain
• Due to paraspinal spasm from inflammation

Trisomy 13 (Patau Syndrome):

Common features in Patau and Edward Syndromes:

• Mental retardation

• Ventricular Septal Defects (VSDs)

• Patent Ductus Arteriosus (PDA)

• Rocker bottom feet (convex feet)

Features (P for Patau):

• Polydactyly → extra finger

• Cleft liP and Palate

• Coloboma → keyhole deformity of eye

• HypoTelorism → Cyclops

• Persistant Hyperplastic Primary Vitreous
• Leukocoria + Triangular opacity + Persistent hyaloid artery

• Rocker bottom feet (convex feet)

• HoloProsencephaly
• single fused monoventricle

Mnemonic: Puberty age = 13

• cleft lip and palate

• Cannot take mother to Pattaya → No maternal age in Patau

• 2 smalls: head and eyes

• Many fingers (13) ➔ Trisomy 13.

• Many fingers in Patau (13), fingers override each other in Edward (18).

Trisomy 18 (Edwards Syndrome):

• 2nd M/c → WITH MATERNAL AGE
• 1st → Down’s syndrome

• Mnemonic: Election age = 18

Features:

• Strawberry skull (small chin, large occiput)
• + Microphthalmia

• Abdominal wall defects

• Low set ears

• Clenched fist → Overlapping fingers

Edward has 2 prominents and 2 smalls:

• The 2 prominents are the highest (Occiput) and the Lowest (Calcaneus).

• ROME
• Rocker bottom feet
• Overlapping fingers
• Micrognathia
• Ear (low set)

• 18 year old → ayapo marriage cheyyan malsaram → Horse ride with strawberry → While riding overlap fingers

Klinefelter Syndrome (47, XXY or 48, XXXY, etc.)

• Most common cancer: Male breast cancer.

• Other cancer: Mature Teratoma

• Associated autoimmune disorder: SLE.

• extra X chromosomes
• d/t non disjunction of X

• Mental Retardation:
• ↑ with ↑↑ extra X chromosomes
• More female → more MR

• Clinical Features:
• Hypogonadism
• Tall stature
• Mitral Valve Prolapse (MVP)
• Sparse hair

• Hormone Profile: Low Testosterone, High LH and FSH.

Turner Syndrome (Monosomy X - 45, XO)

• Basic defect: 45, X0

---

• Turner Mosaicism:
• 45 XO; 46XX (two cell lines present).
• Secondary amenorrhea
• Cardiac abnormalities
• Hearing loss → cholesteatoma
• insulin resistance
• ↑↑ r/o GONADOBLASTOMA
• Prophylactic gonadectomy is done

---

Features

• Primary amenorrhea

• IQ: Usually normal.

• Sensorineural hearing loss

• Amenorrhea (Primary)

• Barr body absent

• ↑↑ Autoimmune Diseases
• Diabetes.
• Hashimoto's thyroiditis.
• Coeliac disease.
• NOT SLE → (SLE in Klinefelters)

Horseshoe kidney

• Turner’s syndrome

• Edward’s syndrome

• Risk of → Wilms T 2

• Edward turned above Horse

• Cystic hygroma

• Short stature

• High Arched Palate

• Nipples are widely spaced on a shield-shaped chest

• Webbed neck
• Due to lymphedema → Post resolution of cystic hygroma
• Webbed neck is associated with more chances of Cardiovascular malformations

• Low posterior hairline

• ↑↑ FSH, LH → Hypergonadotropic hypogonadism

• ↑↑ Carrying angle → Cubitus Valgus

• Short 4th metacarpal & Madelung
• [Short 5th distal phalanx → Downs]

---

• Female with absent Barr body = Turner
• Normal males: 1-1 = 0 Barr body
• Normal females: 2-1 = 1 Barr body
• Turner syndrome females: 1-1=0

---

Cardiac Anomaly: 

• Bicuspid aortic valve (most common) > Coarctation of aorta.

• Most common cause of death → Coarctation of aorta

Ovaries: 

• Rudimentary ovary / Streak ovary.

• Uterus Present

Dysgenetic/Undescended Testes (45XO/46XY):

• Increased malignancy risk.

• Gonadectomy recommended.

• Most common gonadal tumour: Gonadoblastoma.

• Most common gonadal malignancy: Dysgerminoma.

• Mnemonic: CLOWNS
• C → Cardiac, cubitus valgus
• L → Lymphedema
• O → Fibrosed ovaries
• W → Webbed neck
• N → Normal intelligence
• S →Short stature, with short 4th metacarpal and shield chest

Management Strategies

• NO GONADECTOMY

• Growth Hormone (GH):
• Administered only till 8 years old.

• Hormone Replacement Therapy (HRT):
• Oestrogen alone for 1 year.
• Followed by Oestrogen + Progesterone.
• Continued till normal menopause age.

• Pregnancy:
• Relative contraindication.
• Increased risk of cardiac disease.

Comprehensive Investigations

• Echocardiography (Echo): For cardiac anomalies.

• Renal Ultrasound (USG): For renal anomalies (horseshoe-shaped kidney).

• Thyroid Profile: TSH, T3, T4.

• Metabolic Screening:
• Complete Blood Count (CBC).
• Lipid Profile.
• Fasting Glucose.

• Organ Function Tests:
• Renal Function Tests (RFT).
• Liver Function Tests (LFT).

• Audiometry: For sensorineural hearing loss.

• Anti-Endomysial Antibodies: Increased risk of coeliac disease.

• Karyotyping: Definitive diagnostic investigation.

Comparison: Noonan Syndrome vs Turner Syndrome

Feature	Noonan Syndrome	Turner Syndrome
Inheritance	Autosomal dominant	No inheritance pattern
Karyotype	Normal (microscopic deletion)	45, XO
Sex affected	Both boys and girls	Only girls
Intelligence	Intellectual disability present	Normal intelligence
Puberty	Delayed puberty, fertility preserved	Infertile (streak ovaries, rudimentary uterus)
Facial Features	Antimongoloid slant of eyes, low-set ears	Webbed neck (higher CHD risk)
Congenital Heart Disease	More common; Pulmonary stenosis (supravalvular)	Less common, (A/w webbed neck) Bicuspid aortic valve > Coarctation of the aorta (death)

• Children with Noonan syndrome
• More CHD than Turner syndrome

• Webbed neck in Turner
• Higher chance of CHD

• Antimongoloid slant
• Treacher-Collins syndrome
• !st pharyngeal arch defect



• Noonan syndrome
• Cri du chat syndrome
• Mnemonic:
• Teacher (Treacher collin) Noonil (Noonan) Mangalam (Antimongoloid) vayikkum

Cri du chat syndrome

• Chromosome 5

• Hypotonia

• Shrill cry

• Microcephaly, Mental retardation

• Anti mongoloid facies

Noonan Syndrome

• Autosomal dominant inheritance

• Similar to Turner syndrome → due to mutation of chromosome 12
• Noon → At 12 → chromosome 12

• Most common gene: PTPN11

• Seen in both boys and girls

• Mnemonic: Noon () nu dominant () alkkaru vann Pattikkum (PTPT patippanu) → Super aytt Paisa (Supravalvular PS) Pattikkum → avana nammal delete (microscopic deletion) cheyyanam

NOTE

Pseudohypoparathyroid/ Albright Hereditary Osteodystrophy (AHO)

• Maternal

• Type 1 A → AD
• GNAS Mediated

• Mimic secondary Hyper PTH

• Mother → Lie to child (pseudo)

• PTH is high but cannot act

• (Same Pic as CKD, but Normal ALP)

• Psudo pseudo
• knuckle knuckle dimple dimple

• NOTE: If only short 4th Metacarpal
• Turner

PseudopseudohypoPTH

• Paternal

• AD

• Everything is normal

• Father → Lie to child and mother (pseudo pseudo) → but everything will be normal

Madelung

• Distal radial abn

• Seen in Turner’s syndrome

• Radius is not formed

• Radio carpal coalation doesnt take place

ㅤ	Williams syndrome	Marfan syndrome
Mutations	Elastin Mutation	Fibrillin Mutation
Leads to	Supravalvular aortic stenosis	Dilatation of aortic root ↳ Rupture → Death

ㅤ	ㅤ
Supravalvular AS	• Vitamin D toxicity • William syndrome
Supravalvular PS	• Noonan syndrome

ㅤ	Seen in
GNAS	• Mccune Albright • Cardiac Myxoma
GNAS 1	• Pseudohypoparathyroid/ Albright Hereditary Osteodystrophy
GNAQ	• Sturge Weber (Sporadic)

Marfan Syndrome

Q. A 15-year-old boy presented to the Ophthalmology department with an acute reduction in visual acuity in both the eyes. The direct observation of both the eyes is shown here. The ophthalmologist suspected a disorder and ordered for genetic testing, which revealed FBN1 gene mutation. Which of the following is true about the disorder and the protein involved?

Options

• A. The protein reduces TFG-Beta levels

• B. Alpha 2 agonists delay the progression of the disorder

• C. It is an autosomal recessive disorder

• D. The protein involved reduces the elasticity of tissues normally

• Autosomal dominant condition.

• Chromosome affected: 
• Chromosome 15

• Gene affected: 
• FBN1 gene (Fibrillin 1 gene defect)

Fibrillin protein:

• Forms microfibrils in connective tissue.

• Normally reduces TGF beta levels
• TGF β causes necrosis

• With elastin:
• forming scaffolding for elastin
• Increases elasticity
• In Lungs

• Without elastin:
• Increases tensile strength
• In Bone, Tendon, Suspensory Ligament of Linn (Eyes)

Pathophysiology:

• Fibrillin protein ↓↓
• Elasticity, tensile strength ↓↓
• ↑↑ TGF β

• Loss of elasticity:
• Lung gets expanded
• Lung bullae and pneumothorax.
• root of blood vessels.
• Aortic regurgitation and mitral valve prolapse.

• Increased TGF beta levels cause:
• Cystic medial necrosis.
• Dissection of the aorta.

• Loss of tensile strength causes:
• Arachnodactyly
• B/L superotemporal dislocation of the lens.

Clinical Features:

• Mnemonic: MARFANS
• M: Mitral valve prolapse 
• most common cardiac abnormality
• A: Aortic dissection 
• most common cause of death
• R: Retinal detachment
• F: Freely movable joints 
• most common joint: thumb joint
• A: Arachnodactyly 
• (spider-like long fingers, thumb coming out of palm); 
• High arched palate
• N: Nine feet tall (very tall individuals)
• S: Syndrome
• If "disease":
• Dislocation of the lens (Ectopia lentis)
• Direction: Superotemporal (upward and outward)
• Mnemonic: "fan is up, air goes out"
• Differential (opposite dislocation): 
• Homocystinuria (inferonasal)
• If "syndrome":
• Sternal deformity / Pigeon chested individuals

• Cardiovascular:
• Cystic medial necrosis of the aorta
• Aortic root aneurysm, rupture, or dissection
• Most common cause of death
• Mitral valve prolapse

• Lung:
• ↑ Risk of spontaneous pneumothorax

• Overall most common abnormality: 
• Skeletal abnormality 

• Specific Signs:
• Steinberg sign:
• Thumb coming out when folded in fist
• Mnemonic: Stain → Stick ur thumb out and stain it
• Walker sign:
• Little finger and thumb can hold the wrist
• Mnemonic: Walk around the wrist

---

Cause	Subluxation	ㅤ
Blunt trauma	• M/c cause	ㅤ
Marfan’s syndrome	• Superotemporal	FAN → Upper
Homocystinuria	• Inferonasal	URINE → Infero
Weill-Marchesani syndrome	• Anterior • Microspherophakia	March forward → Anterior

---

Revised Gent Criteria: Marfan Gentleman

1. Family history (autosomal dominant)

2. Clinical features 

3. Fibrillin 1 gene mutation

Management:

• Beta blockers or losartan
• reduce TGF beta levels.

Exceptions → Penetrance: 

• The percentage of individuals with a given genotype who express the associated phenotype.
• Example calculation:
• If 70 out of 100 people with the specific genotype are diseased,
• the penetrance is 70%.

Differences Between Homocysteinuria & Marfan's Syndrome

• Fair complexion
• Seen in Homocysteinuria
• Not in Marfans
• (differentiates from Marfan)

Miscellaneous Concepts

Barr Body / Davidson Body

• Definition: Inactive X chromosome in every female.

• Barr Body:
• Extra dot in buccal mucosa cell nucleus.

• Davidson Body:
• Drumstick-like projection in a neutrophil.

• Calculation: No. of Barr bodies = (Number of X chromosomes) - 1.
• Example: 48, XXXY → 3 X chromosomes → 3-1 = 2 Barr bodies.

Co-dominance

• Definition: Two genes expressed together simultaneously, both dominating.

• Examples: 
• AB blood group; 
• HLA gene.
• MHC