• a. Sandal gap (wide space / increased gap between 1st and 2nd toes).
• b. Trisomy 21 (Down syndrome).
• c. Yes (can be present as an isolated benign normal variant in healthy individuals).
• d. Amniotic band constriction / disruption sequence.

• a. Tongue fasciculation $\to$ 1. Spinal Muscular Atrophy (SMA)
• b. Gower sign $\to$ 3. Duchenne Muscular Dystrophy (DMD)
• c. Heliotrope rash $\to$ 2. Juvenile Dermatomyositis
• d. Non-thrombocytopenic purpura $\to$ 4. Henoch-Schönlein Purpura
• e. Thrombocytopenic purpura with eczema $\to$ 5. Wiskott-Aldrich Syndrome

• a. Linear Nevus Sebaceous Syndrome (Schimmelpenning-Feuerstein-Mims syndrome) / Epidermal Nevus Syndrome.
• b. Associated multisystem abnormalities:
  • CNS: Hemimegalencephaly, cortical dysplasia, intractable infantile seizures, intellectual disability, lateral ventriculomegaly.
  • Ophthalmologic: Colobomas (iris/choroid), strabismus, corneal vascularization, scleral choristomas, microphthalmia.
  • Skeletal: Craniofacial asymmetry, localized fibrous dysplasia, hypophosphatemic vitamin D-resistant rickets, kyphoscoliosis.
  • Cardiovascular: Coarctation of aorta, ventricular septal defect.
  • Renal: Horseshoe kidney, renal dysplasia.

• a. Trisomy 13 (Patau Syndrome), Female ($47,\text{XX},+13$).
• b. Characteristic clinical features:
  • Craniofacial / CNS: Holoprosencephaly, microcephaly, sloping forehead, microphthalmia/anophthalmia, coloboma, midline cleft lip and palate, low-set malformed ears.
  • Dermatologic / Extremities: Aplasia cutis congenita (scalp defects over parieto-occipital area), postaxial polydactyly, prominent calcaneus (rocker-bottom feet).
  • Cardiovascular (80%): VSD, PDA, ASD, dextrocardia.
  • Genitourinary: Bicornuate uterus (females), cryptorchidism (males), polycystic kidneys.
    (Note: >80% mortality within the first month of life).

Gene / Oncogene	Chromosomal Location	Associated Cancer / Tumor
RB1	13q14	Retinoblastoma, Osteosarcoma
APC	5q21	Familial Adenomatous Polyposis (FAP), Colorectal carcinoma
WT1	11p13	Wilms tumor, WAGR syndrome
BRCA1	17q21	Hereditary Breast and Ovarian Cancer
NF1	17q11.2	Neurofibromatosis type 1, Optic pathway glioma
NF2	22q12.2	Neurofibromatosis type 2, Bilateral vestibular schwannomas
N-MYC (MYCN)	2p24	Neuroblastoma
ABL1 (BCR-ABL)	9q34 (t(9;22))	Chronic Myeloid Leukemia (CML), B-ALL (Philadelphia chromosome)
PML-RARA	17q21 (t(15;17))	Acute Promyelocytic Leukemia (APL, AML M3)
RET	10q11.2	MEN 2A, MEN 2B, Medullary Thyroid Carcinoma
SIS (PDGFB)	22q12.3	Dermatofibrosarcoma protuberans, Glioblastoma / Glioma

• a. Mitochondrial (Maternal) Inheritance.
  • Explanation: All offspring of an affected female inherit the trait/disease, regardless of sex. Affected males never transmit the disorder to any of their children.
• b. Mechanism: The human ovum contains abundant cytoplasm and mitochondria (along with circular mitochondrial DNA), whereas sperm mitochondria located in the tail/midpiece are destroyed upon fertilization. Hence, all mitochondrial DNA is exclusively maternally inherited.
• c. Examples:
  • 1. Leber's Hereditary Optic Neuropathy (LHON)
  • 2. Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes (MELAS)
  • 3. Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
  • 4. Leigh syndrome (subacute necrotizing encephalopathy)

• a. Autosomal Dominant Inheritance (Vertical transmission across successive generations without skipping, equal male and female involvement, transmission from affected parent to ~50% of offspring).
• b. Examples:
  • 1. Neurofibromatosis type 1 (NF-1)
  • 2. Tuberous Sclerosis
  • 3. Marfan syndrome
  • 4. Achondroplasia
  • 5. Hereditary Spherocytosis
• c. Pedigree representation of monozygotic twins:

• a. X-Linked Recessive Inheritance (Diagonal transmission: unaffected carrier females transmit the disease to 50% of sons; affected males do not transmit to sons but all daughters become obligate carriers).
• b. Examples:
  • 1. Duchenne Muscular Dystrophy (DMD) / Becker Muscular Dystrophy
  • 2. Hemophilia A and B
  • 3. Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency
  • 4. Fragile X syndrome (X-linked dominant with reduced penetrance) / Menkes disease
  • 5. X-linked Adrenoleukodystrophy
• c. For a carrier mother ($X^A{X}^a$):
  • 50% risk for each male child to be affected.
  • 50% chance for each female child to be an asymptomatic carrier (Overall 25% risk per pregnancy of having an affected child).

• a. First-degree relationship / incest (Brother–sister mating; coefficient of relationship $r=1/2$).
• b. First-degree relationship / incest (Parent–offspring mating; $r=1/2$).
• c. Second-degree consanguinity (Uncle–niece or Aunt–nephew mating; $r=1/4$).
• d. Second-degree relationship (Half-siblings mating; $r=1/4$).
• e. Third-degree consanguinity (First cousins mating: children of brother and sister; $r=1/8$).

• a. Multifactorial / Polygenic Inheritance (Interaction of multiple minor additive genes with environmental factors).
• b. Examples:
  • 1. Neural Tube Defects (Anencephaly, Spina bifida)
  • 2. Cleft lip with or without cleft palate
  • 3. Congenital hypertrophic pyloric stenosis
  • 4. Congenital heart defects (isolated VSD, ASD)
  • 5. Hirschsprung disease / Clubfoot (talipes equinovarus)
• c. Recurrence risk after 1 affected child: 3% to 5%.
• d. Recurrence risk after 2 affected children: 10% to 12%.

• a. Distinguishing features:
  • 1. Sex and inheritance: The infant is female (Hurler is Autosomal Recessive; Hunter syndrome is X-Linked Recessive and affects almost exclusively males).
  • 2. Corneal clouding: Corneal clouding is characteristically PRESENT in Hurler syndrome (MPS I) and ABSENT in Hunter syndrome (MPS II).
• b. Diagnostic evaluation:
  • 1. Urine screening for glycosaminoglycans (GAGs): elevated dermatan sulfate and heparan sulfate.
  • 2. Skeletal survey: features of Dysostosis Multiplex (hooked anterior lumbar vertebrae / anterior beaking, spatulate ribs, claw hand deformity).
  • 3. Specific enzyme assay in leukocytes/plasma: severe deficiency of $\alpha$-L-iduronidase (confirmatory).
  • 4. Molecular genetic testing for IDUA gene mutations.
• c. Treatment modalities:
  • 1. Enzyme Replacement Therapy (ERT): Recombinant human $\alpha$-L-iduronidase (Laronidase / Aldurazyme).
  • 2. Hematopoietic Stem Cell Transplantation (HSCT / Bone Marrow Transplant): Curative if performed early (<2 years of age before significant neurocognitive decline).

• a. Autosomal Recessive Inheritance (Horizontal transmission: affected individuals usually in a single sibship of healthy carrier parents, high association with parental consanguinity, equal male and female ratio).
• b. 25% (1 in 4) recurrence risk in each pregnancy.
• c. ii. Niemann-Pick disease (G6PD is X-linked recessive; Meningomyelocele is multifactorial; Tuberous sclerosis is autosomal dominant).

• a. Achondroplasia $\to$ Autosomal Dominant
• b. Hemophilia B $\to$ X-Linked Recessive
• c. Congenital adrenal hyperplasia $\to$ Autosomal Recessive
• d. G6PD deficiency $\to$ X-Linked Recessive
• e. Sickle cell disease $\to$ Autosomal Recessive
• f. Hemophilia A $\to$ X-Linked Recessive
• g. Phenylketonuria $\to$ Autosomal Recessive
• h. Duchenne muscular dystrophy $\to$ X-Linked Recessive
• i. Marfan syndrome $\to$ Autosomal Dominant
• j. Huntington's disease $\to$ Autosomal Dominant
• k. Neurofibromatosis type 1 $\to$ Autosomal Dominant

• a. Consanguineous marriage / relationship (double horizontal bar).
• b. Monozygotic (identical) twins (diagonal lines joined by a horizontal bar).
• c. Dizygotic (fraternal) twins (diagonal lines originating from a common point without horizontal bar).
• d. Proband / Index case (indicated by an arrow pointing to the affected individual).
• e. Stillbirth (symbol with a horizontal strike / diagonal line through shape).
• f. Spontaneous abortion / Miscarriage (small filled or unfilled triangle).

• a. Autosomal Dominant Inheritance.
• b. 50% (1 in 2) risk of transmission to each child.
• c. No (in fully penetrant autosomal dominant traits, unaffected individuals do not carry the gene and cannot transmit it; exceptions include non-penetrance or germline mosaicism).
• d. i. Noonan syndrome (Galactosemia is autosomal recessive; Diabetes is multifactorial; Hypophosphatemic rickets is X-linked dominant).

• a. Edwards Syndrome (Trisomy 18).
• b. $47,\text{XY},+18$.
• c. Associated congenital heart diseases (>90% incidence):
  • 1. Ventricular Septal Defect (VSD)
  • 2. Patent Ductus Arteriosus (PDA)
  • 3. Polyvalvular disease / Atrial Septal Defect (ASD) / Coarctation of aorta.

• a. Turner Syndrome ($45,\text{X}$).
• b.
  • Cardiac: Bicuspid aortic valve (most common), Coarctation of the aorta, Aortic root dilation.
  • Renal: Horseshoe kidney (most common), double collecting system, pelvic kidney.
• c. Medical therapy:
  • 1. Recombinant Human Growth Hormone (rhGH): started early to optimize final adult height.
  • 2. Estrogen and Progesterone replacement therapy: to induce secondary sexual characteristics and maintain bone mineral density.
  • 3. Levothyroxine (for autoimmune hypothyroidism).
• d. Buccal smear for Barr body (shows absent Barr body, i.e., chromatin-negative; definitive test is chromosomal karyotype).
• e. Noonan Syndrome (Autosomal dominant condition with normal karyotype affecting both males and females).

• a.
  • Triple Test Components:
    • 1. Maternal Serum Alpha-Fetoprotein (MSAFP) $\to$ Low
    • 2. Unconjugated Estriol (${\text{uE}}_3$) $\to$ Low
    • 3. Human Chorionic Gonadotropin ($\beta \text{-hCG}$) $\to$ High
  • Screening Targets: Screens for Down syndrome (Trisomy 21), Edwards syndrome (Trisomy 18 - all 3 markers low), and Neural Tube Defects (elevated MSAFP).
• b. Second-trimester ultrasound soft markers for Down syndrome:
  • 1. Increased nuchal fold thickness ($\ge 6\text{ mm}$).
  • 2. Absent / hypoplastic nasal bone.
  • 3. Echogenic intracardiac focus (EICF) / Endocardial cushion defect (AV canal defect).
  • 4. Echogenic bowel, "double bubble" sign (duodenal atresia), short femur/humerus length, mild pyelectasis.
• c. Amniocentesis with fetal karyotyping / Chromosomal Microarray / QF-PCR (performed at 16–20 weeks).

• a. 1% (or maternal age-specific risk, whichever is higher, for free trisomy 21).
• b. 1% to 2% (or 2.5% when father is carrier; if mother is carrier of $t(14;21)$, recurrence risk is 10–15%; if either parent carries $t(21;21)$, recurrence risk is 100%).
• c. 95% of Down syndrome cases result from maternal meiotic non-disjunction ($4\mathrm{\%}$ Robertsonian translocation, $1\mathrm{\%}$ mosaicism).

• a. Fragile X Syndrome (Martin-Bell Syndrome).
• b. Molecular genetic testing: PCR and Southern blot analysis for FMR1 CGG trinucleotide repeat expansion (>200 repeats = full mutation).
• c. Chromosomal locus: Xq27.3 (FMR1 gene on the long arm of the X chromosome, causing transcriptional silencing and loss of FMRP protein).

• a. Malformation $\to$ 3. Primary intrinsic developmental arrest/defect (e.g., ventricular septal defect, cleft lip).
• b. Deformation $\to$ 1. Extrinsic mechanical force distorting normal tissue (e.g., oligohydramnios causing Potter sequence, uterine constraint causing clubfoot).
• c. Disruption $\to$ 4. Destruction/breakdown of previously normal tissue (e.g., amniotic band syndrome causing digital amputations).
• d. Dysplasia $\to$ 2. Abnormal cellular architecture/histogenesis throughout a tissue (e.g., skeletal dysplasia, polycystic kidney disease).

• a. Syndrome $\to$ Trisomy 21 (Down syndrome) / Fetal alcohol syndrome
• b. Sequence $\to$ Pierre Robin sequence / Potter sequence
• c. Association $\to$ VACTERL association / CHARGE association

Definitions:

• Syndrome: A recognizable pattern of multiple congenital anomalies causally related by a single defined etiology.
• Sequence: A cascade of secondary and tertiary structural anomalies all arising from a single primary localized embryonic defect (e.g., Micrognathia $\to$ Glossoptosis $\to$ Cleft palate in Pierre Robin).
• Association: A non-random statistical co-occurrence of multiple congenital anomalies not explainable by a single sequence or syndrome (Vertebral, Anal, Cardiac, Tracheoesophageal, Renal, Limb).

• a. Klinefelter Syndrome ($47,\text{XXY}$).
• b. Salient features:
  • 1. Small, firm testes ($<4\text{ mL}$) with hypergonadotropic hypogonadism (infertility/azoospermia).
  • 2. Bilateral gynecomastia (increased risk of male breast carcinoma).
  • 3. Sparse facial/body hair and female escutcheon.
  • 4. Learning disabilities, speech delay, psychosocial and behavioral challenges.
• c. Tall stature with eunuchoid proportions (disproportionately long legs, decreased Upper Segment to Lower Segment ratio, and arm span exceeding height).

• a. No (An affected father passes his Y chromosome to his sons; all sons are completely normal and cannot inherit hemophilia from him).
• b. The daughter is an obligate carrier ($X^H{X}^h$). When she marries a normal man:
  • Each son has a 50% risk of having hemophilia.
  • Each daughter has a 50% chance of being a carrier (none will be affected).
  • Overall risk of an affected child per pregnancy is 25%.
• c. First-trimester prenatal diagnosis: Chorionic Villus Sampling (CVS) at 10–13 weeks of gestation followed by fetal DNA mutation analysis (e.g., Factor VIII gene inversion/mutation testing via PCR).

• a. Lymphedema of the dorsum of hands and feet, redundant loose nuchal skin folds (pterygium colli / webbed neck), and low posterior hairline.
• b. Cardiac: Bicuspid aortic valve and Coarctation of the aorta.
• c. Endocrine: Primary ovarian insufficiency (hypergonadotropic hypogonadism), Autoimmune Hashimoto's hypothyroidism, and Type 2 diabetes mellitus.
• d. GI: Celiac disease, inflammatory bowel disease, and gastrointestinal telangiectasias/bleeding.
• e. Hormones:
  • 1. Recombinant human Growth Hormone (rhGH)
  • 2. Estrogen (low-dose 17$\beta$-estradiol)
  • 3. Progesterone (cyclical after 2 years of estrogen)
  • 4. Levothyroxine (if hypothyroid)
• f. Skeletal: Short 4th metacarpal/metatarsal bones, cubitus valgus, Madelung deformity of wrist, high-arched palate, and scoliosis.

• a. Atlantoaxial joint (C1–C2): Screen for Atlantoaxial Instability (AAI) (anterior atlanto-dens interval $>4.5\text{–}5\text{ mm}$ on cervical flexion-extension radiographs) because hyperlaxity risks subluxation, spinal cord compression, quadriplegia, and death.
• b. Thyroid function tests (Free T4 and TSH) to screen for treatable acquired autoimmune hypothyroidism.
• c.
  • 1. Complete Blood Count with peripheral smear: surveillance for transient myeloproliferative disorder (TMD), acute megakaryoblastic leukemia (AML-M7), and B-ALL.
  • 2. TSH and anti-tTG IgA serology: annual surveillance for hypothyroidism and celiac disease.
• d. Cytogenetic elaboration:
  • 46: Total number of chromosomes.
  • XY: Sex chromosomes (genetically male).
  • t: Reciprocal translocation.
  • (4;8): Chromosomes involved in the translocation (chromosome 4 and chromosome 8).
  • (p21;q22): Specific breakpoints on the chromosomes: band 21 on short arm (p) of chromosome 4, and band 22 on long arm (q) of chromosome 8.

• a. WAGR Syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, and Range of developmental delays).
• b. Contiguous gene deletion / microdeletion at 11p13 (involving contiguous loss of PAX6 and WT1 genes).
• c. Components of WAGR:
  • W: Wilms tumor (nephroblastoma).
  • A: Aniridia (congenital absence of iris).
  • G: Genitourinary anomalies (cryptorchidism, ambiguous genitalia, streak ovaries).
  • R: Retardation (intellectual disability / developmental delay).
• d. Other Wilms tumor syndromes:
  • 1. Beckwith-Wiedemann Syndrome (BWS) (11p15.5)
  • 2. Denys-Drash Syndrome (DDS) (WT1 point mutation: Wilms tumor, diffuse mesangial sclerosis, male pseudohermaphroditism)
  • 3. Simpson-Golabi-Behmel syndrome / Perlman syndrome.

• a. Achondroplasia.
• b. Autosomal Dominant (approx. 80% arise as de novo mutations associated with advanced paternal age).
• c. Normal IQ / normal intelligence.
• d. Vertebral complications:
  • Infancy: Foramen magnum stenosis leading to cervicomedullary compression, central sleep apnea, hypotonia, and sudden infant death.
  • Childhood/Adulthood: Lumbar spinal canal stenosis (due to narrowing interpedicular distances) causing neurogenic claudication, root compression, paraparesis, and thoracolumbar kyphosis.
• e. Rhizomelic micromelia (proximal limb segment shortening: humerus and femur shorter than forearms and shins).
• f. Chromosome 4p16.3 (FGFR3 gene: Fibroblast Growth Factor Receptor 3; >98% due to G380R point mutation).

• a. Germline mosaicism $\to$ 3. Mutation in germline progenitor cells of an unaffected parent (causes disease recurrence in siblings, e.g., Osteogenesis imperfecta, DMD).
• b. Reduced penetrance $\to$ 1. Proportion of individuals with a genotype who express the phenotype (e.g., Retinoblastoma with 90% penetrance).
• c. Variable expressivity $\to$ 5. Degree of clinical severity differs among individuals with the same genotype (e.g., Neurofibromatosis type 1, Tuberous sclerosis).
• d. Anticipation $\to$ 2. Earlier onset and increased severity in successive generations due to unstable trinucleotide repeat expansion (e.g., Huntington's, Myotonic dystrophy).
• e. Non-paternity $\to$ 4. Apparent genetic conflict arising because the assumed father is not the biological parent.

Disease	Gene / Location	Repeat Sequence
a. Myotonic Dystrophy (DM1)	DMPK (3' UTR)	CTG
b. Friedreich's Ataxia	FXN (Intron 1)	GAA
c. Fragile X Syndrome	FMR1 (5' UTR)	CGG
d. Huntington's Disease	HTT (Exon 1 / Polyglutamine)	CAG

• a. Cri-du-chat Syndrome (5p- syndrome), Female ($46,\text{XX},\text{del}(5\text{p})$).
• b. High-pitched, kitten-like / cat-like cry (due to laryngeal hypoplasia and abnormal vocal cord development), severe microcephaly, round "moon-like" face, hypertelorism, epicanthic folds, low-set ears, micrognathia, hypotonia, and severe intellectual disability.
• c. Most patients survive into adulthood with supportive medical care (normal or near-normal life expectancy).
• d. Terminal or interstitial deletion of the short arm of chromosome 5 (5p15).
• e. In approximately 80% to 85% of cases, the deleted chromosome is of paternal origin (de novo during spermatogenesis).

• a. Beckwith-Wiedemann Syndrome (BWS) (Overgrowth syndrome).
• b. Classical components:
  • 1. Macroglossia (large protruding tongue).
  • 2. Macrosomia / Somatic overgrowth and Hemihypertrophy (asymmetric growth of limbs/body).
  • 3. Abdominal wall defects (Omphalocele, umbilical hernia, diastasis recti).
  • 4. Neonatal hypoglycemia (due to pancreatic islet cell hyperplasia / hyperinsulinism).
  • 5. Anterior ear lobe creases and posterior helical indentations/pits.
• c. Chromosome 11p15.5 (imprinting center defects involving IGF2, H19, and CDKN1C genes).
• d. Embryonal pediatric tumors:
  • 1. Wilms tumor (Nephroblastoma) (most common)
  • 2. Hepatoblastoma
  • 3. Adrenocortical carcinoma, Neuroblastoma, Rhabdomyosarcoma.
       (Requires abdominal USG every 3 months until age 8 and serum alpha-fetoprotein every 3 months until age 4).