"""
Inheritance Patterns - Mendel's Skin Show
| Pattern | Risk (Aff. Parent) | Risk (Carrier Parents) | Notes |
|---|---|---|---|
| AD | 50% | - | Vertical; M=F. E.g., NF1. 📌 "Dominant Dads & Moms pass to 50%". |
| AR | - | 25% | Horizontal; M=F. Consanguinity ↑. E.g., Albinism. 25% risk. |
| XLD | 50% (mother); 100% daughters (father) | - | No male-to-male. Aff. father $\rightarrow$ all daughters. E.g., IP. |
| XLR | - | 50% sons (carrier mother) | Males >> F. No male-to-male. E.g., Fabry. |
| Mito | 100% (mother) | - | Maternal. All offspring of aff. mother. E.g., Kearns-Sayre. |
- Mosaicism: $\geq 2$ cell lines/individual.
- Penetrance: % carriers show phenotype. (e.g., Incomplete)
- Expressivity: Variable phenotype, same genotype.
- Anticipation: Earlier onset / ↑ severity in generations.
- Pleiotropy: 1 gene, many effects.
⭐ AD: New mutations common; affected usually heterozygous. """
Keratin & Adhesion Defects - Faulty Scaffolding
-
Ichthyoses (Cornification Disorders):
- Vulgaris: FLG (filaggrin); fine scales, hyperlinear palms.
- X-linked: STS (steroid sulfatase); dark scales, "dirty neck".
- Lamellar: TGM1 (transglutaminase-1); collodion baby, ectropion.
- Epidermolytic Hyperkeratosis (EHK/Bullous CIE): KRT1/KRT10; birth blisters, then hyperkeratosis.
-
Epidermolysis Bullosa (EB) (Blistering Disorders): 📌 EB Layers Mnemonic: Simple Epidermis, Junctional Lamina Lucida, Dystrophic Dermis.
EB Type Protein (Gene) Level Inheritance Feature Simplex Keratin 5/14 (KRT5/14) Intraepidermal AD Non-scarring blisters Junctional Laminin-332 (LAMA3/B3/C2) Lamina Lucida AR Severe, high mortality Dystrophic Collagen VII (COL7A1) Sublamina Densa AD/AR Scarring, milia, mitten deformity Kindler Kindlin-1 (FERMT1) Multiple levels AR Blisters, poikiloderma, photosensitivity 
⭐ In Dystrophic EB, recurrent blistering and scarring can lead to pseudosyndactyly (mitten deformity) and an ↑ risk of squamous cell carcinoma.
Neurocutaneous & Pigmentary Syndromes - Brain-Skin Signals
| Syndrome | Gene(s) | Key Skin | Key Systemic/Eye |
|---|---|---|---|
| Neurofibromatosis 1 | NF1 | ≥6 Café-au-lait, Axillary freckling, Neurofibromas (≥2 or 1 plexiform) | ≥2 Lisch nodules, Optic glioma |
| Neurofibromatosis 2 | NF2 | Cutaneous schwannomas | Bilateral vestibular schwannomas (diagnostic), Meningiomas |
| Tuberous Sclerosis | TSC1/TSC2 | ≥3 Ash-leaf spots, Angiofibromas, Shagreen patch | Cortical dysplasias, SEGA, Renal AML |
- Pigmentary Disorders:
- Oculocutaneous Albinism (OCA): TYR (OCA1). ↓Melanin, nystagmus.
- Hermansky-Pudlak Syndrome: OCA + bleeding, lung fibrosis.
- Chediak-Higashi Syndrome: OCA + immunodeficiency, giant granules.
- Piebaldism: KIT gene. White forelock, stable depigmented patches.
- Waardenburg Syndrome: PAX3, MITF. White forelock, dystopia canthorum, deafness.
⭐ Bilateral vestibular schwannomas are diagnostic of Neurofibromatosis Type 2.
Genetic Testing & Counseling - Future Derm Maps
- Indications: Suspected genodermatosis, positive family history, pre-conception/prenatal queries.
- Testing Methods:
- Karyotyping, FISH, Chromosomal Microarray (CMA).
- Sanger sequencing (targeted genes).
- NGS: Whole Exome (WES) / Whole Genome (WGS) for diagnostic odysseys.
- Genetic Counseling:
- Core: Non-directiveness, risk assessment, psychosocial support.
- Includes prenatal diagnosis options (e.g., CVS, amniocentesis).
⭐ Whole Exome Sequencing (WES) is a high-yield NGS technique for identifying causative mutations in undiagnosed genodermatoses.
High‑Yield Points - ⚡ Biggest Takeaways
- Autosomal Dominant (AD): Common in NF1, Tuberous Sclerosis, Darier disease. Remember variable expressivity.
- Autosomal Recessive (AR): Key for Xeroderma Pigmentosum, Albinism, most Epidermolysis Bullosa (EB) types.
- X-linked Recessive: Includes Anhidrotic Ectodermal Dysplasia, Wiskott-Aldrich syndrome.
- X-linked Dominant: Incontinentia Pigmenti is a classic example.
- FLG (Filaggrin) gene: Mutations cause Ichthyosis Vulgaris and predispose to Atopic Dermatitis.
- KRT (Keratin) genes: Mutations lead to Epidermolysis Bullosa Simplex.
- Mosaicism explains some sporadic genodermatoses and varied presentations.
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