Final Distilling of Conditions from Unit 2

Sickle Cell Disease

Pathophysiology, system affected : Sickled RBCs lead to impaired oxygen delivery function due to defective B hemoglobin

Symptoms: acute chest syndrome, vaso-occulsive crises pain, high WBC counts

Treatment: hydroxyurea, endari, crizanlizumab, transfusions, GT available but expensive

Genes: HBB

Clinical Criteria and testing : hemoglobin electrophoresis

Molecular testing strategy : targeted testing of point mutation in the 6th codon of the B globin gene

Other notes: other types of sickle cell possible like SC, SB+, SBo, along with SS

Beta-Thalassemia

Symptoms : variable presentation with overall fatigue, jaundice, ex. intolerance, skeletal abnormalities, hepato/splenomegaly

Treatment : chronic transfusions and iron chelation therapy w/

Genes : HBB : codon 26 missense mutation leading to loss of protein function

Clinical Criteria and testing : not mentioned

Molecular testing strategy : HBB gene sequencing

Other notes : also think of Hem E, hair on end appearance of skull on X-ray + facies

Alpha-Thalassemia 

Symptoms :

• trait and silent nothing typically (1-2 del)

• Hemoglobin H disease (3 del) - anemia with fatigue, enlarged liver and spleen, jaundice, poor growth

• Hb barts (4del) - perinatal lethal with hepatosplenomegaly and extreme anemia

Treatment : HbH disease is mostly focused on chronic transfusions, Hb barts is incompatible with life

Genes : HBA1 and HBA2

Clinical Criteria and testing :not really discussed

Molecular testing strategy : assess HBA1/2 for dels/constant spring mutations

Other notes : special considerations for inheritance given the digenic nature of the condition (cis or trans for silent carriers is consideration)

Hypohidrotic ED

Symptoms : lack of hair, sweat, dental abnormalities, prominent forehead, NORMAL Intellectual ability

Treatment : temperature regulation/sweat gland mgmt, dental and oral rehab, surgery if indicated

Genes : all XL AR AD - EDA, EDAR, EDARADD, WNT10A

Clinical Criteria and testing : not extensively discussed

Molecular testing strategy : sequence of genes above

Other notes : also consider SSPS with characteristic eyelid findings and OODD with characteristic complete tooth agenesis. Also WNT10A but HYPERHIDROSIS

Ectrodactyly-Ectodermal Dysplasia Cleft Syndrome (EEC)

Symptoms : missing fingers or toes, facial clefts, skin and hair diffs, pitted nails, abnormal tear ducts, normal intellectual ability

Treatment : temperature regulation/sweat gland mgmt, dental and oral rehab, surgery if indicated

Genes : AD, high de novo at 70%. TP63

Clinical Criteria and testing : not applicable

Molecular testing strategy : seq

Other notes :

Hidrotic Ectodermal Dysplasia

Symptoms : abnormalitiers of hair nails skin, thick skin over palms of hands and feet, join hyperpigmentation, NO SWEATING ISSUES

Treatment : temperature regulation/sweat gland mgmt, dental and oral rehab, surgery if indicated

Genes : GJB6 AD

Clinical Criteria and testing : not applicable

Molecular testing strategy : seq

Other notes :

Epidermolysis Bullosa Simplex

Pathophysiology, system affected : Keratins at the epidermal layer breaks down leading to symptoms

Onset : @ birth or before 18mo

Symptoms :nail dystrophy, blistering, natal teeth w/ no significant mortality

Treatment : minimize skin trauma, aluminum chloride to reduce sweating and blisters, moisturizing

Genes : KRT14, KRT5 (AD)

Clinical Criteria and testing : n/.a

Molecular testing strategy : testing the above genes seq

Other notes : least morbid of the EBs

Epidermolysis Bullosa Dystrophic

Pathophysiology, system affected : basement layer of skin collagen is affected leading to dystrohy, dermis and epidermis anchoring disruption

Onset : birth or infancy (rarely adol. or adulthood)

Symptoms : blisters, nail involvement, lingual papilae absence, pseudosyndac. INCREASED SQUAMOUS CELL CARC. risk

Treatment : minimize skin trauma, aluminum chloride to reduce sweating and blisters, moisturizing

Genes : COL7A1 AD

Clinical Criteria and testing : n/a

Molecular testing strategy : testing the above genes seq

Other notes : 2nd least morbid of the EBs

Epidermolysis Bullosa Junctional

Pathophysiology, system affected : junctional skin layer leading to a disruption of the connection between basement layer and epidermis

Onset : present at birth, sometimes localized in early childhood

Symptoms : blisters, nail involvement,significant oral membrane involvement, 73% infant mortality rate for generalized severe form

Treatment : minimize skin trauma, aluminum chloride to reduce sweating and blisters, moisturizing, avoidance of adhesive bandages

Genes : LAMB3 COL7A1 (AD)

Clinical Criteria and testing : n/a

Molecular testing strategy : testing the above genes seq

Other notes : most morbid of the EBs

Cylindromatosis

Pathophysiology, system affected : TNFa and NF-kB paths disrupted leading to cell hyperproliferation and neoplasm

Onset : progressive over lifetime

Symptoms : neoplasm skin appendages

Treatment : not discussed

Genes : CYLD loss

Clinical Criteria and testing : not discussed

Molecular testing strategy : CYLD seq

Other notes : know as a “mimic” of NF1 and NFKB pathway but unlikely to appear

Hemophilia A

Pathophysiology, system affected : SECONDARY HEMOSTASIS Low Factor VIII - prevents proper clotting but platelet plug is ok

Onset : from birth

Symptoms : bleeding phenotype with variable severity depending on genetic change, occurs after trauma, surgical intervention, etc.

Treatment : prophylaxis and controlling acute bleeds : IV clotting factor, Emicizumab subcutaneous for F8 mimic, Despopressin to increase vW F8, GT avbailable but expensive

Genes : F8 XL

Clinical Criteria and testing : women w/ <40% factor levels are diagnosed with same severity classification as men.

Molecular testing strategy : F8 is very large, test cascade goes : Intron 22 inversion (most severe), intron 1 inversion, point mutations, del/dups

Other notes : nothing else

Hemophilia B

Pathophysiology, system affected : SECONDARY HEMOSTASIS Low Factor IX - prevents proper clotting but platelet plug is ok

Onset : progressive over lifetime

Symptoms : bleeding phenotype with variable severity depending on genetic change, VERY highly variable due to lots of different effects due to different point mutations

Treatment : prophylaxis and controlling acute bleeds : IV clotting factor, Emicizumab subcutaneous for F8 mimic, Despopressin to increase vW F8, GT avbailable but expensive

Genes : F9 XL

Clinical Criteria and testing : women w/ <40% factor levels are diagnosed with same severity classification as men.

Molecular testing strategy : not as big as F8, familial variant seq or just straight NGS of F9

Other notes :

Von Willebrand disease (VWD) T1

Pathophysiology, system affected : primary hemostasis defects, plug can’t form, quantitative

Onset : from birth

Symptoms : prolonged mucocutaneous bleeding, menstrual bleeding, oral mucosa, GI bleeding

Treatment : desmopressin, antifibrinolytics, vW factor concentrate, NSAID avoidance

Genes : AD variable genes

Clinical Criteria and testing : <30% vW factor w/30-50% bleeding symptoms

Molecular testing strategy : sequencing

Other notes : 1C : accelerated vWF clearance

Von Willebrand disease (VWD) T2

Pathophysiology, system affected : primary hemostasis defects, plug can’t form, qualitative

Onset : from birth

Symptoms : prolonged mucocutaneous bleeding, menstrual bleeding, oral mucosa, GI bleeding, variability in presentation

Treatment : desmopressin (NOT IN 2B), antifibrinolytics, vW factor concentrate, NSAID avoidance

Genes : AD variable genes, AR (2N only)

Clinical Criteria and testing : <30% vW factor w/30-50% bleeding symptoms

Molecular testing strategy : sequencing

Other notes : descending severity

• 2A - defect in VWF no platelet plug

• 2B - VWF binds to platelets in bloodstream but not injury site

• 2M - no platelet binding at all

• 2N - rapid FVIII clearance due to no vWF, secondary hemo

Von Willebrand disease (VWD) T3

Pathophysiology, system affected : primary hemostasis defects, plug can’t form, quantitative

Onset : from birth

Symptoms : prolonged mucocutaneous bleeding, menstrual bleeding, oral mucosa, GI bleeding, variability in presentation

Treatment : desmopressin, antifibrinolytics, vW factor concentrate, NSAID avoidance

Genes : AD variable genes, AR (2N only)

Clinical Criteria and testing : <30% vW factor w/30-50% bleeding symptoms

Molecular testing strategy : sequencing

Other notes : descending severity

• T3 very rare very severe with almost no FVIII presence hem A phenocopy

Thrombophilia

Pathophysiology, system affected : inherited predisposition to clotting (VTEs) like PEs, DVTs

Onset : from birth

Symptoms : excess clotting leading to VTEs

Treatment : blood thinning and clot clearance

Genes : Protein C, antithrombin, Protein S genes

Clinical Criteria and testing : prothrombin, thrombin time (TT), fibrinogen activity

Molecular testing strategy : sequencing

Other notes :

Factor V Leiden 

Pathophysiology, system affected : protein C resistance leading to slightly decreased efficacy for factor V

Onset : from birth

Symptoms : excess clotting leading to VTEs

Treatment : none really

Genes : FV DNA analysis for the c.1601G>A change

Clinical Criteria and testing : prothrombin, thrombin time (TT), fibrinogen activity

Molecular testing strategy : sequencing for above var

Other notes : generally very mild with no need for anticoagulant treatment. Most common inherited thrombophilia with 3-15% in european pops

Pendred

Pathophysiology, system affected : SNHL hearing, unilateral or bilateral

Onset : childhood/adol

Symptoms : enalrged vestibular aqueducts, sensorineural, euthyroid goiter

Treatment:

Genes : SLC26A4, FOXI1, KCNJ10 (AR)

Clinical Criteria and testing : hearing testing, growths visible on mri

Molecular testing strategy : gene seq

Other notes :

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Waardenburg

Pathophysiology, system affected : neural crest malformation and SNHL

Onset : from birth

Symptoms : white forelock, blue iris, 60% experience SNHL, abnormalities of the iris, hirchsprung disease

Treatment :

Genes : PAX3, EDN3, EDNRB (AD, AR)

Clinical Criteria and testing :

Molecular testing strategy :

Other notes :

Connexin related hearing loss

Pathophysiology, system affected : NSHL due to loss of connexins

Onset : prelingual to postlingual, variable severity

Symptoms : severe to profound, bilat congenital SNHL

Treatment :

Genes : GLB2/GJB6 (AR)

Clinical Criteria and testing :

Molecular testing strategy :

Other notes

DFNX2 (X linked non-syndromic)

Pathophysiology, system affected :

Onset :

Symptoms : nonsyndromic sensorineural hearing loss

Treatment :

Genes : POU3FA, X-linked nonsyndromic

Clinical Criteria and testing :

Molecular testing strategy :

Other notes :

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DFN16 (moderate autosomal recessive hearing loss)

Pathophysiology, system affected : stereociliary effects leading to SNHL

Onset :

Symptoms : nonsyndromic sensorineural mild to moderate hearing loss

Treatment :

Genes : STRC (AR)

Clinical Criteria and testing :

Molecular testing strategy :

Other notes :

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Alport

Pathophysiology, system affected : degraded collagen tIV leading to SNHL

Onset :

Symptoms : syndromic sensorineural mild to moderate hearing loss with very high variability. Kidney diagnosis

Treatment :

Genes : XL, AD, AR, many genes. COL4A3, COL4A5 (maj 80%), etc.

Clinical Criteria and testing :

Molecular testing strategy : sequence the gene

Other notes :

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Stickler

Pathophysiology, system affected :

Onset :

Symptoms: AD with many allelic disorders, HL might be SNHL or mixed/conductive

Treatment :

Genes :

Clinical Criteria and testing :

Molecular testing strategy :

Other notes :

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Usher Type 1

Pathophysiology, system affected : combination of SNHL and Retinitis Pigmentosa

Onset : birth, extremely profound congenital

Symptoms: vestibular hypofunction leading to significant motor delay, infants dont walk before 18mo. RP

Treatment:

Genes : MY07A, USH1C (AR)

Clinical Criteria and testing :

Molecular testing strategy : seq the genes

Other notes :

Usher Type 2

Pathophysiology, system affected : combination of SNHL and Retinitis Pigmentosa

Onset : congenital, moderate to severe

Symptoms: normal vestibular function. onset of RP in the 2nd decade on average

Treatment:

Genes : USH2A (AR)

Clinical Criteria and testing :

Molecular testing strategy : seq the genes

Other notes :

Usher Type 3

Pathophysiology, system affected : combination of SNHL and Retinitis Pigmentosa, ciliary

Onset : postlingual, variable

Symptoms: variable RP and vestibular defects

Treatment:

Genes : CLRN1 (AR)

Clinical Criteria and testing :

Molecular testing strategy : seq the genes

Other notes :

STRC

Pathophysiology, system affected :

Onset : birth, congenital and profound

Symptoms : nonsyndromic sensorineural hearing loss

Treatment :

Genes : CATSPER2-STRC

Clinical Criteria and testing :

Molecular testing strategy :

Other notes :

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HHT T1

Pathophysiology, system affected : endoglin affected

Onset : lifetime

Symptoms : pulmonary and vascular AVMs

Treatment :

Genes : ENG

Clinical Criteria and testing : curacao criteria - Recurrent epistaxis (nosebleeds)

• Multiple mucocutaneous telangiectasis in characteristic locations (lip, oral cavity, fingers, nose)

• Visceral arteriovenous malformations (AVMs). Typically pulmonary, cerebral, hepatic, spinal, gastrointestinal

• First-degree relative with HHT diagnosed according to the Curaçao criteria

Molecular testing strategy :

Other notes :

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HHT T2

Pathophysiology, system affected : ALK1 affected

Onset : lifetime

Symptoms : Liver AVMs

Treatment :

Genes : ALK1

Clinical Criteria and testing :curacao criteria - Recurrent epistaxis (nosebleeds)

• Multiple mucocutaneous telangiectasis in characteristic locations (lip, oral cavity, fingers, nose)

• Visceral arteriovenous malformations (AVMs). Typically pulmonary, cerebral, hepatic, spinal, gastrointestinal

• First-degree relative with HHT diagnosed according to the Curaçao criteria

Molecular testing strategy :

Other notes :

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PTEN

Pathophysiology, system affected :

Onset : lifetime

Symptoms : macrocephaly, cancer risk

Treatment :

Genes : PTEN AD

Clinical Criteria and testing :curacao criteria - Recurrent epistaxis (nosebleeds)

• Multiple mucocutaneous telangiectasis in characteristic locations (lip, oral cavity, fingers, nose)

• Visceral arteriovenous malformations (AVMs). Typically pulmonary, cerebral, hepatic, spinal, gastrointestinal

• First-degree relative with HHT diagnosed according to the Curaçao criteria

Molecular testing strategy :

Other notes :

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Bannayan-Riley-Ruvalcabe

Pathophysiology, system affected :

Onset : Pediatric / Childhood

Symptoms : LOW TO MODERATE cancer risk, Macrocephaly (striking/universal, ~90%+), glans penis pigmentation High prevalence of juvenile hamartomatous polyps

Treatment :

Genes : PTEN AD

Clinical Criteria and testing : ngs panel

Molecular testing strategy :

Other notes :

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PIK3CA

honestly just know this gene as related to overgrowth

cloves is congenital lipomatous asym., vasc. malformations, skeletal anomalies

MCAP (macroceph and broad over)

PRoteus asymmetirc vascular anomalies

CM-AVM

• RASA1 related mostly visceral?

retinitis pigmentosa

• rod cone disease w/ AR/XL/AD

• wes approach

Leber congenital amaurosis

Severe retinal dystrophy, often

noticed at birth or early childhood.

• Symptoms include:

• Signs of low vision/ not

tracking objects

• Franschetti oculo-digital sign

• Keratoconus

• Nystagmus

• Photophobia

AR : RPE65 (luxturna treatable), CEP290

AD : CRX

PAX6-Related Disorders

• WAGR

• PAX6 related. Wilms, aniridia, genitourinary signs, ID

45,X/46,XY Mixed Gonadal Dysgenesis

• Pathophysiology: Mosaic loss of Y chromosome; Reproductive/Endocrine.

• Onset: Congenital / Infancy.

• Symptoms: Ambiguous genitalia, asymmetric streak/dysplastic gonads, short stature, elevated gonadoblastoma risk.

• Treatment: Prophylactic gonadectomy, HRT, growth hormone, surgical repair.

• Genes: Mosaicism (45,X/46,XY).

• Clinical Criteria & Testing: Karyotype, pelvic imaging, serum AMH and testosterone.

• Molecular Strategy: G-banded karyotype, FISH, or Chromosomal Microarray (CMA).

• Other Notes: Presence of Y material in dysplastic gonads drives high tumor risk.

Complete 46,XY DSD (SRY Knockout / Swyer Syndrome)

• Pathophysiology: Inability to initiate testicular differentiation; Reproductive/Endocrine.

• Onset: Adolescence (primary amenorrhea).

• Symptoms: Phenotypic female, bilateral streak gonads, presence of uterus/tubes, elevated gonadoblastoma risk.

• Treatment: Bilateral gonadectomy, estrogen/progesterone HRT.

• Genes: SRY loss-of-function mutation or deletion (also NR5A1, MAP3K1).

• Clinical Criteria & Testing: 46,XY karyotype, hypergonadotropic hypogonadism, pelvic ultrasound (uterus present).

• Molecular Strategy: SRY sequencing or DSD NGS panel, reflex MLPA/CMA.

• Other Notes: Uterus is functional; pregnancy is possible via donor egg IVF.

Partial 46,XY DSD (Partial Gonadal Dysgenesis)

• Pathophysiology: Partial impairment of testis determination/androgen production; Reproductive/Endocrine.

• Onset: Congenital / Neonatal.

• Symptoms: Ambiguous genitalia, dysplastic/streak gonads, partial Müllerian retention, variable puberty.

• Treatment: Multidisciplinary DSD care, HRT, elective genitoplasty, gonadal surveillance/removal.

• Genes: NR5A1, WT1, MAP3K1, SOX9, GATA4.

• Clinical Criteria & Testing: Ambiguous genitalia, low hCG-stimulated testosterone, low AMH, 46,XY karyotype.

• Molecular Strategy: DSD NGS panel, reflex MLPA/CMA or Whole Exome Sequencing (WES).

Partial 46,XY AIS (Partial Androgen Insensitivity Syndrome)

• Pathophysiology: Partial androgen receptor resistance despite normal testosterone production; Endocrine/Reproductive.

• Onset: Congenital or Adolescence.

• Symptoms: Ambiguous genitalia, micropenis, hypospadias, gynecomastia; functional testes present (no streak gonads).

• Treatment: High-dose androgen therapy, hypospadias repair, gynecomastia management.

• Genes: AR gene (X-linked).

• Clinical Criteria & Testing: Elevated testosterone + elevated LH, normal AMH, testes on ultrasound, 46,XY karyotype.

• Molecular Strategy: AR gene sequencing (NGS/Sanger) and MLPA.

• Other Notes: Normal gonadal histology (testes, not streak); undescended testes carry post-pubertal tumor risk.

46,XX / 46,XY CAH (Congenital Adrenal Hyperplasia)

• Pathophysiology: Adrenal enzyme defect altering steroidogenesis; Endocrine/Metabolic/Reproductive.

• Onset: Neonatal / Early Childhood.

• Symptoms:

  • 46,XX: Virilized ambiguous genitalia, normal ovaries/uterus (no streak gonads).

  • 46,XY: Normal or undervirilized genitalia, normal testes (no streak gonads).

  • Both: Risk of fatal salt-wasting adrenal crisis.

• Treatment: Hydrocortisone, fludrocortisone, stress-dosing, reconstructive surgery if needed.

• Genes: CYP21A2 (~95%), CYP11B1, HSD3B2 (Autosomal Recessive).

• Clinical Criteria & Testing: Elevated 17-OHP on newborn screen, electrolyte imbalance, normal gonads on ultrasound.

• Molecular Strategy: Targeted CYP21A2 analysis (NGS + MLPA) or adrenal NGS panel.

• Other Notes: Enzyme deficiency, not a chimerism condition; gonads develop normally.