M2C Conditions

Kabuki Syndrome

• multiple genes (KMT2D)

• dominant de novo

• long palpebral fissures

• ID, heart defects, cleft palate, GI issues

• poor growth, endocrine abnormalities, feeding problems, hearing loss

Cornelia De Lange Syndrome (CDLS)

• most often dominant de novo

• multiple genes, most common is NIBPL

• extremely variable phenotype

• heart defects, hearing loss, genital anomalies, self-destructive behavior, feeding difficulties

Kleefstra Syndrome

• variant in EHMT1 or del of 9q34.3 (encompassing gene)

• seizures, behavioral changes after puberty (apathy + catatonia), heart/kidney/genital defects, severe respiratory infections

Fanconi Anemia

• autosomal recessive

  • biallelic pathogenic variants in genes within pathway

• radial chromosome

• bone marrow failure, skeletal defects, hypopigmentation, early cancer onset, renal/cardiac/GI/reproductive systems affected

Prader-Willi

• paternal loss of active material

• developmental delay

• failure to thrive + feeding problems folled by insatiable appetite as child/adult

• severe hypotonia

• short stature, obesity

• distinct facial features

Angelman

• maternal loss of active material

• ID

• ataxia

• seizures

• non-verbal

• happy disposition

• microcephaly

Prader-Willi/Angelman mechanism

• region on 15q11q13

• typically due to del of this entire region

• assumed to be de novo in child

• if you have a del, you will have either condition

• ch’s parent of origin determines which disorder

achondroplasia

• problem with cell signaling

• gain-of-function mutation

• FGFR3 receptor remains on, telling cartilage to turn into bone

noonan syndrome

• RASopathy

• structural abnormalities of the heart- pulmonary stenosis + hypertrophic cardiomyopathy common

• developmental delay, cafe au lait spots, short stature, kidney + urinary concerns, hypertelorism, impaired clot formation

androgen insensitivity syndrome

• non-functional version of the AR gene

  • AR gene not functional —> patients who are XY fail to fully develop male characteristics during development and puberty, and display female characteristics instead

• body doesn’t respond to androgens

• classified as complete, partial, or mild

• testes develop partially or fully + testosterone is produced normally

• may present with ambiguous genitalia, abnormal female puberty, absence of periods

Barth syndrome

• X-linked, affecting males

• nonfunctional tafazzin enzyme

  • gene TAFAZZIN encodes enzyme tafazzin, that helps synthesize and remodel the fatty acid chains into a specific shape/composition

  • correct cardiolipin isn’t formed

• dilated cardiomyopathy (heart failure and abnl heart rhythms)

• neutropenia (low WBCs)

• muscle weakness, growth delay

• elevation of 3-methylglutaconic acid in urine

Tay-Sachs disease

• babies born nl and regress, death around age 2

• lysosomal issue- malfunctioning HexA protein cannot break down sugar in ganglioside —> ganglioside accumulates in lysosome

• leads to cell death/malfunctioning

• recessive

• common in ashkenazi jewish population, but can arise in any pt

• progressive neurodegeneration