Genetics of Stature

  1. T/F: aneuploidy syndrome means that the mutation is an inherited chromosomal disorder that is usually autosomal recessive
    False; most is not inherited, the mutation occurs through nondisjunction during meiosis
  2. Monosomy X refers to _____ syndrome, affecting ___ (gender)
    • Turner
    • Females
  3. Short stature syndromes:
    • Tuner (Monosomy X)
    • Noonan Syndrome
    • Achondroplasia
    • Albright hereditary osteodystrophy (ASO)
  4. Turner syndrome chromosomal mutation is ______
    Females with only one X chromosome
  5. Clinical presentation of Monosomy X:
    • Webbed neck
    • Wide spaced nipples
    • Low hairline
    • Heart and skeletal defects
  6. What is the pseudoautosomal regions of X and Y chromosome?
    • PAR 1 and PAR 2
    • They behave like an autosome and recombine during meiosis, so genes in this region can be inherited in an autosomal rather than a strictly sex-linked fashion
    • Basically, genes in this region escape female X-inactivation, which is why Turner syndrome (Monosomy X) actually manifest clinically
  7. What is the gene that is located in PAR 1 that contributes to Turner Syndrome features?
    SHOX (short stature homeobox-containing) – important in bone development and growth
  8. Males have ____ (quantity) PAR gene(s), and females of _____ PAR gene(s). Those with Turner Syndrome have ______ gene(s)
    • 2
    • 2
    • 1; haploinsufficiency of SHOX gene
  9. T/F: Turner syndrome has excessive expression of SHOX, a gene located in PAR 1 on sex chromosomes
    False; turner syndrome has haploinsufficiency SHOX (one missing; SHOX is responsible for bone development and growth). Klinefelter has an excessive expression of SHOX, as there at least an extra X chromosome there
  10. Tall stature syndromes:
    • Klinefelter syndrome (XXY)
    • Beckwith-Wiedemann Syndrome (BWS)
    • Marfan Syndrome
  11. Klinefelter is a(n) _____ chromosomal condition with karyotype _____, affecting ______, resulting in ____ stature.
    • Sex chromosome
    • XXY
    • Males
    • Tall
  12. Which chromosomal condition results in males with feminine body pattern, i.e: broad hips, narrow shoulders, sparse body hair, gynecomastia
    • Klinefelter syndrome (XXY).
    • Also small testes, absent spermatogenesis, androgen deficiency, obesity, diabetes and autoimmune disorders
  13. T/F: Extra X chromosomes in Klinefelter syndrome derives equally from paternal or maternal gamete that formed the individual
  14. SHOX haploinsufficiency is seen in ____ syndrome, excessive SHOX is seen in _____ syndrome
    • Turner (short stature)
    • Klinefelter (tall stature)
  15. T/F: Noonan syndrome is X-linked recessive when inherited, but most are de novo
    False; noonan when inherited is Autosomal DOMINANT, but it’s true that most are de novo
  16. Which syndrome could lead to critical congenital heart disease, bleeding disorder, and children with 8-fold increase risk of leukemia or other cancer?
    Noonan syndrome
  17. T/F: like Turner’s, Noonan syndrome is short stature seen in females, just this one is an Autosomal dominant condition instead of a chromosomal condition
    False; Noonan can cause short stature in both males and females. It is Autosomal Dominant
  18. Noonan syndrome is due to disruption of _____ signaling pathway in 70% of cases, causing ______ (length of) activation of the pathway.
    • RAS-MAPK (gain of function)
    • Prolonged activation of pathway
  19. Which gene is mutated in 50% of Noonan syndrome and what is the name of the proto-oncogene that it encodes?
    Mutations in PTPN11 which encodes SHP-2 (proto-oncogene)
  20. Proto-Oncogene ______, which is encoded by ______, induces _____ (symptom) in half of Noonan syndrome cases
    • SHP-2
    • PTPN11
    • Growth retardation – which results in the short stature
  21. T/F: Achondroplasia is an autosomal dominant disorder that results in small head and torso but regular long bone length
    False; it is autosomal dominant, however it is short-limb dwarfism, which is short arms and legs (long-bones) but normal or enlarged head and normal torso
  22. What is the mutation in achondroplasia?
    • Chromosome 4, G380R (glycine to arginine mutation), affecting FGFR3 (fibroblast growth factor 3)
    • Problem converting cartilage into bone
  23. What is the function of FGFR3?
    • It is normally a negative regulator of long bone growth, which mean when it is on it stops long bone growth
    • Mutation seen in achondroplasia turns this receptor permanently on, which leads to severely shortened long bones
  24. FGFR3 ____ chondrocyte proliferation, _____ hypertrophy.
    • Decrease
    • Decrease
    • No new bone formation, (mutation seen in achondroplasia)
  25. T/F: Achondroplasia is autosomal dominant, usually heterozygous because if homozygous you’d be dead
  26. T/F: Achondroplasia is autosomal dominant but can be a de novo mutation as well, but if you get it from de novo mutation, you will not pass it down to your offspring
    False; it can be de novo, but if you get it de novo, your kids are at risk (50%) of getting it now too
  27. Albright hereditary osteodystrophy inheritance pattern?
    Autosomal Dominant, loss of function in GNAS gene
  28. What is GNAS gene? In which condition is this gene mutated in causing short stature?
    • GNAS codes for G protein that helps regulate activity and production of certain hormones and regulating bone development
    • Loss-of-function mutation is seen in Albright hereditary osteodystrophy (ASO)
  29. In Albright hereditary osteodystrophy, pseudo hypoparathyroidism type 1A is inherited from _______, pseudo pseudohypoparathyroidism (PPHP) is inherited from ______. Which one effects parathyroid an calcium level?
    • Mother – type 1A
    • Father – pseudo pseudo
    • Type 1A from mom results in the body not responding to parathyroid hormone causing low levels of calcium in bones and blood
  30. Clinical presentation of Albright hereditary osteodystrophy?
    • Obesity (Michelin baby!)
    • Round face
    • Short fingers and toes
    • Absent 4th knuckles
    • Short 4th metacarpals
  31. Which condition is a result from an imbalance in the expression of imprinted genes in the 11p15 region, leading to overgrowth?
    Beckwith-Widemann syndrome
  32. Beckwith-Widemann syndrome clinical presentation:
    • Large infant, larger than peer during childhood
    • Some children with opening in the wall of the abdomen that lets the organs to protrude through the belly-button
    • Abnormally large tongue (macroglossia)
    • Neonatal hypoglycemia
    • Ear creases
  33. Beckwith-Widemann syndrome have increased risk of which childhood cancers?
    • Wilms tumor (kidney)
    • Hepatoblastoma
  34. Stature conditions that may lead to cancer?
    • Beckwith-Widemann (wilms tumor (kidney) or hepatoblastoma)
    • Noonan syndrome (leukemia)
  35. T/F: Adults with Beckwith-Widemann are usually tall, probably half the people in the NBA have this
    False; growth slows by age 8, and adults are generally no unusually tall
  36. Abnormally large tongue, may interfere with breathing, swallowing and speaking, is seen in _____ syndrome
  37. Beckwith-Widemann syndrome genetic defects is seen in ____ region: abnormal DNA methylation in this area, which leads to overactivity of _____ gene, a growth factor, and/or no active ____ gene or _____ gene which are tumor suppressor and growth suppressor, respectively
    • 11p15
    • IGF2 (growth factor)
    • CDKN1C (tumor suppressor)
    • H19 (growth suppressor)
  38. Genes that are affected in Beckwith-Widemann syndrome, which is from paternal allele, and which is from maternal allele?
    • IGF 2 from paternal allele – promote growth
    • H19 and CDKN1C from maternal – constrains growth (these are the gene that are not active in this condition)
  39. Scoliotic person with flexible joints, tall stature, thin, and dislocated lens in eyes and a bad heart (mitral valve prolapse and aortic aneurysm), most probably have _______ syndrome
  40. Inheritance pattern for Marfan is ________
    Autosomal dominant
  41. What is mutated in Marfan syndrome?
    Fibrilin gene (FBN1) resulting in abnormal connective tissue
  42. T/F: Marfan syndrome is gain of function mutation in FGFR3, resulting in increased bone growth
    • False false false! Marfan is mutation in fibrilin gene FBN1, which results in abnormal CONNECTIVE TISSUE, NOT BONE!
    • FGFR3 mutation is achondroplasia
  43. Mutations in: FGFR3 is ______, PTPN11 is _______, GNAS is ______, FBN1 is ________
    • Achondroplasia
    • Noonan
    • Albright hereditary osteodystrophy
    • Marfan
  44. Increased in MAPK pathway is ______ and _______.
    Achondroplasia and noonan
  45. Turner syndrome related heart defect:
    Coarctation of the aorta
  46. Marfan related heart defect:
    • Mitral valve prolapse
    • Aortic aneurysm
  47. Heart defect in Noonan:
    Congenital heart Dz
  48. T/F: Male patient with Klinefelters (XXY), is at increased risk for breast cancer
    True; there are more breast tissue in Klinefelter patients than normal males
Card Set
Genetics of Stature
Endo Exam 1