Category Archives: Genetic Disorders Info

Ewings’ sarcoma Info

t(11;22)(q24;q12)
The t(11;22) is a relatively specific chromosome rearrangement found in over 80% of Ewings’ Sarcomas.  This rearrangement has also been described in neurogenic tumors such as peripheral neuroepithelioma, Askins’ tumor, and esthesioneuroblastoma.  Trisomy 8 is a common secondary chromosome change.

Factor II (Prothrombin) Info

Genetics
Clotting factor II, or prothrombin, located on chromosome 11, is a vitamin K–dependent proenzyme that functions in the blood coagulation cascade.  Factor II deficiency is a rare, inherited or acquired bleeding disorder.  The prothrombin G20210A mutation alters the polyadenylation site of the gene and results in increased mRNA synthesis with a subsequent increase in protein expression.  This mutation results in increased levels of plasma prothrombin and a concurrent increased risk for the development of thrombosis and hypercoagulability which may contribute to infertility.

Incidence

  • The prothrombin mutation is seen in approximately 6–7% of thrombosis patients and 1–2% of healthy individuals
  • The gene may be inherited heterozygous, or much more rarely, homozygous (1 in 10,000), and is not related to gender or blood type
  • The mutation is uncommon in African Americans (approximately 0.5%) and is rare in Asians, Africans, and Native Americans, and seen in 2% of Caucasian US population

Symptoms/Characteristics

  • Deep vein thrombosis (DVT)
  • A pulmonary embolism (PE) or a blood clot in an unusual site (such as the mesenteric or cerebral sinus vein)
  • A heart attack or stroke at a young age
  • A history of recurrent pregnancy loss or stillbirth

Clinical Management

Anticoagulants are often prescribed to individuals with Factor II Mutation.
Having a DVT and PE in the past increases your risk of developing another one in the future; however, having the prothrombin mutation does not increase the risk of future blood clots.  This reflects the fact that the prothrombin mutation is not a very strong risk factor for blood clots.  Patients who have not had a blood clot in the past should not be routinely treated with blood thinning medication.  Instead, they should be counseled about reducing or eliminating other risk factors.

Fragile X Syndrome Info

Genetics
Fragile X syndrome is the most common inherited form of mental retardation.  It is an X-linked dominant condition that is associated with an expansion of a trinucleotide repeat sequence (CGG)n located on chromosome Xq27.3.  This expansion results in a failure to express the FMR1 gene product, which is required for normal neural development.  In individuals with Fragile X syndrome, the FMR1 allele contains over 200 copies of the (CGG) trinucleotide repeat sequence.  Risk for Fragile X syndrome is determined by the length of the repetitive (CGG) sequence;

  • Normal (<40 CGG repeats)
  • Intermediate or Gray Zone (41 – 60 CGG repeats)
  • Premutation (61-200 CGG repeats)
  • Full Mutation (more than 200 CGG repeats)

Incidence

  • Affects approximately 1 in 3,600 males and approximately 1 in 4,000-6,000 females
  • It is estimated that 1 in 250 females and 1 in 800 males are premutation carriers
  • Fragile X syndrome is an X-linked dominant condition
  • Women with ovarian failure or an elevated follicle-stimulating hormone level before 40 years of age without a known cause should be screened to determine whether they have the fragile X premutation

Major Phenotypic features

  • Childhood onset
  • Mental deficiency
  • Dysmorphic  facies
  • Male maro-orchidism
  • Affected females present with variable phenotypic features due to random X inactivation

Facial Features

  • Elongated face
  • Large or protruding ears
  • Prominent jaw and forehead

Clinical Management
Currently, medical treatment for Fragile X syndrome is not available.  Patients may benefit from behavioral therapy, special education, medication, and treatment of physical abnormalities.

Gaucher Disease Info

Genetics
Gaucher disease is an autosomal recessive, lysosomal storage disorder, caused by a mutation in the acid β-glucosidase gene, located on chromosome 1q21.  This results in the accumulation of the substrate glucosylceramide and other glycolipids due to a deficiency of beta-glucocerebrosidase.  Gaucher disease is divided into three phenotypic forms:

  • Type I disease (or nonneuropathic type) is most common.  It involves bone disease, anemia, an enlarged spleen and thrombocytopenia.  Type I affects both children and adults.
  • Type II disease (or acute infantile neuropathic Gaucher disease) usually begins in infancy with severe neurologic involvement and is rapidly progressive leading to death by age 2-4 years
  • Type III disease (chronic neuropathic form) may cause liver, spleen, and brain complications.  Often more slowly progressive, patients may survive into the third or fourth decade.

Incidence
High carrier frequency in individuals of Ashkenazi Jewish descent (1:16)

Major Phenotypic Features

  • Bone lesions
  • Hematologic changes
  • Enlarged spleen (splenomegaly)
  • Enlarged liver (hepatomegaly)
  • Cognitive impairment

Clinical Management
Enzyme replacement and substrate reduction therapies may be effective.  Some patients may benefit from blood transfusion.  Other patients may require joint replacement surgery to improve mobility and quality of life.  Other treatment options include antibiotics for infections, anti-epileptics for seizures, bisphosphonates for bone lesions, bone marrow transplants, and liver transplants.

Kallmann Syndrome Info

Genetics

  • Kallmann syndrome is characterized by the association of congenital hypogonadotropic hypogonadism with anosmia (HHA)
  • Kallmann syndrome 1 (KS1), caused by mutations in KAL1, is inherited in an X-linked manner
  • KS2 (caused by mutations in FGFR1), KS3 (caused by mutations in PROKR2), and KS4 (caused by mutations in PROK2) are inherited in an autosomal dominant manner
  • KAL1FGFR1PROKR2, and PROK2 are the only genes known to be associated with Kallmann syndrome (KS).  Together, mutations in these genes account for about 20%-25% of KS.

Incidence
Estimates of the overall incidence of KS vary from approximately 1:10,000 to 1:86,000

Major Phenotypic Features

  • Hypogonadotropic hypogonadism
  • Low or normal serum concentration of LH (luteinizing hormone) and FSH (follicle stimulating hormone) in the setting of low circulating concentrations of sex steroids [total testosterone (T) <100 ng/dL in males and estradiol (E2) <50 pg/mL in females]
  • Congenital anosmia (complete inability to smell) or hyposmia (decreased ability to smell)
  • Absence of secondary sexual features
  • It can occasionally be associated with;
    • Optic problems, such as color blindness or optic atrophy
    • Nerve deafness
    • Cleft palate
    • Cryptorchidism
    • Renal agenesis
    • Bimanual synkinesia

Clinical Management
Treatment is directed at restoring the deficient hormones.  Males are administered human chorionic gonadotropin (hCG) or testosterone.  Females are treated with estrogen and progestins.