Genetics
Trisomy 18 or Edwards Syndrome is a genetic disorder caused by the presence of an extra copy of all or part of chromosome 18.  The extra chromosome 18 is retained because of a nondisjunction event during meiosis. The incidence increases as the mother’s age increases. The syndrome has a very low rate of survival, resulting from heart abnormalities, kidney malformations, and other internal organ disorders.

Incidence
One in 3,000 pregnancies and approximately one in 6,000 live births

Symptoms/Characteristics
In utero, the most common characteristic are

• cardiac anomalies
• central nervous system anomalies
• choroid plexus cysts
• polyhydramnios

All infants born with Edwards syndrome present with

• kidney malformations
• Structural heart defects
• Omphalocele
• Esophageal atresia
• Mental retardation
• Developmental delays
• Growth deficiency
• Feeding difficulties
• Breathing difficulties
• Arthrogryposis

Some other physical finding may include

• Short breast bone
• Clenched hands
• Underdeveloped thumbs and or nails
• Absent radius
• Webbing of the second and third toes
• Clubfoot or Rocker bottom feet
• Undescended testicles in males.

Facial Features

• Microcephaly accompanied by a prominent back portion of the head
• Low-set, malformed ears
• abnormally small jaw (micrognathia)
• Cleft lip/cleft palate
• Upturned nose
• Narrow eyelid folds (palpebral fissures)
• Widely-spaced eyes (ocular hypertelorism)

Clinical Management

The survival rate of Edwards Syndrome is very low. About 95% die in utero. Of liveborn infants, only 50% live to 2 months, and only 5–10% will survive their first year of life. Major causes of death include apnea and heart abnormalities. It is impossible to predict the exact prognosis of an Edwards Syndrome child during pregnancy or the neonatal period. Because major medical interventions are routinely withheld from these children, it is difficult to determine what the survival rate or prognosis would be with aggressive medical treatment. The median life span is five to fifteen days. One percent of children born with this syndrome live to age ten, typically in cases of the less severe, mosaic Edwards syndrome.

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.

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.

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.

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.