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
• KAL1, FGFR1, PROKR2, 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.

Genetics
Klinefelter’s syndrome, 47,XXY or XXY syndrome is a condition caused by a chromosome aneuploidy. Affected individuals have at least two X chromosomes and at least one Y chromosome. The extra X chromosome is retained because of a nondisjunction event during meiosis (sex cell division).

Incidence

The XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about 1 in 500 live male births.

Symptoms/Characteristics

• In adults, possible characteristics vary widely and include little or no indicatinon of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue).
• Mean I.Q. between 85-90

1. Affected males are almost always effectively sterile
2. Some degree of language learning impairment may be present
3. Hypogonadism, patients will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels.
4. Microorchidism (i.e. small testicles)
5. Increased risk of germ cell tumors, breast cancer, and osteoporosis

Clinical Management
Although genetic variation is irreversible, symptoms associated with Klinefelter syndrome can be altered or treated in a number of ways, including the use of testosterone treatment

add(14)(q32) or 14q+
Additional chromosome material of unknown origin attached to band 14q32 has been observed in ALL and lymphoma.  It is also a relatively frequent finding in B-cell CLL, prolymphocytic leukemia, hairy cell leukemia, Waldenstroms macroglobulinemia, multiple myeloma, plasma cell leukemia, ATL, mycosis fungoides and Sezary’s syndrome.

t(8:14)(q24;q32) and t(2;8)(p12;q24)
Translocations between chromosomes 8 and 14 and 2 and 8 are observed in Burkitt’s non-Hodgkins lymphomas and B-cell ALL-L3.  In general, the t(2;8) and t(8;14) neoplasms are aggressive and associated with poor patient prognosis.

t(14;18)(q32;q21)
The t(14;18) has been observed in a wide variety of lymphoid neoplasms, but most often in non-Hodgkin’s lymphomas specifically, the follicular, small cleaved-cell type.  There have been a few reports of the t(14;18) having been found in Hodgkin’s disease.  It is not unusual to observe other chromosome changes associated with the presence of the t(14;18).

Rearrangements of 1q
Rearrangements of the chromosome 1 long arm have been observed in a wide variety of neoplastic and preneoplastic disease, most frequently in acute lymphocytic leukemia and non-Hodgkin’s lymphoma.

Genetics
Maple Syrup Urine Disease (MSUD) is caused by a deficiency of the metabolic enzyme branched-chain α-keto acid dehydrogenase (BCKDH).  This deficiency leads to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products in the blood and urine.  Several forms of the disease include classic severe MSUD, intermediate MSUD, intermittent MSUD, thiamine-responsive MSUD and E3-Deficient MSUD with lactic acidosis.  MSUD is inherited in an  autosomal recessive manner.

Incidence

• Affects approximately 1 in 180,000 individuals
• There is a much higher incidence of MSUD in individuals of Amish and Mennonite descent

Symptoms/Characteristics

In infants, symptoms include:

• Sweet-smelling urine
• Poor feeding
• Vomiting
• Dehydration
• Lethargy
• Hypotonia
• Seizures
• Ketoacidosis
• Neurological decline

Clinical Management

• A diet with minimal levels of the amino acids leucine, isoleucine, and valine must be maintained in order to prevent neurological damage
• Specialized protein preparations containing substitutes and adjusted levels of the amino acids have been synthesized for use in individuals with MSUD