A. Features

1. Inherited disorder of hypogonadism and anosmia
2. Most common cause of isolated GnRH deficiency
3. May be associated with various neurologic abnormalities
4. Due to defect in migration and targeting of two neuronal cell populations
   1. Olfactory neurons
   2. GnRH producing neurons
5. Five times as common in men than in women

B. Types

1. X-Linked form
   1. KAL gene identified on Xp22.3
   2. Escapes X inactivation (also found on Y chromosome)
   3. 679 Amino acid, 210K protein
   4. Likely adhesion molecule with 4-disulfide core domain and fibronectin type III repeat
2. Autosomal form - gene has not been cloned to date
3. Both have isolated GnRH deficiency
4. Normal karyotype (46XY)

C. Symptoms and Findings [2]

1. Abnormal Smell
   1. Anosmia, Hyposmia
   2. Absence of olfactory gyri, bulbs and tracts on MRI Scan
2. Delay in appearance of secondary (2°) sex characteristics
   1. Eunuchoid habitus
   2. Gynecomastia
   3. Micropenis
   4. Cryptorchidism / small testes (larger than in Klinefelter patients)
   5. Infertility
3. Other Neurological Symptoms
   1. Cerebellar Dysfunction - ataxia
   2. Oculomotor Dysfunction - eye movement defects
   3. Cleft Palate
4. Unilateral renal aplasia
5. Congenital Heart Disease
6. Increased arm spans (unlike Klinefelter patients)

D. Laboratory Testing

1. FSH and LH low or undetectable
2. No response of FSH or LH to GnRH
3. Testosterone detectable, but at levels in the mid-female range

References

1. Adashi EY and Hennebold JD. 1999. NEJM. 340(9):709
2. Rugarli EI and Ballabio A. 1993. JAMA. 270(22):2713