What Can Cause Kallman Syndrome In Infants?

Kallmann syndrome is the most common form of genetically disease, with autosomal recessive, X-linked, and autosomal dominant forms of inheritance. Clinically, it is characterized by its association with anosmia or hyposmia; 85% of the cases are autosomal . The X-linked form (KAL1) is caused by mutations of the KAL1 gene at Xp22.3. This leads to failure of olfactory axons and GnRH-expressing neurons to migrate from their common origin in the olfactory placode to the brain. The KAL gene product anosmin-1, an extracellular 95 kDa matrix glycoprotein, facilitates neuronal growth and migration. The KAL gene is also expressed in various parts of the brain, facial mesenchyme, and mesonephros and metanephros, thus explaining some of the associated findings in patients with Kallmann syndrome, such as synkinesia (mirror movements), hearing loss, midfacial defects, and renal agenesis. Some kindreds contain anosmic individuals with or without hypo￾gonadism; others contain hypogonadal individuals who are anosmic. Cleft lip and palate, hypotelorism, median facial clefts, sensorineural hearing loss, unilateral renal aplasia, neurologic deficits, and other findings occur in some affected patients. When Kallmann syndrome is caused by terminal or interstitial deletions of the Xp22.3 region, it may be associated with other contiguous gene syndromes, such as steroid sulfatase deficiency, chondrodysplasia punctata, X-linked ichthyosis, or ocular albinism. The autosomal dominant form of Kallmann syndrome (KAL2) occurs in up to 10% of patients, and is caused by a loss of function mutation in the fibroblast growth factor receptor 1 (FGFR1) gene. Cleft lip and palate are associated with KAL2 but not with KAL1. Oligodontia and hearing loss may occur with both KAL1 and KAL2. A variety of other genes, including FGF8, PROK2/PROKR2, NELF, CHD7 (responsible for CHARGE [coloboma of the eye, heart anomaly, choanal atresia, retardation, and genital and ear anomalies] syndrome, which includes hypogonadism in its phenotype), HS6ST1, WDR11, and SEMA3A, are associated with defects in neuronal migration that can result in Kallmann syndrome, but in most patients the affected gene remains undefined