It can be inherited in an autosomal dominant or autosomal recessive manner; it is possible for two parents with Waardenburg syndrome type 1 to have a child carrying both mutated copies of the PAX3 gene (25% chance) and present with Waardenburg syndrome type 3. A missense mutation has been documented to have this effect. However, it is also possible for Waardenburg syndrome type 3 to present spontaneously with just one mutated copy of PAX3. A deletion of the paired domain region of the gene has been documented to have this effect. However, no major correlation has been found between type of mutation and disease severity. Severity tends to be dictated by mutations in other genes (epistasis), as evidenced by distinct familial patterns in severity not tied to Waardenburg mutation type. Mutations in both copies of PAX3 have sometimes led to death before or shortly after birth, and mice with loss-of-function mutations in both copies of the gene do not survive. Type 4 is caused by a mutation in any of a range of genes, the most common being SOX10, when it is classed as type 4C. Type 4A is caused by an autosomal dominant or autosomal-recessive mutation in the gene EDNRB. Type 4B is caused by an autosomal dominant or autosomal-recessive mutation in the gene EDN3.
Extremely high levels of FSH (>45 ID/mL) have been correlated with successful microdissection testicular sperm extraction.Serum inhibin-B weakly indicates presence of sperm cells in the testes, raising chances for successfully achieving pregnancy through testicular sperm extraction (TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval [CI]: 0.56–0.74) and a specificity of 0.83 (CI: 0.64–0.93) for prediction the presence of sperm in the testes in non-obstructive azoospermia.Seminal plasma proteins TEX101 and ECM1 were recently proposed for the differential diagnosis of azoospermia forms and subtypes, and for prediction of TESE outcome. Mount Sinai Hospital, Canada started clinical trial to test this hypothesis in 2016.Primary hypopituitarism may be linked to a genetic cause. So a genetic evaluation may be done for men with azoospermia as a result. Azoospermic men with testicular failure are advised to undergo karyotype and Y-micro-deletion testing. Treatment
Pre- and post-testicular azoospermia are frequently correctible, while testicular azoospermia is usually permanent. In the former the cause of the azoospermia needs to be considered and it opens up possibilities to manage this situation directly. Thus men with azoospermia due to hyperprolactinemia may resume sperm production after treatment of hyperprolactinemia or men whose sperm production is suppressed by exogenous androgens are expected to produce sperm after cessation of androgen intake. In situations where the testes are normal but unstimulated, gonadotropin therapy can be expected to induce sperm production.