Mild androgen insensitivity syndrome
Mild androgen insensitivity syndrome is an intersex condition that results in a mild impairment of the cell's ability to respond to androgens. The degree of impairment is sufficient to impair spermatogenesis and / or the development of secondary sexual characteristics at puberty in males, but does not affect genital differentiation or development. Female genital and sexual development is not significantly affected by the insensitivity to androgens; as such, MAIS is only diagnosed in males. The clinical phenotype associated with MAIS is a normal male habitus with mild spermatogenic defect and / or reduced secondary terminal hair.
MAIS is one of three types of androgen insensitivity syndrome, which is divided into three categories that are differentiated by the degree of genital masculinization: complete androgen insensitivity syndrome is indicated when the external genitalia is phenotypically female, mild androgen insensitivity syndrome is indicated when the external genitalia is phenotypically male, and partial androgen insensitivity syndrome is indicated when the external genitalia is partially, but not fully masculinized.
Androgen insensitivity syndrome is the largest single entity that leads to 46,XY undermasculinization.
Signs and symptoms
Individuals with mild androgen insensitivity syndrome are born phenotypically male, with fully masculinized genitalia; this category of androgen insensitivity is diagnosed when the degree of androgen insensitivity in an individual with a 46,XY karyotype is great enough to impair virilization or spermatogenesis, but is not great enough to impair normal male genital development. MAIS is the mildest and least known form of androgen insensitivity syndrome.The existence of a variant of androgen insensitivity that solely affected spermatogenesis was theoretical at first. Cases of phenotypically normal males with isolated spermatogenic defect due to AR mutation were first detected as the result of male infertility evaluations. Until then, early evidence in support of the existence of MAIS was limited to cases involving a mild defect in virilization, although some of these early cases made allowances for some degree of impairment of genital masculinization, such as hypospadias or micropenis. It is estimated that 2-3% of infertile men have AR gene mutations. It is also estimated that MAIS is responsible for 40% of male infertility.
Examples of MAIS phenotypes include isolated infertility, mild gynecomastia in young adulthood, decreased secondary terminal hair, high pitched voice, or minor hypospadias repair in childhood. The external male genitalia are otherwise normal in individuals with MAIS. Internal genitalia, including Wolffian structures and the prostate, is also normal, although the bitesticular volume of infertile men is diminished; male infertility is associated with reduced bitesticular volume, varicocele, retractile testes, low ejaculate volume, male accessory gland infections, and mumps orchitis. The incidence of these features in infertile men with MAIS is similar to that of infertile men without MAIS. MAIS is not associated with Müllerian remnants.
Spinal and bulbar muscular atrophy
Spinal and bulbar muscular atrophy, also known as Kennedy's disease, is a severe neurodegenerative syndrome that is associated with a particular mutation of the androgen receptor's polyglutamine tract called a trinucleotide repeat expansion. SBMA results when the length of the polyglutamine tract exceeds 40 repetitions.Although technically a variant of MAIS, SBMA's presentation is not typical of androgen insensitivity; symptoms do not occur until adulthood and include neuromuscular defects as well as signs of androgen inaction. Neuromuscular symptoms include progressive proximal muscle weakness, atrophy, and fasciculations. Symptoms of androgen insensitivity experienced by men with SBMA are also progressive and include testicular atrophy, severe oligospermia or azoospermia, gynecomastia, and feminized skin changes despite elevated androgen levels. Disease onset, which usually affects the proximal musculature first, occurs in the third to fifth decades of life, and is often preceded by muscular cramps on exertion, tremor of the hands, and elevated muscle creatine kinase. SBMA is often misdiagnosed as amyotrophic lateral sclerosis .
The symptoms of SBMA are thought to be brought about by two simultaneous pathways involving the toxic misfolding of proteins and loss of AR functionality. The polyglutamine tract in affected pedigrees tends to increase in length over generations, a phenomenon known as "anticipation", leading to an increase in the severity of the disease as well as a decrease in the age of onset for each subsequent generation of a family affected by SBMA.