Micropenis and the AR gene: Mutation and CAG repeat-length analysis

Various mutations of the AR gene and expanded CAG repeats at exon 1 of that gene have been reported in patients with hypospadias or genital ambiguity. However, the role of the AR gene has not been systemically studied in thos e with isolated micropenis lacking hypospadias or genital ambiguity. We stu died 64 Japanese boys with isolated micropenis (age, 0-14 yr; median, 7 yr) , whose stretched penile lengths were between -2.5 and -2.0 SD (borderline micropenis) in 31 patients (age, 0-13 yr; median, 8 yr) and below -2.5 SD ( definite micropenis) in 33 patients (age, 0-14 yr; median, 6 yr). Mutation analysis of the AR gene was performed for exons 1-8 and their flanking intr ons, except for the CAG and GGC repeat regions at exon 1, by denaturing HPL C and direct sequencing, identifying a substitution of cytosine to thymine at a position -3 in the 3' splice site of intron 1 in a patient with defini te micropenis. CAG repeat length at exon 1 was determined by electrophoresi s with internal size markers and direct sequencing, revealing no statistica lly significant difference in the distribution of CAG repeat lengths [media n (range) and mean +/- total patients with isolated micropenis, 24 (14-34) and 23.5 +/- 0.38; patients with borderline micropenis, 24 (15-29) and 23.5 +/- 0.53; patients with definite micropenis, 23 (14-34) and 23.5 +/- 0.56; and 100 control males, 23 (16-32) and 23.5 +/- 0.29] or in the frequency o f long CAG repeats (percentage of CAG repeats greater than or equal to 26 a nd greater than or equal to 28: total patients with isolated micropenis, 17 .2 and 4.7%; patients with borderline micropenis, 19.4 and 6.5%; patients w ith definite micropenis, 15.2 and 3.0%; and 100 control males, 21.0 and 10. 0%). These results suggest that an AR gene mutation is rare and that CAG re peat length is not expanded in children with isolated micropenis.