Klinefelter syndrome with penoscrotal transposition and diphallia: A case study

Klinefelter syndrome (KS) is a common sex chromosome aneuploidy affecting males and is primarily characterized by small testes and infertility; however, the external genitalia usually appear as the normal male type. In rare cases, micropenis, undescended testes, bifid scrotum, and hypospadias have been reported in KS patients; such external genital abnormalities might be caused by androgen insufficiency during the fetal period. Penoscrotal transposition (PST) is a rare genital anomaly involving penile malposition. Diphallia is another rare genital anomaly, varying from a small accessory penis or duplication of the glans, to complete penile duplication. Both PST and diphallia are considered embryonic malformations, rather than androgen insufficiencies, but their exact genetic and environmental causes are unknown. This is the first report of a patient with KS presenting with PST and diphallia, along with micropenis, bifid scrotum, and hypospadias. The patient was born at 37 weeks of gestation and showed ambiguous external genitalia (Figure 1A–C). The main penis was 14 mm in length and duplicate penises were located posterior to the bifid scrotum. The urethral meatus opened at the base of the main penis, which was complicated by hypospadias. The gonads (1 mL each) were palpated in the bifid scrotum. No other physical abnormalities were observed. No uterus or ovaries were detected on abdominal ultrasonography and pelvic magnetic resonance imaging, and the urological and renal structures were normal (Figure 1D,E). The serum electrolyte levels, urinary steroid profile, and newborn screening results were all normal. Serum hormone levels measured at 21 days of age were within the normal ranges (luteinizing hormone: 2.6 mIU/mL, follicle-stimulating hormone: 4.5 mIU/mL, testosterone: 1.19 ng/mL, and anti-Müllerian hormone: 122 ng/mL [reference range 105–271]). However, the serum testosterone level was low (0.07 ng/mL) at 117 days of age. Presence of 47, XXY karyotype confirmed KS. Next-generation sequencing detected no pathogenic variants in the 46, XY disorder of sex development gene panel (including AR, HSD17B3, HSD3B2, NR5A1, SRD5A2, SRY, WT1, ANOS1, CHD7, FGF8, FGFR1). CAG repeat analysis of the androgen receptor gene on the X chromosome showed 22 repeats for both alleles. We ascertained that the patient exhibited PST and diphallia in addition to micropenis, bifid scrotum, and hypospadias associated with KS. The causes of lack of androgen action include insufficient androgen production in utero and insufficient androgen receptor (AR) action. Fetal testosterone levels in KS measured from the 12th week of gestation were reported to be comparable to those in female fetuses. There are reports of low testosterone levels in neonates with KS, reflecting Leydig cell dysfunction. Correspondingly, testosterone levels were low at 4 months of age in our patient. Thus, insufficient androgen production during the fetal period can cause external genitalia anomalies in KS patients. Longer CAG repeat lengths in AR are also reported to cause masculinization failure. In this case, the repeat length was not as long as those in previous reports, and was not considered to be the cause of the external genital abnormalities. PST and diphallia appear to be signs of embryological malformation rather than an insufficiency in androgen action. Although there is no animal model of PST and diphallia, the gubernaculum is a prerequisite for the ultimate location of both the testis and scrotum, and disruption of its function may result in PST. It is postulated that both polygenic and environmental factors are involved in the development of the penis and scrotum. Six cases of KS complicated by PST have been reported (Table S1). However, the specific environmental and genetic factors for PST and diphallia are also unclear. The complex external genital anomalies associated with this KS patient were due to embryological abnormalities combined with Received: 30 December 2022 Revised: 11 March 2023 Accepted: 22 March 2023