A rare case of a young girl with genital manifestations of Proteus syndrome

A female aged 3 years presented with progressive clitoral and left lower limb enlargement, notably over the past year, and recent hearing reduction, with no birth abnormalities. Examination revealed asymmetric left lower limb enlargement with 4-cm length discrepancy and increased girth, epidermal nevi on the upper thighs and below the left knee (Fig. 1), and hypertrophied clitoris and the left buttock (Fig. 2); the labia, urethra, and vagina appeared normal. Blood workups were normal, the Barr body test confirmed female sex (XX), and renal ultrasonography demonstrated relative left kidney enlargement. Genetic testing for AKT1 mutation was not performed, as this molecular assay was unavailable at our local institution, and the patient’s family could not afford referral to distant medical centers for further genetic analysis. The multidisciplinary team opted for conservative management. Clinical features guided diagnosis, with differentials including neurofibromatosis type 1, Klippel–Trenaunay syndrome, hemihyperplasia, and Parkes–Weber syndrome. Proteus syndrome is a rare, sporadic mosaic overgrowth disorder caused by postzygotic activating AKT1 gene mutation, characterized by progressive, asymmetric, disproportionate overgrowth of multiple tissues—particularly bone, connective tissue, skin, adipose tissue, and vascular structures—producing marked phenotypic variability and distortion.^[1,2] Few cases with genital involvement in Proteus syndrome have been documented. This manifests as asymmetric external genital enlargement (penis, scrotum, labia, or clitoris), lipomatous or fibroadipose overgrowth, vascular malformations, and cutaneous lesions (epidermal nevi or cerebriform connective tissue nevi) in genital, perineal, or other regions.^[1,3] Internal genital structures are rarely involved; functional, cosmetic, and psychosocial implications may necessitate individualized surgical management, ideally after growth stabilization.^[4,5] This condition shares overlapping clinical manifestations with other overgrowth syndromes, and the current diagnosis was established purely on clinical manifestations due to the absence of molecular genetic confirmation. It should be noted that clinical diagnosis alone has inherent limitations, given the substantial phenotypic overlap between Proteus syndrome and other congenital overgrowth disorders, which may lead to potential diagnostic uncertainty. As observed by Turner et al.^[2], many similar cases are likely underdiagnosed or misdiagnosed. This case serves as a reminder to clinicians to rule out Proteus syndrome in cases with ambiguous genitalia.

Figure 1.

The asymmetric left lower limb enlargement and epidermal nevi on both upper thighs and below the left knee in a female aged 3 years.

Figure 2.

The perineal region. (A) Asymmetrically hypertrophied clitoris pointing rightward with pubic hair at Turner stage 1. (B) Relatively enlarged left buttock; the labia, urethra, and vagina appeared normal. The image has been anonymized to protect patient identity.

Acknowledgments

None.

Statement of ethics

Institutional review board approval was not required for this clinical image. Written informed consent was obtained. All procedures involving human participants adhered to institutional and national research committee ethical standards and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Funding source

None.

Author contributions

DDL: Participated in conceptualization and writing;

MRM: Participated in review and editing. MBM: Participated in supervision, review, and editing.

Data availability

No data were generated from this study.