- Hand–Foot–Genital Syndrome is a rare genetic disorder characterized by congenital malformations affecting the limbs and the genitourinary tract. It belongs to the group of homeobox (HOX) gene–related developmental disorders, caused by mutations in the HOXA13 gene. This gene encodes a transcription factor that plays a critical role in regulating embryonic development, particularly the formation of the distal limbs, lower urinary tract, and reproductive system. Pathogenic mutations often involve polyalanine tract expansions or, less commonly, point mutations and deletions. These changes disrupt HOXA13’s normal function, leading to a spectrum of malformations.
- The hallmark limb features in HFGS include abnormalities of the hands and feet. Affected individuals typically have short thumbs, hypoplastic or absent first metacarpals, and limited thumb movement. The feet may show similar changes with shortened great toes or toe malformations. Some individuals also present with mild brachydactyly (shortened fingers and toes), clinodactyly (curved digits), or subtle skeletal anomalies. Despite these structural differences, overall limb function may remain relatively preserved, though fine motor skills can be affected in more severe cases.
- In addition to skeletal anomalies, genitourinary malformations are a key diagnostic feature. Females often present with Müllerian duct anomalies, such as a bicornuate uterus (two-horned uterus), uterine septa, or vaginal malformations, which can result in recurrent pregnancy loss, menstrual irregularities, or fertility issues. Males may have hypospadias, chordee (abnormal penile curvature), or other anomalies of the urethra and reproductive tract. Both sexes are at risk of urinary tract abnormalities, including vesicoureteral reflux and hydronephrosis, which may predispose to recurrent urinary tract infections or kidney damage if left untreated.
- HFGS is inherited in an autosomal dominant pattern, though penetrance and expressivity vary. This means that a single mutated copy of HOXA13 can cause disease, but the severity of features can differ significantly even within the same family. Some individuals may present with only mild limb anomalies, while others show the full spectrum of hand, foot, and genitourinary malformations. Rare de novo (spontaneous) mutations can also cause HFGS in individuals without a family history.
- Diagnosis is based on a combination of clinical examination, radiographic imaging, and molecular genetic testing. Identifying a mutation in HOXA13 confirms the diagnosis, which is especially useful in mildly affected individuals or families with variable presentation. Prenatal ultrasound can sometimes detect severe limb or genitourinary anomalies, particularly in families with a known genetic history.
- Currently, there is no curative treatment for HFGS, and management is multidisciplinary. Orthopedic evaluation may be needed for hand or foot function, and reconstructive surgery can help correct certain anomalies. Urologic monitoring is essential to detect vesicoureteral reflux or hydronephrosis early, and surgical correction may be required for genitourinary malformations such as hypospadias. In females, gynecologic evaluation and interventions can help address Müllerian anomalies to improve fertility outcomes. Long-term follow-up is often necessary, particularly for urinary and reproductive health.
- Overall, Hand–Foot–Genital Syndrome is an instructive example of how subtle alterations in transcription factor function can have profound developmental consequences. While most affected individuals survive into adulthood, the syndrome can cause lifelong medical and reproductive challenges, emphasizing the importance of early diagnosis, genetic counseling, and tailored management.
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