STAR syndrome

Overview

STAR syndrome is an extremely rare genetic disorder characterized by a distinct set of clinical features, summarized by the acronym STAR: Syndactyly (fusion of fingers or toes), Telecanthus (increased distance between the inner corners of the eyes), Anogenital malformations, and Renal abnormalities. This syndrome predominantly affects females and is considered an X-linked dominant condition with male lethality — meaning affected males usually do not survive gestation.

First described in the early 2000s, STAR syndrome has since been linked to mutations in the FAM58A gene. While its features can vary widely between individuals, early recognition of the key symptoms can prompt appropriate genetic testing and a multidisciplinary approach to care. Due to its rarity, only a limited number of cases have been documented globally.

Causes

STAR syndrome is caused by mutations in the FAM58A gene, located on the X chromosome. The FAM58A gene encodes Cyclin M, a protein believed to be involved in regulating the cell cycle and development. The mutation disrupts normal cell processes, particularly those related to limb formation, genitourinary development, and renal function.

STAR syndrome is inherited in an X-linked dominant pattern. Because males have only one X chromosome, mutations in FAM58A are believed to be lethal in male embryos. Females, with two X chromosomes, may survive with a single mutated copy, though severity can vary due to X-chromosome inactivation patterns.

Symptoms

Symptoms of STAR syndrome can differ significantly among individuals, but typically include a combination of physical, renal, and genitourinary abnormalities. Major clinical features include:

Limb Abnormalities

• Syndactyly: Webbing or fusion of fingers or toes, often involving the second and third toes or fingers.

• Clinodactyly (curved fingers), brachydactyly (short fingers), or other digit anomalies.

Craniofacial Features

• Telecanthus: Increased distance between the inner corners of the eyes.

• Broad nasal bridge, low-set ears, and other subtle dysmorphic features may be present.

Urogenital Abnormalities

• Anogenital malformations: Imperforate anus, vaginal anomalies, or abnormal positioning of the urethra or vagina.

• Hypoplastic or malformed uterus and/or ovaries in some individuals.

Renal Abnormalities

• Kidney malformations such as hypoplastic kidneys, cystic kidneys, or renal agenesis (absence of one or both kidneys).

• Potential for chronic kidney disease or impaired renal function.

Other Possible Features

• Developmental delay or learning disabilities (mild to moderate)

• Hearing loss or vision problems (in some cases)

• Dental anomalies

Not all features are present in every case, and the severity can range from mild anomalies to life-threatening complications, especially when kidney function is compromised.

Diagnosis

Diagnosing STAR syndrome involves a combination of clinical evaluation, imaging studies, and genetic testing:

• Clinical examination: Assessment of characteristic physical features including syndactyly, telecanthus, and genital or renal anomalies.

• Imaging: Ultrasound or MRI to evaluate kidney structure and function, and identify genitourinary abnormalities.

• Genetic testing: Confirmatory diagnosis is achieved by identifying pathogenic mutations in the FAM58A gene using sequencing or deletion/duplication analysis.

• Prenatal diagnosis: Possible in pregnancies with a known familial mutation using chorionic villus sampling (CVS) or amniocentesis.

Treatment

There is no cure for STAR syndrome, and treatment is focused on managing symptoms and preventing complications through a multidisciplinary care approach. Specific interventions depend on the individual’s presentation:

Orthopedic Management

• Surgical correction of syndactyly for improved hand or foot function.

• Physical and occupational therapy for fine motor development.

Renal Care

• Regular monitoring of kidney function through blood and urine tests.

• Management of chronic kidney disease or hypertension, if present.

• In severe cases, dialysis or kidney transplantation may be required.

Urogenital and Anorectal Management

• Surgical correction of anorectal and vaginal malformations if needed.

• Urologic interventions to maintain proper urinary function and avoid infections.

Developmental Support

• Early intervention for speech, learning, and motor development.

• Individualized education plans (IEPs) for school-aged children with learning difficulties.

Genetic Counseling

• Recommended for families to understand recurrence risk and reproductive options.

Prognosis

The prognosis for individuals with STAR syndrome varies depending on the severity of renal and genitourinary abnormalities. Many affected individuals can lead relatively normal lives with supportive care, although ongoing medical follow-up is essential.

When kidney function is severely impaired or when complex urogenital anomalies are present, the condition may lead to significant health challenges. However, with early diagnosis and coordinated multidisciplinary care, quality of life can be significantly improved, and many complications can be effectively managed.

Research is ongoing to better understand the role of FAM58A and related pathways, which may offer insights into targeted therapies in the future.