Are there any genetic conditions that cause uterine fibroids, keloids, fibrocystic breast disease, and non-alcoholic fatty liver disease (NAFLD)?

No Single Genetic Condition Links All Four Entities

There is no established genetic syndrome that causes all four conditions—uterine fibroids, keloids, fibrocystic breast disease, and NAFLD—together. However, each condition has distinct genetic components that warrant individual consideration.

Genetic Factors in Each Condition

Uterine Fibroids

• Fibroids demonstrate significant genetic heterogeneity with specific chromosomal abnormalities identified, including the 12:14 translocation causing abnormal expression of the high-mobility group IC gene 1, 2
• Loss of the tuberous sclerosis 2 gene has been shown to result in leiomyoma development 1, 2
• Fibroids represent clonal neoplasms arising from genetic alterations in individual myometrial cells, with up to 50% recurrence rates suggesting underlying genetic predisposition 2, 3
• Race represents a major genetic risk factor, with Black women having over 80% incidence by age 50 compared to 70% in White women 1, 4, 2

NAFLD (Non-Alcoholic Fatty Liver Disease)

• The PNPLA3 I148M variant (rs738409) is the best-characterized genetic modifier of NAFLD, confirmed across multiple cohorts and ethnicities as affecting severity across the entire histological spectrum 1
• The TM6SF2 E167K variant represents another validated disease modifier affecting liver fat content and NASH risk 1
• These genetic variants increase liver fat and NASH risk but are NOT systematically associated with features of insulin resistance, distinguishing them from metabolic syndrome-related NAFLD 1
• In Korean populations, PNPLA3 and SAMM50 polymorphisms are associated with NAFLD prevalence and severity 1
• Hispanic ethnicity and family history of diabetes represent genetic risk factors for NAFLD 1

Keloids

• The evidence notes that keloids are benign, monoclonal fibroblast tumors characterized by increased collagen production, similar to fibroids in their pathophysiology 1
• However, no specific genetic syndromes linking keloids to the other three conditions are identified in the available evidence

Fibrocystic Breast Disease

• The NCCN explicitly states that insufficient evidence exists to include fibrocystic disease of the breast as a diagnostic criterion for Cowden Syndrome/PTEN hamartoma tumor syndrome 1
• While uterine fibroids are mentioned in the same context, they are also excluded as diagnostic criteria for Cowden Syndrome 1

Potential Shared Pathophysiologic Mechanisms (Not a Single Syndrome)

Fibroproliferative Disorders

• Both fibroids and keloids share characteristics as monoclonal tumors with dysregulated growth factors and increased collagen production 1
• Transforming growth factor-β (TGF-β) pathways are implicated in both conditions, with TGF-β3 elevated 5-fold in leiomyomas compared to normal myometrium 1

Metabolic Syndrome Overlap

• NAFLD is strongly associated with metabolic syndrome components (obesity, diabetes, dyslipidemia, hypertension) 1
• However, the genetic variants causing NAFLD (PNPLA3, TM6SF2) are NOT systematically associated with insulin resistance features, indicating distinct pathogenic pathways 1

Critical Clinical Pitfalls

• Do not assume a unifying genetic diagnosis exists when patients present with multiple fibroproliferative conditions—each requires independent evaluation 1
• Routine genetic testing for PNPLA3 or TM6SF2 in NAFLD is not recommended outside of selected patients or clinical studies, despite their validated associations 1
• When evaluating patients with multiple conditions, screen for metabolic syndrome components systematically, as these represent modifiable risk factors for NAFLD independent of genetic predisposition 1
• Cowden Syndrome/PTEN hamartoma tumor syndrome should be considered if patients have macrocephaly, specific mucocutaneous lesions, or thyroid/breast cancers, but fibrocystic breast disease and uterine fibroids are explicitly excluded as diagnostic criteria 1

Practical Approach

• Evaluate each condition independently using condition-specific diagnostic criteria and genetic testing when indicated 1
• For NAFLD, prioritize screening in patients with diabetes, metabolic syndrome, or persistently elevated liver enzymes using ultrasound as the primary modality 1
• For fibroids, consider genetic counseling regarding recurrence risk (27% at 10 years after myomectomy), particularly in Black women and those with multiple fibroids 1, 4, 2
• Consider referral to genetics if features suggest a specific syndrome (e.g., Cowden Syndrome with appropriate clinical criteria), but do not expect a single unifying diagnosis for all four conditions 1