What cancers are associated with multiple colonic polyps, elevated ferritin with low transferrin saturation, and urinary findings of hematuria and proteinuria?

Constitutional Mismatch Repair Deficiency (CMMRD) Syndrome

The constellation of multiple colonic polyps, elevated ferritin with low transferrin saturation, hematuria, and proteinuria is most consistent with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome, a rare autosomal recessive condition caused by biallelic mutations in mismatch repair genes (MLH1, MSH2, MSH6, or PMS2).

Primary Cancer Associations

CMMRD presents with a distinctive multi-system cancer spectrum that directly correlates with your clinical findings:

Gastrointestinal Malignancies

• Colorectal carcinoma is the most common gastrointestinal malignancy in CMMRD, with all patients developing polyposis by the third decade of life, ranging from a few up to >100 polyps that mimic attenuated familial adenomatous polyposis 1
• Cancers of the small bowel occur even in the first decade of life, representing part of the Lynch syndrome-associated malignancy spectrum seen in CMMRD 1
• The median age of onset for the first tumor in CMMRD is 7.5 years, with a wide range from 0.4 to 39 years 1

Hematologic Malignancies

• Non-Hodgkin lymphomas, particularly T-lymphoblastic NHL, are the most commonly observed hematopoietic malignancies in CMMRD, with a median age at diagnosis of 6.6 years 1
• T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia have also been reported in CMMRD patients 1
• Two-thirds of patients with CMMRD who do not develop cancer until adulthood will present with colorectal cancer in the setting of multiple colonic polyps 1

Central Nervous System Tumors

• Malignant brain tumors are the most common cancer type in CMMRD, followed by gastrointestinal and hematologic malignancies, with a median age at diagnosis of 10.3 years 1
• Most brain tumors are malignant gliomas, including high-grade gliomas, primitive neuroectodermal tumors, and medulloblastomas 1

Genitourinary Cancers

• Urinary tract cancers occur in CMMRD patients, explaining the hematuria and proteinuria in your clinical presentation 1
• These genitourinary cancers are part of the Lynch syndrome-associated malignancies that occur in CMMRD, even in the first decade of life 1
• Ovarian and endometrial cancers are also part of the CMMRD spectrum 1

Understanding the Iron Studies Abnormality

The elevated ferritin with low transferrin saturation pattern requires careful interpretation in this context:

• While iron studies showing elevated ferritin with low TSAT typically suggest anemia of chronic disease or inflammation, in a patient with multiple colonic polyps, this may reflect chronic gastrointestinal blood loss from the polyps themselves 1
• The presence of hematuria and proteinuria suggests multi-organ involvement, which is characteristic of CMMRD's systemic nature 1
• Importantly, one study found that elevated transferrin saturation (not low TSAT) was associated with increased odds of colon adenomas 2, but your patient's presentation with LOW TSAT is more consistent with blood loss from existing polyps rather than iron-mediated carcinogenesis

Genetic Basis and Inheritance Pattern

CMMRD follows an autosomal recessive inheritance pattern, distinguishing it from Lynch syndrome:

• Biallelic mutations have been reported in all Lynch syndrome-associated MMR genes (MSH2, MLH1, MSH6, and PMS2) 1
• The most commonly involved genes are PMS2 and MSH6, whereas MSH2 and MLH1 mutations are rare, which differs strikingly from Lynch syndrome 1
• Both parents are obligate carriers, though family history is often noncontributory due to the recessive pattern 1
• The rate of consanguinity varies according to countries of origin, with high rates especially among homozygous cases 1

Differential Diagnosis Considerations

While CMMRD best fits your presentation, other syndromes warrant brief consideration:

Lynch Syndrome (Monoallelic MMR Mutations)

• Lynch syndrome has a lifetime colorectal cancer risk of approximately 80% and increased risk for endometrial, ovarian, gastric, urinary tract, small intestinal, pancreatic, biliary tract, and brain tumors 1, 3
• However, Lynch syndrome typically does NOT present with multiple colonic polyps (historically classified as "nonpolyposis") and would not explain the childhood presentation or hematologic malignancies 1, 4

Familial Adenomatous Polyposis (FAP)

• FAP presents with hundreds to thousands of adenomatous polyps and is caused by APC gene mutations 1
• FAP is associated with duodenal, papillary thyroid, and childhood hepatoblastoma, but NOT with hematologic malignancies or the specific urinary tract findings seen in your patient 1

Attenuated FAP

• AFAP features 10-100 polyps with lower risk for extracolonic neoplasms compared to classic FAP 1
• AFAP does not explain the hematologic malignancies or urinary tract involvement 1

Clinical Pitfalls and Key Diagnostic Features

Critical distinguishing features that point to CMMRD over other polyposis syndromes:

• Café-au-lait spots are a hallmark of CMMRD and may be mistaken for neurofibromatosis type 1 1
• The combination of childhood hematologic malignancies with colonic polyposis is virtually pathognomonic for CMMRD 1
• CNS and other hyper- and hypopigmented skin alterations have been reported in CMMRD 1
• The presence of urinary tract involvement (hematuria and proteinuria) with multiple colonic polyps strongly suggests CMMRD rather than FAP or other polyposis syndromes 1

Recommended Diagnostic Approach

To confirm CMMRD diagnosis:

• Perform genetic testing for biallelic mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) using hereditary colon cancer gene panel testing 1
• Tumor tissue from any malignancy should show deficient mismatch repair (dMMR) in both tumor AND normal colon tissue, which distinguishes CMMRD from Lynch syndrome 1
• Examine the patient for café-au-lait spots and other dermatologic manifestations 1
• Comprehensive cancer surveillance should be initiated immediately given the high risk of multiple primary malignancies 1