91¹ú²ú¾«Æ·

A 21-year-old African American man presented with a one-month history of abdominal pain, intractable emesis, and a 14 kg weight loss. He had a history of T-cell lymphoma diagnosed at age 7 years that was treated with an unrelated bone marrow transplant when he was 14 years old; he is currently in remission. On physical examination, he was cachectic, had diffuse abdominal tenderness, and had multiple café au lait spots on the chest and extremities. An MRI of the abdomen showed severe thickening of the wall of the second portion of the duodenum, retroperitoneal adenopathy, and multiple liver lesions suggestive of metastasis. Nonmalignant lesions, including hepatic and spinal hemangiomas, were also present. Upper endoscopy demonstrated a polyp with narrowing and ulceration in the second portion of the duodenum. Colonoscopy revealed multiple large polyps throughout the colon (Figure 1). Biopsy of the duodenal polyp reported poorly differentiated adenocarcinoma with signet ring features. Immunohistochemistry for mismatch repair (MMR) genes showed loss of nuclear expression of PMS2 in both neoplastic and normal cells (Figure 2), while MLH1, MSH2, and MSH6 were intact. Liver biopsy confirmed metastatic moderately differentiated adenocarcinoma. Neoadjuvant chemoimmunotherapy was started. The patient’s family pedigree is demonstrated in Figure 3.

Figure 1. Rectal and Sigmoid polyps

Figure 2.Immunohistochemistry from duodenal adenocarcinoma

Figure 3. Family Pedigree

Which of the following is the most likely baseline condition?

1. Neurofibromatosis type 1
2. Lynch syndrome
3. Constitutional mismatch repair deficiency
4. Intestinal T-cell lymphoma

Answer: C

Explanation:

Constitutional mismatch repair deficiency (CMMRD) belongs to the rare and highly penetrant cancer predisposing syndromes.¹ It is caused by a biallelic mutation on one of the four major MMR genes: PMS2, MLH1, MSH2, or MSH6. It is autosomal recessive and leads to a predisposition to childhood cancer. Monoallelic mutations of MMR genes are well known causes of the autosomal dominant disorder Lynch syndrome (LS), which should be differentiated from the biallelic MMR mutations that cause cancers in CMMRD.

The most common malignancies in CMMRD include leukemia/lymphoma (most commonly T-cell lymphomas), brain cancers (usually high-grade gliomas), and gastrointestinal cancers (typically colorectal and small bowel carcinoma). Nonmalignant features include adenomas, polyps, and café au lait spots.^1,2 Because café au lait spots are commonly associated with other genetic disorders such as neurofibromatosis, it can be challenging to differentiate CMMRD from other inherited cancer predisposition syndromes. The differences between CMMRD, LS, and neurofibromatosis type 1 (NF-1) are described in Table 1.^2,3

Table 1. Differences between CMMRD, LS, and NF-1.

High clinical suspicion is the key in diagnosing CMMRD. In theory, the parents should have monoallelic PMS2 mutation for our patient to inherit biallelic mutation. It is important to note that patients with CMMRD often lack a family history of LS cancer spectrum, especially with a heterozygous PMS2 mutation that may have low penetrance,¹ with 85 percent of CMMRD pedigrees lacking LS-associated malignancies.⁴ In 2014, the European Consortium “Care for CMMRD” (C4CMMRD) described diagnostic criteria (Table 2); if three or more points are obtained, CMMRD testing is indicated.²

Table 2. Diagnostic criteria for CMMRD syndrome per the European Consortium C4CMMRD.²

Abbreviations: LS, Lynch syndrome; NHL, non-Hodgkin lymphoma; sPNET, supratentorial primitive neuroectodermal tumors. *Colorectal, endometrial, small bowel, ureter, renal pelvis, biliary tract, stomach, bladder carcinoma.

In patients for whom CMMRD has been confirmed, cancer surveillance is imperative and is outlined in Table 3 per Dr. Carol A. Durno and colleagues. ⁵ A positive diagnosis of CMMRD also merits genetic testing and surveillance for family members.

Table 3. Surveillance guidelines for CMMRD per Durno et al.⁵

CMMRD is a relatively newly described condition that is now known as a distinct childhood cancer predisposition syndrome. Despite this, it is often underdiagnosed due to lack of awareness, variable phenotype, and similarity to other more known conditions such as NF-1. Early diagnosis is warranted for the proper screening of the patient and their family members.

References

1. Wimmer K, Kratz CP, Vasen HFA, et al. . J Med Genet. 2014;51:355-365.
2. Bakry D, Aronson M, Durno C, et al. . Eur J Cancer. 2014;50:987-996.
3. Ripperger T, Beger C, Rahner N, et al. . Haematologica. 2010;95:841-844.
4. Urganci N, Bahar Genc D, Kose G, et al. . Pediatrics. 2015;136:e1047-e1050.
5. Durno CA, Sherman PM, Aronson M, et al. . Eur J Cancer. 2015;51:977-983.

Note: Figures 1 through 2 are obtained and used with permission from the Jackson Memorial Hospital. Figure 3 was created by Dr. Yuen Lo Yau Leung.

Contributed by Drs. Yuen Lo Yau Leung and W. Andres Vásconez, Pediatrics Resident Physicians, Jackson Memorial Hospital, Miami, FL.