Dyskeratosis congenita (DC), which is also known as Zinsser-Cole-Engman syndrome, was originally reported by Zinsser in 1906 . It is a rare inherited bone marrow failure syndrome and is classically characterized by dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. At least two of these features or one feature plus two or more of the following findings are suspicious for DC: eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), dental abnormalities (caries, periodontal disease, taurodontism), alopecia, developmental delay, short stature, microcephaly, hypogonadism, esophageal stenosis, urethral stenosis, liver disease, osteoporosis, and avascular necrosis of the hips or shoulders . In addition, individuals with DC often develop pulmonary fibrosis and malignancies. However, the phenotype is highly variable. The main causes of mortality are bone marrow failure and immune defects (6070%), followed by pulmonary complications and cancers [3,4,5]. Affected patients have very short telomeres [6,7] and/or pathogenic variants in one of the telomere biology genes:ACD,CTC1,DKC1,NHP2,NOP10,PARN,RTEL1,TERC,TERT,TINF2, andWRAP53. However, the mode of inheritance of DC varies by genes.TERCandTINF2demonstrate an autosomal dominant (AD) pattern, andCTC1,NHP2,NOP10,PARN, andWRAP53have an autosomal recessive (AR) pattern.RTEL1,TERT, andACDshow either an AD or AR pattern.
DKC1is a causative gene for X-linked recessive inheritance of DC [OMIM:MIM305000] [8,9,10]. In this case, in general, only males are affected by DC.DKC1codes for dyskerin, which functions in both the stabilization of the telomerase RNA component and the pseudouridylation of ribosomal RNA molecules [6,11,12].
Approximately 810% of patients with DC develop malignancies [3,13]. The most frequent tumor in patients with DC is head and neck squamous cell carcinoma (40%), followed by skin and anorectal cancers. The incidence of malignancy is 11-fold higher in patients with DC than in the general population.
In this report, we describe a patient with aDKC1missense variant, c.361AG (p.Ser121Gly), who developed multiple rectal cancers in young adulthood after bone marrow failure. Because the clinical features of this patient with DC were atypical except for bone marrow failure, it was difficult to make an accurate diagnosis. Comprehensive RNA sequencing enabled us to diagnose the patient as having DC.
A 15-year-old Japanese boy was admitted to our hospital because of bloody stool. He had chronic otitis media at the age of approximately 2years and purpuric lesions on his face and feet at the age of 9years. At the age of 12years, he had erythrocytopenia and thrombocytopenia (total white blood cells, 3.1103/l; red blood cells, 2.63106/l; hemoglobin, 9.6 mg/dl; platelets, 7103/l) and was diagnosed with aplastic anemia.
Since progression of his aplastic anemia, treatment with steroid had been performed after high-dose gamma-globulin therapy at the age of 14 years at another hospital.
Characteristics of patients with Ser121Gly substitution inDKC1
According to a previous report on colorectal cancer, the average age at diagnosis of rectal cancer in six patients with DC was 28years, whereas two patients withDC with colon cancer were diagnosed at 20 and 25 years old, respectively . One patient with DC with rectal cancer has been reported from Japan: a 24-year-old Japanese man with DC complicated by noncirrhotic portal hypertension, signet ring carcinoma of the rectum, andPneumocystis cariniipneumonia . Our patient with DC also was complicated by noncirrhotic portal hypertension and rectal cancer, but the tumor demonstrated well-differentiated or moderately differentiated adenocarcinoma. Thus, patients with DC develop colorectal cancers earlier than the general population does. It is suggested that defects in pseudouridylation could lead to an impairment of translation, probably including tumor suppressors [19,20]. Because the previously reported patients with variants in the TruB domain had a severe phenotype and poor prognosis, they probably died before cancer developed. Proteomic analysis may elucidate whether the impairment of translation due to defects in the pseudouridylation activity of dyskerin is related to the development of malignancy in patients with DC. Although it is unknown howDKC1is involved in cancer development, DC often develops various tumors in the digestive system, such as in the rectum, stomach, esophagus, colon, pancreas, and liver, at an early age.
In conclusion, our patient developed rectal cancers twice at an early-onset age compared with other previously reported patients with DC who developed colorectal cancer.DKC1might be involved in predisposition to colorectal cancer in young adulthood; therefore, appropriate surveillance may be required, such as with fecal occult blood test, digital rectal examination, and/or endoscopic examination from the age of 10 years, considering our patients case.
- AD:Autosomal dominant
- AR:Autosomal recessive
- CMMRD:Constitutive mismatch repair deficiency
- DC:Dyskeratosis congenita
- MSI:Microsatellite instability