Germ‐line interstitial deletions involving the 14q32 chromosomal region, resulting in 14q32 deletion syndrome, are rare. DICER1 is a recently described cancer‐predisposition gene located at 14q32.13. ...We report the case of a male child with a ∼5.8 Mbp 14q32.13q32.2 germ‐line deletion, which included the full DICER1 locus. We reviewed available clinical and pathological material, and conducted genetic analyses. In addition to having congenital dysmorphic features, the child developed multiple DICER1 syndrome‐related tumors before age 5 y: a pediatric cystic nephroma (pCN), a ciliary body medulloepithelioma (CBME), and a small lung cyst (consistent with occult pleuropulmonary blastoma Type I/Ir cysts seen in DICER1 mutation carriers). He also developed a cerebral spindle‐cell sarcoma with myogenous differentiation. Our investigations revealed that the deletion encompassed 31 protein‐coding genes. In addition to the germ‐line DICER1 deletion, somatic DICER1 RNase IIIb mutations were found in the CBME (c.5437G > A, p.E1813K), pCN (c.5425G > A, p.G1809R), and sarcoma (c.5125G > A, p.D1709N). The sarcoma also harbored a somatic TP53 mutation: c.844C > T, p.R282W. Additional copy number alterations were identified in the CBME and sarcoma using an OncoScan array. Among the 8 cases with molecularly‐defined 14q32 deletions involving DICER1 and for whom phenotypic information is available, our patient and one other developed DICER1‐related tumors. Biallelic DICER1 mutations have not previously been reported to cause cerebral sarcoma, which now may be considered a rare manifestation of the DICER1 syndrome. Our study shows that DICER1‐related tumors can occur in children with 14q32 deletions and suggests surveillance for such tumors may be warranted.
Patients with esophageal atresia/tracheoesophageal fistula (EA-TEF) can develop Barrett esophagus as a long-term consequence of their condition. Intestinal metaplasia (IM), a risk factor for ...developing adenocarcinoma of the esophagus, has not been well characterized in the pediatric population.
Retrospective review of patients with EA-TEF followed at 3 academic pediatric centers between the years 1997 and 2014.
Among 542 children and adolescents, 1.3% (7 patients, 5 girls) were diagnosed with IM based on endoscopy and pathology. Six of the patients had EA-TEF type C, whereas the last patient had a "long gap" type A atresia. Patients were diagnosed with gastric metaplasia either before the IM diagnosis in 4 patients or concomitantly in 3. The median (range) age of diagnosis for gastric metaplasia was 7.9 (range 2-17.2) and for IM 10.9 (2-17.2) years. Gastroesophageal reflux (GER) symptoms were nonspecific. Five patients were on proton pump inhibitor therapy for symptomatic GER at the time of diagnosis of IM. 2 of the 7 patients had previously undergone Nissen fundoplication. One patient, who had undergone a Nissen fundoplication, was restarted on proton pump inhibitor once the diagnosis of IM was made. All patients had repeated endoscopy and dysplasia was not observed with a median follow-up of 1.7 (range 1-4.9) years.
IM occurs in patients with EA-TEF, some as young as 2 years. Therefore, early endoscopic surveillance should be considered in this GER-prone population.
Germ-line
RB
-
1
mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line
DICER1
mutation in a child with a ...PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of
DICER1
mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for
DICER1
mutations; three patients were known carriers of germ-line
DICER1
mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify
DICER1
mutations in blood gDNA and/or tumour gDNA. Testing for somatic
DICER1
mutations was also conducted on one case with a known germ-line
DICER1
mutation. From the eighteen PinBs, we identified four deleterious
DICER1
mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic
DICER1
RNase IIIb mutations were identified. One PinB arising in a germ-line
DICER1
mutation carrier was found to have LOH. This study suggests that germ-line
DICER1
mutations make a clinically significant contribution to PinB, establishing
DICER1
as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line
DICER1
mutation. The means by which the second allele is inactivated may differ from other
DICER1
-related tumours.
Abstract Introduction Calretinin, a calcium-binding protein, has been reported to be an important new marker in Hirschsprung's disease (HD). The aim is to study the diagnostic value of Calretinin in ...total colonic aganglionosis (TA), prematurity, and superficial biopsy when nerve hyperplasia may not be accessed by ACE activity. Methods Records of patients diagnosed with HD at our institution from 1985 to 2010 were studied and patients with TA identified. We examined tissue samples from those TA, partial colectomies for HD, biopsies for suspicion of HD, and rectal tissue from aborted fetuses. Immunohistochemical analysis of Calretinin was compared with ACE gold standard method in all cases. Results In the majority of the cases, the diagnosis was ascertained by ACE activity and Calretinin staining. However, in 9 cases, the diagnosis was possible with Calretinin staining but not with ACE: in 4 TA because of the absence of nerve hyperplasia, and in 5 cases because the biopsies were too superficial to examine the nerve hyperplasia. In addition, Calretinin was expressed in the gut as early as 22 gestational weeks. Conclusion The use of Calretinin staining may be superior to ACE activity, particularly in the context of TA, superficial biopsies, and prematurity, allowing earlier diagnosis.
Summary Embryonal rhabdomyosarcoma (ERMS), a soft tissue sarcoma, is one of the most common pediatric cancers. Certain ERMSs are associated with the DICER1 syndrome, a tumor predisposition syndrome ...caused by germ-line DICER1 mutations. Characteristic somatic mutations have also been identified in DICER1 -associated tumor types. These “hotspot” mutations affect the catalytic activity of the DICER1 ribonuclease IIIb domain. Primary ovarian ERMS (oERMS) is extremely rare. We present a case of a 6-year-old girl with an oERMS harboring 2 DICER1 mutations. The girl also exhibited other DICER1 phenotypes: cystic nephroma (CN) and multinodular goiter. Somatic investigations of the CN identified a hotspot DICER1 mutation different from that in the oERMS. Significantly, the CN presented at 12 years of age, which is much older than the previously reported age range of susceptibility. This report documents the occurrence of DICER1 mutations in a case of oERMS, expanding the spectrum of DICER1 -associated tumors.
DICER1 syndrome is an inherited disorder associated with at least a dozen rare, mainly pediatric‐onset tumors. Its characterization remains incomplete. Some studies suggested that neuroblastoma (NB) ...may be involved in this syndrome. Here, we describe the case of a 14‐year‐old female presenting with a multinodular goiter (MNG) and a collision tumor composed of NB and cystic nephroma (CN). She is a carrier of a deleterious germline mutation in exon 23 of DICER1 and harbored different somatic mutations in the CN and MNG. However, no second hit was found in the NB, questioning its status as a DICER1‐related tumor.
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