Introduction
Methods
Patient
Histopathology and immunohistochemistry
Molecular and bio-informatic analyses
Literature review
Results
Clinical history of the patient
Histopathological and fluorescence in situ hybridization (FISH) analysis
Molecular analysis
Literature review
Pt | Sex, age | KMT2D/KDM6A variant | COSMIC/SOM | Clinical diagnosis (variant neg/NA)b | Malignancyc | Histopathological features | Molecular tumor features | Common/general (clinical) presentation for reported tumor entity?d | Other potential predisposing or contributing factors?e | Ref. case |
---|---|---|---|---|---|---|---|---|---|---|
Bone- and soft-tissue tumors (n = 5) | ||||||||||
1 | F (10) | KMT2D, c.2558_2559delCT, p.(Pro853Argfs*3) | NO | Embryonal rhabdo-myosarcoma (ERMS, small pelvis) | Small blue round cell tumor with spindle cell features. No alveolar or anaplastic characteristics. desmin + , Myf4 ± , keratin ± , CD99 + , Myod1-, synaptophysin- | ERMS-methylation profile, typical ERMS CNVs | Typical age for ERMS. Small pelvis less common site and presentation | Nonef | this study | |
GL-variant KMT2D confirmed (Het.) | ||||||||||
2 | F (16) | NR. Normal karyotype, subtelomeric study and 22q11.2 FISH | (compatible with) Kabuki syndrome | Synovial sarcoma (SS) (right lung mass > 10 cm) | NR | NR | Common age. SS most common at extremities, trunk and head/neck. Thorax/lung is unusual but reported primary site | NR | [20] | |
3 | F (10) | NR, clinical diagnosis. G-banded karyotype normal | (compatible with) Kabuki syndrome | Low-grade fibromyxoid sarcoma (right postero-lateral chest wall) | Myxoid background, spindle cell population, curvilinear blood vessels. Vimentin + , S100-, desmin-, SMA-, CD34- | NR | Most common in young adults, slight male preponderance. 10 yrs is typical pediatric age, Trunk common presentation | NR | [21] | |
4 | F (10 & 12) | KMT2D, c.7307_7308insT (frameshift), p.(Ser2438Ilefs*11) | NO | Giant cell fibroblastomag (neck right-side) | 10 yr: mesenchymal mass, vascular malformations, spindle cells, CD34 + , SMA-, S-100-, GFAP-, EMA-, Ki-67 15% | NR | Pediatric tumor. Overall male preponderance. Head- and neck region uncommon but reported. Local recurrence is common | NR | [22] | |
12 yr: mesenchymal mass, vascular malformations, spindle cells, multinucleated giant cells, CD34 + , Vimentin + , SMA-, S-100-, CD99-, CD31-, EMA-, Ki-67 15% | NR | |||||||||
5 | F (10) | KMT2D, c.11233C > T, p.(Gln3745*) | YES/NO | Aggressive desmoid fibromatosis (occipital bone) | Locally invasive fibroblastic proliferation. Spindle-shaped cells, SMA + | NR | For pediatric age-group typical age. Head- and neck region less common but recurrently involved site | NR | [23] | |
Hematologic malignancies (n = 5) | ||||||||||
6 | M (5) | KMT2D, c.511-1G > A, p.? | YES/YES | Burkitt lymphoma (rhino-pharyngeal mass) | “Starry-sky” pattern, CD20 + , CD79 + , CD10 + , CD38 + , BCL6 + , BCL2-, CD3-, TdT-, Ki-67 > 98% | t(8;14) + h | Typical age and sex | NR | [24] | |
c.511-1G > A KMT2D heterozygous | ||||||||||
7 | M (3) | NR, clinical diagnosis. Normal karyotypei | (compatible with) Kabuki syndrome | Burkitt lymphoma (abdominal, mesenterium/ upper right quadrant, mesenteric lymphadenopathy) | Diffuse proliferation of lymphocytes. “Starry-sky” pattern, CD20 + , CD22 + , EBER-1 + (ISH), LMP-, EBNA-2- | NR | Typical age and sex | EBV + | [26] | |
8 | M (3) | KMT2D and KDM6A negative | (compatible with) Kabuki syndrome | Burkitt lymphoma (abdominal) | NR | NR | Typical age and sex | NR/insufficient information | [27] | |
9 | M (≥ 32) | KMT2D, c.12985C > T, p.(Gln4329*) | YES/YES | Hodgkin lymphoma | NR | NR | Age distribution and % EBV + vary according to (c)HL subtype | EBV + (under immunosuppression) | [28] | |
10 | F (2) | NR; 46,XX; no 22q11 or 4p16,3 microdeletion, normal subtelomeric FISH, normal CGH | (compatible with) Kabuki syndrome | Pre-B-ALL (BM) | CD19 + , CD24 + , CD13-, CD23-, CD65S- (BM smear) | diploid (DNA index 1.00), BCR/ABL, MLL/AF4, TEL/AML1, MLL/ENL negative | Typical age for pre- B-ALL, B-ALL > > T-ALL | Maternal uncle with leukemia at age: 3 1/2 years | [29] | |
CHARGE syndrome can not be fully excluded based on clinical features | ||||||||||
Embryonal tumors (n = 4) | ||||||||||
11 | F (3) | KMT2D, c.13285C > T, p.(Gln4429)* | NO | Wilms tumor/nephroblastoma | Mixed-type nephroblastoma, no anaplastic features. Blastemal and epithelial elements | NR | Typical pediatric renal tumor and age | NR | [30] | |
12 | F (0) | NR, clinical diagnosis. PTPN11 negative, normal array-CGH | (compatible with) Kabuki syndrome | Neuroblastoma (adrenal mass) | NR | no MYCN amplification | Most common extracranial pediatric tumor, majority diagnosed < 5 years (median ≈18 M.) | NR | [32] | |
13 | F (NR) | NR, clinical diagnosis | (compatible with) Kabuki syndrome | Neuroblastoma | NR | NR | NR | [31] | ||
14 | M (6) | NR, clinical diagnosis | (compatible with) Kabuki syndrome | Fetal-type hepatoblastoma | NR | NR | Most common malignant pediatric liver tumor, majority diagnosed < 5 years (median ≈ 18 M.) | NR | [32] | |
Other (n = 4) | ||||||||||
15 | F (23) | KMT2D, c.16085_16086delAG, p.Lys5362Serfs*96 | NO | Ependymoma (lumbar endocanalar mass, filum terminale) | Oval/elongated cells, mild nuclear atypia, eosinophilic fibrillary stroma, fascicular/ vaguely perivascular growth pattern. GFAP + , EMA + , Ki-67 3–5% | NR | Intracranial ependymoma's are more prevalent in the pediatric age group, spinal more typical presentation for adults | NR | [33] | |
16 | F (15) | KMT2D, c.8594dupC | NO | Hepatocellular carcinoma (HCC) | Hepatic adenomatosis, macrovesicular steatosis, extramedullary hematopoiesis. Well-differentiated HCC with a hepatic adenoma (> 8 cm), > 10 satellite lesions | NR | OC use is associated with hepatic adenomatosis and hepatic adenomas may transform to HCC. HCC is a clinical and molecular highly heterogeneous disease | Hepatic adenomatosis, high-dose estrogen OC | [34] | |
17 | F (16) | KMT2D c.2871dupA, p.(Glu958Argfs*11) | NO | Carcinoma, unknown primary origin. Lymphadenopathy from neck to abdomen, sternal, liver and kidney lesions | Cervical lymph node: poorly differentiated carcinoma, EBV-associated | NR | NA | EBV-associated? | [35] | |
18 | F (≤ 31)j | KDM6A, c.1846dupA, p.Thr616Asnfs*5 | NO | Endometrial cancer | NA | NA | ≤5% of endometrial cancer diagnosed in women ≤ 40 years | NA | [4] |