Table 1.
Summary of literature review of patients with Kabuki syndrome and a malignancya
| 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] | |
B-ALL B-cell acute lymphoblastic leukemia, BAP break-apart probe, BCL B-cell lymphoma, BM bone marrow, CD cluster of differentiation, CGH comparative genomic hybridization, CHARGE syndrome/MIM#214800 coloboma, heart defects, choanal atresia, retardation of growth/development, genital- and ear abnormalities, CNV copy number variation, COSMIC catalogue of somatic mutations in cancer, EBNA-2 Epstein-Barr nuclear-antigen 2, EBV Epstein-Barr virus, EMA epithelial membrane antigen, FISH fluorescence in situ hybridization, GFAP glial fibrillary acidic protein, GL germline, Het heterozygous, ISH in situ hybridization, Ki-67 Kiel clone 67, M months, Myf4 myogenin, MYOD1 myogenic differentiation 1, NA not analyzed/available Neg negative, NR not reported, OC Oral contraceptive, Pt patient, SMA smooth muscle actin, SOM reported as somatic variant in COSMIC database, TdT terminal deoxynucleotidyl transferase, T-ALL T-cell acute lymphoblastic leukemia, WHO World Health Organization, Yr year
aPatients S1 with Burkitt lymphoma with insufficient clinical information regarding Kabuki syndrome is not present in this table but is included in Supporting Table S4
bClinical diagnosis based on assessment of clinical features presented in the individual manuscripts by the author’s of the present study, see the “supplementary materials and methods” section
cDiagnosis, clinico- and histopathologic features as provided in the original manuscript. These may not fulfil the present WHO-criteria for the respective tumors
dReferences for common/general (clinical) presentation of individual tumor entities in Supporting data
eIncludes (other)potential predisposing (genetic) factors for the reported malignancy
fMorphology does not show anaplastic features suggestive of a TP53 germline variant [143, 144]
gInitial tumor diagnosed as spindle cell hemangioma, 2nd tumor at same site as giant cell fibroblastoma
hDiagnosed by long-distance polymerase chain reaction (PCR)
iKaryotype at time of tumor diagnosis (peripheral blood)
jAge at last examination