Article

Open Access  |  Case Report
J Transl Genet Genom 2023;7:166-82. 10.20517/jtgg.2022.18 © The Author(s) 2023.

Kabuki syndrome and rare tumors in a young girl carrying a frameshift KMT2D mutation

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1Pediatric Neurology, University Hospital of Pisa, Pisa 56124, Italy.

2Pediatric Endocrinology, University Hospital of Pisa, Pisa 56124, Italy.

3Department of Surgery, University Hospital of Pisa, Pisa 56124, Italy.

4Medical Genetics, University Hospital of Pisa, Pisa 56124, Italy.

5Pediatric Clinic, University Hospital of Pisa, Pisa 56124, Italy.

Correspondence to: Dr. Tommaso Baldaccini, Pediatric Clinic, University Hospital of Pisa, via Roma 67, Pisa 56124, Italy. E-mail: tommasobaldaccini94@gmail.com

This article belongs to the Special Issue Genetics of Neurodevelopmental Disorders
© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Abstract

Kabuki syndrome (KS) is a genetic disorder characterized by typical facial dimorphisms, various degrees of cognitive disability, and congenital anomalies involving the heart, kidneys, gastrointestinal system, and bones. It is accompanied by hypotonia, failure to thrive, obesity, and immunodeficiency. Association with neoplastic lesions has been recently described. We report a 13-year-old girl with KS, an insulinoma, and a benign phyllodes breast tumor with two hepatic lesions: a neuroendocrine tumor metastasis and a ciliated foregut cyst associated with hepatic fibrosis. She had a pilomatrixoma and a junctional melanocytic nevus with cytological atypia. Genetic analysis revealed a heterozygous frameshift variant in the KMT2D gene. Somatic KMT2D variants are in various types of tumors. The role of KMT2D variants in malignancies in KS appears to be related to defective transcription regulation and altered gene expression; however, the mechanism remains unclear. This aims to clarify the relationship between KMT2D gene variants, KS, and susceptibility to neoplastic lesions. For this purpose, a more extensive case series will be needed to accurately describe the patients' neoplastic phenotypes and precise genetic characterization.

Keywords

Kabuki syndrome, KMT2D gene, neoplastic lesions

INTRODUCTION

Kabuki syndrome (KS, OMIM ID: 147920; http://www.omim.org) is a congenital disorder characterized by atypical facies resembling Japanese traditional Kabuki actors. It is associated with mild-to-moderate cognitive disability, immunodeficiency, seizures, and internal malformations involving the heart, kidneys, eyes, skeleton, and gastrointestinal system.

Two genes are involved in KS: KMT2D (lysine methyltransferase 2D; NM_003482.3; formerly MLL2) at 12q13.12 (KS subtype-1; OMIM ID: 147920) and KDM6A (lysine (K)-specific demethylase 6A; NM_021140.2) at Xp11.3 (X-linked KS subtype-2; OMIM ID: 300867)[1,2]. Most patients (> 80%) with a clinical diagnosis of KS harbor pathogenic variants in KMT2D, whereas a smaller number (6%-10%) have KDM6A. Other genes in KS-like phenotypes include RAP1A/RAP1B, HNRNPK, and ZMZ1. Other genes associated may exist[3]. More than 650 genetic variants of the KMT2D gene have been described, including missense deletions, indels, duplications, frameshifts, and splice site variants; most of these variants lead to truncated protein synthesis[4] [Table 1].

Table 1

The known variants of KMT2D and KDM6A are associated with Kabuki syndrome[5]

ID Inheritance Exon/intron Variant AA change
KMT2D
Non-sense
KB49 NA ex 5 c.669T > G p. (Tyr223*)
KB343 NA ex 8 c.1016G > A p. (Trp339*)
KB35 NA ex 10 c.1921G > T p. (Glu641*)
KB33 NA ex 16 c.4419G > A p. (Trp1473*)
KB63 NA ex 19 c.4895delC p. (Ser1632*)
KB317 NA ex 22 c.5212G > T p. (Glu1738*)
KB336 De novo ex 22 c.5269C > T p. (Arg1757*)
KB262 NA ex 26 c.5674C > T p. (Gln1892*)
KB429 NA ex 26 c.5707C > T p. (Arg1903*)
KB26 NA ex 31 c.6295C > T p. (Arg2099*)
KB502 De novo ex 31 c.7228C > T p. (Arg2410*)
KB66 NA ex 31 c.7246C > T p. (Gln2416*)
KB59 NA ex 31 c.7903C > T p. (Arg2635*)
KB153 De novo ex 31 c.7903C > T p. (Arg2635*)
KB226 De novo ex 31 c.7903C > T p. (Arg2635*)
KB338 De novo ex 31 c.7933C > T p. (Arg2645*)
KB198 De novo ex 31 c.7936G > T p. (Glu2646*)
KB352 NA ex 32 c.8227C > T p. (Gln2743*)
KB323 NA ex 33 c.8311C > T p. (Arg2771*)
KB289 NA ex 34 c.8743C > T p. (Arg2915*)
KB422 De novo ex 34 c.9396C > A p. (Cys3132*)
KB186 De novo ex 34 c.9961C > T p. (Arg3321*)
KB56 De novo ex 34 c.10135C > T p. (Gln3379*)
KB168 De novo ex 39 c.10750C > T p. (Gln3584*)
KB46 De novo ex 39 c.10841C > G p. (Ser3614*)
KB41 NA ex 39 c.11119C > T p. (Arg3707*)
KB44 NA ex 39 c.11119C > T p. (Arg3707*)
KB42 De novo ex 39 c.11269C > T p. (Gln3757*)
KB25 NA ex 39 c.11434 C > T p. (Gln3812*)
KB244 De novo ex 39 c.11674 C > T p. (Gln3892*)
KB178 NA ex 39 c.11704C > T p. (Gln3902*)
KB425 De novo ex 39 c.11731C > T p. (Gln3911*)
KB461a NA ex 39 c.11749C > T p. (Gln3917*)
KB463 NA ex 39 c.11845C > T p. (Gln3949*)
KB181 NA ex 39 c.11869C > T p. (Gln3957*)
KB358 NA ex 39 c.11944C > T p. (Arg3982*)
KB40 NA ex 39 c.12274C > T p. (Gln4092*)
KB114 De novo ex 39 c.12274C > T p. (Gln4092*)
KB65 NA ex 39 c.12076C > T p. (Gln4026*)
KB333 NA ex 39 c.12703C > T p. (Gln4235*)
KB410 NA 39 c.12760C > T p. (Gln4254*)
KB82 De novo ex 39 c.12844C > T p. (Arg4282*)
KB350 De novo ex 39 c.12844C > T p. (Arg4282*)
KB189 De novo ex 39 c.12955A > T p. (Arg4319*)
KB183 De novo ex 39 c.13450C > T p. (Arg4484*)
KB450 NA ex 39 c.13450C > T p. (Arg4484*)
KB175 De novo ex 39 c.13507C > T p. (Gln4503*)
KB73 De novo ex 40 c.13666A > T p. (Lys4556*)
KB83 NA ex 48 c.15022G > T p. (Glu5008*)
KB377 NA ex 48 c.15061C > T p. (Arg5021*)
KB45 NA ex 48 c.15079C > T p. (Arg5027*)
KB72 NA ex 48 c.15079C > T p. (Arg5027*)
KB362 NA ex 50 c.16018C > T p. (Arg5340*)
KB130 NA ex 52 c.16360C > T p. (Arg5454*)
Frameshift
KB454 NA ex 3 c.234_235delGC p. (Gln79Alafs*7)
KB469 NA ex 3 c.345dupA p. (Ser116Ilefs*7)
KB337 NA ex 4 c.446_449delTATG p. (Val149Glyfs*58)
KB75 De novo ex 4 c.472delT p. (Cys158Valfs*50)
KB8 De novo ex 5 c.588delC p. (Cys197Alafs*11)
KB58 NA ex 6 c.705delA p. (Glu237Serfs*24)
KB57 NA ex 8 c.1035_1036delCT p. (Cys346Serfs*17)
KB89 NA ex 10 c.1345_1346delCT p. (Leu449Valfs*5)
KB156 De novo ex 10 c.1503dupT p. (Pro502Serfs*7)
KB116 NA ex 10 c.1634delT p. (Leu545Argfs*385)
KB349 NA ex 10 c.1634delT p. (Leu545Argfs*385)
KB545 NA 10 c.2091dupC p. (Thr698Hisfs*6)
KB369 NA ex 11 c.3596_3597del p. (Leu1199Hisfs*7)
KB48 De novo ex 11 c.2993dupC p. (Met999Tyrfs*69)
KB203 NA ex 11 c.3161_3171del
CGTTGAGTCCC
p. (Pro1054Hisfs*10)
KB309 NA ex 11 c.3730delG p. (Val1244Serfs*86)
KB142 De novo ex 13 c.4021delG p. (Val1341Leufs*35)
KB311 NA ex 14 c.4135_4136delAT p. (Met1379Valfs*52)
KB524 NA 14 c.4135_4136delAT p. (Met1379Valfs*52)
KB188 De novo ex 16 c.4454delC p. (Pro1485Leufs*21)
KB159 NA ex 19 c.4896_4905del
AGATGCCCTT
p. (Asp1633Alafs*86)
KB443a De novo ex 25 c.5575delG p. (Asp1859Thrfs*17)
KB3 NA ex 26 c.5652dup p. (Lys1885Glnfs*18)
KB84 NA ex 26 c.5779delC p. (Gln1927Lysfs120*)
KB146 De novo ex 27 c.5857delC p. (Leu1953Trpfs*94)
KB208 NA ex 28 c.5954delC p. (Thr1985Lysfs*62)
KB221 De novo ex 29 c.6149_6150delGA p. (Arg2050Lysfs*6)
KB525 NA 30 c.6212_6213delAC p. (His2071Profs*10)
KB152 De novo ex 31 c.6583delA p. (Thr2195Profs*69)
KB267 NA ex 31 c.6594delC p. (Tyr2199Ilefs*65)
KB79 De novo ex 31 c.6595delT p. (Tyr2199Ilefs*65)
KB102 De novo ex 31 c.6595delT p. (Tyr2199Ilefs*65)
KB342 NA ex 31 c.6595delT p. (Tyr2199Ilefs*65)
KB67 De novo ex 31 c.6638_6641delGCGC p. (Gly2213Alafs*50)
KB176 NA ex 31 c.6738delA p. (Lys2246Asnfs*18)
KB253 NA ex 31 c.6794delG p. (Gly2265Glufs*21)
KB278 NA ex 31 c.7481dupT p. (Ala2496Serfs*10)
KB313 De novo ex 32 c.8196delG p. (Ser2733Valfs*24)
KB80 NA ex 33 c.8273delG p. (Gly2758Alafs*29)
KB243 De novo ex 34 c.8430_8431insAA p. (Gln2811Asnfs*41)
KB182 NA ex 34 c.9203delA p. (Gln3068Glyfs*3)
KB30 NA ex 38 c.10606delC p. (Arg3536Alafs*122)
KB101 De novo ex 39 c.11066_11078delCT
GGATCCCTGGC
p. (Ala3689Valfs*56)
KB504 De novo ex 39 c.11093dupG p. (Phe3699Leufs*14)
KB495 De novo ex 39 c.11715delG p. (Gln3905Hisfs*74)
KB172 NA ex 39 c.12647delC p. (Pro4216Leufs*62)
KB192 De novo ex 39 c.12966delA p. (Gln4322Hisfs*62)
KB54 NA ex 39 c.13129dupT p. (Trp4377Leufs*33)
KB121 De novo ex 39 c.13277dupT p. (Ala4428Serfs*59)
KB540 NA 41 c.13780delG p. (Ala4594Profs*23)
KB123 De novo ex 42 c.13884dupC p. (Thr4629Hisf*18)
KB481 NA ex 42 c.13895dupC p. (Ser4633Ilefs*14)
KB197 De novo ex 47 c.14592dupG p. (Pro4865Alafs*48)
KB125 NA ex 48 c.15031delG p. (Glu5011Serfs*40)
KB16 De novo ex 48 c.15374dupT p. (Phe5126Leufs*12)
KB535 NA 50 c.16043_16044delAC p. (His5348Leufs*14)
KB355 NA ex 53 c.16438_16441delAACT p. (Asn5480Val*6)
KB64 NA ex 53 c.16469_16470delAA p. (Lys5490Argfs*21)
KB533 NA 53 c.16469_16470delAA p. (Lys5490Argfs*21)
Missense
KB21a inherited M ex 3 c.346T > C p. (Ser116Pro)
KB21a,b inherited M ex 4 c.510G > C p. Gln170His
KB256 NA ex 5 c.626C > T p. (Thr209Ile)
KB458 NA ex 8 c.1076G > C p. (Arg359Pro)
KB269 inherited M ex 10 c.1940C > A p. (Pro647Gln)
KB126 NA ex 10 c.2074C > A p. (Pro692Thr)
KB374c inherited M ex 10 c.2074C > A p. (Pro692Thr)
KB487 NA ex 10 c.2654C > T p. (Pro885Leu)
KB370a Inherited P-M ex 11 c.2837C > G p. (Ala946Gly)
KB215 Inherited M ex 11 c.3392C > T p. (Pro1131Leu)
KB341 Inherited M ex 11 c.3392C > T p. (Pro1131Leu)
KB222 Inherited P-M ex 11 c.3572C > T p. (Pro1191Leu)
KB32 Inherited P ex 11 c.3773G > A p. (Arg1258Gln)
KB307 De novo ex 14 c.4171G > A p. (Glu1391Lys)
KB28a Inherited M ex 15 c.4249A > G p. (Met1417Val)
KB28a Inherited M ex 15 c.4252C > A p. (Leu1418Met)
KB174 Inherited M ex 15 c.4283T > C p. (Ile1428Thr)
KB138 NA ex 16 c.4427C > G p. (Ser1476Cys)
KB34 Inherited P ex 16 c.4565A > G p. (Gln1522Arg)
KB535 NA 25 c.5549G > A p. (Gly1850Asp)
KB119 Inherited M ex 31 c.6638G > A p. (Gly2213Asp)
KB204c Inherited M ex 31 c.6638G > A p. (Gly2213Asp)
KB330a NA ex 31 c.6733C > G p. (Leu2245Val)
KB326c Inherited M ex 31 c.6811C > T p. (Pro2271Ser)
KB107a NA ex 31 c.6970C > A p. (Pro2324Thr)
KB430 NA ex 31 c.7378C > T p. (Arg2460Cys)
KB122 Inherited M ex 31 c.7829T > C p. (Leu2610Pro)
KB287 Inherited M ex 31 c.7829T > C p. (Leu2610Pro)
KB27 NA ex 34 c.8521C > A p. (Pro2841Thr)
KB330a NA ex 34 c.8774C > T p. (Ala2925Val)
KB443a Inherited M ex 34 c.9971G > T p. (Gly3324Val)
KB326c Inherited P ex 34 c.10192A > G p. (Met3398Val)
KB357 Inherited P ex 34 c.10192A > G p. (Met3398Val)
KB297 NA ex 35 c.10256A > G p. (Asp3419Gly)
KB378 NA ex 35 c.10256A > G p. (Asp3419Gly)
KB292 De novo ex 37 c.10499G > T p. (Gly3500Val)
KB86a NA ex 39 c.10966C > T p. (Arg3656Cys)
KB374c Inherited P ex 39 c.11380C > T p. (Pro3794Ser)
KB293 Inherited P ex 39 c.11794C > G p. (Gln3932Glu)
KB204c Inherited P ex 39 c.12070A > G p. (Lys4024Glu)
KB385 NA ex 39 c.12302A > C p. (Gln4101Pro)
KB247 NA ex 39 c.12485G > A p. (Arg4162Gln)
KB107a NA ex 39 c.12488C > T p. (Pro4163Leu)
KB170 Inherited M ex 39 c.13256C > T p. (Pro4419Leu)
KB512 NA 45 c.14381A > G p. (Lys4794Arg)
KB86a NA ex 48 c.14893G > A p. (Ala4965Thr)
KB38a De novo ex 48 c.15084C > G p. (Asp5028Glu)
KB154 NA ex 48 c.15088C > T p. (Arg5030Cys)
KB185 De novo ex 48 c.15088C > T p. (Arg5030Cys)
KB423 Inherited P ex 48 c.15089G > A p. (Arg5030His)
KB38a De novo ex 48 c.15100T > G p. (Phe5034Val)
KB76 De novo ex 48 c.15176A > C p. (His5059Pro)
KB129 NA ex 48 c.15292A > C p. (Thr5098Pro)
KB462 De novo ex 48 c.15310T > C p. (Cys5104Arg)
KB171 Inherited M ex 48 c.15565G > A p. (Gly5189Arg)
KB264 NA ex 48 c.15640C > T p. (Arg5214Cys)
KB376 NA ex 48 c.15640C > T p. (Arg5214Cys)
KB24 De novo ex 48 c.15641G > A p. (Arg5214His)
KB219 NA ex 48 c.15641G > A p. (Arg5214His)
KB408 De novo ex 48 c.15641G > A p. (Arg5214His)
KB109 De novo ex 48 c.15649T > C p. (Trp5217Arg)
KB17 De novo ex 50 c.16019G > A p. (Arg5340Gln)
KB169 De novo ex 51 c.16273G > A p. (Glu5425Lys)
KB90 NA ex 51 c.16295G > A p. (Arg5432Gln)
KB467 NA ex 51 c.16295G > A p. (Arg5432Gln)
KB480 NA ex 52 c.16385A > G p. (Asp5462Gly)
KB177 De novo ex 52 c.16412G > T p. (Arg5471Met)
KB489 NA ex 53 c.16498C > T p. (Arg5500Trp)
KB120 De novo ex 54 c.16528T > G p. (Tyr5510Asp)
Indel
KB404 Inherited M ex 10 c.2283_2309del p. (Ala765_Gln773del)
KB274 NA ex 10 c.2532_2591del p. (Arg845_Pro864del)
KB370d De novo ex 14 c.4202_4210del p. (Ser1401_Cys1403del)
KB384 NA ex 39 c.11220_11222dup p. (Gln3745dup)
KB461a,d NA ex 39 c.11220_11222dup p. (Gln3745dup)
KB281 Inherited M ex 39 c.11714_11716dup p. (Gln3905dup)
KB71 Inherited M ex 39 c.11819_11836dup p. (Leu3940_Gln3945dup)
KB227 Inherited P ex 39 c.11843_11860del p. (L3948_Q3953del)
KB228 Inherited P ex 39 c.11854_11874dup p. (Q3952_Q3958dup)
KB77 NA ex 48 c.15163_15168dup p. (Asp5055_Leu5056dup)
KB403 De novo ex 53 c.16489_16491del p. (Ile5497del)
KB53 NA ex 53 c.16489_16491del p. (Ile5497del)
Splice site
KB286 De novo int 2-3 c.177-2A > C r.177_400del224;
p. S59Rfs*86
KB31 NA int 3-4 c.400 þ 1 G > A r.177_400del224;
p. Ser59Argfs*86
KB20 De novo int 3-5 c.401-3 A > G r.400_401insAG;
p. Gly134Glufs*75
KB442 NA int 6-7 c.840-6delC r.?
KB519 NA int 13-14 c.4132-2A > G r.?
KB529 NA int 16-17 c.4584-6C > G r.?
KB210 De novo in 17-18 c.4693 þ 1G > A r.4681_4693del13;
p. Val1561Argsfsplice*11
KB29 NA int 42-43 c.13999 þ 5 G > A r.13840_13999del160;
p. Asn4614Ilefs*5
KB290 De novo int 47-48 c.14643 þ 1G > A r.14644_14875del232;
p. Glu4882Profs*36
KB195 De novo int 47-48 c.14644-3C > G r.14644_14875del232;
p. Gln4882Profs*36
KB7 De novo int 44-45 c.14252-6_14252-5insGAAA r.14252_14382del131;
p. Val4751_Glufsplice*22
KB360 NA int 47-48 c.14644-2A > T r.?
KB496 NA int 53-54 c.16520_16521 þ 1delAGG r.?
Gross deletion
KB43e NA ex 48-51 c.15785-238_16168delins p.?
KDM6A
Non-sense KB215f De novo ex 6 c.514C > T p. (Arg172*)
KB341 De novo ex 6 c.514C > T p. (Arg172*)
Frameshift
KB39 NA ex 16 c.1846_1849del p. (Thr616tyrfs*8)
KB141 NA ex 17 c.2118_2119ins p. (G707Hfs*13)
KB434 NA ex 17 c.2515_2518del p. (Asn839Valfs*27)
KB381 NA ex 20 c.3044delC p. (Thr1015Metfs*33)
Missense
KB415 NA ex 16 c.1843C > T p. (Leu615Phe)
KB272 NA ex 17 c.2326G > T p. (Asp776Tyr)
KB131 De novo ex 20 c.2939A > T p. (Asp980Val)
KB380 De novo ex 26 c.3743A > G p. (Gln1248Arg)
Gross deletions
KB11 NA ex 1-2 p. ?
KB50 De novo ex 5-9 p. ?
Splice site
KB314 De novo int 11-12 c.975-1G > A r.876_1320del; p. Cys293IlefsX26
KB127 De novo int 22-23 c.3384 þ 3_3384 þ 6del r.3210_3284del; p. Asn1070_Lys1094del
KMT2D
Non-sense
KB49 NA ex 5 c.669T > G p. (Tyr223*)
KB343 NA ex 8 c.1016G > A p. (Trp339*)
KB35 NA ex 10 c.1921G > T p. (Glu641*)
KB33 NA ex 16 c.4419G > A p. (Trp1473*)
KB63 NA ex 19 c.4895delC p. (Ser1632*)
KB317 NA ex 22 c.5212G > T p. (Glu1738*)
KB336 De novo ex 22 c.5269C > T p. (Arg1757*)
KB262 NA ex 26 c.5674C > T p. (Gln1892*)
KB429 NA ex 26 c.5707C > T p. (Arg1903*)
KB26 NA ex 31 c.6295C > T p. (Arg2099*)
KB502 De novo ex 31 c.7228C > T p. (Arg2410*)
KB66 NA ex 31 c.7246C > T p. (Gln2416*)
KB59 NA ex 31 c.7903C > T p. (Arg2635*)
KB153 De novo ex 31 c.7903C > T p. (Arg2635*)
KB226 De novo ex 31 c.7903C > T p. (Arg2635*)
KB338 De novo ex 31 c.7933C > T p. (Arg2645*)
KB198 De novo ex 31 c.7936G > T p. (Glu2646*)
KB352 NA ex 32 c.8227C > T p. (Gln2743*)
KB323 NA ex 33 c.8311C > T p. (Arg2771*)
KB289 NA ex 34 c.8743C > T p. (Arg2915*)
KB422 De novo ex 34 c.9396C > A p. (Cys3132*)
KB186 De novo ex 34 c.9961C > T p. (Arg3321*)
KB56 De novo ex 34 c.10135C > T p. (Gln3379*)
KB168 De novo ex 39 c.10750C > T p. (Gln3584*)
KB46 De novo ex 39 c.10841C > G p. (Ser3614*)
KB41 NA ex 39 c.11119C > T p. (Arg3707*)
KB44 NA ex 39 c.11119C > T p. (Arg3707*)
KB42 De novo ex 39 c.11269C > T p. (Gln3757*)
KB25 NA ex 39 c.11434 C > T p. (Gln3812*)
KB244 De novo ex 39 c.11674 C > T p. (Gln3892*)
KB178 NA ex 39 c.11704C > T p. (Gln3902*)
KB425 De novo ex 39 c.11731C > T p. (Gln3911*)
KB461a NA ex 39 c.11749C > T p. (Gln3917*)
KB463 NA ex 39 c.11845C > T p. (Gln3949*)
KB181 NA ex 39 c.11869C > T p. (Gln3957*)
KB358 NA ex 39 c.11944C > T p. (Arg3982*)
KB40 NA ex 39 c.12274C > T p. (Gln4092*)
KB114 De novo ex 39 c.12274C > T p. (Gln4092*)
KB65 NA ex 39 c.12076C > T p. (Gln4026*)
KB333 NA ex 39 c.12703C > T p. (Gln4235*)
KB410 NA 39 c.12760C > T p. (Gln4254*)
KB82 De novo ex 39 c.12844C > T p. (Arg4282*)
KB350 De novo ex 39 c.12844C > T p. (Arg4282*)
KB189 De novo ex 39 c.12955A > T p. (Arg4319*)
KB183 De novo ex 39 c.13450C > T p. (Arg4484*)
KB450 NA ex 39 c.13450C > T p. (Arg4484*)
KB175 De novo ex 39 c.13507C > T p. (Gln4503*)
KB73 De novo ex 40 c.13666A > T p. (Lys4556*)
KB83 NA ex 48 c.15022G > T p. (Glu5008*)
KB377 NA ex 48 c.15061C > T p. (Arg5021*)
KB45 NA ex 48 c.15079C > T p. (Arg5027*)
KB72 NA ex 48 c.15079C > T p. (Arg5027*)
KB362 NA ex 50 c.16018C > T p. (Arg5340*)
KB130 NA ex 52 c.16360C > T p. (Arg5454*)
Frameshift
KB454 NA ex 3 c.234_235delGC p. (Gln79Alafs*7)
KB469 NA ex 3 c.345dupA p. (Ser116Ilefs*7)
KB337 NA ex 4 c.446_449delTATG p. (Val149Glyfs*58)
KB75 De novo ex 4 c.472delT p. (Cys158Valfs*50)
KB8 De novo ex 5 c.588delC p. (Cys197Alafs*11)
KB58 NA ex 6 c.705delA p. (Glu237Serfs*24)
KB57 NA ex 8 c.1035_1036delCT p. (Cys346Serfs*17)
KB89 NA ex 10 c.1345_1346delCT p. (Leu449Valfs*5)
KB156 De novo ex 10 c.1503dupT p. (Pro502Serfs*7)
KB116 NA ex 10 c.1634delT p. (Leu545Argfs*385)
KB349 NA ex 10 c.1634delT p. (Leu545Argfs*385)
KB545 NA 10 c.2091dupC p. (Thr698Hisfs*6)
KB369 NA ex 11 c.3596_3597del p. (Leu1199Hisfs*7)
KB48 De novo ex 11 c.2993dupC p. (Met999Tyrfs*69)
KB203 NA ex 11 c.3161_3171del
CGTTGAGTCCC
p. (Pro1054Hisfs*10)
KB309 NA ex 11 c.3730delG p. (Val1244Serfs*86)
KB142 De novo ex 13 c.4021delG p. (Val1341Leufs*35)
KB311 NA ex 14 c.4135_4136delAT p. (Met1379Valfs*52)
KB524 NA 14 c.4135_4136delAT p. (Met1379Valfs*52)
KB188 De novo ex 16 c.4454delC p. (Pro1485Leufs*21)
KB159 NA ex 19 c.4896_4905del
AGATGCCCTT
p. (Asp1633Alafs*86)
KB443a De novo ex 25 c.5575delG p. (Asp1859Thrfs*17)
KB3 NA ex 26 c.5652dup p. (Lys1885Glnfs*18)
KB84 NA ex 26 c.5779delC p. (Gln1927Lysfs120*)
KB146 De novo ex 27 c.5857delC p. (Leu1953Trpfs*94)
KB208 NA ex 28 c.5954delC p. (Thr1985Lysfs*62)
KB221 De novo ex 29 c.6149_6150delGA p. (Arg2050Lysfs*6)
KB525 NA 30 c.6212_6213delAC p. (His2071Profs*10)
KB152 De novo ex 31 c.6583delA p. (Thr2195Profs*69)
KB267 NA ex 31 c.6594delC p. (Tyr2199Ilefs*65)
KB79 De novo ex 31 c.6595delT p. (Tyr2199Ilefs*65)
KB102 De novo ex 31 c.6595delT p. (Tyr2199Ilefs*65)
KB342 NA ex 31 c.6595delT p. (Tyr2199Ilefs*65)
KB67 De novo ex 31 c.6638_6641delGCGC p. (Gly2213Alafs*50)
KB176 NA ex 31 c.6738delA p. (Lys2246Asnfs*18)
KB253 NA ex 31 c.6794delG p. (Gly2265Glufs*21)
KB278 NA ex 31 c.7481dupT p. (Ala2496Serfs*10)
KB313 De novo ex 32 c.8196delG p. (Ser2733Valfs*24)
KB80 NA ex 33 c.8273delG p. (Gly2758Alafs*29)
KB243 De novo ex 34 c.8430_8431insAA p. (Gln2811Asnfs*41)
KB182 NA ex 34 c.9203delA p. (Gln3068Glyfs*3)
KB30 NA ex 38 c.10606delC p. (Arg3536Alafs*122)
KB101 De novo ex 39 c.11066_11078delCT
GGATCCCTGGC
p. (Ala3689Valfs*56)
KB504 De novo ex 39 c.11093dupG p. (Phe3699Leufs*14)
KB495 De novo ex 39 c.11715delG p. (Gln3905Hisfs*74)
KB172 NA ex 39 c.12647delC p. (Pro4216Leufs*62)
KB192 De novo ex 39 c.12966delA p. (Gln4322Hisfs*62)
KB54 NA ex 39 c.13129dupT p. (Trp4377Leufs*33)
KB121 De novo ex 39 c.13277dupT p. (Ala4428Serfs*59)
KB540 NA 41 c.13780delG p. (Ala4594Profs*23)
KB123 De novo ex 42 c.13884dupC p. (Thr4629Hisf*18)
KB481 NA ex 42 c.13895dupC p. (Ser4633Ilefs*14)
KB197 De novo ex 47 c.14592dupG p. (Pro4865Alafs*48)
KB125 NA ex 48 c.15031delG p. (Glu5011Serfs*40)
KB16 De novo ex 48 c.15374dupT p. (Phe5126Leufs*12)
KB535 NA 50 c.16043_16044delAC p. (His5348Leufs*14)
KB355 NA ex 53 c.16438_16441delAACT p. (Asn5480Val*6)
KB64 NA ex 53 c.16469_16470delAA p. (Lys5490Argfs*21)
KB533 NA 53 c.16469_16470delAA p. (Lys5490Argfs*21)
Missense
KB21a inherited M ex 3 c.346T > C p. (Ser116Pro)
KB21a,b inherited M ex 4 c.510G > C p. Gln170His
KB256 NA ex 5 c.626C > T p. (Thr209Ile)
KB458 NA ex 8 c.1076G > C p. (Arg359Pro)
KB269 inherited M ex 10 c.1940C > A p. (Pro647Gln)
KB126 NA ex 10 c.2074C > A p. (Pro692Thr)
KB374c inherited M ex 10 c.2074C > A p. (Pro692Thr)
KB487 NA ex 10 c.2654C > T p. (Pro885Leu)
KB370a Inherited P-M ex 11 c.2837C > G p. (Ala946Gly)
KB215 Inherited M ex 11 c.3392C > T p. (Pro1131Leu)
KB341 Inherited M ex 11 c.3392C > T p. (Pro1131Leu)
KB222 Inherited P-M ex 11 c.3572C > T p. (Pro1191Leu)
KB32 Inherited P ex 11 c.3773G > A p. (Arg1258Gln)
KB307 De novo ex 14 c.4171G > A p. (Glu1391Lys)
KB28a Inherited M ex 15 c.4249A > G p. (Met1417Val)
KB28a Inherited M ex 15 c.4252C > A p. (Leu1418Met)
KB174 Inherited M ex 15 c.4283T > C p. (Ile1428Thr)
KB138 NA ex 16 c.4427C > G p. (Ser1476Cys)
KB34 Inherited P ex 16 c.4565A > G p. (Gln1522Arg)
KB535 NA 25 c.5549G > A p. (Gly1850Asp)
KB119 Inherited M ex 31 c.6638G > A p. (Gly2213Asp)
KB204c Inherited M ex 31 c.6638G > A p. (Gly2213Asp)
KB330a NA ex 31 c.6733C > G p. (Leu2245Val)
KB326c Inherited M ex 31 c.6811C > T p. (Pro2271Ser)
KB107a NA ex 31 c.6970C > A p. (Pro2324Thr)
KB430 NA ex 31 c.7378C > T p. (Arg2460Cys)
KB122 Inherited M ex 31 c.7829T > C p. (Leu2610Pro)
KB287 Inherited M ex 31 c.7829T > C p. (Leu2610Pro)
KB27 NA ex 34 c.8521C > A p. (Pro2841Thr)
KB330a NA ex 34 c.8774C > T p. (Ala2925Val)
KB443a Inherited M ex 34 c.9971G > T p. (Gly3324Val)
KB326c Inherited P ex 34 c.10192A > G p. (Met3398Val)
KB357 Inherited P ex 34 c.10192A > G p. (Met3398Val)
KB297 NA ex 35 c.10256A > G p. (Asp3419Gly)
KB378 NA ex 35 c.10256A > G p. (Asp3419Gly)
KB292 De novo ex 37 c.10499G > T p. (Gly3500Val)
KB86a NA ex 39 c.10966C > T p. (Arg3656Cys)
KB374c Inherited P ex 39 c.11380C > T p. (Pro3794Ser)
KB293 Inherited P ex 39 c.11794C > G p. (Gln3932Glu)
KB204c Inherited P ex 39 c.12070A > G p. (Lys4024Glu)
KB385 NA ex 39 c.12302A > C p. (Gln4101Pro)
KB247 NA ex 39 c.12485G > A p. (Arg4162Gln)
KB107a NA ex 39 c.12488C > T p. (Pro4163Leu)
KB170 Inherited M ex 39 c.13256C > T p. (Pro4419Leu)
KB512 NA 45 c.14381A > G p. (Lys4794Arg)
KB86a NA ex 48 c.14893G > A p. (Ala4965Thr)
KB38a De novo ex 48 c.15084C > G p. (Asp5028Glu)
KB154 NA ex 48 c.15088C > T p. (Arg5030Cys)
KB185 De novo ex 48 c.15088C > T p. (Arg5030Cys)
KB423 Inherited P ex 48 c.15089G > A p. (Arg5030His)
KB38a De novo ex 48 c.15100T > G p. (Phe5034Val)
KB76 De novo ex 48 c.15176A > C p. (His5059Pro)
KB129 NA ex 48 c.15292A > C p. (Thr5098Pro)
KB462 De novo ex 48 c.15310T > C p. (Cys5104Arg)
KB171 Inherited M ex 48 c.15565G > A p. (Gly5189Arg)
KB264 NA ex 48 c.15640C > T p. (Arg5214Cys)
KB376 NA ex 48 c.15640C > T p. (Arg5214Cys)
KB24 De novo ex 48 c.15641G > A p. (Arg5214His)
KB219 NA ex 48 c.15641G > A p. (Arg5214His)
KB408 De novo ex 48 c.15641G > A p. (Arg5214His)
KB109 De novo ex 48 c.15649T > C p. (Trp5217Arg)
KB17 De novo ex 50 c.16019G > A p. (Arg5340Gln)
KB169 De novo ex 51 c.16273G > A p. (Glu5425Lys)
KB90 NA ex 51 c.16295G > A p. (Arg5432Gln)
KB467 NA ex 51 c.16295G > A p. (Arg5432Gln)
KB480 NA ex 52 c.16385A > G p. (Asp5462Gly)
KB177 De novo ex 52 c.16412G > T p. (Arg5471Met)
KB489 NA ex 53 c.16498C > T p. (Arg5500Trp)
KB120 De novo ex 54 c.16528T > G p. (Tyr5510Asp)
Indel
KB404 Inherited M ex 10 c.2283_2309del p. (Ala765_Gln773del)
KB274 NA ex 10 c.2532_2591del p. (Arg845_Pro864del)
KB370d De novo ex 14 c.4202_4210del p. (Ser1401_Cys1403del)
KB384 NA ex 39 c.11220_11222dup p. (Gln3745dup)
KB461a,d NA ex 39 c.11220_11222dup p. (Gln3745dup)
KB281 Inherited M ex 39 c.11714_11716dup p. (Gln3905dup)
KB71 Inherited M ex 39 c.11819_11836dup p. (Leu3940_Gln3945dup)
KB227 Inherited P ex 39 c.11843_11860del p. (L3948_Q3953del)
KB228 Inherited P ex 39 c.11854_11874dup p. (Q3952_Q3958dup)
KB77 NA ex 48 c.15163_15168dup p. (Asp5055_Leu5056dup)
KB403 De novo ex 53 c.16489_16491del p. (Ile5497del)
KB53 NA ex 53 c.16489_16491del p. (Ile5497del)
Splice site
KB286 De novo int 2-3 c.177-2A > C r.177_400del224;
p. S59Rfs*86
KB31 NA int 3-4 c.400 þ 1 G > A r.177_400del224;
p. Ser59Argfs*86
KB20 De novo int 3-5 c.401-3 A > G r.400_401insAG;
p. Gly134Glufs*75
KB442 NA int 6-7 c.840-6delC r.?
KB519 NA int 13-14 c.4132-2A > G r.?
KB529 NA int 16-17 c.4584-6C > G r.?
KB210 De novo in 17-18 c.4693 þ 1G > A r.4681_4693del13;
p. Val1561Argsfsplice*11
KB29 NA int 42-43 c.13999 þ 5 G > A r.13840_13999del160;
p. Asn4614Ilefs*5
KB290 De novo int 47-48 c.14643 þ 1G > A r.14644_14875del232;
p. Glu4882Profs*36
KB195 De novo int 47-48 c.14644-3C > G r.14644_14875del232;
p. Gln4882Profs*36
KB7 De novo int 44-45 c.14252-6_14252-5insGAAA r.14252_14382del131;
p. Val4751_Glufsplice*22
KB360 NA int 47-48 c.14644-2A > T r.?
KB496 NA int 53-54 c.16520_16521 þ 1delAGG r.?
Gross deletion
KB43e NA ex 48-51 c.15785-238_16168delins p. ?
KDM6A
Non-sense KB215f De novo ex 6 c.514C > T p. (Arg172*)
KB341 De novo ex 6 c.514C > T p. (Arg172*)
Frameshift
KB39 NA ex 16 c.1846_1849del p. (Thr616tyrfs*8)
KB141 NA ex 17 c.2118_2119ins p. (G707Hfs*13)
KB434 NA ex 17 c.2515_2518del p. (Asn839Valfs*27)
KB381 NA ex 20 c.3044delC p. (Thr1015Metfs*33)
Missense
KB415 NA ex 16 c.1843C > T p. (Leu615Phe)
KB272 NA ex 17 c.2326G > T p. (Asp776Tyr)
KB131 De novo ex 20 c.2939A > T p. (Asp980Val)
KB380 De novo ex 26 c.3743A > G p. (Gln1248Arg)
Gross deletions
KB11 NA ex 1-2 p. ?
KB50 De novo ex 5-9 p. ?
Splice site
KB314 De novo int 11-12 c.975-1G > A r.876_1320del;
p. Cys293IlefsX26
KB127 De novo int 22-23 c.3384 þ 3_3384 þ 6del r.3210_3284del;
p. Asn1070_Lys1094del

Both genes affect chromatin opening and promote gene expression. Most pathogenic variants in KMT2D and KDM6A are associated with loss-of-function (resulting in haploinsufficiency) or missense variants[3]. Individuals with pathogenic missense variants of KMT2D involving exons 38 or 39 may have features atypical for KS. Patients may have choanal atresia, hypoplastic or absent nipples, external and internal ear anomalies with hearing loss, brachial sinus abnormalities, interstitial lung disease, hypothyroidism, hypoparathyroidism, variable developmental delay, and dysmorphic features. A possible gain-of-function mechanism has also been hypothesized. KMT2D variants may also be associated with isolated alobar holoprosencephaly[1,3]. No other phenotypes have been associated with germline pathogenic variants in KDM6A[1].

The clinical variability of KS may be attributable to differences in genotypes and unknown genetic and epigenetic factors[3]. Outcomes vary based on systemic involvement. Early recognition of eventual complications is essential to improving outcomes, mainly because the treatments for non-KS and KS patients are identical.

Interestingly, although the concurrence of neoplastic lesions in the context of KS has been limited to isolated and sporadic case reports, reports in the last ten years have allowed the drawing of associations between tumors and KS[6,7]. Only 18 cases of KS with malignancies have been reported, including cases of Wilms tumor[8], hepatoblastoma and neuroblastoma, pilomatrixoma[9], spinal ependymoma[10,11], Burkitt’s lymphoma[12], and embryonal rhabdomyosarcoma[13] [Table 2]. Here, we describe a girl with KS who carries a KMT2D frameshift variant; she developed rare neoplasms in childhood, an insulinoma, liver metastasis, a benign phyllodes tumor of the breast, a pilomatrixoma, and an atypical melanocytic nevus.

Table 2

The known solid organ malignancies reported in Kabuki syndrome patients

Tumor types Reference
Wilms tumor Teranishi et al.[8]
Hepatoblastoma Bernier et al.[9]
Neuroblastoma Bernier et al.[9]
Pilomatrixoma Bernier et al.[9]
Spinal ependymoma Roma et al.[10,11]
Burkitt’s lymphoma De Billy et al.[12]

CASE REPORT

Our patient is a 13-year-old girl born from a normal, full-term pregnancy from unrelated parents. At around three years old, she was diagnosed with KS due to the delay in psychomotor development, typical facial dysmorphisms, and other typical features, including tetralogy of Fallot, cleft lip and palate, congenital hip dysplasia, epilepsy, and immunodeficiency.

During school age, she presented sporadic focal seizures, which were well controlled by therapy with valproic acid.

During a recurrence of seizures at 13 years, a reduced blood glucose level [35 mg/dL (1.9 mmol/L)] was observed. In the subsequent six months, she was admitted to the hospital because of several episodes of transient confusion,NArrowing of consciousness, sialorrhea, and myoclonic seizures, occasionally prolonged with at least two episodes of status epilepticus requiring anesthesia support. Her adherence to therapy was good.

While hospitalized, an electroencephalogram revealed focal electrical anomalies in the right hemisphere in a poorly modulated tracing with an excess of rapid activity. Cerebral magnetic resonance imaging showed specific anomalies and a supra-vermian arachnoid cyst. Due to recurrent daily seizures, treatment with valproic acid was started with topiramate but was later replaced with perampanel, followed by symptomatic improvement.

Gene sequencing was performed based on the clinical picture. Genetic analysis revealed a heterozygous c.446_449del variant in the KMT2D gene, confirming the diagnosis of KS-1. Continuous glucose monitoring (CGM; Ipro2, Medtronic, Milan, Italy) revealed several prolonged episodes of low blood glucose at night, early morning, and lunchtime. Blood insulin levels during two hypoglycemic episodes on two consecutive days were low (18.5 µU/mL and 20.3 µU/mL). She started diazoxide (10 mg/kg/day divided into three doses per day) but discontinued it due to the lack of benefit and the development of adverse effects (hypotension, tachycardia, and cold sweats). Ultrasound of the abdomen revealed no abnormalities; contrast-enhanced computer tomography revealed a 2.4 × 2.0 cm lesion at the head of the pancreas without local invasion and two small hepatic lesions.

Laboratory data were notable for increased circulating chromogranin A (29 U/L, n.v. 2-18 U/L), normal gastrin (50 pg/mL, n.v 6-108 pg/mL), neuron-specific enolase (NSE; 14.8 ng/mL, n.v. < 16.3 ng/mL), vasoactive intestinal peptide (33 ng/mL, n.v. < 200 ng/mL), and glucagon (30 pg/mL, n.v. 25-250 pg/mL).

The patient underwent pylorus-preserving pancreatoduodenectomy, partial hepatectomy, and microwave ablation of the remaining hepatic lesions. Histological examination of the pancreatic lesion confirmed the presence of a well-differentiated neuroendocrine tumor of intermediate grade, expressing insulin, chromogranin, CD56, and synaptophysin [Figure 1A-D]. One of the two hepatic lesions was a neuroendocrine tumor metastasis (3 mm) with a solid immunoreactivity for chromogranin with mitosis count (seven per ten high-power fields). The remaining metastasis-free liver tissue of the specimen showed some degree of fibrosis, diffuse neogenesis of intrahepatic bile ductules, and diffuse dilation and congestion of the portal veins [Figure 1E and F]. The other hepatic lesion was a ciliated hepatic foregut cyst (CHFC) [Figure 1G]. After surgery, her blood glucose levels returned to the normal range.

Kabuki syndrome and rare tumors in a young girl carrying a frameshift <i><i>KMT2D</i></i> mutation

Figure 1. (A) Hematoxylin-eosin (H&E) stained section of the pancreatic endocrine neoplasm. Immunostaining revealed a strong expression of insulin; (B) chromogranin (C) and CD56 (D). The section was also strongly positive for Ki-67 and synaptophysin staining (not shown). The morphology indicates a well-differentiated neuroendocrine tumor and a mitotic count of 20 per 10 high-power fields and a Ki-67 index (%) of 20 % indicates a tumor of intermediate-grade (G2). (A, H&E, original magnification × 200; B-D, immunohistochemistry, original magnification × 200); (E) H&E stained section of the metastasis-free liver tissue showing fibrous bands encircling small islets of hepatic tissue; (F) Numerous small bile ducts were scattered in the fibrous tissue well evidenced by cytokeratin 7 immunostaining. We also observed a diffuse, pronounced, dilation and congestion of the portal veins (E, H&E, original magnification ×100; F, immunohistochemistry, original magnification × 100); (G) Liver tissue with a cyst entirely lined with ciliated columnar epithelium, showing pseudo-stratification, surrounded by smooth muscle (G, H&E, original magnification ×400); (H) H&E x25 Leaf-like processes with a moderately cellular stroma phyllodes tumour; (I) H&E x200 cellular spindle cell stroma. No evidence of mitoses or necrosis in low-grade phyllodes tumor.

Two months later, during a physical examination, we perceived two small nodules in the left breast. Ultrasound examination confirmed the presence of two rounded masses of 50 mm and 16 mm (without malignant appearance). Because of the growth pattern over the subsequent 12 months, the nodules were removed. Histological examination showed they were benign phyllodes tumors, a rare fibroepithelial breast tumor at a young age [Figure 1H and I]. Follow-up revealed another neoplasm in the right shoulder, diagnosed as a pilomatrixoma and a junctional melanocytic nevus with cytological atypia, which was completely excised.

At the six-year follow-up, the girl showed no neoplasms and presented reasonable control of epileptic seizures. The Array-CGH was negative, and no other variants associated with predisposition to cancer were detected. However, whole exome sequencing was not performed.

DISCUSSION

The genetic analysis in our patient revealed a heterozygous c.446_449del frameshift variant in the KMT2D gene, predicted to generate the p.(Val149Glyfs*58) protein. Frameshift variants are the most common mechanisms of gene loss-of-function, reported in 36.67% of cases[14].

The c.446_449del variant of the KMT2D gene has been described only in one previous KS case; however, the precise clinical description is lacking[5]. Our KS patient is notable because she developed very rare tumors. Insulinoma, phyllodes tumor of the breast, CHFC, and melanocytic nevus with cytological atypia have never been described in patients with KS.

Benign tumors, especially pilomatrixoma, have rarely been described in patients with KS[9]. Associations between KS and other tumors are uncommon; however, there have been significant reports in the last ten years.

Somatic variants of KMT2D, particularly loss-of-function, have been reported in gastric cancer, lymphoma, and medulloblastoma; somatic variants of KDM6A have recently been described in some malignancies (most commonly in urothelial carcinoma, T-cell acute lymphoblastic leukemia, and breast cancer)[1]. KMT2D encodes a lysine-specific methyltransferase, responsible for post-translational histone 3 lysine 4 (H3K4) mono-, di- and tri-methylation, which is exclusively associated with actively transcribed genes[3,6]. KDM6A encodes an X-linked H3K27 demethylase that removes repressive epigenetic marks and interacts with KMT2D in regulating gene expression in the activating signal integrator-2-containing complex[3]. Defective demethylation dysregulates gene expression with the proliferation of neoplastic cells. However, the significance of germline (i.e., present in all tissues) pathogenic variants in neoplasms of KS patients is yet to be determined[6,11].

Insulinoma, the most common functioning neoplasm of the endocrine pancreas, is infrequent in childhood (about 30 cases have been reported) and usually affects individuals in their late 50 s and early 60 s. The clinical presentation is characterized by neuroglycopenic symptoms due to severe hypoglycemia, i.e., irrational behavior, somnolence, impaired school performance, and refractory seizures. Hyperinsulinemic hypoglycemia should be considered in cases of unexplained psychiatric and neurologic disorders or worsening neurologic conditions (e.g., increased seizures or seizures becoming refractory to treatment, as in our case). Diazoxide (5-20 mg/kg/day given orally) may reduce the frequency and severity of hypoglycemic events, although tumor resection is the gold standard.

Phyllodes tumors are rare fibroepithelial tumors of the breast, representing only 0.3%-0.9% of all breast tumors and 2%-3% of fibroepithelial neoplasms in adults. The tumor usually occurs in women aged 35-55; only 35 cases have been reported in girls under 20. Phyllodes tumors are often benign but may be borderline and malignant. Although it presents as a well-delimited, rapidly growing, painless, and mobile mass with an overall good outcome, it often recurs[15], and surgery is the standard treatment[16].

Congenital hepatic malformations have been rarely described in patients with KS[17]. Our patient showed the presence of a CHFC and some degree of hepatic fibrosis. CHFCs are rare cystic lesions of embryological origin. Because metaplastic and malignant epithelial lining has been described in CHFC, complete surgical excision is recommended, given the potential for metaplastic or malignant squamous carcinoma[18]. While CHFC has not been reported in KS, hepatic fibrosis has been described, supporting that hepatic abnormalities may be common in KS[1]. KMT2D is mutated in hepatocellular carcinoma cases, with earlier disease recurrence, more significant microvascular invasion, and a more aggressive phenotype. Therefore, the potential development of malignant liver cancer must be considered in KS patients[11].

Pilomatricoma is a cystic follicular lesion that commonly arises on the head and neck in children. This lesion has been linked to various syndromes (Turner, Gardner, RubinsteinTaybi, Sotos, Trisomy 9, myotonic dystrophy, spina bifida, sarcoidosis, and gliomatosis cerebri); however, only three cases of pilomatrixoma associated with KS have been reported[8]. All three cases had common facial and syndromic features; they were referred to dermatology for lesions described as cutaneous skin-colored papulonodular lesions, which were subsequently diagnosed as pilomatrixoma following biopsy. A somatic variant in CTNNB1 causes the only known mutation confirmed in pilomatrixoma. Predisposition to pilomatrixoma in KS may not be coincidental because CTNNB1 plays a pivotal role in the Wnt pathway, encoding b-catenin, which may recruit KMT2D to regulate Wnt pathway target genes involved in morphogenesis and tumorigenesis[11]. The case of the junctional melanocytic nevus with cytological atypia is the first described in the literature associated with KS. The only previous association was a Becker nevus.

In our patient, the aCGH was negative; no other searches for cancer susceptibility genes were performed; further investigations will be needed to clarify the relationship between KS variants and neoplastic lesion development.

CONCLUSION

Our case broadens the phenotypic spectrum of KS, especially the neoplasms associated with this syndrome. This case agrees with the most recent literature showing a significant association between KS and tumors, even if the molecular basis of this relationship is not well understood.

A large case series with an accurate description of the neoplastic phenotypes and precise genetic characterization of the patients are needed to clarify the relationship between KMT2D gene variants, KS, susceptibility to neoplastic lesions, and eventual specific tumor phenotypes associated with KS. To date, there are no indications for oncologic screening in KS patients. Studies are needed in this regard. Finally, although a second genetic syndrome in the patient is unlikely, we cannot rule out a tumor predisposition syndrome.

DECLARATIONS

Acknowledgments

We thank the family for their continuing interest and cooperation. We also thank the Genomic and Genetic Disorders Biobank, a Telethon Network of Genetic Biobanks member funded by Telethon Italy (project no. GTB12001G) for biospecimens banking.

Authors’ contributions

Substantial contributions to the conception and design of the study and performed data analysis and interpretation: Bonuccelli A, Federico G, Orsini A, Boggi U

Data acquisition, administrative, technical, and material support: Baldaccini T, Santangelo A, Alberti E, Del Pistoia M

Contributed to reviewing the manuscript: Peroni D, Randazzo E

Provided genetic counseling: Toschi B

Availability of data and materials

Data regarding the case report can be found in the database of the Pediatric Clinic of Pisa. Data regarding the literature review are referenced in the manuscript as footnotes and can be found on PubMed.

Financial support and sponsorship

None.

Conflicts of interest

All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate

The article consists of the retrospective description of a clinical case. In these cases the approval of the ethics committee is not required. Consent to partecipate has been obtained from the parents of the patient.

Consent for publication

Consent for publication has been obtained from the parents of the patient.

Copyright

© The Author(s) 2023.

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Cite This Article

OAE Style

Bonuccelli A, Baldaccini T, Orsini A, Alberti E, Del Pistoia M, Boggi U, Toschi B, Santangelo A, Randazzo E, Peroni D, Federico G. Kabuki syndrome and rare tumors in a young girl carrying a frameshift KMT2D mutation. J Transl Genet Genom 2023;7:166-82. http://dx.doi.org/10.20517/jtgg.2022.18

AMA Style

Bonuccelli A, Baldaccini T, Orsini A, Alberti E, Del Pistoia M, Boggi U, Toschi B, Santangelo A, Randazzo E, Peroni D, Federico G. Kabuki syndrome and rare tumors in a young girl carrying a frameshift KMT2D mutation. Journal of Translational Genetics and Genomics. 2023; 7(3): 166-82. http://dx.doi.org/10.20517/jtgg.2022.18

Chicago/Turabian Style

Bonuccelli, Alice, Tommaso Baldaccini, Alessandro Orsini, Elisabetta Alberti, Marta Del Pistoia, Ugo Boggi, Benedetta Toschi, Andrea Santangelo, Emioli Randazzo, Diego Peroni, Giovanni Federico. 2023. "Kabuki syndrome and rare tumors in a young girl carrying a frameshift KMT2D mutation" Journal of Translational Genetics and Genomics. 7, no.3: 166-82. http://dx.doi.org/10.20517/jtgg.2022.18

ACS Style

Bonuccelli, A.; Baldaccini T.; Orsini A.; Alberti E.; Del Pistoia M.; Boggi U.; Toschi B.; Santangelo A.; Randazzo E.; Peroni D.; Federico G. Kabuki syndrome and rare tumors in a young girl carrying a frameshift KMT2D mutation. J. Transl. Genet. Genom. 2023, 7, 166-82. http://dx.doi.org/10.20517/jtgg.2022.18

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