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Case Report  |  Open Access  |  19 Jul 2023

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

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

IDInheritanceExon/intronVariantAA change
KMT2D
Non-sense
KB49NAex 5c.669T > Gp. (Tyr223*)
KB343NAex 8c.1016G > Ap. (Trp339*)
KB35NAex 10c.1921G > Tp. (Glu641*)
KB33NAex 16c.4419G > Ap. (Trp1473*)
KB63NAex 19c.4895delCp. (Ser1632*)
KB317NAex 22c.5212G > Tp. (Glu1738*)
KB336De novoex 22c.5269C > Tp. (Arg1757*)
KB262NAex 26c.5674C > Tp. (Gln1892*)
KB429NAex 26c.5707C > Tp. (Arg1903*)
KB26NAex 31c.6295C > Tp. (Arg2099*)
KB502De novoex 31c.7228C > Tp. (Arg2410*)
KB66NAex 31c.7246C > Tp. (Gln2416*)
KB59NAex 31c.7903C > Tp. (Arg2635*)
KB153De novoex 31c.7903C > Tp. (Arg2635*)
KB226De novoex 31c.7903C > Tp. (Arg2635*)
KB338De novoex 31c.7933C > Tp. (Arg2645*)
KB198De novoex 31c.7936G > Tp. (Glu2646*)
KB352NAex 32c.8227C > Tp. (Gln2743*)
KB323NAex 33c.8311C > Tp. (Arg2771*)
KB289NAex 34c.8743C > Tp. (Arg2915*)
KB422De novoex 34c.9396C > Ap. (Cys3132*)
KB186De novoex 34c.9961C > Tp. (Arg3321*)
KB56De novoex 34c.10135C > Tp. (Gln3379*)
KB168De novoex 39c.10750C > Tp. (Gln3584*)
KB46De novoex 39c.10841C > Gp. (Ser3614*)
KB41NAex 39c.11119C > Tp. (Arg3707*)
KB44NAex 39c.11119C > Tp. (Arg3707*)
KB42De novoex 39c.11269C > Tp. (Gln3757*)
KB25NAex 39c.11434 C > Tp. (Gln3812*)
KB244De novoex 39c.11674 C > Tp. (Gln3892*)
KB178NAex 39c.11704C > Tp. (Gln3902*)
KB425De novoex 39c.11731C > Tp. (Gln3911*)
KB461aNAex 39c.11749C > Tp. (Gln3917*)
KB463NAex 39c.11845C > Tp. (Gln3949*)
KB181NAex 39c.11869C > Tp. (Gln3957*)
KB358NAex 39c.11944C > Tp. (Arg3982*)
KB40NAex 39c.12274C > Tp. (Gln4092*)
KB114De novoex 39c.12274C > Tp. (Gln4092*)
KB65NAex 39c.12076C > Tp. (Gln4026*)
KB333NAex 39c.12703C > Tp. (Gln4235*)
KB410NA39c.12760C > Tp. (Gln4254*)
KB82De novoex 39c.12844C > Tp. (Arg4282*)
KB350De novoex 39c.12844C > Tp. (Arg4282*)
KB189De novoex 39c.12955A > Tp. (Arg4319*)
KB183De novoex 39c.13450C > Tp. (Arg4484*)
KB450NAex 39c.13450C > Tp. (Arg4484*)
KB175De novoex 39c.13507C > Tp. (Gln4503*)
KB73De novoex 40c.13666A > Tp. (Lys4556*)
KB83NAex 48c.15022G > Tp. (Glu5008*)
KB377NAex 48c.15061C > Tp. (Arg5021*)
KB45NAex 48c.15079C > Tp. (Arg5027*)
KB72NAex 48c.15079C > Tp. (Arg5027*)
KB362NAex 50c.16018C > Tp. (Arg5340*)
KB130NAex 52c.16360C > Tp. (Arg5454*)
Frameshift
KB454NAex 3c.234_235delGCp. (Gln79Alafs*7)
KB469NAex 3c.345dupAp. (Ser116Ilefs*7)
KB337NAex 4c.446_449delTATGp. (Val149Glyfs*58)
KB75De novoex 4c.472delTp. (Cys158Valfs*50)
KB8De novoex 5c.588delCp. (Cys197Alafs*11)
KB58NAex 6c.705delAp. (Glu237Serfs*24)
KB57NAex 8c.1035_1036delCTp. (Cys346Serfs*17)
KB89NAex 10c.1345_1346delCTp. (Leu449Valfs*5)
KB156De novoex 10c.1503dupTp. (Pro502Serfs*7)
KB116NAex 10c.1634delTp. (Leu545Argfs*385)
KB349NAex 10c.1634delTp. (Leu545Argfs*385)
KB545NA10c.2091dupCp. (Thr698Hisfs*6)
KB369NAex 11c.3596_3597delp. (Leu1199Hisfs*7)
KB48De novoex 11c.2993dupCp. (Met999Tyrfs*69)
KB203NAex 11c.3161_3171del
CGTTGAGTCCC
p. (Pro1054Hisfs*10)
KB309NAex 11c.3730delGp. (Val1244Serfs*86)
KB142De novoex 13c.4021delGp. (Val1341Leufs*35)
KB311NAex 14c.4135_4136delATp. (Met1379Valfs*52)
KB524NA14c.4135_4136delATp. (Met1379Valfs*52)
KB188De novoex 16c.4454delCp. (Pro1485Leufs*21)
KB159NAex 19c.4896_4905del
AGATGCCCTT
p. (Asp1633Alafs*86)
KB443aDe novoex 25c.5575delGp. (Asp1859Thrfs*17)
KB3NAex 26c.5652dupp. (Lys1885Glnfs*18)
KB84NAex 26c.5779delCp. (Gln1927Lysfs120*)
KB146De novoex 27c.5857delCp. (Leu1953Trpfs*94)
KB208NAex 28c.5954delCp. (Thr1985Lysfs*62)
KB221De novoex 29c.6149_6150delGAp. (Arg2050Lysfs*6)
KB525NA30c.6212_6213delACp. (His2071Profs*10)
KB152De novoex 31c.6583delAp. (Thr2195Profs*69)
KB267NAex 31c.6594delCp. (Tyr2199Ilefs*65)
KB79De novoex 31c.6595delTp. (Tyr2199Ilefs*65)
KB102De novoex 31c.6595delTp. (Tyr2199Ilefs*65)
KB342NAex 31c.6595delTp. (Tyr2199Ilefs*65)
KB67De novoex 31c.6638_6641delGCGCp. (Gly2213Alafs*50)
KB176NAex 31c.6738delAp. (Lys2246Asnfs*18)
KB253NAex 31c.6794delGp. (Gly2265Glufs*21)
KB278NAex 31c.7481dupTp. (Ala2496Serfs*10)
KB313De novoex 32c.8196delGp. (Ser2733Valfs*24)
KB80NAex 33c.8273delGp. (Gly2758Alafs*29)
KB243De novoex 34c.8430_8431insAAp. (Gln2811Asnfs*41)
KB182NAex 34c.9203delAp. (Gln3068Glyfs*3)
KB30NAex 38c.10606delCp. (Arg3536Alafs*122)
KB101De novoex 39c.11066_11078delCT
GGATCCCTGGC
p. (Ala3689Valfs*56)
KB504 De novoex 39c.11093dupGp. (Phe3699Leufs*14)
KB495 De novoex 39c.11715delGp. (Gln3905Hisfs*74)
KB172NAex 39c.12647delCp. (Pro4216Leufs*62)
KB192 De novoex 39c.12966delAp. (Gln4322Hisfs*62)
KB54NAex 39c.13129dupTp. (Trp4377Leufs*33)
KB121 De novoex 39c.13277dupTp. (Ala4428Serfs*59)
KB540NA41c.13780delGp. (Ala4594Profs*23)
KB123 De novoex 42c.13884dupCp. (Thr4629Hisf*18)
KB481NAex 42c.13895dupCp. (Ser4633Ilefs*14)
KB197 De novoex 47c.14592dupGp. (Pro4865Alafs*48)
KB125NAex 48c.15031delGp. (Glu5011Serfs*40)
KB16 De novoex 48c.15374dupTp. (Phe5126Leufs*12)
KB535NA50c.16043_16044delACp. (His5348Leufs*14)
KB355NAex 53c.16438_16441delAACTp. (Asn5480Val*6)
KB64NAex 53c.16469_16470delAAp. (Lys5490Argfs*21)
KB533NA53c.16469_16470delAAp. (Lys5490Argfs*21)
Missense
KB21ainherited Mex 3c.346T > Cp. (Ser116Pro)
KB21a,binherited Mex 4c.510G > Cp. Gln170His
KB256NAex 5c.626C > Tp. (Thr209Ile)
KB458NAex 8c.1076G > Cp. (Arg359Pro)
KB269 inherited Mex 10c.1940C > Ap. (Pro647Gln)
KB126NAex 10c.2074C > Ap. (Pro692Thr)
KB374cinherited Mex 10c.2074C > Ap. (Pro692Thr)
KB487NAex 10c.2654C > Tp. (Pro885Leu)
KB370aInherited P-Mex 11c.2837C > Gp. (Ala946Gly)
KB215 Inherited Mex 11c.3392C > Tp. (Pro1131Leu)
KB341 Inherited Mex 11c.3392C > Tp. (Pro1131Leu)
KB222 Inherited P-Mex 11c.3572C > Tp. (Pro1191Leu)
KB32Inherited Pex 11c.3773G > Ap. (Arg1258Gln)
KB307De novoex 14c.4171G > Ap. (Glu1391Lys)
KB28aInherited Mex 15c.4249A > Gp. (Met1417Val)
KB28aInherited Mex 15c.4252C > Ap. (Leu1418Met)
KB174Inherited Mex 15c.4283T > Cp. (Ile1428Thr)
KB138NAex 16c.4427C > Gp. (Ser1476Cys)
KB34Inherited Pex 16c.4565A > Gp. (Gln1522Arg)
KB535NA25c.5549G > Ap. (Gly1850Asp)
KB119Inherited Mex 31c.6638G > Ap. (Gly2213Asp)
KB204cInherited Mex 31c.6638G > Ap. (Gly2213Asp)
KB330aNAex 31c.6733C > Gp. (Leu2245Val)
KB326cInherited Mex 31c.6811C > Tp. (Pro2271Ser)
KB107aNAex 31c.6970C > Ap. (Pro2324Thr)
KB430NAex 31c.7378C > Tp. (Arg2460Cys)
KB122Inherited Mex 31c.7829T > Cp. (Leu2610Pro)
KB287Inherited Mex 31c.7829T > Cp. (Leu2610Pro)
KB27NAex 34c.8521C > Ap. (Pro2841Thr)
KB330aNAex 34c.8774C > Tp. (Ala2925Val)
KB443aInherited Mex 34c.9971G > Tp. (Gly3324Val)
KB326cInherited Pex 34c.10192A > Gp. (Met3398Val)
KB357Inherited Pex 34c.10192A > Gp. (Met3398Val)
KB297NAex 35c.10256A > Gp. (Asp3419Gly)
KB378NAex 35c.10256A > Gp. (Asp3419Gly)
KB292De novoex 37c.10499G > Tp. (Gly3500Val)
KB86aNAex 39c.10966C > Tp. (Arg3656Cys)
KB374cInherited Pex 39c.11380C > Tp. (Pro3794Ser)
KB293Inherited Pex 39c.11794C > Gp. (Gln3932Glu)
KB204cInherited Pex 39c.12070A > Gp. (Lys4024Glu)
KB385NAex 39c.12302A > Cp. (Gln4101Pro)
KB247NAex 39c.12485G > Ap. (Arg4162Gln)
KB107aNAex 39c.12488C > Tp. (Pro4163Leu)
KB170Inherited Mex 39c.13256C > Tp. (Pro4419Leu)
KB512NA45c.14381A > Gp. (Lys4794Arg)
KB86aNAex 48c.14893G > Ap. (Ala4965Thr)
KB38aDe novoex 48c.15084C > Gp. (Asp5028Glu)
KB154NAex 48c.15088C > Tp. (Arg5030Cys)
KB185De novoex 48c.15088C > Tp. (Arg5030Cys)
KB423Inherited Pex 48c.15089G > Ap. (Arg5030His)
KB38aDe novoex 48c.15100T > Gp. (Phe5034Val)
KB76De novoex 48c.15176A > Cp. (His5059Pro)
KB129NAex 48c.15292A > Cp. (Thr5098Pro)
KB462De novoex 48c.15310T > Cp. (Cys5104Arg)
KB171Inherited Mex 48c.15565G > Ap. (Gly5189Arg)
KB264NAex 48c.15640C > Tp. (Arg5214Cys)
KB376NAex 48c.15640C > Tp. (Arg5214Cys)
KB24De novoex 48c.15641G > Ap. (Arg5214His)
KB219NAex 48c.15641G > Ap. (Arg5214His)
KB408De novoex 48c.15641G > Ap. (Arg5214His)
KB109De novoex 48c.15649T > Cp. (Trp5217Arg)
KB17De novoex 50c.16019G > Ap. (Arg5340Gln)
KB169De novoex 51c.16273G > Ap. (Glu5425Lys)
KB90NAex 51c.16295G > Ap. (Arg5432Gln)
KB467NAex 51c.16295G > Ap. (Arg5432Gln)
KB480NAex 52c.16385A > Gp. (Asp5462Gly)
KB177De novoex 52c.16412G > Tp. (Arg5471Met)
KB489NAex 53c.16498C > Tp. (Arg5500Trp)
KB120De novoex 54c.16528T > Gp. (Tyr5510Asp)
Indel
KB404Inherited Mex 10c.2283_2309delp. (Ala765_Gln773del)
KB274NAex 10c.2532_2591delp. (Arg845_Pro864del)
KB370dDe novoex 14c.4202_4210delp. (Ser1401_Cys1403del)
KB384NAex 39c.11220_11222dupp. (Gln3745dup)
KB461a,dNAex 39c.11220_11222dupp. (Gln3745dup)
KB281Inherited Mex 39c.11714_11716dupp. (Gln3905dup)
KB71Inherited Mex 39c.11819_11836dupp. (Leu3940_Gln3945dup)
KB227Inherited Pex 39c.11843_11860delp. (L3948_Q3953del)
KB228Inherited Pex 39c.11854_11874dupp. (Q3952_Q3958dup)
KB77NAex 48c.15163_15168dupp. (Asp5055_Leu5056dup)
KB403De novoex 53c.16489_16491delp. (Ile5497del)
KB53NAex 53c.16489_16491delp. (Ile5497del)
Splice site
KB286De novoint 2-3c.177-2A > Cr.177_400del224;
p. S59Rfs*86
KB31NAint 3-4c.400 þ 1 G > Ar.177_400del224;
p. Ser59Argfs*86
KB20De novoint 3-5c.401-3 A > Gr.400_401insAG;
p. Gly134Glufs*75
KB442NAint 6-7c.840-6delCr.?
KB519NAint 13-14c.4132-2A > Gr.?
KB529NAint 16-17c.4584-6C > Gr.?
KB210De novoin 17-18c.4693 þ 1G > Ar.4681_4693del13;
p. Val1561Argsfsplice*11
KB29NAint 42-43c.13999 þ 5 G > Ar.13840_13999del160;
p. Asn4614Ilefs*5
KB290De novoint 47-48c.14643 þ 1G > Ar.14644_14875del232;
p. Glu4882Profs*36
KB195De novoint 47-48c.14644-3C > Gr.14644_14875del232;
p. Gln4882Profs*36
KB7De novoint 44-45c.14252-6_14252-5insGAAAr.14252_14382del131;
p. Val4751_Glufsplice*22
KB360NAint 47-48c.14644-2A > Tr.?
KB496NAint 53-54c.16520_16521 þ 1delAGGr.?
Gross deletion
KB43eNAex 48-51c.15785-238_16168delinsp.?
KDM6A
Non-sense KB215fDe novoex 6c.514C > Tp. (Arg172*)
KB341De novoex 6c.514C > Tp. (Arg172*)
Frameshift
KB39NAex 16c.1846_1849delp. (Thr616tyrfs*8)
KB141NAex 17c.2118_2119insp. (G707Hfs*13)
KB434NAex 17c.2515_2518delp. (Asn839Valfs*27)
KB381NAex 20c.3044delCp. (Thr1015Metfs*33)
Missense
KB415NAex 16c.1843C > Tp. (Leu615Phe)
KB272NAex 17c.2326G > Tp. (Asp776Tyr)
KB131De novoex 20c.2939A > Tp. (Asp980Val)
KB380De novoex 26c.3743A > Gp. (Gln1248Arg)
Gross deletions
KB11NAex 1-2p. ?
KB50De novoex 5-9p. ?
Splice site
KB314De novoint 11-12c.975-1G > Ar.876_1320del; p. Cys293IlefsX26
KB127De novoint 22-23c.3384 þ 3_3384 þ 6delr.3210_3284del; p. Asn1070_Lys1094del
KMT2D
Non-sense
KB49NAex 5c.669T > Gp. (Tyr223*)
KB343NAex 8c.1016G > Ap. (Trp339*)
KB35NAex 10c.1921G > Tp. (Glu641*)
KB33NAex 16c.4419G > Ap. (Trp1473*)
KB63NAex 19c.4895delCp. (Ser1632*)
KB317NAex 22c.5212G > Tp. (Glu1738*)
KB336De novoex 22c.5269C > Tp. (Arg1757*)
KB262NAex 26c.5674C > Tp. (Gln1892*)
KB429NAex 26c.5707C > Tp. (Arg1903*)
KB26NAex 31c.6295C > Tp. (Arg2099*)
KB502De novoex 31c.7228C > Tp. (Arg2410*)
KB66NAex 31c.7246C > Tp. (Gln2416*)
KB59NAex 31c.7903C > Tp. (Arg2635*)
KB153De novoex 31c.7903C > Tp. (Arg2635*)
KB226De novoex 31c.7903C > Tp. (Arg2635*)
KB338De novoex 31c.7933C > Tp. (Arg2645*)
KB198De novoex 31c.7936G > Tp. (Glu2646*)
KB352NAex 32c.8227C > Tp. (Gln2743*)
KB323NAex 33c.8311C > Tp. (Arg2771*)
KB289NAex 34c.8743C > Tp. (Arg2915*)
KB422De novoex 34c.9396C > Ap. (Cys3132*)
KB186De novoex 34c.9961C > Tp. (Arg3321*)
KB56De novoex 34c.10135C > Tp. (Gln3379*)
KB168De novoex 39c.10750C > Tp. (Gln3584*)
KB46De novoex 39c.10841C > Gp. (Ser3614*)
KB41NAex 39c.11119C > Tp. (Arg3707*)
KB44NAex 39c.11119C > Tp. (Arg3707*)
KB42De novoex 39c.11269C > Tp. (Gln3757*)
KB25NAex 39c.11434 C > Tp. (Gln3812*)
KB244De novoex 39c.11674 C > Tp. (Gln3892*)
KB178NAex 39c.11704C > Tp. (Gln3902*)
KB425De novoex 39c.11731C > Tp. (Gln3911*)
KB461aNAex 39c.11749C > Tp. (Gln3917*)
KB463NAex 39c.11845C > Tp. (Gln3949*)
KB181NAex 39c.11869C > Tp. (Gln3957*)
KB358NAex 39c.11944C > Tp. (Arg3982*)
KB40NAex 39c.12274C > Tp. (Gln4092*)
KB114De novoex 39c.12274C > Tp. (Gln4092*)
KB65NAex 39c.12076C > Tp. (Gln4026*)
KB333NAex 39c.12703C > Tp. (Gln4235*)
KB410NA39c.12760C > Tp. (Gln4254*)
KB82De novoex 39c.12844C > Tp. (Arg4282*)
KB350De novoex 39c.12844C > Tp. (Arg4282*)
KB189De novoex 39c.12955A > Tp. (Arg4319*)
KB183De novoex 39c.13450C > Tp. (Arg4484*)
KB450NAex 39c.13450C > Tp. (Arg4484*)
KB175De novoex 39c.13507C > Tp. (Gln4503*)
KB73De novoex 40c.13666A > Tp. (Lys4556*)
KB83NAex 48c.15022G > Tp. (Glu5008*)
KB377NAex 48c.15061C > Tp. (Arg5021*)
KB45NAex 48c.15079C > Tp. (Arg5027*)
KB72NAex 48c.15079C > Tp. (Arg5027*)
KB362NAex 50c.16018C > Tp. (Arg5340*)
KB130NAex 52c.16360C > Tp. (Arg5454*)
Frameshift
KB454NAex 3c.234_235delGCp. (Gln79Alafs*7)
KB469NAex 3c.345dupAp. (Ser116Ilefs*7)
KB337NAex 4c.446_449delTATGp. (Val149Glyfs*58)
KB75De novoex 4c.472delTp. (Cys158Valfs*50)
KB8De novoex 5c.588delCp. (Cys197Alafs*11)
KB58NAex 6c.705delAp. (Glu237Serfs*24)
KB57NAex 8c.1035_1036delCTp. (Cys346Serfs*17)
KB89NAex 10c.1345_1346delCTp. (Leu449Valfs*5)
KB156De novoex 10c.1503dupTp. (Pro502Serfs*7)
KB116NAex 10c.1634delTp. (Leu545Argfs*385)
KB349NAex 10c.1634delTp. (Leu545Argfs*385)
KB545NA10c.2091dupCp. (Thr698Hisfs*6)
KB369NAex 11c.3596_3597delp. (Leu1199Hisfs*7)
KB48De novoex 11c.2993dupCp. (Met999Tyrfs*69)
KB203NAex 11c.3161_3171del
CGTTGAGTCCC
p. (Pro1054Hisfs*10)
KB309NAex 11c.3730delGp. (Val1244Serfs*86)
KB142De novoex 13c.4021delGp. (Val1341Leufs*35)
KB311NAex 14c.4135_4136delATp. (Met1379Valfs*52)
KB524NA14c.4135_4136delATp. (Met1379Valfs*52)
KB188De novoex 16c.4454delCp. (Pro1485Leufs*21)
KB159NAex 19c.4896_4905del
AGATGCCCTT
p. (Asp1633Alafs*86)
KB443aDe novoex 25c.5575delGp. (Asp1859Thrfs*17)
KB3NAex 26c.5652dupp. (Lys1885Glnfs*18)
KB84NAex 26c.5779delCp. (Gln1927Lysfs120*)
KB146De novoex 27c.5857delCp. (Leu1953Trpfs*94)
KB208NAex 28c.5954delCp. (Thr1985Lysfs*62)
KB221De novoex 29c.6149_6150delGAp. (Arg2050Lysfs*6)
KB525NA30c.6212_6213delACp. (His2071Profs*10)
KB152De novoex 31c.6583delAp. (Thr2195Profs*69)
KB267NAex 31c.6594delCp. (Tyr2199Ilefs*65)
KB79De novoex 31c.6595delTp. (Tyr2199Ilefs*65)
KB102De novoex 31c.6595delTp. (Tyr2199Ilefs*65)
KB342NAex 31c.6595delTp. (Tyr2199Ilefs*65)
KB67De novoex 31c.6638_6641delGCGCp. (Gly2213Alafs*50)
KB176NAex 31c.6738delAp. (Lys2246Asnfs*18)
KB253NAex 31c.6794delGp. (Gly2265Glufs*21)
KB278NAex 31c.7481dupTp. (Ala2496Serfs*10)
KB313De novoex 32c.8196delGp. (Ser2733Valfs*24)
KB80NAex 33c.8273delGp. (Gly2758Alafs*29)
KB243De novoex 34c.8430_8431insAAp. (Gln2811Asnfs*41)
KB182NAex 34c.9203delAp. (Gln3068Glyfs*3)
KB30NAex 38c.10606delCp. (Arg3536Alafs*122)
KB101De novoex 39c.11066_11078delCT
GGATCCCTGGC
p. (Ala3689Valfs*56)
KB504 De novoex 39c.11093dupGp. (Phe3699Leufs*14)
KB495 De novoex 39c.11715delGp. (Gln3905Hisfs*74)
KB172NAex 39c.12647delCp. (Pro4216Leufs*62)
KB192 De novoex 39c.12966delAp. (Gln4322Hisfs*62)
KB54NAex 39c.13129dupTp. (Trp4377Leufs*33)
KB121 De novoex 39c.13277dupTp. (Ala4428Serfs*59)
KB540NA41c.13780delGp. (Ala4594Profs*23)
KB123 De novoex 42c.13884dupCp. (Thr4629Hisf*18)
KB481NAex 42c.13895dupCp. (Ser4633Ilefs*14)
KB197 De novoex 47c.14592dupGp. (Pro4865Alafs*48)
KB125NAex 48c.15031delGp. (Glu5011Serfs*40)
KB16 De novoex 48c.15374dupTp. (Phe5126Leufs*12)
KB535NA50c.16043_16044delACp. (His5348Leufs*14)
KB355NAex 53c.16438_16441delAACTp. (Asn5480Val*6)
KB64NAex 53c.16469_16470delAAp. (Lys5490Argfs*21)
KB533NA53c.16469_16470delAAp. (Lys5490Argfs*21)
Missense
KB21ainherited Mex 3c.346T > Cp. (Ser116Pro)
KB21a,binherited Mex 4c.510G > Cp. Gln170His
KB256NAex 5c.626C > Tp. (Thr209Ile)
KB458NAex 8c.1076G > Cp. (Arg359Pro)
KB269 inherited Mex 10c.1940C > Ap. (Pro647Gln)
KB126NAex 10c.2074C > Ap. (Pro692Thr)
KB374cinherited Mex 10c.2074C > Ap. (Pro692Thr)
KB487NAex 10c.2654C > Tp. (Pro885Leu)
KB370aInherited P-Mex 11c.2837C > Gp. (Ala946Gly)
KB215 Inherited Mex 11c.3392C > Tp. (Pro1131Leu)
KB341 Inherited Mex 11c.3392C > Tp. (Pro1131Leu)
KB222 Inherited P-Mex 11c.3572C > Tp. (Pro1191Leu)
KB32Inherited Pex 11c.3773G > Ap. (Arg1258Gln)
KB307De novoex 14c.4171G > Ap. (Glu1391Lys)
KB28aInherited Mex 15c.4249A > Gp. (Met1417Val)
KB28aInherited Mex 15c.4252C > Ap. (Leu1418Met)
KB174Inherited Mex 15c.4283T > Cp. (Ile1428Thr)
KB138NAex 16c.4427C > Gp. (Ser1476Cys)
KB34Inherited Pex 16c.4565A > Gp. (Gln1522Arg)
KB535NA25c.5549G > Ap. (Gly1850Asp)
KB119Inherited Mex 31c.6638G > Ap. (Gly2213Asp)
KB204cInherited Mex 31c.6638G > Ap. (Gly2213Asp)
KB330aNAex 31c.6733C > Gp. (Leu2245Val)
KB326cInherited Mex 31c.6811C > Tp. (Pro2271Ser)
KB107aNAex 31c.6970C > Ap. (Pro2324Thr)
KB430NAex 31c.7378C > Tp. (Arg2460Cys)
KB122Inherited Mex 31c.7829T > Cp. (Leu2610Pro)
KB287Inherited Mex 31c.7829T > Cp. (Leu2610Pro)
KB27NAex 34c.8521C > Ap. (Pro2841Thr)
KB330aNAex 34c.8774C > Tp. (Ala2925Val)
KB443aInherited Mex 34c.9971G > Tp. (Gly3324Val)
KB326cInherited Pex 34c.10192A > Gp. (Met3398Val)
KB357Inherited Pex 34c.10192A > Gp. (Met3398Val)
KB297NAex 35c.10256A > Gp. (Asp3419Gly)
KB378NAex 35c.10256A > Gp. (Asp3419Gly)
KB292De novoex 37c.10499G > Tp. (Gly3500Val)
KB86aNAex 39c.10966C > Tp. (Arg3656Cys)
KB374cInherited Pex 39c.11380C > Tp. (Pro3794Ser)
KB293Inherited Pex 39c.11794C > Gp. (Gln3932Glu)
KB204cInherited Pex 39c.12070A > Gp. (Lys4024Glu)
KB385NAex 39c.12302A > Cp. (Gln4101Pro)
KB247NAex 39c.12485G > Ap. (Arg4162Gln)
KB107aNAex 39c.12488C > Tp. (Pro4163Leu)
KB170Inherited Mex 39c.13256C > Tp. (Pro4419Leu)
KB512NA45c.14381A > Gp. (Lys4794Arg)
KB86aNAex 48c.14893G > Ap. (Ala4965Thr)
KB38aDe novoex 48c.15084C > Gp. (Asp5028Glu)
KB154NAex 48c.15088C > Tp. (Arg5030Cys)
KB185De novoex 48c.15088C > Tp. (Arg5030Cys)
KB423Inherited Pex 48c.15089G > Ap. (Arg5030His)
KB38aDe novoex 48c.15100T > Gp. (Phe5034Val)
KB76De novoex 48c.15176A > Cp. (His5059Pro)
KB129NAex 48c.15292A > Cp. (Thr5098Pro)
KB462De novoex 48c.15310T > Cp. (Cys5104Arg)
KB171Inherited Mex 48c.15565G > Ap. (Gly5189Arg)
KB264NAex 48c.15640C > Tp. (Arg5214Cys)
KB376NAex 48c.15640C > Tp. (Arg5214Cys)
KB24De novoex 48c.15641G > Ap. (Arg5214His)
KB219NAex 48c.15641G > Ap. (Arg5214His)
KB408De novoex 48c.15641G > Ap. (Arg5214His)
KB109De novoex 48c.15649T > Cp. (Trp5217Arg)
KB17De novoex 50c.16019G > Ap. (Arg5340Gln)
KB169De novoex 51c.16273G > Ap. (Glu5425Lys)
KB90NAex 51c.16295G > Ap. (Arg5432Gln)
KB467NAex 51c.16295G > Ap. (Arg5432Gln)
KB480NAex 52c.16385A > Gp. (Asp5462Gly)
KB177De novoex 52c.16412G > Tp. (Arg5471Met)
KB489NAex 53c.16498C > Tp. (Arg5500Trp)
KB120De novoex 54c.16528T > Gp. (Tyr5510Asp)
Indel
KB404Inherited Mex 10c.2283_2309delp. (Ala765_Gln773del)
KB274NAex 10c.2532_2591delp. (Arg845_Pro864del)
KB370dDe novoex 14c.4202_4210delp. (Ser1401_Cys1403del)
KB384NAex 39c.11220_11222dupp. (Gln3745dup)
KB461a,dNAex 39c.11220_11222dupp. (Gln3745dup)
KB281Inherited Mex 39c.11714_11716dupp. (Gln3905dup)
KB71Inherited Mex 39c.11819_11836dupp. (Leu3940_Gln3945dup)
KB227Inherited Pex 39c.11843_11860delp. (L3948_Q3953del)
KB228Inherited Pex 39c.11854_11874dupp. (Q3952_Q3958dup)
KB77NAex 48c.15163_15168dupp. (Asp5055_Leu5056dup)
KB403De novoex 53c.16489_16491delp. (Ile5497del)
KB53NAex 53c.16489_16491delp. (Ile5497del)
Splice site
KB286De novoint 2-3c.177-2A > Cr.177_400del224;
p. S59Rfs*86
KB31NAint 3-4c.400 þ 1 G > Ar.177_400del224;
p. Ser59Argfs*86
KB20De novoint 3-5c.401-3 A > Gr.400_401insAG;
p. Gly134Glufs*75
KB442NAint 6-7c.840-6delCr.?
KB519NAint 13-14c.4132-2A > Gr.?
KB529NAint 16-17c.4584-6C > Gr.?
KB210De novoin 17-18c.4693 þ 1G > Ar.4681_4693del13;
p. Val1561Argsfsplice*11
KB29NAint 42-43c.13999 þ 5 G > Ar.13840_13999del160;
p. Asn4614Ilefs*5
KB290De novoint 47-48c.14643 þ 1G > Ar.14644_14875del232;
p. Glu4882Profs*36
KB195De novoint 47-48c.14644-3C > Gr.14644_14875del232;
p. Gln4882Profs*36
KB7De novoint 44-45c.14252-6_14252-5insGAAAr.14252_14382del131;
p. Val4751_Glufsplice*22
KB360NAint 47-48c.14644-2A > Tr.?
KB496NAint 53-54c.16520_16521 þ 1delAGGr.?
Gross deletion
KB43eNAex 48-51c.15785-238_16168delinsp. ?
KDM6A
Non-sense KB215fDe novoex 6c.514C > Tp. (Arg172*)
KB341De novoex 6c.514C > Tp. (Arg172*)
Frameshift
KB39NAex 16c.1846_1849delp. (Thr616tyrfs*8)
KB141NAex 17c.2118_2119insp. (G707Hfs*13)
KB434NAex 17c.2515_2518delp. (Asn839Valfs*27)
KB381NAex 20c.3044delCp. (Thr1015Metfs*33)
Missense
KB415NAex 16c.1843C > Tp. (Leu615Phe)
KB272NAex 17c.2326G > Tp. (Asp776Tyr)
KB131De novoex 20c.2939A > Tp. (Asp980Val)
KB380De novoex 26c.3743A > Gp. (Gln1248Arg)
Gross deletions
KB11NAex 1-2p. ?
KB50De novoex 5-9p. ?
Splice site
KB314De novoint 11-12c.975-1G > Ar.876_1320del;
p. Cys293IlefsX26
KB127De novoint 22-23c.3384 þ 3_3384 þ 6delr.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 typesReference
Wilms tumorTeranishi et al.[8]
HepatoblastomaBernier et al.[9]
NeuroblastomaBernier et al.[9]
PilomatrixomaBernier et al.[9]
Spinal ependymomaRoma et al.[10,11]
Burkitt’s lymphomaDe 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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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

About This Article

Special Issue

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.

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Journal of Translational Genetics and Genomics
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