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Multiple Mongolian spots in an individual with Kleefstra syndrome caused by a novel nonsense euchromatin histone methyltransferase 1 variant

Multiple Mongolian spots in an individual with Kleefstra syndrome caused by a novel nonsense... Short case report 29 Multiple Mongolian spots in an individual with Kleefstra syndrome caused by a novel nonsense euchromatin histone methyltransferase 1 variant Xiang Pan and Jun Lu Clinical Dysmorphology 2023, 32:29–31 Correspondence to Jun Lu, MD, Department of Pediatrics, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No.43 People Department of Pediatrics, Affiliated Haikou Hospital of Xiangya Medical College, Avenue, Meilan District, Haikou, Hainan, 570208, China Central South University, Haikou, China Tel: +86 13976240518; fax: +86 0898 66189688; e-mail: lu139762@163.com Received 31 December 2021 Accepted 25 August 2022 List of key features Case report Mongolian spots An 11-month-old girl born at 37  weeks of gestational Microcephaly age to a 27-year-old G1P0 → 1 mother was referred to Tented upper lip our clinics because of motor developmental delay (DD). Highly arched eyebrows Pregnancy and family history were noncontributory. She Short chin achieved head control by 5  months, and could sit up Developmental retardation independently by 10  months but was not able to crawl or say simple words such as ‘Mom’ or ‘Dad’. Growth parameters were as follows: weight 7.0  kg (<3rd cen- Introduction Kleefstra syndrome (KS) (OMIM #610253) is caused by tile), length 67.5  cm (<3rd centile), head circumference a heterozygous microdeletion of chromosome 9q34.3 41.0  cm (<3rd centile). Indifferent reaction, not easy to region or a pathogenic variation in the euchromatin be amused, unable to actively look at others, no response histone methyltransferase 1 (EHMT1) gene (OMIM to name. The back, buttocks, and the outside of the #607001). The EHMT1 gene located at chromosome right thigh were diffusely distributed with bluish-brown 9q34.3 region, which contains a total of 28 exons, and Mongolian spots (Fig.  1). The head circumference was small (Microcephaly) and the front and back diameter of the initiation of ATG occurs in exon 2 (Kleefstra et al., 2006). Kleefstra et al. (2009) reported 16 patients with 9q the head was short. Special facial features: highly arched subtelomeric deletion syndrome and six patients with an intragenic EHMT1 mutation. All patients presented Fig. 1 with the core phenotype of the deletion syndrome, and there were no phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features, so they concluded that the haploinsuffi- ciency of EHMT1 gene was the basis for the phenotypic features of the deletion syndrome. There are more than 100 cases of KS reported so far, of which about 75% are caused by a heterozygous microdeletion in the 9q34.3 region containing the EHMT1 gene, and 25% are caused by loss-of-function, intragenic EHMT1 variants (Atik et al., 2015). We report an individual with KS1 and multi- ple Mongolian spots (also known as congenital dermal melanocytosis) caused by a novel pathogenic nonsense variant NM_024757:exon 9:c.1468C >T(p.R490*) in the EHMT1 gene. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY- The bluish-brown Mongolian spots are diffusely distributed on the NC-ND), where it is permissible to download and share the work provided it is back. properly cited. The work cannot be changed in any way or used commercially without permission from the journal. 0962-8827 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. DOI: 10.1097/MCD.0000000000000436 30 Clinical Dysmorphology 2023, Vol 32 No 1 eyebrows, widely spaced eyes, slight antimongoloid slant imaging anomalies (50–60%), cardiovascular anomalies palpebral fissures, low-set ears, short nose, tented upper (40–45%), male genital anomalies (45–50%), renal issues lip and short chin (Fig. 2). The muscle tone of the limbs (15–30%), hypoacusia (20–30%) and hernia (15–20%) was low, and the muscle strength was normal. General (Ciaccio et al., 2018). The EHMT1 gene encodes lysine auxiliary examinations included blood routine examina- methyltransferase, which can methylate histones. The tion, tandem mass spectrometry analysis of amino acids/ lack of lysine methyltransferase impairs the proper con- acylcarnitines of dried blood filter paper, urine organic trol of the activity of certain genes in many body organs acid analysis and head MRI showed no abnormalities. and tissues, leading to the developmental abnormali- ties and functional characteristics of KS (Yamada et al., Genetic testing: Through next-generation sequenc- 2018). So far, most of the KS cases reported in the lit- ing technology and bioinformatics analysis, a heterozy- erature involve submicroscopic deletion of 9q34.3, but gous nonsense variant NM_024757:exon 9:c.1468C >T with the development of genetic testing technology, we (p.R490*) was detected in the EHMT1 gene. This var- can detect more intragenic pathogenic variant of EHMT1 iant is novel, can cause the 490th codon of the EHMT1 gene responsible for KS, both result in haploinsufficiency gene to change from the original codon encoding arginine of the EHMT1 gene. to a stop codon, leading to protein truncation. Sanger sequencing confirmed the existence of this novel variant Neural crest cells (NCCs) are pluripotent stem cells (Fig.  3). Her parents did not carry this variant. ACMG- that can differentiate into various types of cells such 2015 (American College of Medical Genetics) criteria as chondrocytes, neurons and melanocytes. Disorders were considered for pathogenicity (PVS1, PS2 and PM2) caused by NCCs abnormalities are collectively known as (Richards et al., 2015). neurocristopathies, which are associated with develop- mental abnormalities in various parts of the body, includ- Discussion ing the head, face, skin and nerve tissue. Studies have KS follows an autosomal dominant inheritance pattern, shown that the lysine methyltransferase encoded by the but so far almost all reported cases have occurred de novo. EHMT1 gene can methylate histones and can regulate The core clinical phenotypes of KS are characterized the development, migration and differentiation of NCCs with DD/intellectual disability, childhood hypotonia, and at the epigenetic regulation. Pathogenic variants in the a recognizable pattern of facial features(brachycephaly, EHMT1 gene may affect these processes to some extent microcephaly, arched eyebrows, flat face, hypertelorism, (Bronner, 2012; Hu et al., 2014). It has been hypothesized short nose, anteverted nostrils and carp-shaped mouth). that Mongolian spots are accumulation of melanocytes in This can be caused by either 9q34.3 subtelomeric dele- the dermis caused by disrupted migration of melanocytes tions or loss-of-function variants in the EHMT1 gene from the neural crest to the epidermis in human embryos (Hadzsiev et al., 2016; Okur et al., 2018). Beside the core (Franceschini et al., 2015). The widespread abnormal phenotypes, the spectrum of KS-related clinical mor- distribution of Mongolian spots may be associated with bidity includes behavioral problems (65–70%), autism some inborn errors of metabolism, the more common spectrum disorder (30–75%), epilepsy (20–50%), brain of which are mucopolysaccharidosis type I (Hurler syn- drome, OMIM #607014) and GM1 gangliosidosis (OMIM #230500), and the others are mucopolysaccharidosis type Fig. 2 II (Hunter syndrome, OMIM #607014), Niemann-Pick disease type A (OMIM #257200), and alpha-mannosido- sis (OMIM #248500), all of which belong to lysosomal storage diseases. In this case, no pathogenic variant in cor- responding genes related to these diseases was detected by next-generation sequencing technology and bioin- formatics analysis, and no hepatosplenomegaly, Hurler- like coarse facial features, skeletal deformities, hearing impairment, visual impairment, epilepsy, tremor, ataxia, etc., so the diagnosis of these diseases are not considered. The craniofacial features and autistic traits of this child with KS were typical, and the multiple Mongolian spots should be paid more attention. There has been case report of congenital hyperaccumulation of melanocytes in the local deep dermis in the child with KS (Ciaccio et al., 2018), but the affected skin area was not as so exten- The special facial features: highly arched eyebrows, widely spaced sive as this case. In this paper, we report a KS caused by eyes, slight antimongoloid slant palpebral fissures, low-set ears, short nose, tented upper lip and short chin. a novel pathogenic variant NM_024757:exon 9:c.1468C >T (p.R490*) in the EHMT1 gene. KS is a rare disease KS caused by a novel nonsense EHMT1 variant Pan and Lu 31 Fig. 3 The sanger sequencing result. (a) The variant site: EHMT1 c.1468C>T(p.R490*) was detected on the child. (b and c) The above-mentioned variant site was not found in the parents of the child. Franceschini D, Dinulos JG (2015). Dermal melanocytosis and associated disor- with a very low incidence. It is of great significance to ders. Curr Opin Pediatr 27:480–485. report a KS patient with a rare genotype and phenotype, Hadzsiev K, Komlosi K, Czako M, Duga B, Szalai R, Szabo A, et al. (2016). and it can deepen the understanding of the disease by Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype. Mol Cytogenet 9:22. clinicians. Hu N, Strobl-Mazzulla PH, Bronner ME (2014). Epigenetic regulation in neural crest development. Dev Biol 396:159–168. Acknowledgements Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM, Magee A, et al. Informed consent has been obtained from patients that (2006). Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am J Hum grants permission for the publication of images as part of Genet 79:370–377. this work. Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Houge G, Foulds N, et al. (2009). Further clinical and molecular delineation of the 9q subtelo- meric deletion syndrome supports a major contribution of EHMT1 haploinsuf- Conflicts of interest ficiency to the core phenotype. J Med Genet 46 :598–606. There are no conflicts of interest. Okur V, Nees S, Chung WK, Krishnan U (2018). Pulmonary hypertension in patients with 9q34.3 microdeletion-associated Kleefstra syndrome. Am J References Med Genet A 176:1773–1777. Atik T, Karaca E, Ozkinay E, Cogulu O (2015). Twins with Kleefstra syndrome due Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al.; ACMG to chromosome 9q34.3 microdeletion. Genet Couns 26:431–435. Laboratory Quality Assurance Committee (2015). Standards and Bronner ME (2012). Formation and migration of neural crest cells in the vertebrate guidelines for the interpretation of sequence variants: a joint consen- embryo. Histochem Cell Biol 138:179–186. sus recommendation of the American College of Medical Genetics and Ciaccio C, Scuvera G, Tucci A, Gentilin B, Baccarin M, Marchisio P, et al. (2018). Genomics and the Association for Molecular Pathology. Genet Med New insights into Kleefstra syndrome: report of two novel cases with pre- 17:405–424. viously unreported features and literature review. Cytogenet Genome Res Yamada A, Shimura C, Shinkai Y (2018). Biochemical validation of EHMT1 mis- 156:127–133. sense mutations in Kleefstra syndrome. J Hum Genet 63:555–562. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Dysmorphology Wolters Kluwer Health

Multiple Mongolian spots in an individual with Kleefstra syndrome caused by a novel nonsense euchromatin histone methyltransferase 1 variant

Clinical Dysmorphology , Volume 32 (1) – Jan 16, 2023

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Wolters Kluwer Health
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Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
ISSN
0962-8827
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1473-5717
DOI
10.1097/mcd.0000000000000436
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Abstract

Short case report 29 Multiple Mongolian spots in an individual with Kleefstra syndrome caused by a novel nonsense euchromatin histone methyltransferase 1 variant Xiang Pan and Jun Lu Clinical Dysmorphology 2023, 32:29–31 Correspondence to Jun Lu, MD, Department of Pediatrics, Affiliated Haikou Hospital of Xiangya Medical College, Central South University, No.43 People Department of Pediatrics, Affiliated Haikou Hospital of Xiangya Medical College, Avenue, Meilan District, Haikou, Hainan, 570208, China Central South University, Haikou, China Tel: +86 13976240518; fax: +86 0898 66189688; e-mail: lu139762@163.com Received 31 December 2021 Accepted 25 August 2022 List of key features Case report Mongolian spots An 11-month-old girl born at 37  weeks of gestational Microcephaly age to a 27-year-old G1P0 → 1 mother was referred to Tented upper lip our clinics because of motor developmental delay (DD). Highly arched eyebrows Pregnancy and family history were noncontributory. She Short chin achieved head control by 5  months, and could sit up Developmental retardation independently by 10  months but was not able to crawl or say simple words such as ‘Mom’ or ‘Dad’. Growth parameters were as follows: weight 7.0  kg (<3rd cen- Introduction Kleefstra syndrome (KS) (OMIM #610253) is caused by tile), length 67.5  cm (<3rd centile), head circumference a heterozygous microdeletion of chromosome 9q34.3 41.0  cm (<3rd centile). Indifferent reaction, not easy to region or a pathogenic variation in the euchromatin be amused, unable to actively look at others, no response histone methyltransferase 1 (EHMT1) gene (OMIM to name. The back, buttocks, and the outside of the #607001). The EHMT1 gene located at chromosome right thigh were diffusely distributed with bluish-brown 9q34.3 region, which contains a total of 28 exons, and Mongolian spots (Fig.  1). The head circumference was small (Microcephaly) and the front and back diameter of the initiation of ATG occurs in exon 2 (Kleefstra et al., 2006). Kleefstra et al. (2009) reported 16 patients with 9q the head was short. Special facial features: highly arched subtelomeric deletion syndrome and six patients with an intragenic EHMT1 mutation. All patients presented Fig. 1 with the core phenotype of the deletion syndrome, and there were no phenotype-genotype correlations between size of the deletions or type of mutations and severity of clinical features, so they concluded that the haploinsuffi- ciency of EHMT1 gene was the basis for the phenotypic features of the deletion syndrome. There are more than 100 cases of KS reported so far, of which about 75% are caused by a heterozygous microdeletion in the 9q34.3 region containing the EHMT1 gene, and 25% are caused by loss-of-function, intragenic EHMT1 variants (Atik et al., 2015). We report an individual with KS1 and multi- ple Mongolian spots (also known as congenital dermal melanocytosis) caused by a novel pathogenic nonsense variant NM_024757:exon 9:c.1468C >T(p.R490*) in the EHMT1 gene. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY- The bluish-brown Mongolian spots are diffusely distributed on the NC-ND), where it is permissible to download and share the work provided it is back. properly cited. The work cannot be changed in any way or used commercially without permission from the journal. 0962-8827 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. DOI: 10.1097/MCD.0000000000000436 30 Clinical Dysmorphology 2023, Vol 32 No 1 eyebrows, widely spaced eyes, slight antimongoloid slant imaging anomalies (50–60%), cardiovascular anomalies palpebral fissures, low-set ears, short nose, tented upper (40–45%), male genital anomalies (45–50%), renal issues lip and short chin (Fig. 2). The muscle tone of the limbs (15–30%), hypoacusia (20–30%) and hernia (15–20%) was low, and the muscle strength was normal. General (Ciaccio et al., 2018). The EHMT1 gene encodes lysine auxiliary examinations included blood routine examina- methyltransferase, which can methylate histones. The tion, tandem mass spectrometry analysis of amino acids/ lack of lysine methyltransferase impairs the proper con- acylcarnitines of dried blood filter paper, urine organic trol of the activity of certain genes in many body organs acid analysis and head MRI showed no abnormalities. and tissues, leading to the developmental abnormali- ties and functional characteristics of KS (Yamada et al., Genetic testing: Through next-generation sequenc- 2018). So far, most of the KS cases reported in the lit- ing technology and bioinformatics analysis, a heterozy- erature involve submicroscopic deletion of 9q34.3, but gous nonsense variant NM_024757:exon 9:c.1468C >T with the development of genetic testing technology, we (p.R490*) was detected in the EHMT1 gene. This var- can detect more intragenic pathogenic variant of EHMT1 iant is novel, can cause the 490th codon of the EHMT1 gene responsible for KS, both result in haploinsufficiency gene to change from the original codon encoding arginine of the EHMT1 gene. to a stop codon, leading to protein truncation. Sanger sequencing confirmed the existence of this novel variant Neural crest cells (NCCs) are pluripotent stem cells (Fig.  3). Her parents did not carry this variant. ACMG- that can differentiate into various types of cells such 2015 (American College of Medical Genetics) criteria as chondrocytes, neurons and melanocytes. Disorders were considered for pathogenicity (PVS1, PS2 and PM2) caused by NCCs abnormalities are collectively known as (Richards et al., 2015). neurocristopathies, which are associated with develop- mental abnormalities in various parts of the body, includ- Discussion ing the head, face, skin and nerve tissue. Studies have KS follows an autosomal dominant inheritance pattern, shown that the lysine methyltransferase encoded by the but so far almost all reported cases have occurred de novo. EHMT1 gene can methylate histones and can regulate The core clinical phenotypes of KS are characterized the development, migration and differentiation of NCCs with DD/intellectual disability, childhood hypotonia, and at the epigenetic regulation. Pathogenic variants in the a recognizable pattern of facial features(brachycephaly, EHMT1 gene may affect these processes to some extent microcephaly, arched eyebrows, flat face, hypertelorism, (Bronner, 2012; Hu et al., 2014). It has been hypothesized short nose, anteverted nostrils and carp-shaped mouth). that Mongolian spots are accumulation of melanocytes in This can be caused by either 9q34.3 subtelomeric dele- the dermis caused by disrupted migration of melanocytes tions or loss-of-function variants in the EHMT1 gene from the neural crest to the epidermis in human embryos (Hadzsiev et al., 2016; Okur et al., 2018). Beside the core (Franceschini et al., 2015). The widespread abnormal phenotypes, the spectrum of KS-related clinical mor- distribution of Mongolian spots may be associated with bidity includes behavioral problems (65–70%), autism some inborn errors of metabolism, the more common spectrum disorder (30–75%), epilepsy (20–50%), brain of which are mucopolysaccharidosis type I (Hurler syn- drome, OMIM #607014) and GM1 gangliosidosis (OMIM #230500), and the others are mucopolysaccharidosis type Fig. 2 II (Hunter syndrome, OMIM #607014), Niemann-Pick disease type A (OMIM #257200), and alpha-mannosido- sis (OMIM #248500), all of which belong to lysosomal storage diseases. In this case, no pathogenic variant in cor- responding genes related to these diseases was detected by next-generation sequencing technology and bioin- formatics analysis, and no hepatosplenomegaly, Hurler- like coarse facial features, skeletal deformities, hearing impairment, visual impairment, epilepsy, tremor, ataxia, etc., so the diagnosis of these diseases are not considered. The craniofacial features and autistic traits of this child with KS were typical, and the multiple Mongolian spots should be paid more attention. There has been case report of congenital hyperaccumulation of melanocytes in the local deep dermis in the child with KS (Ciaccio et al., 2018), but the affected skin area was not as so exten- The special facial features: highly arched eyebrows, widely spaced sive as this case. In this paper, we report a KS caused by eyes, slight antimongoloid slant palpebral fissures, low-set ears, short nose, tented upper lip and short chin. a novel pathogenic variant NM_024757:exon 9:c.1468C >T (p.R490*) in the EHMT1 gene. KS is a rare disease KS caused by a novel nonsense EHMT1 variant Pan and Lu 31 Fig. 3 The sanger sequencing result. (a) The variant site: EHMT1 c.1468C>T(p.R490*) was detected on the child. (b and c) The above-mentioned variant site was not found in the parents of the child. Franceschini D, Dinulos JG (2015). Dermal melanocytosis and associated disor- with a very low incidence. It is of great significance to ders. Curr Opin Pediatr 27:480–485. report a KS patient with a rare genotype and phenotype, Hadzsiev K, Komlosi K, Czako M, Duga B, Szalai R, Szabo A, et al. (2016). and it can deepen the understanding of the disease by Kleefstra syndrome in Hungarian patients: additional symptoms besides the classic phenotype. Mol Cytogenet 9:22. clinicians. Hu N, Strobl-Mazzulla PH, Bronner ME (2014). Epigenetic regulation in neural crest development. Dev Biol 396:159–168. Acknowledgements Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM, Magee A, et al. Informed consent has been obtained from patients that (2006). Loss-of-function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. Am J Hum grants permission for the publication of images as part of Genet 79:370–377. this work. Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Houge G, Foulds N, et al. (2009). Further clinical and molecular delineation of the 9q subtelo- meric deletion syndrome supports a major contribution of EHMT1 haploinsuf- Conflicts of interest ficiency to the core phenotype. J Med Genet 46 :598–606. There are no conflicts of interest. Okur V, Nees S, Chung WK, Krishnan U (2018). Pulmonary hypertension in patients with 9q34.3 microdeletion-associated Kleefstra syndrome. Am J References Med Genet A 176:1773–1777. Atik T, Karaca E, Ozkinay E, Cogulu O (2015). Twins with Kleefstra syndrome due Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al.; ACMG to chromosome 9q34.3 microdeletion. Genet Couns 26:431–435. Laboratory Quality Assurance Committee (2015). Standards and Bronner ME (2012). Formation and migration of neural crest cells in the vertebrate guidelines for the interpretation of sequence variants: a joint consen- embryo. Histochem Cell Biol 138:179–186. sus recommendation of the American College of Medical Genetics and Ciaccio C, Scuvera G, Tucci A, Gentilin B, Baccarin M, Marchisio P, et al. (2018). Genomics and the Association for Molecular Pathology. Genet Med New insights into Kleefstra syndrome: report of two novel cases with pre- 17:405–424. viously unreported features and literature review. Cytogenet Genome Res Yamada A, Shimura C, Shinkai Y (2018). Biochemical validation of EHMT1 mis- 156:127–133. sense mutations in Kleefstra syndrome. J Hum Genet 63:555–562.

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Clinical DysmorphologyWolters Kluwer Health

Published: Jan 16, 2023

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