RESEARCH LETTER
A Case with Neonatal Hyperinsulinemic Hypoglycemia: It is a Characteristic Complication of Sotos Syndrome Yoshie Nakamura1, Masaki Takagi,2 Hiroshi Yoshihashi,3 Masaru Miura,4 Satoshi Narumi,5 Tomonobu Hasegawa,5 Yoshishige Miyake,6 and Yukihiro Hasegawa1,2 1
Division of Genetic Research, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan Division of Endocrinology and Metabolism, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan
2 3
Division of Medical Genetics, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan
4
Division of Cardiology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
5 6
Division of Pediatrics, Ichinomiya Municipal Hospital, Aichi, Japan
Manuscript Received: 27 July 2014; Manuscript Accepted: 11 January 2015
Sotos syndrome (SoS, OMIM #117550) is an overgrowth syndrome. Deletions or intragenic mutations of the NSD1 , which is located at chromosome 5q35, are responsible for more than 75% of SoS. Conventionally, neonatal hypoglycemia was reported briefly as one of the infrequent symptoms of SoS. However, Matsuo et al. published a report describing five patients with SoS who presented with transient hyperinsulinemic hypoglycemia (HIH) in the neonatal period. We report on an additional patient of SoS, who presented transient HIH in the neonatal period. All of this patient and previous patients have microdeletions at the 5q35 chromosome. Therefore, we examined the following three in considering the possibility that other factor than NSD1 caused HIH. 1) This patient had no mutation of four currently known HIH related genes, ABCC8, KCNJ11, GLUD1, and GCK. 2) He had no further deletion than commonly observed region encompassing NSD1 by comparative genomic hybridization to DNA microarrays. 3) He had no mutation in the 5q35 region in the non-deleted chromosome using exsome sequence analysis. In conclusion, our patient supported that HIH could be one of the characteristic symptoms of SoS in the neonatal period, and could be useful for early diagnosis. Ó 2015 Wiley Periodicals, Inc.
Key words: sotos syndrome; hyperinsulinemic hypoglycemia
TO THE EDITOR In a recent issue of the Journal, Matsuo et al. [2013] published a report describing five patients with Sotos syndrome (SoS, OMIM #117550) who presented with transient hyperinsulinemic hypoglycemia (HIH) during the neonatal period. The authors proposed that transient HIH could be a characteristic presentation of SoS in the neonatal period and could be useful for early diagnosis. We read the article with great interest and here report on an additional
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Nakamura Y, Takagi M, Yoshihashi H, Miura M, Narumi S, Hasegawa T, Miyake Y, Hasegawa Y. 2015. A case with neonatal hyperinsulinemic hypoglycemia: It is a characteristic complication of sotos syndrome. Am J Med Genet Part A 167A:1171–1174.
patient of SoS with transient HIH in the neonatal period treated with diazoxide. Furthermore, we considered the mechanisms of HIH caused by SoS in this patient using molecular biological techniques, with the aim of expanding the understanding of the SoS neonatal phenotype. The patient was a 6-year-old Japanese boy born at 40 weeks of gestation after an uncomplicated pregnancy and delivery to healthy, nonconsanguineous parents. He had an Apgar score of 8 and 9 at 1 YN and MT equally contributed to this study. Conflict of interest: none. Grant sponsor: Ministry of Health, Labour and Welfare of Japan; Tokyo Metropolitan Foundation; Grant number: Jitsuyoka (Nanbyo)-Ippan014(23300102). Correspondence to: Yukihiro Hasegawa, Division of Genetic Research, Tokyo Metropolitan Children’s Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo 183-8561, Japan. E-mail : [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 25 February 2015 DOI 10.1002/ajmg.a.36996
1171
1172 and 5 min, respectively. His birth weight was 3365 g (þ0.39 SD), height was 50.0 cm (þ0.33 SD), and head circumference was 36.0 cm (þ2.0 SD). He was referred to our institution for respiratory distress. Initial laboratory investigations performed 2 hr after birth revealed hypoglycemia (1 mg/dl). He was treated with intravenous glucose infusion at a maximum rate of 16.1 mg/kg/min. The patient was diagnosed as having HIH at 11 days of age based on high plasma insulin levels (165.7 mU/ml) and inappropriately suppressed free fatty acids (0.66 mmol/L) in conjunction with severe hypoglycemia. He received diazoxide (7 mg/kg/day) starting 15 days after birth. His HIH was well controlled on diazoxide therapy, and treatment was discontinued at age three. A constellation of malformations such as atrial septal defect, macrocephaly, acromegalic features and hypertelorism was noted, in addition to developmental delay. A heterozygous deletion in the 5q35 locus, detected by fluorescence in situ hybridization (FISH) analysis, confirmed the patient’s clinical diagnosis of SoS at 1 year of age. This combination of two relatively rare conditions, SoS and HIH, led us to perform the following two studies: Comparative genomic hybridization to DNA microarrays (array CGH) to identify larger
AMERICAN JOURNAL OF MEDICAL GENETICS PART A deletions than those commonly involving NSD1 and Whole-exomesequence (WES) to obtain additional information on HIH etiology. Array CGH was assessed using the Agilent 4 180K SurePrint G3 Human CGH Microarray (catalog no. G4449A; Agilent Technologies, Santa Clara, CA). Array CGH revealed a common deletion of SoS with no larger deletions (Fig. 1). For WES, DNA was captured with a SureSelect Human All Exon V5 Kit (Agilent Technologies) and sequenced on a HiSeq 2500 sequencer (Illumina, San Diego, CA) with 100-bp pairedend reads. Image analysis and base calling were performed by sequence control software real-time analysis (RTA) v1.18.61, and CASAVA software v1.8.2 (Illumina). We used BWA 0.7.10 and SAM tools 0.1.18 for alignment and variant detection against the human reference genome (NCBI build 37; hg19) with the default settings. Variant calling as well as coverage and depth calculations were performed with the Genome Analysis Toolkit 3.3–0 (http://www.broadinstitute.org/ gatk/) with default setting. The resulting single-nucleotide variants were annotated with ANNOVAR (Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA). We con-
FIG. 1. Result of array CGH analysis. Graphical representation of the results of the array CGH analysis (Agilent 4 180K SurePrint G3 Human CGH Microarray) shows a common 2.2 Mb interstitial deletion of 5q35. The red arrow indicates the NSD1 gene.
NAKAMURA ET AL.
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TABLE I. List of Genes Located in the 5q35 Deleted Region and Expressed in Pancreas (According to OMIM Gene Map). Gene CLTB RNF44 HK3 NSD1 RAB24 PRE LID1 LMAN2 PDLIM7 DDX41 FAM193B TME D9 FAM153A
Gene/locus name Clathrin, light polypeptide B Ring finger protein 44 Hexokinase 3 Nuclear receptor binding SET domain protein 1
Gene / Locus MIM number 118970
RAS-associated protein 24 PRELI domain containing 1 Lectin, mannose-binding 2 PDZ and LIM domain protein 7 DEAD box polypeptide 41 Family with sequence similarity 193, member B Transmembrane emp24 protein transport domain containing 9 Family with sequence similarity 153, Member A
612415 605733 609551 605903 608170 615813
firmed that there were no mutations in the four currently known HIH-related genes (ABCC8, KCNJ11, GLUD1, and GCK). Since one allele was lost for the region of chromosome 5q35 in the patient, any mutations in the genes on the remained allele in the deleted region could be functionally null. However, no pathological sequence variation of the genes, which are included in the deleted region, was identified (Supplemental Table I). SoS is characterized by excessive growth during childhood, macrocephaly, a characteristic facial appearance, and learning difficulties. Mutations and deletions of the NSD1 gene, located at chromosome 5q35, are responsible for more than 75% of SoS cases [Kurotaki et al., 2002; Baujat and Cormier-Daire, 2007]. Neonatal hypoglycemia has been reported as an infrequent, nonspecific symptom of SoS [Tatton-Brown et al., 2005; Arnoux et al., 2010]. A mechanism by which HIH is associated with SoS has been proposed by Matsuo et al. The authors suggested that NSD1 may be associated with beta cell-specific transcription factors that suppress the expression of the insulin gene. Therefore, disorders of NSD1 may cause abnormal expression of insulin. However, another cause of HIH in 5q35 other than NSD1 could not be excluded in their study. All of the patient in this and the previous study were Japanese with microdeletions at the 5q35 chromosome [Matsuo et al., 2013]. SoS due to deletions encompassing NSD1 are much more frequent than intragenic mutations in Japanese population [Kurotaki et al., 2003]. In the deleted region, there were some genes involved in glucose metabolism. Hexokinase 3 (HK3) is one of the hexokinase isozymes, which catalyze the first step in glucose metabolism (glucose phosphorylation). However, it is considered that deletion of HK3 causes hyperglycemia [Henquin et al., 2013]. The deleted region also included the PDLIM7 gene. PDLIM7 regulates insulininduced glucose transporter 4 (GLUT 4) translocation. Mutation of PDLIM7 gene increased insulin-induced Glut 4 translocation and the uptake of glucose [Barre`s et al., 2006]. PDLIM7 has potential for participating in hypoglycemia, however it could not explain pathogenic mechanism of hyperinsulinism. We have listed the genes located in the deleted region of the present patient and expressed in
142570 606681
Phenotype MIM number
117550 130650 601626
pancreas in Table I. However, their functions and mutated-phenotypes are little known In the next step, we revealed that this patient has no mutation in the 5q35 region in the non-deleted chromosome using WES analysis. Sequence variations of these genes are summarized in Supplemental Table I. Therefore, the possibility of HIH caused by other genes in 5q35 is not likely. In conclusion, this case study further supported the hypothesis that HIH could be a characteristic symptom of SoS in the neonatal period and could be useful for early SoS diagnosis. To determine whether a defect in NSD1 is sufficient for HIH onset or whether other genes could be responsible for clinical HIH, further investigations or case studies of HIH with intragenic mutations in NSD1 may be required.
ACKNOWLEDGMENTS This work was supported by a Grant-in-Aid for the Health Science Research Grant for Research on Applying Health Technology (Jitsuyoka (Nanbyo)-Ippan-014(23300102)) from the Ministry of Health, Labour and Welfare of Japan, and grants from Tokyo Metropolitan Foundation.
REFERENCES Arnoux JB, de Lonlay P, Ribeiro MJ, Hussain K, Blankenstein O, Mohnike K, Valayannopoulos V, Robert JJ, Rahier J, Sempoux C, Bellanne´ C, Verkarre V, Aigrain Y, Jaubert F, Brunelle F, Nihoul-Fe´ke´te´ C. 2010. Congenital hyperinsulinism. Early Hum Dev 86:287–294. Barre`s R, Gre´meaux T, Gual P, Gonzalez T, Gugenheim J, Tran A, Le Marchand-Brustel Y, Tanti JF. 2006. Enigma interacts with adaptor protein with PH and SH2 domains to control insulin-induced actin cytoskeleton remodeling and glucose transporter 4 translocation. Mol Endocrinol 20:2864–2875. Baujat G, Cormier-Daire V. 2007. Sotos syndrome. Orphanet J Rare Dis 2:36. Henquin JC, Sempoux C, Marchandise J, Godecharles S, Guiot Y, Nenquin M, Rahier J. 2013. Congenital hyperinsulinism caused by hexokinase I expression or glucokinase-activating mutation in a subset of b-cells. Diabetes 62:1689–1696.
1174 Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T, Ohashi H, Naritomi K, Tsukahara M, Makita Y, Sugimoto T, Sonoda T, Hasegawa T, Chinen Y, Tomita Ha, Kinoshita HA, Mizuguchi A, Yoshiura T, Ki K, Ohta T, Kishino T, Fukushima Y, Niikawa N, Matsumoto N. 2002. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet 30:365–366. Kurotaki N, Harada N, Shimokawa O, Miyake N, Kawame H, Uetake K, Makita Y, Kondoh T, Ogata T, Hasegawa T, Nagai T, Ozaki T, Touyama M, Shenhav R, Ohashi H, Medne L, Shiihara T, Ohtsu S, Kato Z, Okamoto N, Nishimoto J, Lev D, Miyoshi Y, Ishikiriyama S, Sonoda T, Sakazume S, Fukushima Y, Kurosawa K, Cheng JF, Yoshiura K, Ohta T, Kishino T, Niikawa N, Matsumoto N. 2003. Fifty microdeletions among 112 cases of Sotos syndrome: Low copy repeats possibly mediate the common deletion. Hum Mutat 22: 378–387.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Matsuo T, Ihara K, Ochiai M, Kinjo T, Yoshikawa Y, Kojima-Ishii K, Noda M, Mizumoto H, Misaki M, Minagawa K, Tominaga K, Hara T. 2013. Hyperinsulinemic hypoglycemia of infancy in Sotos syndrome. Am J Med Genet A 161A:34–37. Tatton-Brown K, Douglas J, Coleman K, Baujat G, Cole TR, Das S, Horn D, Hughes HE, Temple IK, Faravelli F, Waggoner D, Turkmen S, CormierDaire V, Irrthum A, Rahman N. 2005. Genotype-phenotype associations in Sotos syndrome: An analysis of 266 individuals with NSD1 aberrations. Am J Hum Genet 77:193–204.
SUPPORTING INFORMATION Additional supporting information may be found in the online version of this article at the publisher’s web-site.
A Case with Neonatal Hyperinsulinemic Hypoglycemia: It is a Characteristic Complication of Sotos Syndrome Yoshie Nakamura1, Masaki Takagi,2 Hiroshi Yoshihashi,3 Masaru Miura,4 Satoshi Narumi,5 Tomonobu Hasegawa,5 Yoshishige Miyake,6 and Yukihiro Hasegawa1,2 1
Division of Genetic Research, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan Division of Endocrinology and Metabolism, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan
2 3
Division of Medical Genetics, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan
4
Division of Cardiology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan
5 6
Division of Pediatrics, Ichinomiya Municipal Hospital, Aichi, Japan
Manuscript Received: 27 July 2014; Manuscript Accepted: 11 January 2015
Sotos syndrome (SoS, OMIM #117550) is an overgrowth syndrome. Deletions or intragenic mutations of the NSD1 , which is located at chromosome 5q35, are responsible for more than 75% of SoS. Conventionally, neonatal hypoglycemia was reported briefly as one of the infrequent symptoms of SoS. However, Matsuo et al. published a report describing five patients with SoS who presented with transient hyperinsulinemic hypoglycemia (HIH) in the neonatal period. We report on an additional patient of SoS, who presented transient HIH in the neonatal period. All of this patient and previous patients have microdeletions at the 5q35 chromosome. Therefore, we examined the following three in considering the possibility that other factor than NSD1 caused HIH. 1) This patient had no mutation of four currently known HIH related genes, ABCC8, KCNJ11, GLUD1, and GCK. 2) He had no further deletion than commonly observed region encompassing NSD1 by comparative genomic hybridization to DNA microarrays. 3) He had no mutation in the 5q35 region in the non-deleted chromosome using exsome sequence analysis. In conclusion, our patient supported that HIH could be one of the characteristic symptoms of SoS in the neonatal period, and could be useful for early diagnosis. Ó 2015 Wiley Periodicals, Inc.
Key words: sotos syndrome; hyperinsulinemic hypoglycemia
TO THE EDITOR In a recent issue of the Journal, Matsuo et al. [2013] published a report describing five patients with Sotos syndrome (SoS, OMIM #117550) who presented with transient hyperinsulinemic hypoglycemia (HIH) during the neonatal period. The authors proposed that transient HIH could be a characteristic presentation of SoS in the neonatal period and could be useful for early diagnosis. We read the article with great interest and here report on an additional
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Nakamura Y, Takagi M, Yoshihashi H, Miura M, Narumi S, Hasegawa T, Miyake Y, Hasegawa Y. 2015. A case with neonatal hyperinsulinemic hypoglycemia: It is a characteristic complication of sotos syndrome. Am J Med Genet Part A 167A:1171–1174.
patient of SoS with transient HIH in the neonatal period treated with diazoxide. Furthermore, we considered the mechanisms of HIH caused by SoS in this patient using molecular biological techniques, with the aim of expanding the understanding of the SoS neonatal phenotype. The patient was a 6-year-old Japanese boy born at 40 weeks of gestation after an uncomplicated pregnancy and delivery to healthy, nonconsanguineous parents. He had an Apgar score of 8 and 9 at 1 YN and MT equally contributed to this study. Conflict of interest: none. Grant sponsor: Ministry of Health, Labour and Welfare of Japan; Tokyo Metropolitan Foundation; Grant number: Jitsuyoka (Nanbyo)-Ippan014(23300102). Correspondence to: Yukihiro Hasegawa, Division of Genetic Research, Tokyo Metropolitan Children’s Medical Center, 2-8-29 Musashidai, Fuchu, Tokyo 183-8561, Japan. E-mail : [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 25 February 2015 DOI 10.1002/ajmg.a.36996
1171
1172 and 5 min, respectively. His birth weight was 3365 g (þ0.39 SD), height was 50.0 cm (þ0.33 SD), and head circumference was 36.0 cm (þ2.0 SD). He was referred to our institution for respiratory distress. Initial laboratory investigations performed 2 hr after birth revealed hypoglycemia (1 mg/dl). He was treated with intravenous glucose infusion at a maximum rate of 16.1 mg/kg/min. The patient was diagnosed as having HIH at 11 days of age based on high plasma insulin levels (165.7 mU/ml) and inappropriately suppressed free fatty acids (0.66 mmol/L) in conjunction with severe hypoglycemia. He received diazoxide (7 mg/kg/day) starting 15 days after birth. His HIH was well controlled on diazoxide therapy, and treatment was discontinued at age three. A constellation of malformations such as atrial septal defect, macrocephaly, acromegalic features and hypertelorism was noted, in addition to developmental delay. A heterozygous deletion in the 5q35 locus, detected by fluorescence in situ hybridization (FISH) analysis, confirmed the patient’s clinical diagnosis of SoS at 1 year of age. This combination of two relatively rare conditions, SoS and HIH, led us to perform the following two studies: Comparative genomic hybridization to DNA microarrays (array CGH) to identify larger
AMERICAN JOURNAL OF MEDICAL GENETICS PART A deletions than those commonly involving NSD1 and Whole-exomesequence (WES) to obtain additional information on HIH etiology. Array CGH was assessed using the Agilent 4 180K SurePrint G3 Human CGH Microarray (catalog no. G4449A; Agilent Technologies, Santa Clara, CA). Array CGH revealed a common deletion of SoS with no larger deletions (Fig. 1). For WES, DNA was captured with a SureSelect Human All Exon V5 Kit (Agilent Technologies) and sequenced on a HiSeq 2500 sequencer (Illumina, San Diego, CA) with 100-bp pairedend reads. Image analysis and base calling were performed by sequence control software real-time analysis (RTA) v1.18.61, and CASAVA software v1.8.2 (Illumina). We used BWA 0.7.10 and SAM tools 0.1.18 for alignment and variant detection against the human reference genome (NCBI build 37; hg19) with the default settings. Variant calling as well as coverage and depth calculations were performed with the Genome Analysis Toolkit 3.3–0 (http://www.broadinstitute.org/ gatk/) with default setting. The resulting single-nucleotide variants were annotated with ANNOVAR (Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA). We con-
FIG. 1. Result of array CGH analysis. Graphical representation of the results of the array CGH analysis (Agilent 4 180K SurePrint G3 Human CGH Microarray) shows a common 2.2 Mb interstitial deletion of 5q35. The red arrow indicates the NSD1 gene.
NAKAMURA ET AL.
1173
TABLE I. List of Genes Located in the 5q35 Deleted Region and Expressed in Pancreas (According to OMIM Gene Map). Gene CLTB RNF44 HK3 NSD1 RAB24 PRE LID1 LMAN2 PDLIM7 DDX41 FAM193B TME D9 FAM153A
Gene/locus name Clathrin, light polypeptide B Ring finger protein 44 Hexokinase 3 Nuclear receptor binding SET domain protein 1
Gene / Locus MIM number 118970
RAS-associated protein 24 PRELI domain containing 1 Lectin, mannose-binding 2 PDZ and LIM domain protein 7 DEAD box polypeptide 41 Family with sequence similarity 193, member B Transmembrane emp24 protein transport domain containing 9 Family with sequence similarity 153, Member A
612415 605733 609551 605903 608170 615813
firmed that there were no mutations in the four currently known HIH-related genes (ABCC8, KCNJ11, GLUD1, and GCK). Since one allele was lost for the region of chromosome 5q35 in the patient, any mutations in the genes on the remained allele in the deleted region could be functionally null. However, no pathological sequence variation of the genes, which are included in the deleted region, was identified (Supplemental Table I). SoS is characterized by excessive growth during childhood, macrocephaly, a characteristic facial appearance, and learning difficulties. Mutations and deletions of the NSD1 gene, located at chromosome 5q35, are responsible for more than 75% of SoS cases [Kurotaki et al., 2002; Baujat and Cormier-Daire, 2007]. Neonatal hypoglycemia has been reported as an infrequent, nonspecific symptom of SoS [Tatton-Brown et al., 2005; Arnoux et al., 2010]. A mechanism by which HIH is associated with SoS has been proposed by Matsuo et al. The authors suggested that NSD1 may be associated with beta cell-specific transcription factors that suppress the expression of the insulin gene. Therefore, disorders of NSD1 may cause abnormal expression of insulin. However, another cause of HIH in 5q35 other than NSD1 could not be excluded in their study. All of the patient in this and the previous study were Japanese with microdeletions at the 5q35 chromosome [Matsuo et al., 2013]. SoS due to deletions encompassing NSD1 are much more frequent than intragenic mutations in Japanese population [Kurotaki et al., 2003]. In the deleted region, there were some genes involved in glucose metabolism. Hexokinase 3 (HK3) is one of the hexokinase isozymes, which catalyze the first step in glucose metabolism (glucose phosphorylation). However, it is considered that deletion of HK3 causes hyperglycemia [Henquin et al., 2013]. The deleted region also included the PDLIM7 gene. PDLIM7 regulates insulininduced glucose transporter 4 (GLUT 4) translocation. Mutation of PDLIM7 gene increased insulin-induced Glut 4 translocation and the uptake of glucose [Barre`s et al., 2006]. PDLIM7 has potential for participating in hypoglycemia, however it could not explain pathogenic mechanism of hyperinsulinism. We have listed the genes located in the deleted region of the present patient and expressed in
142570 606681
Phenotype MIM number
117550 130650 601626
pancreas in Table I. However, their functions and mutated-phenotypes are little known In the next step, we revealed that this patient has no mutation in the 5q35 region in the non-deleted chromosome using WES analysis. Sequence variations of these genes are summarized in Supplemental Table I. Therefore, the possibility of HIH caused by other genes in 5q35 is not likely. In conclusion, this case study further supported the hypothesis that HIH could be a characteristic symptom of SoS in the neonatal period and could be useful for early SoS diagnosis. To determine whether a defect in NSD1 is sufficient for HIH onset or whether other genes could be responsible for clinical HIH, further investigations or case studies of HIH with intragenic mutations in NSD1 may be required.
ACKNOWLEDGMENTS This work was supported by a Grant-in-Aid for the Health Science Research Grant for Research on Applying Health Technology (Jitsuyoka (Nanbyo)-Ippan-014(23300102)) from the Ministry of Health, Labour and Welfare of Japan, and grants from Tokyo Metropolitan Foundation.
REFERENCES Arnoux JB, de Lonlay P, Ribeiro MJ, Hussain K, Blankenstein O, Mohnike K, Valayannopoulos V, Robert JJ, Rahier J, Sempoux C, Bellanne´ C, Verkarre V, Aigrain Y, Jaubert F, Brunelle F, Nihoul-Fe´ke´te´ C. 2010. Congenital hyperinsulinism. Early Hum Dev 86:287–294. Barre`s R, Gre´meaux T, Gual P, Gonzalez T, Gugenheim J, Tran A, Le Marchand-Brustel Y, Tanti JF. 2006. Enigma interacts with adaptor protein with PH and SH2 domains to control insulin-induced actin cytoskeleton remodeling and glucose transporter 4 translocation. Mol Endocrinol 20:2864–2875. Baujat G, Cormier-Daire V. 2007. Sotos syndrome. Orphanet J Rare Dis 2:36. Henquin JC, Sempoux C, Marchandise J, Godecharles S, Guiot Y, Nenquin M, Rahier J. 2013. Congenital hyperinsulinism caused by hexokinase I expression or glucokinase-activating mutation in a subset of b-cells. Diabetes 62:1689–1696.
1174 Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T, Ohashi H, Naritomi K, Tsukahara M, Makita Y, Sugimoto T, Sonoda T, Hasegawa T, Chinen Y, Tomita Ha, Kinoshita HA, Mizuguchi A, Yoshiura T, Ki K, Ohta T, Kishino T, Fukushima Y, Niikawa N, Matsumoto N. 2002. Haploinsufficiency of NSD1 causes Sotos syndrome. Nat Genet 30:365–366. Kurotaki N, Harada N, Shimokawa O, Miyake N, Kawame H, Uetake K, Makita Y, Kondoh T, Ogata T, Hasegawa T, Nagai T, Ozaki T, Touyama M, Shenhav R, Ohashi H, Medne L, Shiihara T, Ohtsu S, Kato Z, Okamoto N, Nishimoto J, Lev D, Miyoshi Y, Ishikiriyama S, Sonoda T, Sakazume S, Fukushima Y, Kurosawa K, Cheng JF, Yoshiura K, Ohta T, Kishino T, Niikawa N, Matsumoto N. 2003. Fifty microdeletions among 112 cases of Sotos syndrome: Low copy repeats possibly mediate the common deletion. Hum Mutat 22: 378–387.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A Matsuo T, Ihara K, Ochiai M, Kinjo T, Yoshikawa Y, Kojima-Ishii K, Noda M, Mizumoto H, Misaki M, Minagawa K, Tominaga K, Hara T. 2013. Hyperinsulinemic hypoglycemia of infancy in Sotos syndrome. Am J Med Genet A 161A:34–37. Tatton-Brown K, Douglas J, Coleman K, Baujat G, Cole TR, Das S, Horn D, Hughes HE, Temple IK, Faravelli F, Waggoner D, Turkmen S, CormierDaire V, Irrthum A, Rahman N. 2005. Genotype-phenotype associations in Sotos syndrome: An analysis of 266 individuals with NSD1 aberrations. Am J Hum Genet 77:193–204.
SUPPORTING INFORMATION Additional supporting information may be found in the online version of this article at the publisher’s web-site.
