Disclosure: We have no conflicts of interest to declare that could be perceived as prejudicing the impartiality of the research reported. This research did not receive any specific grants from any funding agency in the public, commercial, or not-for-profit sector.
Article first published online: 13 DEC 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 161, Issue 1, pages 34–37, January 2013
How to Cite
Matsuo, T., Ihara, K., Ochiai, M., Kinjo, T., Yoshikawa, Y., Kojima-Ishii, K., Noda, M., Mizumoto, H., Misaki, M., Minagawa, K., Tominaga, K. and Hara, T. (2013), Hyperinsulinemic hypoglycemia of infancy in Sotos syndrome. Am. J. Med. Genet., 161: 34–37. doi: 10.1002/ajmg.a.35657
How to Cite this Article: 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. 2012. Hyperinsulinemic hypoglycemia of infancy in Sotos syndrome. Am J Med Genet Part A 161A:34–37.
- Issue published online: 22 DEC 2012
- Article first published online: 13 DEC 2012
- Manuscript Accepted: 5 AUG 2012
- Manuscript Received: 7 APR 2012
- Sotos syndrome;
- congenital hyperinsulinism;
- hypoglycemia NSD1 gene
Sotos syndrome (OMIM #117550) is a congenital syndrome characterized by overgrowth with advanced bone age, macrocephaly, and learning difficulties. Endocrine complications of this syndrome have not yet been fully described in previous reports. We here investigated the clinical manifestations of Sotos syndrome in Japanese patients who presented with hyperinsulinemic hypoglycemia of infancy. We recruited patients diagnosed as having Sotos syndrome who presented with the complication of hyperinsulinemia during the neonatal period using a survey of the abstracts of Pediatric Meetings in domestic areas of Japan from 2007 to 2011. As a result, five patients (four females and one male) were recruited to evaluate the clinical presentation of Sotos syndrome by reference to the clinical record of each patient. A 5q35 deletion including the NSD1 gene was detected in all patients. Major anomalies in the central nervous, cardiovascular, and genito-urinary systems were frequently found. Hypoglycemia occurred between 0.5 and 3 hr after birth and high levels of insulin were initially found within 3 days of birth. The patients were treated with intravenous glucose infusion at a maximum rate of 4.6–11.0 mg/kg/min for 12–49 days. Three of the five patients required nasal tube feeding. One patient received medical treatment with diazoxide. This study shows that patients with Sotos syndrome may present with transient hyperinsulinemic hypoglycemia in the neonatal period. © 2012 Wiley Periodicals, Inc.
Sotos syndrome is a congenital syndrome characterized by overgrowth with advanced bone age, macrocephaly, and learning difficulties [Cole and Hughes, 1994; Leventopoulos et al., 2009]. Haploinsufficiency of the NSD1 gene is a cause of Sotos syndrome and a genotype–phenotype correlation has been noticed: major anomalies have been more frequently seen in patients with 5q35 deletions including the NSD1 gene than in those with point mutations in the NSD1 gene, most likely due to the fact that the genes adjacent to NSD1 may affect the phenotype of this syndrome [Douglas et al., 2003; Kamimura et al., 2003]. The exact prevalence of Sotos syndrome is unknown but was estimated at 1:10,000–1:50,000 [Cole and Hughes, 1990]. Almost half (45%) of all cases of Sotos syndrome in Japanese patients were caused by 5q35 deletions, whereas more than 80% of cases of Sotos syndrome in patients of European origin were caused by intragenic mutations, thus showing obvious ethnic differences in the clinical manifestations [Kurotaki et al., 2003; Nagai et al., 2003]. Endocrine complications of this syndrome have not yet been fully described in previous reports, although hypoglycemia during the neonatal period has sometimes been noticed as a minor complication [Cole and Hughes, 1990; Cole and Hughes, 1994; Hook and Reynolds, 1967].
In this study, we recruited patients diagnosed as having Sotos syndrome who presented with neonatal hyperinsulinemic hypoglycemia and who were admitted to our hospitals from 2007 to 2011. We evaluated the clinical manifestations of this syndrome in these patients and found transient hyperinsulinemic hypoglycemia during infancy to be one of the characteristic presentations of Sotos syndrome.
PATIENTS AND METHODS
We recruited patients diagnosed as having Sotos syndrome who presented with hyperinsulinemia during infancy using a survey of the abstracts of domestic meetings of The Pediatrics Society in Japan from 2007 to 2011. Five patients were identified and enrolled in this study for a detailed evaluation. All patients were admitted to the neonatal intensive care unit (NICU) of the hospitals soon after birth due to neonatal asphyxia, major congenital anomalies, or a poor feeding ability of unknown origin. Several patients were diagnosed as having Sotos syndrome during admission to the NICU, based on accompanying congenital anomalies with facial features typical of the syndrome. The other patients were diagnosed during a follow-up period by 1 year of age, based on the presence of characteristic clinical symptoms, developmental delay, or overgrowth. Cytogenetic evaluation using a fluorescent in situ hybridization (FISH) analysis was carried out on all patients. The clinical symptoms and biochemical data were retrospectively collected from the medical charts of the individual patients.
Characteristics of the Patients
The clinical manifestations of the syndrome, the genetic, and laboratory data of the patients, and the specific treatments used to treat hypoglycemia are presented in Table I. Four patients were female and one was male. A cytogenetic study was performed on each patient and a 5q35 deletion including the NSD1 gene was detected in all patients. Maternal complications of pregnancy were seen in some cases; however, this appeared to be nonspecific to the syndrome. Three of the five patients were born small for their gestational age and four of the five patients suffered from neonatal asphyxia at a mild to moderate grade (Apgar score < 8 at 1 min after birth). Major anomalies in the central nervous, cardiovascular, and genito-urinary systems were frequently found. Hypoglycemia occurred between 0.5 and 3 hr after birth and high levels of insulinemia were initially found almost within 3 days of birth. All of the patients showed hyperirritability; however, none suffered from convulsions as a result of the hypoglycemia. The patients were treated with intravenous glucose infusion at a maximum rate of 4.6–11.0 mg/kg/min for 12–49 days. Three of the five patients required nasal tube feeding due to poor feeding ability and persistent hypoglycemia. One patient received medical treatment with diazoxide.
|5q35 Microdeletion (FISH)||Deletion||Deletion||Deletion||Deletion||Deletion|
|Clinical data in perinatal period|
|Complication of pregnancy||Maternal PIH||Fetal growth arrest||Maternal asthma||Fetal asphyxia||Maternal PIH|
|Duration of pregnancy||41w0d||38w2d||38w3d||38w0d||39w3d|
|Birth weight (g)||3,470||2,555||3,708a||2,330||2,580b|
|Birth length (cm)||55.0a||48.5||52.5a||42.0b||47.0|
|Birth head circumstance (cm)||36.7a||35.0a||35.5a||35.5a||35.0a|
|Birth chest circumstance (cm)||34.5||30.8||N/A||28.5||29|
|Apgar score (1 min/5 min)||6/8||5/7||7/9||2/5||9/10|
|Major congenital anomalies|
|Central nervous system||Volume loss of bilateral occipital lobe||Dilatation of cavum vergae||Dilatation of lateral ventricles||Agenesis of corpus callosum||Dilatation of lateral ventricles|
|Congenital heart defect||None||PDA, ASD, CoA PLSVC||PDA||PDA||None|
|Genito-urinary system||Hydronephrosis (bilaterally)||None||Hydronephrosis (bilaterally)||Hydronephrosis (bilaterally) polycystic kidney (rt)||Hydronephrosis (bilaterally)|
|Others||Lordosis||Mild hearing loss (left)||None||None||None|
|Multiple intracranial bleeding/infarction|
|Hyperinsulinemic hypoglycemia in infancy|
|Onset of hypoglycemia after birth||1 hr||1 hr||3 hr||30 min||1 hr|
|Representative data of glucose [mmol/L]/Insulin[µIU/mL] (days of age)||1.1/23 (day 3)||0.23/43 (day 12)||0.16/7 (day 1)||<0.06/3.2 (day 0)||<1.1/19 (day 0)|
|Data at hypoglycemia||Cortisol 77.3 nmol/L||Cortisol 955 nmol/L GH 7.30 µg/L ACTH 10.8 pmol/L||Cortisol 464 nmol/L GH 11.5 µg/L||Cortisol 345 nmol/L||Cortisol 130 nmol/L ACTH 8.4 pmol/L|
|Treatment for hypoglycemia||IVG||IVG||IVG||IVG||IVG|
|IVG duration (days)||23||49||12||37||22|
|Maximum glucose rate of IVG (mg/kg/min)||8.6||10.4||4.6||11.0||8|
|Diazoxide treatment (maximum dose, duration)||No||Yes (6 mg/kg/day, >2 months)||No||No||No|
|Duration of tube feeding||40 days||>2 months||No||>1 year||No|
|Duration of hyperinsulinemia||6 weeks||>2 months||12 days||20 days||22 days|
The typical manifestations of Sotos syndrome are overgrowth, developmental delay, and learning difficulties in childhood, although clinical symptoms and congenital abnormalities of this syndrome are known to vary considerably [Baujat and Cormier-Daire, 2007]. In a previous report of 266 patients in European countries, the cardinal features that presented in more than 90% of patients included characteristic facial appearances, learning difficulties, and overgrowth of both height and head circumference [Tatton-Brown et al., 2005]. Neonatal hypoglycemia was briefly described in previous reports as a minor feature [Cole and Hughes, 1990; Tatton-Brown et al., 2005]; however, hyperinsulinemic hypoglycemia has been rarely noticed [Giurgea et al., 2006]. This is partly because feeding difficulties in the neonatal period, which are characteristic of this syndrome, are thought to cause hypoglycemia, and blood insulin levels are not routinely measured. In addition, many of the present cases had neonatal asphyxia, suggesting that perinatal stresses might additionally induce hypoglycemia [Stanley, 2006]. These cases indicate that Sotos syndrome should be considered in the differential diagnosis of transient hyperinsulinemia, especially when multiple congenital malformations are accompanying the hypoglycemia. In such cases, specific treatments, such as diazoxide, should be considered, in addition to the intravenous administration of a highly concentrated glucose solution.
The pathophysiology of the hyperinsulinemia that occurs in Sotos syndrome appears to be different from neonatal hyperinsulinemia of severe and permanent types. The mechanism underlying congenital hyperinsulinemia is a dysfunction of the pancreatic ATP-sensitive potassium channel [De Leon and Stanley, 2007]. It is unlikely that the haploinsufficiency of NSD1 directly influences the function of the potassium channel in pancreatic beta cells. NSD1 is a presumed regulator of the chromatin structure and gene expression because it catalyzes specific types of histone methylation, and contributes to the initiation, maintenance, or termination of gene activation or repression [Huang et al., 1998]. The NSD1 molecule has no DNA-binding domain, but binds to both cofactors and methylated histones, suggesting that NSD1 exhibits features of a cofactor complex [Pasillas et al., 2011]. We speculate that the disrupted interaction between NSD1 and histones or cofactors may directly cause the abnormal expression of insulin. In previous studies, the histone methyltransferase Set7/9 was found to be responsible for H3-Lys4 di-methylation and functioned as an effector of Pdx1 for the transcription of the insulin gene in developing and mature islet β cells [Deering et al., 2009]. We speculate that the histone methyltransferase NSD1 may also be associated with beta cell-specific transcription factor(s) to suppress the expression of the insulin gene. In that case, a haploinsufficiency of NSD1 might fail to suppress the expression of the insulin gene. Another explanation of the hyperinsulinemia in patients with Sotos syndrome includes the involvement of factors that influence the biological function of insulin in vivo. The bioactivity of insulin is affected by insulin-like growth factor binding proteins (IGFBPs), especially IGFBP-rP1, depending on their affinity for insulin in the blood [Hwa et al., 1999; Forbes et al., 2012]. Since patients with typical Sotos syndrome showed low plasma IGFBPs levels [de Boer et al., 2004a, b], their serum insulin levels might be affected by the altered IGFBP levels. While the exact mechanism remains unknown, a biochemical analysis of beta cells derived from patients with Sotos syndrome might help to clarify the molecular pathogenesis of abnormal insulin secretion in infancy.
In conclusion, patients with Sotos syndrome may present with transient hyperinsulinemic hypoglycemia in the neonatal period. Therefore, this combination should be taken into account by neonatologists and clinical geneticists in order to make an early diagnosis and to perform appropriate treatments for these patients. Further study with additional patients and detailed biochemical analyses are expected to elucidate the characteristics of hyperinsulinism in Sotos syndrome.
We thank Professor Brian Quinn for his help with this manuscript.
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