Neonatal hyperinsulinemic hypoglycemia in a patient with 9p deletion syndrome

European Journal of Medical Genetics xxx (xxxx) xxx–xxx

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Neonatal hyperinsulinemic hypoglycemia in a patient with 9p deletion syndrome Allan Bayata,∗, Maria Kirchhoffb, Camilla Gøbel Madsenc, Sven Kreiborgd,e a

Department of Pediatrics, University Hospital of Hvidovre, Hvidovre, Denmark Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Denmark c Department for Radiology, Centre for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark d Department of Pediatric Dentistry and Clinical Genetics, School of Dentistry, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark e 3D Craniofacial Image Research Laboratory, School of Dentistry, Copenhagen University Hospital Rigshospitalet, University of Copenhagen, Copenhagen, Denmark b

A R T I C LE I N FO

A B S T R A C T

Keywords: Craniofacial abnormality Craniosynostosis 9p deletion syndrome Neonatal hyperinsulinemic hypoglycemia Ventriculomegaly Thalamic infarction Germinal matrix haemorrhage

We report the clinical and neuroradiological findings in a young boy harboring the 9p deletion syndrome including the novel findings of thalamic infarction and germinal matrix haemorrhage and neonatal hyperinsulinemic hypoglycemia. Both the hypoglycemic events and the ventriculomegaly found in this patient have previously only been reported in two patients, while the thalamic infarction and germinal matrix haemorrhage are novel features.

1. Introduction The chromosome 9p deletion syndrome (OMIM 158170) is a complex condition, involving different organs. The syndrome was first described in 1973 by Alfi (Alfi et al., 1973), who defined a recognizable characteristic phenotype observed in six patients. Since then, several authors have specified the clinical manifestations of this genomic alteration, attempting to establish genotype-phenotype correlations (Abreu et al., 2014; Christ et al., 1999; Swinkels et al., 2008; Faas et al., 2007; Hauge et al., 2008; Kawara et al., 2006). The cardinal features of 9p deletion syndrome are trigonocephaly, midface hypoplasia, flat nasal bridge, long philtrum, short neck, and developmental delay and mental retardation (Alfi et al., 1973; Swinkels et al., 2008). Other frequently seen craniofacial features include hypertelorism, epicanthal folds, upslanting and small palpebral fissures, anteverted nostrils, small, low-set and posteriorly angulated ears, micrognathia, microstomia, and choanal atresia (Huret et al., 1988). There are some musculo-skeletal features like muscular hypotonia and scoliosis and others related specifically to the fingers (e.g. square and hyperconvex nails, dolichomesophalangy, and camptodactyly). More severe but less frequently reported malformations include cardiac defects, inguinal hernia, omphalocele, abnormal external genitals (male to female sex reversal) and non-ketotic hyperglycenemia (Huret et al., 1988; Burton et al., 1989; Shashi et al., 1994; Muroya et al., 2000).

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Although around 100 cases have been reported (Abreu et al., 2014; Christ et al., 1999; Faas et al., 2007; Hauge et al., 2008; Kawara et al., 2006; Swinkels et al., 2008; Huret et al., 1988; Mitsui et al., 2013; Shimojima and Yamamoto, 2009), many aspects of this syndrome still remain unspecified including the neuroradiological findings and endocrinological features such as neonatal hypoglycemia. An analysis of the intracranial radiological aspects of these patients (MRI and CT) has only been published in seven patients (Spazzapan et al., 2016; Hou et al., 2016). The aim of this article is to describe the clinical and neuroradiological findings in a new patient harboring the 9p deletion syndrome including the findings of thalamic infarction and germinal matrix haemorrhage and neonatal hyperinsulinemic hypoglycemia. The ventriculomegaly found in this patient has previously only been described in two patients (Hou et al., 2016; Spazzapan et al., 2016), while the thalamic infarction and germinal matrix haemorrhage are novel features. 2. Case report The proband, a now 10-months-old boy, was born by normal vaginal delivery during the 37th week of gestation after an uneventful pregnancy. Birth weight was 2965 g (0 SD), birth length 50 cm (+1 SD) and head circumference 34 cm (0 SD). There were no maternal fever and no fetal heart rate decelerations during delivery, no meconium-

Corresponding author. E-mail address: [email protected] (A. Bayat).

https://doi.org/10.1016/j.ejmg.2018.03.009 Received 12 December 2017; Received in revised form 25 January 2018; Accepted 21 March 2018 1769-7212/ © 2018 Elsevier Masson SAS. All rights reserved.

Please cite this article as: Bayat, A., European Journal of Medical Genetics (2018), https://doi.org/10.1016/j.ejmg.2018.03.009

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Fig. 1. Clinical photos showing the facial features in our patient with a 9p deletion syndrome (1A-D). Pictures showing trigonocephaly, midface hypoplasia, short neck, flat nasal bridge, hypertelorism, short upslanting palpebral fissures, anteverted nostrils, small, low-set and posteriorly angulated ears, micrognathia and microstomia.

Fig. 2. A and B are achieved using magnetic resonance imaging while Fig. 2C and D are produced using computerized tomography scans. Axial T1 weighted image shows ventriculomegaly and delayed myelination (2A). Coronal Flair image showing a leftsided thalamic infarction (2B). Premature fusion of the metopic suture with ridge formation over the fused suture and a trigonocephalic head shape with bitemporal hollowing (2A-B). The cranial base was flattened with a nasion-sella-basion angle of 142° (2A-B). The jaws were characterized by bimaxillary retrognathia which was most pronounced for the mandible (2A-B).

markings and large sella turcica. The cranial base was flattened with a nasion-sella-basion angle of 142°. The jaws were characterized by bimaxillary retrognathia which was most pronounced for the mandible. The dentition was unremarkable. Abdominal ultrasound examination was normal. An echocardiography showed an atrial septum defect. At the age of 10 months it was apparent that he had significant developmental delay: poor head control and unability to sit or stand. He was referred to the department of ophthalmology but no abnormalities were found. At this age his height was 77 cm (+1 SD), the weight was 8.5 kg (−1.5 SD) and the head circumference was 45 cm (−1 SD). There have been no reports of additional hypoglycemic events. On assessment of the family history, a similar phenotypic presentation could not be found in any of the parents.

stained amniotic fluid and a normal umbilical artery pH. 1- and 5-min Apgar scores were 10 and 10. Both parents had unremarkable medical histories. Due to the low birth weight enteral feeding was initiated early. Two hours after delivery, tremor and irritability were observed, with severe hypoglycemia (1.7 mmol/L). High doses of intravenous glucose (up to 20 mg/kg per minute) were needed to normalize the persistently low blood glucose levels. Diazoxide therapy (with hydrochlorothiazide 1 mg/kg per day) was commenced on day 6 and was gradually increased to a maximum dose of 10 mg/kg per day. During the following four days the patient's glucose requirement normalized and diazoxide could gradually be discontinued, while the patient maintained normoglycemia. The child did not experience any epileptic seizures during this period and there was no suspicion of an infection. During the following months he showed gross motor and social milestone delays. In addition, trigonocephaly, flat midface, short and up-slanting palpebral fissures, highly arched eyebrows, small and lowset ears, flat nose, thin upper lip, short neck, long fingers (pictures of fingers are not available), and hypotonia were obvious (Fig. 1A–B). There was no scoliosis, omphalocele, inguinal hernia, ear pits, macroglossia or a nevus flammeus. Examination of the external genitals appeared normal. A brain MRI (Fig. 2A–B) showed ventrigulomegaly, hypoplastic white matter, vertical straight sinus, parietooccipital and paracentral delayed myelination - and a hypoplastic corpus callosum. A left-sided thalamic lacunar infarction, a right-sided thalamic ischemic lesion and a germinal haemorrhage in the right caudothalamic groove (intraventricular haemorrhage grade 1) was found. The cerebral aqueduct was open, the 4th ventricle had a normal size and the extra-axial spaces were unremarkable. No periventricular edema. An arachnoid cyst was seen in the right cerebellopontine angle, but the basal cisterns were open. A CT scan of the head (Fig. 2C–D) showed premature fusion of the metopic suture with ridge formation over the fused suture and a trigonocephalic head shape with bitemporal hollowing. There were no signs of increased intracranial pressure such as increased digital

3. Methods Standard methods were used for extraction of genomic DNA from blood samples. Array CGH was performed using the Agilent SurePrint G3 Human CGH Microarray kit 2 × 400 K (Agilent Technologies, Santa Clara, California, USA). Labeling and hybridization were performed according to the protocol provided by Agilent (Protocol v6.0, November 2008) as previously described (Schejbel et al., 2011). Parental samples were investigated by metaphase FISH using a subtelomere 9p FISH probe according to the suppliers instructions (Kreatech Poseidon™ probe (D9S917), Leica Biosystems, Nussloch, Germany). MRI was performed to examine for cerebral abnormalities, CT scan of the head to evaluate the skeletal features and ultrasound of the abdomen to examine for renal and intestinal abnormalities. Consent for publication of clinical photos and patient information was obtained.

2

3

0

0

0

0

0

0

X

0

0

0 0

0

X

0 X

X

X

0

0

0

0 0

0

0

0 0

0

X

X X X

Female, newborn Conventional Gbanding analysis and FISH 9p22 deletion de novo

Patient 4 (Spazzapan et al., 2016) (patient 3)

Abbreviations; CGH array: Array comparative genomic hybridization; FISH: fluorescence in situ hybridization.

0 0

0

0

X 0

0 0

X 0

0

0

X

X

X

X

Germinal matrix haemorrhage Thalamic infarction Anterior mesial temporal overconvexity Mesial temporal abnormalities Abnormal gyral structure Gray matter heterotopia

X X X

0 0 0

Large sylvian fissures Frontal compression Defective septum pellucidum Corpus callosum anomalies Hypoplastic white matter Ventriculomegaly Periventricular hypodensities Vertical straight sinus

Terminal 9p deletion and terminal 17p duplication derived from unbalanced t(9; 17) (p22; pter) de novo X X X

16.4 Mb 9p24.3p22.2 deletion de novo

15 Mb 9p24.3p22.3 deletion de novo

Genetic result

Female, 7 months Conventional G-banding analysis and FISH

Patient 3 (Spazzapan et al., 2016) (patient 2)

Female, 6 months FISH and array CGH

Male, 10 months Array CGH

Patient 2 (Spazzapan et al., 2016) (patient 1)

Sex and age Investigation

Patient 1 (From current study)

0

X

X

0 X

0

0

0 X

X

X

X X X

3.2 Mb 9p23p22.3 deletion

Female, newborn FISH and array CGH

Patient 5 (Spazzapan et al., 2016) (patient 4)

0

0

0

0 0

0

X

X 0

X

0

X X X

Female, newborn Conventional Gbanding analysis and FISH 9p22 interstitial deletion de novo

Patient 6 (Spazzapan et al., 2016) (patient 5)

0

0

0

0 0

0

0

0 0

0

0

X X X

Female, 5 months Conventional Gbanding analysis and FISH 9p22 deletion de novo

Patient 7 (Spazzapan et al., 2016) (patient 6)

0

0

0

0 0

0

0

0 0

0

0

0

0

0

0 0

0

0

X 0

0

0

0 0 0

11.78 Mb 9p24.3p23 deletion de novo 18.74 Mb 9p24.3p22.1 deletion de novo 0 0 0

Male, 9 years Array CGH

Patient 9 (Hou et al., 2016) (case 2)

Male, 4½ years Array CGH

Patient 8 (Hou et al., 2016) (case 1)

Table 1 Description of the previously published neuroradiological and genetic findings in cases (including the previously unpublished features in the affected patient from this study) with a 9p deletion syndrome.

1

1

1

1 1

1

2

3 2

4

4

6 6 6

Total

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4. Results

cause of hypoglycemia in transitional neonatal hypoglycemia and in persistent hypoglycemia in various groups of high-risk neonates (such as small for gestational age, birth asphyxia, maternal toxemia, erythroblastosis fetalis, maternal diabetes) (Stanley, 2016; Maiorana and Dionisi-Vici, 2017). Currently, there are 11 genes associated with monogenic forms of HI (ABCC8, GCK, GLUD1, HADH1, HK1, HNF1A, HNF4A, KCNJ11, MCT1, PGM1, and UCP2). (Stanley, 2016; Maiorana and Dionisi-Vici, 2017). We used the STRING database (https://stringdb.org/) (Firth et al., 2009) to investigate if there were evidence of functional links in biological pathways among these 11 genes and the 46 genes encompassed by the 9p deletion. We did not find any firm evidence of functional links related to HI. In normal infants, the neonatal hypoglycemia quickly resolves by 1–2 days after birth and the mild HI usually does not require treatment. The more severe and prolonged HI in high risk neonates or in children with genetic causes often requires interventions, ranging from early feeding to prolonged treatment with diazoxide or continuous feedings. In contrast to children with severe HI associated with KATP mutations, high-risk neonates with HI are usually responsive to treatment with diazoxide to control hypoglycemia (Hoe et al., 2006). In 1988, Huret et al., (1988) summarized the features of 80 patients with 9p deletion syndrome. They divided the patients into one group with 39 cases were the 9p deletion was the sole known genetic anomaly and another group with 41 cases were the 9p deletion was seen with another unbalanced chromosome segment. In the first group, data concerning the gestational age was available in 29 patients and in 26 cases the child was born at term with a mean birth weight of 3.2 kg. In the second group, data concerning the gestational age was available in 27 patients and in 25 cases the child was born at term with a mean birth weight of 2.9 kg. Neonatal hypoglycemic events were not described in either group. In our patient the 9p deletion is the sole known genetic anomaly and the child was born at the 37th week of gestation with a birth weight of 2.9 kg. The birth weight in our patient was only slighty lower and we do not believe that this could be a significant contributing factor to the prolonged hypoglycemic period. Also it is unclear why the child developed a thalamic infarction and a germinal matrix haemorrhage. The pathogenesis of perinatal arterial ischaemic stroke (PAIS) is multifactorial and hypoglycaemia has been identified as a significant neonatal risk factor for PAIS in both preterm and fullterm babies (Benders et al., 2007; Harteman et al., 2012) while predictors of perinatal thalamic infarction and germinal matrix haemorrhage, as seen in our patient, include male gender, fetal distress, emergent cesarean delivery, prematurity, and postmaturity but not low birth weight or hypoglycemia (Armstrong-Wells et al., 2009). Further, genetic research and efforts to identify the precise candidate gene on the chromosome 9 responsible for the 9p deletion syndrome phenotype are needed and will probably provide new answers to treat all aspects of this complex pathology.

4.1. Laboratory investigations During the first five days of life there was a normal alanintransaminase, a normal platelet count and international normalized ratio, a normal thyroid function tests and no signs of hyperbilirubinemia. A comprehensive metabolic examination in the presence of hypoglycemia was performed and showed a serum insulin concentration of 33.2μU/mL (3–20μU/mL) with undetectable ketone bodies and a normal lactate, a serum somatotropin level of 12.4 ng/mL (5–53 ng/ mL) and a serum cortisol of 12 μg/dL (1–24 μg/dL). A urine metabolic screening performed at the age of 10months was normal. Array CGH analysis of the proband showed an approximately 15 Mb terminal deletion of chromosome 9p (arr[GRCh37] 9p24.3p22.3(204193_15359025)×1). The deletion encompassed 46 protein coding genes. FISH analyses of parental samples showed that the deletion was de novo. 4.2. Neuroradiological findings The neuroradiological findings of our and the previously published patients are shown in Table 1. 5. Discussion 9p deletion syndrome is a multiorganic syndrome, with characteristic craniofacial dysmorphism, hypotonia, hyperlaxity with frequent abdominal hernia, abnormalities of the extremities, of the spine, and of the thorax. The most frequent craniofacial features described so far in the literature (Alfi et al., 1973; Huret et al., 1988; Faas et al., 2007), were the trigonocephaly, small ears and long philtrum, upslanting palpebral fissures, flat nasal bridge and hypertelorism and they were all present in our patient. Although more than 100 patients with various breakpoints in 9p21p23 have been reported to date (Abreu et al., 2014; Christ et al., 1999; Faas et al., 2007; Hauge et al., 2008; Kawara et al., 2006; Swinkels et al., 2008; Huret et al., 1988; Hou et al., 2016; Burton et al., 1989), the MRI characteristics have, to our knowledge, only been described in 8 patients (Table 1) and include the altered shape of the corpus callosum and of the septum pellucidum and the diffuse hypoplasia of the white matter (Spazzapan et al., 2016; Hou et al., 2016). In only one of these patients the MRI was described as normal (Hou et al., 2016). In 2016 Spazappan et al. (Spazzapan et al., 2016) reported the MRI findings in 6 patients with 9p deletion and compared these finding with 30 non-syndromic trigonocephalic patients in the control group. Anomalies of the corpus callosum and the septum pellucidum, large sylvian fissures and a white matter hypoplasia of moderate degree were more often seen in the 9p group (Spazzapan et al., 2016). The neuroradiological findings in our patient included a hypoplastic corpus callosum, the delayed myelination, the ventriculomegaly, the thalamic infarction and the germinal matrix haemorrhage (Table 1). The venticulomegaly found in our patient has so far only been documented in two patients (Spazzapan et al., 2016; Hou et al., 2016) while the thalamic infarction, the germinal matrix haemorrhage are previously unpublished features. To our knowledge the hypoglycemic events have only been reported twice: in one published case and in patient 249708 from the Decipher database https://decipher.sanger.ac.uk). We therefore believe that persistent neonatal hypoglycemia seems to be a new association worth to be highlighted. The differential diagnosis of hypoglycemia is extensive, and determining the underlying cause is often difficult. Based on the clinical presentation, the genetic and the metabolic results a likely explanation for the hypoglycemic events in our patient is congenital hyperinsulinism (HI)·HI is the most common cause of hypoglycemia in children (Stanley, 2016). The risk of permanent brain injury in infants with HI continues to be as high as 25–50% due to delays in diagnosis and inadequate treatment (Stanley, 2016). HI is the

Conflicts of interest There are no conflicts of interest. Acknowledgements The authors thank the family for participating in this study. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from [email protected]. References Alfi, O., Donnell, G.N., Crandall, B.F., Derencsenyi, A., Menon, R., 1973. Deletion of the short arm of chromosome no.9 (46,9p-): a new deletion syndrome. Ann. Genet. 16, 17–22.

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