Next Article in Journal
Relationship between Varicocele and Male Hypogonadism: A Review with Meta-Analysis
Next Article in Special Issue
Newborn Screening in Pediatric Endocrine Disorders
Previous Article in Journal / Special Issue
Multiple Endocrine Neoplasia in Childhood: An Update on Diagnosis, Screening, Management and Treatment
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Endocrines
Volume 3
Issue 1
10.3390/endocrines3010008
endocrines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Case Report

Diagnosis of Chromosome 15q-Terminal Deletion Syndrome through Elevated Fasting Serum Growth Hormone Levels

by
Masato Ono
1,
Masato Tanaka
1,
Shota Hiroshima
1,
Kentaro Sawano
1,
Yohei Ogawa
1,2,
Keisuke Nagasaki
1,* and
Akihiko Saitoh
1
1
Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
2
Division of Community Medicine, Department of Community Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
*
Author to whom correspondence should be addressed.
Endocrines 2022, 3(1), 92-99; https://doi.org/10.3390/endocrines3010008
Submission received: 27 December 2021 / Revised: 15 February 2022 / Accepted: 16 February 2022 / Published: 23 February 2022
(This article belongs to the Special Issue Genetics in Pediatric Endocrinology)
Browse Figures
Versions Notes

Abstract

:
Chromosome 15q26-qter deletion syndrome is a rare disease that causes prenatal and postnatal growth retardation, microcephaly, developmental delay, and congenital heart diseases, mainly due to haploinsufficiency of IGF1R. In addition, patients with pathogenic variants of the IGF1R show similar symptoms. We report the case of a 5-month-old girl with prenatal and postnatal growth retardation, microcephaly, and congenital heart disease. At 5 months of age, her length was 54.7 cm (−4.3 SD), her weight was 4.4 kg (−3.1 SD), and her head circumference was 37.4 cm (−2.8 SD), thus presenting severe growth retardation. Repeated pre-feeding serum GH levels were abnormally high (26.1–85.5 ng/mL), and IGF-1 levels (+0.16 to +1.2 SD) were relatively high. The 15q sub-telomere fluorescence in situ hybridization analysis revealed a heterozygous deletion in the 15q terminal region. Whole-genome single nucleotide polymorphism microarray analysis showed a terminal deletion of 6.4 Mb on 15q26.2q26.3. This is the first report showing that fasting GH levels are high in early infancy in patients with IGF1R abnormalities. In addition to relatively high IGF-1 levels, elevated fasting GH levels in early infancy may contribute to the diagnosis of IGF1R abnormalities.

1. Introduction

Chromosome 15q-terminal deletion syndrome (OMIM #612626) is a heterozygous deletion of chromosome 15q26-qter that causes prenatal and postnatal growth retardation, microcephaly, developmental delay, and various abnormalities [1]. Several genes in the 15q26 region, such as insulin-like growth factor 1 receptor (IGF1R) and nuclear receptor subfamily 2 group F member 2 (NR2F2), show different phenotypes resulting from heterozygous deletions. Heterozygous deletion of the IGF1R is associated with intrauterine growth retardation and postnatal growth deficiency, minor facial anomalies including microcephaly, micrognathia and triangular faces, and skeletal anomalies such as cubitus valgus, clinodactyly and brachydactyly [2]. Heterozygous deletion of the NR2F2 is associated with congenital heart diseases (CHD), such as ventricular septal defect (VSD), atrial septal defect (ASD), coarctation of aorta, patent ductus arteriosus, and pulmonary stenosis [3,4]. The deletion of other genes in the 15q26 region may contribute to other phenotypic differences.
Since insulin-like growth factor 1 (IGF-1) and its receptor play an important role in skeletal growth and brain development, IGF1R deletions cause intrauterine and postnatal growth retardation, and mild developmental delay [5]. The binding of IGFs to its receptor results in the autophosphorylation of intracellular tyrosine residues, which activates the phosphatidylinositide-3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK) /extracellular signal-regulated kinase (ERK) signaling pathways. This, in turn, stimulates cell proliferation and growth [6].
Similarly, several patients with pathogenic variants of IGF1R, mainly in the heterozygous state and rarely in the compound heterozygous state, have also been reported to exhibit growth retardation before and after birth [7,8]. Short children born small-for-gestational age (SGA) have been reported to possibly include patients with IGF1R pathogenic variants [9]. Indeed, variable phenotypic expression has already been reported, even in relatives carrying the same molecular defect, which makes the diagnosis of IGF1R defects difficult [8].
Although relatively high serum IGF-1 levels have been reported in patients with IGF1R abnormalities, the serum growth hormone (GH) levels in these patients remain unknown. We report the case of a girl with pre- and post-natal severe growth retardation, microcephaly, and ASD, where high serum GH levels in addition to relatively high IGF-1 levels led to a definitive diagnosis.

2. Case Presentation

The female patient presented with severe fetal growth retardation at 19 weeks of gestation. Fetal echocardiography revealed pericardial effusion and septal hypertrophy. She was delivered at 38 weeks of gestation by emergency cesarean section due to fetal distress. Her father’s height was 174 cm, and her mother’s height was 156 cm. Her birth weight was 2034 g (−2.6 SD), body length was 42 cm (−3.2 SD), and head circumference was 30.5 cm (−1.9 SD); she was born SGA. She had no skeletal abnormalities or dysmorphic facial features. Echocardiogram revealed an ASD type II and VSD. At one week of age, she presented with inspiratory stridor due to laryngomalacia, and required a high-flow oxygen nasal cannula to maintain oxygenation. In addition, nasogastric tube feeding was required due to feeding difficulties until 2 months of age. At 5 months of age, her length was 54.7 cm (−4.3 SD), her weight was 4.4 kg (−3.1 SD), and her head circumference was 37.4 cm (−2.8 SD). She showed delayed motor development, achieved head control at 5 months of age and could not rollover. On the other hand, her social and language skills were not delayed: her social smile was noted at 3 months of age and babbling at 4 months. The patient showed severe growth retardation; thus, she was referred to a pediatric endocrinologist. Repeated pre-feeding serum GH levels were abnormally high, and serum IGF-1 levels were slightly above the age-average levels (Table 1). Although the blood glucose level decreased at 3 months of age, the fasting blood glucose remained at the lower limit of normal between 60 and 90 mg/dL. No severe hypoglycemia was observed during the first 3 months, and after 3 months of age, blood glucose levels were in the normal range. Other tests, such as renal function, liver function, metabolic markers, thyroid function, and chromosomal G-band test also did not reveal any abnormalities. Abdominal ultrasonography showed no morphological abnormalities of the kidneys, and head MRI showed no structural abnormalities of the brain.

3. Diagnostic Assessment: Genetic Testing

We first suspected IGF1R deletion based on the severe growth retardation before and after birth, CHD, high GH levels, and relatively high IGF-1 levels, and performed subtelomere fluorescence in situ hybridization (FISH) analysis focusing only on 15q. The 15q subtelomere FISH analysis revealed a heterozygous deletion in the 15q terminal region (Figure 1). Whole-genome single nucleotide polymorphism (SNP) array analysis using the Affymetrix Genome-Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA, USA) showed a terminal deletion of 6.4 Mb on chromosome 15q26.2-26.3, which contains disease-causing OMIM genes, NR2F2, IGF1R, MEF2A, ADAMTS17, CERS3, LINS1, ALDH1A3 and CHSY1, and 1.7 Mb duplication on 15q26.2 which does not contain the disease-causing OMIM gene (Figure 2). No other pathogenic copy number variation or copy number neutral loss of heterozygosity were observed in the SNP array. We diagnosed her with chromosome 15q26-qter deletion syndrome.
FISH was performed using the TelVysion multi-color FISH probe panel No.10. It contains probe for 10p (green), 10q (red), 15q (orange) and 15q22 (blue). The arrow indicates a deletion in the 15q terminal region.
The physical positions correspond to GRCh37/hg19 of the human genome assembly. The arrows indicate the positions of NR2F2 and IGF1R on 15q26.2-26.3, contained in the deletion range.

4. Discussion

Herein, we describe a 5-month-old girl with a chromosome 15q-terminal deletion syndrome, pre- and postnatal severe growth retardation, microcephaly, CHD, and high fasting GH levels in addition to relatively high IGF-1 levels. Among her 15q-terminal deletions, NR2F2, IGF1R, and MEF2A are genes in which heterozygous deletions cause clinical phenotypes. Among these, heterozygous deletion of NR2F2 cause CHD and heterozygous deletion of IGF1R cause pre- and post-natal severe growth retardation [1,11]. MEF2A has been reported to be associated with autosomal dominant inherited coronary artery disease [12]. Therefore, her current clinical features can be explained by the heterozygous deletion of NR2F2 and IGF1R.
Early diagnostic markers for IGF1R abnormalities have not yet been identified. Most of the patients reported so far have been diagnosed after the age of 2 years due to the short stature of children born SGA. Walenkamp et al. [13] proposed a clinical score to drive molecular investigations of IGF1R abnormalities. This score includes the following 4 criteria: birth length or weight <−1 SD, head circumference at first presentation <−2 SD, height at first presentation <−2.5 SD and serum IGF-1 levels above the mean for age and sex. While our patient was diagnosed in early infancy, she met all of these criteria. However, the initial IGF-1 level was only slightly above the age-average level, making it difficult to suspect IGF1R abnormalities.
It is known that newborns and young infants have low IGF-1 levels due to immaturity of the GH-IGF-1 axis [14]. However, IGF-1 levels in early infancy have not always been reported to be low, reflecting immaturity of the GH-IGF-1 axis. For example, the average IGF-1 level at 3–4 months of age has been reported to be 37.3–93 ng/mL [14]. Since undernourished infants with poor weight gain, such as our case, usually tend to have low IGF-1 levels, the serum IGF-1 levels in the case were determined to be relatively high IGF-1 levels. If IGF-1 levels are low, we also consider abnormalities in GH-IGF-1 signaling pathways such as Laron syndrome, IGF-1 deficiency, STAT5B, ALS, and PAPPA2 deficiencies [15].
Theoretically, in addition to relatively high serum IGF-1 levels, serum GH levels should also be high in IGF1R abnormalities. A summary of IGF1R abnormalities with the described GH levels is presented in Table 2. Previous reports have shown that basal GH levels vary among patients but tend to be higher at younger ages. In the GH stimulation tests, GH peak levels were subnormal to mildly elevated in most cases. All but one of the patients were diagnosed after the age of one year. Typically, GH levels are high at birth, then fall sharply for the first few weeks, and slowly over the next few months reaching pre-pubertal levels around 6 months of age [16]. In particular, SGA newborns had higher serum GH levels at birth than normal newborns in all trimesters, but serum GH levels at 3 days after birth were not significantly different between the 2 groups [17]. Nevertheless, basal GH levels are clearly implicated in the alterations of GH secretion observed in various physiological states (stress, sleep, bleeding, fasting, hypoglycemia, exercise, etc.), and their assessment should be determined in the setting of age, blood glucose levels, and blood sampling procedures. Our patient had significantly higher basal GH levels at 3 months of age, which could be attributed to the testing in early infancy, relatively low blood glucose levels, and venipuncture procedures. High basal GH levels may also be a marker for suspicion of GH-IGF-1 insensitivity disorders in early infancy.
The mechanism of the deletion of the 15q26 region is unclear. The range of IGF1R deletions varies from deletion of the IGF1R exon level to an identifiable size by G-band analysis, with no specific deletion. In previous reports, IGF1R deletions have ranged from 19 kb to 11.2 Mb [8,18]. Besides the deletion of the 15q26.2-26.3 region, a 1.7 Mb duplication was observed in our patient, suggesting that the 15q26-ter deletion may have been caused by an inverted duplication although we have not actually confirmed this. In fact, a 15q-terminal deletion by inverted duplication has been reported [19]. The 1.7 Mb duplicated region upstream of the deletion region does not contain any OMIM disease-related genes. Therefore, we consider it unlikely that this duplication is involves in the phenotype.
NR2F2 plays an important role in angiogenesis and heart development by participating in signaling between the endothelial and mesenchymal compartments [20]. The expression of NR2F2 in the developing human fetal heart including the atria, coronary vessels, and aorta has been substantiated, and NR2F2 mutations have been causally linked to isolated congenital heart disease, including atrio ventricular septal defect, tetralogy of Fallot, aortic stenosis, VSD, coarctation of the aorta and hypoplastic left heart syndrome [11]. In this case, loss of function of NR2F2 due to 15q26-ter deletion caused ASD and VSD.
In summary, to our knowledge, this is the first report showing that fasting GH levels are high in early infancy in patients with IGF1R abnormalities. Previous reports may not necessarily have shown high GH levels because the patients with IGF1R abnormalities were diagnosed after the age of 1 year. However, this study has several limitations. Firstly, since blood was drawn at the same time as the venipuncture, a stress-induced GH elevation cannot be ruled out. Secondly, blood glucose levels were not measured at the same time as the GH test except for once; therefore, we do not know the contribution of hypoglycemia to high serum GH levels. Further clinical studies are needed for analyzing more cases.
Table
Table 2. Summary of IGF1R abnormalities with described serum GH levels in the previous literatures.
Table 2. Summary of IGF1R abnormalities with described serum GH levels in the previous literatures.
IGF-1 (ng/mL)
(Range * or SDS **)		Basal GH
(ng/mL)		Peak GH
(ng/mL)		IGF1R Abnormalities
(Deletion Size)		AgeSexAuthors
(Reference Number)
126 (+1.2) **8.5–85.5NA15q26.2- > 15qter (6.4 Mb)5 mFOur case
72 (33–102) *NA7.6p.Asp1105Glu7 mMSolomon-Zemler et al. [21]
231 (+2.9) **8.0NAp.Arg1256Ser1 y 5 mMJuanes et al. [22]
211 (+1.7) **1.2NAp.Tyr865Cys1 y 9 mFJuanes et al. [22]
NA2.710.015q26.1- > 15qter (5 Mb)1 y 10 mFOkubo et al. [23]
16 (−4.67) **7.6NAp.Tyr487Phe2 yFLabarta et al. [24]
102 (51–303) *6.917.3p.Met1247Thr2 y 1 mFYang et al. [25]
185 (32–213) *10.5Normalp.Trp1249X2 y 5 mFFujimoto et al. [26]
58 (+0.5) **0.27NAp.Asn359Tyr2 y 8 m MJuanes et al. [22]
344 (+3.3) **7.6NAp.Arg431Leu3 y 0 mFKawashima et al., 2012 [27]
298.4 (+3.8) **NANormalp.Gln1250X3 y 0 mMFujimoto et al. [26]
268 (+2.1) **2.414.315q26.2- > 15qter 3 y 1 mFGonc et al. [7]
NA (−0.8 to +1.4) **NA9.8p.Arg59X3 y 2 mMRaile et al. [28]
239 (+1.6) **NA62p.Gly1050Lys3 y 3 mFWalenkamp et al. [29]
253 (54–161) *HighHighp.Glu121lys/p.Glu234Lys3 y 4 mMFang et al. [30]
NormalNormalNormal15q26.1- > 15qter (9.15 Mb)4 yFBenbouchta et al. [31]
159 (+2.6) **NANormalp.Tyr387X4 yMMohn et al. [32]
63 (NA)NA51p.Arg108Gln/p.Lys115Asn4 y 5 mFAbuzzahab et al. [33]
203 (+2.5) **2.5–7.5NA15q26.2- > 15qter (5.2 Mb)4 y 5 mFWalenkamp et al. [34]
222 (+2.3) **NA5.7–21.2p.Arg59X5 y 3 mMAbuzzahab et al. [33]
NA (+1.1) **3.012.1p.Arg511Trp5 y 8 mFLeal et al. [35]
344 (+3.3) **NANormalp.Asp1105Glu6 y 0 mFKawashima et al., 2014 [36]
145 (−0.66) **NA3.7215q26.2- >15qter (3.9 Mb)6 y 5 mFYoon et al. [37]
200 (+0.76) **0.9–2.4Normalp.Gly1125Ala7 y 5 mFKruis et al. [38]
NA (+1.2 to +2.2) **NA4.4–21p.Arg59X8 y 5 mMRaile et al. [28]
164 (123–275) *0.427.6–9.1p.Met1123Argfs * 149 y 6 mMFang et al. [5]
509 (51–303) *0.3615.4p.Cys248Trp10 y 8 mFYang et al. [25]
291 (+1.53) **0.1511.215q26.3- > 15qter 12 y 8 mMGonc et al. [7]
350 (+0.6) **3.712.9p.Ile678Val13 yMGonc et al. [7]
950 (+7) **0.86NAp.Arg10Leu13 y 5 mFGannagé-Yared et al. [39]
100 (−1.11) **0.4610p.Arg461His13 y 5 mMGonc et al. [7]
404.3 (165–300) *7.410.6p.Arg481Gln13 y 6 mFInagaki et al. [40]
671 (+2.13) **25.3NAp.Thr79Met13 y 8 mFGonc et al. [7]
112 (–2.44) **0.6320.3p.Lys704Arg15 yMGonc et al. [7]
389.8 (244–787) *NA18.8p.Ala140Glyfs * 515 y FWang et al. [41]
537 (+0.85) **0.711.7p.Leu19Profs * 2716 y 3 mMGonc et al. [7]
IGF-1, insulin-like growth factor 1; GH, growth hormone; SDS, standard deviation score; NA, data not available; y, years; m, months; M, male; F, female; Peak GH, GH peak was assessed in stimulation test; *, The ranges of IGF-1 levels are those described in the respective manuscripts; **, Patients’ IGF-1 SDS values reported in the respective manuscripts.

5. Conclusions

In addition to relatively high IGF-1 levels, elevated fasting GH levels in early infancy may contribute to the diagnosis of IGF1R abnormalities. Routine testing of specific parameters when growth retardation is detected during pregnancy will definitely enhance the knowledge of the relation to elevated GH and IGF-1 levels.

Author Contributions

Conceptualization, M.T. and K.N.; Data curation, M.T.; writing—original draft, M.O.; writing—review and editing, S.H., K.S., Y.O., K.N. and A.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Ethical review and approval was waived for this study due to the following reasons: Our ethics approval is not required for a single case report.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data presented in this study are available upon request from the corresponding author. The data are not publicly available due to privacy restrictions.

Acknowledgments

The authors deeply appreciate the patient and her family for participating in the study and report.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Rudaks, L.I.; Nicholl, J.K.; Bratkovic, D.; Barnett, C.P. Short stature due to 15q26 microdeletion involving IGF1R: Report of an additional case and review of the literature. Am. J. Med. Genet. A 2011, 155, 3139–3143. [Google Scholar] [CrossRef] [PubMed]
  2. Pinson, L.; Perrin, A.; Plouzennec, C.; Parent, P.; Metz, C.; Collet, M.; Le Bris, M.J.; Douet-Guilbert, N.; Morel, F.; De Braekeleer, M. Detection of an unexpected subtelomeric 15q26.2→qter deletion in a little girl: Clinical and cytogenetic studies. Am. J. Med. Genet. A 2005, 138, 160–165. [Google Scholar] [CrossRef] [PubMed]
  3. Poot, M.; Eleveld, M.J.; van’t Slot, R.; van Genderen, M.M.; Verrijn Stuart, A.A.; Hochstenbach, R.; Beemer, F.A. Proportional growth failure and oculocutaneous albinism in a girl with a 6.87 Mb deletion of region 15q26.2→qter. Eur. J. Med. Genet. 2007, 50, 432–440. [Google Scholar] [CrossRef]
  4. Tönnies, H.; Schulze, I.; Hennies, H.; Neumann, L.M.; Keitzer, R.; Neitzel, H. De novo terminal deletion of chromosome 15q26.1 characterised by comparative genomic hybridisation and FISH with locus specific probes. J. Med. Genet. 2001, 38, 617–621. [Google Scholar] [CrossRef] [Green Version]
  5. Fang, P.; Schwartz, I.D.; Johnson, B.D.; Derr, M.A.; Roberts, C.T., Jr.; Hwa, V.; Rosenfeld, R.G. Familial short stature caused by haploinsufficiency of the insulin-like growth factor I receptor due to nonsense-mediated messenger ribonucleic acid decay. J. Clin. Endocrinol. Metab. 2009, 94, 1740–1747. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Klammt, J.; Pfäffle, R.; Werner, H.; Kiess, W. IGF signaling defects as causes of growth failure and IUGR. Trends Endocrinol. Metab. 2008, 19, 197–205. [Google Scholar] [CrossRef] [PubMed]
  7. Gonc, E.N.; Ozon, Z.A.; Oguz, S.; Kabacam, S.; Taskiran, E.Z.; Kiper, P.O.S.; Utine, G.E.; Alikasifoglu, A.; Kandemir, N.; Boduroglu, O.K.; et al. Genetic IGF1R defects: New cases expand the spectrum of clinical features. J. Endocrinol. Investig. 2020, 43, 1739–1748. [Google Scholar] [CrossRef]
  8. Giabicani, E.; Willems, M.; Steunou, V.; Chantot-Bastaraud, S.; Thibaud, N.; Abi Habib, W.; Azzi, S.; Lam, B.; Bérard, L.; Bony-Trifunovic, H.; et al. Increasing knowledge in IGF1R defects: Lessons from 35 new patients. J. Med. Genet. 2020, 57, 160–168. [Google Scholar] [CrossRef]
  9. Ester, W.A.; van Duyvenvoorde, H.A.; de Wit, C.C.; Broekman, A.J.; Ruivenkamp, C.A.; Govaerts, L.C.; Wit, J.M.; Hokken-Koelega, A.C.; Losekoot, M. Two short children born small for gestational age with insulin-like growth factor 1 receptor haploinsufficiency illustrate the heterogeneity of its phenotype. J. Clin. Endocrinol. Metab. 2009, 94, 4717–4727. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Isojima, T.; Shimatsu, A.; Yokoya, S.; Chihara, K.; Tanaka, T.; Hizuka, N.; Teramoto, A.; Tatsumi, K.I.; Tachibana, K.; Katsumata, N.; et al. Standardized centile curves and reference intervals of serum insulin-like growth factor-I (IGF-I) levels in a normal Japanese population using the LMS method. Endocr. J. 2012, 59, 771–780. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  11. Qiao, X.H.; Wang, Q.; Wang, J.; Liu, X.Y.; Xu, Y.J.; Huang, R.T.; Xue, S.; Li, Y.J.; Zhang, M.; Qu, X.K.; et al. A novel NR2F2 loss-of-function mutation predisposes to congenital heart defect. Eur. J. Med. Genet. 2018, 61, 197–203. [Google Scholar] [CrossRef] [PubMed]
  12. Weng, L.; Kavaslar, N.; Ustaszewska, A.; Doelle, H.; Schackwitz, W.; Hébert, S.; Cohen, J.C.; McPherson, R.; Pennacchio, L.A. Lack of MEF2A mutations in coronary artery disease. J. Clin. Investig. 2005, 115, 1016–1020. [Google Scholar] [CrossRef] [Green Version]
  13. Walenkamp, M.J.E.; Robers, J.M.L.; Wit, J.M.; Zandwijken, G.R.J.; Van Duyvenvoorde, H.A.; Oostdijk, W.; Hokken-Koelega, A.C.S.; Kant, S.G.; Losekoot, M. Phenotypic Features and Response to GH Treatment of Patients with a Molecular Defect of the IGF-1 Receptor. J. Clin. Endocrinol. Metab. 2019, 104, 3157–3171. [Google Scholar] [CrossRef]
  14. Hawkes, C.P.; Grimberg, A. Measuring growth hormone and insulin-like growth factor-I in infants: What is normal? Pediatr. Endcrinol. Rev. 2013, 11, 126–146. [Google Scholar]
  15. Hwa, V.; Fujimoto, M.; Zhu, G.; Gao, W.; Foley, C.; Kumbaji, M.; Rosenfeld, R.G. Genetic causes of growth hormone insensitivity beyond GHR. Rev. Endocr. Metab. Disord. 2021, 22, 43–58. [Google Scholar] [CrossRef]
  16. Ogilvy-Stuart, A.L. Growth hormone deficiency (GHD) from birth to 2 years of age: Diagnostic specifics of GHD during the early phase of life. Horm. Res. 2003, 60, 2–9. [Google Scholar] [CrossRef] [PubMed]
  17. Leger, J.; Noel, M.; Limal, J.M.; Czernichow, P. Growth factors and intrauterine growth retardation. II. Serum growth hormone, insulin-like growth factor (IGF) I, and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects: Prospective study from birth to two years of age. Study Group of IUGR. Pediatr. Res. 1996, 40, 101–107. [Google Scholar] [PubMed] [Green Version]
  18. Klaassens, M.; Galjaard, R.J.; Scott, D.A.; Bruggenwirth, H.T.; van Opstal, D.; Fox, M.V.; Higgins, R.R.; Cohen-Overbeek, T.E.; Schoonderwaldt, E.M.; Lee, B.; et al. Prenatal Detection and Outcome of Congenital Diaphragmatic Hernia (CDH) Associated with Deletion of Chromosome 15q26: Two Patients and Review of the Literature. Am. J. Med. Genet. A 2007, 143, 2204–2212. [Google Scholar] [CrossRef]
  19. Genesio, R.; De Brasi, D.; Conti, A.; Borghese, A.; Di Micco, P.; Di Costanzo, P.; Paladini, D.; Ungaro, P.; Nitsch, L. Inverted duplication of 15q with terminal deletion in a multiple malformed newborn with intrauterine growth failure and lethal phenotype. Am. J. Med. Genet. A 2004, 128, 422–428. [Google Scholar]
  20. Upadia, J.; Gonzales, P.R.; Robin, N.H. Novel de novo pathogenic variant in the NR2F2 gene in a boy with congenital heart defect and dysmorphic features. Am. J. Med. Genet. A 2018, 176, 1423–1426. [Google Scholar] [CrossRef]
  21. Solomon-Zemler, R.; Basel-Vanagaite, L.; Steier, D.; Yakar, S.; Mel, E.; Phillip, M.; Bazak, L.; Bercovich, D.; Werner, H.; de Vries, L. A novel heterozygous IGF-1 receptor mutation associated with hypoglycemia. Endocr. Connect. 2017, 6, 395–403. [Google Scholar] [CrossRef] [PubMed]
  22. Juanes, M.; Guercio, G.; Marino, R.; Berensztein, E.; Warman, D.M.; Ciaccio, M.; Gil, S.; Bailez, M.; Rivarola, M.A.; Belgorosky, A. Three novel IGF1R mutations in microcephalic patients with prenatal and postnatal growth impairment. Clin. Endocrinol. 2015, 82, 704–711. [Google Scholar] [CrossRef]
  23. Okubo, Y.; Siddle, K.; Firth, H.; O’Rahilly, S.; Wilson, L.C.; Willatt, L.; Fukushima, T.; Takahashi, S.; Petry, C.J.; Saukkonen, T.; et al. Cell Proliferation Activities on Skin Fibroblasts from a Short Child with Absence of One Copy of the Type 1 Insulin-Like Growth Factor Receptor (IGF1R) Gene and a Tall Child with Three Copies of the IGF1R Gene. J. Clin. Endocrinol. Metab. 2003, 88, 5981–5988. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Labarta, J.I.; Barrio, E.; Audí, L.; Fernández-Cancio, M.; Andaluz, P.; de Arriba, A.; Puga, B.; Calvo, M.T.; Mayayo, E.; Carrascosa, A.; et al. Familial short stature and intrauterine growth retardation associated with a novel mutation in the IGF-I receptor (IGF1R) gene. Clin. Endocrinol. 2013, 78, 255–262. [Google Scholar] [CrossRef]
  25. Yang, L.; Xu, D.D.; Sun, C.J.; Wu, J.; Wei, H.Y.; Liu, Y.; Zhang, M.Y.; Luo, F.H. IGF1R variants in patients with growth impairment: Four novel variants and genotype-phenotype correlations. J. Clin. Endocrinol. Metab. 2018, 103, 3939–3944. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Fujimoto, M.; Kawashima Sonoyama, Y.; Hamajima, N.; Hamajima, T.; Kumura, Y.; Miyahara, N.; Nishimura, R.; Adachi, K.; Nanba, E.; Hanaki, K.; et al. Heterozygous nonsense mutations near the C-terminal region of IGF1R in two patients with small-for-gestational-age-related short stature. Clin. Endocrinol. 2015, 83, 834–841. [Google Scholar] [CrossRef] [PubMed]
  27. Kawashima, Y.; Higaki, K.; Fukushima, T.; Hakuno, F.; Nagaishi, J.; Hanaki, K.; Nanba, E.; Takahashi, S.; Kanzaki, S. Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation. Clin. Endocrinol. 2012, 77, 246–254. [Google Scholar] [CrossRef]
  28. Raile, K.; Klammt, J.; Schneider, A.; Keller, A.; Laue, S.; Smith, R.; Pfäffle, R.; Kratzsch, J.; Keller, E.; Kiess, W. Clinical and functional characteristics of the human Arg59Ter insulin-like growth factor I receptor (IGF1R) mutation: Implications for a gene dosage effect of the human IGF1R. J. Clin. Endocrinol. Metab. 2006, 91, 2264–2271. [Google Scholar] [CrossRef] [Green Version]
  29. Walenkamp, M.J.; van der Kamp, H.J.; Pereira, A.M.; Kant, S.G.; van Duyvenvoorde, H.A.; Kruithof, M.F.; Breuning, M.H.; Romijn, J.A.; Karperien, M.; Wit, J.M. A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor. J. Clin. Endocrinol. Metab. 2006, 91, 3062–3070. [Google Scholar] [CrossRef] [Green Version]
  30. Fang, P.; Cho, Y.H.; Derr, M.A.; Rosenfeld, R.G.; Hwa, V.; Cowell, C.T. Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R). J. Clin. Endocrinol. Metab. 2012, 97, E243–E247. [Google Scholar] [CrossRef] [Green Version]
  31. Benbouchta, Y.; De Leeuw, N.; Amasdl, S.; Sbiti, A.; Smeets, D.; Sadki, K.; Sefiani, A. 15q26 deletion in a patient with congenital heart defect, growth restriction and intellectual disability: Case report and literature review. Ital. J. Pediatr. 2021, 47, 188. [Google Scholar] [CrossRef] [PubMed]
  32. Mohn, A.; Marcovecchio, M.L.; de Giorgis, T.; Pfaeffle, R.; Chiarelli, F.; Kiess, W. An insulin-like growth factor-I receptor defect associated with short stature and impaired carbohydrate homeostasis in an Italian pedigree. Horm Res. Paediatr. 2011, 76, 136–143. [Google Scholar] [CrossRef] [PubMed]
  33. Abuzzahab, M.J.; Schneider, A.; Goddard, A.; Grigorescu, F.; Lautier, C.; Keller, E.; Kiess, W.; Klammt, J.; Kratzsch, J.; Osgood, D.; et al. IGF-I Receptor Mutations Resulting in Intrauterine and Postnatal Growth Retardation. N. Engl. J. Med. 2003, 349, 2211–2222. [Google Scholar] [CrossRef] [PubMed]
  34. Walenkamp, M.J.; de Muinck Keizer-Schrama, S.M.; de Mos, M.; Kalf, M.E.; van Duyvenvoorde, H.A.; Boot, A.M.; Kant, S.G.; White, S.J.; Losekoot, M.; Den Dunnen, J.T.; et al. Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2→qter deletion detected by multiplex ligation probe amplification. J. Clin. Endocrinol. Metab. 2008, 93, 2421–2425. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Leal, A.C.; Montenegro, L.R.; Saito, R.F.; Ribeiro, T.C.; Coutinho, D.C.; Mendonca, B.B.; Arnhold, I.J.; Jorge, A.A. Analysis of the insulin-like growth factor 1 receptor gene in children born small for gestational age: In vitro characterization of a novel mutation (p.Arg511Trp). Clin. Endocrinol. 2013, 78, 558–563. [Google Scholar] [CrossRef]
  36. Kawashima, Y.; Hakuno, F.; Okada, S.; Hotsubo, T.; Kinoshita, T.; Fujimoto, M.; Nishimura, R.; Fukushima, T.; Hanaki, K.; Takahashi, S.; et al. Familial short stature is associated with a novel dominant-negative heterozygous insulin-like growth factor 1 receptor (IGF1R) mutation. Clin. Endocrinol. 2014, 81, 312–314. [Google Scholar] [CrossRef]
  37. Yoon, J.S.; Hwang, I.T. Microdeletion in the IGF-1 receptor gene of a patient with short stature and obesity: A case report. J. Pediatr. Endocrinol. Metab. 2021, 34, 255–259. [Google Scholar] [CrossRef]
  38. Kruis, T.; Klammt, J.; Galli-Tsinopoulou, A.; Wallborn, T.; Schlicke, M.; Müller, E.; Kratzsch, J.; Körner, A.; Odeh, R.; Kiess, W.; et al. Heterozygous mutation within a kinase-conserved motif of the insulin-like growth factor I receptor causes intrauterine and postnatal growth retardation. J. Clin. Endocrinol. Metab. 2010, 95, 1137–1142. [Google Scholar] [CrossRef] [Green Version]
  39. Gannagé-Yared, M.H.; Klammt, J.; Chouery, E.; Corbani, S.; Meǵarbané, H.; Abou Ghoch, J.; Choucair, N.; Pfäffle, R.; Mégarbané, A. Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations. Eur. J. Endocrinol. 2012, 168, K1–K7. [Google Scholar] [CrossRef]
  40. Inagaki, K.; Tiulpakov, A.; Rubtsov, P.; Sverdlova, P.; Peterkova, V.; Yakar, S.; Terekhov, S.; LeRoith, D. A familial insulin-like growth factor-I receptor mutant leads to short stature: Clinical and biochemical characterization. J. Clin. Endocrinol. Metab. 2007, 92, 1542–1548. [Google Scholar] [CrossRef] [Green Version]
  41. Wang, S.R.; Carmichael, H.; Andrew, S.F.; Miller, T.C.; Moon, J.E.; Derr, M.A.; Hwa, V.; Hirschhorn, J.N.; Dauber, A. Large-scale pooled next-generation sequencing of 1077 genes to identify genetic causes of short stature. J. Clin. Endocrinol. Metab. 2013, 98, E1428–E1437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Endocrines 03 00008 g001 550
Figure 1. The result of fluorescent in situ hybridization (FISH) analysis of the peripheral blood sample.
Figure 1. The result of fluorescent in situ hybridization (FISH) analysis of the peripheral blood sample.
Endocrines 03 00008 g001
Endocrines 03 00008 g002 550
Figure 2. The result of whole-genome single nucleotide polymorphism array analysis.
Figure 2. The result of whole-genome single nucleotide polymorphism array analysis.
Endocrines 03 00008 g002
Table
Table 1. Pre-feeding serum GH levels and IGF-1 levels.
Table 1. Pre-feeding serum GH levels and IGF-1 levels.
Age in Months3 Months4 Months5 Months
Serum GH (ng/mL)85.58.526.1
IGF-1 (ng/mL) (SDS) *NA75 (+0.16)126 (+1.2)
Blood glucose (mg/dL)57NANA
GH, growth hormone; IGF-1, insulin-like growth factor 1; SDS, standard deviation score; NA, No data available; *, The IGF-1 SDS values were calculated by the LMS method using the IGF-1 calculator (https://pfizerpro.jp/cs/sv/ghw/support/igf1_checker.html (accessed on 19 June 2021) based on reference [10].
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Ono, M.; Tanaka, M.; Hiroshima, S.; Sawano, K.; Ogawa, Y.; Nagasaki, K.; Saitoh, A. Diagnosis of Chromosome 15q-Terminal Deletion Syndrome through Elevated Fasting Serum Growth Hormone Levels. Endocrines 2022, 3, 92-99. https://doi.org/10.3390/endocrines3010008

AMA Style

Ono M, Tanaka M, Hiroshima S, Sawano K, Ogawa Y, Nagasaki K, Saitoh A. Diagnosis of Chromosome 15q-Terminal Deletion Syndrome through Elevated Fasting Serum Growth Hormone Levels. Endocrines. 2022; 3(1):92-99. https://doi.org/10.3390/endocrines3010008

Chicago/Turabian Style

Ono, Masato, Masato Tanaka, Shota Hiroshima, Kentaro Sawano, Yohei Ogawa, Keisuke Nagasaki, and Akihiko Saitoh. 2022. "Diagnosis of Chromosome 15q-Terminal Deletion Syndrome through Elevated Fasting Serum Growth Hormone Levels" Endocrines 3, no. 1: 92-99. https://doi.org/10.3390/endocrines3010008

Article Metrics

Back to TopTop