Congenital Hypothyroidism: Facts, Facets & Therapy

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Objective: In the present review, a brief back ground about congenital hypothyroidism, factors associated with. CH leading to thyroid dysgenesis and thyroid ...
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REVIEW ARTICLE ISSN: 1381-6128 eISSN: 1873-4286

Congenital Hypothyroidism: Facts, Facets & Therapy

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Impact Factor: 3.052

BENTHAM SCIENCE

Yedukondalu Kollati1,#, Ranga Rao Ambati2,#, Prakash Narayana Reddy1, N. Satya Sampath Kumar1 , Rajesh K. Patel3,* and Vijaya R. Dirisala1,* 1

Department of Biotechnology, Vignan’s Foundation for Science, Technology and Research University (VFSTRU), Guntur 522213, Andhra Pradesh, India; 2Food Science and Technology Programme, Beijing Normal University-Hong Kong Baptist University United International College, 28, Jinfeng Road, Tangjiawan, Zhuhai-519085, Guangdong, China; 3Sandor Animal Biogenics Pvt. Ltd, 8-2326/5, Road No. 3, Banjara Hills, Hyderabad, Telangana-500034, India

ARTICLE HISTORY

Current Pharmaceutical Design

Received: December 20, 2016 Accepted: January 31, 2017

DOI: 10.2174/1381612823666170206124255

Abstract: Background: Thyroid hormone (T3) is essential for normal development of children enabling brain development and somatic growth. However, certain individuals are genetically predisposed with insufficient or no thyroid hormones. Such a condition is termed congenital hypothyroidism (CH). Objective: In the present review, a brief back ground about congenital hypothyroidism, factors associated with CH leading to thyroid dysgenesis and thyroid dyshormonogenesis is elaborated. Additionally, the guidelines for available treatment options, management and follow-up required for patients diagnosed with CH are discussed. Treatment options in terms of treatment initiation and dosage of hormone replacement are discussed. Conclusion: Though CH is considered as the most common neonatal metabolic disorder, it is also easily treatable compared to other metabolic or hereditary diseases. The outcome of CH treatment depends on the compliance of parents early in life and by patients themselves during later part of life.

Keywords: Congenital hypothyroidism, hormone therapy, levothyroxine, thyroid gland, transcription factors, Thyroid hormone (T3).

1. INTRODUCTION The prime causes of many inborn errors of metabolism and other diseases are due to abnormal amino acids, organic acids and fatty acids metabolism [1-3]. Congenital hypothyroidism (CH) is a condition that affects infants by birth and results from a partial or complete loss of thyroid function (hypothyroidism). It is considered as the most frequent endocrine and metabolic disorder [4]. CH affects one in 3000 to 4000 newborns worldwide [5, 6] and is more common in females [7]. If treatment is delayed, CH leads to severe retardation in growth and mental development [8]. During neonatal period, thyroid hormone plays a crucial role for brain development [9] since it suppresses the proliferation of precursor cells (oligodendrocyte) and promotes their morphological differentiation [10]. It also promotes myelination which participates in neuron migration and synapse formation (fatty sheath surrounding neurons) [11], which in turn induce the electrocortical conductance and neuropathological abnormality in CH [12, 13]. Congenital hypothyroidism is classified into permanent CH and transient CH disorders. Permanent CH is subdivided into primary, secondary and tertiary CH. The incidence of Primary CH is approximately 1 in 400 live born infants. The main causes of primary CH have been divided into dysgenesis which is the abnormality in the structure of thyroid gland and dyshormonogenesis due to defects in the synthesis of thyroid hormone due to an enzyme failure [14]. Secondary or central and tertiary CH is rare and estimated to be one in 50,000 live births. Causes are attributed to defects in thyrotropin-releasing hormone (TRH) formation or binding and TSH production [4]. Permanent CH represents approximately 75-85% *

Address correspondence to these authors at the Department of Biotechnology, Vignan’s Foundation for Science, Technology and Research University (VFSTRU), Guntur-5222, Andhra Pradesh; India, E-mail: [email protected] Sandor Animal Biogenics Private Limited, Sandor Life Sciences, Telangana-500043, India, E-mail id: [email protected] # Both the authors contributed equally to this work. 1873-4286/17 $58.00+.00

cases which is attributed to thyroid dysgenesis and includes 35-40% agenesis, 30-45% ectopy and 5% hypoplasia development of the gland and remaining 20-25% cases are caused by hereditary defects in the synthesis of thyroid hormone which is known as dyshormonogenesis which affects T4 synthesis [15 - 18]. 2. THYROID DYSGENESIS Most cases of permanent CH are sporadic due to thyroid dysgenesis resulting from variations in thyroid development during embryogenesis. Up to 2% of patients with thyroid dysgenesis have similar conditions in their family history suggesting the continuation of genetic factors which could add to the disorder [19]. Several cases of thyroid dysgenesis mutations were shown in different genes responsible for the development of thyroid follicular cells which includes paired box gene eight (PAX-8), thyroid transcription factors (TTF-1 and TTF-2) and thyroid stimulating hormone receptor (TSHR) [20]. These genes encode for transcription factors which are expressed during thyroid embryogenesis as well as normal functioning of thyroid gland [20]. 3. PAIRED BOX GENE EIGHT Among the nine members of mammalian paired homeodomain family, PAX-8 is a transcription factor which has the ability to recognize DNA through the conserved paired domain [21] to act as a main function in mammalian embryonic development where temporal and spatial expression patterns are highly restricted during embryonic development [22]. It activates the transcription of TPO, TG and NIS and acts synergistically with TFF-1 [23]. The human PAX8 gene is located on chromosome 2q12-q14 and contains 12 exons [24, 25]. 4. THYROID TRANSCRIPTION FACTOR 1 Thyroid transcription factor 1 (TTF-1 also known as TITF1, NKX2.1 or T/EBP) is a homeobox transcription factor of the NK-2 gene family [26]. The super family of homeobox gene encodes transcription regulatory proteins that take steps in development and

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Congenital Hypothyroidism

ontogeny by sequence specific DNA binding which is mediated by a structurally conserved homeodomain. It has two independent transcriptional activation domains which is located at the amino terminal and carboxy terminal region with respect to the DNA binding homeodomain [27]. Human TTF-1 protein is 42kDa whose gene is located on chromosome 14q13 containing three exons [28]. TTF-1 is expressed in lungs and ventral forebrain along with thyroid gland [29]. TTF-1 regulates the expression and transcription of TG, TPO and TSHR gene in thyroid follicular cells [30]. 5. THYROID TRANSCRIPTION FACTOR 2 Thyroid transcription factor 2 (TTF-2) also abbreviated as TITF2, FOXE1 or FKHL15 consists of single exon [31, 32] is located on human chromosome 9q22 [33]. TTF-2 is a member of the forkhead/winged helix-domain protein family which plays a key role in regulating the embryonic pattern formation and regional specification [33]. TTF-2 regulates the transcription of target genes such as TG and TPO by binding to specific regulatory DNA sequence in their promoter using forkhead DNA binding domain [34]. TTF-2 is a phosphoprotein consisting of an N terminal region, a highly conserved forkhead domain, an α helical polyalanine tract and unique C terminal residues [35]. Its expression has been confirmed in pharyngeal endoderm derivatives such as tongue, palate, epiglottis and oesophagus and in human thyroid, hair follicle, and prepubertal testis [36]. TTF-2 mutant protein showed impaired DNA binding and loss of transcriptional function. 6. THYROID STIMULATING HORMONE RECEPTOR Thyrotropin (TSH) is a pituitary glycoprotein hormone [37]. Thyroid stimulating hormone receptor (TSHR) present in the basolateral membrane of thyroid follicular cells mediates the effects of thyrotropin (TSH) which acts as a regulator of growth and function of the thyroid gland after reaching its final position [37]. It belongs to the G protein-coupled receptor (GPCR) superfamily [38], sharing with LH/CG and FSH receptors of the same family and consists of seven transmembrane spanning regions and a large extracellular domain that mediates the effects of TSH and plays a key role for the development and function of the thyroid gland [39]. The TSHR gene is located on human chromosome 14q31 [37] and consists of 10 exons encoding for 765 amino acid protein [40] with a large Nterminal ligand-binding extracellular domain. TSH binds to the extracellular domain of TSHR and shows its effects by stimulating intracellular cyclic AMP (cAMP) [41]. The TSHR is preferentially joined together to G protein, which leads to stimulation of the cAMP pathway that positively controls the functions of thyroid hormone secretion and growth of thyrocytes. Increasing concentrations of TSH stimulates the receptor to bind with Gq protein leading to the activation of phospholipase C cascade and stimulating the production of diacylglycerol and inositolphosphate. The phospholipase C pathway is mostly involved in the control of iodination and thyroid hormone synthesis [42]. Mutations in TSHR gene cause TSH resistance by its loss of function and it is one of the causes of CH. Furthermore, the TSHR is involved in late stages of thyroid organogenesis and TSHR gene mutation can cause wide spectrum of thyroid abnormalities, which ranges from severe hypoplasia to an almost normal sized and structured thyroid gland [20]. Mutations causing the activation of receptor have been found in hyperfunctioning thyroid adenomas at the somatic level [43]. A simple heterozygous TSHR mutation was identified causing a milder form of partial TSH resistance [44]. Subclinical hypothyroidism of chronic autoimmune thyroiditis must be distinguished from the rare condition of thyroid resistance to TSH [45] a congenital syndrome of variable hyposensitivity to biologically active TSH [46]. 7. THYROID DYSHORMONOGENESIS Thyroid dyshormonogenesis (DH) is heterogeneous disorder found in the synthesis pathway of complexity hormones. The path-

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way consists of synthesis and secretion of thyroglobulin (TG) into the follicular lumen, modification (i.e. oxidation, iodination and coupling) and storage of TG in the follicular lumen followed by final release of the T3 and T4 hormones by reuptake and degradation of iodinated TG [47]. DH causing genes viz., SLC5A5, thyroid peroxidase (TPO), TG, SLC26A4, dual oxidase 2 (DUOX2), dual oxidase maturation factor (DUOXA2) and iodotyrosine deiodinase (DEHAL1) are involved in the synthesis of thyroid hormone. 8. SLC5A5 SLC5A5 is also known as sodium/iodide symporter (NIS) is a transmembrane glycoprotein responsible for uptake of iodide across the basolateral membrane of thyroid follicular cells. Isolation and characterization of NIS were initially done on a rat thyroid cell line and proposed, encoding an integral membrane protein with 12 potential transmembrane domains [48]. 9. THYROID PEROXIDASE Mutations in the thyroid peroxidase (TPO) gene play a central role in thyroid gland dysfunction and are responsible for more than 50% causes of dyshormonogenesis leading to CH disorder [49]. For the first time mutation in the TPO gene was reported by Abramowicz et al., in 1997 [50]. Inactivating TPO mutations are most recurrently causes of dyshormonogenetic congenital goitrous hypothyroidism due to iodide organification defects [51]. TPO deficiency is recurrently involved and leading to total iodide organification defects (TIOD) [52] where complete discharge of trapped iodide in the thyroid gland by potassium or sodium perchlorate indicates that the iodide was not taken up to incorporate into TG protein [53]. Partial iodide organification defect (PIOD) [54] is a discharge of trapped iodide in the thyroid gland by potassium perchlorate is less than 50% and presents usually with a mild picture of CH [55]. Hypothyroid goiters are the result of inherited autosomal recessive trait in TPO defects [56] leading to failure to convert iodide into organic iodine (Organification defect). TPO is a thyroid specific glycosylated hemoprotein of 110 kDa facing the luminal colloid of the thyroid cell [57], a key enzyme in the biosynthesis of thyroid hormone is located on the apical membrane surface of thyroid follicular cells mainly catalyzing both iodination of tyrosine residues (iodide organification) and the pairing of iodotyroisines residues in the molecule of TG to generate thyroxine (T4) and 3,3ʹ,5-triiodothyronine (T3) [51]. TPO activity requires the presence of hydrogen peroxide (H2O2). Human TPO mRNA is 3048 nucleotides long and it encodes the preprotein comprising of 14 amino acid signal peptide followed by mature peptide containing 919 amino acids. The high concentration of H2O2 produced in response to increase in TSH levels may lead to DNA damage and mutagenic effects [58, 59]. Additionally, organic iodo compounds showed that it had to inhibit thyroid epithelial cell proliferation [60]. 10. MUTATION ANALYSIS OF THE TPO GENE TPO can neither bind heme, nor bind TG or iodide as substrate. TPO has an abnormal cellular localization. The 2669G>A (G860R) is the first mutation resulting in an amino acid substitution in the TPO transmembrane region [61]. It would change the hydrophobic glycine to the positively charged arginine and capable of disturbing the insertion of the TPO enzyme into the plasma membrane [49]. Additionally, there are 6 other different mutations recorded of which four are considered novel namely 2669G>A, 613COT (R175X), 1519_1539del(A477_N483del) and 2089GOA (G667S) [49]. TPO is a membrane bound hemeprotein and the exons 8, 9 and 10 contained putative heme-binding histidine residues and any defects in these exons may affect enzymatic activity [49, 51]. The mutation in the exon 8 is essential because its catalytic activity takes place in the TPO gene [62]. Mutation in 1159G>A leads to change in the ESE-binding site sequence which might disrupt the

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correct splicing of pre-mRNA and lead to the activation of other potential splice sites in exon 8, which subsequently gives rise to the production of different TPO protein isoforms, exon 8 of TPO gene codes for a site that participates in catalytic mechanism. Any alteration or absence of this critical region could cause the translation of TPO protein lacking or, reduced in enzyme activity [51]. Two exons 13 and 14 belong to gene families of the complement control protein (CCP)- like amino acid sequence (742-795) and calciumbinding epidermal growth factor (EFF)- like amino acid sequence (796-839) [63]. Exon 15 encodes for the transmembrane which is the part of protein and exon 16 and 17 encode for its cytoplasmic tail. The shortened protein of 265 amino acids, caused by the novel c.796C>T mutation in exon 7 (p.Q266X), causes the loss of the catalytic part of the enzyme [64]. The mutation in exon 8 is a novel one (C965T) and results in substitution of serine at position 292 with phenyalalnine which effect the protein’s function. The mutated codon 292 which is located in strategic point between two cysteines at positions 286 and 196 involved in two disulfides bonds creates the closed loop of the TPO molecule [65]. 11. THYROGLOBULIN TG is a rare autosomal-recessive disorder with defective congenital goiter with occurrence of 1:40,000 to 1:100,000 live born differentiated by lower serum TG in relation to the degree of TSH stimulation, negative perchlorate discharge test and dilated endoplasmic reticulum (ER) with induction of ER molecular chaperones [66] resulting in the clinical spectrum and phenotypes ranges from euthyroid to mild or serve hypothyroidism [67 - 69]. TG is a 660 kDahomodimeric secretory protein with high degree of glycosylation, which serves as a matrix for synthesis and storage of thyroid hormones T3 and T4 and one more important function is storage of iodine when availability of limited external iodine [70]. Thyroid cells synthesize the TG and secreted into follicular lumen where it comes and contact with the thyroidal iodination machinery [71, 72]. The preprotein monomer is composed of a 19 amino acids signal peptide followed by a 2749 residues polypeptide [73]. Transcription of TG is extremely specific to the thyroid cells and under control of the coordinated action of a set of transcription factors that consist of the homeodomain protein NK-2 gene family TTF-1, the forkhead domain family protein TTF-2 and the paired homeodomain family protein PAX8 [68, 69]. Several chaperones are present in the rough endoplasmic reticulum (RER) cooperate with TG during its maturation and preventing the export of improperly folded TG proteins by a process known as RERassociated degradation [74]. After completion of translation, a rigorous post translation modification process like correct folding of TG takes place in the ER followed by Golgi apparatus, apical membrane and follicular lumen and comprises of homodimers assembly, intrachaindisulphide bond formation, glycosylation, sialyation, sulphatation, phosphorylation, iodination and multimerization [72]. Eighty percent of TG monomers contain three regions comprising repeated cysteine domains covalently bounded with disulfide bonds. Region I encompasses 10 of 11 TG type-1 repeats, a linker and hinge segments. Region II includes three TG type-2 repeats and one TG type-1 at 11th position. Region III comprises 5 TG type-3 repeats. The left over 20% constitutes the carboxy terminal domain of the molecule, which is not repetitive and shows important homology with the acetylcholinesterase (ACHE-like domain) [70]. The requirement of ACHE-like domain is for normal conformational maturation and intracellular transport of TG to the site of iodination and hormonogenesis [75]. This region works as an intramolecular chaperone and as a molecular escort for TG regions I, II and III. Simultaneously, these regions are blocked within ER, thus making it incompetent for cellular export [76].

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12. MUTATION ANALYSIS OF THE TG GENE: The 886C>T transition in exon 7 creates a predicted premature stop codon to give the results in a grossly truncated protein of 276 amino acids (R277X) whose ability to generate thyroid hormones are very limited [77]. Five hormonogenic acceptor site tyrosines were identified and localized at positions 5, 1291, 2554, 2568 and 2747 and other tyrosines were proposed and localized at positions 130, 847 and 1448 outer ring donor site that transfer iodophenoxyl group to an acceptor iodotyrosine. Here, the most important hormonogenic acceptor site is at tyrosine 5 which is after coupling with the donor tyrosine at tyrosine 130. The truncated form of TG described here has both acceptor tyrosine 5 and donor tyrosine 130 residues. However, the premature stop codon which removes the carboxy terminal hormonogenic domain, resulting in the loss of thyroid hormone formation. The novel mutation G to C transversion at position -1 in the acceptor site of introns 34 concludes the possibility that the splice site mutation may cause a removing of the total exon 35 of the TG gene because removal of 63 nucleotides maintains the reading frame [77]. Deletion of exon 22 or 35 of functional protein could change in the protein structure which changes the normal protein folding assembly, leading to reduce the ability to export of protein from the ER with huge induction of selective synthesis of molecular chaperones bind to the misfolded exportable protein [78, 79]. Frame shifting insertion and deletion mutations mostly cause the several altered amino acid residues and a premature stop codon. The mRNA of this type of mutation is usually promptly degraded by nonsense-mediated mRNA decay [80]. 13. SCREENING AND MANAGEMENT OF CH Screening programmes for the diagnosis of congenital hypothyroidism in newborns are used for diagnosis in most of the countries for the past few decades. The incidence of CH was reported at a range of 1:2000 to 1:4000 in most studies [81]. Most of the screening programmes use blood from heel prick collected from a special filter cards and performed within two to five days after birth. Most programmes under take an initial T4 test followed by another TSH testing, only if the specimen shows below the specified values [4]. Due to increased TSH sensitivities some of the programmes prefer an initial TSH screen. Due to rapid changes occurring in T4 and TSH levels during the first few days following birth, cut-off values were developed for confirmation. Most of the hormone levels will come to normal range within first 2-4 weeks of age. A confirmatory test needs to be undertaken if the infant shows positive during initial screening. Many procedures are used for confirmatory identification such as radionuclide uptake and scan, ultrasonography, serum thyroglobulin, maternal antithyroid antibodies and urinary iodine [4]. The goal of the treatment is to assure normal growth and development close to their genetic potential. Most of the studies provide information to understand the components of treatment to achieve best possible neurocognitive outcomes. There is an inverse relationship between intelligent quotient (IQ) and the age to diagnosis [81]. Therefore, most of investigations examine the effects of different starting doses of L-thyroxine and age of treatment initiation on severity of CH, normalization of serum thyroid hormone concentration and on psychometric outcome. Neurological growth and development may be impaired severely if treatment is not optimized during first two to three years of life even if the diagnosis was made early. Therefore, treatment should be initiated to infant showing positive screening right after confirmation tests are drawn. Hormone replacement therapy in newborns is usually achieved by administration of water soluble levothyroxine (L-T4) tablets which are approved for treatment of CH. Recently, a liquid formulation of L-T4 for easy administration to newborns has been introduced in Italy (Tirosint oral drops, IBSA Farmaceutici Italia Srl, Italy) [82]. Both the liquid and tablet formulations were found safe

Congenital Hypothyroidism

and effective using recommended dosages as suggested by guidelines. A slightly higher rate of TSH normalization was achieved with liquid formulation which could be due to higher absorption. Lthyroxine in tablet formulation should be crushed, mixed with breast milk, infant formula or water and fed to infant. There are certain nutritional supplements which are found to interfere with lthyroxine absorption such as soy protein, concentrated iron, calcium and aluminium hydroxide, fiber supplements and sucralfate. Therefore, in infants receiving soy formula it took significantly longer time to achieve TSH normalization [83]. Therefore, the thyroid function should be monitored closely in infants receiving soy formula and the L-T4 should be preferably given midway between the feeds [81]. Even long exposure to heat may reduce the efficacy of l-thyroxine tablets. 14. DOSAGE Dosage and timing of thyroid hormone replacement are important for achieving optimum neurocognitive outcome in infants undergoing CH treatment. It was reported that even a week delay in serum T4 normalization could result in low intelligence scores [84]. Therefore, the goal of the treatment should be to normalize the serum T4 to > 10 µg/dl as early as possible. American Academy of Pediatrics (AAP) and European Society for Pediatric Endocrinology (ESPE) have set forth a recommended dose of 10-15 mcg/kg/day [85]. In the same study, infants who received 12-17 mcg/kg/day achieved a higher performance scores for behavior, reading, spelling and math with IQ scores 11 points higher than the infants who received 10-15 mcg/kg/day [86]. In another study, infants with severe CH receiving higher doses (10-15 mcg/kg/day) achieved the highest intellectual scores than groups receiving 6-8 mcg and 8-10 mcg/kg/day [87]. In another study comparing early vs late treatment with low and high doses in infants with severe CH, results point out those infants who received treatment before 13 days with higher doses achieved normal psychomotor development at 10-30 months [84]. The goals of treatment as outlined by AAP and ESPE guidelines include maintaining serum T4 at 10-16 µg/dl, free T4 at 1.42.3 µg/dl and serum TSH under 5 mU/L during first year after birth [81, 86]. Infants with serum T4 concentrations below 10 µg/dl accompanied by TSH concentrations above 15 mU/L have lower IQ levels than infants with higher serum T4 concentrations [88]. Overall results point out that higher dose of l-thyroxine leads to overall better developmental outcomes. However, some studies indicate that children on high dose exhibited aggression and hyperactivity [89]. The outcome of observed IQ gap may be attributed to reasons such as hypothyroidism during fetal period can induce neural damage which cannot be compensated post natal treatment or it might be related to an unknown molecular pathogenesis. Therefore, these mechanisms might lead to unfavorable neurological and cognitive outcome despite earlier screening and optimal treatment of CH [90]. 15. FOLLOW-UP AND OUTCOME After initiation of therapy the recommended durations to monitor TSH and T4 levels at weekly intervals for 1 month, at monthly intervals until 3 months and a follow-up every three months for first two years of life and 6 month afterwards [91]. CH is one of the most frequent conditions among the spectrum of rare diseases and is also the easily treatable compared to other metabolic diseases or hereditary diseases such as alcaptonuria, phenylketonuria, Gauchers disease and Niemann pick disease. The outcome of CH depends on the compliance of parents early in life and by patients themselves during later part of life. There is an increase in hyperthyrotropinemia reports due to decreased TSH cut-off threshold during screening programmes which increase the risk of over diagnosing and over treating a large number of children. Therefore, appropriate

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justifications are needed for treating children with mild hyperthyrotropinemia due to decreased TSH cut-off levels [92]. CONCLUSION CH treatment should be initiated the moment infant shows positive symptoms in screening. In most of the cases in infants with severe CH, it is treatable by hormone therapy and strict compliance by parents during childhood and by patients themselves during adulthood. Non-compliance with treatment guidelines showed a higher serum TSH in patients and lower serum T4 concentrations than suggested, leading to lower IQ and cognitive outcomes. Therefore, compliance with treatment and proper thyroid levels leads to improved cognitive outcomes. Future research works should be aimed at understanding the treatment options for infants with CH during pregnancy period and continuous clinical evaluation is required to follow up these patients to see how they perform when they become adults for better therapeutic outcomes. LIST OF ABBREVIATIONS AAP = American Academy of pediatrics cAMP = Stimulating intracellular cyclic AMP CH = Congenital hypothyroidism DEHAL1 = Iodotyrosine deiodinase DH = Thyroid dyshormonogenesis DUOXA2 = Dual oxidase maturation factor ER = Endoplasmic reticulum NIS = Sodium iodide symporter TFF = Thyroid transcription factor TG = Thyroglobulin TIOD = Total iodide organification defects TPO = Thyroid peroxidase TRH = Thyrotropin-releasing hormone TSHR = Thyroid stimulating hormone receptor CONFLICT OF INTEREST Authors declare that they have no conflicts of interest. AUTHOR’S CONTRIBUTION YK, ARR, PNR, VRD have drafted the manuscript. NSSK, ARR collected relevant literature pertaining to the manuscript; VRD and RKP have been involved in improving the manuscript and revised it critically. All co-authors approved the submission of article. ACKNOWLEDGEMENTS The authors thank Vignan’s University, India for its in-house administrative and financial resources to execute this work. This work was also partly supported by a early career research grant (ECR/2016/ 000304) from Science and Engineering Research Board (SERB), New Delhi, India under the Young Scientist Scheme. PNR is a National post-doctoral fellow sponsored by Department of Science and Technology, India. Also RRA is thankful to his host institutions in China for their strong encouragement and support. REFERENCES [1]

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