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The Physiology and Mechanism of Growth
ОглавлениеPrimož Kotnik1, 2 · Moshe Phillip3, 4 · S. Ahmed Faisal5
1Department of Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Centre Ljubljana, and 2Department of Pediatrics, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia; 3Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, and 4Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 5Developmental Endocrinology Research Group, Royal Hospital for Sick Children, University of Glasgow, Glasgow, UK
Introduction
The physiology of growth in children is still not fully elucidated. In recent years, with the availability of new technologies, our understanding of the interactions between the genetic, epigenetic, internal (microbiome) and external environments and children’s growth has increased. In this chapter, we will discuss the manuscripts published in peer-review journals in the past year, which contributed to the expansion of our understanding of the physiology of growth and especially the interaction between nutrition and growth. We tried to select the most important manuscripts and added comments of experienced researchers/physicians, which we hope will stimulate the readers to continue and study the amazing phenomena of children’s growth.
Key articles reviewed for this chapter
Chao HC
Front Pediatr 2018; 12: 22
Maas C, Mathes M, Bleeker C, Vek J, Bernhard W, Wiechers C, Peter A, Poets CF, Franz AR
JAMA Pediatr 2017; 171: 16–22
Jansen EC, Zhou L, Perng W, Song PX, Rojo MMT, Mercado A, Peterson KE, Cantoral A
Nutr Res 2018; 56: 41–50
Cho JM, Kim JY, Yang HR
Pediatr Neonatol 2018;pii:S1875-9572(17)30066-9
Marshall TA, Curtis AM, Cavanaugh JE, John J Warren JJ, Levy SM
J Nutr 2018; 148: 1144–1149
Toftlund LH, Halken S, Agertoft L, Zachariassen G
Neonatology 2018; 114: 285–293
Leptin stimulates aromatase in the growth plate: limiting catch-up growth efficiency
Masarwi M, Shamir R, Phillip M, Gat-Yablonski G
J Endocrinol 2018; 237: 229–242
Lui JC, Jee YH, Garrison P, Iben JR, Yue S, Ad M, Nguyen Q, Kikani B, Wakabayashi Y, Baron J
PLoS Biol 2018; 16:e2005263
New genetic tools in the diagnosis of growth defects
Dauber A
Growth Horm IGF Res 2018; 38: 24–28
Regulation of body growth by microRNAs
Lui JC
Mol Cell Endocrinol 2017; 456: 2–8
Klammt J, Neumann D, Gevers EF, Andrew SF, Schwartz ID, Rockstroh D, Colombo R, Sanchez MA, Vokurkova D, Kowalczyk J, Metherell LA, Rosenfeld RG, Pfäffle R, Dattani MT, Dauber A, Hwa V
Nat Commun 2018; 9: 2105
Association of picky eating with growth, nutritional status, development, physical activity, and health in preschool children
Chao HC1, 2
1Division of Gastroenterology, Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung Memorial Hospital, and 2Chang Gung University College of Medicine, Taoyuan, Taiwan
Front Pediatr 2018; 12: 22
Background: Children having strong food preferences, consuming inadequate variety of foods, restricting the intake of some food groups, eating a limited amount of food, or being unwilling to try new foods are called picky eaters. Prevalence of picky eating is high (up to 50%) in both normally developing children as well as in those with medical or developmental disorders. One of the aims of this study was to determine the effect of this type of eating behavior on growth in pre-school children.
Methods: A cross-sectional descriptive study was performed in 300 primary caregivers of children aged 2–4 years, representative of a population in Taiwan. A structured questionnaire was used in face-to-face interviews by a skillful interviewer regarding food preferences, eating behavior, development, physical activity, and possible health issues. Body weight and height were measured.
Results: Approximately one half of children (54%) were regarded as picky eaters. No differences in sex, age, primary caregiver, education levels of caregiver, or family size between picky and non-picky eaters were determined, and families with low economic income possibly influencing food intake were not included in the study. Picky eaters were shorter (mean height percentile, height for age, height SDS, proportion of children <15th percentile) compared to non-picky-eaters. In addition, they had lower weight, weight for height, and BMI for age. Picky-eating also had an effect on children’s development and lower performance values of physical activities.
Conclusions: In this pre-school cohort of children, it was determined that picky eating has a significant detrimental impact on linear growth as well as on anthropometric measures reflecting nutritional status.
| Comments | Picky-eating is prevalent in small children of up to 4 years, and it later declines. It can, however, persist in some individuals and is associated with later eating disorders [1]. Children with picky-eating are at risk for nutritional deficits, their median daily energy intake is lower than the age-appropriate [2]. The effect of picky eating on linear growth has not been thoroughly investigated. In the present study, it was determined that picky eating is associated with lower height in prepubertal children. Picky eating was specifically related to decreased consumption of vegetables, meat, fruit, fish, and specific kinds of vegetables and interestingly with excessive milk-drinking. The present study, therefore, underlines both the importance of adequate caloric intake and diet composition in growth of children up to 4 years. Although no significant effects on growth were previously reported in a longitudinal study, it would be interesting to obtain even more long-term data on the influence of picky eating, for example on final height [1], |
Effect of increased enteral protein intake on growth in human milk-fed preterm infants: a randomized clinical trial
Maas C1, Mathes M1, Bleeker C1, Vek J1, Bernhard W1, Wiechers C1, Peter A3–5, Poets CF1, Franz AR1, 2
1Department of Neonatology, University Children’s Hospital, Eberhard-Karls University, 2Center for Pediatric Clinical Studies, University Children’s Hospital, Eberhard-Karls University, 3Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, and Pathobiochemistry, Department of Internal Medicine IV, University of Tuebingen, and 4Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich, University of Tuebingen, Tübingen, and 5German Center for Diabetes Research (DZD), Müenchen-Neuherberg, Germany
JAMA Pediatr 2017; 171: 16–22
Background: Protein intake has an important effect on early postnatal growth in very preterm infants. This study was aimed at evaluating the effects of different levels of enteral protein supplementation on the growth of predominantly preterm breastfeed infants.
Methods: A total of 60 preterm infants (gestation <32 weeks and weight <1,500 g at birth) were recruited in a randomized clinical and partially blinded single-center trial. In addition to breastfeeding, infants received either a lower protein (1 g of bovine protein/100 mL of breast milk) or a higher protein supplement (1.8 g of bovine protein/100 mL of breast milk or individualized high-protein supplementation based on protein and fat content of administered breast milk) for a median of 6 weeks.
Results: Weight gain was similar in the lower and higher protein supplementation groups: mean (95% CI), 16.3 g/kg/day (15.4–17.1 g/kg/day) in the lower protein group versus 16.0 g/kg/day (15.1–16.9 g/kg/day) in the higher protein group; p = 0.70), despite an increase in the actual protein intake by 0.6 g/kg/day (0.4–0.7 g/kg/day; p < 0.001). In addition, head circumference and lower leg longitudinal growth were also similar.
Conclusions: Further increase in protein intake of human milk-fed preterm infants did not result in enhancement of growth in the studied population. Authors suggest that this might point to a ceiling effect for enteral protein intake with respect to its influence on growth.
| Comments | Fortifying breast milk with fixed dose of protein has been shown to have beneficial effects on the growth of preterm infants [3]. This could, however, be suboptimal in some infants resulting in early postnatal growth restriction compared with preterm formula fed infants [4–6]. Possible reasons are that the protein content in breast milk of certain women could be insufficient or that it could become insufficient over time. The question of protein dosing has, therefore, been addressed in this article: would it be more feasible to further increase the protein intake in breast feed milk by fortification and should protein fortification be more individualized and depend on the protein content in breast milk? The answer to both questions is no. By increasing the average protein intake to 4.3 g/kg/day over an interventional period of 6 weeks, did not improve weight gain, head circumference, and lower leg longitudinal growth, which is similar to another study by Miller et al in more mature infants [7]. In addition, individualizing protein content strategy did not result in additional growth. The results suggest that increasing enteral protein intake beyond 3.5–4.0 g/kg/day might not further improve growth, at least not in this population. |
Vegetables and lean proteins-based and processed meats and refined grains-based dietary patterns in early childhood are associated with pubertal timing in a sex-specific manner: a prospective study of children from Mexico City
Jansen EC1, Zhou L2, Perng W1, Song PX2, Rojo MMT1, 3, Mercado A3, Peterson KE1, 4, Cantoral A3
1Department of Nutritional Sciences, University of Michigan, and 2Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA; 3Center for Nutrition and Health, National Institute of Public Health, Cuernavaca, Morelos, Mexico; 4Center for Human Growth and Development, University of Michigan, Ann Arbor, MI, USA
Nutr Res 2018; 56: 41–50
Childhood diet has been implicated in the timing of sexual maturation with evidence of advanced puberty in those on red meat or energy dense diets. The current investigators hypothesized that dietary patterns characterized by fruits and vegetables during early childhood (age 3 years) would be associated with delayed pubertal timing, whereas energy-dense and meat-based dietary patterns would relate to earlier puberty. The study population included 496 participants from an urban city. The exposures of interest were dietary patterns derived from principal component analysis of dietary data collected via a semi-quantitative food frequency questionnaire when the children were 3 years of age, and the outcomes were physician-assessed pubertal stages of pubic hair, breast (girls), genitalia, and testicular volume (boys) between 9 and 18 years, and initiation of menarche (girls). The investigators found that a diet that consisted of a higher amount of vegetables and lean proteins was related to delayed breast development among girls. In contrast, a higher amount of processed meats and refined grains was related to advanced testicular development among boys. Other patterns of diet were not statistically significantly associated with any of the sexual maturation markers. This study raises interesting questions about the programming of diet on puberty.
Effects of oral zinc supplementation on zinc status and catch-up growth during the first 2 years of life in children with non-organic failure to thrive born preterm and at term
Cho JM1, Kim JY1, Yang HR1, 2
1Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, and 2Seoul National University College of Medicine, Seoul, South Korea
Pediatr Neonatol 2018;pii:S1875-9572(17)30066-9
Abstract: In their study, the authors investigated the effect of oral zinc supplementation on serum insulin-like growth factor-1 (IGF-1) levels and catch up growth in infants with non-organic failure to thrive (NOFTT) who were born preterm as compared to those born at term. A total of 105 NOFTT infants aged 2 years or less participated in the study and were divided into 2 groups according to their gestational age at birth. Oral zinc sulfate was administered for 6 months to 49/66 children born term and 21/39 children born preterm. The authors measured serum zinc, IGF-1, weight, and height at baseline and at 6 months.
The authors found that there were no differences in the parameters measured (beside serum, zinc levels) between those who got the zinc supplement and those who did not get it. The authors concluded that the overall nutritional support rather than supplementation of a single nutrient may be more effective for catch-up growth in NOFTT infants born preterm.
| Comments | Whether zinc supplementation stimulates catch-up growth of children suffering from NOFTT is an open and controversial issue. Unfortunately, most of the studies published in the literature suffer from methodological limitations. In the present study, the authors showed that in both groups (preterm and term children) suffering from NOFTT, zinc supplementation did not change the weight, height or IGF-1 levels compared to the children who did not get zinc supplementation. However, it is unclear whether the children were randomized to the treated and non-treated groups. The lack of placebo group and data on what the children got to eat is missing. And a good prospective randomized, placebo-controlled study, powered appropriately, is still needed. |
Higher longitudinal milk intakes are associated with increased height in a birth cohort followed for 17 years
Marshall TA1, Curtis AM3, Cavanaugh JE2, 3, Warren JJ1, Levy SM1, 4
1Department of Preventive and Community Dentistry, College of Dentistry, 2Department of Statistics and Actuarial Science, College of Liberal Arts and Sciences, Departments of 3Biostatistics, and 4Epidemiology, College of Public Health, The University of Iowa, Iowa City, IA, USA
J Nutr 2018; 148: 1144–1149
Abstract: In the present study, authors investigated the longitudinal association between childhood and adolescent beverage intakes, nutrient adequacy, or energy intake, and height in a birth cohort. The authors accumulated data of 717 participants (353 males, 364 females) through ages 2–17 years. Information on beverages intake was gathered by beverage-frequency questionnaires at 3- to 6-month intervals. Nutrient data were obtained from 3-day food diaries, completed at 3- to 6-month intervals, through age 8.5 years from Block kids’ food frequency questionnaires at 2-years intervals after the age of 8.5 years. The nutrient adequacy ratio was calculated by investigators using age- and sex-specific estimated average requirements. Height was measured when participants were approximately 5, 9, 11, 13, 15, and 17 years old. Linear mixed model were used to study the longitudinal association between dietary components and height. The authors report that milk intake adjusted for mean adequacy ratio, energy intake, and baseline socioeconomic status was associated with height; for each additional 8 ounces (236 mL) of milk consumed per day through childhood and adolescence, height increased, on average by 0.39 cm.
| Comments | Many studies in the past investigated the association between cow milk consumption and height gain [8–10]. Currently, many non-cow milk beverages are produced, marketed, and sold in many countries as a substitute product for children. The present study is special since it follows children from birth, throughout childhood and adolescence. Despite the fact that we know today more than ever what a healthy diet for young children should look like, we still did not figure out the exact mechanism of the interaction between nutrition and growth, and especially between cow’s milk and linear growth. Recently, in a basic research study with animal model it has been shown that even different proteins (casein and whey) might have different effects on longitudinal bone growth and bone structure with complex possible theoretical mechanism that also involves the microbiome [11]. More basic research exploring the mechanism and better well-designed prospective studies are needed to produce the ideal growth-supporting diet for the pediatric age group [3]. |
Catch-up growth, rapid weight growth, and continuous growth from birth to 6 years of age in very-preterm-born children
Toftlund LH, Halken S, Agertoft L, Zachariassen G
Hans Christian Andersen Children’s Hospital, Odense University Hospital, and Faculty of Health, University of Southern Denmark, Odense, Denmark
Neonatology 2018; 114: 285–293
There is great interest in the timing and extent of catch-up growth in very preterm infants and its relationship with early feeding, as there is some evidence to suggest that the pattern of catch-up growth may have a bearing on long-term metabolic outcome. The three broad categories of feeds that infants can receive include unfortified breast milk, fortified breast milk, and preterm formula. The purpose of this study was to assess the influence of post-discharge nutrition on the childhood growth of a large cohort (n = 281) of such infants at 6 years of age. The investigators found that in a large proportion of infants, substantial catch-up growth had already occurred before discharge. When fed unfortified breast milk, catch-up in height seemed to continue until 6 years of age. Rapid weight gain was significantly associated with the type of feeding regimen following discharge and was most pronounced in preterm-formula-fed infants when compared to breastfed infants. Breastfed boys seemed to have a larger growth potential and seemed to show the greatest amount of increase in height and weight. SGA compared to AGA children demonstrated increased linear growth in height for a longer period of time, especially when fed unfortified breast milk. Thus, the investigators concluded that to achieve catch-up growth before discharge, there is no need for very low birth weight infants to have fortified breast milk or enriched formula milk. In addition, they suggested that mothers of preterm infants should be encouraged to breastfeed for as long as possible.
Leptin stimulates aromatase in the growth plate: limiting catch-up growth efficiency
Masarwi M1, 2, Shamir R1–3, Phillip M1, 2, 4, Gat-Yablonski G1, 2, 4
1Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, and 2Felsenstein Medical Research Center, 3Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, and 4The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel
J Endocrinol 2018; 237: 229–242
Background: Catch-up growth is a phase of accelerated growth that follows the correction of disorders that lead to decreased growth. One of these is nutritional deprivation. Leptin is an adipokine whose levels are associated with nutritional intake. Estrogens have an important role in the maturation of the growth plate. Both have roles in the process of endochondral ossification that is responsible for the elongation of long bones and therefore linear growth. In this study, authors investigated the mechanisms by which leptin and sex hormones affect catch-up growth and possible final height after nutritional deprivation.
Methods: Young male Sprague Dawley rats were fed ad libitum or subjected to a period of 40% food restriction, and thereafter to unrestricted re-feeding for up to 90 days. Growth velocity and height of growth plate was measured. Series of in vitro studies were performed in chondrogenic on ATDC5 cells to study the effect of leptin on aromatase gene expression, and protein and estrogen levels.
Results: Food restriction significantly decreased the growth velocity, which increased at re-feeding, and the final height was similar to non-restricted rats. Growth plate was significantly greater after food deprivation but was not different between the groups after re-feeding. Re-feeding was associated with an increase in leptin level, augmented aromatase mRNA expression and protein content, and augmented leptin and estrogen receptors gene expression.
In vitro studies showed that leptin significantly increased aromatase gene expression and protein level as well as the expression of estrogen and leptin receptors in a dose- and time-dependent manner. The effect of leptin was mediated through the MAPK/Erk, STAT3 and PI3K signaling pathways.
Conclusions: In this study, a crosstalk between leptin and aromatase in chondrocytes at the growth plate is described for the first time. Results of the study suggest that re-feeding during puberty may lead to increased estrogen level and activity in the growth plate, and consequently, irreversible premature epiphyseal closure. These results may have important implications for the development of novel treatment strategies for short stature in children.
| Comments | One of the basic mechanisms as to how nutrition influences growth is linked to the effects of leptin on growth plate in longitudinal bones. Nutrition is also linked to timing and progression in pubertal development, both of which have important effects on growth pattern and final height [12, 13]. Therefore, to investigate crosstalk between leptin, main adipokine of the adipose tissue and estrogen, sex hormone that promotes both growth and senescence of the growth plate in the growth plate, is of high importance. In this study, authors link leptin’s actions on aromatase expression and function in growth plate chondrocytes, thereby influencing local estrogen levels. The results of the study could have important consequences on the strategies of weight regain in growing children and treatment strategies for children with short stature where catch-up is the goal. These data also provide new insights into studies that investigated the use of aromatase inhibitors for the promotion of final height by decreasing the rate of growth plate senescence. |
Differential aging of growth plate cartilage underlies differences in bone length and thus helps determine skeletal proportions
Lui JC1, Jee YH1, Garrison P1, Iben JR2, Yue S1, Ad M1, Nguyen Q1, Kikani B1, Wakabayashi Y3, Baron J1
1Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 2Molecular Genomics Core, Office of the Scientific Director, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and 3DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
PLoS Biol 2018; 16:e2005263
Abstract: In their work, the authors tried to shed light on the mechanism responsible for the differences in bone length of the growing animal. They wondered what makes the difference between long bones like the tibia and shorter bones like the phalanges in the fingers and toes. In a very well-designed set of structural, histological, and molecular experiments, they showed that a variety of mechanisms are involved in the process. Bone elongation occurs within the growth plate, and the authors studied the changes within the growth plate in their search for trying to understand why different bones reach different lengths. The authors claimed that the progressive slow growth with age is due to developmental program termed “growth late senescence” which includes decline in cell proliferation and hypertrophy, depletion of cells in all growth plate zones, and extensive underlying changes in the expression of growth-regulating genes. They claimed and showed that these changes occur earlier in the growth plate of the smaller bone (metacarpal and phalanges) than in the larger bones (tibia and femurs). They also showed that the molecular mechanism involves changes of critical paracrine regulatory pathways, including insulin-like growth factor, bone morphogenetic protein, and wingless and Int-1 signaling. They concluded that the disparities in the length of bones in the body is achieved in part by modulating the progression of growth plate senescence.
| Comments | Bone elongation occurs in the growth plate and determines the magnitude of growth pace, and eventually the height of an individual. The mechanism that controls the chondrocytes proliferation and hypertrophy within the growth plate and their interaction with the endocrine and paracrine systems was never fully elucidated. The common theory is that the linear growth is influenced mainly by the genetic coding but it is also influenced by epigenetic and environmental factors. The sophisticated work presented in this article indeed sheds more light on the processes that occur within the growth plate during its growth and senescence. Exploring the mechanisms that control the event within the growth plate might lead to new approaches to children with growth issues and improve the tool of intervention in such cases. |
New genetic tools in the diagnosis of growth defects
Dauber A1, 2
1Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, and 2Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Growth Horm IGF Res 2018; 38: 24–28
Background: Many signaling pathways and genes are involved in the regulation of linear growth in children. Using new genetic tools, we are able to analyze much more genetic material in less time.
Methods: The author reviews two new genetic tools in the determination of genetic causes of idiopathic short stature; chromosomal microarrays for genome-wide copy variants and whole exome sequencing for sequence variant determination.
Results: The principles of the two methods are explained clearly and are placed in the diagnostic flowchart of idiopathic short stature. Feasibility of different approaches are illustrated in case studies, for example, copy number variants approach in large-scale clinical databases and whole genome sequencing in the determination of novel genes involved in ISS as are PAPPA2 and ACAN.
Conclusions: By using copy number variants and whole genome sequencing approach, it is now possible to comprehensively assess the presence of copy number variants as well as sequence variants in essentially all of the protein coding genes in the genome. As there are thousands of genes which can potentially contribute to growth disorders, genomic technologies will be a tremendous benefit for the evaluation of patients with severe short stature, in addition to its role in novel gene discovery.
| Comments | Clinical examination and hormonal laboratory tests are the cornerstone of short stature diagnosis. When no cause can be determined, short stature is called idiopathic. This presents a burden for both the patient and his/her family and also the pediatric endocrinologist as long-term growth outcome is difficult to predict. In addition, treatment with growth hormone cannot be prescribed in certain regions [14]. With the progress of genetic technologies described in this review, new possibilities in several fields of research and therapeutic strategy planning are opened. By determining novel genes and pathways involved in linear growth, possibilities for the development of new therapeutic possibilities are possible [15]. Making the diagnosis is, however, also very important for the child and his/her family and the pediatric endocrinologist. By using novel genetic tools, diagnosis is made in larger proportion of patients. Interestingly, spectrum of clinical features associated with certain growth disorders is broadened. By determining the etiology decision regarding the use of growth hormone and possible other therapeutic modalities can be made in a more informed manner. Currently, costs of these tools are still relatively high, limiting their everyday use for many centers. With further developments in the field, it is expected that this hurdle will also be overcome. |
Regulation of body growth by microRNAs
Lui JC
Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
Mol Cell Endocrinol 2017; 456: 2–8
Regulation of growth is known to occur at a local growth plate level as well as at a systemic endocrine level. This review summarizes recent studies that investigated the role of microRNAs (miRNAs) in controlling both the linear and longitudinal growth of bones. miRNAs are small non-coding RNAs between 18 and 24 nucleotides long and play an important role in the regulation of gene expression. Most genes are regulated by one or more miRNAs, and each miRNA can regulate a larger number of target miRNAs. Because of this ability to regulate gene expression, miRNAs have been shown to play important roles in many physiological and developmental processes, as well as human diseases. It seems that miRNAs may be involved in regulating growth at several levels. At the level of the growth plate and associated chondrocytes, there is accumulating evidence that miR-140, the let-7 family of miRNAs, miR-199a, miR-145 and miR-675 may all play an important role in regulating growth. Evidence is also emerging that miRNAs may play important roles in regulating insulin-like growth factor-1 (IGF-I) signaling. For instance, in breast cancer cells, 2 miRNAs that suppress IGF1R expression, miR-148a and miR-152, were found to be downregulated. Lastly, there is also some evidence that miRNAs may play a role in regulating organ growth. The discovery of this new family of growth regulators opens up a new exciting avenue for understanding as well as modulating growth.
Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation
Klammt J1, Neumann D2, Gevers EF3, 4, Andrew SF5, Schwartz ID6, Rockstroh D1, Colombo R7, 8, Sanchez MA9, Vokurkova D10, Kowalczyk J4, Metherell LA4, Rosenfeld RG11, Pfäffle R1, Dattani MT12, Dauber A5, Hwa V5
1Department of Women’s and Child Health, University Hospital Leipzig, Leipzig, Germany; 2Department of Pediatrics, Faculty of Medicine, University Hospital Hradec Kralove, Charles University, Prague, Czech Republic; 3Department of Pediatric Endocrinology, Royal London Children’s Hospital, Barts Health NHS Trust, and 4Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK; 5Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA; 6Mercy Kids Pediatric Endocrinology and Diabetes, Mercy Children’s Hospital and Mercy Clinic, Springfield, MO, USA; 7Institute of Clinical Biochemistry, Faculty of Medicine, Catholic University and IRCCS Policlinico Agostino Gemelli, Rome, Italy; 8Center for the Study of Rare Hereditary Diseases, Niguarda Ca’ Granda Metropolitan Hospital, Milan, Italy; 9Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA; 10Department of Clinical Immunology and Allergology, Faculty of Medicine, University Hospital Hradec Kralove, Charles University, Prague, 500 05 Hradec Kralove, Czech Republic; 11Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA; 12Section of Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme, University College London, Great Ormond Street Institute of Child Health, London, UK
Nat Commun 2018; 9: 2105
Growth hormone insensitivity syndrome (GHIS) that presents as impaired postnatal growth and low or undetectable serum insulin-like growth factor-1 concentrations despite normal growth hormone (GH) concentration is usually due to autosomal-recessive mutations of the GH receptor and in its classic form has been described as Laron syndrome. STAT5B deficiency is a very rare cause of GHIS, and to date has been described as an autosomal recessive disorder in which the severe short stature was also associated with T-cell lymphopenia and progressive pulmonary disease. In the current study, the investigators describe heterozygous STAT5B germline mutations that exert dominant-negative effects through impaired DNA binding which results in a condition characterized by significant postnatal growth impairment, mild GH insensitivity, eczema, and elevated IgE. None of the cases had the severe form of immune deficiency typically associated with STAT5b deficiency.
