ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2018) 15 4.11 | DOI: 10.1530/ey.15.4.11

Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands


To read the full abstract: J Clin Endocrinol Metab 2018; 103:917-925

SGA is often defined as a birth weight and/or length < −2 SDS for gestational age and gender [43]. A frequent cause of SGA is fetal growth restriction (FGR), often associated with perinatal mortality and morbidity and also implicated in a higher risk of cardio-metabolic disease in adulthood. Currently, no tools are available to predict or prevent FGR. Both genetic and environmental factors may affect fetal growth, but the underlying molecular mechanisms are still unclear. Genetic and epigenetic factors account for 30-50% of the variation in birth weight [44]. Chromosomal anomalies account for up to 19% of FGR fetuses, while the rate of submicroscopic duplications/deletions and single-gene disorders in FGR with normal karyotype is not defined [44]. A recent study showed that genomic microarray analysis (CMA) identifies sub-microscopic anomalies in 6.8% of fetuses with early growth restriction after common aneuploidies were excluded [45]. To date, the use of CMA is recommended for a fetus with one or more major malformations identified by ultrasound. Epigenetic mechanisms also explain abnormal fetal growth in conditions such as Silver-Russell and Beckwith-Wiedemann syndrome.

Here, Stalman et al. investigated the efficacy of a combined genomic analysis to achieve a molecular diagnosis in SGA newborns. In 19% of SGA subjects, the combination of array-CGH, genome-wide methylation disturbances and whole exome sequencing identified a genetic abnormality, likely responsible for the low birth weight. Array-CGH yielded abnormalities in three patients: i) mosaic trisomy of chromosome 16; ii) mosaic monosomy X; and iii) deletion of 11p13-p14.1 causing WAGR syndrome (Wilms tumor, aniridia, genital anomalies, and mental retardation). Differential methylation was seen in 12 patients, of whom 9 had differential methylation in more than one gene. A methylation abnormality potentially involved in SGA was detected in imprinted genes at the 11p15.5 region associated with FGR: CDKN1C, KCNQ1, IGF2AS, INS, and IGF2. CNVs were identified in 14% of patients, a rate higher than that previously reported in SGA [46]. Most variants detected by exome sequencing were of unclear clinical relevance. These findings point out that the cause of FGR is polygenic and in most patients involving genetic changes which alone do not affect growth, being present also in controls. However, the cohort of SGA newborns in this study is too small to draw definitive conclusions, especially taking into account the broad heterogeneity of conditions associated with FGR. The proposed molecular genetics approach needs further evaluation to assess its cost/effectiveness and impact on the clinical management of children born SGA.

43. Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A. Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab. 2007;92:804-10.

44. Lunde A, Melve KK, Gjessing HK, Skjaerven R, Irgens LM. Genetic and environmental influences on birth weight, birth length, head circumference, and gestational age by use of population-based parent-offspring data. Am J Epidemiol. 2007;165:734-41.

45. Borrell A, Grande M, Pauta M, Rodriguez-Revenga L, Figueras F. Chromosomal Microarray Analysis in Fetuses with Growth Restriction and Normal Karyotype: A Systematic Review and Meta-Analysis. Fetal Diagn Ther. 2017.

46. Wit JM, Oostdijk W, Losekoot M, van Duyvenvoorde HA, Ruivenkamp CA, Kant SG. MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature. Eur J Endocrinol. 2016;174:R145-73.

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