A mini review on the diagnosis and management of patients born small for gestational age including the use of growth hormone therapy in those with persistent short stature.
Children born small for gestational age (SGA) are defined as those having birth weight and/or length below –2 standard deviation score (SDS) for gestational age [1]. The SGA definition includes a variety of clinical conditions, ranging from healthy children presenting with exclusively low birthweight to syndromic children with many other comorbidities [2]. The most frequent cause of SGA is Silver–Russell syndrome, characterised by intrauterine growth restriction, SGA, persistent short stature, feeding disorders, and dysmorphic features, including relative macrocephaly, triangular-shaped head with frontal bossing, clinodactyly, and facial and/or body asymmetry [2]. Other genetic causes of SGA may include Temple, IMAGe, and Prader–Willi syndromes; pseudohypoparathyroidism, achondroplasia, hypochondroplasia, and other forms of skeletal dysplasia; and SHOX mutations and RASopathies[2].
Nevertheless, SGA are not necessarily related to genetic disorders. Women with systemic diseases, including inflammatory bowel disease, coeliac disease, HIV, antiphospholipid syndrome, and depression are also prone to give birth to SGA children, as well as those smoking or taking antidepressants, or those who are underweight or do not gain adequate weight during pregnancy [2].
In approximately 90% of cases, SGA children show in the first 2 years of life catch-up growth, namely a growth rate greater than 0 SDS, leading to an adult height within the normal range (ie, >–2 SDS) [1, 2]. However, in the remaining 10%, SGA children fail to achieve catch-up grow, showing persistent short stature, a constantly impaired growth rate, and consequently have decreased adult height [1, 2]. Therefore, auxological evaluation, comprising height, weight, growth rate and head circumference, is required every 3 months for the first year of life and every 6 months for the second year of life [1]. In case of persistent short stature (ie, <–2.5 SDS) or lack of catch-up growth in the previous 6 months by the age of 2 years old, referral to a paediatric endocrinologist is required [1]. Early referral should be considered in SGA patients born very preterm (ie, age at delivery <28 weeks), severely SGA (birth weight and/or birth length <−3 SDS for gestational age), and in those with multiple comorbidities, neurodevelopmental delay or dysmorphic features suggestive for syndromic conditions [1].
Due to the heterogeneous causes of SGA, careful medical history, physical examination focusing on body proportions and dysmorphic features, neurodevelopmental assessment, and laboratory screening for the most common causes of short stature should be performed as first-line in referred SGA patients [1]. In those with major malformations and comorbidities, body disproportion, skeletal abnormalities, dysmorphic features, and neurodevelopmental delay, genetic evaluation should be considered [1]. Genetic testing should also be considered in patients with hormonal evidence of growth hormone (GH)–insulin growth factor (IGF)-1 axis involvement, namely abnormal GH, IGF-1, and IGF binding protein 3 [1].
In SGA patients with persistent short stature, regardless of the underlying causes, treatment with recombinant human GH is recommended, aiming at restoring the normal growth rate and allowing normal adult height, thus reducing the psychosocial and health burden of short stature [1, 3]. In most countries, GH treatment may be started from 4 years of age [1], although an early treatment start (ie, from 2 years) is currently approved in the USA and in Latin America and has been considered worldwide [1], as it has shown to lead to greater benefits in adult height [4]. A starting GH dose of 0.033 mg/kg per day should be adopted, then it should cover the range between 0.033 to 0.067 mg/kg per day, according to the minimum effective dose, until growth rate falls below 2 cm/year, usually occurring during puberty [1].
In a meta-analysis of four studies of SGA children, GH treatment demonstrated an improved growth rate, with a reported mean height gain of 1.25–1.65 SDS at last assessment compared with baseline, and normal or near-normal adult height was reached in the majority of cases [5]. Considering only studies with long-term follow-up (ie, >3 years of GH treatment), similar results were observed, with a mean height increase from baseline of 1.65±0.3 SDS (range: 1.15–2.26) and a mean catch-up growth of 0.66±0.13 SDS (range: 0.35–0.89) [6]. In SGA children, GH treatment is generally very well tolerated and no significant differences from the general population have been observed in terms of mortality and primary cancer risk, nor for abnormalities of glucose metabolism, including impaired glucose tolerance and type 2 diabetes mellitus [7].
In conclusion, SGA children represent a special population requiring specific follow-up from birth, aiming at the prompt identification of patients potentially affected by genetic and systemic disorders and patients potentially benefitting from early GH treatment. Once started, GH treatment could be safely performed until puberty, leading to a significant increase in mean height and to a normal or near-normal adult height at the end of treatment.
