Follow- Up of Young children
An SGA- born child should have measurements of length, weight, and head circumference every 3 months during the first year of life and every 6 months thereafter. Children with microcephaly might have a syndrome (Table 1) and those who do not show significant catch- up in length in the first year and are short by the age of 2 years, may have an underlying disorder that limits growth. These children should be identified and referred to a paediatric endocrinologist with experience in short stature after SGA birth.
Table1. Monogenic disorders in short children born SGA with microcephaly
Diagnostic Approach in Short SGA children
Figure 1 presents a stepwise diagnostic approach for short children born SGA. As a first step, the clinician needs to identify diagnostic signs from the medical history, physical examination, and growth pattern, followed by a screening laboratory panel and an X- ray of the left hand and wrist to assess skeletal age and search for anatomic abnormalities associated with genetic disorders like SHOX, NPR2, ACAN, IHH. In addition, in all girls whose height is well below target height (>1.6 SDS), TS should be excluded, by array analysis (SNP array or CGH array) or a karyotype. The diagnostic power of an array to detect TS is similar to that of a karyotype, but with a SNP array CNVs and uniparental isodisomy can be detected. When there are signs of a secondary growth disorder, conditions like hypothyroidism, celiac disease, GH- IGF- axis disturbance, or chronic disease should be evaluated. Only when serum IGF- I level is low for age and gender, is a GH stimulation test indicated. When there are signs of a primary growth disorder and TS is excluded, further genetic testing could be performed. When there are dysmorphic features and/ or microcephaly, one may consider evaluation by a clinical geneticist. Repeatedly high serum IGF- I levels (> 1 SDS) requires genetic testing of the IGF1R gene. If there is a strong suspicion of a specific genetic syndrome, DNA sequencing combined with an MLPA (Multiplex Ligation- dependent Probe Amplification) test of one specific gene can be performed (‘candidate gene approach’), but one may also decide to perform a growth- specific gene panel or a specific exome- based gene panel targeted to growth- related genes. When the child has a positive Netchine– Harbison score, genetic testing for Silver– Russell syndrome is indicated. In the case of dysmorphic signs or (some) suspicion of a primordial disorder, an array analysis is probably more efficient to find a genetic cause. As last step, RNA sequencing or a methylation array could be considered. In special cases (e.g. if a novel monogenic disorder is suspected), WES in a ‘trio’ (patient and both parents, or including siblings) can be performed. The latter is mostly done after consultation with a clinical geneticist. Presently, the yield of genetic diagnoses after such analyses is disappointingly low in non- syndromic short SGA children. However, as genetic techniques are extended, a cause will be identified in an increasing number of short SGA children and it might turn out that many cases of SGA are caused by a combination of multiple (epi)genetic variants.
Fig1. A stepwise diagnostic approach of a short child born SGA.
