Introduction

Proportionate short stature constitutes the largest group of patients referred for investigation and consideration of therapy to a paediatric endocrinology unit. Short stature has multi-factorial origins, ranging from development defects to environmental, genetic and endocrine causes. In fact, non-endocrine growth disorders should be excluded in any investigational protocol before endocrine causes can be assessed in detail. A reversal of this order of events will lead to non-endocrine aetiologies being missed, resulting in inappropriate management. Of primary importance in the diagnosis of proportionate short stature cases, are the skills of the clinician in history taking and detailed and observant physical examination. The development of biochemical, genetic and radiological investigations have tended to side-line clinical skills, whereas a careful history and examination can orientate the clinician towards the correct diagnosis in the majority of cases. During the out-patient consultation, it is more important to look carefully at the patient than to concentrate on data emerging on the computer screen.

The continuum model of growth hormone (GH)-IGF-1 axis defects¹ will be taken as the basis for this plenary presentation. Two major aetiological groups can now be defined as causative influences in growth disorders. These are defects in the GH-IGF-1 axis¹ and primary growth plate abnormalities². Considerable progress has been made recently in the understanding of growth plate physiology and pathophysiology, however these advances will not be discussed, as they fall outside the title of the lecture. In contrast, biochemical, radiological and genetic advances will be described. Both the topics of investigation and therapy will be addressed separately, but in a logical order, following the continuum model (Figure 1) from severe to mild GH deficiency, then moving through the topic of idiopathic short stature (ISS) into disorders of GH action, known as GH resistance (GHR) defects, which will be considered from the mild forms through to the severe examples of GHR phenotypes. Finally, a conclusion will attempt to address the question in the lecture title, ie ‘where are we?’

Diagnostic progress

The most severe cases of GH deficiency may present in infancy, when the GH deficiency is often associated with additional anterior pituitary defects, notably of TSH, ACTH and gonadotrophins. Such patients require biochemical determination of baseline hormone concentrations. Provocative tests of GH secretion are contraindicated because of the risk of severe hypoglycaemia and GH secretory status can be indirectly assessed by measurement of IGF-1 and IGFBP-3 concentrations. Of primary importance is the performance of a pituitary MRI scan, which may show the characteristic features of hypopituitarism, namely ectopic posterior pituitary gland, thin or invisible pituitary stalk and anterior pituitary hypoplasia³. Alternatively, the MRI may identify a development lesion such as septo-optic dysplasia, a classical organic cause of infantile hypopituitarism. Genetic studies with Sanger sequencing of genes involved in pituitary development such as POU1F1 (POU Class 1 Homeobox 1) and PROP1 (PROP paired-like homeobox) should also be considered.

As the order, described above, of GH-IGF-1 defects in the continuum model progresses, the entity known as idiopathic short stature (ISS) should be considered. It is important to appreciate that ISS is not a clearly defined entity, but constitutes a description of heterogeneous causes of apparent abnormal growth. The most common causes of ISS are normal variants of growth, namely constitutional delay of growth and puberty and particularly genetic short stature, which is, in itself, hugely heterogeneous. The GH-IGF-1 axis is essentially normal in ISS.

As GH sensitivity decreases along the ‘X’ axis of the continuum model, disorders of GH action, known collectively as GH resistance or primary IGF-1 deficiency, need to be considered. Classical GH resistance (GHR), first described in 1966 by Laron et al.⁴, was initially considered to embrace all GHR states. However, we now know that this is not the case as mild GHR phenotypes have increasingly been described during the past ten years. Recent reviews have discussed such cases^5.6, notably including the new PAPPA2 mutations, reported by Jesus Argente from Madrid and collaborators in 2016⁷. The possibility of heterozygous mutations, notably of STAT5b and IGFALS genes also causing a proportional short stature phenotype has been reported⁸. Clinical assessment and biochemical characterisation are also very important aspects of the investigation of GHR defects. In a selected cohort of 102 cases of GHR in whom DNA was sent for genetic analysis, a positive diagnosis was achieved by a combination of Sanger and whole exome sequencing in fifty, ie 49%^6,9. Notably a positive genetic diagnosis was predicted most strongly by two factors, the severity of the short stature and the presence of parental consanguinity⁶.

Advances in therapy

Growth-promoting treatment in proportionate short stature consists, by definition, of replacement therapy with hGH or rhIGF-1. The skill and judgement about when and how to prescribe such therapy are key components of optimal clinical management. Treatment of GH deficiency requires replacement with ‘physiological’ doses of hGH (18-25 μg/kg/day). The more severe the GH deficiency, the more responsive the patient is to hGH replacement, ie the smaller the dose that is needed to be effective. Varying responses to GH have demonstrated that hGH therapy should be individualised.  Children with milder GH deficiency require higher doses (25-35 μg/kg/day). These ‘replacement’ doses contrast with the higher ‘pharmacological’ doses required in non-GH deficiency disorders, such as Turner syndrome and short stature following birth size small for gestational age. In ISS, short children with normal GH secretion who have short healthy parents have poor responses to even pharmacologic doses of hGH.

RhIGF-1 is licensed by EMA since 2007 to treat short children with GHR defined as height <-3 SDS, low IGF-1 (<2.5^th centile) and normal GH secretion. This replacement therapy is effective in doses of 80-120 μg/kg/twice daily. Its long-term efficacy is well documented in classical GHR patients¹⁰, but much less well documented in milder cases⁶. There is evidence that addition of a GnRH analogue can give extra height benefit during puberty¹⁰.

Where are we? What we know and what we do not know

We know that clinical skills are beneficial to early diagnosis and that GH deficiency is best diagnosed from a combination of auxological, biochemical and radiological data. We know that genetic discoveries explain new physiological mechanisms¹¹ and that GHR covers a range of short stature phenotypes from extreme to mild growth delay. We know that hGH dosage should be individualised, poor responses historically are common and adherence to hGH is said to be poor. We know that long-acting preparations are likely to be licensed within the next 3-5 years.

On the other hand, we do not know how much genetic research and analyses contribute to patient management. Neither do we know the relative contributions of growth plate pathology compared to GH-IGF-1 axis defects to proportionate short stature as it is currently referred for investigation. We do not know the best way of detecting and effectively managing poor adherence to hGH. Long-acting hGH is coming, but we do not know if there is interest in developing long-acting rhIGF-1.

Conclusions

The field of short stature continues to develop both diagnostically and therapeutically. Basic research is almost entirely molecular- or gene-based, with new regulatory mechanisms of linear growth being discovered on a regular basis. The field of GH therapy is active with the imminent arrival of long-acting hGH. Considerable challenges remain, with many growth disorders still untreatable and many patients experiencing the stigmata and disadvantages of subnormal height both in childhood and as adults.

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