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Table of Contents    
COMMENTARY
Year : 2018  |  Volume : 66  |  Issue : 6  |  Page : 1685-1686

Diagnosis of childhood growth hormone deficiency: Controversies, consensus and the need for new diagnostic tools


Department of Endocrinology, All India Institute of Medical Scienecs, New Delhi, India

Date of Web Publication28-Nov-2018

Correspondence Address:
Dr. Rajesh Khadgawat
Department of Endocrinology, All India Institute of Medical Scienecs, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.246229

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How to cite this article:
Goyal A, Khadgawat R. Diagnosis of childhood growth hormone deficiency: Controversies, consensus and the need for new diagnostic tools. Neurol India 2018;66:1685-6

How to cite this URL:
Goyal A, Khadgawat R. Diagnosis of childhood growth hormone deficiency: Controversies, consensus and the need for new diagnostic tools. Neurol India [serial online] 2018 [cited 2018 Dec 10];66:1685-6. Available from: http://www.neurologyindia.com/text.asp?2018/66/6/1685/246229




Short stature (SS), defined as a height of two standard deviations below the population mean for a given age and sex, is a common problem for which an endocrinology referral is sought. In a given population, about 3% children are likely to be short and after exclusion of alternative etiologies, growth hormone deficiency (GHD) as a cause of SS needs to be considered. The prevalence of childhood GHD is <1%, varying from 1:4000-1:10,000 across various studies. However, in a pre-selected group of children with SS, GHD has been reported at a prevalence rate of 3-69% across various studies.[1],[2],[3]

The diagnosis of GHD in children is challenging. Once all the common causes of short stature are ruled out with proper investigations, the growth hormone (GH) status of the child needs to be assessed. After the confirmation of diagnosis of GHD, next step in the management is imaging of the pituitary area, preferably by magnetic resonance imaging (MRI) to rule out any mass lesion requiring surgery.

Currently, there is no true gold standard for the diagnosis of GHD. The clinician needs to rely on a combination of carefully performed auxology, clinical presentation, bone age estimation, GH stimulation tests and other adjunctive biochemical parameters for establishing the diagnosis of GHD. Before proceeding for GH stimulation tests, other possible etiologies must be excluded with basic investigations. It is important to test for these etiologies even in the absence of any clinical suggestion, because growth failure can occur either before or in the absence of signs and symptoms of the primary disease. Also, it is important to remember that uncorrected hypothyroidism not only causes growth failure but may also lead to false low GH levels on a provocative test. Due to the pulsatile nature of GH, random GH levels are of no value in the diagnosis of GHD (the only exception being in establishing the diagnosis of GHD in neonates) and we need to rely on various pharmacological agents to stimulate GH secretion.

The various stimulating agents used in testing for GH are arginine, clonidine, insulin, glucagon, GH releasing hormone (GHRH) and levodopa. Blood samples are collected in the fasting state, followed by administration of weight-based calculated dose of the stimulating agent and subsequent collection of blood sample every 30 minutes for the next 2-3 hours. The cut-off level for the diagnosis of GHD on provocative tests has changed over time. The initial cutoff was <2.5 ng/ml, which was based on the patients with severe pituitary insufficiency; however, with the ready availability of recombinant human GH (rhGH), the cut-off value was increased to 5 ng/ml initially and subsequently to 7, and finally, a cut-off of 10 ng/ml is used at all the centres now-a-days.[3] There is inadequate data validating the increased cut-off value, which remain more or less arbitrary. The increased cut-off value for diagnosis of GHD translates into a poor specificity (that is, falsely identifying normal children as having GHD). Hence, to improve specificity, a strategy of two failed provocative tests (all GH values <10 ng/ml) performed on two separate days is recommended. The specificity of the GH provocative test can be increased if a lower cut-off value is used; however, one may miss children with less severe forms of GHD using this approach.

Although GH stimulation tests are considered as the best available tools for confirmation of GHD, many issues such as poor reproducibility and GH assay variability coexist. Most of the stimulating agents are pharmacological stimuli, given in high pharmacological doses and not in physiological doses. The use of a uniform cut-off value for establishing the diagnosis of GHD is, therefore debatable, since it is known that the peak GH levels may vary according to the type of stimulus and the nature of GH assay. Additionally, the role of sex steroid priming in pre-pubertal children before performing the GH stimulation test is still debatable. Moreover, the use of pharmacological stimulants for GH stimulation testing has its own inherent risks. Severe hypoglycemia, seizures and even death have been reported with the use of insulin.[3] Using the same cutoff for assessing children with normal body mass index (BMI) versus a high BMI is another debatable issue as obesity is known to affect GH secretion. Finally, subjecting a young child to multiple sampling on two separate days is a tedious task and requires extreme patience and cooperation from both the parents and the child.

Considering these limitations with GH stimulation tests, there has been a constant search for alternative strategies/tests for a long time in order to develop a convenient method for establishing the diagnosis of GHD. These approaches includes the use of GH dependent biochemical parameters, like measurement of basal serum insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) levels. Both, IGF1 and IGFBP3 are reflective of integrated GH secretion and unlike GH, the levels of these polypeptides are stable throughout the day with minimal diurnal variation. The levels of IGF1 are normally low in young children (<5-6 years) and the values overlap with those of children with GHD, conferring a poor sensitivity (that is, inability to pick up all children with GH deficiency). Moreover, the serum IGF1 levels are dependent on nutrition and pubertal status, and the assay is technically demanding. Serum IGFBP3 levels are affected to a lesser extent by nutrition and age, and the assay is technically simple; however, poor sensitivity remains a major issue.[3] Although both IGF1 and IGFBP3 may not be useful in isolation for confirmation of the GHD status, they could be of some help when used in combination with other diagnostic measures for GHD. Apart from these, other tests like 24-hour urine GH excretion and 24-hour GH secretion profile have been used as alternative methods to diagnose GHD, but have not been found to be very useful. However, there is always the need to develop alternative testing methods that may replace the relatively invasive GH stimulation tests.[4]

Cranial MRI is useful to delineate any structural abnormalities of the pituitary gland and is obtained before initiating GH treatment in all the patients. However, a substantial proportion of patients (especially those with isolated GHD) may have normal pituitary imaging. GHD may be associated with developmental defects of the posterior fossa of brain, leading to a smaller posterior fossa volume in children with GHD compared to the normal population. In this issue of the journal, Tunçyürek et al., have proposed the utility of pons ratio (PR, an indicator of location of the pons relative to the posterior fossa) as a simple and novel tool for the diagnosis of GHD based on cranial MRI.[5] The authors have compared the pons ration [PR] {calculated as the ratio of pons height over the axis between the dorsum sellae and the fourth ventricular hill in the sagittal plane (A) to the total height of the pons (B) [A/B]} in 15 children with GHD and normal MRI, and 33 normal children. The PR was found to be significantly higher in children with GHD compared to controls (mean ± standard deviation [SD]; PR 0.31 ± 0.07 vs. 0.26 ± 0.06), GHD vs. controls, P < 0.05). Also, the measures of posterior fossa volume were significantly lower in children with GHD in agreement with the previous studies.[6] This study provides an interesting observation for further evaluation. However, there are some unanswered questions which need to be pondered upon before drawing any conclusion. The results of this study may only apply to patients with congenital GHD (who would be expected to have developmental defects of posterior fossa) and not to children with acquired GHD. Also, the small sample size and retrospective design imply that the study results need to be validated in future studies with larger numbers of patients and a prospective design. It is also not clear whether or not the comparison between patients and controls were adjusted for pubertal status. As there was no significant difference between the height of the patients and the subjects in the control group, it seems likely that patients were already on treatment with GH, which might have had a confounding effect. It would be interesting to further explore the findings with size correction, as GHD patients would be expected to be much shorter compared to controls.

To conclude, the diagnosis of childhood GHD is challenging and requires careful interpretation of the anthropometric measurements, clinical indicators, GH stimulation tests and other ancillary measures. Despite their limitations, GH stimulation tests continue to remain the backbone of the armamentarium for the diagnosis of GHD. Novel and interesting diagnostic tools such as the PR and the posterior fossa volume need to be validated in well-designed prospective studies with larger numbers, before they could be brought to use in clinical practice as an alternative to the current diagnostic measures.



 
  References Top

1.
Vimpani GV, Vimpani AF, Lidgard GP, Cameron EH, Farquhar JW. Prevalence of severe growth hormone deficiency. Br Med J 1977;2:427-30.  Back to cited text no. 1
    
2.
Lindsay R, Feldkamp M, Harris D, Robertson J, Rallison M. Utah Growth Study: Growth standards and the prevalence of growth hormone deficiency. J Pediatr 1994;125:29-35.  Back to cited text no. 2
    
3.
Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: Summary statement of the GH Research Society. GH Research Society. J Clin Endocrinol Metab. 2000;85:3990-93.  Back to cited text no. 3
    
4.
Cooke DW, DiVall SA, Radovick S. Normal and aberrant growth in children. In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM, editors. Williams Textbook of Endocrinology. 13th ed. Philadelphia: Elsevier; 2016. pp. 964-1073.  Back to cited text no. 4
    
5.
Tunçyürek O, TurgutM, ÜnüvarT, Tubbs RS, ÖzsunarY. Pons ratio as a potential diagnostic biomarker for the detection of growth hormone deficiency in children. Neurol India 2018;66:1680-4.  Back to cited text no. 5
    
6.
Tubbs RS, Wellons JC 3rd, Smyth MD, Bartolucci AA, Blount JP, Oakes WJ, et al. Children with growth hormone deficiency and Chiari I malformation: A morphometric analysis of the posterior cranial fossa. Pediatr Neurosurg 2003;38:324-8.  Back to cited text no. 6
    




 

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