Investigations
1st investigations to order
x-ray wrist
Test
Bone maturation is delayed for the chronological age. This is assessed by radiography. The appearance of representative epiphyseal centres on the x-ray is compared with age- and sex-appropriate published standards. The most commonly used method is that of Greulich and Pyle, which examines the left wrist and hand. Bone age is of limited use in infants, but, if required, other methods such as knee examination may be more helpful than wrist examination. Bone age may also be used to predict final height, using the tables of Bayley and Pinneau.[39]
Result
delayed skeletal age
thyroid function tests
Test
Free thyroxine (T4) and thyroid-stimulating hormone (TSH) should be measured in all children with poor growth to rule out hypothyroidism as the primary cause of short stature. It may help to reveal TSH deficiency in combination with GHD.
Result
normal in isolated GHD; low free T4 and TSH with TSH deficiency
IGF1 and IGFBP3
Test
Values of insulin-like growth factor 1 (IGF1) and its binding protein (IGFBP3) more than two standard deviation scores (SDS) below the mean, corrected for age and sex, are indicative of GHD; however, normal concentrations do not rule out GHD (e.g., in post-irradiation patients).[40][41] The concentrations may be altered in hypothyroidism, malnutrition, and chronic diseases.
Result
low
baseline pituitary function tests
Test
This should include 8 a.m. adrenocorticotrophic hormone, cortisol, luteinising hormone, follicle-stimulating hormone, testosterone/oestradiol, and prolactin tests to look for potentially associated combined pituitary hormone deficiencies (CPHD). The status of the hypothalamo-pituitary-adrenal axis must be known prior to embarking on more detailed GH provocation testing.
Result
low in CPHD
basic haematology and biochemistry screen
Test
All children with short stature should have a full basic haematology and biochemistry screen, including a full blood count, renal and liver function tests, bone profile, serum/plasma electrolytes, and inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) to exclude other causes.
Result
normal
Investigations to consider
GH provocation test
Test
The GH-IGF1 axis can be stimulated with various provocative agents such as insulin, glucagon, arginine, and clonidine. The insulin tolerance test is considered the definitive test for assessing both the GH-IGF1 axis and the hypothalamo-pituitary-adrenal axis. GH provocation tests are contraindicated in children aged under 1 year.[30][57] Two provocation tests improve sensitivity. Priming may be considered in certain age groups.[12][42]
Result
peak GH <7 micrograms/L (<7 nanograms/mL) (range 5-10 micrograms/L [5-10 nanograms/mL])
MRI brain
Test
Helps to identify congenital abnormalities of the forebrain and pituitary, optic chiasm, and optic nerves.[47][48] Anterior and posterior pituitary abnormalities in congenital GHD are highly variable.[2]
MRI will also detect acquired abnormalities such as a solid/cystic suprasellar mass extending into the hypothalamus and third ventricle (craniopharyngioma), optic gliomas, Rathke's cleft cysts, and arachnoid cysts. Inflammatory lesions such as Langerhans cell histiocytosis will be revealed as thickening of the pituitary stalk.
Result
variable: small anterior pituitary, midline forebrain defects, posterior pituitary/stalk abnormalities, central nervous system tumours/cysts
CT brain/x-ray skull
Test
CT of the brain and x-ray of the skull may help to detect bony abnormalities and intracranial calcification (craniopharyngiomas).
Result
calcification
full pituitary hormone evaluation
Test
Confirmation of the diagnosis of GHD requires a full pituitary evaluation to rule out other anterior and/or posterior pituitary hormone dysfunction.
Neonates: low serum insulin in the presence of hypoglycaemia with low serum GH and cortisol concentrations suggests hypopituitarism, although chronic hypoglycaemia can be associated with poor counter-regulatory GH and cortisol responses.[49] The diagnosis of combined pituitary hormone deficiencies (CPHD) should be further confirmed with thyroid function tests (low free thyroxine [T4], low thyroid-stimulating hormone [TSH]) and a low 24-hour plasma cortisol profile.
In older children, a low TSH with low T4 concentrations indicates TSH deficiency. A routine thyrotrophin-releasing hormone (TRH) test may not always be necessary.[50][51][52] Basal serum prolactin concentrations of <217 picomoles/L (<5 nanograms/mL) are usually indicative of prolactin deficiency and may be confirmed by a suboptimal response to TRH. Gonadotrophin deficiency is confirmed by a poor response to gonadotrophin-releasing hormone, depending on age. Adrenocorticotrophic hormone (ACTH) deficiency can be diagnosed as a poor cortisol response after an insulin tolerance test or ACTH. A 24-hour plasma cortisol sampling may be necessary in some patients.[53] Stimulation of testes with human chorionic gonadotrophin (hCG) in males at puberty may also be used to diagnose gonadotrophin deficiency.[54]
Result
normal or variable deficiencies
specialist referral
Test
Patients with eye abnormalities should be referred to an ophthalmologist to rule out optic nerve hypoplasia/septo-optic dysplasia.
Patients with central nervous system tumours should continue to be assessed and monitored by a team of paediatric specialists, including neurologists, neurosurgeons, oncologists, endocrinologists, ophthalmologists, and radiologists.
Other specialist referral may be required as indicated: for example, a psychologist and social services for psychosocial deprivation.
Result
variable
genetic studies
Test
The role of genetics in congenital GHD remains to be established, but is increasingly offered within the clinical rather than research setting. Parental consanguinity, positive family history, craniofacial and brain midline abnormalities, and other syndromic features all make a genetic diagnosis more likely. Appropriate mutational screening is an important adjunct to assessment and management of the patient, because it provides a better understanding of the pathophysiological process, although mutations are rare in patients with sporadic hypopituitarism.[10][55] However, detection of mutations may lead to early diagnosis of additional hormone deficiencies if patients have mutations in genes with a well-established hormonal phenotype (e.g., PROP1, POU1F1 mutations).
Result
identify mutations in congenital GHD
random GH
Test
A single, randomly taken GH level <7 micrograms/L (<7 nanograms/mL), during the first week of life, has been found to be 90% sensitive and 98% specific in diagnosing neonatal GHD.[35]
Result
<7 micrograms/L (<7 nanograms/mL) during the first week of life; <5 micrograms/ L (<5 nanograms/mL) in the presence of other pituitary hormone abnormalities
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