Approach

The diagnosis of growth hormone deficiency (GHD) is based on a combination of assessing the clinical phenotype, GH provocative testing, measurement of insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3), and neuroradiology. GH provocation tests are contraindicated in children aged under 1 year.

Most commonly, patients with congenital GHD present in late infancy or childhood, typically with a low growth velocity and short stature. In patients with combined pituitary hormone deficiencies (CPHD), the signs and symptoms are of the individual hormone abnormalities.

Investigations for GHD and referral to a paediatric endocrinologist are indicated in any child with:[1][30]

  • Severe short stature (>3 standard deviation scores [SDS] below mean for population)

  • Height >2 SDS below mean and a growth velocity over 1 year of >1 SDS below mean or a decrease in the height SDS of >0.5 over 1 year in children aged over 2 years

  • Height SDS >1.5 SDS below target height SDS

  • Height velocity >2 SDS below mean over 1 year or >1.5 SDS below mean over 2 years in the absence of short stature

  • An intracranial lesion

  • CPHD

  • Suggestive perinatal/neonatal history

  • Post-cranial irradiation

  • Positive family history

Evaluation for GHD and/or other pituitary hormone deficits must be carried out by a paediatric endocrinologist in a specialised centre. Pituitary hormone deficiencies can evolve, so regular monitoring, both clinically and with investigations, is needed.

Congenital GHD

Poor growth and/or short stature in childhood are typically the primary complaints in patients with congenital GHD. However, growth failure may present even in infancy.[31][32]​ The diagnosis may also be evident in the presence of optic nerve hypoplasia or other midline defects at an early age.

Patients have a characteristic facial appearance and body habitus. The head seems large with frontal bossing, a small nose, truncal obesity, immature facies, mid-facial hypoplasia, and delayed dentition. They have a reduced lean body mass and increased total body fat. Some patients are diagnosed only after an absent pubertal growth spurt, despite development of secondary sexual characteristics (unless co-existing gonadotrophin deficiency is also present).

The diagnosis of isolated congenital GHD is rarely made in the neonatal period unless in the presence of obvious risk factors such as midline defects (e.g., holoprosencephaly, septo-optic dysplasia, or severe bilateral cleft lip and palate). Birth weight and birth length have been reported to be normal in patients with congenital GHD. However, GHD in combination with CPHD may present in the newborn period with poor feeding, apnoea, recurrent sepsis, and seizures. Hypoglycaemia may indicate adrenocorticotrophic hormone (ACTH) deficiency, although it may also be present with isolated GHD.[33] Hypothyroidism due to thyroid-stimulating hormone (TSH) deficiency results in temperature instability and prolonged neonatal jaundice. Although ACTH does not regulate the renin-angiotensin system, patients can present with hyponatraemia but without hyperkalaemia. Occasionally, patients present with arginine vasopressin deficiency (AVP-D; previously known as central diabetes insipidus) in the neonatal period, particularly with associated midline defects. Gonadotrophin deficiency may present as undescended testes and a small penis at birth (or with delayed puberty in adolescence); a small phallus may be present even in the absence of gonadotrophin deficiency in isolated GHD.

Perinatal history may reveal other gestational-perinatal complications such as prematurity, gestational bleeding, complications of delivery, fetal distress, or asphyxia.[7] Breech or other instrumental delivery is more common.[31] However, it is difficult to differentiate whether hypopituitarism is actually responsible for these perinatal complications or whether perinatal problems themselves lead to hypopituitarism.

During the neonatal period, GH concentrations are higher in the term neonate during the first week of life than throughout childhood, but fall rapidly over the following weeks.[34] By contrast, IGF1 concentrations (stimulated by GH) are unreliable as a screening test in neonates as they remain low for at least the first 18 months of age.[35] A random GH concentration of less than or equal to 5 micrograms/L (5 nanograms/mL) during the first 7 days of life accompanied by other pituitary hormone deficiencies and/or the classical imaging triad of pituitary stalk interruption syndrome (PSIS) is sufficient to diagnose GHD.[34] A GH cut-off of 7 micrograms/L (7 nanograms/mL) as measured on a neonatal screening card by a highly sensitive polyclonal enzyme-linked immunosorbent assay (ELISA) has been shown to have 100% sensitivity and 98% specificity.[35] GH stimulation tests are contraindicated during the neonatal period, and a low GH concentration at the time of hypoglycaemia in isolation is not enough to diagnose GHD. It is important to note that the sensitivity and specificity of laboratory tests are limited in this cohort, particularly in premature infants because of hypothalamo-pituitary axis immaturity, and lack of normative data and reference intervals. A high index of suspicion for CPHD and early treatment in these patients is vital to avoid clinical decompensation. Treatment involves the physiological replacement of the relevant hormone deficiencies and requires close lifelong monitoring.[34]

Acquired GHD

A detailed history should be taken to assess for a postnatal acquired cause of GHD in every child with poor growth and short stature. Patients with acquired GHD after central nervous system (CNS) tumours or radiotherapy may sometimes be diagnosed only after planned investigations to assess the pituitary damage.

At presentation, most children with suprasellar tumours such as a craniopharyngioma and optic glioma have symptoms related to increased intracranial pressure, including headache, vomiting, and visual disturbances, because of the proximity of the sellar area to vital structures (ventricles, optic nerves, and chiasm).[13][14][15][36]​ Compared with adults, the incidence of headache, nausea or vomiting, and hydrocephalus are significantly higher in children with craniopharyngiomas.[15] Most patients also have other endocrine manifestations, particularly AVP-D, but these can be missed if not specifically looked for. Importantly, symptoms and signs of hormonal excess may also point to a secreting pituitary adenoma, most commonly a prolactinoma (e.g., galactorrhoea, oligo/amenorrhoea).

Certain lesions have a predisposition to causing specific endocrine dysfunction on top of GHD at diagnosis. The presence of AVP-D should also raise suspicion of other neoplastic lesions such as suprasellar germinoma, or infiltrative and inflammatory disorders such as Langerhans cell histiocytosis and, rarely, hypophysitis and sarcoidosis. Optic pathway gliomas (particularly in association with neurofibromatosis type 1) and hypothalamic hamartomas may present with central (gonadotrophin-dependent) precocious puberty, while human chorionic gonadotrophin (hCG)-secreting germ cell tumours may cause gonadotrophin-independent precocious puberty. Treatments causing damage to the hypothalamus and/or pituitary gland such as surgery and radiotherapy can further increase the risk of developing GHD.

Traumatic brain injury has been recognised as a cause of acquired GHD in adults, but there are limited data in children. Somatotroph cells are located in the wings of the pituitary gland. Their vascular supply comes from portal vessels and they are vulnerable to the disruption of blood supply after head injury. GHD is the most common deficiency seen after trauma.[17][18] Hormone deficiencies may be identified in the first days to weeks post-trauma (acute phase) or may develop over time (late effect). Because there is overlap between the symptoms and signs of hypopituitarism and those of neuropsychological sequelae, it is possible that late-evolving or partial deficiencies can remain undiagnosed for long periods.

Children with thalassaemia usually maintain their growth rate in childhood, with growth failure manifesting at puberty, leading to disproportionate short stature and truncal shortening. The anterior pituitary is sensitive to iron overload, and the gonadotroph cells seem to be particularly vulnerable. Failure of pubertal development and growth impairment are the most prominent endocrine complications and may occur despite early initiation of chelation. It is estimated that 56% of thalassaemic patients have at least one endocrinopathy, almost one half have hypogonadism (40% to 59%), and 33% to 36% manifest growth failure that is attributed to GHD in some patients.[19]

Pituitary tuberculosis is extremely rare and there may be other clinical features of the disease leading to the diagnosis. When the pituitary is involved, GHD is the most common endocrine abnormality. A previous history of meningitis or encephalitis should also be sought.

A full social history should be undertaken in all patients, particularly those who present with poor weight gain and faltering growth. Children who have been subjected to abuse and neglect present with short stature and a characteristic behavioural pattern that includes hyperphagia, abnormal eating habits that mimic organic compulsive eating disorders, vomiting, and polydipsia. They may have documented GHD that becomes reversible after removal from the abusive environment.[20]

Growth assessment

It is important to assess serial measurements plotted on a growth chart, which should be taken at a minimum interval of 6 months. Care must be taken to plot the height and weight based on the child's actual chronological age. Length should have been measured supine in infants until the age of 2 years and standing thereafter. Ideally, measurements should be made using a device such as a Harpenden stadiometer, and by the same measurer on consecutive occasions so as to reduce inter-observer error.[37]

Short stature in GHD is proportionate (involving both the torso and the lower extremities equally) and typically with a high weight-to-height ratio. Decreased or normal weight-to-height ratio may suggest chronic illness secondary to a CNS tumour, infection, or inadequate caloric intake due to psychosocial deprivation. Head circumference should also be plotted in children aged <3 years to detect hydrocephalus.

Growth is strongly related to genetic potential. A child's target height is calculated as follows:

  • Girl = (height of mother in cm + height of father in cm)/2 - 6.5 cm

  • Boy = (height of mother in cm + height of father in cm)/2 + 6.5 cm

Height in GHD typically crosses percentiles in the downward direction, reflecting an abnormally low growth velocity.

Initial investigations

Bone age

  • 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, but other methods such as knee examination may be more helpful in infants. Bone age may also be used to predict final height using the tables of Bayley and Pinneau.[38]

Thyroid function tests (TFTs)

  • Free thyroxine (FT4) and TSH should be measured in all children with poor growth to rule out hypothyroidism as the primary cause of short stature or to detect associated TSH deficiency.

IGF1 and IGFBP3

  • Values below -2 SDS, corrected for age and sex, are indicative of GHD; however, normal concentrations do not rule out GHD (e.g., in post-irradiation patients).[39][40] The concentrations can also be altered in hypothyroidism, malnutrition, and chronic diseases.

Pituitary function tests

  • Apart from the above, a full set of baseline pituitary function tests should be performed. This should include an 8 a.m. ACTH, cortisol, luteinising hormone, follicle-stimulating hormone, testosterone/oestradiol, and prolactin to look for potentially associated CPHD. The status of the hypothalamo-pituitary-adrenal axis must be known prior to embarking on more detailed GH provocation testing.

Basic haematology and biochemistry screen

  • 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, coeliac screen, and inflammatory markers (erythrocyte sedimentation rate, C-reactive protein) to exclude other causes.[41]​ See Assessment of short stature.

Additional investigations

GH provocation tests

  • The GH-IGF1 axis can be stimulated with various provocative agents such as insulin, glucagon, arginine, and clonidine. Various cut-offs have been used ranging between 5 to 10 micrograms/L (5-10 nanograms/mL), but GHD is generally defined in the UK as a value of <7 micrograms/L (<7 nanograms/mL) on two occasions.[1][42] The insulin tolerance test is considered the definitive test for assessing both the GH-IGF1 axis and the hypothalamo-pituitary-adrenal axis. However, the test can be extremely unsafe in infants and young children.[43] Growth hormone-releasing hormone (GHRH) should not be used where GH deficiency is suspected to be of hypothalamic origin, such as in patients with a history of radiotherapy.[44] Two provocation tests improve sensitivity. GH provocation tests are contraindicated in children aged under 1 year.

  • During puberty, GH concentrations are higher physiologically in children who do not have GHD. Both the British Society for Paediatric Endocrinology and Diabetes (BSPED) and the Pediatric Endocrine Society suggest that priming should be done in certain age groups (the BSPED recommends this in boys >10 years of age with testicular volumes of <6 mL and girls >9 years of age with Tanner stage B1-2).[42][45] However, practice across Europe remains inconsistent.[46]

  • Hypothyroidism must be excluded before GH testing.

  • 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] Guidance suggests that a random GH level of <5 micrograms/L (<5 nanograms/mL) in neonates with hypoglycaemia is associated with additional pituitary hormone deficits and/or an abnormal pituitary magnetic resonance imaging (MRI) scan.[42]​​

Neuroimaging

  • MRI of the brain helps 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.[3]

  • 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.

  • CT of the brain and x-ray of the skull may help to detect bony abnormalities and intracranial calcification (craniopharyngiomas).

Full pituitary evaluation

  • 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 CPHD should be further confirmed with TFTs (low FT4 and low or inappropriately normal TSH) and a suboptimal cortisol response to synthetic ACTH (tetracosactide) stimulation.

  • In older children, a low or inappropriately normal TSH with low FT4 concentrations indicates TSH deficiency. A routine thyrotrophin-releasing hormone (TRH) test is not routinely recommended.[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. ACTH deficiency can be diagnosed as a poor cortisol response after an insulin tolerance test or ACTH. In some patients, 24-hour plasma cortisol sampling may be necessary.[53] Stimulation of the testes with hCG in males at puberty may also be used to diagnose gonadotrophin deficiency.[54]

Specialist referral and other tests based on clinical evaluation

  • Patients with eye abnormalities should be referred to an ophthalmologist to rule out optic nerve hypoplasia/septo-optic dysplasia.

  • Patients with CNS 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.

Genetic studies

  • The role of genetics in congenital GHD diagnosis remains to be established, but is increasingly offered within the clinical rather than research setting. Next-generation sequencing technologies, which can analyse multiple genes simultaneously, have become more affordable and accessible, leading to an increase in their use in confirming a genetic diagnosis.[41] ​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.[11][55] However, detection of mutations may lead to early diagnosis of additional hormone deficiencies in those patients with mutations in genes where the hormonal phenotype is well established (e.g., PROP1, POU1F1 mutations).

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