History and exam
Key diagnostic factors
common
short stature
The following parameters in a child warrant investigations for GHD:[12][30] severe short stature (height >3 standard deviation scores [SDS] below mean for population); height SDS >1.5 SDS below target height SDS; height >2 SDS below mean in combination with a growth velocity over 1 year of >1 SDS below mean, a decrease in the height SDS of >0.5 over 1 year in children >2 years of age.
Short stature in GHD is proportionate (involving both the torso and the lower extremities equally) and typically with a high weight-to-height ratio.
poor growth velocity
The following parameters should warrant referral for investigations of GHD:[12][30] height >2 standard deviation scores (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 >2 years of age; height velocity >2 SDS below mean over 1 year or >1.5 SDS over 2 years in the absence of short stature. Growth failure may even occur in early infancy.[31][32]
short for target height
A height standard deviation score (SDS) >1.5 SDS below target height SDS should be investigated for GHD.[30] 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.
absent pubertal growth spurt ± delayed puberty
uncommon
central nervous system (suprasellar) tumor symptoms
At presentation most children with suprasellar tumors 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).
Compared with adults, the incidence of headache, nausea or vomiting, and hydrocephalus are significantly higher in children with craniopharyngiomas.[13][14][15][38]
A large head due to hydrocephalus may be present.
symptoms of other pituitary hormone dysfunction
Adrenocorticotropic hormone deficiency may present with lethargy, poor feeding, recurrent infections with prolonged recovery, apnea, hypoglycemia (can also occur in isolated GHD), and hyponatremia without hyperkalemia. Thyroid-stimulating hormone deficiency may present with lethargy, temperature instability, prolonged neonatal jaundice, constipation, and weight gain. Gonadotropin deficiency may present with a small penis (can also occur in isolated GHD) and undescended testes, and delayed or arrested puberty. Diabetes insipidus will present with polyuria, polydipsia, or secondary nocturnal enuresis. With acquired sellar/suprasellar lesions, signs of hormonal excess may also be seen, such as central precocious puberty or galactorrhea.
characteristic facial appearance
The characteristic facial appearance of congenital GHD includes midfacial hypoplasia, delayed dentition, and frontal bossing. Patients have a reduced lean body mass and increased total body fat. However, the condition is highly variable with respect to clinical presentation.
Other diagnostic factors
uncommon
assisted birth
Instrumental delivery is more common.[31]
visual impairment
Present with varying severity in patients with optic nerve hypoplasia or may occur after suprasellar tumors (e.g., craniopharyngioma or optic gliomas).
associated dysmorphic features
Include nasal and ocular defects with holoprosencephaly, single central incisor, cleft lip and palate, hypospadias, and eye defects.
Additional abnormalities such as limited neck rotation or cerebellar symptoms may point toward specific genetic defects (LHX3, LHX4 mutations).[12]
focal neurologic deficits
May be seen with acquired GHD after central nervous system tumors or trauma.
hyperphagia/obesity
Symptom of hypothalamic dysfunction commonly seen in patients with midline defects, suprasellar lesions, or those with extensive hypothalamo-pituitary surgery.
temperature dysregulation/sleep disorder
Symptom of hypothalamic dysfunction commonly seen in patients with midline defects or those with extensive hypothalamo-pituitary surgery.
behavioral problems
Children who have been subjected to abuse and neglect present with short stature and a characteristic behavioral pattern that includes hyperphagia, bizarre eating habits that mimic organic compulsive eating disorders, vomiting, and polydipsia.[55] They may have documented GHD that becomes reversible after removal from the stressful environment.
Risk factors
strong
family history of GHD
GHD may be sporadic or familial. Between 5% and 30% are familial cases and there are 6 defined types of isolated GHD: type IA, type IB, and types II-V. These may be due to mutations in GH1, GHRHR, SOX3, BTK, or RNPC3.[25][26][27][28] Familial GHD combined with other pituitary hormone deficiencies may be due to mutations in a rapidly expanding list of genes.[7][8][9][12]
other pituitary hormone deficiencies
Diagnosis of another pituitary hormone deficiency should warrant testing for GHD. Somatotropes, the cells synthesizing GH, constitute 40% to 50% of the pituitary gland cell population and are usually first to be involved in any congenital or acquired form of hypopituitarism.
central nervous system (CNS) tumors/cysts
Tumors and other lesions in the hypothalamo-pituitary area may cause GHD either directly as a result of direct pressure of the expanding mass on the anterior pituitary cells and, in cases of hypothalamic and stalk involvement, secondary to reduced synthesis and transport of hypothalamic-releasing hormones, or secondary to treatment (surgery, radiation therapy).[13][14][15]
radiation therapy
Irradiation for CNS tumors (locally and distally) and CNS irradiation for hematologic malignancies and bone marrow transplant can result in GHD; the risk increases when the dose is directed to the hypothalamus and pituitary gland.[16]
midline abnormalities
Septo-optic dysplasia (SOD) is a rare congenital heterogeneous anomaly characterized by any 2 of 3 features: midline forebrain defects, optic nerve hypoplasia (ONH), and hypopituitarism (62% of patients). GHD is the most common endocrine abnormality.[2][29]
Abnormal cleavage of the forebrain leading to holoprosencephaly (HPE) is also associated with abnormalities of corpus callosum, hypothalamus, and pituitary gland. Although diabetes insipidus is the most common endocrine abnormality, anterior pituitary hormone deficiencies may be associated.
Other midline defects that increase the risk of pituitary hormone dysfunction include anencephaly, single central incisor, cleft lip and palate, hypospadias, eye defects, Rieger syndrome, and Pallister-Hall syndrome.
weak
CNS infiltrative disorders
Includes Langerhans cell histiocytosis, sarcoidosis, or autoimmune lymphocytic hypophysitis. Diabetes insipidus and GHD are the most common endocrine manifestations of these chronic diseases.
perinatal complications
Perinatal complications such as prematurity, gestational bleeding, complicated delivery, fetal distress, or asphyxia may also be risk factors.[6] However, there is controversy over whether these are true risk factors or complications of hypopituitarism.
CNS trauma
Pituitary damage may occur after traumatic brain injury (e.g., road traffic accidents, nonaccidental injury) or after neurosurgery. The rich vascular network of the hypothalamus and pituitary and the structure of the pituitary stalk make it vulnerable to the effects of trauma. Hormone deficiencies may be identified in the first days to weeks post trauma (acute phase) or may develop over time (late effect). GHD seems to be the main permanent endocrine sequela, followed by gonadotropin deficiency.[17][18]
preexisting iron overload disorder
Includes hemochromatosis, thalassemia, and other diseases requiring chronic transfusions. The anterior pituitary is sensitive to iron overload resulting in defective GH secretion, reduced responsiveness of GH to growth hormone-releasing hormone (GHRH), and hypogonadotropic hypogonadism. 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 thalassemic patients have at least one endocrinopathy; almost one half have hypogonadism (40% to 59%), and 33% to 36% manifest growth failure.[19]
child abuse
Children subjected to chronic and severe abuse and neglect can present with short stature and a behavioral pattern that includes hyperphagia, vomiting, and polydipsia. On testing, they may also demonstrate GHD that is reversible after removal from the stressful environment.[20]
CNWS infections
Tuberculous meningitis or an intracranial tuberculoma commonly affect GH either in isolation (30%) or in combination with gonadotropin deficiency (40%). Other rare infective causes include bacterial or viral meningitis, encephalitis, and a pituitary abscess.
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