Growth Hormone Deficiency

Vijayakumar Madhava
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Growth Hormone Deficiency
Growth hormone deficiency is not a single disease, but is a group of different disorders with different causes. It can present as isolated GH deficiency or associated with other anterior and posterior pituitary hormone deficiencies. Some may have various extra pituitary features like optic nerve hypoplasia and midline defects. Majority remains as idiopathic but more and more cases are being diagnosed as due to genetic defects. Mutations of the genes encoding the transcriptional factors cause the major bulk of GH deficiencies.
As per the current studies, the incidence varies from 1 in 4000 to 1 in 10000 live births. Familial cases account for 5- 30% of all cases. (Table 1)

Table 1: Genetic disorders presenting with growth hormone deficiency
Genetic forms Hormones affected Other features Inheritance
POU1F1 ( PIT1) GH,TSH,PRL Manifestations limited to pituitary gland AR
PROP1 GH,TSH,PRL,LH,FSH,ACTH Manifestations limited to pituitary gland AR
LHX3 GH,TSH,PRL,LH,FSH Short neck, limited neck rotation AR
LHX4 GH,TSH,ACTH, Arnold chiari malformation, cerebellar abnormalities AD
HESX1 Variable deficiencies Septo optic dysplasia AR,AD
SOX2 GH Anophthalmia, learning difficulties, esophageal atresia  
SOX3 Variable deficiencies Mental retardation XR
GLI2 Variable deficiencies Holoprosencephaly, midline defects AD
GLI3   Pallister – Hall syndrome AD
SHH   Single central incisor AD
Isolated Growth hormone deficiencies (IGHD)
GHRHR GH   AR
GH1 defects
Type 1 A
GH- severe short stature Anti GH antibodies on treatment AR
GH1 – type 1B GH – less severe short stature Good response to treatment AR
GH1- type ii GH- less severe short stature   AD
GH 1 – type iii GH hypogammaglobulinemia XL



Acquired causes of GH deficiency (Table 2)
1. Any lesion that damages pituitary gland, pituitary stalk and/or hypothalamus can cause hypopituitarism. They usually cause multiple pituitary hormone deficiencies. Posterior pituitary gland involvement leading to diabetes insipidus is more common in acquired hypopituitarism. Somatotropes are most vulnerable to radiation injury and pressure effects, followed by gonadotropes and thyrotropes. Hence growth failure is the commonest endocrine manifestation followed by pubertal disorders and hypothyroidism in such cases.
2. Traumatic brain injury: Brain trauma causes pituitary hormone deficiency by hampering the blood supply to the pituitary stalk or causing direct injury to the pituitary gland, stalk or hypothalamus. Perinatal trauma results in isolated or multiple pituitary hormone deficiencies. Hypopituitarism is more commonly seen in children born after breech extraction, forceps deliveries, prolonged labor and babies who have suffered hypoxic attacks. In children, GH deficiency is reported following child abuse, road traffic accidents and after intra cranial bleeds.
3. CNS tumors: midline brain tumors like craniopharyngioma, germinoma, glioma and meningioma produce hypothalamic or pituitary insufficiency. They will have associated features of raised intracranial tension, visual defects and visual field defects. Craniopharyngioma produce panhypopituitarism.
4. Cranial irradiation: cranial irradiation directly impairs hypothalamic or pituitary functions. Irradiation at a low dose radiation results in isolated growth hormone deficiency and high dose produce multiple pituitary hormone deficiencies. After 5 years of radiotherapy almost all children who received > 3000 cGy over three weeks have developed growth hormone deficiency.
5. CNS infections: inflammation of the brain resulting from bacterial, viral or fungal infections can produce hypopituitarism. Among bacteriae, Mycobacterium tuberculosis, H- influenza and Group – B- Streptococcus predominate.
6. Systemic diseases: Various systemic diseases like sarcoidosis, SLE, autoimmune thyroiditis and Langerhans cell histiocytosis (LCH) can produce hypophysitis leading to hypopituitarism. Diabetes insipidus is the commonest endocrinopathy caused by LCH.
7. Hemolytic anemia: Iron overload in hemolytic anemia like thalassemia causes hypopituitarism leading to growth delay and pubertal development.

Table 2: Causes of acquired hypopituitarism
Lesions Examples
Tumors Craniopharyngioma, germinoma, optic glioma, dysgerminoma, ependymoma, meningioma, pituitary adenoma
Radiotherapy Radiotherapy of CNS tumors, cranial irradiation in hematological malignancies, BMT
Brain Trauma Birth injuries(breech extraction, forceps), Traumatic brain injuries (Road traffic accidents, child abuse), subarachnoid hemorrhage , post neurosurgery
Infection & inflammation Pyogenic meningitis, tuberculous meningitis, viral encephalitis, sarcoidosis, autoimmune conditions (SLE, thyroiditis)
Infiltration Langerhans cell histiocytosis
Iron overload: thalassemia, hemochromatosis
Psychosocial deprivation Cause functional but reversible pituitary deficiency


A neonate with hypopituitarism presents with non-specific features like poor feeding, lethargy, apnea, poor weight gain, jitteriness or seizures. Useful clinical features are as follows (TABLE 3):

Table 3: Common clinical features of Hypopituitarism in a neonate
Clinical presentation Possible cause
Hypoglycemia Associated ACTH deficiency
Temperature instability TSH deficiency
Prolonged unconjugated hyperbilirubinemia TSH deficiency
Conjugated hyperbilirubinemia Cortisol deficiency
Microphallus GH deficiency, Gonadotropin (LH) deficiency
Undescended testes Gonadotropin deficiency
Diabetes insipidus (rare) Associated midline defects


Clinical features- Childhood

Majority of affected children present with short stature. Most of the babies have normal birth weight and length. By 6 months of age, clinically appreciable growth faltering is seen and by the age of 2 years, they will be shorter than their peers, severity increases as the age advances. Their body proportions are normal for age. The following auxilogical criteria warrant investigations for GH deficiency:
• Severe short stature (height more than3 SD below the mean) for the population
• Height more than 2 SD below the mean for population with a growth velocity over 12 months more than 1 SD (25th percentile) below the mean
• Height SD more than 1.5 SD below the mid parental height
• Height velocity more than 2SD below the mean over 1 year or more than 1.5 SD below the mean for 2 years
• Other anterior pituitary hormone deficiencies ( central hypothyroidism, DI, micropenis)
• Neonatal symptoms and signs of growth hormone deficiency
• Signs indicative of an intra cranial lesion

Boys usually present with micropenis even in isolated GH deficiency. Some may have associated gonadotropin deficiency. The latter also present with arrested pubertal growth and delayed puberty. Delayed development and mental retardation are rare manifestations of GH deficiency. They denote associated central hypothyroidism, prolonged untreated neonatal hypoglycemia or a birth injury. Prolonged DI with electrolyte imbalances also produces brain damage. Infants have poor development of musculature, resulting in some delay in attaining gross motor mile stones. Facial bone growth is retarded (mid facial hypoplasia) and nasal bridge is under developed. Fontanels close late. Growth of the skull is normal in relation to face resulting in cephalofacial disproportion and appearance of relatively large head. Voice remains infantile (high pitched) because of the hypoplasia of larynx. Eyes are prominent and often protuberant. Teeth are crowded and erupt late. Hands and feet are small. The characteristic facial appearance is often called as “doll like appearance”. Features of diabetes insipidus, presenting as polyuria and polydipsia are rare, and they will have associated midline defects such as septo-optic dysplasia or holoprosencephaly. Occasionally these symptoms may be an initial manifestation of LCH. Even though many cases are described with truncal obesity, such a presentation is rare in Indian scenario. Presence of midline abnormalities like single upper central incisor, cleft palate, impaired vision and nystagmus are features of genetic forms of GH deficiency. Please refer to table 1.


References
Growth Hormone Deficiency Growth Hormone Deficiency 4/4/2016
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