Growth hormone deficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Isolated GH deficiency is the most common hormone deficiency of pituitary gland. There are three types of GH deficiency: congenital, acquired, and idiopathic. Congenital causes include genetic mutations in POU1F1, PROP-1, and GH-1 genes. Structural causes of GH deficiency includes optic nerve hypoplasia, agenesis of corpus callosum, septo-optic dysplasia, empty sella syndrome, and holoprosencephaly. Acquired causes of growth hormone deficiency include brain surgery, radiation therapy for brain tumors, central nervous system infection, craniopharyngioma, and pituitary adenoma. The somatotroph cells of the anterior pituitary gland produce growth hormone. During the development of the anterior pituitary gland, the temporal and spatial expression of early (Hesx1, Sox2, Sox3, Lhx3, Lhx4, Ptx1, Ptx2, and Otx2) and late (Prop1 and Pou1f1) transcription factors and signaling molecules has a major role in the pathogenesis of growth hormone deficiency(GHD). Growth hormone deficiency in children must be differentiated from other diseases that cause short stature in children such as Achondroplasia, constitutional growth delay, familial short stature, and growth hormone resistance. Prevalence and incidence data of growth hormone deficiency vary widely due to the lack of standard diagnostic criteria. Genetic screening of growth hormone deficiency is indicated for patients with early and severe symptoms. Common complications of growth hormone deficiency include osteopenia, dyslipidemia, delayed puberty, and higher mortality rates than normal subjects. Prognosis is generally good with treatment. Measurement of a random serum GH level alone is not helpful. Measurement of Insulin-like growth factor I (IGF-I) and Insulin-like growth factor binding protein-3 (IGFBP-3) is more helpful than GH level alone. GH stimulation tests are indicated for most patients suspected to have GHD. Growth hormone (GH) is indicated for children with GH deficiency whose epiphyses are open. Serum levels of insulin-like growth factor I (IGF-I) should be measured several weeks after beginning GH treatment or making a dose adjustment. GH side effects include headaches, Idiopathic intracranial hypertension, Slipped capital femoral epiphysis, worsening of existing scoliosis, Pancreatitis, and Gynecomastia.

In the mid 1940s, Li and Evans were the first to purify bovine GH. In 1981, Genentech developed the first recombinant human GH. In 1981, Genentech developed the first recombinant human GH for the therapy of severe childhood GHD. By 1985, GH extracted from human pituitary glands were used to treat growth hormone deficiency.

Growth hormone deficiency can be classified by cause into congenital type in which infants show symptoms such as hypoglycemia, neonatal growth failure, neonatal jaundice, and asphyxia or acquired type presents with severe growth failure, delayed bone age, delayed puberty, or Idiopathic growth hormone deficiency which defined as having a height significantly shorter than the normal population with no detectable cause for short stature.

The somatotroph cells of the anterior pituitary organ create development hormone (GH). The most widely studied impact of growth hormone is increasing weight. GH causes epiphyseal plate broadening and ligament development. GH inadequacy brings about changes in the physiology of various frameworks of the body, showing as modified lipid digestion, expanded subcutaneous instinctive fat, diminished bulk. The hereditary premise of inborn development hormone insufficiency relies upon numerous qualities, for instance, POU1F1 quality transformations are the most widely recognized hereditary reason for the joined pituitary hormone lack. Quality erasures, frameshift transformations, and jabber changes of GH1 quality have been portrayed as reasons for familial GHD.

Causes of growth hormone deficiency could be congenital or acquired. Congenital causes include genetic mutations in POU1F1, PROP-1, and GH-1 genes. Structural causes can cause growth hormone deficiency such as optic nerve hypoplasia, agenesis of corpus callosum, septo-optic dysplasia, empty sella syndrome, and holoprosencephaly. Acquired causes can cause growth hormone deficiency such as GHD following brain surgery and radiation therapy for brain tumors, central nervous system infection, craniopharyngioma, and pituitary adenoma.

Growth hormone deficiency in children must be differentiated from different infections that cause short stature in kids, for example, achondroplasia, constitutional growth delay, familial short stature, growth hormone resistance, Noonan syndrome, panhypopituitarism, pediatric hypothyroidism, Short stature accompanying systemic disease, psychosocial Short Stature, Silver-Russell Syndrome, Turner syndrome, and idiopathic short stature.

Prevalence and incidence data of growth hormone deficiency vary widely due to the lack of standard diagnostic criteria. Diagnosis of growth hormone deficiency is made during 2 broad age peaks; the first age peak occurs at 5 years. The second age peak occurs in girls aged 10-13 years and boys aged 12-16 years. There is no apparent racial difference in the incidence of GHD. In seventy-three percent of patients with idiopathic GHD, due to societies that concern more about males short stature than the females. Patients with GHD from organic causes such as tumors and radiation, in which no gender bias should be present, there was still 62% male.

There are no established risk factors for growth hormone deficiency.

Genetic screening of increase hormone deficiency(GHD) is indicated for patients with early and severe signs. GHD patients have been screened for mutations within the GH1 and GHRH gene. understanding of genetic contributions to GHD opens the opportunity for a greater affordable technique to the diagnosis and management of GHD.

If left untreated, patients with growth hormone deficiency can also development to develop delayed postnatal growth, delayed bone age, delayed puberty, infantile fat distribution, and infantile voice. common complications of growth hormone deficiency encompass osteopenia, dyslipidemia, delayed puberty, and higher mortality rates than regular subjects. prognosis is usually desirable with treatment. GH treatment can improve GH-deficient adults signs and symptoms. since recombinant DNA–derived growth hormone have become to be had, most children with growth hormone deficiency attain normal adult stature.

The hallmark of growth hormone deficiency is growth failure. The most common symptoms of GHD in infants are delayed Bone age, perinatal asphyxia, hypoglycemia, and jaundice. Adults symptoms include increased lean body mass, fractures of the lumbar spine, and osteopenia.

Patients with growth hormone deficiency usually look tired and less energetic than normal subjects. Extremities show Clubbing, muscle atrophy, neonatal jaundice, neonatal cyanosis. Head may show infantile facies, delayed dentition, and brittle hair. Children may show hyporeflexia and delayed puberty.

An immediate investigation should be started in severe short stature defined as a short child more than 3 standard deviations below the mean of children at the same age. Measurement of a random serum GH level alone is not helpful. Measurement of Insulin-like growth factor I (IGF-I) and Insulin-like growth factor binding protein-3 (IGFBP-3) is more helpful than GH level alone. GH stimulation tests are indicated for most patients suspected to have GHD. If the clinical and other laboratory criteria are sufficient to make the diagnosis of GHD, there is no need to perform the test. Pharmacologic stimuli include clonidine, glucagon, arginine, and insulin-induced hypoglycemia. Administration of sex steroids for a few days prior to the provocative GH testing reduces the chance of a false-positive result.

An x-ray may be helpful in the diagnosis of delayed bone age associated with growth hormone deficiency.

Pituitary CT scan may be helpful in the diagnosis of growth hormone deficiency if an MRI is not available. Brain CT of pituitary apoplexy is insensitive to the diagnosis of apoplexy unless intracranial hemorrhage is present. Brain CT of adrenal adenoma shows typically has attenuation similar to the brain and calcification is rarely found.

Brain MRI may be helpful in the diagnosis of growth hormone deficiency. On T1-weighted imaging, a clear demarcation can be made between the adenohypophysis and the neurohypophysis, which appears as hyperintense. Other pituitary abnormalities such as anterior pituitary hypoplasia, pituitary stalk agenesis, and posterior pituitary ectopia can be diagnosed using MRI.

There are no ultrasound findings associated with growth hormone deficiency.

There are no other imaging findings associated with growth hormone deficiency.

There are no other diagnostic studies associated with growth hormone deficiency.

Growth hormone (GH) is indicated for children with GH deficiency whose epiphyses are open. The dose for children is between 0.16 and 0.24 mg/kg/week, divided into once daily injections. Serum levels of insulin-like growth factor I (IGF-I) should be measured several weeks after beginning GH treatment or making a dose adjustment. GH side effects include headaches, Idiopathic intracranial hypertension, Slipped capital femoral epiphysis, worsening of existing scoliosis, Pancreatitis, and Gynecomastia. There is a possible role for GH in cancer risk.

Surgical intervention is not recommended for the management of growth hormone deficiency.

There are no established measures for the primary prevention of growth hormone deficiency.

Patients who are receiving growth hormone therapy should be followed up 2-4 times per year. Growth rate usually increases during the first year of treatment, with an average increase of 8-10 cm/y. A slow growth rate more than expected should be investigated to exclude other causes such as hypothyroidism or inflammatory bowel disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

In the mid 1940s, Li and Evans were the first to purify bovine GH. In 1981, Genentech developed the first recombinant human GH. In 1981, Genentech developed the first recombinant human GH for the therapy of severe childhood GHD. By 1985, GH extracted from human pituitary glands were used to treat growth hormone deficiency.

• In the mid 1940s, Li and Evans were the first to purify bovine GH at the University of California.^[1]
• In 1956, Li and Papkoff were the first to isolate growth hormone from the human pituitary gland at California University.
• In 1981, Genentech developed the first recombinant human GH for the therapy of severe childhood GHD. ^[2]
• By 1985, GH extracted from human pituitary glands were used to treat growth hormone deficiency.^[3]
• In 1985, treatment with GH extracts was stopped completely due to reports of four young adults in the United States with Creutzfeldt Jacob Disease who had been treated with GH.^[4]
• List of indications for GH use in non-GH-deficient children and adults have increased with time.^[5]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Growth hormone deficiency can be classified by cause into congenital, acquired or idiopathic. In the congenital type, infants show symptoms such as hypoglycemia, neonatal growth failure, neonatal jaundice, and asphyxia. In acquired type of growth hormone deficiency, patients present with severe growth failure, delayed bone age, delayed puberty. The Idiopathic growth hormone deficiency which is defined as having a height significantly shorter than the normal population with no attributable cause for short stature.

Growth hormone deficiency can be classified into 3 based on the cause into:

• Symptoms manifest on the first day of life however, in some cases symptoms do not present until 6 months of life.
• Congenital growth hormone deficiency can be classified into three subtypes:
  • Growth hormone deficiency IA: It is an autosomal recessive disease characterized by growth retardation in utero. Affected children are small in relation to their siblings. The infant has a normal response to administration of human growth hormone (hGH) at first, but then develops antibodies to the hormone and grows into a very short adult.^[1]
  • Growth Hormone Deficiency IB: It is also autosomal recessive and similar to IA. This is due to decreased levels of growth hormone (GH) present in the child at birth. This child continues to respond to GH treatments.^[2]
  • Growth Hormone Deficiency IIB and III: they are similar to IB, but IIB is autosomal dominant and III is X-linked.^[3]

• It may first appear in children or adults. Children with GHD present with severe growth failure, delayed bone age, delayed puberty, immature face with an underdeveloped nasal bridge, frontal bossing, sparse hair growth, and infantile fat distribution.^[4]
• Adults with GHD can be grouped into those who had prior childhood GHD, those who acquire GHD secondary to structural lesions or trauma, and those with idiopathic GHD. Childhood GHD is generally further divided into those with organic causes and those in whom the cause is unknown.^[5]

• Idiopathic growth hormone deficiency is defined as having a height significantly shorter than the normal population with no attributable cause for short stature.^[6]
• Idiopathic growth hormone deficiency is generally defined as having less than the calculated mid-parental height.
• The clinical and biological presentation of idiopathic growth hormone deficiency varies, demonstrating the variety of its pathogenic features.^[7]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

The somatotroph cells of the anterior pituitary organ produce growth hormone (GH). The most widely studied impact of growth hormone is increasing weight. GH causes epiphyseal plate broadening and ligament development. GH deficiency results in alterations in the physiology of different systems of the body, manifesting as altered lipid metabolism, increased subcutaneous visceral fat, decreased muscle mass, decreased bone density, low exercise performance, and reduced quality of life. The hereditary premise of inborn growth hormone deficiency relies upon numerous factors; POU1F1 quality transformations are the most widely recognized hereditary reason for the joined pituitary hormone lack. Quality deletions, frameshift transformations, and jabber changes of GH1 quality have been described as reasons for familial GHD.

• The somatotroph cells of the anterior pituitary gland produce growth hormone.^[1]
• They are regulated by two hypothalamic hormones; GH-releasing hormone (GHRH) stimulates and somatostatin inhibits them.

• GH increases body mass by:
  • Increasing total body protein content and is associated with an increase in amino acid incorporation into cartilage and bone.^[2]
  • Stimulation of lipolysis decreasing total body fat content.
  • Increasing bone mass by stimulating skeletal insulin-like growth factor-I, causing hypertrophy of osteoblasts, bone remodeling, and mineralization.
  • Decreasing the expression of adipocyte maturation regulators (C/EBPα, PPARγ) and prominent genes related to lipid synthesis such as FAS and FABP.
  • Increasing the mRNA expression of adiponectin and UCP1 in mature adipocytes causing epiphyseal plate widening and cartilage growth.^[3]

• GH deficiency results in alterations in the physiology of different systems of the body, manifesting as altered lipid metabolism, increased subcutaneous visceral fat, decreased muscle mass, decreased bone density, low exercise performance, and reduced quality of life.

• The secretion of growth hormone is controlled by a complex regulatory system. Primarily, it is controlled by two hormones; GH-releasing hormone and somatostatin.

• The adenylate cyclase–cyclic AMP–protein kinase A plays a major role in the control of GH secretion by GH-releasing hormone.
• GH gene expression is also of importance in determining the GH response.
• GH secretion is pulsatile; between pulses, serum GH concentration may be undetectable. It is thought that the pulses of GH release are mediated by the reduction in inhibition by somatostatin with an increase of GHRH.

• The glucocorticoids play a principal role in the functional maturation of GH cells in the fetal pituitary glands, inducing GH and GHRH-receptor gene expression, and development of the GH secretory system.
• During puberty, there is a temporary increase in GH secretion with a subsequent return to the normal values in early adulthood.

• Growth hormone acts by binding to the receptor homodimer in the liver.
• The receptor consists of an extracellular ligand-binding domain and a cytoplasmic signaling part.
• GH acts to stimulate hepatic synthesis and secretion of insulin-like growth factor-1 (IGF-1).
• IGF-1 is a protein responsible for most of the growth-promoting activities of GH.
• IGF-1 directly inhibits GH secretion and GH receptor function by a negative feedback effect.
• GH stimulates cell proliferation in osteoblasts. Human trabecular osteoblasts produce mainly IGF-II, IGFBP-3 and fewer quantities of IGF-I in culture.
• IGFs and their binding proteins may exert important regulatory effects on the GH effect on osteoblasts.

• A single GH molecule binds with two GH receptor molecules, followed by activation of JAK2 tyrosine kinase by phosphorylation.
• Phosphorylation of JAK2 leads to phosphorylation of intracellular proteins called STAT proteins, MAP kinase activation, and induction of gene expression.
• These STAT proteins are phosphorylated by JAK2 and directly translocated to the cell nucleus, where they play the major control of GH-specific gene effects by binding to nuclear DNA.
• STAT5 plays an important role in the regulation of expression of some genes in the liver cells.
• A defect in GH-mediated JAK-STAT signal transduction could be a cause of the GH resistance.

• This is the most common known genetic cause of the combined pituitary hormone deficiency.^[4]
• It is responsible for pituitary-specific transcription of genes for GH, prolactin, thyrotropin, and the growth hormone-releasing hormone (GHRH) receptor.^[5]
• PROP1 mutations result in failure to activate POU1F1/Pit1 gene expression and probably cause pituitary hypoplasia.^[6]

• GH1 gene encoding GH is located on chromosome 17.
• Gene deletions, frameshift mutations, and nonsense mutations of GH1 have been described as causes of familial GHD.

• Bioinactive GH has the main symptoms and signs of isolated GHD with normal basal GH levels and low insulin-like growth factor I concentrations.^[7]

• It is essential for normal signaling of the GH receptor. Mutations in the gene encoding signal transducer decrease the response of receptors to GH.^[8]

• Mutations in the gene encoding IGF-I cause a unique syndrome of GHD.^[9]
• Patients with IGF-I gene mutations have prenatal growth failure, microcephaly, significant neurocognitive deficits, and sensorineural hearing loss.

• Acid-labile subunit is important for the stabilization of the IGF-I.
• Mutations in the gene coding for it causes less stable and subsequently less effective end product.^[10]

• Mutations in the gene encoding the receptor for the IGF-I result in partial loss of function of the IGF-I receptor.^[11]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Causes of growth hormone deficiency could be congenital or acquired. Congenital causes can be genetic or structural. The genetic causes are due to genetic mutations in POU1F1, PROP-1, and GH-1 genes while the structural causes include optic nerve hypoplasia, agenesis of corpus callosum, septo-optic dysplasia, empty sella syndrome, and holoprosencephaly. Acquired causes of growth hormone deficiency include brain surgery and radiation therapy for brain tumors, central nervous system infection, craniopharyngioma, and pituitary adenoma.

It is usually recognized by the presence of affected relatives and confirmed by molecular testing for the causative genes, which include POU1F1, PROP-1, and GH1:

• The POU1F1 gene is responsible for pituitary-specific transcription of genes for GH, prolactin, thyrotropin, and the growth hormone-releasing hormone (GHRH) receptor.^[1]
• PROP1 mutations result in failure to activate POU1F1/Pit1 gene expression and probably cause pituitary hypoplasia and familial multiple pituitary hormone deficiencies.^[2]
• Gene deletions, frameshift mutations, and nonsense mutations of GH1 which codes for GH, have been described as causes of familial GHD.^[3][4]

• GHD is highly likely to be permanent in these patients
• It is associated with midline craniofacial anomalies causing agenesis of the hypothalamic-pituitary stalk:^[5]
  • Optic nerve hypoplasia
  • Midline facial defects
  • Agenesis of corpus callosum
  • Arachnoid cyst
  • Holoprosencephaly
  • Septo-optic dysplasia
  • Encephalocele
  • Empty Sella syndrome
  • Hydrocephalus

• GHD following brain surgery and radiation therapy for brain tumors. Permanent GHD is highly likely to be permanent in infants or young children^[6]
• Central nervous system infection^[5]
• Pituitary adenoma^[7]
• Craniopharyngioma
• Rathke’s cleft cyst
• Glioma/astrocytoma
• Germinoma
• Infiltrative/granulomatous disease:^[8]
  • Langerhans cell histiocytosis
  • Sarcoidosis^[9]
  • Tuberculosis
  • Hypophysitis^[10]
• Surgery of the pituitary or hypothalamus^[11]
• Sheehan’s syndrome^[12]
• Idiopathic

• This is the most common known cause of genetically-mediated growth hormone insensitivity (GHI).^[13]
• Growth hormone insensitivity is an absence of the effects of growth hormone despite a normal production of GH.
• Laron syndrome is characterized by growth failure and normal levels of GH.
• It is caused by mutations in the growth hormone receptor gene which affects the GH-binding of the receptor.
• Its severity correlates to IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3) levels.

Haleigh Williams, B.S. Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Growth hormone deficiency in children must be differentiated from other diseases that cause short stature such as: Achondroplasia, constitutional growth delay, familial short stature, growth hormone resistance, Noonan Syndrome, Panhypopituitarism, pediatric hypothyroidism, short stature accompanying systemic disease, psychosocial short stature, Silver-Russell Syndrome, Turner Syndrome, and idiopathic short stature.

Growth hormone deficiency in children must be differentiated from other diseases that cause short stature. Short stature is defined as the height that is 2 standard deviations(SD) or more below the mean height for children of that sex and chronological age in a given population.^[1] Theses causes include:

• Achondroplasia
• Constitutional growth delay
• Familial short stature
• Growth hormone resistance
• Noonan syndrome
• Panhypopituitarism
• Pediatric hypothyroidism
• Short stature accompanying systemic disease
• Psychosocial short stature
• Silver-Russell syndrome
• Turner syndrome
• Idiopathic short stature

Diseases	History and symptoms	Physical Examination				Laboratory findings
		Puberty development	Height velocity	Parents height	Characteristic facies	Bone age	Genetic analysis	GH level
Growth hormone deficiency[2]	Children: delayed developmental milestones and muscle weakness Adults: increased lean body mass, osteopenia, and dyslipidemia	Delayed	Decreased	Normal	Doll-like fat distribution pattern Immature face with under developed nasal bridge Infantile voice	Delayed	POU1F1 gene mutations  GH1 gene mutations	Low
Achondroplasia[3]	Normal Intelligence quotient A trunk of average size Arms and legs of diminished length Spinal stenosis Kyphosis and lordosis	Normal	Decreased	Decreased	Large heads Prominent forehead Midface hypoplasia	Delayed	FGFR3 gene mutations	Normal
Familial short stature[4]	A normal variant with normal signs, investigations. Positive family history	Normal	Decreased	Decreased	Normal	Normal	Heterozygous IGF1 Splicing mutation	Normal
Constitutional growth delay[5]	Family history of delayed growth spurt and puberty Childhood short stature but relatively normal adult height Normal size at birth A delayed growth rate begins at three to six months of age A family history of delayed growth and puberty in one or both parents	Delayed .	Normal	Normal	Normal	Normal	Mutations in Variation in FGFR1, GNRHR, TAC3, and TACR3 genes	Normal
Growth Hormone Resistance[6]	Growth hormone insensitivity is an absence of the biological effects of growth hormone despite a normal production of GH. Its severity correlates to IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3) levels.	Delayed	Decreased	Normal	Small face in relation to head circumference Delayed dentition	Delayed	Growth hormone receptor mutations IGF-I gene mutations	Normal
Pediatric hypothyroidism[7]	Low muscle tone Cold intolerance Persistent constipation Fatigue and weaknessExcessive sleeping Exaggerated jaundice	Delayed	Decreased	Normal	Puffy face Macroglossia Large fontanels Micrognathia	Delayed	Mutations in: Paired box 8 (PAX8) Thyroid Transcription factor-2 (TTF2) Transcription factors NK2	Normal
Turner syndrome[8]	Females only Infertility Webbed neck Widely spaced nipples Broad chest Genu valgum Short neck Ovarian failure	Absent	Decreased	Decreased	Low hairline Low-set ears Characteristic facial features	Normal	45 X0	Normal
Silver-Russell Syndrome[9]	Hemihypertrophy Hypoglycemia Wide fontanelle Clinodactyly Precocious puberty	Delayed	Decreased	Decreased	Prominent forehead Triangular face Downturned corners of the mouth Small jaw Pointed chin	Normal	Methylation involving the H19 and IGF2 genes	Normal
Noonan syndrome[10]	Bleeding tendency Webbed neck Cryptorchidism Intellectual disability	Delayed	Decreased	Decreased	Minor facial dysmorphism	Normal	PTPN11 and SOS1 genes abnormality	Normal
Psychosocial short stature[11]	A disorder of short stature or growth that is observed in association with emotional deprivation A disturbed relationship between child and caregiver is usually noted. A history of abuse or neglect and emotional deprivation The relationship between the caregiver and the child appears to be abnormal.	Delayed	Decreased	Normal	Failure to thrive Poor dental hygiene Sad Affect	Normal	Normal	Maybe low
Short stature accompanying systemic disease[12]	Growth failure is seen in children with systemic diseases such as chronic kidney disease, malignancy, Chron’s disease, and Cushing disease. The primary causes of growth failure in children include metabolic acidosis, poor nutrition secondary to dietary restrictions, disturbances of growth hormone metabolism and its main mediator, insulin-like growth factor-I (IGF-I).	Delayed	Decreased	Normal	Failure to thrive	Delayed	Normal	Normal
Idiopathic short stature[13]	A height below 2 standard deviations (SD) of the mean for age, in the absence of any endocrine, metabolic, or other diagnosis	Normal	Decreased	Normal	Normal	Delayed	SHOX gene mutations[14]	Normal

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Prevalence and incidence data of growth hormone deficiency vary widely due to the lack of standard diagnostic criteria. Diagnosis of growth hormone deficiency is made during 2 broad age peaks; the first age peak occurs at 5 years. The second age peak occurs in girls aged 10-13 years and boys aged 12-16 years. There is no apparent racial difference in the incidence of GHD. In societies that concern more about male short stature than the females, 73% of males were found to have idiopathic GHD. When GHD is caused from organic causes such as tumors and radiation, in which no gender bias should be present, there was still 62% male.

• Prevalence and incidence data vary widely due to the lack of standard diagnostic criteria.^[1]
• The incidence of persistent GHD is 12.0%.^[2]
• There is no significant difference in the incidence of pituitary hypoplasia between the patients with persistent and transient GHD.

• Seventy-three percent of patients with idiopathic GHD occur in societies that care a lot about short stature of males more than females.^[3]
• Prevalence of GHD from organic causes such as tumors and radiation is 62% male.
• A survey of pediatric endocrinologists show that growth hormone treatment was 1.3 times more common in boys than in girls.^[4]

• Growth hormone deficiency has a bimodal distribution; the first age peak occurs at 5 years.
• The second age peak occurs in girls aged 10-13 years and boys aged 12-16 years.
• Congenital GHD and most cases of idiopathic GHD are thought to be present from birth, diagnosis is often delayed until the patient’s short stature is noticed in relation to their peers.

• There is no racial predilection of growth hormone deficiency.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

The risk factors for growth hormone deficiency is due to the mutations involving the POU1F1 gene, GH1 gene, IGF-I gene. GH receptor signal transduction, syndrome of bioinactive GH and growth hormone insensitivity.

• Growth hormone insensitivity is an absence of the effects of growth hormone despite a normal production of GH.^[1]
• It is caused by mutations in the growth hormone receptor gene which affects the GH-binding of the receptor.
• Its severity correlates to IGF-I and insulin-like growth factor-binding protein 3 (IGFBP-3) levels.

• It is the most common known genetic cause of the combined pituitary hormone deficiency.^[2]
• It is responsible for pituitary-specific transcription of genes for GH, prolactin, thyrotropin, and the growth hormone-releasing hormone (GHRH) receptor.^[3]
• PROP1 mutations result in failure to activate POU1F1/Pit1 gene expression and probably cause pituitary hypoplasia.^[4]

• It is GH1 is the gene encoding GH, located on chromosome 17.
• Gene deletions, frameshift mutations, and nonsense mutations of GH1 have been described as causes of familial GHD.

• Bioinactive GH has the main symptoms and signs of isolated GHD with normal basal GH levels and low insulin-like growth factor I concentrations.^[5]

• It is essential for normal signaling of the GH receptor. Mutations in the gene encoding signal transducer decrease the response of receptors to GH.^[6]

• Mutations in the gene encoding IGF-I cause a unique syndrome of GHD.^[7]
• Patients with IGF-I gene mutations have prenatal growth failure, microcephaly, significant neurocognitive deficits, and sensorineural hearing loss.

• Acid-labile subunit is important for the stabilization of the IGF-I.
• Mutations in the gene coding for it causes less stable and subsequently less effect.^[8]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

Genetic screening of growth hormone deficiency(GHD) is indicated for patients with early and severe symptoms. GHD patients have been screened for mutations in the GH1 and GHRH gene. Understanding the genetic contributions to GHD opens the possibility for a more reasonable approach to the diagnosis and management of GHD.

• Genetic screening indications:^[1]
  • Early onset of growth failure
  • Positive family history and possible consanguinity
  • Height of 3 standard deviations or more below the mean
  • Extremely low GH response to provocation tests, including GHRH, and very low IGF-I and IGF-binding protein-3 (IGFBP-3) levels

• GHD patients have been screened for mutations in the GH1 and GHRH gene.^[2]

• A recent study recommended testing for GH1 and GHRH mutations in children with severe GHD and a family history of GHD.^[3]
• The patient with the HMGA2 mutation had severe short stature, low IGF-I, abnormal response to GH stimulation testing, and abnormal MRI, and responded well to growth hormone therapy.^[4]
• The importance of the HMGA2 gene in growth has been described through a study of patients with 12q14 microdeletion syndrome, which is characterized by developmental delay, severe short stature, and abnormal facies.^[5]
• Testing for a polymorphism in the IGFBP-3 gene may also aid in the diagnosis of GHD and prediction of response to therapy. ^[6]

• Understanding the genetic basis of GHD opens the possibility for a more advanced approach to the diagnosis and management of GHD.^[7]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammed Abdelwahed M.D[2]

If left untreated, patients with growth hormone deficiency may progress to develop delayed postnatal growth, delayed bone age, delayed puberty, infantile fat distribution, and infantile voice. Common complications of growth hormone deficiency include osteopenia, dyslipidemia, delayed puberty, and higher mortality rates than normal subjects. Prognosis is generally good with treatment. GH treatment can improve GH-deficient adults symptoms. Since recombinant DNA–derived growth hormone became available, most children with growth hormone deficiency reach normal adult stature.

• The symptoms of growth hormone deficiency usually develop in the first days of life and start with symptoms such as perinatal asphyxia, neonatal hypoglycemia, reduced birth length, and prolonged jaundice especially if associated with ACTH deficiency. If left untreated, patients with growth hormone deficiency may progress to develop delayed postnatal growth, delayed bone age, delayed puberty, infantile fat distribution, and infantile voice.

• Increased risk of recurrent illnesses when compared to their counterparts

• Fractures of the lumbar spine are somewhat lower in patients with adult-onset GH deficiency^[1]
• The degree of osteopenia appears to correlate directly with the degree of GH deficiency^[2]

• Cardiovascular complications:
  • Dyslipidemia^[3]
  • Increased inflammatory markers (ESR)^[4]
  • Increased biochemical markers of endothelial dysfunction^[5]
  • High coronary calcium scores (a marker of subclinical atherosclerosis)

• Mortality
  • Patients with growth hormone deficiency have a mortality rate twice that of normal subjects, a difference due to an increased number of cardiovascular events.^[6]

• Recombinant DNA–derived growth hormone has significantly improved the prognosis of growth hormone deficiency.^[7]
• If initiated early, children with growth hormone deficiency tend to achieve normal height potential.

• In the first year of treatment, the growth rate may increase from half as fast as other children are growing to twice as fast.

• Growth typically slows in the following years but remains above normal.
• As a result, the treated child may grow into the normal height range. Excess adipose tissue may be reduced.
• The SOCS2 polymorphism is a genetic marker that could identify among GH-treated patients who are predisposed to have less favorable outcomes.^[8]

• GH treatment can improve symptoms such as lack of energy and can improve bone density.
• Muscle mass may increase with decreased adipose tissue.^[9]
• Adults with hypopituitarism have been shown to have a reduced life expectancy and a cardiovascular mortality rate more than normal.^[6]
• Treatment has not improved mortality even after improved blood lipid levels.^[10]
• Rates of fractures have not been shown to improve, although, bone density improve with treatment.

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