A child with GHD is usually of normal size at birth. In a few cases, the infant may become hypoglycemic (low blood sugar) during the newborn period. If male, the child may also have a small penis (micropenis). Later, children with GHD have delayed rates of development of facial bones, slow tooth eruption, delayed lengthening of long bones, fine hair, and poor nail growth. They may also demonstrate truncal obesity, a high pitched voice, and delayed closure of the sutures of the skull, leaving open spaces called fontanelles.
Growth increments are the most important criteria in the diagnosis of GHD in children. Normal levels of growth usually follow a pattern, and if growth during a recorded six to twelve month period is within those levels it is unlikely that a growth disorder exists.
Growth in the first six months of life is usually 16 to 17 cm. and in the second six months approximately 8 cm. During the second year 10 cm or more is normal. Growth in the third year should equal 8 cm or more and 7 cm in the fourth year. In the years between four and ten, an average of 5 or 6 cm is normal. Ten percent decrease in these norms results in a growth velocity insufficient for the child to keep up on his or her growth curve. When that is recognized, even before the child has fallen to a significantly low percentile (1.2% = -2 SD), he/she should then be tested for abnormally low levels of growth hormone.
An individual who acquires GHD later in life presents more generalized symptoms. They may notice a relative increase in fat mass, especially abdominal and visceral, along with a decrease in muscle mass. Decreased energy levels, anxiety, and/or depression are also common. Lipid levels are also affected, resulting in an increase in LDL-cholesterol and triglyceride levels.
Congenital GHD results from genetic error, and may be associated with brain structure defects or with midline facial defects such as a cleft palate or single central incisor.
Several genetic defects have been identified:
Growth hormone deficiency IA is autosomal recessive and is characterized by growth retardation in utero. Affected children are small in relation to their siblings. The infant usually 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.
Growth Hormone Deficiency IB is also autosomal recessive and is similar to IA. However, there is some growth hormone (GH) present in the child at birth and usually the child continues to respond to hGH treatments.
Growth Hormone Deficiency IIB and III are similar to IB, but IIB is autosomal dominant and III is X-linked.
Classic genetic diseases are the product of the interaction of two genes, one received from the father and one from the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.
X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with X-linked disorders is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Acquired GHD can occur as a result of many different causes including brain trauma (perinatal or postnatal), central nervous system infection, tumors of the hypothalamus or pituitary (pituitary adenoma, craniopharyngioma, Rathke’s cleft cyst, glioma, germinoma, metastases), radiation therapy, infiltrative diseases (Langerhans cell histiocytosis, sarcoidosis, tuberculosis), or, if without another diagnosis, it is considered idiopathic.
Prevalence and incidence data vary widely due to the lack of standard diagnostic criteria. While 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. Diagnosis most often occurs during two age ranges. The first is around 5 years of age when children begin school. The second is around 10-13 years old in girls and 12-16 years in boys associated with the delay in the pubertal growth spurt.
There is no apparent racial difference in the incidence of GHD. However, the National Cooperative Growth Study (NCGS), Genentech’s now closed large North American database, revealed that 85% of patients receiving GH treatment for idiopathic GHD were white, 6% were black, and 2% were Asian. Similar distributions were seen with patients with other forms of short stature. In addition, patients from other racial groups tend to be shorter than their white counterparts at the time of diagnosis, reinforcing the assertion of, if not racial, a socio-economic disparity.
Growth hormone deficiency affects males and females equally except for GHD III which affects only males. However, given the greater concern for boys with short stature in most societies, diagnosis tends to favor males over females. 73% of patients with idiopathic GHD in the NCGS were male. Additionally, patients with GHD from organic causes such as tumors and radiation, in which no gender bias should be present, were still 62% male.
Testing is very important in determining whether the child with growth retardation does indeed have growth hormone deficiency. Various agents may be used including insulin (hypoglycyemia), arginine, clonidine and l-dopa. These tests are meant to stimulate the pituitary to secrete GH allowing for the testing of blood samples for the levels of GH at timed intervals.
Physicians often test for other hormone deficiencies that may be the underlying cause of short stature. FreeT4, TSH, cortisol, celiac antibodies, etc. are measured to ensure they are within normal levels and deficiencies must be normalized with appropriate therapy before GHD can be diagnosed.
IGF-1, a protein produced primarily by the liver but present in all tissues in response to GH stimulation, can be measured to screen for GHD and later to titrate GH therapy.
Children with severe GHD should be re-tested after completing growth to see if they meet the requirements for GH therapy as an adult.
When a diagnosis of GHD is made, treatment may then be initiated. Children with GHD should be started on recombinant human growth hormone as soon as the disorder is recognized to optimize growth potential. The dosage is gradually increased to its highest during puberty, and discontinued at or near completion of skeletal maturation when the patient may require retesting to see if GH is needed as an adult.
The FDA has approved the use of somatropin (Nutropin [Genentech)] Humatrope [Lilly], Genotropin [Pfizer], Saizen [EMD Serono], Norditropin [Novo Nordisk], Tev-Tropin [Teva], and Omnitrope [Sandoz] for the treatment of growth hormone deficiency.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about growth hormone deficiency:
Richard A. Levy, MD
Director of Pediatric Endocrinology
Rush University Medical Center
1725 W. Harrison St.
Chicago, IL 60612
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