Growth Disorders
Growth Disorders
Why Do Some Children Not Grow Normally?
Growth disorders are conditions of abnormal growth in children. The disorders may be caused by poor nutrition, abnormal levels of certain hormones involved in growth, genetic disorders of bone growth, and other diseases.
KEYWORDS
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Endocrinology
Genetics
Human growth disorders
Human growth hormone
Puberty
Jeremy’s Story
When Jeremy turned eight, he looked like he was trapped inside the body of a four-year-old. “My friends teased me and called me ’Shorty,’” he said. “I felt terrible being so much shorter than my brother who was three years younger.”
His parents took him to see a pediatric endocrinologist*. The doctor took his medical history, blood tests, x-rays, and measurements. Jeremy’s parents were told that his body was not making enough growth hormone. Daily shots of human growth hormone have helped Jeremy, and he is now taller than his brother.
- * endocrinologist
- (en-do-krin-OL-o-jist) is α doctor who specializes in treating patients with hormone-related disorders.
What Is Normal Growth?
Everyone has a different size and shape, and there is a very wide range of what doctors consider “normal growth.” In order to monitor growth, doctors use an established range of normal heights and weights for different age groups. From the time a child first goes to the doctor, measurements of height and weight are taken. The doctor uses a growth chart to compare a child’s height and growth rate with those of others the same age. As a newborn, everyone starts out at about the same size. Yet, some end up short and some tall.
When developing a standard growth chart, researchers take a large number of children of different ages and make a graph of their heights and weights. The height at the 50th percentile means the height at which half of the children of that age are taller and half are shorter. The 25th percentile means that three quarters (75 percent) of the children are taller at that age, and one quarter (25 percent) are shorter. The 75th percentile means that three quarters of the children (75 percent) will be shorter and one quarter (25 percent) taller.
People vary greatly, and if children are between the 3rd and 97th percentile, and if they growing at a normal rate, they usually are regarded as normal. If children are outside these ranges (over 97th percentile or under 3rd percentile), the doctor may look for some explanation. Most often, these children simply have inherited “short” or “tall” genes from their parents, and they will continue to grow at a normal pace.
Growth and Puberty
At the time of adolescence, a growth spurt normally occurs. Generally, growth spurts for girls start about two years earlier than growth spurts for boys. Rates of growth and change during puberty vary with the individual. Parents’ growth and puberty patterns often are passed on through their genes to their children: If one or both parents had a late puberty, then their children are more likely to reach puberty later and to experience a later growth spurt. The medical term for this “late bloomer” pattern is constitutional growth delay.
Sex hormones
The increase in growth rate that occurs during puberty is driven by the body’s increase in production of sex hormones: estrogen from the ovaries in girls, and testosterone from the testicles in boys. These hormones cause the skeleton to grow and to mature more rapidly. Hormones produced by the adrenal glands at puberty contribute to the development of pubic hair (near the genitals) and underarm hair, but have little effect on bone growth. It follows, then, that disorders of pubertal development can affect a child’s growth pattern and ultimate height. Pubertal disorders usually are grouped into two categories: precocious or premature puberty (which starts earlier than expected), and delayed or late puberty.
Precocious puberty
In general, puberty is considered precocious (early) if changes in sexual development occur before age eight for girls and before age ten for boys. Most cases of precocious puberty result from the premature “switching on” of the puberty control center in the brain, located in the part of the brain called the hypothalamus (hy-po-THAL-a-mus). Hormones from the hypothalamus trigger the release of hormones from the pituitary gland (located at the base of the brain), which in turn stimulate the ovaries in girls and the testicles in boys to produce the higher levels of sex hormones needed to bring about the bodily changes of puberty.
Children with precocious puberty experience early growth spurts because of the abnormally early rise in sex hormone levels in their bodies. Although initially this causes these children to grow taller than others their age, their skeletons mature more rapidly, often causing them to stop growing at an early age. Therefore, if precocious puberty is left untreated, it may lead to a decrease in a child’s ultimate height.
There are many possible causes for precocious puberty, including brain tumors and other disorders of the central nervous system; and tumors or other conditions that cause the gonads or adrenal glands to overproduce sex hormones. In girls, however, the majority of cases of precocious puberty are idiopathic (id-ee-o-PATH-ik), which means the precise cause is unknown.
Precocious puberty often can be treated effectively or controlled with medications that decrease the overproduction of sex hormones or that block their effects on the body. In many cases, this type of treatment can prevent or decrease the shortening of the child’s ultimate height that would otherwise occur.
Delayed puberty
Delayed puberty occurs when the hormonal changes of puberty occur later than normal, or not at all. Puberty is considered late if it has not begun by age 13 in girls or by age 15 in boys. Most children who experience delayed puberty are following the normal pattern called constitutional growth delay discussed previously.
Several medical conditions (such as disorders of the hypothalamus, pituitary, ovaries, and testicles) can result in delayed puberty by interfering with the pubertal rise in sex hormones. Many chronic disorders of other body organs and systems (such as the intestines and lungs), as well as long-term treatments with certain medications (such as cortisone) also may cause delayed puberty.
As would be expected, children with delayed puberty do not experience growth spurts at the usual age, so they lag behind in height as their peers grow rapidly and mature sexually. When puberty finally occurs for these children, on its own or as a result of treatment, they “catch up”: They may continue to grow into their late teens and may even exceed the final adult heights of some of their peers.
How Does Growth Take Place?
Growth occurs when bones of the arms, legs, and back increase in size. The long bones of the limbs have a growth plate at the end. The growth plate is made of cartilage, which is a tough, elastic tissue. Cartilage cells in the growth plate multiply and move down the bone to produce a matrix, or tissue from which new bone is formed. These cartilage cells then die, leaving spaces. Special cells called osteoblasts (OS-tee-o-blasts), meaning bone beginners, then produce bone (by laying down the minerals calcium and phosphorus) to fill the spaces and replace the matrix. Once all the cartilage in the growth plate has been turned to bone, growth stops. This usually occurs before ages 16 to 18. An x-ray of the hand or knee can show the doctor the bone age (maturity of the bone) and how much potential growth remains.
Why Do Some Children Not Grow Normally?
Nutrition
Children with poor nutrition may have poor growth. A balanced diet and adequate protein are essential for normal growth. Some parts of the world have serious problems with malnutrition, and the growth of children may be affected in these areas.
Chronic diseases
Chronic diseases that may impair growth include diabetes, congenital heart disorders, sickle cell disease, chronic kidney failure, cystic fibrosis, and rheumatoid arthritis.
Bone Disorders
One form of extreme short stature (height) is caused by abnormal formation and growth of cartilage and bone. Children with skeletal dysplasia* or chondrodystrophies* are short and have abnormal body proportions. Their intelligence levels usually are normal. Most of these conditions are inherited or occur due to genetic mutations (changes).
- * dysplasia
- (dis-PLAY-zha) means abnormal growth or development.
- * chondrodystrophy
- (kon-dro-DIS-trof-ee) means abnormal growth at the ends of the bones.
Intrauterine growth retardation (IUGR)
If growth in the uterus is interrupted while a fetus is forming or developing, the condition is called intrauterine (meaning within the uterus) growth retardation or IUGR. IUGR is not the same as when a baby is born prematurely. The small size of a premature infant usually is normal according to the gestational (jes-TAY-shun-al) age (or the age from conception).
Failure to grow normally in the uterus may result from a problem with the placenta (the organ that supplies nutrients and oxygen to the baby). Growth of the fetus can be affected if the mother smokes cigarettes or drinks alcohol during the pregnancy. Infections, such as German measles, may cause the problem, and sometimes the cause cannot be determined.
Failure to thrive (FTT)
Failure to thrive (FTT), or inadequate weight gain anytime after birth, occurs frequently in infants. There are many possible causes, and the doctor must examine the child carefully. Often, the baby or child simply is not getting enough to eat. Sometimes there are other illnesses interfering with weight gain that must be treated.
Genetic conditions
Several genetic conditions may involve problems with growth. One such condition is Turner syndrome. Girls with Turner syndrome have only one X chromosome or a second X chromosome that may be abnormal or incomplete. Affected girls are short and have underdeveloped ovaries.
Marfan syndrome is a hereditary condition affecting connective tissue and is associated with tall stature. People with Marfan syndrome have very long arms and legs, eye problems, and differences in facial features. Other physical problems, such as heart abnormalities, also may be present. It is commonly believed that Abraham Lincoln had Marfan syndrome.
Hormones and Growth Disorders
Growth is controlled by hormones (chemical messengers) from various glands. One of the most important, growth hormone, is secreted by the pituitary gland. The gland looks like a peanut sitting at the base of the brain. Other hormones also are essential for growth. The thyroid gland in the neck secretes thyroxine, a hormone required for normal bone growth. Sex hormones from the ovaries (estrogen) and testicles (testosterone) are essential for the growth spurt and other body changes that occur at puberty.
Pituitary hormones
The pituitary gland is attached by a stalk to the hypothalamus, an area of the brain that controls the function of the pituitary. The anterior or front part of the pituitary gland secretes the following hormones that can affect growth:
- Growth hormone to regulate bone growth
- Thyroid-stimulating hormone to control the production and secretion of thyroid hormones
- Gonad-stimulating hormones for development of the sex glands (gonads) and secretion of sex hormones
- Adrenal-stimulating hormone to regulate the secretion of adrenal gland hormones.
Too little growth hormone (hypopituitarism)
Sometimes the pituitary gland does not make enough growth hormone. Usually, this will slow a child’s growth rate to less than 2 inches a year. The deficiency may appear at any time during infancy or childhood. When doctors have ruled out other causes of growth failure, they may recommend special tests for growth hormone (GH) deficiency. Children with growth hormone deficiency are treated with daily injections of the hormone, often for a period of years. With early diagnosis and treatment, these children usually increase their rate of growth, and may catch up to achieve average or near-average height as adults.
In pituitary dwarfism, caused by low amounts of growth hormone, the person is short but has normal body proportions. This is different from other forms of dwarfism due to genetic skeletal dysplasias. In these cases, the person with dwarfism is short, and the growth of the arms, legs, torso, and head often is out of proportion. For example, the person’s arms and legs may appear relatively smaller than the head or torso.
Too much growth hormone (hyperpituitarism)
Two conditions arise from excessive amounts of growth hormone in the body: acromegaly (ak-ro-MEG-a-lee) and gigantism. The cause usually is a benign* pituitary tumor.
- * benign
- means not cancerous or spreading and contained in one area.
Acromegaly, a condition caused by increased secretion of growth hormone after normal growth has been completed, occurs in adults. The condition is rare, occurring in 6 out of 100,000 people. Because the adult cannot grow taller, the excess growth hormone in acromegaly causes adult bones to thicken and other structures and organs to grow larger. Usually, it does not appear until middle age, when the person notes a tightening of a ring on the finger, or an increase in shoe size. Tests at that time may reveal a pituitary tumor.
Gigantism occurs when excessive secretion of growth hormone occurs in children before normal growth has stopped. This results in the overgrowth of long bones. The vertical growth in height is accompanied by growth in muscle and organs. The result is a person who is very tall, with a large jaw, large face, large skull, and very large hands and feet. Many health problems may be associated with gigantism, including heart disease and vision problems. Delayed puberty also may occur in this condition. Surgery or radiation can correct the problem. Hormone replacement may be necessary if there is pituitary damage from this treatment.
Too little thyroid hormone (hypothyroidism)
The thyroid gland looks like a big butterfly at the base of the neck. One wing is on one side of the windpipe or trachea, and the other on the other side. The wings are joined by a thin strip of thyroid tissue. The thyroid gland makes the hormone thyroxine (thy-ROX-een).
The thyroid is controlled by the pituitary gland, which makes thyroid-stimulating hormone. The hormone thyroxine controls the rate of chemical reactions (or metabolism) in the body. Too much thyroxine, or hyperthyroidism, speeds up metabolism.
Hypothyroidism is the opposite. Hypothyroidism is caused by the body’s underproduction of thyroid hormone, and this affects many different body processes.
A child with thyroid hormone deficiency has slow growth and is physically and mentally sluggish. The lack of this hormone may be present at birth, if the thyroid gland did not develop properly in the fetus. Or the problem may develop during childhood or later in life as a result of certain diseases of the thyroid.
In most states, babies are tested for hypothyroidism at birth. Blood tests can detect the problem, and treatment usually is a daily pill that replaces the missing thyroid hormone. Early diagnosis and continuing treatment help these children grow and develop normally.
Too much Cortisol (Cushing’s syndrome)
The adrenal glands, which are located on top of the kidneys in the abdomen, secrete the hormone Cortisol. If too much Cortisol is made by the child’s adrenals, or if large doses of the hormone are given to the child to treat certain diseases, Cushing’s syndrome may develop. Children with this syndrome grow slowly, gain weight excessively, and may experience delayed puberty due to the effects of the abnormally large amounts of Cortisol in the body.
A Complex Problem
There are many causes for growth problems. In order to detect these disorders early, it is important for doctors to track growth carefully in infants and children. Many of these conditions can be treated effectively, resulting in more normal adult heights for children with growth disorders.
See also
Birth Defects
Cushing’s Syndrome
Dietary Deficiencies
Dwarfism
Resources
U.S. National Institute of Child Health and Human Development, and other institutes at the National Institutes of Health (NIH), offer many fact sheets and online resources about growth disorders. The NIH search engine is user friendly and provides many useful hypertext links.http://www.nih.gov
March of Dimes Birth Defects Foundation, 1275 Mamaroneck Avenue, White Plains, NY 10605. This large, national organization provides information about achondroplasia, other growth disorders, and many birth defects. Telephone 888-MODIMES
http://www.modimes.org
KidsHealth.org from the Nemours Foundation posts a fact sheet that answers frequently asked questions about visiting an endocrinologist, http://kidshealth.org
Growth Disorders
Growth Disorders
Growth, which usually refers to skeletal growth since it determines final adult height, is an extremely complex process. As such, it is susceptible to a wide range of genetic and physiologic disturbances. Indeed, growth is adversely affected by many if not most chronic diseases of childhood, through many different mechanisms.
Skeletal growth depends on hormonal signals for regulation. It also requires the production of adequate amounts of cartilage, because most bone forms within a model or template made from cartilage. Primary disorders of growth, that is, disorders in which growth is intrinsically affected, therefore fall into two major categories: disorders of the endocrine (hormone) system and disorders of the growing skeleton itself (skeletal dysplasias). Many of the former and most of the latter are genetic disorders.
Endocrine Disorders
Growth hormone (GH) is produced by the pituitary gland at the base of the brain and is a major regulator of growth. Deficiency of the hormone is the prototype of the inherited endocrine disorders of growth. Although normal in size at birth, infants with GH deficiency exhibit severe postnatal growth deficiency while maintaining normal body proportions. If untreated, children typically have a "baby-doll" facial appearance and a high-pitched voice that persists after puberty.
Isolated GH deficiency most often results from deletion of all or part of the GH gene. Humans carry two copies of the GH gene, but having just one good copy is usually sufficient to prevent GH deficiency. Thus, this disorder is inherited as an autosomal recessive trait. Rarely, point mutations of this gene can lead to a dominantly inherited form of GH deficiency, in which the product of the mutant GH allele is thought to interact with and prevent secretion of the product of the normal GH allele.
GH deficiency also results from mutations of genes that encode transcription factors , such as PIT1, PROP1, and POU2F1, which are necessary for development of the pituitary gland and of the cells that produce pituitary hormones. Patients usually have small pituitary glands and exhibit deficiencies of several pituitary hormones, including gonadotropins (FSH, LH), prolactin, and thyroid-stimulating hormone (TSH) in addition to GH. Multiple pituitary hormone deficiency of this type is inherited in an auto-somal recessive fashion.
At their target cells, hormones exert their efforts by binding to receptors. The clinical manifestations of GH deficiency can also result from mutations of the GH receptor, in the autosomal recessive Laron syndrome. There are also a number of birth-defect syndromes in which hypopituitarism (reduced pituitary output) results in the abnormal development of craniofacial structures. Examples include anencephaly, holoprosencephaly, Palister-Hall syndrome, and some cases of severe cleft lip and cleft palate.
Deficiencies of other hormones relevant to growth and their receptors also occur on a genetic basis. For instance, thyroid hormone deficiency can be due to reduced TSH, as discussed above, but it can also result from loss-of-function mutations of enzymes that are involved in thyroid hormone biosynthesis. There are also several forms of thyroid hormone resistance due to mutations of thyroid hormone nuclear receptors. The biosynthetic defects are inherited as recessive traits, whereas thyroid resistance is usually inherited in a dominant fashion. Mental retardation, growth deficiency, and delayed skeletal development are the main clinical manifestations of thyroid hormone deficiency.
Skeletal Dysplasias
In contrast to endocrine growth disorders, the hallmark of the skeletal dysplasias ("-plasia" means "growth") is disproportionate short stature. In other words, the limbs are disproportionately shorter than the trunk or vice versa. These disorders result from mutations of genes whose products are required for normal skeletal development. In most cases they are involved in endochondral ossification , the process by which the skeleton grows through the production of the cartilage template that is converted into bone. The mutated genes encode cartilage and bone extracellular matrix proteins, growth factors, growth factor receptors, intracellular signaling molecules, transcription factors, and other molecules whose functions are needed for bone growth.
Growth Factor Receptor Mutations.
The prototype of the skeletal dysplasias is achondroplasia, which is one of a graded series of dwarfing disorders that result from activating mutations of fibroblast growth factor receptor 3 (FGFR3). Achondroplasia is the most common form of dwarfism that is compatible with a normal life span, while thanatophoric dysplasia, which lies at the severe end of the spectrum of FGFR3 disorders, is the most common lethal dwarfing condition in humans. Both are characterized by the shortening of limbs, especially proximal limb bones, and a large head with a prominent forehead and hypoplasia (reduction of growth) of the middle face. The mildest disorder in this group is hypochondroplasia, in which patients exhibit mild short stature and few other features.
All of the disorders in this group result from heterozygous mutations of FGFR3. Except for the lethal thanatophoric dysplasia, they are inherited as autosomal dominant traits. The vast majority of mutations arise anew, during sperm formation (spermatogenesis), and especially in older fathers. FGFR3 is a very mutable (easily mutated) gene and there are certain extremely mutable regions within the gene where disease-causing mutations cluster.
There is a very strong correlation between clinical phenotypes and specific mutations. In fact, essentially all patients with classic features of achondroplasia have the same amino acid substitution in the receptor. The mutations that cause these disorders enhance the transduction of signals through FGFR3 receptors in chondrocytes in growing bones. This inhibits the proliferation of these cells that is necessary for linear growth to occur.
Cartilage Matrix Protein Mutations.
Another major class of skeletal dysplasias result from mutations of genes that encode cartilage matrix proteins such as collagen types II, IX, X, and XI, and cartilage oligomeric matrix protein (COMP). The type II collagen mutations cause a spectrum of autosomal dominant disorders called spondyloepiphyseal dysplasias because they primarily affect the spine (spondylo) and the ends of growing limb bones (epiphyses). They range in severity from lethal before birth to extremely mild. In addition to dwarfism that affects the trunk more than the limbs, patients with these disorders develop precocious osteoarthritis of weight-bearing joints such as the hips and knees. Many patients have eye problems that reflect disturbances of type II collagen in the vitreous portion of the eye.
Mutations of COMP cause two clinically distinct disorders: pseudo-achondroplasia and multiple epiphyseal dysplasia. Both are inherited as autosomal dominant disorders, have onset after birth, and are dominated by osteoarthritis of hips and knees. Dwarfism is severe and skeletal deformities are common in pseudoachondroplasia.
Cartilage collagens and COMP are multimeric molecules, that is, they are composed of multiple subunits, three for collagens and five for COMP. Like a square wheel on a car, the products of mutant alleles interfere functionally with the products of normal alleles when they combine during molecular assembly, a so-called dominant negative effect. Most collagen mutations are thought to act through this mechanism to reduce the number of collagen molecules in cartilage matrix, which in turn alters the ability of cartilage to function as a template for bone growth.
Similar types of mutations occur in genes encoding type I collagen, which is the principal matrix protein of bone. These mutations lead to osteogenesis imperfecta (OI), which is a spectrum of disorders of varying severity. The hallmark of OI is bone fractures, although patients often have blue sclerae (the "whites" of the eye), fragile skin, and dental problems that reflect the widespread distribution of type I collagen in many connective tissues.
Excessive Growth
Genetic growth disorders also include conditions with excessive growth. Beckwith-Wiedemann syndrome is characterized by an enlarged tongue, abdominal wall defects (omphalocele), and generalized overgrowth during the fetal and neonatal period. Most of the findings can be attributed to the excess availability of insulin-like growth factor II (IGF2) that results from duplication, loss of heterozygosity, or disturbed imprinting of the IGF2 gene. The syndrome behaves as an autosomal dominant trait in many families. The excessive growth slows with age, but patients are predisposed to childhood tumors, especially Wilms tumor .
Simpson-Golabi-Behmel syndrome is an X-linked overgrowth syndrome with many of the features of Beckwith-Wiedemann syndrome. It results from mutations of glypican 3, which is a cell surface proteoglycan that binds and may sequester growth factors such as IGF2. Glypican 3 mutations appear to enhance IGF2 signaling through its receptor, explaining the clinical similarities between the two syndromes.
see also Birth Defects; Disease, Genetics of; Genetic Counseling; Hormonal Regulation; Imprinting; Inheritance Patterns; Signal Transduction.
William Horton
Bibliography
Karsenty, G., and E. F. Wagner. "Reaching a Genetic and Molecular Understanding of Skeletal Development." Developmental Cell 2, no. 4 (2002): 389-406.
MacGillivray, M. H. "The Basics for the Diagnosis and Management of Short Stature: A Pediatric Endocrinologist's Approach." Pediatric Annual 29 (Sept., 2000): 570-575.
Wagner, E. F., and G. Karsenty. "Genetic Control of Skeletal Development." Current Opinion in Genetic Development 5 (Oct., 2001): 527-532.