Growth Disorders
Genetics | 2003 | Horton, William | COPYRIGHT 2003 The Gale Group Inc. (Hide copyright information) Copyright
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.

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