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.