What is the physiological basis for gigantism and dwarfism

Pituitary dwarfism and pituitary hypoplasia

Pituitary dwarfism is characterized by short stature, delayed dentition, and delayed skeletal maturation. Most cases of sporadic or isolated growth hormone deficiency have a normal-appearing pituitary gland on MRI, although a small adenohypophysis may be observed, particularly in cases of panhypopituitarism. Nonsense mutation of the growth hormone-releasing hormone receptor completely inactivates the receptor and causes a familial form of isolated growth hormone deficiency. These patients have severe growth hormone deficiency and pituitary hypoplasia on MRI (Murray et al., 2000).

Combined pituitary hormone deficiencies (growth hormone and at least one other adenohypophyseal hormonal deficiency) are less frequent than isolated growth hormone deficiency. These disorders may be caused by mutations of genes which encode a variety of transcription factors (HESX1, LHX3, LHX4, PROP1, and PIT-1) implicated in pituitary organogenesis (Argyropoulou and Kiortsis, 2005).

Pituitary hypoplasia may be associated with septo-optic dysplasia (see subsequent section), holoprosencephaly, Chiari malformation, and solitary central maxillary incisor. The identification of a markedly hypoplastic pituitary gland should trigger a search for other midline defects (Abernethy, 1998).

Treatment

Definitive treatment of GH-secreting tumors requires surgical ablation, either transsphenoidally or with a more aggressive surgical approach if large. As described inChapter 9, somatostatin analogues, dopamine agonists, and GH-receptor antagonists are important components of treatment programs for GH excess.

In the past, most patients treated for familial tall stature were females. The number of patients treated in the United States has fallen markedly over the past four decades as tall stature in girls has become increasingly acceptable socially and psychologically. Treatment regimens were generally with estrogen prior to pubertal onset to induce early epiphyseal maturation1630 and considered girls with predicted heights greater than 183 cm (6 feet 0 inches). Treatment regimens varied considerably, and there are no randomized trials testing treatment effectiveness. Controversy surrounds the treatment of girls with tall stature, especially in light of long-term studies that raised the possibility of effects on fertility.1631 One-fifth of pediatric endocrinologists reported use of estrogens for treatment of tall stature in 1999,1632 a percentage that is likely diminishing. In males, androgens have been used to accelerate skeletal maturation via aromatization to estrogen, but virilization is rapid.

Dwarfism

Pituitary dwarfism, the earliest reported form of dwarfism in the rabbit, has been noted in both the United States (Greene, 1940; Greene et al., 1934) and Europe (Kröning, 1939; Nachtsheim, 1973; Schnecke, 1941). The American (gene symbol Dw) and European (gene symbol nan) mutations appear to be similar, and may well be the same mutation occurring in different stocks.

Both were originally reported as autosomal recessive mutations symbolized by dw and nan, respectively. The homozygous animals are typically unable to nurse and die within a few days of birth, although some have survived for longer. Because the mutation came to be considered an incomplete dominant lethal or semi-lethal, the mutant symbol was changed from dw to Dw (Latimer and Sawin, 1955; Sawin, 1955). The birth weight and adult body size of heterozygous animals are approximately one-third that of unaffected littermates (Castle and Sawin, 1941; Latimer and Sawin, 1955).

The affected animals are perfectly proportioned miniatures, with the exception of shortened ears and a disproportionately large central nervous system (CNS) (Castle and Sawin, 1941; Latimer and Sawin, 1955). Thus, the animals have bulging foreheads and protuberant eyes, and the skulls of those surviving more than 2 or 3 days have numerous large foramina (Sawin and Crary, 1964). Cause of death is attributable to either the CNS lesions or to hydronephrosis, which also develops in many of these animals.

Another dwarf mutation was observed in 1957 at the Institute of Human Genetics at the University of Münster (Germany). It was described by Degenhardt (1960) as a single autosomal recessive gene and designated zw. Hydrocephaly was observed as a common occurrence with the zw gene. The animals had features similar to the Dw and nan mutations and may well be another variant of the same gene.

Screening for Pituitary Failure

As the onset of hypopituitarism may be extremely slow, subclinical pituitary failure is often not apparent to the patient or physician. Screening for pituitary dysfunction should be undertaken in patients with hypothalamic or pituitary mass lesions, developmental craniofacial abnormalities, inflammatory disorders, brain granulomatous disease, prior head or neck irradiation, head trauma, prior skull base surgery, those with newly discovered empty sella, and those who have previously experienced pregnancy-associated hemorrhage or blood pressure changes.559

As hypopituitarism may develop insidiously and is often not readily clinically apparent, screening of appropriate patients is important to prevent long-term morbidity. Therefore all patients harboring hypothalamic or pituitary masses should be screened for hypopituitarism (Table 8.15). PRL should be measured because many patients with hypopituitarism may also present with secondary hyperprolactinemia. Upto two-thirds of patients harboring pituitary macroadenomas, craniopharyngiomas, and other parasellar lesions have compromised pituitary reserve function. Less commonly, patients with intrasellar aneurysms, pituitary metastases, parasellar meningiomas, optic gliomas, and hypothalamic astrocytomas may also have pituitary failure. Although about a third of patients with hypopituitarism undergoing pituitary surgery recover function after decompression, about 25% of patients experience further loss of pituitary function after surgery and therefore should be screened annually. Treatment regimens for pituitary failure are described inTable 8.16.

Idiopathic hypopituitary dwarfism

Idiopathic hypopituitary dwarfism is usually caused by a deficiency of hypothalamic releasing factors. In the untreated state, patients with deficient GnRH have delayed or absent puberty and, in contrast, patients with isolated GH deficiency ultimately undergo spontaneous, if delayed, pubertal development, without exogenous gonadal steroids, when the bone age reaches the pubertal stage of 11–13 years. Common to many patients with idiopathic hypopituitary dwarfism is early onset of growth failure; late onset of diminished growth suggests the presence of a CNS tumor or other serious problems. Breech delivery, especially in males, perinatal distress, idiopathic hypopituitarism, and malformations of the pituitary stalk demonstrable by MRI are common in such patients. Familial forms of multiple pituitary hormone deficiencies with either autosomal-recessive or X-linked inheritance are less common.

Treatment of prepubertal children having isolated GH deficiency with GH can increase the rate of pubertal development. Alternatively, if GH treatment is instituted in children already in puberty who have a limited height potential, limitation of the amount of growth attained with GH treatment often results; in these instances, the use of GnRH agonists to suppress pubertal development in addition to the use of GH has been invoked in the hopes of increasing adult height but results are mixed and this is neither approved use nor recommended. The judicious use of low-dose testosterone in affected boys of pubertal age with associated gonadotropin deficiency does not seem to impair growth achieved by GH replacement.

THYROID

Thyroid hormone is a composite of three (T3) or four (T4) iodinated tyrosine residues. T3 and T4 together are called thyroid hormone. Thyroid hormone, although derived from an amino acid, acts like a steroid hormone. In the plasma, 99% of thyroid hormone is transported bound to thyroid-binding globulin. Thyroid hormone binds to an intracellular receptor protein and alters DNA transcription and translation. Thyroid hormone effects are chronic. Of the two hormones, the biological effect of T3 is more rapid and requires 3 days for peak effect. The biological effect of T4 is slower and requires 11 days for peak effect.

PATHOLOGY

Thyroid hormone increases metabolism. It enhances carbohydrate consumption and increases the size and density of mitochondria. Thyroid hormone promotes growth and is required for normal growth in children. Thyroid hormone also increases mental activity and increases other endocrine secretions.

Thyroid hormone assists in acclimatization to cold environments by increasing the metabolic rate. Cold stimulates thyroid hormone release, and the basal metabolic rate is increased, generating heat as a by-product of metabolism.

Pituitary Dwarfism

References to pituitary dwarfism continue to be uncommon in the paleopathological literature. One possible case in a female has been reported from a Roman cemetery in Gloucester, England (Roberts, 1987). The long bones are proportionally short and gracile. The estimate of stature is about 131 cm, with the typical stature of a female during this period being about 153 cm. A further case has been reported in an individual from Bronze Age Tuva, Russia (Aristova et al., 2006). This well-preserved individual is considered to be 45+ years, with skeletal dimensions of those expected in a modern 7-year-old. They have an estimated stature of 124–131 cm, delayed maturation of the long bones, pelvis, and sternum, and lytic lesions on the left acetabulum suggesting inflammation of the hip. Histological examination reveals vascular canals that are sparse, and secondary osteons are absent.

The report of a Native American skeleton of a child estimated to be about 3 years of age highlights the importance of evaluating both the skull and postcranial skeleton in arriving at a diagnosis of abnormally small skulls and/or skeletons (Richards, 1985). The burial is from an archeological site in California, United States, that is dated between ad 1100 and 1700. The skull is abnormally small, with disproportionate development of the cranial vault relative to the bones of the face. Unlike the skull, the postcranial bones are only slightly smaller than normal. Richards (1985) argues for a diagnosis of microcephaly, and this seems probable, given the relatively normal development of the postcranial skeleton. However, if one only had the skull to analyze, differentiating this case from pituitary dwarfism would be more challenging.

A probable case of pituitary dwarfism is in the collections of the National Museum of Natural History, Washington, DC, United States (NMNH 314306). This remarkable case is from the Hawikuh site in New Mexico, which includes late precontact and early historical components. The skeleton is fragile and damaged but includes most of the bones. The features of dental and skeletal maturation used in estimating age are affected by a deficiency of pituitary hormone. Therefore, the age of the skeleton cannot be determined with certainty. However, the second permanent molars have erupted. There is no evidence of a third molar in the left mandibular fragment; however, this absence might be due to agenesis rather than young age. All the teeth that are present are normal in size, which has created severe crowding in the small jaws.

In the postcranial skeleton most epiphyses are unfused. The primary elements of the innominate have fused but the ischiopubic ramus is unfused. The distal epiphysis of the humerus has fused. These features, added to the dental eruption, clearly indicate an age in excess of 12 years in a normal individual. Because of the delayed development and fusion of epiphyses in pituitary dwarfism, a minimum age in the 20s would seem more likely. The skull is somewhat deformed postmortem but is obviously much smaller than normal (Fig. 16.5A and B). The maximum length is 145 mm; the maximum width is 108 mm. Typical skull measurements for a 12-year-old child from the same site would be a maximum length of 160 mm and a maximum width of 127 mm. The relative proportions of the skull are normal although more typical of a child than a 20-year-old. Unfortunately, the base of the skull has been damaged and lost, making observations of the pituitary fossa impossible. The postcranial long bones are very slender and shorter than normal (Fig. 16.5C and D). Stewart (1968: 133) indicates that the approximate femoral length (without epiphyses) of a 12-year-old is 310 mm. The femoral length of the dwarf is about 280 mm or 90% of the expected length of a 12-year-old. If, as seems likely, the dwarf was fully grown, the expected femur length would be about 370 mm and thus would have been only three-fourths as tall as normal. The torsion angle of the left femur is unusually large and probably would be associated with an abnormal gait during life.

The vertebrae are small but of normal proportions, although the bodies of thoracic vertebrae T5–T11 show a slight eccentric development to the right, which might be associated with a slight scoliosis. The sacrum and innominates are small but of fairly normal proportions, although the anteroposterior dimension of the pelvis is longer than would be expected. The pubic symphysis is poorly formed, lacking the normal features of the symphyseal face and the ridge formation. The bones of the hands and feet are of normal shape, although they are very small. The overall appearance of the skeleton conveys the impression of proportional, diminished growth and development. The features of the face, particularly the large but depressed nasal aperture, are features that are associated with less than normal growth at the basi-occipital and sphenoidal synchondroses and that occur in hypothyroidism and achondroplasia. The general morphology of the skull and long bones, however, would rule out either of these possibilities. In general there has been diminished growth and delayed fusion of epiphyses, both of which are compatible with a diagnosis of pituitary dwarfism.

Another specimen in the collection of the National Museum of Natural History, United States, is of interest in the context of pituitary dwarfism. The specimen consists of only the skull from Chilca, Peru (NMNH 379510). The archeological date is unknown. The skull was initially donated by Wells (1942). He reports that the skull was microcephalic, with a cranial capacity of 485 cm3. He concludes that the skull does not resemble congenital hypothyroidism as described in the clinical literature. Hrdlička (1943) added additional data and observations in a subsequent report. Hrdlička (1943:77) concluded that except for its small size, “the skull is unquestionably a ‘normal’ specimen, that is, it shows nothing of any pathological nature.”

The profile of the Peruvian skull reveals diminished development of the frontal region of the skull (Fig. 16.6). A measure of this feature is the length of the arc from nasion to bregma. On the Peruvian skull this arc is 76 mm. This arc on the New Mexico pituitary dwarf is 100 mm. To the extent that diminished frontal bone development is indicative of brain abnormality, this Peruvian individual would appear to have suffered from congenital hypothyroidism (cretinism), usually as the result of maternal iodine deficiency (see later) rather than pituitary dwarfism or microcephaly.

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