CHAPTER 18 HYPOTHALAMIC AND PITUITARY DISORDERS IN INFANCY AND CHILDHOOD
Principles and Practice of Endocrinology and Metabolism
CHAPTER 18 HYPOTHALAMIC AND PITUITARY DISORDERS IN INFANCY AND CHILDHOOD
ALAN D. ROGOL
Growth Pattern Concepts
Body Segment Ratio
Skeletal and Dental Maturation
Other Growth Concepts
Diagnosis and Treatment of Growth Failure
Disorders of the hypothalamus and pituitary gland in infants and children often manifest as abnormalities of growth. Pediatric manifestations may involve secondarily the thyroid gland, sexual development, or glucose homeostasis (see Chap. 47 and Chap. 161).
GROWTH PATTERN CONCEPTS
A child’s growth pattern arises from a complex mixture of genetic potential, nutrition, psychological factors, and the secretion and interaction of many hormones (see Chap. 7, Chap. 91 and Chap. 198).
The patterns of growth and adolescent development can provide useful data that signal specific problems or simplify differential diagnoses. The rate of stature change, the growth velocity, may be derived from the growth chart (see Chap. 7). The growth chart also has a graph that depicts percentiles of weight for attained linear stature. This information may prove useful in evaluating problems such as malabsorption syndromes or chronic illness, in which most children are relatively underweight for height, or hypopituitarism, in which children are relatively overweight for height.
BODY SEGMENT RATIO
The body segment ratio (upper segment/lower segment ratio) is determined by measuring the lower segment (pubis to soles), subtracting that value from the height to calculate the upper segment (crown to pubis), and dividing the upper by the lower. These proportions change throughout development. At birth, the trunk is relatively long compared with the extremities, but by the end of puberty, the extremities are relatively longer than the trunk (Fig. 18-1). The body segment ratio at birth is ~1.7:1; it becomes ~1:1 by 8 to 10 years of age, reflecting the growth of long bones. Blacks are relatively long-limbed compared with whites and have upper/lower segment ratios of ~0.90 after puberty (Fig. 18-2). Tables of normal body segment ratios and arm span measurements have been published.1
FIGURE 18-1. Changes in body proportions with growth. The horizontal lines divide the figures into quarters. Note the following normal phenomena: progressive decrease in the relative size of the head, increase in the relative size of the lower extremities, and the progressive anatomic descent of the midpoint of the body. (From Sinclair D. Human growth after birth. Oxford: Oxford University Press, 1985:128.)
FIGURE 18-2. Normal standards for upper segment/lower segment (US:LS) body ratio during growth. (Measurements were obtained from 2100 Baltimore school children.) There is a significantly lower US:LS ratio for blacks (B) than for whites (A) at all ages because of a shorter upper segment and longer lower segment in blacks. There were no sex differences within either racial group up until approximately age 15 years. (Modified from McKusick VA. Heritable disorders of connective tissue, 3rd ed. St. Louis: Mosby, 1966:50.)
The body segment ratio is affected in certain growth disorders. For example, many patients with chondrodystrophy have relatively short limbs compared with their upper segment; hypogonadal patients have increased limb length compared with their upper segment (eunuchoid proportions); and children with hypothyroidism may have a more infantile upper/lower segment ratio. Others have used the span (fingertip-to-fingertip) to delineate altered body proportions. The height and the span normally are within 5 cm of each other.
SKELETAL AND DENTAL MATURATION
Skeletal and dental maturation may be used to assess a child’s developmental (physiologic) status. A number of methods for obtaining the bone age have been developed, but the method of Greulich and Pyle2 has proved to be the most practical screening procedure. A single radiograph of the left hand and wrist is obtained, and the epiphyseal development is compared with that of children of normal stature using an atlas. Other systems evaluate ossification centers in the hand, knee, and foot (Fig. 18-3). Together, these criteria allow a child’s growth and developmental pattern to be determined (Fig. 18-3; Table 18-1). These data should help to determine whether a child’s growth is within the range of normal (see Chap. 7 and Chap. 217) or should be further evaluated.
TABLE 18-1. Age-at-Appearance Percentiles for Major Postnatal Ossification Centers
FIGURE 18-3. The 20 ossification centers of maximum predictive value in boys (A) and girls (B). The postnatal centers that have the greatest utility in skeletal assessment are in the hand, the knee, and the foot. The numbers indicate the relative predictive value of these postnatal ossification centers, number 1 being the most predictive. (From Garn SM, Rohman CG, Silverman FN, et al. Med Radiogr Photogr 1967; 43:45. Reprinted courtesy of Eastman Kodak Company.)
OTHER GROWTH CONCEPTS
Height age is the age for which a person’s present height would be at the 50th percentile on the growth chart. Short stature usually is given a statistical definition, that is, a specific number of standard deviations (SD) below the expected mean for children of a certain chronologic age. A common definition is 2–3 SD below the mean for age; 2.5 SD, equivalent to the third percentile, often is used. Tall stature may be defined as 2–3 SD above the mean height for age; 2.5 SD, equivalent to the 97th percentile, often is used.
Growth velocity, or rate of incremental change, also has a normal range. Growth failure is often defined below the 10th to 25th percentile of the mean height velocity for age. The lowest values for both boys and girls between the ages of 2 and 12 years approximate 1.75 inches (4.5 cm) per year. The average height increment during these years is ~2.5 inches (6.3 cm).
These principles and their use in the diagnosis, differential diagnosis, and therapy for growth-retarded children are described in Chapter 92 and Chapter 198. Dental maturation is discussed in Chapter 217.
Growth failure may be classified as follows: hypopituitarism; emotional deprivation; chromosomal defects; systemic illness (moderate to severe); metabolic diseases; and chondrodystrophies.
This classification is not all-inclusive but rather serves as a framework for discussing the approach to children with a failure to grow adequately. The major emphasis of this chapter is on hypopituitarism and emotional deprivation.
Hypothalamic and pituitary dysfunction (partial or complete) may be classified using a number of systems: congenital versus acquired; isolated, partial, or panhypopituitarism; transient versus permanent; idiopathic versus organic; and primary (pituitary) versus secondary (affecting releasing factors).
The outline shown in Table 18-2 is a convenient list with which to organize a differential diagnosis of hypopituitarism in infants and children. It is not all-inclusive but highlights major categories of pituitary insufficiency. The criteria for the diagnosis of the growth hormone (GH) deficiency of hypopituitarism are as follows: short stature; growth failure; no significant underlying illness; no evidence for emotional deprivation; delayed bone age; normal body proportions; low circulating levels of insulin-like growth factor-I (IGF-I); and subnormal responses to at least two stimuli for GH release.
TABLE 18-2. Classification of Hypothalamic and Pituitary Insufficiency
Developmental Pituitary Disorders. Developmental pituitary disorders may be so severe that they are incompatible with life. In some children, there is hypoplasia or absence of the pituitary gland, but in others, developmental anomalies of the hypothalamus appear to be responsible for the lack of pituitary development.3,4 Anencephaly and holoprosencephaly (including arrhinencephaly, holotelencephaly, cyclopia, and cebocephaly) usually are incompatible with life. This group of anomalies compose a spectrum of developmental anomalies associated with failure of complete midline cleavage of the embryonic fore-brain. The children either have no pituitary or a hypoplastic gland and have maldevelopment of the target organs. Atrophy of the adrenal glands always is present, and death usually occurs from adrenal insufficiency. A partial form of holoprosencephaly exists (Kallmann syndrome) in which patients have anosmia caused by the agenesis of the olfactory lobes, and hypogonadotropic hypogonadism secondary to failure of hypothalamic gonadotropin-releasing hormone secretion5 (see Chap. 16 and Chap. 115).
Absence or hypoplasia of the anterior pituitary is also an uncommon cause of hypopituitarism. The former usually is incompatible with life, but the latter has a spectrum ranging from severe to mild deficiency. The clinical presentation depends on the amount of functioning hypothalamic and pituitary tissue. The main features are severe hypoglycemia and shock because of adrenal failure.
The anterior pituitary lobe develops from an upward diverticulum of the primitive buccal cavity (Rathke pouch) in the nasopharynx and must migrate to its usual location within the sella turcica. There are a number of ectopic sites in which the gland may lodge, from the submucosa of the nasopharynx (pharyngeal pituitary) to the base of the brain. The pituitary stalk is the main neural connection between the hypothalamus (median eminence) and the posterior lobe of the pituitary. In addition to these neurons, there are the capillary loops of the hypothalamic-pituitary portal system providing the principal blood supply to the various portions of the anterior lobe.
Pituitary stalk interruption syndrome (hypoplasia of the anterior lobe, ectopic position of the posterior lobe, and interruption of the stalk) is strongly correlated with multiple anterior pituitary hormone deficiencies.6 Injury may be developmental or secondary to transection of the stalk. A number of other anomalies of the craniofacial area may coexist with hypopituitarism. The syndrome of basal encephalocele and hypothalamic–pituitary dysfunction should be mentioned because these patients all have a nasoepipharyngeal mass or unexplained “nasal polyp.”7 The diagnosis should be considered when evaluating a nasal mass, especially in conjunction with the associated findings of hypertelorism, broad nasal root, midline facial defects, optic atrophy, or optic coloboma.
Inherited Pituitary Disorders
GENETIC DISORDERS OF GROWTH HORMONE DEFICIENCY. Five to 30 percent of children with growth hormone deficiency have an affected first-degree relative, which is consistent with a genetic cause. These genetic anomalies may result in isolated or combined pituitary hormone deficiencies. The more common are POU1F1, homolog of the mouse Pit-1, and PROP-1 deficiencies, which lack not only GH, prolactin (Prl), and thyroid-stimulating hormone (TSH), but also the gonadotropins. The specific genes encode members of the homeodomain family of transcription factors, which play an important role in the development of the human pituitary gland.8 Other deficiencies are caused by growth hormone-releasing hormone receptor mutations.
ISOLATED GROWTH HORMONE DEFICIENCY AND PITUITARY DWARFISM. The classification of familial GH deficiency primarily is descriptive and is based on the inheritance of the appropriate phenotype and lack of response to pharmacologic stimuli for GH secretion.9 Six distinct groups based on the mode of inheritance and other hormone deficiencies have been defined (see Table 18-2). In only one, isolated GH deficiency type IA, have the pathophysiologic characteristics been defined: absence of the structural gene for GH (hGH-N).10 The others apparently are a result of the lack of synthesis or secretion of the hypothalamic-releasing hormone, growth hormone–releasing hormone (GHRH), or to an excessive secretion of the inhibitory hormone, somatostatin. However, heterogeneity of structure and function exists within and among families with isolated GH deficiency and within and among families with pituitary deficiency, making the determination of the precise location of the defect difficult—hypothalamus or pituitary.11
Boys with severe GH deficiency and other anterior pituitary deficits may present with microphallus and hypoglycemia. The physical examination of the genitalia should alert the physician to determine the level of plasma glucose frequently and to use GH and cortisol to treat refractory hypoglycemia.12
CRANIOPHARYNGIOMA. The most common tumor in the area of the pituitary of children is the craniopharyngioma13 (see Chap. 11). It arises from the embryonic remains of the craniopharyngeal duct (Rathke pouch) and is of epithelial origin. This neoplasm commonly is cystic and often contains dark, thick, viscous fluid (“machinery oil”). Although congenital, it is so slow-growing that signs and symptoms often are not manifested until late in the first decade or in the second decade of life or even into adulthood. In addition to the signs of hypopituitarism, children and adolescents may have neurologic symptoms, including prolonged frontal headache, vomiting, or vision deficits—decreased acuity, diplopia, or photophobia. On examination, papilledema, optic nerve atrophy, and impaired visual fields are found in most; they indicate raised intracranial pressure. Older children and adolescents may have obesity or amenorrhea. In the asymptomatic patient, the diagnosis may be made by noting flecks of calcium in the suprasellar region or changes within the suprasellar area as evaluated on computed tomographic (CT) or magnetic resonance imaging (MRI; Fig. 18-4) studies. In a symptomatic patient, CT or MRI scanning is extremely helpful in confirming the diagnosis and determining the extent of the neoplasm.
FIGURE 18-4. Computed tomographic (CT) scans of the brain of a 3-year-old girl with a craniopharyngioma. A, Sagittal view showing large suprasellar mass. B, Coronal view showing compression of pituitary gland and large suprasellar mass. (Courtesy of Dr. W. Cail, University of Virginia.)
Although craniopharyngioma is most commonly found in children, optic and third ventricle gliomas and arteriovenous malformations must be considered. The treatment is surgical and may be possible through the transsphenoidal approach. Aspiration of the cyst can decompress the mass and relieve symptoms but rarely is curative. Radiation therapy including intracystic application of radioactive pellets, although controversial, may be effective as adjuvant therapy to surgery. Tumor recurrence, even after “total” removal, is common. Hypopituitarism, especially GH deficiency, may be found preoperatively. Postoperatively, it is present in most patients, often in association with other defects in anterior pituitary function and central diabetes insipidus. Meticulous follow-up of growth velocity and pituitary target-organ function, and early replacement therapy greatly decrease the morbidity and mortality after surgery.
DIENCEPHALIC SYNDROME. The diencephalic syndrome usually comprises a tumor in the diencephalon and the clinical picture of severe emaciation with relative conservation of growth rate, alert appearance, and relatively few neurologic signs. It is nearly always, but not exclusively, found in infancy.14,15 There is a striking lack of subcutaneous fat. Often, the child seems inappropriately happy (Fig. 18-5). Some clinicians believe that it is related to the age of onset of compression of the hypothalamus because it is not seen in patients with craniopharyngiomas or other tumors within the same anatomic area that present later in childhood, although such tumors displace the third ventricle in a manner similar to that of opticochiasmatic gliomas. Although endocrinologic deficits may be present, they are inconstant and do not help in the diagnostic process. Most tumors are gliomas located in the anterior hypothalamus or in the optico-chiasmatic system. The syndrome in infants with tumors placed more posteriorly is characterized by the early onset of vomiting and the absence or late onset of nystagmus, tremor, pallor, polyuria, papilledema, or optic atrophy. These patients are more likely to have malignant cells and raised protein concentrations in the cerebrospinal fluid than are children with more anteriorly placed tumors. These latter patients more often have nystagmus and optic atrophy. Vomiting appears later.16
FIGURE 18-5. A 10-month-old child with diencephalic syndrome (left next to a normal child of the same age (right). Despite striking emacia tion, the infant appeared happy and alert and was extremely hyperac tive. There was nystagmus. The feet and hands appeared large in comparison with the body. Basal growth hormone levels were high and were not suppressed adequately with glucose administration. At cra niotomy, there was an optic glioma involving the optic nerves and chi asma that extended into the anterior hypothalamus and the posterior portion of the third ventricle. (From Häger A, Thorell JI. Studies on growth hormone secretion in a patient with the diencephalic syndrome of emaciation. Acta Paediatr Scand 1973; 62:231.)
Radiographic studies in patients with anteriorly placed tumors may show enlarged optic foramina and, less commonly, sellar alterations, evidence of increased intracranial pressure, and, rarely, calcification. Computed tomographic and MRI scans may be the best tools for defining the exact nature and extent of disease because the optic nerves, chiasm, and sellar and suprasellar regions can be visualized precisely.
The prognosis is poor, and the treatment remains controversial. Surgery is rarely curative, but it is important to obtain a pathologic diagnosis. Radiation therapy can dramatically reduce the mass of the tumor. However, the natural history is uncertain and variable. Thus, treatment for these often slow-growing tumors varies from no therapy, to surgical excision, to radiation therapy; however, one must be concerned with ultimate brain growth if a child younger than 2 to 3 years old undergoes radiation therapy. Because most series have been small and their data were collected over several decades when the approach to diagnosis, therapy, intensive postoperative care, and endocrinologic replacement therapy was in great flux, it is not surprising that no single therapeutic protocol has proved to be clearly superior.
Defects in the Structure, Metabolism, or Secretion of Growth Hormone or Insulin-Like Growth Factor I
BIOLOGICALLY INACTIVE GROWTH HORMONE. Children with growth failure who have normal or elevated basal GH concentrations or a normal or increased response to pharmacologic stimuli, but diminished IGF-I concentrations that cannot be attributed to malnutrition, chronic illness, or other causes, may secrete a bioinactive (subactive) GH molecule. Bone and dental development are significantly delayed, and the body proportions are more appropriate for chronologic than height age. Although some investigators have proposed this hypothesis for short stature in the few children who fit into the diagnostic category, there is sparse evidence. Clearly, it is not the public health problem it was originally considered.17 Findings in a single patient indicate that aggregation of serum GH may be responsible.18 However, a mutation in the GH gene itself can produce a mutated form of GH (found to be expressed in Escherichia coli), which is clinically associated with short stature in the affected child.19 The mutated GH binds avidly to the GHG receptor in the IM-9 cell line, but does not stimulate intracellular signaling pathways. Thus, it inhibits the bioeffects of native GH.
The growth hormone insensitive syndrome (GHIS) represents another defect in the mechanism of GH action3,20 (Fig. 18-6). These patients with familial dwarfism and clinical features of GH deficiency tend to be of normal birth weight, but growth velocity is retarded soon after birth. Motor development, bone maturation, and dental eruption are slow, and the anterior fontanelle may close later than average. The facial bones grow more slowly than the cranial vault. When the child has a small mid-face and mandible and a bulging forehead, macrocephaly should be considered. The children tend to be obese and have a high-pitched voice. Although many of the original patients were of Semitic origin, subsequent patients have come from many ethnic backgrounds.
FIGURE 18-6. Three Ecuadorian patients with growth hormone receptor deficiency resulting from a point mutation at codon 180 of exon 6 of the growth hormone receptor: a boy aged 26 months (height, –8.2 SD), a girl aged 4.8 years (height –7.4 SD), and a woman aged 19 years (height, –6.5 SD). The vertical dimension of the face is decreased, the nasal bridge is hypoplastic, and the forehead is of normal dimension, giving the impression of craniomegaly, especially in the children. (Courtesy of J. Guevara-Aguirre, Institute for Endocrinology, Metabolism, and Reproduction, Quito, Ecuador; and A.L. Rosenbloom, University of Florida College of Medicine.)
GH values are high basally and are elevated in response to pharmacologic stimuli, but IGF-I levels are low. The circulating GH molecules are biologically active. The pathogenesis of the defect is failure of the liver to respond to GH by generating IGF-I. Because the extracellular domain of the GH receptor is a growth hormone–binding protein (GHBP), this protein might be expected to be absent or defective in GHIS.21 The initial direct evidence for a GH receptor defect in GHIS was that hepatocytes obtained at biopsy from a patient with this disorder did not bind tracer quantities of radiolabeled GH, although samples from control subjects undergoing abdominal surgery did.22 Subsequently, the similarity of the circulating GHBP to the GH receptor (the former is the extracellular domain of the latter) led to the finding that GHBP was absent in patients with GHIS. The clinical and biochemical characteristics of GHIS have been reviewed.23 Prominent biochemical abnormalities include low circulating levels of IGF-I, IGF-II, insulin-like growth factor–binding protein-3 (IGFBP-3), and GHBP; and levels of IGF-I, IGF-II, and IGFBP-3 that are higher in adults than in children without a change in the level of GHBP.22 A number of treatment trials with recombinant human IGF-I are under way. In all the young patients, the growth rate is accelerated. Many patients had growth rates during therapy in the range of 8 to 10 cm per year. Because of the low IGFBP-3 levels at the onset of treatment and the lack of a buffer for the injected IGF-I, some patients experienced hypoglycemia.
GROWTH HORMONE NEUROSECRETORY DYSFUNCTION. Children with dysregulation of GH secretion meet the following criteria: short stature; growth failure; bone age 2 or more years behind chronologic age; IGF-I levels low for age; and results for provocative tests for GH within normal limits.24 The children with GH deficiency meet these same criteria except that they have subnormal peak responses to provocative stimuli. Results of functional tests for other pituitary and target-gland hormones are normal. Malnutrition, systemic disease, and psychosocial dwarfism must be considered.
The normal child usually has more than six secretory episodes of GH per day, but children within this category usually have fewer than four. The number of secretory episodes, the amount of GH secreted, and the peak GH concentrations all are intermediate between values found for GH-deficient and normal children.
As greater numbers of slowly growing children are tested for GH neurosecretory dysfunction, the boundaries between normal and subnormal become more indistinct. It is not possible to determine with certitude from the 24-hour GH secretory pattern which children will respond favorably to therapy with GH. Given the expense and difficulty in determining a 24-hour secretory pattern, it may be prudent in selected children with growth failure to administer a 6-month therapeutic trial with GH. Marked acceleration in growth rate is the criterion for continued therapy. However, a number of such children respond to gonadal steroid hormone therapy with marked increases in endogenous GH secretion and growth rate.25,26,27 and 28 In fact, for boys, if the child is within the pubertal age range, treatment with low doses of testosterone (50–100 mg intramuscularly each month) would be more appropriate than GH. The question of whether low-dose estradiol will augment GH secretion and ultimate growth in girls has been insufficiently explored.
During Birth. Perinatal complications, including breech or face presentation, can lead to pituitary insufficiency because of vascular compromise to the anterior hypophysis or to the hypothalamic area. Review of the birth records of patients with non-familial hypopituitarism indicates that more than half of all hypopituitary patients have an abnormal perinatal history—an incidence much higher than in the normal population. Magnetic resonance imaging studies may show an ectopic posterior pituitary gland (“bright spot”) or interruption of the pituitary stalk.
After Birth. Trauma continues to be an important cause for hypopituitarism beyond the neonatal period. A blow to the head or face can cause bleeding in the hypothalamic area or may shear the pituitary stalk. Varying degrees of hypopituitarism result, but when the pituitary remains relatively intact, all the anterior pituitary hormones circulate in low concentrations except for high levels of prolactin.
The infiltrative diseases, whether infectious or granulomatous, may invade the hypothalamic areas that synthesize the releasing hormones or carry these factors to the median eminence. Pituitary insufficiency occurs whether the underlying disease is Langer-hans cell histiocytosis (relatively commonly associated with hypopituitarism), meningitis or encephalitis caused by a number of organisms (e.g., tuberculosis), or is a result of autoimmune phenomena from primary or metastatic deposits in the hypothalamic area (see Chap. 11 and Chap. 17). These latter causes are uncommon in adults and rare in children and adolescents.
All forms of hypothalamic–pituitary dysfunction may occur after intracranial surgery, irradiation therapy, or chemotherapy for neoplastic diseases. Data indicate growth failure and an abnormal GH secretory pattern among children who have survived acute lymphoblastic leukemia but who had received irradiation to the craniospinal axis or intrathecal therapy with antineoplastic agents.29 The growth rate of such children should be followed carefully to determine which of the children might benefit from GH therapy (see Chap. 198).
Aneurysms of the internal carotid area and arteriovenous malformations in the hypothalamic area are uncommon. However, they represent emergent but potentially treatable causes of hypopituitarism. Their diagnosis has been made much simpler with the confirmation provided by CT or MRI scanning and vascular contrast studies. Their treatment is mainly surgical.
Lymphocytic hypophysitis is rare, especially in children. It may be part of a multiple endocrine organ autoimmune syndrome or appear as an isolated condition (see Chap. 11). There are no specific clues to the diagnosis except when it is found in association with other endocrine gland dysfunction. However, this condition may be responsible for varying degrees of hypopituitarism postpartum, especially in women without an obvious hypotensive episode.
The deprivational dwarfism syndrome (psychosocial dwarfism) is characterized by behavioral aberrations, emotional disturbances in association with growth failure, and abnormalities of pituitary function30 (Fig. 18-7). These are transient and are reversed by changes in the child’s home environment. As originally described, truly bizarre behavior (e.g., eating from garbage pails or dog dishes, drinking from toilet bowls, and exhibiting severe sleep disturbances) was common. Growth failure was invariant and, early after hospitalization, test results for GH and corticotropin (ACTH) reserve were usually abnormal. The transient nature of the hypopituitary state became obvious when these children grew and gained weight at phenomenal speed during hospitalization—a rate of 1 inch per month was not unusual. The results of pituitary function tests for GH and ACTH reserve often reverted to normal within days to weeks. Return to the same home environment can cause the syndrome to recur.
FIGURE 18-7. Left, A 5-year, 4-month-old child with deprivational dwarfism related to parental neglect, abuse, and malnutrition. The child is 84.5 cm (33.5 in.) in height, corresponding to a height age of 22 months; there is moderate mental retardation. There was patchy alopecia of the scalp, moderate hirsutism of the body, and a paucity of sweating. Note the sparse abdominal fat and the prominent abdomen; hepatomegaly was present. Right, the child was hospitalized, attended to, and provided unlimited food intake. Four months later, he had gained 5.2 kg (11.5 lb) and had grown 3.8 cm (1.5 in.). He became more active and playful, the body hair diminished, and he perspired normally. (From Copps SC, Gerritsen T, Smith DW, Waisman HA. Urinary excretion of 3,4-dihydroxyphenylalanine [DOPA] in two children of short stature and malnutrition. J Pediatr 1963;62:208.)
Dysfunction of central neurotransmitter function has been postulated to explain the hypopituitarism and the sleep disturbance. The role of malnutrition is controversial but probably is unimportant in those children older than 2 years of age who can fend for themselves, although in a disturbed manner. However, for younger infants, inadequate caloric intake may play some role.
The clinical presentations are inconstant but include variable age of onset, short stature, growth failure, bizarre eating and drinking (polydipsia) behavior, and sleep disturbance with nighttime roaming and foraging. The family social situation is best described as disorganized and disrupted. Often, only one member of a larger sibship is affected.
The diagnosis is clinical, based on the detailed history and observations of the growth failure in the child and the family’s behavior. The results of endocrine tests for GH and ACTH (e.g., arginine and insulin tolerance tests) are likely to be abnormal during the first few days of hospitalization but may quickly revert to normal. There are no data concerning the use of direct tests of pituitary reserve by GHRH or corticotropin-releasing hormone.
Removal of such children from their environment is the only method of confirming the diagnosis and treating them. Truly remarkable acceleration of linear growth (catch-up growth) and weight gain are not unusual during the first few months in a more nurturing environment. The prognosis for weight gain, growth, and pubertal development are excellent, provided these children remain outside the deleterious environment or that environment is sufficiently changed to become more nurturing. Long-term psychological therapy for both the parents and the child is often necessary.
Cushing disease is mentioned here not because the pituitary adenomas associated with this condition cause growth failure, but because the excessive circulating levels of cortisol in response to the elevated ACTH concentrations are potent inhibitors of growth. In fact, excess glucocorticoids from any source can adversely affect the growth rate by inhibiting both GH secretion and GH action. Diseases of glucocorticoid excess are considered in Chapter 75 and Chapter 83.
DIAGNOSIS AND TREATMENT OF GROWTH FAILURE
The differential diagnosis of growth failure is broad; even when hypopituitarism is documented by proper testing in the appropriate clinical situation, the precise diagnosis may be elusive. The key features of the major disease entities and their criteria for diagnosis have been outlined in other chapters.
The treatment of hypopituitarism is dependent on the hormonal deficits and may include anterior and posterior pituitary hormones and some target-organ hormones or analogs. The replacement therapy strategy for diminished gonadotropin, thyroid-stimulating hormone, and ACTH concentrations is to use the target-gland hormones (Table 18-3). For diabetes insipidus, deamino-D-arginine vasopressin is preferred.
TABLE 18-3. Replacement Therapy for Pituitary Hormonal Deficiencies
Until recently, the only therapeutic option for GH deficiency was to administer human cadaveric pituitary-derived material, usually at a dose of 1 to 2 U intramuscularly three times a week. With the more purified material produced within the last decade, the incidence of circulating antibody formation was low, and only rarely was the titer high enough to attenuate growth. However, because of the limited supply, not all children with hypopituitarism could be treated, and detailed pharmacologic studies to determine the optimal dose, route, and interdose interval could not be performed. With the recent concern over the transmission of Creutzfeldt-Jakob disease by materials derived from human brain, the recombinant DNA-produced GHs are the only agents presently available.
The last several years have been exciting in terms of the development of agents for the treatment of GH insufficiency. First, the human GH structural gene has been cloned and expressed in bacteria that can produce the hormone indefinitely. The purified product is available and as potent as the native hormone.
Second, GHRH has been extracted and purified, its structure determined, and large quantities of it and other stimulatory analogs produced. Early trials with subcutaneous administration in an intermittent, pulsatile fashion have proved efficacious.31,32 Studies to determine the optimal form, dose, route, and frequency of administration are being vigorously pursued. More recent experience shows that GH-deficient children accelerate their growth when the GH dosage of 0.3 mg/kg per week is administered subcutaneously (typically subdivided into daily doses, e.g., 0.045 mg/kg per day) or when GHRH therapy is given subcutaneously (~8 g/kg per dose twice daily) or using a portable minipump (2 g/kg per dose every 3 hours).33,34 Because most children with hypopituitarism, even those with structural lesions, have suprasellar defects, this form of therapy holds promise for large numbers of GH-deficient children.35
A hexapeptide, GH-releasing peptide (GHRP), has been developed synthetically but is not homologous to the GHRH-related peptides of 40 or 44 amino acids. Its activity in humans is not diminished by somatostatin, and its ability to cause release of GH when submaximal quantities of GHRH are present is at least additive and possibly synergistic. The role of this peptide or its analogs, or the native homolog if one exists, has not yet been defined, but preliminary data from a clinical trial with one analog are available.36,37
IGF-I is also available for therapeutic protocols in the treatment of GH-deficient patients. Its major use is in patients with GHIS and in patients with GH gene deletion treated with GH and producing anti–human GH antibodies. Preliminary data are consistent with growth rates in the range of 8 to 12 cm per year, similar to those among GH-deficient children treated with recombinant GH.
The other conditions (chromosomal defects, moderate to severe systemic illness, metabolic diseases, and chondrodystrophies)38 are beyond the scope of this chapter. An extensive differential diagnosis of syndromes associated with short stature has been published.39
Usually, children more than 2 to 3 SD above the mean height for age are considered tall. Most, of course, have a normal growth rate and are considered to be “constitutionally tall” without a pathologic cause. Many are the children of tall parents and are merely fulfilling their genetic potential.
In addition to constitutional tall stature, other nonendocrine conditions associated with tall stature or excessive growth rate are cerebral gigantism, Marfan syndrome, homocystinuria, and Beckwith-Wiedemann syndrome. Endocrine dysfunctional disorders include gigantism and aberrant sexual maturation (sexual precocity, hypogonadism). From a cultural viewpoint, excessively tall girls are more likely than boys to seek therapy to diminish their predicted adult height. Although, in girls, estrogen therapy in large doses has been used in the past, with some diminution from predicted adult height, the actual and potential side effects are severe enough that this form of therapy cannot be recommended except in particularly unusual circumstances.40 Open discussion of the actions and potential deleterious effects of these potent sex steroids is often sufficient to dissuade their use.
Cerebral gigantism (Sotos syndrome) is a disorder in which a rapid growth rate and tall stature are noted in infancy and early childhood.41 These children tend to be large at birth and grow excessively the first 3 or 4 years of life (Fig. 18-8). There are a number of dysmorphic features in addition to the tall stature: prominent forehead, high-arched palate, hypertelorism, and a long head are found in more than 80% of the children, who also are likely to be developmentally retarded. The excessive body and skeletal growth and the increased incidence of malignancies suggest that this condition is primarily a disorder of growth factors, but there are no data relevant to the etiology and pathogenesis.
FIGURE 18-8. A, Patient with cerebral gigantism at age 11 years. B, Growth curve (mean and 2 SD) of the patient shown in (A). (From Hook EB, Reynolds JW. Cerebral gigantism: endocrinological and clinical observations of six patients including a congenital giant, concordant monozygotic twins, and a child who achieved adult gigantic size. J Pediatr 1967; 70:900.)
Diagnosis is based on the constellation of signs noted and cerebral ventricular widening on CT or MRI scans. The endocrine function is normal. No specific therapy exists, and although they become tall adults, few are excessively tall. The developmental delay and mental retardation do not progress.
Marfan syndrome is a heritable disorder of connective tissue in which the patient tends to be tall and to have long slim limbs, arachnodactyly, lax joints, dislocation (subluxation) of the lens, and dilation with or without dissecting aneurysm of the ascending aorta42 (see Chap. 189). During growth and development, there is a marked tendency to scoliosis (Fig. 18-9). The prognosis depends on the vascular complications. The diagnosis is clinical, with therapy directed toward the vascular lesions. The specific abnormality has now been identified.43
FIGURE 18-9. A 14-year-old girl with Marfan syndrome. There is excessive height (183 cm; 72 in.), a thin body habitus, and normal pubertal development. The face is long and thin, and the limbs, hands, and feet are elongated and spidery. Scoliosis necessitated the wearing of a body brace. There is muscle hypotonia and diminution of subcutaneous fat. There also was subluxation of the lenses. The patient was treated unsuccessfully with estrogen in an attempt to hasten skeletal maturation. Transmission of this condition is autosomal dominant. (From Rallison ML. Growth disorders in infants, children and adolescents. New York: Churchill Livingstone, 1986:330.)
Homocystinuria, also a heritable disorder of connective tissue, is characterized by tall stature, fair complexion, mild mental retardation (inconstant), slim skeletal build, and arachnodactyly resembling Marfan syndrome but with severe osteoporosis and subluxation of the lens. The latter usually is not present at birth but has been described in patients 2 years old42 (see Chap. 191).
The pathogenesis is cystathionine synthase deficiency, which is characterized by elevated plasma concentrations of methionine and homocystine and by the excretion of homocystine in the urine. The diagnosis is based on the clinical findings and the presence of homocystine in the urine. The prognosis depends on the marked tendency to form life-threatening arterial and venous thromboses. Many patients die of coronary or carotid occlusion in the second or third decade of life.42
The goals of dietary therapy are to eliminate potentially toxic substances accumulating proximal to the enzymatic deficiency and to supply those substances that are deficient distal to the defect.44
Beckwith-Wiedemann syndrome is characterized by exomphalos (omphalocele), macroglossia, neonatal hypoglycemia, and postnatal gigantism42 (Fig. 18-10). The birth weight usually is increased, but polyhydramnios and prematurity are common. Although the early growth rate is often slow, these infants subsequently show accelerated growth with macrosomia, a large muscle mass, and thick subcutaneous tissue. Most children grow near the 90th percentile and have an advanced bone age. A characteristic face with macroglossia and a protruding tongue are prominent. Visceromegaly is invariant, and there is a susceptibility to abdominal malignancies because of the loss of heterozygosity of the chromosomal locus 11p15.5, an area that contains the genes for IGF-II and a tumor-suppressor gene. The most serious problem is neonatal hypoglycemia, usually with elevated circulating concentrations of insulin; however, as these infants mature, the episodes of hypoglycemia wane. The prognosis depends on the early control of the hypoglycemic episodes. This may require systemic glucocorticoid therapy for the first few months of life.
FIGURE 18-10. A 2.5-month old infant with Beckwith-Wiedemann syndrome. There was macroglossia at birth, and an omphalocele (congenital protrusion of omentum and intestine through an abdominal opening) necessitated surgical repair in the first 24 hours of life. It had been noted that the baby was big, had large facial features, and had mild weakness of the limbs. At the time this photograph was made, the infant was in the 97th percentile for weight and the 90th percentile for length. There were prominent inner canthal folds, marked enlargement of the tongue, and a high-arched palate. The nose was broad, and there was a long upper lip philtrum. There was a flat, red flame nevus in the center of the forehead and other nevi on the cheeks as well as on the eyelids. (The midline nevus as well as the bilateral double linear indentations of the ear lobes are typical.) Other findings in this infant included a short neck, large muscle mass, hepatosplenomegaly, and a residual ventral hernia. Occasionally girls with this syndrome may have clitoromegaly at birth, and some boys have cryptorchidism. The final adult height attained is relatively tall. Mild mental retardation is common, but not uniform. The relative tongue size may regress or may necessitate surgery. The condition usually appears sporadically, but autosomal-recessive transmission has been suspected. (From Filippi G, McKusick VA. The Beckwith-Wiedemann syndrome. Medicine [Baltimore] 1970; 49:279.)
Pituitary gigantism (GH excess) is an extremely uncommon cause of accelerated growth and tall stature. The usual cause is a pituitary adenoma composed of somatotropes. However, excessive GHRH from the hypothalamus or from an ectopic source (e.g., a pancreatic islet cell tumor) may lead to a syndrome indistinguishable from that caused by a pituitary adenoma.45,46 Theoretically, lack of somatostatin secretion or excessive secretory episodes of GHRH could cause an increased release of GH.
Clinically, the patients (often adolescents) have an augmented growth rate—crossing previously defined growth percentiles in an upward direction (Fig. 18-11). They may have evidence of the acral enlargement characteristic of an adult with acromegaly (see Chap. 12). Headache, visual field abnormalities (classically, bitemporal hemianopsia), decreased visual acuity, and other signs or symptoms of increased intracranial pressure may be prominent.
FIGURE 18-11. Pituitary gigantism in two children. Growth hormone excess before the fusion of the epiphyses is characterized predominantly by rapid growth rate and excessive size and weight for age. After epiphyseal closure, growth hormone excess induces acromegalic features, including overgrowth of soft tissue, thickening of skin, widening of bones, and prominence of acral parts of the body (face, hands, feet).Many pituitary giants exhibit both increased size and acral changes, particularly if the growth hormone excess persists into adulthood. Gigantism diagnosed during childhood also may show varying degrees of acromegaly. A, A 31-month-old girl with pituitary gigantism who began to grow rapidly in her second year of life. The rapid growth and large size had been noted by the parents, who also remarked on the excessive sweating and strong body odor. The height was 104 cm (41 in.), which was 5.5 cm (2.5 in.) greater than the estimated 97th percentile. The child resembled a 4-year-old. The facial features were normal, and the hands and feet were only slightly prominent. B and C, A girl who is 5 years, 8 months old with pituitary gigantism. Her height of 118 cm (50.5 in.) corresponds approximately to a height age of 8 years, 6 months. However, this child had considerably enlarged hands and feet and marked enlargement of the jaw, nose, and ears. (A from Espiner EA, Carter TA, Abbott GD, Wrightson P. Pituitary gigantism in a 31-month-old girl: endocrine studies and successful response to hypophysectomy. J Endocrinol Invest 1981; 4:445; B and C from Hurxthal LM. Pituitary gigantism in a child five years of age: effect of x-radiation, estrogen therapy and self-imposed starvation diet during an eleven year period. J Clin Endocrinol Metab 1961; 21:343.)
Laboratory confirmation of this basically clinical diagnosis includes high circulating levels of GH and especially IGF-I and failure of the elevated GH concentrations to be suppressed after an oral glucose load.
Standard CT imaging techniques with and without contrast medium, and especially MRI, are useful in defining the anatomic limits of the pituitary tumor (see Chap. 20). Transsphenoidal microsurgery often is curative, although some groups advocate radiation therapy, either as primary treatment or in addition to intracranial surgery. With large tumors, craniotomy with direct visualization and tumor removal is preferred (see Chap. 23).
ABERRANT SEXUAL MATURATION
Aberrant sexual maturation, whether precocious in children or hypogonadal in adolescents, is associated with tall stature and an excessive growth rate47,48 (see Chap. 77 and Chap. 90, Chap. 91 and Chap. 92). The more commonly encountered conditions are listed in Table 18-4.
TABLE 18-4. Aberrant Sexual Maturation
Precocious Sexual Development. Sexual precocity occurs more commonly in girls than in boys and may be secondary to early maturation of the hypothalamic–pituitary–gonadal axis (precocious puberty) or a result of sex steroid production from the adrenal or gonad (sexual precocity, pseudoprecocious puberty). The signs of sexual maturation usually precede those of accelerated growth velocity, just as they do during normal pubertal development.
Precocious puberty may be caused by organic lesions (Fig. 18-12) or may be idiopathic (see Chap. 92).
FIGURE 18-12. Nine-year-old boy with rapid growth and sexual precocity resulting from a hamartoma of the hypothalamus.
The introduction of a long-acting gonadotropin-releasing hormone (GnRH) agonist, whose activity is based on the pharmacologic precept of down-regulation (desensitization) of the GnRH receptor on the gonadotropes, has made the goals for therapy of this condition realizable.47,48 and 49 These goals are arrest or reversal of secondary sexual maturation; decrease of the linear growth rate to a normal prepubertal velocity; slowing of skeletal maturation to increase adult stature; preservation of fertility as an adult; and prevention or amelioration of any emotional disturbance. The therapy for organic lesions causing sexual precocity, including precocious puberty, is mainly surgery or radiation with, if needed, postoperative replacement of target-gland hormones.
The most common cause of heterosexual precocity in girls is congenital virilizing adrenal hyperplasia (adrenogenital syndrome; see Chap. 77). The excessive growth is caused by the failure of adequate ACTH suppression by cortisol and the subsequent overproduction of biologically active adrenal androgens. During the first few years, the goal of administering adequate but not excessive amounts of glucocorticoids is not always easily obtainable. Although children with inadequate adrenal suppression grow excessively, the bone age matures at an even greater rate, causing the patient to be tall as a child but to enter puberty early and become short as an adult.
Hypogonadal Syndromes. A number of hypogonadal syndromes—either hypogonadotropic or hypergonadotropic—exist. The pathophysiologic disturbance that leads to excessive stature and eunuchoid body proportions is failure of epiphyseal maturation (bone age) beyond ~13 years of age and, thus, continued, albeit often slow, growth into the third decade of life (see Chap. 115).50 The therapy is mainly with gonadal steroids to produce secondary sexual characteristics and increased libido (see Table 18-3). Treatment of hypogonadotropic patients with GnRH or the gonadotropins themselves is appropriate when fertility is desired (see Chap. 16, Chap. 97 and Chap. 115).
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