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Short stature. Part II
T H E J O U R N A L OF
PEDIATRICS MAY
1978
V o l u m e 92
Number
5
M E D I C A L PROGRESS Short stature. Part H David L. Rimoin, M.D., Ph.D., and William A. Horton, M.D.,* Torrance, Calif.
THERE ARE MANY CAUSES of short stature, secondary to a variety of causes; several examples are shown in Fig. 5. Numerous classifications of short stature have been proposed based on a variety of clinical, radiographi c, genetic, and biomedical criteria; our classification is based primarily on etiology or specific pathogenic defects. Each of the major types of short stature will be reviewed, with particular emphasis on those related to pituitary dysfunction and to the skeletal dysplasias. FAMILIAL
SHORT
STATURE
Because of the wide variation in normal height, both within and among populations, many individuals who are normal for their genetic constitution may consider themselves abnormally short, i f an individual who has no signs or symptoms of disease falls above the third percentile on charts allowing for parental height adjustment, he can he said to be normal for his genetic constitution and the diagnosis of familial short stature can be made. Familial From the Division of Medical Genetics, UCLAHarbor General Hospital. Supported in part by United States Public Health Service research and training grants (HD-11966, HD00417) and research grants from the National Foundation March of Dimes and the Easter Seal Research Foundation. *Reprint address: Department of Pediatrics, UCLA School of Medicine, Harbor General Hospital Campus, 1000 W. Carson St., Torrance, CA 90509.
0022-3476/78/0592-0697500.80/0 9 1978 The C. V. Mosby Co.
short stature is Probably the most common cause of referral for short stature. CONSTITUTIONAL
GROWTH
DELAY
The second most common cause of referral for short stature is known as constitutional delay of growth, or constitutional slow maturation. Such children have no endocrine disease, are small for age, and have skeletal maturation that is commensurately delayed. These persons can be expected to undergo puberty at a relatively late age, but they have a normal pubertal growth spurt Abbreviations used hGH: human growth hormone MPHD: multitropic pituitary hormone deficiency IGHD: isolated human growth hormone deficiency LHRH: luteinizing hormone-releasing liormone GHRF: growth hormone-releasing factor TRH: thyrotropin-releasing hormone TSH: thyroid-stimulating hormone FSH: follicle-stimulating hormone LH: luteinizing hormone and reach the normal adult range for stature. Constitutional growth delay, therefore, represents the lower end of the normal curve depicting the rate Of Skeletal and pubertal development. Slow maturation is observed more frequently in boys; a similar history is often found in Other family members. Height prediction charts can be valuable in reassuring the child that he will eventually be normal in height?' 9 In the absence of severe psychologic
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Fig. 5. Children of approximately the same age (5 to 7 years) with several forms of short stature (scale in centimeters). A, Bloom syndrome, autosomal recessive, associated with intrauterine growth retardation, proportionate short stature, photosensitive rash, and predispostion to leukemia. B, Psychosocial dwarfism. Note the proportionate short stature, young appearance, and protruding abdomen. C, Multitropic pituitary hormone deficiency. Note the youthful appearance and proportionate short stature similar to Patient B. D, Achondroplasia. Note the short limbs with the arms extending only to the hip level and the peculiar facies with scooped out bridge of the nose. E, Spondyloepiphyseal dysplasia with a short trunk. Note the normal head and short neck. problems related to short stature and delayed puberty, treatment is not recommended. PSYCHOSOCIAL DWARFISM (EMOTIONAL DEPRIVATION SYNDROME) In certain children, severe emotional disturbance results in marked growth retardation (Fig. 5). A history of emotional deprivation is often difficult to obtain, and these children often have siblings of normal stature. Transient hypopituitarism, with a lack of normal hGH and adrenocorticotropic hormone responsiveness, may be demonstrated in some, but not all, patients. 17 Bone age is usually markedly delayed. The only way to establish the diagnosis is to remove the child from his environment and observe the striking catch-up growth which then occurs. The disorder presumably reflects a defect in the release of the hypothalamic-releasing hormones, secondary to central nervous system input. MALNUTRITION Chronic malnutrition retards growth. In kwashiorkor (severe protein deficiency) elevated hGH and low so~natomedin levels are consistently found; these levels return to normal after improvement of n~trition? ~ An acquired defect in somatomedin generation is likely, as well as the
absence of suitable substrates for growth. In marasmus normal or even low levels of hGH have been found? 9 CHRONIC
DISEASES
Many chronic diseases of childhood are associated with retarded growth. Decreased somatomedin concentrations have been found in chronic renal failure TM and chronic liver disease, 19 and have been associated with excess corticosteroids, 12 whether produced endogenously or administered. Many chronic diseases result in a' chronic catabolic state with negative nitrogen balance. Poor absorption of nutrients may be found in gastrointestinal disorders, such as regional ileitis. There is also a tendency for chronically ill children to have delayed puberty, suggesting that hypothalamic suppression and decreased hGH secretion also contribute to growth retardation. After cure or control of the disease, there is usually catchup growth, the final adult stature depending on the duration and severity of the disorder. INTRAUTERINE RETARDATION
GROWTH
Intrauterine growth retardation eous group of disorders. In most obscure. Many o f these children, nized syndromes, which include
includes a heterogencases, the etiology is however, have recogthe Bloom syndrome
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Short stature
(Fig. 5), Seckel syndrome, Donahue syndrome, and Dubowitz syndrome (all apparently autosomal recessive), and progeria, Hallermann-Streiff syndrome, RussellSilver dwarfism, Cornelia De Lange syndrome, and Williams syndrome, which usually occur sporadically. In addition, a variety of known intrauterine insults may severely reduce growth. These include intrauterine infections such as rubella, syphilis, toxoplasmosis, and cytomegalic inclusion disease, as well as the maternal consumption of teratogens such as ethanol, nicotine, hydantoins, and warfarin. In all of these disorders there is probably a defect in cellular proliferation. CHROMOSOMAL
ANOMALIES
Most chromosomal anomalies are associated with growth retardation, which is usually evident at birth. Many of those that are consistent with survival beyond infancy (trisomy 21, a variety of partial deletion and duplication syndromes, and most syndromes associated with abnormal X chromosomes) are characterized by continued slow growth into adulthood and, often, a lack of the pubertal growth spurt. End organ failure is suggested by normal hGH levels and the elevated somatomedin levels in the Turner syndrome. 2~In contrast, the XXY and XYY syndromes are associated with tall stature. ~1
D I S O R D E R S OF hGH S E C R E T I O N AND ACTION Pituitary defciency, a recognized cause of proportionate short stature, represents a heterogeneous group of disorders secondary to a variety of genetic and acquired defects in hGH secretion or action. Indeed, defects at all levels of the hypothalamic-pituitary-somatomedin-chondro-osseous axis have now been described. 2I The types of pituitary dwarfism can be classified on the basis of (1) the level of the defect; (2) whether it is genetic or acquired and, if genetic, on the mode of inheritance; (3) whether or not there is an obvious developmental or degenerative disease of the hypothalamus or pituitary; (4) whether the pituitary deficiency is monotropic (isolated growth hormone deficiency) or multitropic; and (5) in those cases due to a defect in growth hormone action, whether somatomedin generation is normal or defective. Acquired pituitary insufficiency. The most common causes of acquired prepubertal pituitary insufficiency are birth trauma, cranial irradiation for neoplasia, craniopharyngioma, in which the expanding tumor mass compromises pituitary function, and histiocytosis X, in which histiocytic 'infiltration of the hypothalamus Occurs.
Major developmental malformations. A number of developmental anomalies of the hypothalamus and pitui-
699
tary result in hGH deficieny with or without other tropic hormone deficiencies.2l These anomalies include congenital absence of the pituitary, anencephaly, and a spectrum of malformation syndromes associated with imparied cleavage of midline central nervous system structures (holoprosencephaly) and facial structures. These syndromes range in severity from cyclopia with severe holoprosencephaly through septo-optic dysplasia to simple cleft lip and palate associated with pituitary insufficiency. Multitropic pituitary hormone deficiency. Multitropic pituitary hormone deficiency, formerly called panhypopituitary dwarfism, is associated with hGH deficiency and a deficieny of one or more of the other pituitary tropic hormones. Although the great majority are sporadic, at least two genetic types of the disease have been described-autosomal recessive and X-linked recessive. ~ There is both interfamilial and intrafamilial variation in the associated hormonal deficiencies; in certain families one individual may lack all of the tropic hormones, whereas another may lack only hGH and gonadotropin. However, at least hGH and gonadotropin deficiency occur in all affected members; there have been no familial crossovers between MPHD and isolated hGH deficiency reported. Unfortunately, there are no clinical or endocrine differences between the two genetic forms of MPHD and the more common acquired disease. The clinical features of MPHD depend on which of the tropic hormones are deficient. The hGH deficiency results in proportionate dwarfism, increased subcutaneous adipose tissue, a characteristic high-pitched voice, and wrinkled skin. Gonadotropin deficiency results in sexual infantilism and infertility. TSH deficiency, when it occurs, is usually mild and does not often result in severe thyroid deficiency. ACTH deficiency m a y contribute to severe hypoglycemia in infancy and childhood. Isolated human growth hormone deficiency. An isolated deficiency of hGH with otherwise normal pituitary function results in proportionate dwarfism with normal sexual development (Fig. 5). Although most examples of hGH deficiency have a typical physical appearance and characteristic metabolic abnormalities, it is now apparent that IGHD is a heterogeneous group of disorders. 22 The most common form of IGHD, Type I, is inherited as an autosomal recessive and is associated with proportionate dwarfism, increased subcutaneous fat, typical round, full facies with high forehead, high-pitched voice, and, in adulthood, wrinkled skin. These patients may have spontaneous hypoglycemic episodes in infancy; hypoglycemia is not a problem after early childhood, although hypersensitivity to exogenous insulin is maintained into adulthood. 22 As adults, these patients charac-
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teristically have abnormal glucose tolerance associated with insulinopenia, both of which revert to normal with hGH therapy. Puberty occurs spontaneously but is frequently delayed to the late teens or early twenties; however, puberty frequently appears during the first few months o f h G H therapy. Thus, in the prepubertal individual, IGHD cannot be clinically distinguished from a combined deficiency of hGH and gonadotropins, at least until the early twenties. Stimulation studies of luteinizing hormone-releasing hormone may prove to be valuable in distinguishing between these two disorders. Deficiency of hGH, inherited as an autosomal dominant trait, has been called Type II IGHD. Individuals with this deficiency do not have the wrinkled skin or characteristic voice seen in other pituitary dwarfs. They have glucose intolerance, but have an increased, rather than a decreased, insulin response to both glucose ingestion and arginine infusion. ~2 First reports indicated that they were relatively resistant to exogenous insulin and to the metabolic effects of exogenous hGH. 2:~ It is now clear that further heterogeneity exists in the 1GHD syndromes, since there have been families reported with apparent dominant inheritance who have the metabolic features of the recessive form and there may be nongenetic forms of the disorder. TM 25 Pathogenetic mechanisms in pituitary dwarfism. An abnormality in growth hormone secretion could theoretically be due to a structural or degenerative defect of the hypothalamus or pituitary or a defect in the structure, synthesis, or secretion of growth hormone-releasing factor, somatostatin, or hGH. The anomalies associated with hGH deficiency have demonstrated that structural abnormalities of the hypothalamus and pituitary do exist; it is possible that less conspicuous anomalies limited to the hypothalamus or pituitary cause some of the idiopathic forms of hGH deficiency. It is difficult to visualize a metabolic defect or structural gene mutation that could result in a deficiency of two or more tropic hormones that lack a common subunit; thus, it is quite likely that a structural, degenerative, or secretory defect in the pituitary or hypothalamus exits in hereditary MPHD. Thyrotropin-releasing hormone and LHRH administration have been found to result in secretion of thyroidstimulating hormone and luteinizing hormone, respectively, in approximately two-thirds of patients with MPHD. In those patients with a positive response to the hypothalamic-releasing hormone, the pituitary is capable of synthesizing and secreting the tropic hormone, indicating that the basic defect lies in the hypothalamus. In the minority of cases who do not respond to TRH or LHRH, a defect located in the pituitary itself is more likely. Since the structure of GHRF~s not yet known, it is presently impossible to utilize releasing hgrmone stimula-
The Journal of Pediatrics May 1978
tion studies to pinpoint the defect in IGHD. Autopsies in three cases of IGHD Type I have revealed the presence of typical somatotropic ceils in the pituitary and, in one case, the presence ofimmunoreactive growth hormone, demonstrating the capability of the pituitary to synthesize hGH. 25 Thus, the defect in these patients appears to be a deficiency of GHRF or a defect in the releasing-hormone receptor of the somatotropic cell. Once the structure of GHRF becomes known and its synthesis possible, it will be of great therapeutic importance to delineate the exact mechanism in each patient with pituitary dwarfism, in order to determine whether GHRF or hGH will be required for growth stimulation. Laron dwarfism. Laron ~ and his colleagues described an autosomal recessive syndrome with the clinical features of pituitary dwarfism associated with high, rather than low, plasma concentrations of immunoreactive hGH. These individuals have the clinical appearance of patients with IGHD but to an exaggerated extent, with severe growth retardation, severely pinched facies, high-pitched voice, and small genitalia if male. They have spontaneous hypoglycemic episodes in infancy and have insulinopenia in response to glucose and arginine. Secretion of ACTH, TSH, gonadotropin, and vasopressin is normal. Fasting plasma hGH concentrations are usually elevated, but may fluctuate from normal levels to over 100 ng/ml in the same patient. Plasma somatomedin levels are low and, unlike those in hGH-deficient patients, do not respond to administration of hGH. The patients are relatively unresponsive to the metabolic and growth promoting effects of growth hormone. Laron dwarfism appears to involve a defect in somatomedin generation. The African pygmies. Peripheral unresponsiveness to human growth hormone administration, in the presence of normal concentrations of immunoreactive plasma hGH and normal somatomedin activity, has been documented in the African pygmies. 27 They resemble pituitary dwarfs in size and skeletal proportions, but do not have the trnncal obesity, peculiar facies, and wrinkled skin of pituitary dwarfism. After insulin-induced hypogly.cemia and arginine infusion, plasma hGH levels are normal. Like patients with Type I IGHD, pygmies are insulinopenic and hypersensitive to the effects of exogenous insulin. They are unresponsive to the lipolytic, insulinotropic, and nitrogen retaining properties of hGH, and their small size is presumably secondary to a similar unresponsiveness to the growth promoting properties of the molecule. Unlike Laron dwarfs, who are unable to generate somatornedin, the African pygmies may have a defect in somatomedin receptors. Although no welldocumented instances of peripheral unresponsiveness to hGH with normal plasma hGH and somatomedin activity
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Short stature
70 1
have been described in other ethnic groups, it is possible that growth hormone resistance may be a relatively common cause of short stature. The normal variation in stature that exists within and among all ethnic groups may be due, in part, to variation in the peripheral responsiveness to hGH and somatomedin. THE SKELETAL
DYSPLAS1AS
The skeletal dysplasias compose a heterogeneous group of disorders associated with abnormalities in the size and shape of the limbs, trunk, and skull which frequently result in disproportionate short stature. Until the 1960s, most disproportionate dwarfs were considered to have either achondroplasia (those with short limbs), or Morquio disease (those with short trunk). It is now apparent that there are well over 50 distinct chondrodystrophies; they have been classified on the basis of roentgenographic or clinical characteristics. 2~-~~ Current nomenclature for these disorders is most confusing and is based on the part of the skeleton that is affected roentgenographically (the epiphyseal dysplasias, the metaphyseal dysplasias), on a Greek term that describes the appearance of the bone or the course of the disease (diastrophic [twisted] dysplasia, thanatophoric [death seeking] dysplasia) or on an eponym (Kniest dysplasia, Ellis-van Creveld syndrome). The extent of the heterogeneity in these disorders and the variety of methods used for classification have resulted in confusion. Clinical classifications have divided the chondrodystrophies into those with short-limbed dwarfism versus short trunk dwarfism: achondroplasia or spondyloepiphyseal dysplasia (Fig. 5). The short-limbed varieties have been further subdivided on the basis of the segment of the long bones that is most severely involved; rhizomelic or proximal segment shortening (achondroplasia), mesomelic or middle segment shortening (dyschondrosteosis) and acromelic or distal segment shortening (peripheral dysostosis). Other clinical classifications have been based on the age of onset of the disorder: those disorders that manifest themselves at birth (achondroplasia) versus those that first manifest in later life (pseudoachondroplasia). Associated clinical abnormalities have also been used in subdividing these disorders. Examples are the myopia of spondyloepiphyseal dysplasia congenita, the cleft palate of the Kniest dysplasia, the fine hair of cartilage-hair hypoplasia, and the polydactyly and congenital heart disease of the Ellis-van Creveld syndrome. Other disorders have been classified on the basis of their apparent mode of inheritance; for example, the dominant and the X-linked varieties of spondyloepiphyseal dysplasia. The most widely used method for differentiating the
Fig. 6. Classification of chondrodystrophies based on radiologic involvement of long bones (A,B,C) and vertebrae (D,E). Involvement
A+ B+ C+ B+ C+
D D D E E
Disease category
Normal Epiphyseal dysplasia Metaphyseal dysplasia Spondyloepiphyseal dysplasia Spondylometaphyseal dysplasia
skeletal dysplasias, however, has been the detection of skeletal roentgenographic abnormalities. The radiographic Classifications are based on the different parts of the long bones that are abnormal (epiphyses, metaphyses, or diaphyses) (Fig. 6). Thus, there are epiphyseal and metaphyseal dysplasias, which can be further divided, depending on whether or not the spine is also involved (spondyloepiphyseal dysplasias, spondylometaphyseal dysplasias). Furthermore, each of these classes can be further divided into several distinct disorders based on a variety of other clinical or radiographic differences. In an attempt to develop a uniform nomenclature for these syndromes, an international nomenclature for constitutional diseases of bone was proposed in 1970 and updated in 1977. The international nomenclature divided the skeletal dysplasias into two major groups: the osteochondrodysplasias (abnormalities of cartilage or bone growth and development); and the dysostoses (malformations of individual bones, singly or in combination). The osteochondrodysplasias are further subclassified into: (1) defects of growth of tubular bones or spine or both (achondroplasia), which are frequently named the chondrodystrophies; (2) disorganized development of cartilage and fibrous components of the skeleton (multiple cartilagenous exostoses); and (3) abnormalities of density or of cortical diaphyseal structure or of metaphyseal modeling (osteogenesis imperfecta). The chondrodystrophies are further subdivided into those disorders that are manifest at birth, as opposed to those that first become apparent later. This division may be purely artificial, since identical pathogenic mechanisms of differing severity may occur in
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Table I. Pathophysiologic classification of the skeletal dysplasias Site of defect 1. Limb bud development 2. Cartilage anlage development 3. Chondrocyte metabolism 4. Chondrocyte proliferation 5. Chondrocyte maturation a n d degeneration 6. Epiphyseal ossification 7. Membranous ossification
8. Ossificationgeneralized 9. Calcified cartilage resorption 10. Bone resorption
11. Aberrant chondrocyte growth
12. Premature epiphyseal fusion
Mechanism
Possible examples
Arrest in fetal bone development
Grebe disease 3~'
Cartilage anlage from which bone arises develops abnormally in size or shape or both A metabolic defect may lead to abnormalities in the matrix secreted or reduced survival of the resting chondrocyte Reduced cell division in the proliferative zone results in diminished linear bone growth Abnormalities of the normal chondrocyte maturation degeneration sequence (column development) lead to irregular metaphyseal vascular invasion and bone formation Abnormality in development of epiphyseal ossification centers (secondary ossification) Failure of fibroblast cells in periosteum to transform into osteoblasts or produce normal bone matrix (osteoid) results in irregular cortical ossification Abnormality in bone matrix composition or mineralization Failure to resorb calcified cartilage spicules leads to increased skeletal density Failure to resorb cortical bone results in poorly modeled bones of increased density
Achondrogenesis: Parenti-Fraccaro type~~ some forms of mesomelic dwarfism3~
Erratic and excessive growth of chondrocytes disturbs the normal growth plate and extends into (enchondroma) or outside (exostosis) the metaphysis Early closure of growth plate produces shortening of tubular bones
allelic disorders. Thus, the more severe mutation could result in abnormalities obvious at birth, whereas in the milder disorder the clinical appearance may be normal at birth. Furthermore, m a n y disorders that share c o m m o n radiographic features and have been classified into one group, such as the spondyloepiphyseal dysplasias, may result from completely different pathologic mechanisms. In recent years, we and others have defined the histochemical and ultrastructural characteristics o f cartilage and bone in m a n y of the chondrodystrophies. 3~ :~ These studies have yielded numerous clues to the pathogenesis of these disorders. On the basis of these observations, we propose a tentative pathophysiologic classification of the skeletal dysplasias (Table I). Those disorders which appear to best illustrate the postulated mechanisms have been chosen as examples. The pathologic mechanisms involved in m a n y of these disorders may only be surmised; in several, a n u m b e r of different mechanism appear to be operating. Moreover, in some disorders, we have absolutely no information on which to base a
Diastrophic dysplasia32; Kniest dysplasia3~; achondrogenesis: Langer-Saldino type~~ mucopolysaccharidoses ~~ Adenosine deaminase deficiency~3; achondroplasia~~ Metaphyseal chondrodysplasias3~ thanatophoric dysplasia~~
Multiple epiphyseal dysplasias 3' Melnick-Needles syndrome ~
Osteogenesis imperfecta~4; hypophosphatasia ~" Osteopetrosis35; dysosteosclerosis ~s Hyperostotic bone dysplasias 3~.~' (craniometaphyseal dysplasia, Engelmann disease) Oilier disease~4; multiple exostosis syndrome
Tricho-rhino-phalangeal syndrome ~~
classification. Nevertheless, this scheme represents an attempt to classify these disorders pathophysi01ogically and may serve as a model for future studies. Not until the basic biochemical defect and specific mechanism underlying each of the skeletal dysplasias is identified will a completely adequate classification be possible. CLINICAL STATURE
EVALUATION
OF SHORT
Once an abnormality in stature is established by the use of the appropriate growth curves with adjustment for ethnic background and parental height, the general category of disease must be identified; skeletal, endocrine, nutritional, cytogenetic, or intrauterine growth retardation. In general, patients with disproportionate short stature have skeletal dysplasias, whereas those with relatively normal body proportions have endocrine, nutritional, prenatal, or other nonskeletal defects. There are exceptions to these rules, as cretinism can lead to disproportionate short stature, and a variety of skeletal dyspla-
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sias, such as osteogenesis imperfecta and hyp0phosphatasia, may result in normal body proportions. A disproportionate body habitus may not be readily apparent on casual physical examination. Thus measurements, such as upper to lower segment ratio, sitting height, and arm span, must be obtained, before the possibility of a mild skeletal dysplasia, such as hypochondroplasia or multiple epiphyseal dysplasia, can be excluded. In those patients with normal body proportions and no evidence of body deformity, a nonskeletal form of short stature should be considered. A history of small birth length for gestational age suggests one of the forms of intrauterine growth retardation or a cytogenetic abnormality, whereas a proportionate child whose birth length was normal is more likely to have an endocrine, metabolic, nutritional, emotional or other chronic disease. Complete history and physical examination will often help rule out nutritional, metabolic, and chronic disease states. In those patients with intrauterine growth retardation, a careful search for other dysmorphic features may result in the diagnosis of a specific syndrome. A blood karyotype in these latter patients may be diagnostic. Proportionate short stature with postnatal onset, in the absence of other manifestations of chronic'disease, suggests an endocrine, metabolic, emotional, or nutritional disorder. Bone age is frequently useful in determining whether skeletal development is severely retarded, with bone age less than height age, as would be the case in multitropic pituitary hormone deficiency or cretinism. If bone age is equal to height age, constitutional delay, the emotional deprivation syndrome, and isolated growth hormone deficiency should be considered. Patients with constitutional delay, however, are usually not as severely growth retarded as those with organic or emotional hypopituitarism. In those patients with significant proportionate short stature of postnatal onset, endocrine laboratory evaluation is essential. If the growth delay is not severe, or if there are no other clinical signs of endocrine deficiency disease, a simple stimulatory test for hGH secretion may be sufficient. Since basal plasma hGH levels are normally low to absent, provocative tests are required to rule out hGH deficiency?~ In our experience, an L-dopa stimulation test is the best screening procedure for hGH deficiency; it can be done on an outpatient, does not require intravenous fluids, and takes only 90 minutes. The exercise stimulation test is also a useful outpatient procedure. Priming the patient with estrogen or propanolol may also be useful. Since normal individuals frequently fail to respond to any one of the hGH stimuli, if L-dopa or exercise fails to produce a rise in plasma hGH to over 7 ng/ml., arginine- or insulin-induced hypoglycemia tests should be performed. Lateral skull radio-
Short stature
703
graphs, tomographs of the sella turcica, or CAT scans should also be performed in patients suspected of having growth hormone deficiency to rule Out a congenital anomaly of the sella or an intrasellar tumor. The other pituitary tropic hormones can be readily evaluated by plasma thyroxinel TSH, testosterone, FSH, and LH assays and a plasma cortisol and metapyrone test. If TSH or LH deficiencies are found, TRH and LHRH stimulatory studies are indicated to determine whether there is a pituitary or hypothalamic abnormality. The differential diagnosis of disproportionate dwarfism requires a variety of clinical observations: Are the limbs relatively short compared to the trunk (short limb dwarfism), or is the trunk primarily affected (short trunk dwarfsim)? Are all of the segments of the limbs equally shortened, or does the shortening primarily affect the proximal (rhizomelic), middle (mesomelic), or distal (acromelic) segments? Is the disease limited to the skeleton, or are there extraskeletal abnormalities such as lax ligaments, myopia, or hearing loss? The answers to these questions may be sufficient to allow an accurate diagnosis, or at least to limit the differential diagnosis to a relatively small number of disorders. The next step in the evaluation of the disproportionately short patient is to obtain skeletal radiographs. A series of skeletal views, including the skull, spine, pelvis and extremities, is usually required. Skeletal radiographs alone will often be sufficient to make an accurate diagnosis, since the classification of the chondrodystrophies has been based primarily on roentgenology. Attention should be paid to the specific parts of the skeleton that are involved (spine, limbs, pelvis, skull) and, within each bone, where the lesion appears to lie (epiphysis, metaphysis, diaphysis). The skeletal radiographic features of many of these diseases change with age and it is usually beneficial to review radiographs taken at different ages when possible. In some disorders, the radiographic abnormalities following epiphyseal fusion are nonspecific, so that the accurate diagnosis of an adult disproportionate dwarf may be impossible unless prepubertal films are available. In many instances, the general type of dysplasia can be readily subclassified, such as spondyloepiphyseal dysplasia, but further information may be required to diagnose its exact form: The family history is often helpful. For example, if two dwarfed siblings are born to normal parents, achondroplasia, which is an autosoma! dominant trait, is unlikely. Furthermore, different modes of inheritance have been observed in disorders that cannot be distinguished clinically, such as the tarda forms of spondyloepiphyseal dysplasia. In some instances, microscopic and ultrastructural eval-
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uation of chondroosseous tissue may be helpful in making an accurate diagnosis of the chondrodystrophies? ~ 35 In many of the chondrodystrophies, specific histologic alterations have been identified. Histologic evaluation of autopsy tissue from a deceased affected relative may aid in the diagnosis. In some disorders, however, no histopathologic alterations are present, or they are nonspecific: pathologic examination in these cases is useful only in ruling out a diagnosis. Unfortunatelv. biochemical procedures are presently of little value in the diagnosis of the chondrodystrophies. Exceptions are urinary mucopolysaccharide and lysosomal enzyme assays in the mucopolysaccharidoses, and serum calcium, phosphorus, and alkaline phosphatase determinations in disorders such as hypophosphatemic rickets and hypophosphatasia W h e n the basic biochemical defect in each of these disorders is elucidated and biochemical markers become available, diagnosis of the chondrodystrophies will be much easier. Thus. the clinical evaluation of short stature requires a wide variety of clinical, radiographic, pathologic, and biochemical tools. Although specific therapy to promote growth is available only in the endocrinopathies and the acquired nutritional, emotional, and chronic disease states, once the pathogenesis of the remaining forms of short stature is identified, specific forms of treatment or prevention may evolve. Furthermore, diagnosis of the specific form o f short stature can have great importance in prognosis, prevention and treatment of these disorders, and for accurate genetic counseling.
The Journal o f Pediatrics May 1978
21.
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23.
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25.
26.
27.
28. 29.
30. 31.
32.
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17. Powell GF, Brazel JA, Raiti S, and Blizzard RM: Emotional deprivation and growth retardation simulating idiopathic hypopituitanism, II endocrinologic evaluation of patients, N Engl J Med 276:1279, 1967. 18. Saenger P, Wiedemann G, Schwartz E, Karth-Schutz S, Lewy JE, Riggio RR, Rubin AL, Stenzel KH, and New MI: Somatomedin and growth after renal transplantation, Pediatr Res 8:163, 1974. 19. Wu A, Grant DB, Hambley J, and Levi A J: Reduced serum somatomedin activity in patients with chronic liver disease. Reduced serum somatomedin activity in patients with chronic liver disease, Clin Sci Mol Med 47:359, 1974. 20. Daughaday WH, Laron Z, Pertzelan A, and Hems JN:
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Defective sulfation.factor generation: A possible etiologic link in dwarfism, Trans Assoc Amer Physicians 82:129, 1969. Rimoin DL, and Schimke RN: Genetic disorders of the endocrine glands, St. Louis, 1971, The CV Mosby Company. Rimoin DL: Hereditary forms of growth hormone deficiency and resistance, Birth Defects: Original Article Series 12:15, 1976. Merimee TJ, Rimoin DL, Hall JG, and McKusick VA: A metabolic and hormonal basis for classifying ateliotic dwarfs, Lancet 1:963, 1969. Poskitt EME, and Rayner PHW: Isolated growth hormone deficiency, two families with autosomal dominant inheritance, Arch Dis Child 49:55, 1974. Rimoin DL: Hereditary forms of growth hormone deficiency and resistance, Birth Defects: Original Article Series 12:15, 1976. Laron Z: Syndrome Of familial dwarfism and high plasma immunoreactive growth hormone, Isr J Med Sci 10:1247, 1974. Merimee TJ, Rimoin DL, Penetti G, and Cavalli-Sforza LL: Growth retardation in the African pygmy, J Clin Invest 51:395, 1972. Maroteaux P: Les maladies osseuses de l'enfant, Paris, i974, Flammarion Medicine-Sciences. Spranger JW, Langer LO, and Wiedemann HR: Bone dysplasias: An atlas of constitutional disorders of skeletal development, Philadelphia 1974, WB Saunders Company. Rimoin DL: The chondrodystrophics, Adv Hum Genet g: 1, 1975. Stanescu V, Stanescu R, and Maroteaux P: Etude morphologique et biochemique du cartilage de croisSance dans.les osteochondrodysplasias, Arch Fr Pediatr 34 (Suppl 3): 1, 1977. Horton WA, and Rimoin DL: Histochemical evaluation of the growth plate, a new approach to studying the chondr0cystr0phies , Birth Defects: Original Article Series (in press). Kaitila I, Rimoin DL, Cederbaum SD, Stiehm ER, and Lachman RS: Chondroosseous histopathology in adenosine deaminase deficient combined immuno-deficiency disease, Birth Defects: Original Article Series 12:115, 1976. Rimoin DL: Pathogenetic mechanisms of limb malformation in the skeletal dysplasias, Birth Defects: Original Article Series 13:339 , 1977. Kaitila I, and Rimoin DL: Histologic heterogeneity in the hyperostotic bone dysplasias, Birth Defects: Original Article Series 12:71, 1976. Frasier SD: A review of growth hormone stimulation tests in children, Pediatrics 53:929, 1974.
PEDIATRICS MAY
1978
V o l u m e 92
Number
5
M E D I C A L PROGRESS Short stature. Part H David L. Rimoin, M.D., Ph.D., and William A. Horton, M.D.,* Torrance, Calif.
THERE ARE MANY CAUSES of short stature, secondary to a variety of causes; several examples are shown in Fig. 5. Numerous classifications of short stature have been proposed based on a variety of clinical, radiographi c, genetic, and biomedical criteria; our classification is based primarily on etiology or specific pathogenic defects. Each of the major types of short stature will be reviewed, with particular emphasis on those related to pituitary dysfunction and to the skeletal dysplasias. FAMILIAL
SHORT
STATURE
Because of the wide variation in normal height, both within and among populations, many individuals who are normal for their genetic constitution may consider themselves abnormally short, i f an individual who has no signs or symptoms of disease falls above the third percentile on charts allowing for parental height adjustment, he can he said to be normal for his genetic constitution and the diagnosis of familial short stature can be made. Familial From the Division of Medical Genetics, UCLAHarbor General Hospital. Supported in part by United States Public Health Service research and training grants (HD-11966, HD00417) and research grants from the National Foundation March of Dimes and the Easter Seal Research Foundation. *Reprint address: Department of Pediatrics, UCLA School of Medicine, Harbor General Hospital Campus, 1000 W. Carson St., Torrance, CA 90509.
0022-3476/78/0592-0697500.80/0 9 1978 The C. V. Mosby Co.
short stature is Probably the most common cause of referral for short stature. CONSTITUTIONAL
GROWTH
DELAY
The second most common cause of referral for short stature is known as constitutional delay of growth, or constitutional slow maturation. Such children have no endocrine disease, are small for age, and have skeletal maturation that is commensurately delayed. These persons can be expected to undergo puberty at a relatively late age, but they have a normal pubertal growth spurt Abbreviations used hGH: human growth hormone MPHD: multitropic pituitary hormone deficiency IGHD: isolated human growth hormone deficiency LHRH: luteinizing hormone-releasing liormone GHRF: growth hormone-releasing factor TRH: thyrotropin-releasing hormone TSH: thyroid-stimulating hormone FSH: follicle-stimulating hormone LH: luteinizing hormone and reach the normal adult range for stature. Constitutional growth delay, therefore, represents the lower end of the normal curve depicting the rate Of Skeletal and pubertal development. Slow maturation is observed more frequently in boys; a similar history is often found in Other family members. Height prediction charts can be valuable in reassuring the child that he will eventually be normal in height?' 9 In the absence of severe psychologic
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Fig. 5. Children of approximately the same age (5 to 7 years) with several forms of short stature (scale in centimeters). A, Bloom syndrome, autosomal recessive, associated with intrauterine growth retardation, proportionate short stature, photosensitive rash, and predispostion to leukemia. B, Psychosocial dwarfism. Note the proportionate short stature, young appearance, and protruding abdomen. C, Multitropic pituitary hormone deficiency. Note the youthful appearance and proportionate short stature similar to Patient B. D, Achondroplasia. Note the short limbs with the arms extending only to the hip level and the peculiar facies with scooped out bridge of the nose. E, Spondyloepiphyseal dysplasia with a short trunk. Note the normal head and short neck. problems related to short stature and delayed puberty, treatment is not recommended. PSYCHOSOCIAL DWARFISM (EMOTIONAL DEPRIVATION SYNDROME) In certain children, severe emotional disturbance results in marked growth retardation (Fig. 5). A history of emotional deprivation is often difficult to obtain, and these children often have siblings of normal stature. Transient hypopituitarism, with a lack of normal hGH and adrenocorticotropic hormone responsiveness, may be demonstrated in some, but not all, patients. 17 Bone age is usually markedly delayed. The only way to establish the diagnosis is to remove the child from his environment and observe the striking catch-up growth which then occurs. The disorder presumably reflects a defect in the release of the hypothalamic-releasing hormones, secondary to central nervous system input. MALNUTRITION Chronic malnutrition retards growth. In kwashiorkor (severe protein deficiency) elevated hGH and low so~natomedin levels are consistently found; these levels return to normal after improvement of n~trition? ~ An acquired defect in somatomedin generation is likely, as well as the
absence of suitable substrates for growth. In marasmus normal or even low levels of hGH have been found? 9 CHRONIC
DISEASES
Many chronic diseases of childhood are associated with retarded growth. Decreased somatomedin concentrations have been found in chronic renal failure TM and chronic liver disease, 19 and have been associated with excess corticosteroids, 12 whether produced endogenously or administered. Many chronic diseases result in a' chronic catabolic state with negative nitrogen balance. Poor absorption of nutrients may be found in gastrointestinal disorders, such as regional ileitis. There is also a tendency for chronically ill children to have delayed puberty, suggesting that hypothalamic suppression and decreased hGH secretion also contribute to growth retardation. After cure or control of the disease, there is usually catchup growth, the final adult stature depending on the duration and severity of the disorder. INTRAUTERINE RETARDATION
GROWTH
Intrauterine growth retardation eous group of disorders. In most obscure. Many o f these children, nized syndromes, which include
includes a heterogencases, the etiology is however, have recogthe Bloom syndrome
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Short stature
(Fig. 5), Seckel syndrome, Donahue syndrome, and Dubowitz syndrome (all apparently autosomal recessive), and progeria, Hallermann-Streiff syndrome, RussellSilver dwarfism, Cornelia De Lange syndrome, and Williams syndrome, which usually occur sporadically. In addition, a variety of known intrauterine insults may severely reduce growth. These include intrauterine infections such as rubella, syphilis, toxoplasmosis, and cytomegalic inclusion disease, as well as the maternal consumption of teratogens such as ethanol, nicotine, hydantoins, and warfarin. In all of these disorders there is probably a defect in cellular proliferation. CHROMOSOMAL
ANOMALIES
Most chromosomal anomalies are associated with growth retardation, which is usually evident at birth. Many of those that are consistent with survival beyond infancy (trisomy 21, a variety of partial deletion and duplication syndromes, and most syndromes associated with abnormal X chromosomes) are characterized by continued slow growth into adulthood and, often, a lack of the pubertal growth spurt. End organ failure is suggested by normal hGH levels and the elevated somatomedin levels in the Turner syndrome. 2~In contrast, the XXY and XYY syndromes are associated with tall stature. ~1
D I S O R D E R S OF hGH S E C R E T I O N AND ACTION Pituitary defciency, a recognized cause of proportionate short stature, represents a heterogeneous group of disorders secondary to a variety of genetic and acquired defects in hGH secretion or action. Indeed, defects at all levels of the hypothalamic-pituitary-somatomedin-chondro-osseous axis have now been described. 2I The types of pituitary dwarfism can be classified on the basis of (1) the level of the defect; (2) whether it is genetic or acquired and, if genetic, on the mode of inheritance; (3) whether or not there is an obvious developmental or degenerative disease of the hypothalamus or pituitary; (4) whether the pituitary deficiency is monotropic (isolated growth hormone deficiency) or multitropic; and (5) in those cases due to a defect in growth hormone action, whether somatomedin generation is normal or defective. Acquired pituitary insufficiency. The most common causes of acquired prepubertal pituitary insufficiency are birth trauma, cranial irradiation for neoplasia, craniopharyngioma, in which the expanding tumor mass compromises pituitary function, and histiocytosis X, in which histiocytic 'infiltration of the hypothalamus Occurs.
Major developmental malformations. A number of developmental anomalies of the hypothalamus and pitui-
699
tary result in hGH deficieny with or without other tropic hormone deficiencies.2l These anomalies include congenital absence of the pituitary, anencephaly, and a spectrum of malformation syndromes associated with imparied cleavage of midline central nervous system structures (holoprosencephaly) and facial structures. These syndromes range in severity from cyclopia with severe holoprosencephaly through septo-optic dysplasia to simple cleft lip and palate associated with pituitary insufficiency. Multitropic pituitary hormone deficiency. Multitropic pituitary hormone deficiency, formerly called panhypopituitary dwarfism, is associated with hGH deficiency and a deficieny of one or more of the other pituitary tropic hormones. Although the great majority are sporadic, at least two genetic types of the disease have been described-autosomal recessive and X-linked recessive. ~ There is both interfamilial and intrafamilial variation in the associated hormonal deficiencies; in certain families one individual may lack all of the tropic hormones, whereas another may lack only hGH and gonadotropin. However, at least hGH and gonadotropin deficiency occur in all affected members; there have been no familial crossovers between MPHD and isolated hGH deficiency reported. Unfortunately, there are no clinical or endocrine differences between the two genetic forms of MPHD and the more common acquired disease. The clinical features of MPHD depend on which of the tropic hormones are deficient. The hGH deficiency results in proportionate dwarfism, increased subcutaneous adipose tissue, a characteristic high-pitched voice, and wrinkled skin. Gonadotropin deficiency results in sexual infantilism and infertility. TSH deficiency, when it occurs, is usually mild and does not often result in severe thyroid deficiency. ACTH deficiency m a y contribute to severe hypoglycemia in infancy and childhood. Isolated human growth hormone deficiency. An isolated deficiency of hGH with otherwise normal pituitary function results in proportionate dwarfism with normal sexual development (Fig. 5). Although most examples of hGH deficiency have a typical physical appearance and characteristic metabolic abnormalities, it is now apparent that IGHD is a heterogeneous group of disorders. 22 The most common form of IGHD, Type I, is inherited as an autosomal recessive and is associated with proportionate dwarfism, increased subcutaneous fat, typical round, full facies with high forehead, high-pitched voice, and, in adulthood, wrinkled skin. These patients may have spontaneous hypoglycemic episodes in infancy; hypoglycemia is not a problem after early childhood, although hypersensitivity to exogenous insulin is maintained into adulthood. 22 As adults, these patients charac-
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teristically have abnormal glucose tolerance associated with insulinopenia, both of which revert to normal with hGH therapy. Puberty occurs spontaneously but is frequently delayed to the late teens or early twenties; however, puberty frequently appears during the first few months o f h G H therapy. Thus, in the prepubertal individual, IGHD cannot be clinically distinguished from a combined deficiency of hGH and gonadotropins, at least until the early twenties. Stimulation studies of luteinizing hormone-releasing hormone may prove to be valuable in distinguishing between these two disorders. Deficiency of hGH, inherited as an autosomal dominant trait, has been called Type II IGHD. Individuals with this deficiency do not have the wrinkled skin or characteristic voice seen in other pituitary dwarfs. They have glucose intolerance, but have an increased, rather than a decreased, insulin response to both glucose ingestion and arginine infusion. ~2 First reports indicated that they were relatively resistant to exogenous insulin and to the metabolic effects of exogenous hGH. 2:~ It is now clear that further heterogeneity exists in the 1GHD syndromes, since there have been families reported with apparent dominant inheritance who have the metabolic features of the recessive form and there may be nongenetic forms of the disorder. TM 25 Pathogenetic mechanisms in pituitary dwarfism. An abnormality in growth hormone secretion could theoretically be due to a structural or degenerative defect of the hypothalamus or pituitary or a defect in the structure, synthesis, or secretion of growth hormone-releasing factor, somatostatin, or hGH. The anomalies associated with hGH deficiency have demonstrated that structural abnormalities of the hypothalamus and pituitary do exist; it is possible that less conspicuous anomalies limited to the hypothalamus or pituitary cause some of the idiopathic forms of hGH deficiency. It is difficult to visualize a metabolic defect or structural gene mutation that could result in a deficiency of two or more tropic hormones that lack a common subunit; thus, it is quite likely that a structural, degenerative, or secretory defect in the pituitary or hypothalamus exits in hereditary MPHD. Thyrotropin-releasing hormone and LHRH administration have been found to result in secretion of thyroidstimulating hormone and luteinizing hormone, respectively, in approximately two-thirds of patients with MPHD. In those patients with a positive response to the hypothalamic-releasing hormone, the pituitary is capable of synthesizing and secreting the tropic hormone, indicating that the basic defect lies in the hypothalamus. In the minority of cases who do not respond to TRH or LHRH, a defect located in the pituitary itself is more likely. Since the structure of GHRF~s not yet known, it is presently impossible to utilize releasing hgrmone stimula-
The Journal of Pediatrics May 1978
tion studies to pinpoint the defect in IGHD. Autopsies in three cases of IGHD Type I have revealed the presence of typical somatotropic ceils in the pituitary and, in one case, the presence ofimmunoreactive growth hormone, demonstrating the capability of the pituitary to synthesize hGH. 25 Thus, the defect in these patients appears to be a deficiency of GHRF or a defect in the releasing-hormone receptor of the somatotropic cell. Once the structure of GHRF becomes known and its synthesis possible, it will be of great therapeutic importance to delineate the exact mechanism in each patient with pituitary dwarfism, in order to determine whether GHRF or hGH will be required for growth stimulation. Laron dwarfism. Laron ~ and his colleagues described an autosomal recessive syndrome with the clinical features of pituitary dwarfism associated with high, rather than low, plasma concentrations of immunoreactive hGH. These individuals have the clinical appearance of patients with IGHD but to an exaggerated extent, with severe growth retardation, severely pinched facies, high-pitched voice, and small genitalia if male. They have spontaneous hypoglycemic episodes in infancy and have insulinopenia in response to glucose and arginine. Secretion of ACTH, TSH, gonadotropin, and vasopressin is normal. Fasting plasma hGH concentrations are usually elevated, but may fluctuate from normal levels to over 100 ng/ml in the same patient. Plasma somatomedin levels are low and, unlike those in hGH-deficient patients, do not respond to administration of hGH. The patients are relatively unresponsive to the metabolic and growth promoting effects of growth hormone. Laron dwarfism appears to involve a defect in somatomedin generation. The African pygmies. Peripheral unresponsiveness to human growth hormone administration, in the presence of normal concentrations of immunoreactive plasma hGH and normal somatomedin activity, has been documented in the African pygmies. 27 They resemble pituitary dwarfs in size and skeletal proportions, but do not have the trnncal obesity, peculiar facies, and wrinkled skin of pituitary dwarfism. After insulin-induced hypogly.cemia and arginine infusion, plasma hGH levels are normal. Like patients with Type I IGHD, pygmies are insulinopenic and hypersensitive to the effects of exogenous insulin. They are unresponsive to the lipolytic, insulinotropic, and nitrogen retaining properties of hGH, and their small size is presumably secondary to a similar unresponsiveness to the growth promoting properties of the molecule. Unlike Laron dwarfs, who are unable to generate somatornedin, the African pygmies may have a defect in somatomedin receptors. Although no welldocumented instances of peripheral unresponsiveness to hGH with normal plasma hGH and somatomedin activity
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70 1
have been described in other ethnic groups, it is possible that growth hormone resistance may be a relatively common cause of short stature. The normal variation in stature that exists within and among all ethnic groups may be due, in part, to variation in the peripheral responsiveness to hGH and somatomedin. THE SKELETAL
DYSPLAS1AS
The skeletal dysplasias compose a heterogeneous group of disorders associated with abnormalities in the size and shape of the limbs, trunk, and skull which frequently result in disproportionate short stature. Until the 1960s, most disproportionate dwarfs were considered to have either achondroplasia (those with short limbs), or Morquio disease (those with short trunk). It is now apparent that there are well over 50 distinct chondrodystrophies; they have been classified on the basis of roentgenographic or clinical characteristics. 2~-~~ Current nomenclature for these disorders is most confusing and is based on the part of the skeleton that is affected roentgenographically (the epiphyseal dysplasias, the metaphyseal dysplasias), on a Greek term that describes the appearance of the bone or the course of the disease (diastrophic [twisted] dysplasia, thanatophoric [death seeking] dysplasia) or on an eponym (Kniest dysplasia, Ellis-van Creveld syndrome). The extent of the heterogeneity in these disorders and the variety of methods used for classification have resulted in confusion. Clinical classifications have divided the chondrodystrophies into those with short-limbed dwarfism versus short trunk dwarfism: achondroplasia or spondyloepiphyseal dysplasia (Fig. 5). The short-limbed varieties have been further subdivided on the basis of the segment of the long bones that is most severely involved; rhizomelic or proximal segment shortening (achondroplasia), mesomelic or middle segment shortening (dyschondrosteosis) and acromelic or distal segment shortening (peripheral dysostosis). Other clinical classifications have been based on the age of onset of the disorder: those disorders that manifest themselves at birth (achondroplasia) versus those that first manifest in later life (pseudoachondroplasia). Associated clinical abnormalities have also been used in subdividing these disorders. Examples are the myopia of spondyloepiphyseal dysplasia congenita, the cleft palate of the Kniest dysplasia, the fine hair of cartilage-hair hypoplasia, and the polydactyly and congenital heart disease of the Ellis-van Creveld syndrome. Other disorders have been classified on the basis of their apparent mode of inheritance; for example, the dominant and the X-linked varieties of spondyloepiphyseal dysplasia. The most widely used method for differentiating the
Fig. 6. Classification of chondrodystrophies based on radiologic involvement of long bones (A,B,C) and vertebrae (D,E). Involvement
A+ B+ C+ B+ C+
D D D E E
Disease category
Normal Epiphyseal dysplasia Metaphyseal dysplasia Spondyloepiphyseal dysplasia Spondylometaphyseal dysplasia
skeletal dysplasias, however, has been the detection of skeletal roentgenographic abnormalities. The radiographic Classifications are based on the different parts of the long bones that are abnormal (epiphyses, metaphyses, or diaphyses) (Fig. 6). Thus, there are epiphyseal and metaphyseal dysplasias, which can be further divided, depending on whether or not the spine is also involved (spondyloepiphyseal dysplasias, spondylometaphyseal dysplasias). Furthermore, each of these classes can be further divided into several distinct disorders based on a variety of other clinical or radiographic differences. In an attempt to develop a uniform nomenclature for these syndromes, an international nomenclature for constitutional diseases of bone was proposed in 1970 and updated in 1977. The international nomenclature divided the skeletal dysplasias into two major groups: the osteochondrodysplasias (abnormalities of cartilage or bone growth and development); and the dysostoses (malformations of individual bones, singly or in combination). The osteochondrodysplasias are further subclassified into: (1) defects of growth of tubular bones or spine or both (achondroplasia), which are frequently named the chondrodystrophies; (2) disorganized development of cartilage and fibrous components of the skeleton (multiple cartilagenous exostoses); and (3) abnormalities of density or of cortical diaphyseal structure or of metaphyseal modeling (osteogenesis imperfecta). The chondrodystrophies are further subdivided into those disorders that are manifest at birth, as opposed to those that first become apparent later. This division may be purely artificial, since identical pathogenic mechanisms of differing severity may occur in
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Table I. Pathophysiologic classification of the skeletal dysplasias Site of defect 1. Limb bud development 2. Cartilage anlage development 3. Chondrocyte metabolism 4. Chondrocyte proliferation 5. Chondrocyte maturation a n d degeneration 6. Epiphyseal ossification 7. Membranous ossification
8. Ossificationgeneralized 9. Calcified cartilage resorption 10. Bone resorption
11. Aberrant chondrocyte growth
12. Premature epiphyseal fusion
Mechanism
Possible examples
Arrest in fetal bone development
Grebe disease 3~'
Cartilage anlage from which bone arises develops abnormally in size or shape or both A metabolic defect may lead to abnormalities in the matrix secreted or reduced survival of the resting chondrocyte Reduced cell division in the proliferative zone results in diminished linear bone growth Abnormalities of the normal chondrocyte maturation degeneration sequence (column development) lead to irregular metaphyseal vascular invasion and bone formation Abnormality in development of epiphyseal ossification centers (secondary ossification) Failure of fibroblast cells in periosteum to transform into osteoblasts or produce normal bone matrix (osteoid) results in irregular cortical ossification Abnormality in bone matrix composition or mineralization Failure to resorb calcified cartilage spicules leads to increased skeletal density Failure to resorb cortical bone results in poorly modeled bones of increased density
Achondrogenesis: Parenti-Fraccaro type~~ some forms of mesomelic dwarfism3~
Erratic and excessive growth of chondrocytes disturbs the normal growth plate and extends into (enchondroma) or outside (exostosis) the metaphysis Early closure of growth plate produces shortening of tubular bones
allelic disorders. Thus, the more severe mutation could result in abnormalities obvious at birth, whereas in the milder disorder the clinical appearance may be normal at birth. Furthermore, m a n y disorders that share c o m m o n radiographic features and have been classified into one group, such as the spondyloepiphyseal dysplasias, may result from completely different pathologic mechanisms. In recent years, we and others have defined the histochemical and ultrastructural characteristics o f cartilage and bone in m a n y of the chondrodystrophies. 3~ :~ These studies have yielded numerous clues to the pathogenesis of these disorders. On the basis of these observations, we propose a tentative pathophysiologic classification of the skeletal dysplasias (Table I). Those disorders which appear to best illustrate the postulated mechanisms have been chosen as examples. The pathologic mechanisms involved in m a n y of these disorders may only be surmised; in several, a n u m b e r of different mechanism appear to be operating. Moreover, in some disorders, we have absolutely no information on which to base a
Diastrophic dysplasia32; Kniest dysplasia3~; achondrogenesis: Langer-Saldino type~~ mucopolysaccharidoses ~~ Adenosine deaminase deficiency~3; achondroplasia~~ Metaphyseal chondrodysplasias3~ thanatophoric dysplasia~~
Multiple epiphyseal dysplasias 3' Melnick-Needles syndrome ~
Osteogenesis imperfecta~4; hypophosphatasia ~" Osteopetrosis35; dysosteosclerosis ~s Hyperostotic bone dysplasias 3~.~' (craniometaphyseal dysplasia, Engelmann disease) Oilier disease~4; multiple exostosis syndrome
Tricho-rhino-phalangeal syndrome ~~
classification. Nevertheless, this scheme represents an attempt to classify these disorders pathophysi01ogically and may serve as a model for future studies. Not until the basic biochemical defect and specific mechanism underlying each of the skeletal dysplasias is identified will a completely adequate classification be possible. CLINICAL STATURE
EVALUATION
OF SHORT
Once an abnormality in stature is established by the use of the appropriate growth curves with adjustment for ethnic background and parental height, the general category of disease must be identified; skeletal, endocrine, nutritional, cytogenetic, or intrauterine growth retardation. In general, patients with disproportionate short stature have skeletal dysplasias, whereas those with relatively normal body proportions have endocrine, nutritional, prenatal, or other nonskeletal defects. There are exceptions to these rules, as cretinism can lead to disproportionate short stature, and a variety of skeletal dyspla-
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sias, such as osteogenesis imperfecta and hyp0phosphatasia, may result in normal body proportions. A disproportionate body habitus may not be readily apparent on casual physical examination. Thus measurements, such as upper to lower segment ratio, sitting height, and arm span, must be obtained, before the possibility of a mild skeletal dysplasia, such as hypochondroplasia or multiple epiphyseal dysplasia, can be excluded. In those patients with normal body proportions and no evidence of body deformity, a nonskeletal form of short stature should be considered. A history of small birth length for gestational age suggests one of the forms of intrauterine growth retardation or a cytogenetic abnormality, whereas a proportionate child whose birth length was normal is more likely to have an endocrine, metabolic, nutritional, emotional or other chronic disease. Complete history and physical examination will often help rule out nutritional, metabolic, and chronic disease states. In those patients with intrauterine growth retardation, a careful search for other dysmorphic features may result in the diagnosis of a specific syndrome. A blood karyotype in these latter patients may be diagnostic. Proportionate short stature with postnatal onset, in the absence of other manifestations of chronic'disease, suggests an endocrine, metabolic, emotional, or nutritional disorder. Bone age is frequently useful in determining whether skeletal development is severely retarded, with bone age less than height age, as would be the case in multitropic pituitary hormone deficiency or cretinism. If bone age is equal to height age, constitutional delay, the emotional deprivation syndrome, and isolated growth hormone deficiency should be considered. Patients with constitutional delay, however, are usually not as severely growth retarded as those with organic or emotional hypopituitarism. In those patients with significant proportionate short stature of postnatal onset, endocrine laboratory evaluation is essential. If the growth delay is not severe, or if there are no other clinical signs of endocrine deficiency disease, a simple stimulatory test for hGH secretion may be sufficient. Since basal plasma hGH levels are normally low to absent, provocative tests are required to rule out hGH deficiency?~ In our experience, an L-dopa stimulation test is the best screening procedure for hGH deficiency; it can be done on an outpatient, does not require intravenous fluids, and takes only 90 minutes. The exercise stimulation test is also a useful outpatient procedure. Priming the patient with estrogen or propanolol may also be useful. Since normal individuals frequently fail to respond to any one of the hGH stimuli, if L-dopa or exercise fails to produce a rise in plasma hGH to over 7 ng/ml., arginine- or insulin-induced hypoglycemia tests should be performed. Lateral skull radio-
Short stature
703
graphs, tomographs of the sella turcica, or CAT scans should also be performed in patients suspected of having growth hormone deficiency to rule Out a congenital anomaly of the sella or an intrasellar tumor. The other pituitary tropic hormones can be readily evaluated by plasma thyroxinel TSH, testosterone, FSH, and LH assays and a plasma cortisol and metapyrone test. If TSH or LH deficiencies are found, TRH and LHRH stimulatory studies are indicated to determine whether there is a pituitary or hypothalamic abnormality. The differential diagnosis of disproportionate dwarfism requires a variety of clinical observations: Are the limbs relatively short compared to the trunk (short limb dwarfism), or is the trunk primarily affected (short trunk dwarfsim)? Are all of the segments of the limbs equally shortened, or does the shortening primarily affect the proximal (rhizomelic), middle (mesomelic), or distal (acromelic) segments? Is the disease limited to the skeleton, or are there extraskeletal abnormalities such as lax ligaments, myopia, or hearing loss? The answers to these questions may be sufficient to allow an accurate diagnosis, or at least to limit the differential diagnosis to a relatively small number of disorders. The next step in the evaluation of the disproportionately short patient is to obtain skeletal radiographs. A series of skeletal views, including the skull, spine, pelvis and extremities, is usually required. Skeletal radiographs alone will often be sufficient to make an accurate diagnosis, since the classification of the chondrodystrophies has been based primarily on roentgenology. Attention should be paid to the specific parts of the skeleton that are involved (spine, limbs, pelvis, skull) and, within each bone, where the lesion appears to lie (epiphysis, metaphysis, diaphysis). The skeletal radiographic features of many of these diseases change with age and it is usually beneficial to review radiographs taken at different ages when possible. In some disorders, the radiographic abnormalities following epiphyseal fusion are nonspecific, so that the accurate diagnosis of an adult disproportionate dwarf may be impossible unless prepubertal films are available. In many instances, the general type of dysplasia can be readily subclassified, such as spondyloepiphyseal dysplasia, but further information may be required to diagnose its exact form: The family history is often helpful. For example, if two dwarfed siblings are born to normal parents, achondroplasia, which is an autosoma! dominant trait, is unlikely. Furthermore, different modes of inheritance have been observed in disorders that cannot be distinguished clinically, such as the tarda forms of spondyloepiphyseal dysplasia. In some instances, microscopic and ultrastructural eval-
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uation of chondroosseous tissue may be helpful in making an accurate diagnosis of the chondrodystrophies? ~ 35 In many of the chondrodystrophies, specific histologic alterations have been identified. Histologic evaluation of autopsy tissue from a deceased affected relative may aid in the diagnosis. In some disorders, however, no histopathologic alterations are present, or they are nonspecific: pathologic examination in these cases is useful only in ruling out a diagnosis. Unfortunatelv. biochemical procedures are presently of little value in the diagnosis of the chondrodystrophies. Exceptions are urinary mucopolysaccharide and lysosomal enzyme assays in the mucopolysaccharidoses, and serum calcium, phosphorus, and alkaline phosphatase determinations in disorders such as hypophosphatemic rickets and hypophosphatasia W h e n the basic biochemical defect in each of these disorders is elucidated and biochemical markers become available, diagnosis of the chondrodystrophies will be much easier. Thus. the clinical evaluation of short stature requires a wide variety of clinical, radiographic, pathologic, and biochemical tools. Although specific therapy to promote growth is available only in the endocrinopathies and the acquired nutritional, emotional, and chronic disease states, once the pathogenesis of the remaining forms of short stature is identified, specific forms of treatment or prevention may evolve. Furthermore, diagnosis of the specific form o f short stature can have great importance in prognosis, prevention and treatment of these disorders, and for accurate genetic counseling.
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21.
22.
23.
24.
25.
26.
27.
28. 29.
30. 31.
32.
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17. Powell GF, Brazel JA, Raiti S, and Blizzard RM: Emotional deprivation and growth retardation simulating idiopathic hypopituitanism, II endocrinologic evaluation of patients, N Engl J Med 276:1279, 1967. 18. Saenger P, Wiedemann G, Schwartz E, Karth-Schutz S, Lewy JE, Riggio RR, Rubin AL, Stenzel KH, and New MI: Somatomedin and growth after renal transplantation, Pediatr Res 8:163, 1974. 19. Wu A, Grant DB, Hambley J, and Levi A J: Reduced serum somatomedin activity in patients with chronic liver disease. Reduced serum somatomedin activity in patients with chronic liver disease, Clin Sci Mol Med 47:359, 1974. 20. Daughaday WH, Laron Z, Pertzelan A, and Hems JN:
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Defective sulfation.factor generation: A possible etiologic link in dwarfism, Trans Assoc Amer Physicians 82:129, 1969. Rimoin DL, and Schimke RN: Genetic disorders of the endocrine glands, St. Louis, 1971, The CV Mosby Company. Rimoin DL: Hereditary forms of growth hormone deficiency and resistance, Birth Defects: Original Article Series 12:15, 1976. Merimee TJ, Rimoin DL, Hall JG, and McKusick VA: A metabolic and hormonal basis for classifying ateliotic dwarfs, Lancet 1:963, 1969. Poskitt EME, and Rayner PHW: Isolated growth hormone deficiency, two families with autosomal dominant inheritance, Arch Dis Child 49:55, 1974. Rimoin DL: Hereditary forms of growth hormone deficiency and resistance, Birth Defects: Original Article Series 12:15, 1976. Laron Z: Syndrome Of familial dwarfism and high plasma immunoreactive growth hormone, Isr J Med Sci 10:1247, 1974. Merimee TJ, Rimoin DL, Penetti G, and Cavalli-Sforza LL: Growth retardation in the African pygmy, J Clin Invest 51:395, 1972. Maroteaux P: Les maladies osseuses de l'enfant, Paris, i974, Flammarion Medicine-Sciences. Spranger JW, Langer LO, and Wiedemann HR: Bone dysplasias: An atlas of constitutional disorders of skeletal development, Philadelphia 1974, WB Saunders Company. Rimoin DL: The chondrodystrophics, Adv Hum Genet g: 1, 1975. Stanescu V, Stanescu R, and Maroteaux P: Etude morphologique et biochemique du cartilage de croisSance dans.les osteochondrodysplasias, Arch Fr Pediatr 34 (Suppl 3): 1, 1977. Horton WA, and Rimoin DL: Histochemical evaluation of the growth plate, a new approach to studying the chondr0cystr0phies , Birth Defects: Original Article Series (in press). Kaitila I, Rimoin DL, Cederbaum SD, Stiehm ER, and Lachman RS: Chondroosseous histopathology in adenosine deaminase deficient combined immuno-deficiency disease, Birth Defects: Original Article Series 12:115, 1976. Rimoin DL: Pathogenetic mechanisms of limb malformation in the skeletal dysplasias, Birth Defects: Original Article Series 13:339 , 1977. Kaitila I, and Rimoin DL: Histologic heterogeneity in the hyperostotic bone dysplasias, Birth Defects: Original Article Series 12:71, 1976. Frasier SD: A review of growth hormone stimulation tests in children, Pediatrics 53:929, 1974.