Abnormalities of Linear Growth I. Normal growth A. Growth is an index of general health, nutrition, and genetics Growth Rates by Age 1-6 months 18-22 cm/yr 6-12 months 14-18 cm/yr 1 yr 11 cm/yr 2 yrs 8 cm/yr 3 yrs 7 cm/yr 4-puberty 5-6 cm/yr B. Between 2 years of age and the onset of puberty, children maintain the same percentile on growth curve. A growth rate of less than 5 cm/yr after age 3 years, requires further assessment. C. Deviations from the normal pattern of growth can be caused by to wide variety of endocrine and non-endocrine disorders. Prior to age three and particularly during the first 18 months of life, it is not unusual for children born of tall stature to decelerate down to a family appropriate percentile. Your birth length is primarily correlated with maternal weight, not familial stature. So, many infants born at the 95th percentile for length come from average or below average families, and during the first 18 months of life, they will really settle at a family appropriate percentile. However, after the age of two and until the onset of puberty, it is distinctly pathological for a child to cross percentiles. A standard method of measuring a child who is more than two years of age requires a wall-mounted ruler and a straight edge, but we need to be sure that the child is standing feet flat, upright against the board, with the eyes and the chin straight ahead, parallel to the measuring device. Scale mounted measuring devices are notoriously unreliable and should not be used in assessing linear growth during childhood.II. Short Stature A. Defined as height below the third percentile (<1.88 SD) for age and sex. The pattern of growth, rather than absolute position on growth curve, is the most critical factor. Epidemiology of Short Stature Normal variants (Familial/constitutional) 80% Medical causes 10% GH deficient 0.3% Other 0.7% B. Differential Diagnosis of Short Stature 1. Normal Variants a. Familial or genetic short stature is characterized by a family history of short stature and a child who grows at or below third percentile, and he grows parallel to normal curve. There is usually no delay in bone age or puberty. b. Constitutional delay is not associated with a history of systemic disease. There is usually a family history of delayed puberty. Typically the child grows parallel to the normal curve until early adolescence. These children have a delayed onset of puberty, and delayed bone age is characteristic. The final heial height prediction is normal. c. Many children with genetic short stature also have a component of constitutional delay Short stature is defined as a height less than the 3rd percentile, which is only less than 1.88 standard deviations. Much more important is that short stature should be defined in the context, not only by the absolute height, but the pattern of growth. Children growing less than 5 cm/year after the age of three require further assessment. Common causes of short stature. Eighty percent of children with short stature have familial or constitutional delay in growth. Ten percent of them have one of several medical causes such as inflammatory bowel disease, chronic renal disease or chronic cardiac disease. Three percent were found to be growth hormone deficient and seven percent had a variety of other miscellaneous syndromes. The majority of children that you see in your offices with short stature are going to be variants of normal. The pattern of growth is the most important parameter to follow. The child with a congenital problem starts off small and progressively deviates away from the normal curve. The child with an acquired abnormality which impairs linear growth typically grows at the 25th or the 50th percentile all during childhood and then suddenly begins to lose percentiles and begins to demonstrate deceleration in growth rate. A very pathological, very concerning, growth pattern. The child who is short and 2.5 standard deviations below the mean, but who continues to grow along the same percentile, paralleling the curve all through childhood and not losing percentiles. has the classic pattern of a child with familial or constitutional or familial short stature Differential diagnosis of short stature. The vast majority of children will fall into the normal variant category, the familial or constitutional short stature. There are some semantic differences but most people lump them together. These are children that are genetically programmed to be short and they frequently have a component of delay in their onset of puberty so that they actually end up taller as adults than they are as children because they do have delayed puberty. Pathologic causes of short stature are divided into children whose body proportions are either proportionate or disproportionate. The most common causes of disproportionate short stature include multiple skeletal dysplasias as well as rickets.2. Pathological Causes of Short Stature a. Disproportionate Types of Short Stature. These children have abnormal body proportions, such as with "short limbed" dwarfism, skeletal dysplasias, and rickets. b. Proportionate Types of Short Stature. These children have normal body proportions, and the disorder often has a prenatal onset characterized by intrauterine growth retardation. The disorder m,ay be caused by a various syndromes (eg, Russell-Silver) or by chromosomal disorders (eg, Turner Syndrome). Postnatal onset of proportionate short stature may be caused by chronic disease, malnutrition, psychosocial dwarfism, and endocrine disorders (GH deficiency, GH resistance, hypothyroidism, Cushing syndrome, pseudohypoparathyroidism) Children with familial or constitutional delay have been growing at or below the 3rd percentile for the entire growing years. They frequently have an annual growth rate that is just below 5 cm/year. Frequently they are growing at 4-4.5 cm/year. They have a completely normal physical examination. Their bone ages are somewhat delayed and they frequently have a positive family history. They frequently manifest a delay in the onset of puberty and this can be predicted at a young age because of the severe significant delay in bone age. Normal weight and everything about these children is completely normal. Determining whether a child is proportionate or disproportionate in the pathologic group. The ratio of the upper to the lower segment is determined by directly measuring the lower segment, which is the measurement from the symphysis pubis to the floor. The upper segment is obtained by subtracting the measured lower segment from the total height and forming a ratio. Newborns have an upper-lower segment ratio of approximately 1.6 at age seven or eight months. Most Caucasian children will have an upper-lower segment ratio of approximately 1.0 which drops down to about 0.9 and remains there throughout adult life. Black individuals have lower upperloowe segment ratios at most ages, particularly during and after puberty. Another measurement of body proportionality is the relationship between arm span and height. This is the relationship between arm span and height in boys and in girls. Prior to the onset of puberty, the difference between arm span and height is rarely more than 2 cm for boys and 1 cm for girls. After the onset of puberty, these differences can be as much as 5 cm for boys and 2 cm for girls. But abnormalities in these relationships will allow you to differentiate between normal and abnormal proportionality short stature. Most pathologic forms of short stature fall into the normal proportion category. They include entities which result on growth retardation that actually begin in utero and that include all the various causes of in utero growth retardation, such as syndromes, drugs and chromosomal disorders and a more common group of disorders in which growth impairment manifests itself primarily after birth. These include a variety of chronic disorders, malnutrition, psychosocial dwarfism and all of the endocrine causes of short stature. C. Causes of Growth Hormone Deficiency 1. Congenital Causes a. Idiopathic (isolated or multiple deficiencies) b. Genetic (autosomal dominant and recessive) c. Associated anatomic defects: Septo-optic dysplasia, midline facial defects 2. Acquired a. Trauma (peri and postnatal) b. Neoplasms of hypothalamus or pituitary: Craniopharyngioma, optic of hypothalamic gliomas neurofibromas), germinomas c. Cranial irradiation d. Infections or infiltrative lesions e. Transient? The most common form of prenatal short stature is the syndrome of gonadal dysgenesis or Turner's syndrome. Essentially all of these girls will fall below the 5th percentile for the normal population. Some of the girls have the classical stigmata that we normally associate with Turner's syndrome including webbed neck and increased carrying angle. Up to 50% of girls with Turner's syndrome will have few, if any, clinical stigmata, other than short stature and gonadal dysgenesis. Among the endocrine disorders which can result in short stature are growth hormone deficiency, which probably is the most important; a very rare syndrome of growth hormone resistance; hypothyroidism; glucocorticoid in excess, primarily from exogenous glucocorticoids, syndrome can result in short stature although it is an extremely uncommon entity in pediatrics; and then the very rare syndrome of pseudohypoparathy which also includes short stature as one of its main features. Etiology of growth hormone deficiency. Idiopathic growth hormone deficiency, either as an isolated hormonal problem or in combination with multiple other anterior pituitary deficiencies is the most common form of growth hormone deficiency. It accounts for 60% of children receiving growth hormone. There is a very dramatic sex difference with three-quarters of the patients being male and one-quarter of the patients being female. This presumably reflects a bias both in referral and in families interest in treating short stature. There is no evidence to indicate that congenital idiopathic growth hormone deficiency is more common in males than in females, although the females seem to reach medical attention less often. Organic causes include a whole host of insults to the central nervous system, including tumors, radiation and infections, as well as some congenital dysgenetic abnormalities, upper hypothalamus and pituitary. The gender differences are less marked and for septo-optic dysplasia -there is almost an equal distribution between males and females. But even in the organic group there is an excess of males which again appears to represent a referral basis and not a true difference in incidence of the abnormalities. Children with congenital isolated growth hormone deficiency frequently have a very distinct phenotype which includes aD. Clinical Evaluation of short stature 1. An evaluation is recommended for any child who crosses percentiles between ages 2 and 9 years of age and any child with a growth rate less than the 25th percentile for age and pubertal stage. 2. Evaluation is also recommended for children with height less than 3 standard deviations below the mean. 3. A bone age/height prediction is completed. If the growth rate is less than the 25th percentile, an investigation should be initiated. 4. History. Birth/family Developmental Systems review. 5. Examination. Height and weight, body proportions (eg, upper/lower, arm span), dysmorphic features, fundi and visual fields, thyroid enlargement, and Tanner staging. 6. Laboratory. CBC, SMA-12, electrolytes, ESR, UA, free T4, TSH, karyotype for girls a. Bone age is a nonspecific test, and it is delayed in most short kids; however, it shows growth potential b. IGF-1/IGFBP3 is a screening test for GH deficiency. Levels are age and sex dependent and are affected by nutritional status, pubertal status. Low levels are seen in many chronic diseases, and false negatives have been reported 7. Diagnosis of GH Deficiency a. Diagnosis is based on clinical and laboratory criteria The GH stimulation tests remains the cornerstone of diagnosis. b. The test is abnormal if the peak GH less than 10 ng/ml after 2 tests. The test has poor reproducibility, and it is age, sex and puberty dependent. c. 12-24 hr GH profiles may be of more value because they are more reproducible and there is overlap between normals and abnormals. The test is expensive and difficult to perform III. Tall Stature A. Tall stature is defined as height greater than the 97th percentile for age and sex. It is a much less common cause for consultation than is short stature B. Differential Diagnosis 1. Present at birth. Maternal diabetes mellitus, cerebral pudginess and infantile appearance. These children have increased pectoral and abdominal fat, immature faces, and they can have a high-pitched, so-called "Mickey Mouse" voice. In contrast, the growth pattern of a young man with acquired growth hormone deficiency is at the 75th percentile until approximately age 10 years when his growth curve really flattens out. They stop growing, and fail to enter puberty. Craniopharyngiomas are the most common parapituitary tumors of childhood, and a skull film is actually an excellent screen for craniopharyngioma. It is a very bad screen for almost any other form of central nervous system tumor. Probably the main cause for concern is anybody who loses percentiles between the ages of two and on. Children who grow less than the 25th percentile for age and pubertal status, require an evaluation and anybody who is more than 3 standard deviations below the normal range should undergo at least an initial evaluation. Children who fall between -2 and -3 standard deviations for the general population simply need to be monitored. If their growth velocities are normal, then they just need to be continued to be monitored and no further evaluation is necessary. If their growth velocity is abnormally low, then further workup is indicated. For children who are already more than 3 standard deviations below the mean, some evaluation is appropriate. A very careful and complete and comprehensive history, a very complete physical examination are completed, and you need to do a baseline evaluation, a complete blood count, a sed rate, an SMA 12 with electrolytes, and thyroid function studies are adequate for baseline evaluation. If you have suspicion for malabsorption then obviously other things might be appropriate. If you have suspicion of renal disease, a urinalysis in addition to a BUN creatinine is reasonable. Probably the best single screening for growth hormone deficiency is a careful serial monitoring of growth rate and growth pattern. This accounts for the most abnormal children and they are relatively easy to diagnose. You still need to perform provocative tests of growth hormone to establish a diagnosis of growth hormone deficiency.gigantism (Soto's), Beckwith-Wiedemann 2. Postnatal onset. Familial or genetic tall stature, exogenous obesity, precocious puberty, GH excess, Marfan syndrome, homocystinuria, XYY, androgen/estrogen deficiency or resistance. References Rosenfeld, RG. Disorders of growth and insulin-like growth factor secretion and action. In, Sperling, MA ed. Pediatric Endocrinology. WB Saunders. 1996. 117-169. Cowell, CT. Short stature. In, Brook, CGD ed. Clinical Paediatric Endocrinology. Blackwell Science. 1995. 136-172. Rosenreid, RG, Albertsson-Wikland, K, Cassorla, F, et al. Diagnostic controversy: the diagnosis of childhood growth hormone deficiency revisited. J Clin Endocrinol Metab 1995;80:1532-40. Lindsay, R, Feldkamp, M, Harris, D, et al. Utah growth study: growth standards and the prevalence of growth hormone deficiency. J Pediatr 1994; 125:29-35.