SHORT STATURE DUE TO NONENDOCRINE CAUSES
There are many causes of decreased childhood growth and short adult height (Table 6–1). The following discussion covers only the more common conditions, emphasizing those that might be included in an endocrine differential diagnosis. Shorter than average stature need not be considered a disease, because variation in stature is a normal feature of human beings, and a normal child should not be burdened with a misdiagnosis. Although the classifications described later may apply to most patients, some will still be resistant to definitive diagnosis.
TABLE 6–1Causes of abnormalities of growth. |Favorite Table|Download (.pdf) TABLE 6–1 Causes of abnormalities of growth.
|I. CAUSES OF SHORT STATURE |
Constitutional short stature
Genetic short stature
Intrauterine growth retardation and SGA
Syndromes of short stature
Turner syndrome and its variants
Other autosomal abnormalities and dysmorphic syndromes
Left to right shunt
Congestive heart failure
Disorders of swallowing
Sickle cell anemia
Renal tubular acidosis
Connective tissue disease
Juvenile rheumatoid arthritis
Central nervous system disorders
Decreased bioavailability of nutrients
Anorexia of cancer chemotherapy
GH deficiency and variants
Congenital GH deficiency
Isolated GH deficiency
With other pituitary hormone deficiencies
With midline defects
Acquired GH deficiency
Central nervous system infections
GH deficiency following cranial irradiation
Central nervous system vascular accidents
Empty sella syndrome
Abnormalities of GH action
Primary IGF-I deficiency
IGF-I receptor defect
Glucocorticoid excess (Cushing syndrome)
Psuedohypoparathyroidism/Albrights Hereditary Osteodystrophy
Disorders of vitamin D metabolism
Diabetes mellitus, poorly controlled
II. CAUSES OF TALL STATURE
Constitutional tall stature
Genetic tall stature
Syndromes of tall stature
XYY and XYYY syndromes
Infants of diabetic mothers
1. CONSTITUTIONAL SHORT STATURE
Constitutional short stature (constitutional delay in growth and adolescence) is not a disease but rather a variation from normal for the population and is considered a slowing of the pace of development. There is usually an associated delay in pubertal development as well as a decrease in growth (see Constitutional Delay in Adolescence, Chapter 15). It is characterized by moderate short stature (usually not far below the 3rd percentile), thin habitus, and retardation of bone age. The family history often includes similarly affected members (eg, mother with delayed menarche or father who first shaved later than peers and continued to grow past his teen years).
All other causes of decreased growth must be considered and ruled out before this diagnosis can be made with confidence. The patient may be considered physiologically (but not mentally) delayed in development. Characteristic growth patterns include normal birth length and height, with a gradual decrease in percentiles of height for age by 2 years; in contrast, a rapid decrease in percentiles is an ominous sign of pathology. Onset of puberty is usually delayed for chronologic age but normal for skeletal age. Adult height is in the normal range but varies according to parental heights. Adult height is often less than the predicted height, because growth is less than expected during puberty. Aromatase inhibitors have been used in clinical studies for boys with constitutional delay in growth to inhibit the conversion of androgens to estrogen so that bone age does not advance and growth continues longer. While this is still an experimental treatment, most studies suggest that it causes no ill effects, although long-term data dealing with effects on bone mineral density as a result of the use of these agents are not available. Elevated testosterone levels and testicular enlargement result from aromatase inhibition.
2. FAMILIAL SHORT STATURE
Short stature may also occur in a familial pattern without retarded bone age or delay in puberty; this is considered familial short stature. Affected children are closer to the mean on the normal population growth charts after familial correction for mid-parental height by calculation of the target height (see Figures 6–6 and 6–7). Adult height depends on the mother’s and father’s heights. Patients with the combination of constitutional short stature and genetic short stature are quite noticeably short due to both factors, and these patients are most likely to seek evaluation. Boys are brought to consultation more often than girls. Children in these families may be born AGA but exhibit slowed growth in the first two postnatal years; this process is gradual in comparison to the striking changes in growth rate that are characteristic of diseases that primarily affect growth, but it may still be difficult to tell the difference without extended observation.
Although the majority of SGA infants show catch-up growth, about 20% may follow a lifelong pattern of short stature. In comparison, AGA premature infants usually catch up to the normal range of height and weight by 1 to 2 years of age. Severely premature infants with birth weights less than 800 g (that are AGA), however, may maintain their growth retardation at least through their third year; only follow-up studies will determine whether this group of premature infants reaches reduced adult heights. Bone age and yearly growth rate are normal in SGA patients until puberty occurs, and the patients are characteristically thin. However, SGA is a risk factor for premature thelarche or early menarche, although catch up growth after SGA may be responsible for this tendency, so bone age may advance more rapidly in this subset of SGA (see Chapter 15).
Within this grouping are many distinctive genetic or sporadically occurring syndromes. The most common example is Russell-Silver dwarfism (OMIM #180860), characterized by small size at birth, triangular facies, and a variable degree of asymmetry of the extremities; this condition is due to epigenetic changes of DNA hypomethylation at the telomeric imprinting control region (ICR1) on chromosome 11p15, involving the H19 and IGF-II genes or to maternal, uniparental disomy of chromosome 7. Intrauterine infections with Toxoplasma gondii, rubella virus, cytomegalovirus, herpesvirus, and HIV are noted to cause SGA. Furthermore, maternal drug usage, either illicit (eg, cocaine), legal but ill-advised (eg, alcohol during pregnancy), or legally prescribed medication (eg, phenytoin) may cause SGA. Reports of other syndromes in SGA infants can be found in sources listed in the bibliography.
Although SGA is not an endocrine cause of short stature, GH treatment is approved by the FDA and leads to increased adult height. Those SGA infants with the Δ3-isoform (genomic deletion of exon 3) of the GH receptor (GHR) are more likely to catch up on GH therapy, as are girls with Turner syndrome, although this benefit is transient and some data refute this differential response to treatment.
There are many endocrine sequelae with SGA birth including premature adrenarche, puberty, and menarche in girls and dyslipidemia and insulin resistance in boys and girls. Girls have a predilection to develop PCOS after being SGA. GH antagonizes the action of insulin and given the tendency for SGA children to have insulin resistance, there may be concerns regarding the potential additive effects. Recent studies of insulin sensitivity in SGA subjects receiving GH treatment indicate that in most cases the effects are not long lasting and do not seem to have clinical significance.
4. SYNDROMES OF SHORT STATURE
Many syndromes include short stature as a characteristic feature, and some also include SGA. Common conditions are described briefly later. Laurence-Moon, Biedl-Bardet, or Prader-Willi syndrome may combine obesity with short stature (as do the endocrine conditions, hypothyroidism, glucocorticoid excess, pseudohypoparathyroidism with Albright Hereditary Osteodystrophy (OMIM #103580), and GH deficiency). Moderately obese but otherwise normal children without these conditions tend to have slightly advanced bone age and advanced physiologic maturation with increased stature during childhood and early onset of puberty. Thus, short stature in an overweight child must be considered to have an organic cause until proven otherwise.
Turner Syndrome and Its Variants
Although classic Turner syndrome of 45, XO gonadal dysgenesis (see Chapter 14) is often correctly diagnosed, it is not always appreciated that any phenotypic female with short stature may have a variant of Turner syndrome. Thus, a karyotype determination should be performed for every short girl if no other cause for short stature is found, especially if puberty is delayed (see Chapter 15). The short stature of Turner syndrome is due to a mutation of the short stature homeobox (SHOX) gene on the short (p) arm in the pseudoautosomal region of the X chromosome (OMIM #312865). A mutation of the SHOX gene may also cause the Léri-Weill dyschondrosteosis form of short-limbed dwarfism (OMIM #127300).
Noonan Syndrome (Pseudo-Turner Syndrome) (OMIM #163950)
This syndrome shares several phenotypic characteristics of Turner syndrome, including short stature, webbed neck, low posterior hairline, and facial resemblance to Turner syndrome, but the karyotype is 46,XX in the female or 46,XY in the male with Noonan syndrome, and other features clearly differentiate it from Turner syndrome. For example, in Turner syndrome, there is characteristically left-sided heart disease and in Noonan syndrome right-sided heart disease. Noonan syndrome is an autosomal dominant disorder at gene locus 12q24 (see Chapter 14). GH therapy is approved by the FDA for Noonan syndrome to increase height. About half of patients with Noonan syndrome have a mutation of the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) (OMIM #176876). These children have a decreased response to GH treatment and tend to have low IGF-I and ALS with normal IGFBP-3 levels. Noonan syndrome patients are prone to develop neoplasia and the PTPN11 mutation, among others, increases the risk adding a concern over GH treatment in them and underscores the need for surveillance for cancer.
Prader-Willi Syndrome (OMIM #176270)
This condition is characterized by poor intrauterine movement, acromicria (small hands and feet), developmental delay, and almond-shaped eyes along with infantile hypotonia. Short stature is common but not invariable. Although hypotonia limits feeding in infancy, later insatiable hunger develops and leads to extreme obesity. Glucose intolerance and delayed puberty are characteristic. This syndrome is due to deletion of the small nuclear riboprotein polypeptide N (SNRPN) on paternal chromosome 15 (q11-13), uniparental disomy of maternal chromosome 15, or methylation of this region of chromosome 15 of paternal origin. If a mutation of the same locus is derived from the mother, Angelman syndrome results. GH therapy is approved by the FDA for Prader-Willi syndrome to increase height, but the most important effects are improvement of body composition and muscle strength. There are several reported cases of the development of obstructive sleep apnea with GH treatment, which can be fatal, and so sleep patterns must be carefully monitored, and a sleep study must be performed, if there is question of sleep apnea before the administration of GH is begun.
These autosomal recessive, but genetically heterogeneous conditions, are characterized by obesity, short stature, mental retardation, kidney dysfunction, polydactyly, and retinitis pigmentosa. Hypogonadotropic hypogonadism and primary hypogonadism have variously been reported in affected patients (#209900). There are presently 19 identified subtypes of this condition listed in Online Mendalian Inheritance in Man.
Autosomal Chromosome Disorders and Syndromes
Numerous other autosomal disorders and syndromes of dysmorphic children with or without developmental disorders are characterized by short stature. Often the key to diagnosis is the presence of several major or minor physical abnormalities that indicate the need for karyotype determination. Other abnormalities may include unusual body proportions, such as short extremities, leading to aberrant US:LS ratios, and arm spans quite discrepant from stature. Details of these syndromes can be found in the references listed at the end of the chapter.
There are more than 100 known types of genetic skeletal dysplasias (osteochondrodysplasias). Often they are noted at birth because of the presence of short limbs or trunk, but some are only diagnosed after a period of postnatal growth. The most common condition is autosomal dominant achondroplasia (OMIM #100800). This condition is characterized by short extremities in the proximal regions, a relatively large head with a prominent forehead due to frontal bossing and a depressed nasal bridge, and lumbar lordosis in later life. Adult height is decreased, with a mean of 132 cm for males and 123 cm for females. Intelligence is normal. Mutations of the tyrosine kinase domain of the fibroblast growth factor receptor 3 (FGFR3) gene locus 4p16.3 (OMIM #134934) have been identified in this condition. Limb lengthening operations are used to increase stature in a few centers but the techniques are complex, and complications appear to be frequent.
Height, height velocity, weight, and BMI curves from birth to 16 years of age are available for achondroplasia at http://pedinfo.org/growth.php. Children with achondroplasia who have received GH have in some instances demonstrated improved growth; however, atlanto-occipital dislocation is reported. The potential for abnormal brain growth and its relationship to aberrant skull shape mandates the caution that GH is not established therapy for this condition.
Hypochondroplasia (OMIM #146000) is manifested on a continuum from severe short-limbed dwarfism to apparent normal development until puberty, when there is an attenuated or absent pubertal growth spurt, leading to short adult stature. This disorder may be caused by an abnormal allele in the same gene causing achondroplasia (FGFR3 at locus 4p16.3).
Severe chronic disease involving any organ system can cause poor growth in childhood and adolescence. In many cases, there are adequate historical or physical findings by the time of consultation to permit diagnosis. In some cases, however—most notably celiac disease and regional enteritis—short stature and decreased growth may precede obvious signs of malnutrition or gastrointestinal disease. In some cases, growth is only delayed and may spontaneously improve. In others, growth can be increased by improved nutrition; patients with gastrointestinal disease, kidney disease, or cancer may benefit from nocturnal parenteral nutritional infusions.
Cystic fibrosis combines several causes of growth failure: lung disease impairs oxygenation and predisposes to chronic infections, gastrointestinal disease decreases nutrient availability, and late-developing abnormalities of the endocrine pancreas cause diabetes mellitus. Children with cystic fibrosis experience decreased growth rates after 1 year of age following a normal birth size. The pubertal growth spurt is often decreased in magnitude and delayed in its timing; secondary sexual development may be delayed, especially in those with impaired pulmonary function. Study of growth in these patients allowed development of a cystic fibrosis specific growth chart and indicates that a reasonable outcome is an adult height in the 25th percentile. GH treatment in several studies demonstrated improved pulmonary function and increased growth and weight gain in cystic fibrosis. While growth charts for subjects with cystic fibrosis are available, use of standard charts for monitoring is also suggested.
Children with congestive heart failure, due to a variety of congenital heart diseases or acquired myocarditis, grow poorly unless successfully treated with medications or surgery. Patients with cyanotic heart disease and pulmonary hypertension appear to be most affected.
Celiac disease is present in about 1% of the population and may present initially with growth failure, but delayed puberty and menarche, osteopenia, osteoporosis, and other findings can arise. Early diagnosis can be made by determination of tissue transglutaminase antibodies, if IgA values are in the normal range while on a normal wheat-containing diet. However, a biopsy may still be required for diagnosis. On a gluten-free diet, patients experience catch-up growth. Adult height may still be impaired, depending on the duration of the period without treatment. Untreated patients with celiac disease have decreased serum IGF-I concentrations, presumably due to malnutrition, while IGF-I concentrations rise with dietary therapy. Thus, serum IGF-I in this condition, as in many with nutritional deficiencies, is not a reliable indicator of GH secretory status. Crohn’s disease is associated with poor growth in 15% to 40% of cases. There is poor quality of evidence over the best manner to treat the condition and increase growth rate.
Patients with chronic hematologic diseases, such as sickle cell anemia or thalassemia, often have poor growth, delayed puberty, and short adult stature: iron deposition may itself cause endocrine complications. Juvenile rheumatoid arthritis may compromise growth before or after therapy with glucocorticoids. GH treatment is reported to increase the growth rate of these children. Hypophosphatemic vitamin D-resistant rickets usually leads to short adult stature, but treatment with 1,25-hydroxyvitamin D and oral phosphate in most cases will improve bone growth as well as increase adult stature. Chronic renal disease is known to interfere with growth, but increased growth rate occurs with improved nutrition. GH therapy is approved for affected children who still grow poorly.
Proximal or distal renal tubular acidosis (RTA) may cause short stature. Proximal RTA demonstrates bicarbonate wasting at normal or low plasma bicarbonate concentrations; patients have hypokalemia, alkaline urine pH, severe bicarbonaturia, and later, acidemia. The condition may be inherited, sporadic, or secondary to many metabolic or medication-induced disorders. Distal RTA is caused by inability to acidify the urine; it may occur in sporadic or familial patterns or be acquired as a result of metabolic disorders or medication. Distal RTA is characterized by hypokalemia, hypercalciuria, and occasional hypocalcemia. The administration of bicarbonate is the primary therapy for proximal RTA, and proper treatment can substantially improve growth rate.
Obstructive sleep apnea is associated with poor growth. The amount of energy expended during sleep in children with sleep apnea appears to limit weight and length gain, a pattern which reverses with the resolution of the obstruction. Obstructive sleep apnea is also associated with obesity and Prader-Willi syndrome. Diagnosis is made by polysomnography.
Malnutrition (other than that associated with chronic disease) is the most common cause of short stature worldwide and is the cause of much short stature in the developing world. Diagnosis in the developed world is based on historical and physical findings, particularly the dietary history. Food faddism and anorexia nervosa—as well as excessive voluntary dieting—can cause poor growth. Infections with parasites, such as Ascaris lumbricoides or Giardia lamblia, can decrease growth and are a principal cause of short stature in the developing world.
Specific nutritional deficiencies can have particular effects on growth. For example, severe iron deficiency can cause a thin habitus as well as growth retardation. Zinc deficiency can cause anorexia, decreased growth, delayed puberty, developmental problems, hair loss, diarrhea, impotence, eye and skin abnormalities, and taste changes leading to weight loss. Acrodermatitis enteropathica is a rash giving a visual clue to Zn deficiency. It arises usually in the presence of chronic systemic disease or infection. Children with nutritional deficiencies characteristically demonstrate failure of weight gain before growth rate decreases, and before weight for height decreases. This is in contrast to many endocrine causes of poor growth, where weight for height remains in the normal or high range. This simple rule often determines whether nutritional or endocrine evaluations are most appropriate. There are no simple laboratory tests for diagnosis of malnutrition. Serum IGF-I concentrations are low in malnutrition, as they are in GH deficiency. This distinction is important since misdiagnosing GH deficiency instead of malnutrition would be tragic as well as costly.
Children with hyperactivity disorders (or those incorrectly diagnosed as such) are frequently managed with chronic methylphenidate administration or similar medication. These agents can decrease weight gain by decreasing appetite and can lower growth rate, albeit inconsistently. These drugs must be used in moderation and only in children who definitely respond to them during careful evaluation and follow-up.
Exogenous glucocorticoids are a potent cause of poor growth (discussed later), as are excessive endogenous glucocorticoids.
SHORT STATURE DUE TO ENDOCRINE DISORDERS
Using the conservative criteria of height (<3rd percentile) and growth velocity (<5 cm/y for inclusion in the study), the incidence of endocrine disease in 114,881 Utah children who met these cutoff results was 5%, with a higher incidence in boys than girls by a ratio of more than 2.5:1. In this population, 48% of the children with Turner syndrome or GH deficiency were not diagnosed prior to the careful evaluation afforded by this study.
1. GROWTH HORMONE DEFICIENCY AND ITS VARIANTS
The incidence of GH deficiency is estimated to be between 1:4000 and 1:3500, so the disorder should not be considered rare.
There may be abnormalities at various levels of the hypothalamic-pituitary, GH-IGF-I axis. Most patients with idiopathic GH deficiency lack GHRH. One autopsied GH-deficient patient had an adequate number of pituitary somatotrophs that contained considerable GH stores. Thus, the pituitary gland produced GH, but it could not be released. Long-term treatment of such patients with GHRH can cause GH release and increase growth, but this therapy is not presently in use. Patients with pituitary tumors or those rare patients with congenital absence of the pituitary gland lack somatotrophs. Several kindreds have been described that lack various regions of the GH gene (responsible for producing GH). Alternatively, gene defects responsible for the embryogenesis of the pituitary gland may cause multiple pituitary deficiencies. Absence of the PIT1 gene encoding a pituitary-specific transcription factor causes deficient GH, TSH, and prolactin synthesis and secretion. Mutations of the prophet of PIT1 (PROP1) gene cause deficiencies of GH, TSH, FSH, LH, and ACTH production.
Congenital Growth Hormone Deficiency
Congenital GH deficiency presents with slightly decreased birth length (–1 SD), but the growth rate decreases in some cases strikingly soon after birth. The disorder is identified by careful measurement in the first year and becomes more obvious by 1 to 2 years of age. Patients with classic GH deficiency have short stature, increased fat mass leading to a chubby or cherubic appearance with immature facial appearance, immature high-pitched voice, and delay in skeletal maturation. Less severe forms of partial GH deficiency are described with few abnormal characteristics apart from short stature, decreased growth rate, and delayed bone age. GH-deficient patients lack the lipolytic effects of GH, partially accounting for the pudgy appearance. There is a higher incidence of hyperlipidemia with elevated total cholesterol and low-density lipoprotein (LDL) cholesterol in GH deficiency, and longitudinal studies demonstrate increases in high-density lipoprotein (HDL) cholesterol levels with GH treatment. Males with GH deficiency may have microphallus (penis <2 cm in length at birth), especially if the condition is accompanied by gonadotropin-releasing hormone (GnRH) deficiency (Figure 6–8). GH deficiency in the neonate or child can also lead to symptomatic hypoglycemia and seizures; if ACTH deficiency is also present, hypoglycemia is usually more severe. The differential diagnosis of neonatal hypoglycemia in a full-term infant who has not sustained birth trauma must include neonatal hypopituitarism. If microphallus (in a male subject), optic hypoplasia, or some other midline facial or CNS defect is noted, the diagnosis of congenital GH deficiency is more likely (see later). Congenital GH deficiency is also correlated with breech delivery. Intelligence is normal in GH deficiency unless repeated or severe hypoglycemia is present or a significant anatomic defect has compromised brain development. When thyrotropin-releasing hormone (TRH) deficiency is also present, there may be additional signs of hypothyroidism. Secondary or tertiary congenital hypothyroidism is not usually associated with physical findings of cretinism or developmental delay as is congenital primary hypothyroidism, but a few cases of isolated TRH deficiency and severe mental retardation are reported.
A 12-month-old boy with congenital hypopituitarism. He had hypoglycemic seizures at 12 hours of age. At 1 year, he had another hypoglycemic seizure (plasma glucose, 25 mg/dL) associated with an episode of otitis media, and it was noted that his penis was extremely small. At 12 months, body length was 66.5 cm (–2 SD) and weight was 8.5 kg (–3 SD). The penis was less than 1.5 cm long, and both testes were descended (each 1 cm in diameter). Plasma GH did not rise above 1 ng/mL after arginine and levodopa testing (no insulin tolerance test was performed because of the history of hypoglycemia). LH rose very little after administration of GnRH (gonadorelin), 100 μg. Serum thyroxine was low (T4, 6.6 μg/dL; T4 index, 1.5), and after administration of 200 μg of protirelin (TRH), serum TSH rose with a delayed peak characteristic of tertiary hypothyroidism. Plasma ACTH rose only to 53 pg/mL after metyrapone. Thus, the patient had multiple defects in the hypothalamic-pituitary axis including decreased secretion of GH, ACTH, and TSH due to deficient secretion of hypothalamic hormones. He was given six doses of 2000 units each of human chorionic gonadotropin (hCG) intramuscularly over 2 weeks, and plasma testosterone rose to 62 ng/dL, indicating normal testicular function. He was then treated with 25 mg of testosterone enanthate every month for 3 months, and his phallus enlarged to 3.5 × 1.2 cm without significant advancement of bone age. With hGH therapy (0.05 mg/kg intramuscularly every other day), he grew at a greater than normal rate for 12 months (catch-up growth), and growth then continued at a normal rate.
Congenital GH deficiency may present with midline anatomic defects. Optic hypoplasia with visual defects ranging from nystagmus to blindness is found with variable hypothalamic endocrinopathies in 71.7% of one series: 64.1% of subjects had GH axis abnormalities, 48.5% hyperprolactinemia, 34.9% hypothyroidism, 17.1% adrenal insufficiency, and 4.3% diabetes insipidus (DI) in this group of 47 subjects. About half of patients with optic hypoplasia have absence of the septum pellucidum on computed tomography (CT) or magnetic resonance imaging (MRI), leading to the diagnosis of septo-optic dysplasia. Septo-optic dysplasia is most often sporadic in occurrence but some affected individuals are reported with mutations of the homeobox gene expressed in ES cells (HESX1) (OMIM #601802) and septo-optic dysplasia (OMIM #182230). Cleft palate or other forms of oral dysraphism are associated with GH deficiency in about 7% of cases. Such children may need nutritional support to improve their growth. An unusual midline defect associated with GH deficiency is described in children with a single maxillary incisor.
Congenital absence of the pituitary gland, which occurs in an autosomal recessive pattern, leads to severe hypopituitarism with hypoglycemia. Affected patients have shallow development of or absence of the sella turcica. This defect is quite rare but clinically devastating due to ACTH deficiency if treatment is delayed. This is the most common MRI manifestation of PROP1 gene mutation (OMIM #601538).
Hereditary GH deficiency is described in several different mutations. Various genetic defects of the GHN gene (17q22-24) occur in affected families. Isolated type 1A GH deficiency (IGHDIA OMIM #262400) is inherited in an autosomal recessive pattern. Patients have deletions, frameshifts, and nonsense mutations in the GH gene. Unlike those with classic sporadic GH deficiency, some of these children are reported with significantly shortened birth lengths. Patients with absent or abnormal GH genes initially respond to exogenous human GH (hGH) administration, but some soon develop high antibody titers that eliminate the effect of therapy. Patients with high titers of blocking antibodies are reported to benefit from IGF-I therapy in place of GH therapy. Isolated GH deficiency (IGHD) type 1B (OMIM #612781) patients have autosomal recessive splice site mutations and incomplete GH deficiency and are less severely affected. Type 2 (IGHD2) (OMIM #173100) patients have autosomal dominant GH deficiency due to splice site or missense mutations. Type 2 patients have X-linked GH deficiency often associated with hypogammaglobulinemia.
A few patients are described with abnormalities of the GHRH gene. Mutations in pituitary transcription factors can lead to various combinations of pituitary hormone deficiencies as noted earlier. Mutations in PIT1/POU1F1 (POU class 1 homeobox 1) (OMIM #173110) lead to GH, PRL, and TSH deficiencies. Mutations in PROP1 (Prophet of PIT1, paired-like homeodomain transcription factor) (OMIM #601538) lead to GH, PRL, TSH, LH, FSH, and sometimes ACTH deficiencies. Mutations in HESX1 lead to GH, PRL, TSH, LH, FSH, ACTH, IGHD, and CPHD deficiencies.
Acquired Growth Hormone Deficiency
Onset of GH deficiency in late childhood or adolescence, particularly if accompanied by other pituitary hormone deficiencies, is ominous and may be due to a hypothalamic-pituitary tumor. The development of posterior pituitary deficiency, in addition to anterior pituitary deficiency, makes a tumor even more likely. The empty sella syndrome is more frequently associated with hypothalamic-pituitary abnormalities in childhood than in adulthood; thus, GH deficiency may be found in affected patients.
Some patients, chiefly boys with constitutional delay in growth and adolescence, may have transient GH deficiency on testing before the onset of puberty. When serum testosterone concentrations begin to increase in these patients, GH secretion and growth rate also increase. This transient state may incorrectly suggest bona fide GH deficiency but does not require therapy. A priming dose of estrogen is sometimes invoked to increase GH secretion maximally so that spurious GH deficiency is not diagnosed spuriously. CNS conditions that cause acquired GH deficiency (eg, craniopharyngiomas, germinomas, gliomas, histiocytosis X) are described in Chapter 4. It is remarkable that after craniopharyngioma removal, some patients, mainly obese subjects, continue to grow quite well in spite of the absence of GH secretion. This persistent growth appears to be caused by hyperinsulinemia.
Cranial irradiation of the hypothalamic-pituitary region to treat CNS tumors or acute lymphoblastic leukemia may result in GH deficiency starting approximately 12 to 18 months later, owing to radiation-induced hypothalamic (or perhaps pituitary) damage. Higher doses of irradiation, such as the 24-Gy regimen previously used for the treatment of CNS leukemia, have greater effect (adult height may be as much as 1.7 SD below the mean) than the lower (eg, 18 Gy) regimens and higher doses are more likely to cause TSH, ACTH, and gonadotropin deficiency as well as hyperprolactinemia or even precocious puberty. Girls treated at an early age with this lower regimen still appear to be at risk of growth failure. All children must be carefully observed for growth failure after irradiation since growth failure may occur years later. If these patients receive spinal irradiation, upper body growth may also be impaired, causing a decreased US-LS ratio and a further tendency to short stature. Abdominal irradiation for Wilms tumor may also lead to decreased spinal growth (estimated loss of 10 cm height from megavoltage therapy at 1 year of age, and 7 cm from treatment at 5 years of age). Others receiving gonadal irradiation (or chemotherapy) have impaired gonadal function, lack onset or progression of puberty, and/or have diminished or absent pubertal growth spurt. Chemotherapy for acute lymphocytic leukemia without irradiation may also lead to GH deficiency, so follow-up of growth after treatment for cancer is always necessary.
CNS trauma is well established as a cause of hypopituitarism in adults. Cross sectional studies in children reveal both high and low rates of subsequent hypopituitarism after head trauma, but the rare prospective studies demonstrate lower risk in children than in adults.
Other Types of GH Dysfunction
Primary IGF-I deficiency is due to GH insensitivity (Laron syndrome and its variants (OMIM #262500)). These disorders reflect GH receptor or post-receptor defects that are inherited in autosomal recessive fashion. The soluble GH-binding protein (GHBP) found in the circulation arises from the extracellular portion of the GH receptor, and since they derive from the same gene, circulating GHBP reflects the abundance of GH receptors. Patients with decreased or absent GH receptors have decreased serum GHBP levels, whereas those with post-receptor defects have normal GHBP concentrations. Affected children are found throughout the world, including Israel, where the syndrome was first reported, and Ecuador, where several generations of a large kindred were studied in great detail. Defects in various kindreds include nonsense mutations, deletions, RNA processing defects, and translational stop codons. GH/JAK-STAT axis signal-transduction impairment leads to short stature, when this intracellular system fails to activate in response to receptor occupancy by the GH ligand. Defects in the dimerization of the GH receptors, a required step in GH action, also lead to short stature. Serum GH is elevated in all forms of GH resistance, due to decreased or absent IGF-I, which results in lack of negative feedback inhibition. Patients are short at birth, confirming the importance of IGF-I in fetal growth (demonstrated previously in murine IGF-I gene knockout studies). About one-third have hypoglycemia, and half of boys have microphallus. The condition does not respond to GH treatment. Patients treated with recombinant IGF-I grow at an improved rate but do not respond quite as well to IGF-I as GH-deficient children do to GH treatment, indicating that GH may have a direct role in fostering growth above and beyond that conferred by IGF-I.
Other forms of GH resistance are described, but the majority of patients with disorders of the GH axis have abnormalities of GH secretion, not action. Very short, poorly growing children with delayed skeletal maturation, normal GH and IGF-I values, and no signs of organic disease have responded to GH therapy with increased growth rates equal to those of patients with bona fide GH deficiency. These patients may have a variation of constitutional delay in growth or genetic short stature, but a subtle abnormality of GH secretion or action is possible.
Pygmies (OMIM #265850) have normal serum GH, low IGF-I after puberty, and normal IGF-II concentrations. They have a congenital inability to raise IGF-I concentrations after puberty, which has greater importance in stimulating growth than IGF-II. Pygmy children are reported to lack a pubertal growth spurt, suggesting that IGF-I is essential to attain a normal peak growth velocity. Efe pygmies, the shortest of the pygmies, are significantly smaller at birth than neighboring Africans who are not pygmies, and their growth is slower throughout childhood, leading to statures displaced progressively below the mean. A few patients are reported with defects of the IGF-I gene or with deficiency of the IGF-I receptor (IGF-IR) (OMIM #147370) and extreme short stature that is not responsive to IGF-I. Intrauterine growth deficiency, microcephaly, developmental delay, and other psychological findings are reported in these cases. Why do certain normal children, perhaps within a short family, have stature significantly lower than the mean? There is no definite answer to this persistent question, but some patients have decreased serum GHBP concentration, which suggests a decrease in GH receptors in these children. A minority of short, poorly growing children have definable genetic abnormalities of their GH receptors. Genome Wide Association studies are uncovering various genetic influences on normal and pathologic stature. Short stature is the final common pathway of numerous biochemical abnormalities.
Adults who had GH deficiency in childhood or adolescence have decreased bone mass compared with normals even when bone mass is corrected for their smaller size. There is progressive bone loss in adults who are GH deficient even if bone density was improved with childhood therapy; GH is approved for adults with GH deficiency and can reverse this trend (see Chapter 4).
Diagnosis of GH Deficiency
Because basal values of serum GH are low in normal children and GH-deficient patients alike, the diagnosis of GH deficiency has classically rested on demonstration of an inadequate rise of serum GH after provocative stimuli or on some other measure of GH secretion. This process is complicated because different radioimmunoassay systems vary widely in their measurements of GH in the same blood sample (eg, a result on a single sample may be above 10 ng/mL in one assay but only 6 ng/mL in another). The physician must be familiar with the standards of the laboratory being used. Most insurance companies and state agencies accept inability of GH to rise above 10 ng/mL with stimulation as diagnostic of GH deficiency.
Another complicating factor is the state of pubertal development. Prepubertal children secrete less GH than pubertal subjects and, especially as they approach the onset of puberty, may have sufficiently reduced GH secretion to suggest falsely bona fide GH deficiency. This factor is sometimes addressed by administering a dose of estrogen to such subjects before testing. The very concept of GH testing provides a further complication. GH is released in episodic pulses. Although a patient who does not secrete GH in response to standard challenges is generally considered to be classically GH-deficient, a normal GH response to these tests may not rule out the efficacy of GH treatment. Testing should occur after an overnight fast; carbohydrate or fat ingestion suppresses the GH response. Obesity suppresses GH secretion, and an overweight or obese child may falsely appear to have GH deficiency. Even within the normal range, variations of BMI affect peak GH after stimulation.
Because 10% or more of healthy children do not have an adequate rise in GH with one test of GH reserve, at least two methods of assessing GH reserve are necessary before the diagnosis of classic GH deficiency is assigned. Of course, if GH rises above 10 ng/mL in a single test, classic GH deficiency is eliminated. Serum GH values should rise after 10 minutes of vigorous exercise; this is used as a screening test. After an overnight fast, GH levels should rise in response to arginine infusion (0.5 g/kg body weight [up to 20 g] over 30 minutes), oral levodopa (125 mg for up to 15 kg body weight, 250 mg for up to 35 kg, or 500 mg for >35 kg), or clonidine (0.1 mg/m2 orally). Side effects of levodopa include nausea; those of clonidine include some drop in blood pressure and drowsiness. Glucagon stimulation testing is used to determine both GH and ACTH secretory ability. It is accomplished by administration of 30 μg/kg glucagon (maximum 1 mg) and collecting GH samples at 0, 30, 60, 90, 120, 150, and 180 minutes afterwards; nausea and hyperglycemia are possible side effects.
The insulin tolerance test is another way to assess GH reserve but can be dangerous to perform and is rarely invoked. GH levels rise after acute hypoglycemia due to insulin administration; however, this test carries a risk of seizure if the blood glucose level drops excessively. An insulin tolerance test may be performed if a 10% to 25% dextrose infusion is available for emergency administration in the face of hypoglycemic coma or seizure and if the following conditions are satisfied: (1) an intravenous infusion line with heparin lock or low-rate saline infusion is available before the test begins, (2) the patient can be continuously observed by a physician, and (3) the patient has no history of hypoglycemic seizures. The patient must have a normal glucose concentration at the beginning of the test in the morning after an overnight fast (water intake is acceptable). Regular insulin, 0.075 to 0.1 U/kg in saline, may be given as an intravenous bolus. In 20 to 40 minutes, a 50% drop in blood glucose will occur, and a rise in serum GH and cortisol and ACTH should follow. Serum glucose should be monitored, and an intravenous line must be maintained for emergency dextrose infusion in case the patient becomes unconscious or has a hypoglycemic seizure. If dextrose infusion is necessary, it is imperative that blood glucose not be raised far above the normal range, because hyperosmolality has been reported from overzealous glucose replacement; undiluted 50% dextrose should not be used (see Chapter 4). This is a dangerous test and is rarely indicated!
A family of synthetic penta- and hexapeptides called GH-releasing peptides (GHRPs) stimulate GH secretion in normal individuals and in GH-deficient subjects. GHRPs act via ghrelin receptors of the hypothalamus that are different from the GH-releasing factor (GHRF) receptors, and their effects are additive to that of GHRF. Ghrelin is a gastrointestinal-derived peptide that naturally binds to these receptors in the hypothalamic ventromedial nucleus, arcuate nucleus and ventral tegmental area (dopaminergic neurons), causing GH secretion, it also stimulates appetite and is classified as an orexigenic agent. Recently, mutations in the GH secretagogue receptor (GHSR) that binds GHRPs and ghrelin were found in children with short stature; treatment with GH increased growth rate in these children.
Patients who respond to the pharmacologic stimuli noted earlier, but not to physiologic stimuli, such as exercise or sleep, are said to have neurosecretory dysfunction. These patients have decreased 24-hour secretion of GH (or integrated concentrations of GH) compared with healthy subjects, patterns similar to those observed in GH-deficient patients. It is not clear how frequently this condition is encountered.
This long discussion of the interpretation of GH after secretagogue testing brings into question the very standard for the diagnosis of GH deficiency. It is clear that pharmacologic testing cannot always determine which patients truly need GH therapy, and many authorities suggest that we abandon such dynamic testing in favor of measurements of IGF-I and IGFBP-3, although dynamic GH testing may still be required by insurance plans. Serum IGF-I values are low in most GH-deficient subjects, but, as noted earlier, some short patients with normal serum IGF-I concentrations may require GH treatment to improve growth rate. Moreover, starvation lowers IGF-I values in healthy children and incorrectly suggests GH deficiency. Children with psychosocial dwarfism—who need family therapy or foster home placement rather than GH therapy—have low GH and IGF-I concentrations and may falsely appear to have GH deficiency. Likewise, patients with constitutional delay in adolescence have low IGF-I values for chronologic age, but normal values for skeletal age, and may have temporarily decreased GH response to secretagogues. Thus, IGF-I determinations are not infallible in the diagnosis of GH deficiency. They must be interpreted with regard to nutrition, psychosocial status, and skeletal ages. IGFBP-3 is GH-dependent, and if its concentration is also low, it provides stronger evidence of GH deficiency than does the IGF-I determination alone.
The Growth Hormone Research Society produced criteria that attempt to deal with the diagnosis of GH deficiency in childhood in spite of the uncertainty of the methods. These criteria use clinical findings of various conditions associated with GH deficiency, the severity of short stature, and the degree and duration of decreased growth velocity to identify individuals that may have GH deficiency. The guidelines and diagnostic considerations in this chapter include most of the GH Society criteria. (See “Consensus guidelines” reference in the Short Stature section at the end of this chapter for details of the Growth Hormone Research Society statement.) A 3- to 6-month therapeutic trial of GH therapy may be necessary to determine growth response; if growth increases more than 2 cm/y, it is likely that the child will benefit from GH treatment, no matter what the tests originally showed.
Treatment of GH Deficiency
Before 1986, the only available method of treatment for GH deficiency was replacement therapy with hGH derived from cadaver donors. In 1985 and thereafter, Creutzfeldt-Jakob disease, a degenerative neurologic disease rare in patients so young, was diagnosed in some patients who had received natural hGH up to 10 to 15 years before. Because of the possibility that prions contaminating donor pituitary glands were transmitted to the GH-deficient patients, causing their deaths, natural GH from all sources was removed from distribution. Recombinant hGH now accounts for the world’s current supply.
Commercial hGH has the 191-amino acid natural sequence. hGH is now available in virtually unlimited amounts, allowing innovative treatment regimens not previously possible owing to scarce supplies. The potential for abuse of hGH in athletes or in children of normal size whose parents wish them to be taller than average, however, must now be addressed.
Growth disturbances due to disorders of GH release or action are shown in Table 6–2. GH-deficient children require biosynthetic somatropin (natural sequence hGH) at a dose of 0.18–0.3 mg/kg/wk administered in one subcutaneous dose per day 6 or 7 times per week during the period of active growth before epiphyseal fusion. An increased dose is approved by the FDA for use during puberty. The increase in growth rate (Figures 6–9, 6–10, and 6–11) is most marked during the first year of therapy. Older children do not respond as well and may require larger doses. Higher doses, up to double the standard starting dose, are approved by the FDA for use in puberty, but there are varying reports of the effect of these higher doses on adult height as, by far, most of the effect of GH on adult height is exerted in the years before puberty. GH does not increase growth rate without adequate nutrition and euthyroid status. During the roughly 50 years since the first use of GH in children, long-term effects are reported in several series. If only the children most recently treated with recombinant hGH are considered, the mean adult height was 1.4 SD below the mean, a significant improvement over the –2.9 SD mean height at the start of therapy but not a true normalization of height in most patients. With earlier diagnosis and treatment, using new pubertal dosing schedules, adult height can reach genetic potential.
TABLE 6–2Level of defect in growth. |Favorite Table|Download (.pdf) TABLE 6–2 Level of defect in growth.
|Site of Defect ||Clinical Condition |
|Hypothalamus ||Idiopathic GH deficiency due to decreased GHRH secretion; hypothalamic tumors or congenital defects |
|Pituitary gland ||Dysplasia, trauma, surgery, or tumor of the pituitary gland; defect in GH gene or in pituitary transcription factors |
|Sites of IGF production ||Primary IGF-I deficiency: GH receptor defect (Laron dwarfism with high GH and low IGF concentrations) |
| ||ALS deficiency |
| ||Growth hormone/JAK-STAT axis signal transduction defect |
| ||Pygmies with normal GH, low IGF-I, and normal IGF-II concentrations |
|Cartilage || |
Glucocorticoid-induced growth failure
Resistance to IGF-I
Examples of abnormal growth charts. Squares represent the growth pattern of a child (such as patient A in Figure 6–11) with precocious sexual development and early excessive growth leading to premature closure of the epiphyses and cessation of growth. Circles represent growth of a boy (such as patient B in Figure 6–11) with GH deficiency who showed progressively poorer growth until 6 years of age, when he was treated with hGH (arrow), after which catch-up growth occurred. The curves describe SDs from the mean.
Two examples of abnormal growth plotted on a height velocity chart simplified from the charts in Figure 6–3. A. The plot is taken from the data recorded as squares in Figure 6–9, describing a patient with precocious puberty such as patient A in Figure 6–11, with premature epiphysial closure, and cessation of growth. B. The plot is taken from the data recorded as circles in Figure 6–9, describing a patient with GH deficiency (such as patient B in Figure 6–11) who was treated with hGH (arrow) at age 6. Initial catch-up growth is noted for 2 years, with a lower (but normal) velocity of growth following. These charts display growth rate over 6 month growth intervals rather than 12-month intervals as shown on Figures 6–3 and 6–4.
Two boys demonstrating extremes of growth. The boy at left in each photograph (A) has precocious puberty due to a CNS lesion. At 4½ years, he was 125.1 cm tall, which is 4.5 SDs above the mean. (The mean height for a 4-year-old is 101.5 cm.) His testes measured 2 × 3.5 cm each, his penis 9.8 × 2.8 cm (all pubertal measurements). He was muscular and had acne and a deep voice. His bone age was 10 years, the testosterone level was 480 ng/dL, and the LH rose after 100 μg of GnRH (gonadorelin) to a pubertal response. His brain CT scan revealed a hamartoma of the tuber cinereum. The boy at right (B) at 6 years of age was 85 cm tall, which is more than 5 SD below the mean. He had the classic physical and historical characteristics of idiopathic GH deficiency, including early growth failure and a cherubic appearance. His plasma GH values were nondetectable and did not rise after provocative testing.
Monitoring of GH replacement is mainly accomplished by measuring growth rate and annually assessing bone age advancement. Serum IGF-I and IGFBP-3 will rise with successful therapy while GHBP will not change appreciably. Controlled clinical studies reported the utility of titrating the dose of GH to restore serum IGF-I to the high-normal range, monitoring serum IGF-I levels during clinical treatment. There is concern if the IGF-I levels rise more than two SDs above the mean and, if so, the GH dose is decreased. Serum bone-specific alkaline phosphatase rises with successful therapy. Urinary hydroxyproline, deoxypyridinoline, and galactosyl-hydroxylysine reflect growth rate and are used in clinical studies to reflect increased growth rate with therapy.
Antibodies to GH may be present in measurable quantities in the serum of children receiving GH. However, a high titer of blocking antibodies with significant binding capacity is rare except in patients with absence or abnormality of GH genes. Only a few patients are reported to have temporarily ceased growing because of antibody formation. GH exerts anti-insulin effects. Although clinical diabetes is not a likely result of GH therapy, the long-term effects of a small rise in glucose in an otherwise healthy child are unknown. If a tendency toward diabetes is already present, GH may cause the onset of clinical manifestations more quickly. Another potential risk is the rare tendency to develop slipped capital femoral epiphyses in children receiving GH therapy; slipped capital femoral epiphyses occur at times of increased growth rate. Recent data have weakened the link between slipped capital femoral epiphyses and GH therapy, but the final import of the relationship is not yet clear. Slipped capital femoral epiphyses, if associated with endocrinopathies, are most common in treated hypothyroid patients (50% one series of 80 episodes of slipped capital femoral epiphyses), followed by treated GH-deficient patients (25% of the series). This condition may occur bilaterally, and prophylactic treatment of the nonaffected side is recommended by several authorities. Pseudotumor cerebri may rarely occur with GH therapy, is usually associated with severe headache and may be more common in obese individuals receiving GH treatment. It is reported to reverse after cessation of GH therapy, but if allowed to continue, it may impair vision due to pressure on the optic nerve and cause severe complications. Organomegaly and skeletal changes like those found in acromegaly are other theoretical side effects of excessive GH therapy but do not occur with standard doses. Furthermore, prepubertal gynecomastia is reported with GH therapy.
Lack of compliance with GH therapy is a frequent cause of poor growth leading to undertreatment. Reported non-compliance is in the range of 33%. Lack of normalization of IGF-I with treatment is an indication of noncompliance.
The discovery of leukemia in young adults previously treated with GH was worrisome, but no cause and effect relationship has been established, and GH treatment is not considered a cause of leukemia. GH does not increase the recurrence rate of tumors existing before therapy. Thus, patients with craniopharyngiomas, for example, may receive GH, if indicated, after the disease is clinically stable, without significant worry that the GH will precipitate a recurrence. Clinicians usually wait 1 year after completion of tumor therapy before starting patients on GH therapy, but doing so is not a requirement. There are reports of a small increase in risk of colonic carcinoma decades after natural GH treatment in GH-deficient children, but no such information on long-term follow-up of children treated with recombinant hGH is available. GH deficiency is associated with an adverse lipid profile with elevated LDL cholesterol and decreased HDL cholesterol in addition to an increased BMI; GH-deficient adolescents treated with GH develop these findings within a few years after discontinuation of GH therapy. Low-dose GH therapy is now approved for use in adults with childhood-onset GH deficiency and is said to forestall these metabolic changes. Further, adult GH therapy maintains muscle strength and bone density in GH-deficient adults. One can, therefore, inform the parents of a child with GH deficiency that the patient may still benefit from GH therapy even after he or she stops growing if profound GH deficiency remains after repeat testing once off GH for at least 1 month.
GH has been combined with other substances to increase its impact on height. In patients who were diagnosed late, have entered puberty, and appear to have limited time to respond to GH before epiphyseal fusion causes the cessation of growth, a GnRH agonist has been used to delay epiphyseal fusion in clinical trials with varying success, but this was not recommended by a consensus conference on the use of GnRH agonist therapy, due to lack of strong evidence of effectiveness. This off-label use is not yet established as safe and effective. Aromatase inhibitors have been combined with GH in some clinical studies, but this is not yet regular clinical practice; there was a reported effect of decreasing bone age advancement, while allowing increased growth and height.
There are other conditions for which the FDA has approved the use of GH. GH therapy will increase adult height in Turner syndrome to an average of 5.1 cm if started early enough; the addition of low-dose oxandrolone is reported to further increase growth rate. Estrogen is used to promote feminization and maintain bone mineral density; the optimal time to initiate treatment with estrogen should be individualized based on bone age, height, and psychological factors. Usually estrogen is administered during the adolescent years in low doses and only after the normal age of onset of puberty is reached to preserve maximal adult height, although earlier initiation of therapy is gaining credence (see Chapter 15).
Recently, French researchers released data from a large ongoing prospective study and reported an increased risk of hemorrhagic stroke in early adulthood after hGH therapy during childhood and adolescence. However the cause and effect of hGH treatment on stroke remain to be established. The FDA is presently investigating these data, but findings have not changed clinical practice in the United States, and the FDA has not suggested that the clinical use of GH change. Present evidence does not support an increase in all cause mortality or neoplasia from hGH treatment.
In the most successful series of children with SGA treated with hGH, the agent increased adult height between 2.0 SD and 2.7 SD. Girls with Turner syndrome treated with hGH reach adult height of more than 150 cm, an increase from the average untreated height which is about 144 cm. When treatment starts at or before 4 years, an adult height is achieved in the normal range.
Treatment with GH is approved for chronic renal disease in childhood. GH increases growth rate above the untreated state without excessive advancement in bone age. Prader-Willi syndrome may also be treated with GH to increase growth rate, lean tissue mass, and bone density. A recent study indicated that parental education exerted the most significant effect on body composition in these children. However, there are reports that patients with Prader-Willi syndrome have died of obstructive sleep apnea following GH treatment, demonstrating a need for sleep studies to exclude sleep apnea before initiating treatment and constant surveillance after treatment has been initiated. The treatment of Noonan syndrome is described earlier. In general, males are more often treated with GH than females in the United States, but this is not the case in other developed countries.
The FDA has approved the use of GH in otherwise normal children, whose stature is below 2.25 SDs for age and who are predicted to fall short of reaching normal adult height (<1 percentile of adult height). There may be pressure for treatment of children predicted to be taller than these guidelines from parents, but the FDA approval is for specific indications. While GH may increase the height of such severely affected children, it should not be used for a child whose predicted adult height is in the normal range. Treatment costs $30,000 to $40,000 per year or about $35,000 per cm gained. In the United States, males are treated more often than females, while the ratio is more equal in other countries, presumably due to social/cultural issues.
GHRH has been isolated, sequenced, and synthesized. It is available for use in diagnosis and treatment. GH-deficient patients demonstrate lower or absent GH secretion after administration of GHRH. However, episodic doses of GHRH can restore GH secretion, IGF-I production, and growth in children with idiopathic GH deficiency. The ability of GHRH administration to stimulate pituitary GH secretion further supports the concept that idiopathic GH deficiency is primarily a disease of the hypothalamus, not of the pituitary gland.
IGF-I is now produced by recombinant DNA technology. IGF-I is useful in the treatment of certain types of short stature, particularly Laron dwarfism (and perhaps for African pygmies, should treatment be desired) where neither GH nor any other treatment is effective. IGF-I has been studied clinically for more than 12 years. Side effects, such as hypoglycemia (observed in 49% of treated subjects), injection site lipohypertrophy (32%), and tonsillar/adenoidal hypertrophy (22%), are common but not said to be severe. However, there is concern among some authorities as to the safety of this therapy.
B. Psychologic management and outcome
Research into the psychologic outcome of patients with short stature is flawed by lack of consistent methods of investigation and lack of controlled studies, but some results are of interest.
Studies vary in their conclusions, as to whether short stature is harmful to a child’s psychologic development or not, and whether, by inference, GH is helpful in improving the child’s psychologic functioning. Children with GH deficiency are the most extensively studied; earlier investigations suggested that they have more passive personality traits than do healthy children, may have delayed emotional maturity, and suffer from infantilization from parents, teachers, and peers. Many of these children have been held back in school because of their size without regard to their academic abilities. Some patients retain a body image of short stature even after normal height has been achieved with treatment. More recent studies challenge these views and suggest that self-image in children with height below the 5th percentile, who do not have GH deficiency, is closely comparable to a population of children with normal height. These findings may not be representative of the patient population discussed earlier in that a normal ambulatory population of short children may differ from the selected group that seeks medical attention. The data suggest that short stature itself is not cause for grave psychologic concern, and such concerns should not be used to justify GH therapy. We cannot avoid the fact that our heightist society values physical stature and equates it with the potential for success, a perception that is not lost on the children with short stature and their parents. A supportive environment in which they are not allowed to act younger than their age, nor to occupy a privileged place in the family is recommended for children with short stature. Psychologic help is indicated in severe cases of depression or maladjustment.
Photograph and growth chart of a 9½-year-old boy with psychosocial dwarfism. He had a long history of poor growth (<3 cm/y). The social history revealed that he was given less attention and punished more frequently than his seven siblings. He ate from garbage cans and begged for food, though he was not apparently deprived of food at home. When the photograph was taken, he was 99 cm tall (–7 SD) and weighed 14.7 kg (–3 SD). His bone age was 5 years, with growth arrest lines visible. Serum thyroxine was 7.8 μg/dL. Peak serum GH varied from nondetectable to 8 ng/mL on different provocative tests between age 6 years and 8½ years. He was placed in a hospital chronic care facility (arrow) for a 6-month period and grew 9 cm, which projects to a yearly growth velocity of 18 cm. On repeat testing, the peak serum GH was 28 ng/mL.
Children with psychosocial dwarfism present with poor growth, a pot-bellied and immature appearance. They often display bizarre eating and drinking habits. Parents may report that the affected child begs for food from neighbors, forages in garbage cans, and drinks from toilet bowls. As a rule, this tragic condition occurs in only one of several children in a family. Careful questioning and observation reveal a disordered family structure in which the child is either ignored or severely disciplined. Caloric deprivation or physical battering may or may not be a feature of the history. These children have functional hypopituitarism. Testing often reveals GH deficiency at first, but after the child is removed from the home, GH function quickly returns to normal. Diagnosis rests on improvement in behavior or catch-up growth in the hospital or in a foster home. Separation from the family is therapeutic, but the prognosis is guarded. Family psychotherapy may be beneficial, but long-term follow-up is lacking.
Growth disorder due to abnormal parent–child interaction in a younger infant is maternal deprivation no matter which parent is most closely associated with the condition. Caloric deprivation due to parental neglect may be of greater significance in this younger age group. Even in the absence of nutritional restriction or full-blown psychosocial dwarfism, constant negative interactions within a family may inhibit the growth of a child.
It is essential to consider family dynamics in the evaluation of a child with poor growth. It is not appropriate to recommend GH therapy for emotional disorders.
Thyroid hormone deficiency decreases postnatal growth rate and skeletal development. Congenital hypothyroidism leads to severe developmental delay unless treatment is rapidly provided after birth. Screening programs for the diagnosis of congenital hypothyroidism have been instituted all over the world. Early treatment following diagnosis in the neonatal period markedly reduces growth failure and has virtually eliminated developmental abnormalities caused by this disorder. Early treatment of congenital hypothyroidism results in normal growth. Acquired hypothyroidism in older children (eg, due to lymphocytic thyroiditis) may lead to growth failure. Characteristics of hypothyroidism are decreased growth rate and short stature, retarded bone age, and an increased US-LS ratio for chronologic age due to poor growth of the extremities. Patients are apathetic and sluggish and have constipation, bradycardia, coarsening of features and loss of hair, hoarseness, and delayed pubertal development, if the condition is untreated. Intelligence is unaffected in late-onset hypothyroidism, but the apathy and lethargy may make it seem otherwise. Although weight gain is possible with hypothyroidism, in contrast to common wisdom, it is not extreme.
The diagnosis of congenital hypothyroidism is usually made on the basis of neonatal screening studies. In this standard procedure, currently in use throughout the world, a sample of blood is taken from the heel or from the umbilical cord at birth and analyzed for total T4 or TSH. A low total T4 or free T4 for age or an elevated TSH is usually indicative of congenital hypothyroidism; actual values differ by state and laboratory. A low total T4 alone may be associated with low circulating thyroxine-binding globulin (TBG), but the significantly elevated TSH is diagnostic of primary hypothyroidism. The diagnosis may be accompanied by radiologic evidence of retarded bone age or epiphyseal dysgenesis in severe congenital hypothyroidism.
In older children, serum TSH is the most reliable diagnostic test. Elevated TSH with decreased free T4 may eliminate the potential confusion resulting from the use of total T4, which may vary with the level of TBG or other thyroxine-binding proteins. A positive test for serum thyroglobulin antibodies or thyroperoxidase antibodies would lead to the diagnosis of autoimmune thyroid disease (Hashimoto thyroiditis) as an explanation for the development of hypothyroidism (see Chapter 7). If both FT4 and TSH are low, the possibility of central hypothyroidism (pituitary or hypothalamic insufficiency) must be considered (this would not be revealed in a newborn screening programs that use primarily TSH screening). This should lead to a search for other hypothalamic-pituitary endocrine deficiencies such as GH deficiency and CNS disease (see Chapter 4).
Treatment is accomplished by thyroxine replacement. The dose varies from a range of 10 to 15 μg/kg in infancy to 2 to 3 μg/kg in older children and teenagers. Suppression of TSH to normal values for age is a useful method for assessing the adequacy of replacement in acquired primary hypothyroidism. However, there are additional considerations in treatment of neonates as suppression of TSH is not appropriate in all affected newborns, and consultation with a pediatric endocrinologist is essential in this age group to ensure optimal dosing and adequate CNS development.
Excess glucocorticoids (either exogenous or endogenous) lead to decreased growth before obesity and other signs of Cushing syndrome develop. The underlying disease may be bilateral adrenal hyperplasia due to abnormal ACTH-cortisol regulation in Cushing disease, autonomous adrenal adenomas, or adrenal carcinoma. The appropriate diagnosis may be missed if urinary cortisol and 17-hydroxycorticosteroid determinations are not interpreted on the basis of the child’s body size or if inappropriate doses of dexamethasone are used for suppressive testing (appropriate doses are 20 μg/kg/d for the low-dose and 80 μg/kg/d for the high-dose dexamethasone suppression test) (see Chapter 9). Furthermore, daily variations in cortisol production necessitate several urinary or plasma cortisol determinations before Cushing disease can be appropriately diagnosed or ruled out. The high-dose dexamethasone test was positive in 68% of a recent series of children with Cushing disease. The corticotropin-releasing hormone test was positive in 80% of affected patients, whereas MRI of the pituitary was positive in only 52%. Inferior petrosal sampling (see Chapters 4 and 9) was 100% accurate in the diagnosis of Cushing disease, although technically difficult in children. The development of salivary cortisol assays makes the sampling of early morning salivary cortisol following a midnight dexamethasone dose an easier method to diagnose Cushing disease in children. Transsphenoidal microadenomectomy is the treatment of choice for Cushing disease.
Exogenous glucocorticoids used to treat asthma or even overzealous use of topical corticosteroid ointments or creams may suppress growth. These iatrogenic causes of Cushing syndrome, if resolved early, may allow catch-up growth and so may not affect adult height. Thus, an accurate history of prior medications is important in diagnosis. Treatment of the underlying disorder (eg, transsphenoidal microadenomectomy for Cushing disease) will restore growth rate to normal (catch-up growth may occur initially) if epiphyseal fusion has not occurred, but adult height will depend on the length of the period of growth suppression.
Pseudohypoparathyroidism type 1A (OMIM #103580) is a rare disorder consisting of a characteristic phenotype and biochemical signs of hypoparathyroidism (low serum calcium and high serum phosphate) in its classic form. Phosphate is elevated in states of deficient parathyroid hormone (PTH) action, compared to vitamin D deficiency where phosphate levels are decreased while PTH is elevated. Circulating PTH levels are elevated in pseudohypoparathyroidism, but target tissues fail to respond to exogenous PTH administration. Children with classic pseudohypoparathyroidism are short and overweight, with characteristic round facies and short fourth and fifth metacarpals. This constellation of physical findings is called Albright hereditary osteodystrophy, which may be expressed separately from the biochemical disorders (see later). Developmental delay is common. The condition is due to heterozygous loss of function mutations in the alpha subunit of the Gs protein transducer (GNAS1 gene). When imprinted paternally, this results in a defect in the G-protein that couples PTH receptors to adenylyl cyclase due to inheritance of the defective maternal allele. Thus, patients with pseudohypoparathyroidism type 1A have a blunted rise of urinary cAMP in response to administration of PTH. Remarkably, a defect occurs in the same regulatory protein system affected in McCune-Albright syndrome, in which hyperactive endocrine events result (see Chapters 1 and 8). A rarer variant of this disorder (pseudohypoparathyroidism type 1B; OMIM #603233) appears to be due to mutations in noncoding regions of the GNAS1 gene. Treatment with high-dose vitamin D or 1,25-dihydroxyvitamin D (calcitriol) and exogenous calcium as well as phosphate-binding agents (if needed) will help correct the biochemical defects and control hypocalcemic seizures in patients with pseudohypoparathyroidism.
Two remarkable cousins are reported with pseudohypoparathyroidism and premature Leydig cell maturation, both due to abnormalities in the same G protein. The defective protein was shown to be inactive at normal body temperature, leading to defective PTH activity at the level of the kidney and bone. However, it was hyperactive at the cooler temperatures in the scrotum, leading to ligand-independent activation of Leydig cell function.
Children with the phenotype of Albright hereditary osteodystrophy but with normal circulating levels of calcium, phosphate, and PTH have pseudopseudohypoparathyroidism (OMIM #612463). They require no calcium or vitamin D therapy (see Chapter 8).
6. DISORDERS OF VITAMIN D METABOLISM
Short stature and poor growth are features of rickets in its obvious or more subtle forms. The cause may be vitamin D deficiency due to inadequate oral intake, fat malabsorption, inadequate sunlight exposure, anticonvulsant therapy, and/or renal or hepatic disease. Classic findings of vitamin D-deficient rickets include bowing of the legs, chest deformities (rachitic rosary), and characteristic radiographic findings of the extremities associated with decreased serum calcium and phosphate levels and elevated serum alkaline phosphatase levels. There are two forms of hereditary vitamin D-dependent rickets. Autosomal recessive type 1 hypophosphatemic rickets (OMIM #241520) involves a renal 25 OH vitamin D 1-hydroxylase deficiency, and type 2 (OMIM #613312) involves an absent or defective vitamin D receptor. However, the most common type of rickets in the United States is X-linked hypophosphatemic rickets (OMIM #307800), a dominant genetic disorder affecting renal reabsorption of phosphate. It is associated with short stature, severe and progressive bowing of the legs (but no changes in the wrists or chest), normal or slightly elevated serum calcium, very low serum phosphate, and urinary phosphate wasting. Short stature is linked with rickets in other renal disorders associated with renal phosphate wasting. Examples include Fanconi syndrome (including cystinosis and other inborn errors of metabolism) and RTA.
When treatment is effective in these disorders (eg, vitamin D for vitamin D deficiency or alkali therapy for appropriate types of RTA), growth rates will improve. Replacement of vitamin D and phosphate is appropriate therapy for vitamin D-resistant rickets. It improves the bowing of the legs and leads to improved growth, although there is a risk of nephrocalcinosis with vitamin D treatment. This necessitates annual renal ultrasound examinations when patients are receiving vitamin D therapy.
In the Williams-Bureun syndrome of elfin facies, supravalvular aortic stenosis, and mental retardation with gregarious personality, patients have SGA and greatly reduced height in childhood and as adults; this disorder may include infantile hypercalcemia but is no longer considered a disorder of vitamin D metabolism because a genetic defect in the elastin gene at 7q11.23 occurs in most affected patients (#194050).
Growth in type 1 diabetes mellitus depends on the efficacy of therapy. Well-controlled diabetes mellitus is compatible with normal growth, whereas poorly controlled diabetes often causes slow growth. Liver and spleen enlargement in a poorly controlled, short, diabetic child is known as Mauriac syndrome, rarely seen now owing to improved diabetes care. Another factor that may decrease growth rate in children with type 1 diabetes mellitus is the increased incidence of Hashimoto thyroiditis in this population. Yearly thyroid function screening is advisable, especially as the peripubertal period approaches. GH concentrations are higher in children with diabetes, and this factor may play a role in the development of diabetic complications. IGF-I concentrations tend to be normal or low, depending on glucose control, but judging from the elevated GH noted earlier, the stimulation of IGF-I production by GH appears to be partially blocked in these children. Celiac disease may occur in 10% of children with type 1 diabetes and can itself lead to growth failure.
Polyuria and polydipsia due to inadequate vasopressin (central or neurogenic diabetes insipidus) or inability of the kidney to respond to vasopressin (nephrogenic diabetes insipidus) lead to poor caloric intake and decreased growth. With appropriate treatment (see Chapter 5), the growth rate should return to normal. Acquired neurogenic or central diabetes insipidus may indicate the development of a hypothalamic-pituitary tumor, and growth failure may be due to associated GH deficiency.
DIAGNOSIS OF SHORT STATURE
TABLE 6–3Basic diagnosis of short stature. |Favorite Table|Download (.pdf) TABLE 6–3 Basic diagnosis of short stature.
Birth weight and gestational age
Prenatal substance abuse
Birth trauma or complications
Age of puberty or menarche in family
Family history of or symptoms of chronic diseases
Measured and charted height
Measured and charted weight and BMI
Signs of syndromes
Findings of chronic disease
TABLE 6–4The laboratory evaluation of short stature. |Favorite Table|Download (.pdf) TABLE 6–4 The laboratory evaluation of short stature.
|Test ||Rationale |
|CBC ||Anemia: nutritional, chronic disease, malignancy |
| ||Leukocytosis: inflammation, infection |
| ||Leukopenia: bone marrow failure syndromes |
| ||Thrombocytopenia: malignancy, infection |
|ESR, CRP ||Inflammation of infection, inflammatory diseases, malignancy |
|Chemistry panel (electrolytes, liver enzymes, BUN) ||Signs of acute or chronic hepatic, renal, adrenal dysfunction; hydration and acid-base status |
|Carotene, folate, tissue transglutaminase antibody, or reflex celiac panel ||Assess malabsorption; detect celiac disease |
|Urinalysis ||Signs of renal dysfunction, hydration; renal tubular acidosis |
|Karyotype, candidate gene analysis, SNP analysis using microarrays on DNA chips, array-comparative genomic hybridization (array-CGH), or other genomic techniques ||Evaluate for genetic syndromes |
|Cranial MRI imaging ||Assesses hypothalamic-pituitary tumors (craniopharyngioma, glioma, germinoma) or congenital midline defects |
|Bone age ||Determine physiologic maturation, and evaluate height potential |
|IGF-I, IGF BP3 ||Reflects growth hormone status or nutrition |
|Free thyroxine and TSH ||Detects hypothyroidism |
|Prolactin ||Elevated in hypothalamic dysfunction or destruction, suppressed in pituitary disease |
TABLE 6–5Growth hormone testing. |Favorite Table|Download (.pdf) TABLE 6–5 Growth hormone testing.
Growth hormone testing is last and only performed if no other diagnosis is found
Never get basal serum GH unless you suspect gigantism!
Insulin-induced hypoglycemia (very dangerous)
Growth hormone–releasing peptides (GRP)
Evaluation of Short Stature
An initial decision must determine whether a child is pathologically short or simply distressed because height is not as close to the 50th percentile as desired by the patient or the parents. Performing unnecessary tests is expensive and may be a source of long-term concern to the parents—a concern that could be avoided by appropriate reassurance. Alternatively, missing a diagnosis of pathologic poor growth may cause the patient to lose inches of final height or may allow progression of serious disease.
If a patient’s stature, growth rate, or height adjusted for midparental height is sufficiently decreased to warrant evaluation, an orderly approach to diagnosis will eliminate unnecessary laboratory testing. The medical history will provide invaluable information as to the intrauterine course and toxin exposure and the possibility of birth trauma as well as an indication of other acute or chronic diseases and dietary intake. Birthweight and gestational age determine whether the child is SGA or AGA. The evaluation for dietary deficiencies and for symptoms of any chronic disease is important since almost any systemic disease or nutritional compromise can decrease growth rate (see Table 6–1). Review of past growth charts is important, but in this modern era, children often change doctors frequently, and these data may not be available. Asking whether the child has changed clothing sizes or shoe sizes is useful in the absence of any other data that may allow determination of growth rate. Heights of parents and age of puberty of parents are recorded although usually only a mother will recall her age of menarche while the father will not likely remember anything about his pubertal development (unless the father continued to grow after he left high school which might indicate constitutional delay in puberty). The height of siblings and specifically their percentile of height and whether they entered puberty at an appropriate time is important. The presence of chronic disease in the family is also noted in the history. Evaluation of psychosocial factors affecting the family and the relationship of parents and child can be carried out during the history-taking encounter. Often the diagnosis can be made at this point.
It goes without saying that accurate measurement of growth is essential. The physical examination requires determination of height as described earlier, and comparison is carried out with any previous data available. Measurement of weight and the calculation of BMI are performed so that neither obesity nor malnutrition is missed. If past heights are not available, a history of lack of change in clothing and shoe sizes or failure to lengthen skirts or pants may reflect poor growth. Questions about how the child’s stature compares with that of his or her peers and whether the child’s height has always had the same relationship to that of classmates are useful. One of the most important features of the evaluation process is to determine height velocity and compare the child’s growth rate with the normal growth rate for age. Adjustment for midparental height is calculated and nutritional status determined. Arm span, head circumference, and US-LS ratio are measured. Physical examination is directed to uncover signs of chronic disease, CNS condition or a midline defect of the CNS that may be related to hypothalamic pituitary dysfunction. Physical stigmas of syndromes or systemic diseases are evaluated. Neurologic examination is essential.
Any clues to a diagnosis in the history or physical examination are pursued. However, if no historical or physical features lead to an etiology, laboratory examinations are performed (see Table 6–4). A list of chronic diseases causing short stature is presented in Table 6–1. Complete blood count and serum chemistry screening with electrolyte measurements may reveal anemia, abnormalities of hepatic or renal disease, glucose intolerance, acidosis, calcium disorder, or other electrolyte disturbances. Age-adjusted values must be used (eg, the normal ranges of serum alkaline phosphatase and phosphorus values are higher in children than in adults). An elevated sedimentation rate, low serum carotene, or a positive antinuclear, or tissue transglutaminase antibody determination (if IgA determination first eliminates the possibility of IgA deficiency providing a false negative test) may indicate connective tissue disease, Crohn’s disease, celiac disease, or malabsorption syndrome. Serum TSH and free T4 are important measurements to exclude existing thyroid disease. Urinalysis is done, with attention to specific gravity (to rule out diabetes insipidus) and ability to acidify urine (to evaluate possible RTA). Skeletal age evaluation does not alone provide a diagnosis; however, if the study shows delayed bone age, the possibility of constitutional delay in growth, hypothyroidism, or GH deficiency must be considered. The tests used for the diagnosis of GH deficiency are detailed earlier (see Table 6–5). If serum IGF-I is normal for age, classic GH deficiency or malnutrition is unlikely; if serum IGF-I is low, it must be considered in relation to skeletal age, nutritional status, and general health status before interpretation of the value can be made. Since IGF-I values are low under 2 or 3 years of age, the simultaneous measurement of IGFBP-3 is useful in infants. If either or both IGF-I and IGFBP-3 are low, the diagnosis may be GH deficiency if poor nutrition is ruled out. If GH deficiency or impairment is found or if there is another hypothalamic-pituitary defect, an MRI is indicated with particular attention to the hypothalamic-pituitary area to rule out a congenital defect or neoplasm in the area. The appearance of an ectopic location of the posterior pituitary on MRI is relatively frequent in congenital GH deficiency, as is a decreased pituitary volume or apparent interruption of the pituitary stalk. Serum gonadotropin and sex steroid determinations are performed in pediatric assays if puberty is delayed (see Chapter 15). Serum prolactin may be elevated in the presence of a hypothalamic disorder.
Celiac disease is quite common as a cause of gastrointestinal distress and/or short stature. Serum IgA levels and tissue transglutaminase antibody measurements are indicated in the evaluation of growth disorders. A karyotype is obtained in any short girl without another diagnosis to rule out Turner syndrome, especially if puberty is delayed or gonadotropins are elevated. If Turner syndrome is diagnosed, evaluation of thyroid function and determination of thyroid antibodies is also important.
Elevated urinary free cortisol (normal: <60 μg/m2/24 h [<18.7 μmol/m2/24 h]), elevated late night salivary cortisol, or abnormal dexamethasone suppression testing signifies Cushing syndrome.
If no diagnosis is apparent after all of the above have been considered and evaluated, more detailed procedures, such as provocative testing for GH deficiency, are indicated. It must be emphasized that a long and expensive evaluation is not appropriate until psychologic or nutritional factors are ruled out. Likewise, if a healthy-appearing child presents with borderline short stature, normal growth rate, and short familial stature, a period of observation may be more appropriate than laboratory tests.
TALL STATURE DUE TO NONENDOCRINE CAUSES
1. CONSTITUTIONAL TALL STATURE
A subject who has been taller than his or her peers through most of childhood is growing at a velocity within the normal range with a moderately advanced bone age, and has no signs of the disorders listed later, may be considered to be constitutionally advanced. Predicted final height will usually be in the normal adult range for the family.
Obesity in an otherwise healthy child will often, especially in the presence of a melanocortin 4 receptor (MC4R) mutation, lead to moderate advancement of bone age, slightly increased growth rate, and tall stature in childhood. Age of puberty will begin in the early range of normal, and adult stature will conform to genetic influences. Thus, an obese child without endocrine disease should be tall; short stature and obesity are worrisome.
2. FAMILIAL/GENETIC TALL STATURE
Children with exceptionally tall parents have a genetic tendency to reach a height above the normal range. The child will be tall for age and will grow at a normal to high normal rate. Bone age will be close to chronologic age, leading to a tall height prediction. Occasionally, children will be concerned about being too tall as adults. These worries are more common in girls and will often be of greater concern to the parents than to the patient. Adult height was limited in the past by promoting early epiphyseal closure with estrogen in girls or testosterone in boys, but such therapy is no longer considered appropriate. Testosterone therapy decreases HDL cholesterol levels. Acne fulminans may be caused by testosterone therapy and progression may occur, even after therapy has been withdrawn. Estrogen carries the theoretical risk of thrombosis, ovarian cysts, and galactorrhea, and recent report of decreased fertility. High-dose estrogen therapy is estimated to decrease predicted final height by as much as 4.5 to 7 cm but only if started 3 to 4 years before epiphyseal fusion. Such height-limiting therapy is extremely rare in the present era although, recently, long-acting somatostatin agonists have been used in an attempt to limit height in selected subjects. Counseling and reassurance are more appropriate.
3. SYNDROMES OF TALL STATURE
The sporadic syndrome of rapid growth in infancy, prominent forehead, high-arched palate, sharp chin, and hypertelorism [Sotos syndrome (OMIM #117550)] is caused by mutation in the nuclear receptor–binding SET domain protein 1 (NSD1) gene and is not associated with GH excess. Mentation is usually impaired. The growth rate decreases to normal in later childhood, but stature remains tall.
Marfan syndrome (OMIM #154700) is an autosomal dominant abnormality of connective tissue exhibiting variable penetrance. The disorder is due to mutation of the fibrillin 1 gene located on 15q21.1. This condition may be diagnosed by characteristic physical manifestations of tall stature, long thin fingers (arachnodactyly), hyperextension of joints, and superior lens subluxation. Pectus excavatum and scoliosis may be noted. Furthermore, aortic or mitral regurgitation or aortic root dilation may be present, and aortic dissection or rupture may ultimately occur. In patients with this syndrome, arm span exceeds height, and the US-LS ratio is quite low owing to long legs. Aortic root ultrasound and slit lamp ophthalmologic examinations are indicated.
Patients with homocystinuria (OMIM #236200) have an autosomal recessive deficiency of cystathionine beta-synthase (gene locus 21q22.3) and phenotypes similar to those of patients with Marfan syndrome. Additional features of homocystinuria include developmental delay, increased incidence of seizures, osteoporosis, inferior lens dislocation, and increased urinary excretion of homocystine with increased plasma homocystine and methionine but low plasma cystine. Thromboembolic phenomena may precipitate a fatal complication. This disease is treated by restricting dietary methionine and, in responsive patients, administering pyridoxine.
Patients with Beckwith-Wiedemann syndrome (OMIM #130650) demonstrate macrosomia (birth weight >90th percentile) in 88% of cases, increased postnatal growth, omphalocele in 80%, macroglossia in 97%, and hypoglycemia due to the hyperinsulinism of pancreatic hyperplasia in 63%. Other reported features include fetal adrenocortical cytomegaly and large kidneys with medullary dysplasia. The majority of patients occur in a sporadic pattern due to a mutation at 11p15.5, but analysis of some pedigrees suggests the possibility of familial patterns. There is a risk of Wilms tumor, hepatoblastoma, adrenal carcinoma, and gonadoblastoma in this condition.
Patients with one (47,XYY) or more (48,XYYY) extra Y chromosomes achieve greater than average adult heights. They have normal birth lengths but higher than normal growth rates. Excess GH secretion has not been documented (see Chapter 14).
Patients with Klinefelter syndrome (see Chapters 12 and 14) tend toward tall stature, but this is not a constant feature.
TALL STATURE DUE TO ENDOCRINE DISORDERS
Pituitary gigantism is caused by excess GH secretion before the age of epiphyseal fusion. The increased GH secretion may be due to somatotroph-secreting tumors or constitutive activation of GH secretion as is sometimes found in the McCune-Albright syndrome. Alternatively, it may result from excess secretion of GHRH. Patients—besides growing excessively rapidly—have coarse features, large hands and feet with thick fingers and toes, and often frontal bossing and large jaws.
Although this condition is quite rare, the findings appear similar to those observed in the more frequently diagnosed acromegaly (which occurs with GH excess after epiphyseal fusion). Thus, glucose intolerance or frank diabetes mellitus, hypogonadism, and thyromegaly are predicted. Treatment is accomplished by surgery (the transsphenoidal approach is used if the tumor is small enough), radiation therapy, or by medical therapy with a somatostatin analog.
Early onset of estrogen or androgen secretion leads to abnormally increased height velocity. Because bone age is advanced, there is the paradox of the tall child who, because of early epiphyseal closure, is short as an adult. The conditions include complete and incomplete sexual precocity (including virilizing congenital adrenal hyperplasia) (see Chapter 14).
Excessive thyroid hormone, due to endogenous overproduction or overtreatment with exogenous thyroxine, leads to increased growth, advanced bone age, and, if occurring in early life, craniosynostosis. If the condition remains untreated, adult height will be reduced due to early epiphyseal closure.
4. INFANTS OF DIABETIC MOTHERS
Birth weight and size in infants of diabetic mothers are quite usually high, although severely affected, poorly controlled mothers with type 1 diabetes may have infants with IUGR due to placental vascular insufficiency. Severe hypoglycemia and hypocalcemia are evident in the affected infants soon after birth. The appearance and size of such infants is so striking that women have been diagnosed with gestational diabetes as a result of giving birth to large affected infants. By 10 years of age, infants of diabetic mothers have an increased prevalence of obesity as well as insulin resistance and all of the comorbidities of the condition.