Case 3-2005 — A 14-Year-Old Boy with Recent Slowing of Growth and Delayed Puberty
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《新英格兰医药杂志》
Presentation of Case
A 14-year-old boy was evaluated in the pediatric endocrinology clinic because of decreased endurance, slow growth, and delayed onset of puberty.
Ten weeks before his presentation at the clinic, he saw his pediatrician because of concern regarding his short stature, lack of energy, and youthful appearance relative to his male peers. The patient had been well until approximately four years previously, when he had had an episode of diarrhea that persisted for 19 days and was associated with a weight loss of approximately 1.5 kg, without fever or abdominal pain. The patient's father also had diarrhea during some of that time. The boy was treated with metronidazole for a presumptive diagnosis of giardia, and his stools became solid. The results of stool examination for the presence of ova and parasites, and of routine bacterial cultures for Clostridium difficile, rotavirus, and yersinia were negative. The boy returned to his usual state of health, but his mother noted that after the illness he seemed to have dark circles under his eyes, had poor skin color, and reported intermittent bouts of foul-smelling flatulence. In the year before this evaluation, he began to have behavior problems and increasing difficulty focusing on schoolwork. He was referred to the pediatric endocrinology clinic of this hospital.
The patient had been born by cesarean section, which had been indicated for cephalopelvic disproportion, at a gestational age of 39 weeks, and weighed 3.5 kg at birth. He had no allergies, was taking no medications when he came to the clinic, and had had the usual childhood immunizations. He was a student in the eighth grade. In the interval since his visit to the pediatrician, he had begun to notice underarm odor and to use deodorant, and pubic hair had developed.
The mother's height was 173 cm and father's 183 cm. Other female relatives ranged in height from 165 to 173 cm, and male relatives from 183 to 191 cm. A female cousin had had a delayed puberty for which she had been treated with hormone therapy; several second-degree female relatives had thyroid disease. The maternal grandfather had a history of rickets in childhood and had been thin all his life; at 75 years of age, he was told that he could not absorb vitamin B12 and had required B12 shots thereafter. He died at 78 years of age of diffuse large-B-cell lymphoma.
On physical examination, the boy's height was 159 cm and the weight was 42.9 kg (Figure 1). The blood pressure was 112/74 mm Hg and the pulse 68 beats per minute. The head circumference was 55 cm and the arm span 159 cm, and he had an upper-to-lower body-segment ratio of 0.8. He had a slightly high-arched palate, and shotty lymphadenopathy was present at the angle of the mandible bilaterally. His thyroid was palpable and not enlarged. His head, eyes, ears, nose, throat, lungs, heart, abdomen, and extremities all appeared normal; the neurologic examination showed no abnormalities. The estimated testicular volume was 5 ml on the left and 4 ml on the right. His pubic hair, as assessed by the Tanner classification of sexual development, was stage 2 and his axillary hair was stage 1 (the range is from 1, for preadolescent characteristics, to 5, for adult characteristics).
Figure 1. Growth Chart.
The black Xs indicate growth points before and at the time of the patient's initial evaluation. The rate of weight gain began to slow at approximately 10 years of age, and the rate of height increase began to slow one year later. The red Xs indicate growth points after treatment.
A radiograph of the left hand obtained at a chronologic age of 14 years 2 months showed a bone age of 12 years 6 months (Figure 2). Results of laboratory tests are shown in Table 1. A diagnostic procedure was performed.
Figure 2. Radiographs of the Patient's Left Hand at a Chronologic Age of 14 Years 2 Months (Panel A) and the Hand of a Normal 14-Year-Old (Panel B).
In the patient's hand, unlike the normal hand, the sesamoid bone of the thumb has not developed, and the epiphyses (arrows) of the phalanges are shorter and not cupped. According to the bone-age standards of Greulich and Pyle,1 the patient's bone age is between 12 years and 12 years 6 months, indicating a slight delay in growth.
Table 1. Laboratory-Test Results.
Differential Diagnosis
Dr. Lynne L. Levitsky: May we review the bone-age radiograph?
Dr. Sudha A. Anupindi: On the basis of the standards compiled by Greulich and Pyle,1 the bone age of a child is calculated on a radiograph of the left hand (Figure 2A). The configuration, development, and length of the epiphyses of the phalanges of the fingers and carpal bones of a patient are compared with those of the established standard bone ages (Figure 2B). The presence of the sesamoid bone of the thumb is a critical feature; the sesamoid appears in girls by age 11 and in boys by age 13. The bone age should fall within 2 SD of the chronologic age. If the bone age is more than 2 SD below the chronologic age, the child's bone growth is delayed, and if the bone age is more than 2 SD greater than the chronologic age, the child is advanced in bone age. At a chronologic age of 14 years 2 months, the hand radiograph appeared to have a bone age between 12 years and 12 years 6 months (SD, 10.7 months), which would mean that the child's bone growth was slightly delayed (at the lower limit of the normal range).
Dr. Levitsky: This young man presented with modest attenuation in weight gain and longitudinal growth. He was within the normal percentiles, and his growth rate was within the normal range for a boy with delayed puberty in the phase of prepubertal growth attenuation (the third percentile for growth rate during prepubertal growth attenuation is about 3.5 cm per year).2 By the time I saw him, it appeared, looking at his growth plot on a standard cross-sectional growth curve, that he was beginning to grow normally, although his height was in a lower percentile than it had been previously (Figure 1). Diminished weight gain predated the height deceleration, but recent weight gain also appeared to be normal, between the 10th and the 25th percentile over the course of the year before his first visit to the clinic.
The differential diagnosis of growth attenuation or short stature is reviewed in Table 2. In general, children with endocrine disorders have attenuated linear growth, rather than attenuated weight gain. In contrast, children with underlying chronic illness have attenuation in weight gain before linear growth slows.3 The history and physical examination of this patient were helpful in eliminating many of the categories of growth disorders delineated in Table 3. The patient had no prenatal problems, no family history of short stature, and no history of medication that could interfere with growth, and he had normal body proportions and appearance, making a genetic abnormality of bone or cartilage growth unlikely. A second-degree female relative did have delayed puberty.
Table 2. Differential Diagnosis of Growth Attenuation or Short Stature.
Table 3. Laboratory Evaluation of Short Stature and Growth Attenuation.
I thought that either the patient was a normal boy who was delayed in his maturation or that he had a chronic illness. I, therefore, screened for an underlying chronic illness, and I did not obtain most of the studies listed in Table 3. He had mild anemia, which is unusual in a boy his age, and therefore when the IgA antiendomysial antibody study returned strongly positive at a titer of 1:1280, suggesting celiac disease, I was not entirely surprised.
The incidence of celiac disease in children with short stature ranges from 2 to 8 percent,4,5 depending on the selection criteria, the age of the subjects, and the definition of short stature. Nonetheless, celiac disease must be considered in the differential diagnosis of any child with growth attenuation, particularly if there is also attenuation in weight. The relationship of this chronic gastrointestinal disorder to growth attenuation is not clear.
Undernutrition is not the complete answer. Severe growth attenuation develops in many children with celiac disease who are minimally underweight, and many normal, thin children grow well. Children with severe undernutrition may have low levels of peripheral insulin-like growth factor I (IGF-I). Circulating IGF-I, produced largely by the liver, is both growth hormone–dependent and insulin-dependent. Low levels of circulating IGF-I may be a cause of growth attenuation.6 An increase in the production of inflammatory cytokines in the gut may interfere with growth-factor production or action at the cellular level and may play a role in growth attenuation.7 Other gastrointestinal disorders, such as inflammatory bowel disease, may be associated with growth attenuation before the onset of substantial weight loss or subjective bowel symptoms.
Dr. Esther J. Israel: This young man was referred to the pediatric gastroenterology and nutrition unit to confirm that he had celiac disease — an immune-mediated enteropathy that is triggered in genetically susceptible persons by the ingestion of gluten and results in malabsorption. Since the classic presentation of celiac disease, with diarrhea, abdominal distention, and poor weight gain, typically occurs between the ages of six months and two years, after the introduction of cereals into the diet, it was not initially considered by this patient's pediatrician. However, in the past 15 years, new diagnostic tools — which can test for antigliadin, antiendomysial, and anti–tissue transglutaminase antibodies — have led to the recognition of the disease in increasing numbers of patients without the classic presentation, as well as in the general population.8 Screening has resulted in a marked increase in the estimated prevalence of the disease worldwide: in the United States the prevalence, once estimated to be as low as 1 of every 10,000 people, is now estimated to be 1 of every 111 people.9
Clinical Spectrum of Celiac Disease
Nonclassic manifestations of celiac disease can be divided into two categories: those that appear to be due to malabsorption, and those due to associated autoimmune diseases. Presentation with symptoms related to malabsorption is seen in all age groups. Younger patients may present with recurrent abdominal pain, anemia, or, as demonstrated in this patient, attenuated growth and delayed puberty. Almost 30 percent of children with subclinical celiac disease have short stature as their leading symptom.10 Iron-deficiency anemia, which this boy also had, is the most common clinical symptom in adults; whereas adults may have episodic or nocturnal diarrhea, many do not.11 Abdominal discomfort and bloating are common and often lead to the initial diagnosis of irritable bowel syndrome.8
Other manifestations of malabsorption that should prompt evaluation for celiac disease include macrocytic anemia due to the malabsorption of folate and, less commonly, vitamin B12; coagulopathy due to vitamin K deficiency; and hypocalcemia, osteopenia, and bone fractures as a result of poor absorption of vitamin D. A recent report12 described a man with celiac disease who presented with low back and leg pain due to vitamin D deficiency and osteomalacia.
Manifestations that reflect the autoimmune nature of celiac disease include dermatitis herpetiformis, arthritis, diabetes, and hepatitis, none of which this patient had. Clinically silent celiac disease is found in up to 30 percent of children with type 1 diabetes mellitus.13 The prevalence of autoimmune disorders is higher than usual in celiac disease14 and is proportional to the duration of exposure to gluten,15 suggesting that the occurrence of such disorders could be prevented by the early detection of celiac disease and the elimination of gluten from the patients' diets.8 Thus, primary care physicians need to have a high index of suspicion for celiac disease in patients with autoimmune disorders.
Serologic Testing for Celiac Disease
Antigliadin antibodies are sensitive indicators of the diagnosis of celiac disease, but they may also be present in persons without celiac disease. They are, however, excellent tools for measuring a patient's adherence to a gluten-free diet.16 An immunofluorescence test for the antiendomysial antibody, directed against a connective-tissue protein in the gastrointestinal tract, was found to have a sensitivity and specificity for celiac disease in the range of 95 to 97 percent. More recently, tissue transglutaminase was discovered to be the antigen for the endomysial antibody, and an enzyme-linked immunosorbent assay (ELISA) was developed, which is more reproducible but slightly less specific than the immunofluorescence test.17 Most commercial laboratories use the ELISA, so that even if antiendomysial-antibody testing is requested, it is usually a tissue transglutaminase antibody that is measured.
Diagnostic Criteria for Celiac Disease
Given the positive antiendomysial-antibody test in this patient, what is the next step in confirming the diagnosis? The advent of serologic testing has changed the algorithm for the diagnosis of celiac disease. Previously,18 it was a three-step process: a small-bowel biopsy that showed evidence of mucosal injury in a patient with gastrointestinal symptoms compatible with celiac disease, resolution of symptoms and pathological abnormalities while the patient followed a gluten-free diet, and a gluten challenge with repeated small-bowel biopsy that showed recurrence of the disease. Revised criteria, established in 1990,19 still call for a small-bowel biopsy to confirm the diagnosis of celiac disease, if serologic studies suggest the disease. The serologic studies are repeated six months to a year after the patient has adopted a gluten-free diet. The resolution of symptoms and disappearance of antibodies confirm the diagnosis of celiac disease, and a gluten challenge is not needed.
For diagnostic testing of various groups for celiac disease, I would suggest the algorithm proposed in Figure 3. Patients in any of the categories shown should have a tissue transglutaminase antibody test and an assessment of their total IgA levels. If the patient is not IgA-deficient and the test for tissue transglutaminase antibody is negative, celiac disease is unlikely and a biopsy is not needed. If the antibody test is positive, biopsy of the small bowel should be performed; if changes associated with celiac disease are present, the diagnosis is established. If results of the small-bowel biopsy are not diagnostic, the patient should be monitored with sequential measurements of bone density, and an assessment of vitamin status and a repeated biopsy should be considered. HLA typing for the DQ2 and DQ8 haplotypes can be performed; however, since these haplotypes are present in 30 percent of the population, their presence is not specific.
Figure 3. Algorithm for the Diagnosis of Celiac Disease in Different Populations.
Patients with classic symptoms of celiac disease, those with atypical symptoms, patients from at-risk populations, and those who have undergone small-bowel biopsy for other reasons that suggest possible celiac disease should have a test for tissue transglutaminase (TTG) antibodies and measurement of total IgA. If the patient is not IgA-deficient and the TTG-antibody test is negative, celiac disease is unlikely. If the TTG-antibody test is positive, a biopsy of the small bowel should be performed; if changes associated with celiac disease are present, the diagnosis is established. If the small-bowel biopsy is not diagnostic, the patient should be monitored and a repeated biopsy considered. HLA typing for DQ2 and DQ8 haplotypes can be performed; if the assay is negative, the patient does not have celiac disease.
In this patient, the combination of growth attenuation and a positive test for antiendomysial antibodies was strongly indicative of celiac disease. I performed upper gastrointestinal endoscopy to obtain a biopsy specimen of his small intestine. The esophagus and stomach appeared normal; there was subtle flattening of the mucosal folds in the duodenum.
Dr. Esther J. Israel's Diagnosis
Celiac disease.
Pathological Discussion
Dr. Martha B. Pitman: We received six biopsy specimens from the duodenum, two from the gastric antrum, and two from the esophagus. The esophagus and antrum were normal. The duodenal mucosa was architecturally distorted, with partial-to-total villous atrophy, crypt hyperplasia, and an increase in the number of intraepithelial lymphocytes. All of these morphologic changes are consistent with celiac disease in a patient with antiendomysial or anti–tissue transglutaminase antibodies (Figure 4).
Figure 4. Duodenal-Biopsy Specimen (Hematoxylin and Eosin).
In Panel A, the duodenal mucosa shows villi that are markedly atrophic to absent, with hyperplastic crypts and extensive intraepithelial lymphocytosis — findings that are typical of the destructive stage of celiac disease (Marsh type 3). Panel B shows a higher-power version of the same image, in which damaged cuboidal enterocytes, mitotic figures in the hyperplastic crypts (arrow), and many intraepithelial lymphocytes (arrowheads) are evident. An image of normal duodenal mucosa from another patient (Panel C) shows tall, thin villi, with no crypt hyperplasia, a normal crypt-to-villus ratio of 1:3, and only a few intraepithelial lymphocytes. Panel D shows a higher-power image of the normal mucosa, in which tall columnar enterocytes and a few widely scattered intraepithelial lymphocytes (arrow) are evident.
It is recommended that a minimum of four biopsy specimens of the duodenum be obtained for evaluation of patients in whom celiac disease is suspected, to ensure that at least some tissue fragments will have the proper orientation, and because villous injury can be patchy. Many conditions can cause villous injury and even produce a flat mucosa20 (Table 4), but few have the three elements of villous injury, crypt hyperplasia, and intraepithelial lymphocytosis, and most have clinical manifestations that differ from those of celiac disease. The diagnosis of celiac disease should always be included in the differential diagnosis when a duodenal biopsy shows intraepithelial lymphocytosis, with or without villous injury. This is important, since it may be the first time the diagnosis is considered, especially in a patient with nonspecific gastrointestinal symptoms or none.
Table 4. Histologic Differential Diagnosis of Celiac Disease.
The sequential histologic changes that occur in celiac disease have been classified by Marsh into five stages21 (Table 5). This patient's biopsy specimen was classified as Marsh type 3, which is the most commonly observed lesion in celiac disease and which, in combination with elevated antibody titers, is considered diagnostic of celiac disease. All stages include an increase in the number of intraepithelial lymphocytes. Although Marsh states that as many as 40 intraepithelial lymphocytes per 100 enterocytes can be normal, other studies have shown that the range of the number of intraepithelial lymphocytes in duodenal-biopsy specimens from patients with confirmed celiac disease is much broader,22,23,24,25 and it can be as low as 13 per 100 enterocytes. Thus, celiac disease may be underdiagnosed by pathologists who adhere strictly to the higher threshold, especially in evaluating biopsy specimens with only minor or focal villous injury.
Table 5. The Marsh Classification of Mucosal Injury in Celiac Disease.
The pathophysiology of mucosal injury in celiac disease has been partially elucidated. The immune reaction to gliadin occurs only in persons who have the HLA haplotype HLA-DQ2 (90 to 95 percent of patients with celiac disease) or HLA-DQ8 (5 to 10 percent), both of which are major histocompatibility complex proteins that have a particular affinity for gliadin.26,27,28,29 The immunogenic peptide is a 33-amino-acid peptide of alpha-gliadin that is produced during normal gastrointestinal digestion and that is resistant to digestion by all gastric, pancreatic, and intestinal brush-border membrane proteases.29,30 This peptide can bind directly to the HLA class II molecules on the surface of enterocytes.30 Tissue transglutaminase, a ubiquitous intracellular enzyme, deaminates the peptide, thereby increasing its affinity for the binding site of the HLA molecule.31,32 The tightly bound antigen efficiently stimulates CD4+ helper T cells in the lamina propria; these, in turn, stimulate CD8+ cytotoxic T cells,25,33 which infiltrate the epithelium as intraepithelial lymphocytes and generate cytokines that contribute to the damage to the villi.33,34 B cells produce antibodies against gliadin and tissue transglutaminase, which are the antibodies used in screening for celiac disease, but it is not clear that these antibodies play a role in the tissue injury.
The 33-amino-acid peptide may also cross the intestinal barrier through either a transcellular route29,35 or a paracellular route. The integrity of the intercellular junctions that control intestinal permeability is regulated, at least in part, by a molecule called zonulin36,37,38; this molecule is up-regulated in patients with celiac disease, increasing the permeability of the epithelial barrier.
The cycle of injury is perpetuated only in the presence of the antigen, so a lifelong gluten-free diet is effective treatment. Digestion of the toxic 33-amino-acid peptide by bacterial endopeptidase has been demonstrated in vitro and in vivo,39 and this finding may hold promise for future therapy.
Discussion of Management
Dr. Israel: The main objective of management of this condition is the pursuit of an entirely gluten-free diet, eliminating all food products made from wheat, rye, and barley. Oats have traditionally also been prohibited, but studies in both adults and children40 suggest that they may be consumed safely. The management of celiac disease in this patient began with a consultation with a nutritionist who is well versed in the gluten-free diet. It is much simpler to keep to a gluten-free diet now than it was even 10 years ago, since the number of commercially available products that are free of gluten has expanded and there is now an international symbol to identify a gluten-free food product. Support groups for patients with celiac disease have published lists of gluten-free products, which the parents in this case consulted. Food additives, medications, emulsifiers, and stabilizers are important hidden sources of gluten that need to be reviewed. If the patient had had diarrhea or bloating, we would have recommended a lactose-free diet, as well, for the first one to two months, since the damage to the villi may cause transient lactose intolerance.
The need for micronutrient replacement in patients with celiac disease should be assessed. Iron, folate, vitamin D, and vitamin K may need to be supplemented, especially in those who have clinical evidence of malabsorption. This patient had very mild anemia on presentation, but his serum iron studies and vitamin B12 and folate levels were normal, so supplements were not prescribed. Associated conditions such as thyroiditis and diabetes should be ruled out in patients with this disease.
Finally, we recommended screening for anti–tissue transglutaminase antibodies in the patient's first-degree relatives, since their risk of having celiac disease is about 10 percent.9,41,42 Both parents have been tested, and the results were negative.
Complications of Celiac Disease
More than 70 percent of patients with clinical symptoms respond within two weeks of the initiation of the gluten-free diet. If the symptoms persist, the possibility of hidden sources of gluten in the diet should be considered. Testing for antigliadin antibody is very sensitive for the ingestion of gluten. Persistent diarrhea may be caused by coexisting lactose intolerance, irritable bowel syndrome, or pancreatic insufficiency. Refractory celiac disease may indicate the presence of lymphoma.43 Enteropathy-type T-cell lymphoma, adenocarcinoma of the small bowel, and squamous-cell carcinoma of the esophagus are associated with celiac disease44; elimination of gluten from the diet appears to reduce the risk of death from some of these disorders.45
Dr. Levitsky: This patient and his family were very conscientious in adhering to a gluten-free diet, although this was difficult for all of them. Within three months, he had gained 2.72 kg and grown about 1 cm taller; four months later he had grown another 4 cm and gained 3.76 kg. At his most recent visit, 17 months after the diagnosis, he is in puberty; his height is 174 cm and weight 56.8 kg (Figure 1). The levels of IgA antiendomysial antibody fell from 1:1280 to 1:40 at 7 months, were undetectable at 12 months, but were again positive at 1:40 at 17 months on a gluten-free diet.
Dr. Harris: What is the current recommendation for screening populations for celiac disease?
Dr. Israel: The World Health Organization has established a set of principles to guide the development of screening programs.46 Celiac disease meets most of these criteria: it is a disorder that is difficult to diagnose clinically, failure to make an accurate diagnosis can have profound ramifications, there is an effective treatment for the condition, and there is a highly sensitive and specific means of detecting even clinically silent cases. What has not been determined, however, is whether the risk–benefit ratio favors mass screening of asymptomatic patients. The current recommendations for the screening of asymptomatic persons include the testing of patients with conditions associated with celiac disease, such as type 1 diabetes, as well as first-degree relatives of patients who have celiac disease. Mass screening is not recommended at this point.
Anatomical Diagnosis
Celiac disease.
Source Information
From the Department of Pediatrics, the Divisions of Pediatric Gastroenterology and Nutrition (E.J.I.) and Pediatric Endocrinology (L.L.L.) and the Departments of Radiology (S.A.A.) and Pathology (M.B.P.), Massachusetts General Hospital; and the Departments of Pediatrics (E.J.I., L.L.L.), Radiology (S.A.A.), and Pathology (M.B.P.), Harvard Medical School.
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Wilson JM. Principles and practice of screening for diseases. Geneva: World Health Organization, 1968.(Esther J. Israel, M.D., L)
A 14-year-old boy was evaluated in the pediatric endocrinology clinic because of decreased endurance, slow growth, and delayed onset of puberty.
Ten weeks before his presentation at the clinic, he saw his pediatrician because of concern regarding his short stature, lack of energy, and youthful appearance relative to his male peers. The patient had been well until approximately four years previously, when he had had an episode of diarrhea that persisted for 19 days and was associated with a weight loss of approximately 1.5 kg, without fever or abdominal pain. The patient's father also had diarrhea during some of that time. The boy was treated with metronidazole for a presumptive diagnosis of giardia, and his stools became solid. The results of stool examination for the presence of ova and parasites, and of routine bacterial cultures for Clostridium difficile, rotavirus, and yersinia were negative. The boy returned to his usual state of health, but his mother noted that after the illness he seemed to have dark circles under his eyes, had poor skin color, and reported intermittent bouts of foul-smelling flatulence. In the year before this evaluation, he began to have behavior problems and increasing difficulty focusing on schoolwork. He was referred to the pediatric endocrinology clinic of this hospital.
The patient had been born by cesarean section, which had been indicated for cephalopelvic disproportion, at a gestational age of 39 weeks, and weighed 3.5 kg at birth. He had no allergies, was taking no medications when he came to the clinic, and had had the usual childhood immunizations. He was a student in the eighth grade. In the interval since his visit to the pediatrician, he had begun to notice underarm odor and to use deodorant, and pubic hair had developed.
The mother's height was 173 cm and father's 183 cm. Other female relatives ranged in height from 165 to 173 cm, and male relatives from 183 to 191 cm. A female cousin had had a delayed puberty for which she had been treated with hormone therapy; several second-degree female relatives had thyroid disease. The maternal grandfather had a history of rickets in childhood and had been thin all his life; at 75 years of age, he was told that he could not absorb vitamin B12 and had required B12 shots thereafter. He died at 78 years of age of diffuse large-B-cell lymphoma.
On physical examination, the boy's height was 159 cm and the weight was 42.9 kg (Figure 1). The blood pressure was 112/74 mm Hg and the pulse 68 beats per minute. The head circumference was 55 cm and the arm span 159 cm, and he had an upper-to-lower body-segment ratio of 0.8. He had a slightly high-arched palate, and shotty lymphadenopathy was present at the angle of the mandible bilaterally. His thyroid was palpable and not enlarged. His head, eyes, ears, nose, throat, lungs, heart, abdomen, and extremities all appeared normal; the neurologic examination showed no abnormalities. The estimated testicular volume was 5 ml on the left and 4 ml on the right. His pubic hair, as assessed by the Tanner classification of sexual development, was stage 2 and his axillary hair was stage 1 (the range is from 1, for preadolescent characteristics, to 5, for adult characteristics).
Figure 1. Growth Chart.
The black Xs indicate growth points before and at the time of the patient's initial evaluation. The rate of weight gain began to slow at approximately 10 years of age, and the rate of height increase began to slow one year later. The red Xs indicate growth points after treatment.
A radiograph of the left hand obtained at a chronologic age of 14 years 2 months showed a bone age of 12 years 6 months (Figure 2). Results of laboratory tests are shown in Table 1. A diagnostic procedure was performed.
Figure 2. Radiographs of the Patient's Left Hand at a Chronologic Age of 14 Years 2 Months (Panel A) and the Hand of a Normal 14-Year-Old (Panel B).
In the patient's hand, unlike the normal hand, the sesamoid bone of the thumb has not developed, and the epiphyses (arrows) of the phalanges are shorter and not cupped. According to the bone-age standards of Greulich and Pyle,1 the patient's bone age is between 12 years and 12 years 6 months, indicating a slight delay in growth.
Table 1. Laboratory-Test Results.
Differential Diagnosis
Dr. Lynne L. Levitsky: May we review the bone-age radiograph?
Dr. Sudha A. Anupindi: On the basis of the standards compiled by Greulich and Pyle,1 the bone age of a child is calculated on a radiograph of the left hand (Figure 2A). The configuration, development, and length of the epiphyses of the phalanges of the fingers and carpal bones of a patient are compared with those of the established standard bone ages (Figure 2B). The presence of the sesamoid bone of the thumb is a critical feature; the sesamoid appears in girls by age 11 and in boys by age 13. The bone age should fall within 2 SD of the chronologic age. If the bone age is more than 2 SD below the chronologic age, the child's bone growth is delayed, and if the bone age is more than 2 SD greater than the chronologic age, the child is advanced in bone age. At a chronologic age of 14 years 2 months, the hand radiograph appeared to have a bone age between 12 years and 12 years 6 months (SD, 10.7 months), which would mean that the child's bone growth was slightly delayed (at the lower limit of the normal range).
Dr. Levitsky: This young man presented with modest attenuation in weight gain and longitudinal growth. He was within the normal percentiles, and his growth rate was within the normal range for a boy with delayed puberty in the phase of prepubertal growth attenuation (the third percentile for growth rate during prepubertal growth attenuation is about 3.5 cm per year).2 By the time I saw him, it appeared, looking at his growth plot on a standard cross-sectional growth curve, that he was beginning to grow normally, although his height was in a lower percentile than it had been previously (Figure 1). Diminished weight gain predated the height deceleration, but recent weight gain also appeared to be normal, between the 10th and the 25th percentile over the course of the year before his first visit to the clinic.
The differential diagnosis of growth attenuation or short stature is reviewed in Table 2. In general, children with endocrine disorders have attenuated linear growth, rather than attenuated weight gain. In contrast, children with underlying chronic illness have attenuation in weight gain before linear growth slows.3 The history and physical examination of this patient were helpful in eliminating many of the categories of growth disorders delineated in Table 3. The patient had no prenatal problems, no family history of short stature, and no history of medication that could interfere with growth, and he had normal body proportions and appearance, making a genetic abnormality of bone or cartilage growth unlikely. A second-degree female relative did have delayed puberty.
Table 2. Differential Diagnosis of Growth Attenuation or Short Stature.
Table 3. Laboratory Evaluation of Short Stature and Growth Attenuation.
I thought that either the patient was a normal boy who was delayed in his maturation or that he had a chronic illness. I, therefore, screened for an underlying chronic illness, and I did not obtain most of the studies listed in Table 3. He had mild anemia, which is unusual in a boy his age, and therefore when the IgA antiendomysial antibody study returned strongly positive at a titer of 1:1280, suggesting celiac disease, I was not entirely surprised.
The incidence of celiac disease in children with short stature ranges from 2 to 8 percent,4,5 depending on the selection criteria, the age of the subjects, and the definition of short stature. Nonetheless, celiac disease must be considered in the differential diagnosis of any child with growth attenuation, particularly if there is also attenuation in weight. The relationship of this chronic gastrointestinal disorder to growth attenuation is not clear.
Undernutrition is not the complete answer. Severe growth attenuation develops in many children with celiac disease who are minimally underweight, and many normal, thin children grow well. Children with severe undernutrition may have low levels of peripheral insulin-like growth factor I (IGF-I). Circulating IGF-I, produced largely by the liver, is both growth hormone–dependent and insulin-dependent. Low levels of circulating IGF-I may be a cause of growth attenuation.6 An increase in the production of inflammatory cytokines in the gut may interfere with growth-factor production or action at the cellular level and may play a role in growth attenuation.7 Other gastrointestinal disorders, such as inflammatory bowel disease, may be associated with growth attenuation before the onset of substantial weight loss or subjective bowel symptoms.
Dr. Esther J. Israel: This young man was referred to the pediatric gastroenterology and nutrition unit to confirm that he had celiac disease — an immune-mediated enteropathy that is triggered in genetically susceptible persons by the ingestion of gluten and results in malabsorption. Since the classic presentation of celiac disease, with diarrhea, abdominal distention, and poor weight gain, typically occurs between the ages of six months and two years, after the introduction of cereals into the diet, it was not initially considered by this patient's pediatrician. However, in the past 15 years, new diagnostic tools — which can test for antigliadin, antiendomysial, and anti–tissue transglutaminase antibodies — have led to the recognition of the disease in increasing numbers of patients without the classic presentation, as well as in the general population.8 Screening has resulted in a marked increase in the estimated prevalence of the disease worldwide: in the United States the prevalence, once estimated to be as low as 1 of every 10,000 people, is now estimated to be 1 of every 111 people.9
Clinical Spectrum of Celiac Disease
Nonclassic manifestations of celiac disease can be divided into two categories: those that appear to be due to malabsorption, and those due to associated autoimmune diseases. Presentation with symptoms related to malabsorption is seen in all age groups. Younger patients may present with recurrent abdominal pain, anemia, or, as demonstrated in this patient, attenuated growth and delayed puberty. Almost 30 percent of children with subclinical celiac disease have short stature as their leading symptom.10 Iron-deficiency anemia, which this boy also had, is the most common clinical symptom in adults; whereas adults may have episodic or nocturnal diarrhea, many do not.11 Abdominal discomfort and bloating are common and often lead to the initial diagnosis of irritable bowel syndrome.8
Other manifestations of malabsorption that should prompt evaluation for celiac disease include macrocytic anemia due to the malabsorption of folate and, less commonly, vitamin B12; coagulopathy due to vitamin K deficiency; and hypocalcemia, osteopenia, and bone fractures as a result of poor absorption of vitamin D. A recent report12 described a man with celiac disease who presented with low back and leg pain due to vitamin D deficiency and osteomalacia.
Manifestations that reflect the autoimmune nature of celiac disease include dermatitis herpetiformis, arthritis, diabetes, and hepatitis, none of which this patient had. Clinically silent celiac disease is found in up to 30 percent of children with type 1 diabetes mellitus.13 The prevalence of autoimmune disorders is higher than usual in celiac disease14 and is proportional to the duration of exposure to gluten,15 suggesting that the occurrence of such disorders could be prevented by the early detection of celiac disease and the elimination of gluten from the patients' diets.8 Thus, primary care physicians need to have a high index of suspicion for celiac disease in patients with autoimmune disorders.
Serologic Testing for Celiac Disease
Antigliadin antibodies are sensitive indicators of the diagnosis of celiac disease, but they may also be present in persons without celiac disease. They are, however, excellent tools for measuring a patient's adherence to a gluten-free diet.16 An immunofluorescence test for the antiendomysial antibody, directed against a connective-tissue protein in the gastrointestinal tract, was found to have a sensitivity and specificity for celiac disease in the range of 95 to 97 percent. More recently, tissue transglutaminase was discovered to be the antigen for the endomysial antibody, and an enzyme-linked immunosorbent assay (ELISA) was developed, which is more reproducible but slightly less specific than the immunofluorescence test.17 Most commercial laboratories use the ELISA, so that even if antiendomysial-antibody testing is requested, it is usually a tissue transglutaminase antibody that is measured.
Diagnostic Criteria for Celiac Disease
Given the positive antiendomysial-antibody test in this patient, what is the next step in confirming the diagnosis? The advent of serologic testing has changed the algorithm for the diagnosis of celiac disease. Previously,18 it was a three-step process: a small-bowel biopsy that showed evidence of mucosal injury in a patient with gastrointestinal symptoms compatible with celiac disease, resolution of symptoms and pathological abnormalities while the patient followed a gluten-free diet, and a gluten challenge with repeated small-bowel biopsy that showed recurrence of the disease. Revised criteria, established in 1990,19 still call for a small-bowel biopsy to confirm the diagnosis of celiac disease, if serologic studies suggest the disease. The serologic studies are repeated six months to a year after the patient has adopted a gluten-free diet. The resolution of symptoms and disappearance of antibodies confirm the diagnosis of celiac disease, and a gluten challenge is not needed.
For diagnostic testing of various groups for celiac disease, I would suggest the algorithm proposed in Figure 3. Patients in any of the categories shown should have a tissue transglutaminase antibody test and an assessment of their total IgA levels. If the patient is not IgA-deficient and the test for tissue transglutaminase antibody is negative, celiac disease is unlikely and a biopsy is not needed. If the antibody test is positive, biopsy of the small bowel should be performed; if changes associated with celiac disease are present, the diagnosis is established. If results of the small-bowel biopsy are not diagnostic, the patient should be monitored with sequential measurements of bone density, and an assessment of vitamin status and a repeated biopsy should be considered. HLA typing for the DQ2 and DQ8 haplotypes can be performed; however, since these haplotypes are present in 30 percent of the population, their presence is not specific.
Figure 3. Algorithm for the Diagnosis of Celiac Disease in Different Populations.
Patients with classic symptoms of celiac disease, those with atypical symptoms, patients from at-risk populations, and those who have undergone small-bowel biopsy for other reasons that suggest possible celiac disease should have a test for tissue transglutaminase (TTG) antibodies and measurement of total IgA. If the patient is not IgA-deficient and the TTG-antibody test is negative, celiac disease is unlikely. If the TTG-antibody test is positive, a biopsy of the small bowel should be performed; if changes associated with celiac disease are present, the diagnosis is established. If the small-bowel biopsy is not diagnostic, the patient should be monitored and a repeated biopsy considered. HLA typing for DQ2 and DQ8 haplotypes can be performed; if the assay is negative, the patient does not have celiac disease.
In this patient, the combination of growth attenuation and a positive test for antiendomysial antibodies was strongly indicative of celiac disease. I performed upper gastrointestinal endoscopy to obtain a biopsy specimen of his small intestine. The esophagus and stomach appeared normal; there was subtle flattening of the mucosal folds in the duodenum.
Dr. Esther J. Israel's Diagnosis
Celiac disease.
Pathological Discussion
Dr. Martha B. Pitman: We received six biopsy specimens from the duodenum, two from the gastric antrum, and two from the esophagus. The esophagus and antrum were normal. The duodenal mucosa was architecturally distorted, with partial-to-total villous atrophy, crypt hyperplasia, and an increase in the number of intraepithelial lymphocytes. All of these morphologic changes are consistent with celiac disease in a patient with antiendomysial or anti–tissue transglutaminase antibodies (Figure 4).
Figure 4. Duodenal-Biopsy Specimen (Hematoxylin and Eosin).
In Panel A, the duodenal mucosa shows villi that are markedly atrophic to absent, with hyperplastic crypts and extensive intraepithelial lymphocytosis — findings that are typical of the destructive stage of celiac disease (Marsh type 3). Panel B shows a higher-power version of the same image, in which damaged cuboidal enterocytes, mitotic figures in the hyperplastic crypts (arrow), and many intraepithelial lymphocytes (arrowheads) are evident. An image of normal duodenal mucosa from another patient (Panel C) shows tall, thin villi, with no crypt hyperplasia, a normal crypt-to-villus ratio of 1:3, and only a few intraepithelial lymphocytes. Panel D shows a higher-power image of the normal mucosa, in which tall columnar enterocytes and a few widely scattered intraepithelial lymphocytes (arrow) are evident.
It is recommended that a minimum of four biopsy specimens of the duodenum be obtained for evaluation of patients in whom celiac disease is suspected, to ensure that at least some tissue fragments will have the proper orientation, and because villous injury can be patchy. Many conditions can cause villous injury and even produce a flat mucosa20 (Table 4), but few have the three elements of villous injury, crypt hyperplasia, and intraepithelial lymphocytosis, and most have clinical manifestations that differ from those of celiac disease. The diagnosis of celiac disease should always be included in the differential diagnosis when a duodenal biopsy shows intraepithelial lymphocytosis, with or without villous injury. This is important, since it may be the first time the diagnosis is considered, especially in a patient with nonspecific gastrointestinal symptoms or none.
Table 4. Histologic Differential Diagnosis of Celiac Disease.
The sequential histologic changes that occur in celiac disease have been classified by Marsh into five stages21 (Table 5). This patient's biopsy specimen was classified as Marsh type 3, which is the most commonly observed lesion in celiac disease and which, in combination with elevated antibody titers, is considered diagnostic of celiac disease. All stages include an increase in the number of intraepithelial lymphocytes. Although Marsh states that as many as 40 intraepithelial lymphocytes per 100 enterocytes can be normal, other studies have shown that the range of the number of intraepithelial lymphocytes in duodenal-biopsy specimens from patients with confirmed celiac disease is much broader,22,23,24,25 and it can be as low as 13 per 100 enterocytes. Thus, celiac disease may be underdiagnosed by pathologists who adhere strictly to the higher threshold, especially in evaluating biopsy specimens with only minor or focal villous injury.
Table 5. The Marsh Classification of Mucosal Injury in Celiac Disease.
The pathophysiology of mucosal injury in celiac disease has been partially elucidated. The immune reaction to gliadin occurs only in persons who have the HLA haplotype HLA-DQ2 (90 to 95 percent of patients with celiac disease) or HLA-DQ8 (5 to 10 percent), both of which are major histocompatibility complex proteins that have a particular affinity for gliadin.26,27,28,29 The immunogenic peptide is a 33-amino-acid peptide of alpha-gliadin that is produced during normal gastrointestinal digestion and that is resistant to digestion by all gastric, pancreatic, and intestinal brush-border membrane proteases.29,30 This peptide can bind directly to the HLA class II molecules on the surface of enterocytes.30 Tissue transglutaminase, a ubiquitous intracellular enzyme, deaminates the peptide, thereby increasing its affinity for the binding site of the HLA molecule.31,32 The tightly bound antigen efficiently stimulates CD4+ helper T cells in the lamina propria; these, in turn, stimulate CD8+ cytotoxic T cells,25,33 which infiltrate the epithelium as intraepithelial lymphocytes and generate cytokines that contribute to the damage to the villi.33,34 B cells produce antibodies against gliadin and tissue transglutaminase, which are the antibodies used in screening for celiac disease, but it is not clear that these antibodies play a role in the tissue injury.
The 33-amino-acid peptide may also cross the intestinal barrier through either a transcellular route29,35 or a paracellular route. The integrity of the intercellular junctions that control intestinal permeability is regulated, at least in part, by a molecule called zonulin36,37,38; this molecule is up-regulated in patients with celiac disease, increasing the permeability of the epithelial barrier.
The cycle of injury is perpetuated only in the presence of the antigen, so a lifelong gluten-free diet is effective treatment. Digestion of the toxic 33-amino-acid peptide by bacterial endopeptidase has been demonstrated in vitro and in vivo,39 and this finding may hold promise for future therapy.
Discussion of Management
Dr. Israel: The main objective of management of this condition is the pursuit of an entirely gluten-free diet, eliminating all food products made from wheat, rye, and barley. Oats have traditionally also been prohibited, but studies in both adults and children40 suggest that they may be consumed safely. The management of celiac disease in this patient began with a consultation with a nutritionist who is well versed in the gluten-free diet. It is much simpler to keep to a gluten-free diet now than it was even 10 years ago, since the number of commercially available products that are free of gluten has expanded and there is now an international symbol to identify a gluten-free food product. Support groups for patients with celiac disease have published lists of gluten-free products, which the parents in this case consulted. Food additives, medications, emulsifiers, and stabilizers are important hidden sources of gluten that need to be reviewed. If the patient had had diarrhea or bloating, we would have recommended a lactose-free diet, as well, for the first one to two months, since the damage to the villi may cause transient lactose intolerance.
The need for micronutrient replacement in patients with celiac disease should be assessed. Iron, folate, vitamin D, and vitamin K may need to be supplemented, especially in those who have clinical evidence of malabsorption. This patient had very mild anemia on presentation, but his serum iron studies and vitamin B12 and folate levels were normal, so supplements were not prescribed. Associated conditions such as thyroiditis and diabetes should be ruled out in patients with this disease.
Finally, we recommended screening for anti–tissue transglutaminase antibodies in the patient's first-degree relatives, since their risk of having celiac disease is about 10 percent.9,41,42 Both parents have been tested, and the results were negative.
Complications of Celiac Disease
More than 70 percent of patients with clinical symptoms respond within two weeks of the initiation of the gluten-free diet. If the symptoms persist, the possibility of hidden sources of gluten in the diet should be considered. Testing for antigliadin antibody is very sensitive for the ingestion of gluten. Persistent diarrhea may be caused by coexisting lactose intolerance, irritable bowel syndrome, or pancreatic insufficiency. Refractory celiac disease may indicate the presence of lymphoma.43 Enteropathy-type T-cell lymphoma, adenocarcinoma of the small bowel, and squamous-cell carcinoma of the esophagus are associated with celiac disease44; elimination of gluten from the diet appears to reduce the risk of death from some of these disorders.45
Dr. Levitsky: This patient and his family were very conscientious in adhering to a gluten-free diet, although this was difficult for all of them. Within three months, he had gained 2.72 kg and grown about 1 cm taller; four months later he had grown another 4 cm and gained 3.76 kg. At his most recent visit, 17 months after the diagnosis, he is in puberty; his height is 174 cm and weight 56.8 kg (Figure 1). The levels of IgA antiendomysial antibody fell from 1:1280 to 1:40 at 7 months, were undetectable at 12 months, but were again positive at 1:40 at 17 months on a gluten-free diet.
Dr. Harris: What is the current recommendation for screening populations for celiac disease?
Dr. Israel: The World Health Organization has established a set of principles to guide the development of screening programs.46 Celiac disease meets most of these criteria: it is a disorder that is difficult to diagnose clinically, failure to make an accurate diagnosis can have profound ramifications, there is an effective treatment for the condition, and there is a highly sensitive and specific means of detecting even clinically silent cases. What has not been determined, however, is whether the risk–benefit ratio favors mass screening of asymptomatic patients. The current recommendations for the screening of asymptomatic persons include the testing of patients with conditions associated with celiac disease, such as type 1 diabetes, as well as first-degree relatives of patients who have celiac disease. Mass screening is not recommended at this point.
Anatomical Diagnosis
Celiac disease.
Source Information
From the Department of Pediatrics, the Divisions of Pediatric Gastroenterology and Nutrition (E.J.I.) and Pediatric Endocrinology (L.L.L.) and the Departments of Radiology (S.A.A.) and Pathology (M.B.P.), Massachusetts General Hospital; and the Departments of Pediatrics (E.J.I., L.L.L.), Radiology (S.A.A.), and Pathology (M.B.P.), Harvard Medical School.
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Wilson JM. Principles and practice of screening for diseases. Geneva: World Health Organization, 1968.(Esther J. Israel, M.D., L)