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Clinical Pathologic Correlation
J Pediatr Adolesc Gynecol (2002) 15:105–107
Communications in Brief Clinical Pathologic Correlation: Recurrent Abdominal Pain and Primary Amenorrhea H. Omar, MD Department of Pediatrics, University of Kentucky, Lexington, Kentucky
Case Report A 13-yr-old white female was referred to the Adolescent Clinic for evaluation of recurrent lower abdominal pain. According to the patient, this pain started one evening approximately two years ago and was crampy and sharp in nature, continued several hours, and was improved with use of ibuprofen. However, the pain continued to recur at unpredictable intervals and had led to hospitalization for an appendectomy (the appendix was normal on histological examination) 6 months earlier and hospitalization for abdominal pain 3 months ago with no improvement whatsoever. This pain continued to occur 2–3 times a month. Specific questioning of this patient revealed that she had frequent, small, and sometimes liquid stools, which alternated with periods of rare bowel movements and considerable straining. On several occasions, her stools were very hard and tinged with blood. The patient had been evaluated by a gastroenterologist, who ruled out Crohn’s disease via colonoscopy and biopsy (normal). Complete blood work including blood count and differential, electrolytes, and liver function tests were all normal. An abdominal computerized scan was reportedly normal (it was not available for review in our clinic). The patient has also had a normal intravenous pyelogram. A history of recurrent abdominal pain lasting over two years is both disturbing and reassuring. Obviously this pain is not due to any of the causes of acute abdomen, since that would have been aggravated by now. The diffuse nature of the pain and the unpredictable recurrence rate makes it less likely to be due to a
Address reprint requests to: Hatim A. Omar, MD, Associate Professor of Pediatrics, Director, Adolescent Medicine, University of Kentucky, Kentucky Clinic J422, Lexington, KY 40536; E-mail: [email protected] © 2002 North American Society for Pediatric and Adolescent Gynecology Published by Elsevier Science Inc.
serious organic problem, especially since the patient has already undergone appendectomy.
The patient also had been overweight and her mother was worried about her pubertal development. According to the mother, the patient started developing her breasts at age 10 and also developed some pubic hair. A few months later her pubertal development stopped and since then it had not developed any further. The history of starting pubertal development at age 10 followed by arrest of that development is concerning for premature ovarian failure.
Past medical history was significant for having been diagnosed twice with urinary tract infections. The patient was taking no medications and reported allergy to cephalosporins. She was born at 37 weeks by c-section because of breech presentation but did well after delivery and had no complications in the neonatal period. The patient was doing very well in school, although she has missed many days because of pain and physician visits. Her family history was significant for obesity in both parents. Review of systems was positive for occasional headaches, occasional dizziness, and excessive sweating and odor, as well as the reported abdominal pain and the delay in pubertal development. On physical examination, the patient’s height (169 cm) and weight (108.2 kg) were both over the 95th percentile for age. Her body mass index was 38, which is extremely high and well above the 95th percentile for her age. The patient appeared to be an overweight female in no acute distress with no dysmorphic features. Her abdomen was soft without hepatosplenomegaly or masses, but there was some tenderness on palpation in the periumbilical and pelvic region, more on the left side of the abdomen than on the right. Skin showed no lesions, pigmentations, rashes, or birthmarks. Breasts were Tanner stage (TS) I–II with 1083-3188/02/$22.00 PII S1083-3188(02)00133-X
106
Omar et al: Clinical Pathologic Correlation
very little, if any, breast tissue. The pubic exam showed sparse pubic hairs that were straight with some pigmentation. No axillary hair was noted. Pelvic exam showed normal labia majora and minora and no clitoromegaly. The hymen was intact, crescentic shaped, patent, and poorly estrogenized. Speculum exam showed a normal-sized vagina with very poor estrogenization and no discharge. A normal-appearing, prepubertal cervix with patent external os was seen. The uterus was very small, consistent with prepubertal size. Ovaries were not palpated. Rectal exam revealed a significant amount of hard stool in the rectum. The rest of the physical exam was normal. Based on the history and physical exam findings, two problems that may or may not be related had to be addressed. Recurrent abdominal pain in this case was likely the result of chronic constipation. The arrest of pubertal development (or lack of development) could be simple constitutional delay or primary ovarian failure.
An x-ray of the abdomen was obtained that showed significant fecal impaction throughout the colon (Fig. 1). Pelvic ultrasound showed a small, tubular uterus with no evidence of fundal enlargement. Ovaries were not clearly identified.
At this point, it was explained to the patient and her mother that more studies were needed for evaluating the amenorrhea. Morning blood drawing was arranged for gonadotropins; prolactin, karyotype, thyroid function, and a bone age study were also requested. A bowel clean-up program (with Fleet enemas and magnesium citrate) was recommended followed by maintenance with mild stool softeners. On follow-up visit two weeks later, the patient reported large amounts of stools evacuated in the first week. She was feeling very well and denied having any episodes of abdominal pain. Laboratory evaluations showed: normal prolactin and thyroid function tests, follicle stimulating hormone (FSH) of 65 mIU/ mL (normal 1.0–10.8 for her age and TS), luteinizing hormone (LH) of 25 mIU/mL (normal 0.02–4.7), estradiol less than 0.8 ng/dL (normal for age and TS 1– 2.4), and total testosterone was undetectable. Bone age matched the chronological age of 13 years and 3 months. Karyotype was 46,XY. Magnetic resonance imaging (MRI) of the abdomen was obtained and showed a prepubertal uterus with absent ovaries and no gonadal tissue in the abdomen or inguinal canal. The findings and the diagnosis of 46,XY sex reversal were explained to the patient and her parents. She was reassured that she will continue to function as a normal female and that she will need hormone replacement for life. With current technology and compliance with hormone replacement, pregnancy may be possible via ovum donation and in vitro fertilization. The patient was initially started on 0.325 mg conjugated estrogen daily for 3 months followed by 1.25 mg daily for the next 9 months. She is noticing some breast development and is not having any significant side effects from the estrogen. The abdominal pain has completely resolved with the bowel clean-up program and maintenance.
Discussion
Fig. 1. X-ray of the abdomen showing significant fecal impaction throughout the colon.
Recurrent abdominal pain is common in adolescence, and the differential diagnosis is extensive including gastrointestinal, renal, gynecologic, and psychosomatic causes. By the time these patients are referred to the adolescent medicine clinic, they have had thousands of dollars’ worth of work-up. Many patients are taken to surgery for appendectomy and/or cholecystectomy with no pathology in the appendix or gall bladder, and their complaints continue with no relief from surgery (as is the case in this patient, where the appendectomy did not change the course of her recurrent abdominal pain). Chronic constipation is a common problem among adolescents that may be due to developmental and lifestyle factors. Adolescents are usually reluctant to use
Omar et al: Clinical Pathologic Correlation
school bathrooms for defecation. When this is added to the usual lack of physical activity, poor fluid intake, and bad nutrition habits, many adolescents develop chronic constipation. This can cause various complaints ranging from recurrent abdominal pain to periodic nausea and vomiting to poor appetite and weight loss followed by fatigue and lack of energy. Almost all of these patients will say yes when asked if they have regular bowel movements even if they are only once a week. This may be how they have been for as long as they remember, and to them that is normal unless someone tells them otherwise. It is thus important to ask specific questions when interviewing adolescents and to rule out simple causes of recurrent abdominal pain prior to performing surgeries and/or extensive work-up. The fact that this patient has already exceeded her expected adult height required investigating the delayed pubertal development. Bone age matching chronological age, in addition to the above-mentioned height, is not consistent with simple constitutional delay. The finding of small uterus and no identifiable ovaries on pelvic ultrasound dictated follow-up studies. The diagnosis of 46,XY sex reversal was made based on the karyotype; physical exam findings of poor development despite adult height; hypergonadotropic hypogonadism; presence of normal vagina, uterus, and fallopian tubes; and undetectable testosterone. Patients with testicular feminization (complete androgen insensitivity syndrome) share the same karyotype but usually have no uterus or fallopian tubes1 and tend to have normal breast development, elevated testosterone levels, gonadal structures with high potential for malignancy, and frequently shorter vaginal pouch.1 Some clinicians may opt for an exploratory laparoscopy to further rule out any presence of gonads. 46,XY female sex reversal has complicated genetic mechanisms and may be the result of deletion of the sex-determining region on Y (SRY) from the Y chromosome during meiotic recombination with X or inac-
107
tivating mutations in the SRY gene.2–6 Clinically, patients with 46,XY sex reversal tend to have normal to tall stature and normal external and internal genitalia, with the exception of the ovaries,7 which are usually replaced by connective tissue. They need psychosocial support and reassurance of their gender identity as females. Editor’s note: In cases such as this in which a Y chromosome or Y-chromosomal fragment has been identified, there is the risk of gonadal malignancy. Such patients must undergo bilateral gonadectomy. If only streak gonads are identified at the time of surgical exploration, those streaks must be removed with frozen sections performed at each border to ensure complete resection of gonadal tissue. References 1. Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF, et al: Complete androgen insensitivity syndrome: long-term medical, surgical and psychosexual outcome. J Clin Endocrinol Metab 2000; 85(8):2664 2. Wolf U: The molecular genetics of human sex determination. J Mol Med 1995; 73:325 3. McElreavy K, Vilain E, Cotinot C, Payen E, Fellous M: Control of sex determination in animals. Eur J Biochem 1993; 218:769 4. Fechner P: The role of SRY in mammalian sex determination. Act Paediatr Jpn 1996; 38:380 5. Muller J, Schwartz M, Skakkebaek N: Analysis of the sexdetermining region of the Y chromosome (SRY) in sex reversed patients: point-mutation in SRY causing sex-reversion in a 46, XY female. J Clin Endocrinol Metab 1992; 75:331 6. McElreavy K, Fellous M: Sex determination and the Y chromosome. Am J Med Genet (Semin Med Genet) 1999; 89:176 7. Berkowitz GD, Fechner PY, Zacur HW, et al: Clinical and pathologic spectrum of 46, XY gonadal dysgenesis: its relevance to the understanding of sex differentiation. Medicine (Baltimore) 1991; 70:375
Communications in Brief Clinical Pathologic Correlation: Recurrent Abdominal Pain and Primary Amenorrhea H. Omar, MD Department of Pediatrics, University of Kentucky, Lexington, Kentucky
Case Report A 13-yr-old white female was referred to the Adolescent Clinic for evaluation of recurrent lower abdominal pain. According to the patient, this pain started one evening approximately two years ago and was crampy and sharp in nature, continued several hours, and was improved with use of ibuprofen. However, the pain continued to recur at unpredictable intervals and had led to hospitalization for an appendectomy (the appendix was normal on histological examination) 6 months earlier and hospitalization for abdominal pain 3 months ago with no improvement whatsoever. This pain continued to occur 2–3 times a month. Specific questioning of this patient revealed that she had frequent, small, and sometimes liquid stools, which alternated with periods of rare bowel movements and considerable straining. On several occasions, her stools were very hard and tinged with blood. The patient had been evaluated by a gastroenterologist, who ruled out Crohn’s disease via colonoscopy and biopsy (normal). Complete blood work including blood count and differential, electrolytes, and liver function tests were all normal. An abdominal computerized scan was reportedly normal (it was not available for review in our clinic). The patient has also had a normal intravenous pyelogram. A history of recurrent abdominal pain lasting over two years is both disturbing and reassuring. Obviously this pain is not due to any of the causes of acute abdomen, since that would have been aggravated by now. The diffuse nature of the pain and the unpredictable recurrence rate makes it less likely to be due to a
Address reprint requests to: Hatim A. Omar, MD, Associate Professor of Pediatrics, Director, Adolescent Medicine, University of Kentucky, Kentucky Clinic J422, Lexington, KY 40536; E-mail: [email protected] © 2002 North American Society for Pediatric and Adolescent Gynecology Published by Elsevier Science Inc.
serious organic problem, especially since the patient has already undergone appendectomy.
The patient also had been overweight and her mother was worried about her pubertal development. According to the mother, the patient started developing her breasts at age 10 and also developed some pubic hair. A few months later her pubertal development stopped and since then it had not developed any further. The history of starting pubertal development at age 10 followed by arrest of that development is concerning for premature ovarian failure.
Past medical history was significant for having been diagnosed twice with urinary tract infections. The patient was taking no medications and reported allergy to cephalosporins. She was born at 37 weeks by c-section because of breech presentation but did well after delivery and had no complications in the neonatal period. The patient was doing very well in school, although she has missed many days because of pain and physician visits. Her family history was significant for obesity in both parents. Review of systems was positive for occasional headaches, occasional dizziness, and excessive sweating and odor, as well as the reported abdominal pain and the delay in pubertal development. On physical examination, the patient’s height (169 cm) and weight (108.2 kg) were both over the 95th percentile for age. Her body mass index was 38, which is extremely high and well above the 95th percentile for her age. The patient appeared to be an overweight female in no acute distress with no dysmorphic features. Her abdomen was soft without hepatosplenomegaly or masses, but there was some tenderness on palpation in the periumbilical and pelvic region, more on the left side of the abdomen than on the right. Skin showed no lesions, pigmentations, rashes, or birthmarks. Breasts were Tanner stage (TS) I–II with 1083-3188/02/$22.00 PII S1083-3188(02)00133-X
106
Omar et al: Clinical Pathologic Correlation
very little, if any, breast tissue. The pubic exam showed sparse pubic hairs that were straight with some pigmentation. No axillary hair was noted. Pelvic exam showed normal labia majora and minora and no clitoromegaly. The hymen was intact, crescentic shaped, patent, and poorly estrogenized. Speculum exam showed a normal-sized vagina with very poor estrogenization and no discharge. A normal-appearing, prepubertal cervix with patent external os was seen. The uterus was very small, consistent with prepubertal size. Ovaries were not palpated. Rectal exam revealed a significant amount of hard stool in the rectum. The rest of the physical exam was normal. Based on the history and physical exam findings, two problems that may or may not be related had to be addressed. Recurrent abdominal pain in this case was likely the result of chronic constipation. The arrest of pubertal development (or lack of development) could be simple constitutional delay or primary ovarian failure.
An x-ray of the abdomen was obtained that showed significant fecal impaction throughout the colon (Fig. 1). Pelvic ultrasound showed a small, tubular uterus with no evidence of fundal enlargement. Ovaries were not clearly identified.
At this point, it was explained to the patient and her mother that more studies were needed for evaluating the amenorrhea. Morning blood drawing was arranged for gonadotropins; prolactin, karyotype, thyroid function, and a bone age study were also requested. A bowel clean-up program (with Fleet enemas and magnesium citrate) was recommended followed by maintenance with mild stool softeners. On follow-up visit two weeks later, the patient reported large amounts of stools evacuated in the first week. She was feeling very well and denied having any episodes of abdominal pain. Laboratory evaluations showed: normal prolactin and thyroid function tests, follicle stimulating hormone (FSH) of 65 mIU/ mL (normal 1.0–10.8 for her age and TS), luteinizing hormone (LH) of 25 mIU/mL (normal 0.02–4.7), estradiol less than 0.8 ng/dL (normal for age and TS 1– 2.4), and total testosterone was undetectable. Bone age matched the chronological age of 13 years and 3 months. Karyotype was 46,XY. Magnetic resonance imaging (MRI) of the abdomen was obtained and showed a prepubertal uterus with absent ovaries and no gonadal tissue in the abdomen or inguinal canal. The findings and the diagnosis of 46,XY sex reversal were explained to the patient and her parents. She was reassured that she will continue to function as a normal female and that she will need hormone replacement for life. With current technology and compliance with hormone replacement, pregnancy may be possible via ovum donation and in vitro fertilization. The patient was initially started on 0.325 mg conjugated estrogen daily for 3 months followed by 1.25 mg daily for the next 9 months. She is noticing some breast development and is not having any significant side effects from the estrogen. The abdominal pain has completely resolved with the bowel clean-up program and maintenance.
Discussion
Fig. 1. X-ray of the abdomen showing significant fecal impaction throughout the colon.
Recurrent abdominal pain is common in adolescence, and the differential diagnosis is extensive including gastrointestinal, renal, gynecologic, and psychosomatic causes. By the time these patients are referred to the adolescent medicine clinic, they have had thousands of dollars’ worth of work-up. Many patients are taken to surgery for appendectomy and/or cholecystectomy with no pathology in the appendix or gall bladder, and their complaints continue with no relief from surgery (as is the case in this patient, where the appendectomy did not change the course of her recurrent abdominal pain). Chronic constipation is a common problem among adolescents that may be due to developmental and lifestyle factors. Adolescents are usually reluctant to use
Omar et al: Clinical Pathologic Correlation
school bathrooms for defecation. When this is added to the usual lack of physical activity, poor fluid intake, and bad nutrition habits, many adolescents develop chronic constipation. This can cause various complaints ranging from recurrent abdominal pain to periodic nausea and vomiting to poor appetite and weight loss followed by fatigue and lack of energy. Almost all of these patients will say yes when asked if they have regular bowel movements even if they are only once a week. This may be how they have been for as long as they remember, and to them that is normal unless someone tells them otherwise. It is thus important to ask specific questions when interviewing adolescents and to rule out simple causes of recurrent abdominal pain prior to performing surgeries and/or extensive work-up. The fact that this patient has already exceeded her expected adult height required investigating the delayed pubertal development. Bone age matching chronological age, in addition to the above-mentioned height, is not consistent with simple constitutional delay. The finding of small uterus and no identifiable ovaries on pelvic ultrasound dictated follow-up studies. The diagnosis of 46,XY sex reversal was made based on the karyotype; physical exam findings of poor development despite adult height; hypergonadotropic hypogonadism; presence of normal vagina, uterus, and fallopian tubes; and undetectable testosterone. Patients with testicular feminization (complete androgen insensitivity syndrome) share the same karyotype but usually have no uterus or fallopian tubes1 and tend to have normal breast development, elevated testosterone levels, gonadal structures with high potential for malignancy, and frequently shorter vaginal pouch.1 Some clinicians may opt for an exploratory laparoscopy to further rule out any presence of gonads. 46,XY female sex reversal has complicated genetic mechanisms and may be the result of deletion of the sex-determining region on Y (SRY) from the Y chromosome during meiotic recombination with X or inac-
107
tivating mutations in the SRY gene.2–6 Clinically, patients with 46,XY sex reversal tend to have normal to tall stature and normal external and internal genitalia, with the exception of the ovaries,7 which are usually replaced by connective tissue. They need psychosocial support and reassurance of their gender identity as females. Editor’s note: In cases such as this in which a Y chromosome or Y-chromosomal fragment has been identified, there is the risk of gonadal malignancy. Such patients must undergo bilateral gonadectomy. If only streak gonads are identified at the time of surgical exploration, those streaks must be removed with frozen sections performed at each border to ensure complete resection of gonadal tissue. References 1. Wisniewski AB, Migeon CJ, Meyer-Bahlburg HF, et al: Complete androgen insensitivity syndrome: long-term medical, surgical and psychosexual outcome. J Clin Endocrinol Metab 2000; 85(8):2664 2. Wolf U: The molecular genetics of human sex determination. J Mol Med 1995; 73:325 3. McElreavy K, Vilain E, Cotinot C, Payen E, Fellous M: Control of sex determination in animals. Eur J Biochem 1993; 218:769 4. Fechner P: The role of SRY in mammalian sex determination. Act Paediatr Jpn 1996; 38:380 5. Muller J, Schwartz M, Skakkebaek N: Analysis of the sexdetermining region of the Y chromosome (SRY) in sex reversed patients: point-mutation in SRY causing sex-reversion in a 46, XY female. J Clin Endocrinol Metab 1992; 75:331 6. McElreavy K, Fellous M: Sex determination and the Y chromosome. Am J Med Genet (Semin Med Genet) 1999; 89:176 7. Berkowitz GD, Fechner PY, Zacur HW, et al: Clinical and pathologic spectrum of 46, XY gonadal dysgenesis: its relevance to the understanding of sex differentiation. Medicine (Baltimore) 1991; 70:375