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Temporary protein C deficiency associated with cerebral arterial thrombosis in childhood
Volume 113 Number 5
tion fragment size permits the detection of the -c~/-c~v genotype. Am J Hematol 1987;26:329-39. 12. Sarnaik SA, Lusher JMi Neurological complications of sickle cell anemia. Am J Pediatr Hematol/Oncol 1982;4:386-94. 13. Fabian RH, Peters BH. Neurological complications of hemoglobin SC disease. Arch Neurol 1984i4h289-92. 14. Mears JG, Schoenbrun M, Schaefer KE, et al. Frequent
Clinical and laboratory observations
849
association of alpha-thalassemia with splenic sequestration crisis and splenomegaly in sickle cell subjects [Abstract]. Blood 1982;60(suppl 1):47a. 15. Rao S, Gooden S. Splenic sequestration in sickle cell disease: role of transfusion therapy. Am J Pediatr Hcmatol/Oncol 1985;7:298-301.
Interested readers may want to compare the older patients discussed in the following article with the neonates described by Manco-Johnson et al., in the August 1988 issue (J PEDIATR 1988;112:35963). -J.M.G.
Temporary protein C deficiency associated with cerebral arterial thrombosis in childhood Anne Dusser, MD, Catherine Boyer-Neumann, MD, and Martine Wolf From the Universit6 Paris-Sud, D~partement de P6diatrie, Unite de Neurop6diatrie and Laboratoire d'H6matologie, HOpital Bicetre, Kremlin-Bic~tre, France
Protein C in association with its cofactor protein S (both vitamin K-dependent plasma proteins) is a potent anticoagulant that regulates coagulation by inhibiting activated cofactors V and VIII C and by stimulating fibrinolysis. The association of recurrent venous thrombosis and hereditary protein C deficiency has been reported since 1981, ~4 suggesting the existence of a relationship between thrombosis and protein C deficiency. We report two observations of cerebral arterial thrombosis associated with a partial and temporary plasma protein C deficiency. METHODS Protein C antigen was measured by enzyme-linked immunosorbent assay, as described previously, s When the PPC antigen value was found to be decreased, PPC activity was also determined by a method based on the ability of activated protein C to prolong the activated partial thromboplastin time of normal plasma. 6 Protein C antigen and activity were expressed in units per milliliter, 1 unit being defined as the amount of protein C present in 1 ml of reference plasma, which was obtained from a pool of 25 healthy donors and stored at - 8 0 ~ C in small aliquots. At the ages of the two patients reported below, PPC level should have.reached the normal adult level. 7 Therefore, for
Submitted for publication March 21, 1988; accept~ed June 29, 1988. Reprint requests: Anne Dusser, MD, Unit6 Neurop6diatrie HSpital BicStre, 78, avenue du g6n6ral leclerc, 96270 Krem!in-BicStre, France.
the normal values of PPC antigen and activity, ranging from 0.70 to 1.30 U / m l (95% confidence interval), we referred to the values obtained in 100 healthy adults. CASE R E P O R T S Patient 1. A previously healthy 13-year-old white girl, an on!y child, suddenly developed a left-sided t?emiplegia with sensory I
PPC CT
Plasma protein C Computed tomography
I
impairment and hemianopsia. The CT scan showed a focal hypodensity in the internal part of the right occipital region and in the posteroinferior part of the right basal ganglia. Arteriography demonstrated a narrow and irregular caliber of the proximal portion of the right posterior cerebral artery and a reduced number of right posterior thalamoperforating branches. Biochemical and hemostatic tests were first performed 1 week after the stroke and were all within the normal range, with the exception of decreased PPC antigen (0.66 U/ml) and activity (0.63 U/ml) values while the patient was receiving no medications. The PPC level was decreased on four other determinations over a period of 8 months after the infarction (Figure). During this period; the patient was treated with 0.2 mg/kg/day of acetylsalicylic acid and half-month sequences of various drugs (levodopa, piribedil, febarbamate-phenobarbital, propran01ol), each administered alone to control a severe post-stroke dyskinesia. The PPC value spontaneously normalized approximately 1 year after the stroke (Figure). Protein C antigen and activity values were normal in the patient's father but decreased in her mother (ranging from 0.50 to 0.67 U/ml) on four different determinations performed within 1 year. Case 2. A previously healthy 2~2-year-old girl, of Malian origin
850
Clinical and laboratory observations
The Journal of Pediatrics November 1988 DISCUSSION
1.2-[ E e--
._o
0 tO
o
1.0
0.8
C::
0 r
0
0.6
C
0.4 0
10 TIME (months)
20
stroke Figure. Course of PPC values after stroke in two children with cerebral arterial thrombosis. Each point corresponds to a PPC value de~ermined by immunologic method. Closed circles, Patient 1; open circles, Patient 2; stippled area, decreased levels of PPC. but born in France, suddenly had brief seizures followed by alteration of consciousness. She awakened 12 hours later and had a right-sided hemiplegia and aphasia. Brachiofacial motor handicap, mental retardation, and daily seizures led to admission in our serviee 5 months after the acute episode. The CT scan showed a large hypodensity in the left frontoparietotemporal cortex. Arteriography demonstrated a nearly avascu!ar left hemisphere. The left anterior cerebral artery was not opacified, and the middle and posterior left cerebral arteries appeared narrow. Results of biologic investigations were normal except for a decrease of protein C antigen (0.62 U/ml) and activity (0.49 U/ml) values. Deficiency of PPC was observed over an 11-month period (Figure), during which the child received 0.2 mg/kg/day of acetylsalicylic acid and antiepileptic medications (valproic acid, phenytoin, and phenobarbital, each administered alone or in association). The protein C level was found to be normal 15 months after the stroke (Figure). The protein C antigen concentration was normal in the patient's father, but it could not be tested in her mother and siblings, who lived in Africa. Additional findings in cases 1 and 2. Cardiac evaluation, including echocardiography and metabolic screen (urinary and blood amino acid determination), showed no abnormality in either child. There was no evidence of hyperlipidemia.or hyperglycemia. Platelet count, prothrombin time, levels of fibrinogen, factor II, factor VII + X, and factor V, activated partial thromboplastin time, and plasma antithrombin III levels were monitored during the protein C follow-up and were normal. Total protein S antigen, measured once in each child, was also in the normal range.
Ischemie strokes in childhood, caused by cerebral arterial thrombosis, are not rare and usually occur without apparent cause? Some of these so-called idiopathic cerebral infarctions might be related tO coagulation abnormalities, such as PPC deficiency. In contrast with the known association of venous thrombosis and congenital Protein C deficiency, ~4 arterial thrombosis associated with a congenital partial protein C defect has been described only rarely?, ~0 One report described a myocardial infarction of unknown cause in a 28-year-old m a n ? The second observation concerned a toddler who had a sudden neurologic deficit1~ in this case the thrombotic origin of the neurologic event was uncertain. W e report two observations of arterial cerebral thrombosis in children associated with a partial protein C defect that spontaneously normalized approximately 1 year after the acute event. These case reports suggest a relationship between the protein C defect and the arterial thrombosis. However, this relationship is unclear. The protein C deficiency levels found in our patients were in the same range (0.40 to 0.60 U / m l ) as those responsible for thrombotic episodes in partial inherited PPC deficiency. Inasmuch as the discovery was delayed a f t e r the stroke, it is impossible to assert that the protein C deficiency existed before the infarction and was the cause of the thrombosis. The protein C deficiencies reported here differ from the congenital or acquired deficiencies described previously. Because one of the mothers was heterozygous for protein C defect, the possibility of an inherited deficiency in both children was raised. However, the existence of a congenital deficiency cannot be certain, because no reports have described the return of protein C to a normal level in subjects who are heterozygous for protein C defect. Acquired protein C deficiencies have been reported in liver diseases, u during vitamin K antagonist therapy, ~2 in disseminated intravascular coagulopathy, and in malignancies. n In all these circumstances the protein C deficiency was rarely isolated but rather, was associated with other abnormalities of coagulation. In our patients the protein C deficiency was isolated, with no liver dysfunction, disseminated intravascular coagulation, or other coagulation abnormalities. A drug might be responsible for the protein C deficiency in patient 2, but none of the administered medications have been reported to induce a decreased protein C level. Finally, we cannot exclude the possibility that protein C deficiency could be due to the arterial thrombosis. However, such an association has not been described. These observations of a partial, temporary protein C defect associated with cerebral arterial infarction suggest a
Volume 113 Number 5
relationship between protein C deficiency and arterial thrombosis, and indicate t h a t prolonged, temporary, isolated protein C deficiency m a y occur. REFERENCES
1. Griffin JH, Evatt B, Zimmerman TS, Kleiss A J, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981;68:1370-3. 2. Bertina RM, Broekmans AW, Van der Linden IK, Mertens K. Protein C deficiency in a Dutch family with thrombotic disease. Thromb Haemost 1982;48:1-5. 3. Broekmans AW, Veltkamp J J, Bertina RM. Congenital protein C deficiency and venous thromboembolism: a study of three Dutch families. N Engl J Med 1983;309:340-4. 4. Wintzen AR, Broekmans AW, Bertina RM, et al. Cerebral haemorrhagic infarction in young patients with hereditary protein C deficiency: evidence for "spontaneous" cerebral venous thrombosis. Br Med J 1985;290:350-2. . 5. Boyer C, Rothschild C, Wolf M, Amiral J, Meyer D, Larrieu MJ. A new method for the estimation of protein C by ELISA. Thromb Res 1984;36:579-89.
Clinical and laboratory observations
851
6. Francis RB, Patch MJ. A functional assay for protein C in human plasma. Thromb Res 1983;32:605-13. 7. Nardi M, Karpatkin M. Prothrombin and protein C in early childhood: normal adult levels are not achieved until the fourth year of life. J PED1ATR 1986;109:843-5. 8. Dusser A, Gouti6res F, Aicardi J. Ischemic strokes in children. J Child Neurol 1986;1:131-6. 9. Barbui T, Finazzi G, Mussoni L, et al. Hereditary dysfunctional protein C (protein C Bergamo) and thrombosis [Letter]. Lancet 1984;2:819. 10. Israels SJ, Seshia SS. Childhood stroke associated with protein C or S deficiency. J PED1ATR 1987;111:562-4. 11. Griffin JH, Mosher DF, Zimmerman TS, Kleiss AJ. Protein C, an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation. Blood 1982;60:261-4. 12. Vigano S, Mannucci PM, Solinas S, Botasso B, Mariani G. Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulant therapy. Br J Haematol 1984;57:213-20.
Johanson-Blizzard syndrome and hypopituitarism Kristleifur Kristjansson, MD, William H. Hoffman, MD, David B. Flannery, MD, and Morris J. Cohen, PhD From the Department of Pediatrics, Medical College of Georgia, Augusta
Since J o h a n s o n and Blizzard 1 reported three girls with aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absent p e r m a n e n t teeth, and malabsorption, 19 additional cases have been reported. 2-17 Subsequent reports have d e m o n s t r a t e d variability of the syndrome, with hypoplasia of the alae nasi being the only consistent finding (Table). W e report a patient with the Johanson-Blizzard syndrome who has hypopituitarism and, at the age of 33 months, has no clinical or laboratory evidence of pancreatic exocrine insufficiency. CASE REPORT A 33-month-old boy had been referred at 10 days of age for evaluation of a low screening thyroxine value and unusual facies. The infant was born by normal spontaneous vaginal delivery to a 27-year-old mother after an uncomplicated 36-week pregnancy. There was no consanguinity. Apgar scores were 1 and 9 at 1 and 5 Submitted for publication April 12, 1988; accepted June 27, 1988. Reprint requests: William H. Hoffman, MD, Section of Pediatric Endocrinology, Department of Pediatrics, Medical College of Georgia, Augusta, GA 30912.
minutes, respectively. Birth weight was 2.4 kg (35th percentile), length 45.5 cm (25th percentile), and head circumference 33 cm (50th percentile). Physical findings included a malformed, lowset, and rotated right ear and an atretic right external canal. There was a branchial cleft sinus inferior to the crus of the helix. The TBG TRH TSH
Thyroxine-binding globulin Thyroid-releasing hormone Thyroid-stimulating hormone
penis measured 1.0 cm in length, with a normal urethral orifice. The testes measured 0.5 • 0.5 Cm. Laboratory studies included a serum thyroxine concentration of 2.7 #g/dl and thyroid-stimuling hormone 10.1 #IU/ml. Thryoxine-binding globulin was 30/zg/ml (normal 11 to 36). A prometaphase karyotype was 46, XY. Sonogram of the kidneys was normal. After initiation of L-thyroxine therapy, the infant had improved muscle tone and feeding. At 9 weeks of age the patient was readmitted because of generalized tonic-clonic seizures associated with recurrence of hypoglycemia. During one of the hypoglycemic episodes (glucose, 20 mg/dl), the plasma cortisol concentration was 6 #g/dl (normal >15) and the growth hormone value was 3.8 ng/ml (normal >7).
tion fragment size permits the detection of the -c~/-c~v genotype. Am J Hematol 1987;26:329-39. 12. Sarnaik SA, Lusher JMi Neurological complications of sickle cell anemia. Am J Pediatr Hematol/Oncol 1982;4:386-94. 13. Fabian RH, Peters BH. Neurological complications of hemoglobin SC disease. Arch Neurol 1984i4h289-92. 14. Mears JG, Schoenbrun M, Schaefer KE, et al. Frequent
Clinical and laboratory observations
849
association of alpha-thalassemia with splenic sequestration crisis and splenomegaly in sickle cell subjects [Abstract]. Blood 1982;60(suppl 1):47a. 15. Rao S, Gooden S. Splenic sequestration in sickle cell disease: role of transfusion therapy. Am J Pediatr Hcmatol/Oncol 1985;7:298-301.
Interested readers may want to compare the older patients discussed in the following article with the neonates described by Manco-Johnson et al., in the August 1988 issue (J PEDIATR 1988;112:35963). -J.M.G.
Temporary protein C deficiency associated with cerebral arterial thrombosis in childhood Anne Dusser, MD, Catherine Boyer-Neumann, MD, and Martine Wolf From the Universit6 Paris-Sud, D~partement de P6diatrie, Unite de Neurop6diatrie and Laboratoire d'H6matologie, HOpital Bicetre, Kremlin-Bic~tre, France
Protein C in association with its cofactor protein S (both vitamin K-dependent plasma proteins) is a potent anticoagulant that regulates coagulation by inhibiting activated cofactors V and VIII C and by stimulating fibrinolysis. The association of recurrent venous thrombosis and hereditary protein C deficiency has been reported since 1981, ~4 suggesting the existence of a relationship between thrombosis and protein C deficiency. We report two observations of cerebral arterial thrombosis associated with a partial and temporary plasma protein C deficiency. METHODS Protein C antigen was measured by enzyme-linked immunosorbent assay, as described previously, s When the PPC antigen value was found to be decreased, PPC activity was also determined by a method based on the ability of activated protein C to prolong the activated partial thromboplastin time of normal plasma. 6 Protein C antigen and activity were expressed in units per milliliter, 1 unit being defined as the amount of protein C present in 1 ml of reference plasma, which was obtained from a pool of 25 healthy donors and stored at - 8 0 ~ C in small aliquots. At the ages of the two patients reported below, PPC level should have.reached the normal adult level. 7 Therefore, for
Submitted for publication March 21, 1988; accept~ed June 29, 1988. Reprint requests: Anne Dusser, MD, Unit6 Neurop6diatrie HSpital BicStre, 78, avenue du g6n6ral leclerc, 96270 Krem!in-BicStre, France.
the normal values of PPC antigen and activity, ranging from 0.70 to 1.30 U / m l (95% confidence interval), we referred to the values obtained in 100 healthy adults. CASE R E P O R T S Patient 1. A previously healthy 13-year-old white girl, an on!y child, suddenly developed a left-sided t?emiplegia with sensory I
PPC CT
Plasma protein C Computed tomography
I
impairment and hemianopsia. The CT scan showed a focal hypodensity in the internal part of the right occipital region and in the posteroinferior part of the right basal ganglia. Arteriography demonstrated a narrow and irregular caliber of the proximal portion of the right posterior cerebral artery and a reduced number of right posterior thalamoperforating branches. Biochemical and hemostatic tests were first performed 1 week after the stroke and were all within the normal range, with the exception of decreased PPC antigen (0.66 U/ml) and activity (0.63 U/ml) values while the patient was receiving no medications. The PPC level was decreased on four other determinations over a period of 8 months after the infarction (Figure). During this period; the patient was treated with 0.2 mg/kg/day of acetylsalicylic acid and half-month sequences of various drugs (levodopa, piribedil, febarbamate-phenobarbital, propran01ol), each administered alone to control a severe post-stroke dyskinesia. The PPC value spontaneously normalized approximately 1 year after the stroke (Figure). Protein C antigen and activity values were normal in the patient's father but decreased in her mother (ranging from 0.50 to 0.67 U/ml) on four different determinations performed within 1 year. Case 2. A previously healthy 2~2-year-old girl, of Malian origin
850
Clinical and laboratory observations
The Journal of Pediatrics November 1988 DISCUSSION
1.2-[ E e--
._o
0 tO
o
1.0
0.8
C::
0 r
0
0.6
C
0.4 0
10 TIME (months)
20
stroke Figure. Course of PPC values after stroke in two children with cerebral arterial thrombosis. Each point corresponds to a PPC value de~ermined by immunologic method. Closed circles, Patient 1; open circles, Patient 2; stippled area, decreased levels of PPC. but born in France, suddenly had brief seizures followed by alteration of consciousness. She awakened 12 hours later and had a right-sided hemiplegia and aphasia. Brachiofacial motor handicap, mental retardation, and daily seizures led to admission in our serviee 5 months after the acute episode. The CT scan showed a large hypodensity in the left frontoparietotemporal cortex. Arteriography demonstrated a nearly avascu!ar left hemisphere. The left anterior cerebral artery was not opacified, and the middle and posterior left cerebral arteries appeared narrow. Results of biologic investigations were normal except for a decrease of protein C antigen (0.62 U/ml) and activity (0.49 U/ml) values. Deficiency of PPC was observed over an 11-month period (Figure), during which the child received 0.2 mg/kg/day of acetylsalicylic acid and antiepileptic medications (valproic acid, phenytoin, and phenobarbital, each administered alone or in association). The protein C level was found to be normal 15 months after the stroke (Figure). The protein C antigen concentration was normal in the patient's father, but it could not be tested in her mother and siblings, who lived in Africa. Additional findings in cases 1 and 2. Cardiac evaluation, including echocardiography and metabolic screen (urinary and blood amino acid determination), showed no abnormality in either child. There was no evidence of hyperlipidemia.or hyperglycemia. Platelet count, prothrombin time, levels of fibrinogen, factor II, factor VII + X, and factor V, activated partial thromboplastin time, and plasma antithrombin III levels were monitored during the protein C follow-up and were normal. Total protein S antigen, measured once in each child, was also in the normal range.
Ischemie strokes in childhood, caused by cerebral arterial thrombosis, are not rare and usually occur without apparent cause? Some of these so-called idiopathic cerebral infarctions might be related tO coagulation abnormalities, such as PPC deficiency. In contrast with the known association of venous thrombosis and congenital Protein C deficiency, ~4 arterial thrombosis associated with a congenital partial protein C defect has been described only rarely?, ~0 One report described a myocardial infarction of unknown cause in a 28-year-old m a n ? The second observation concerned a toddler who had a sudden neurologic deficit1~ in this case the thrombotic origin of the neurologic event was uncertain. W e report two observations of arterial cerebral thrombosis in children associated with a partial protein C defect that spontaneously normalized approximately 1 year after the acute event. These case reports suggest a relationship between the protein C defect and the arterial thrombosis. However, this relationship is unclear. The protein C deficiency levels found in our patients were in the same range (0.40 to 0.60 U / m l ) as those responsible for thrombotic episodes in partial inherited PPC deficiency. Inasmuch as the discovery was delayed a f t e r the stroke, it is impossible to assert that the protein C deficiency existed before the infarction and was the cause of the thrombosis. The protein C deficiencies reported here differ from the congenital or acquired deficiencies described previously. Because one of the mothers was heterozygous for protein C defect, the possibility of an inherited deficiency in both children was raised. However, the existence of a congenital deficiency cannot be certain, because no reports have described the return of protein C to a normal level in subjects who are heterozygous for protein C defect. Acquired protein C deficiencies have been reported in liver diseases, u during vitamin K antagonist therapy, ~2 in disseminated intravascular coagulopathy, and in malignancies. n In all these circumstances the protein C deficiency was rarely isolated but rather, was associated with other abnormalities of coagulation. In our patients the protein C deficiency was isolated, with no liver dysfunction, disseminated intravascular coagulation, or other coagulation abnormalities. A drug might be responsible for the protein C deficiency in patient 2, but none of the administered medications have been reported to induce a decreased protein C level. Finally, we cannot exclude the possibility that protein C deficiency could be due to the arterial thrombosis. However, such an association has not been described. These observations of a partial, temporary protein C defect associated with cerebral arterial infarction suggest a
Volume 113 Number 5
relationship between protein C deficiency and arterial thrombosis, and indicate t h a t prolonged, temporary, isolated protein C deficiency m a y occur. REFERENCES
1. Griffin JH, Evatt B, Zimmerman TS, Kleiss A J, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981;68:1370-3. 2. Bertina RM, Broekmans AW, Van der Linden IK, Mertens K. Protein C deficiency in a Dutch family with thrombotic disease. Thromb Haemost 1982;48:1-5. 3. Broekmans AW, Veltkamp J J, Bertina RM. Congenital protein C deficiency and venous thromboembolism: a study of three Dutch families. N Engl J Med 1983;309:340-4. 4. Wintzen AR, Broekmans AW, Bertina RM, et al. Cerebral haemorrhagic infarction in young patients with hereditary protein C deficiency: evidence for "spontaneous" cerebral venous thrombosis. Br Med J 1985;290:350-2. . 5. Boyer C, Rothschild C, Wolf M, Amiral J, Meyer D, Larrieu MJ. A new method for the estimation of protein C by ELISA. Thromb Res 1984;36:579-89.
Clinical and laboratory observations
851
6. Francis RB, Patch MJ. A functional assay for protein C in human plasma. Thromb Res 1983;32:605-13. 7. Nardi M, Karpatkin M. Prothrombin and protein C in early childhood: normal adult levels are not achieved until the fourth year of life. J PED1ATR 1986;109:843-5. 8. Dusser A, Gouti6res F, Aicardi J. Ischemic strokes in children. J Child Neurol 1986;1:131-6. 9. Barbui T, Finazzi G, Mussoni L, et al. Hereditary dysfunctional protein C (protein C Bergamo) and thrombosis [Letter]. Lancet 1984;2:819. 10. Israels SJ, Seshia SS. Childhood stroke associated with protein C or S deficiency. J PED1ATR 1987;111:562-4. 11. Griffin JH, Mosher DF, Zimmerman TS, Kleiss AJ. Protein C, an antithrombotic protein, is reduced in hospitalized patients with intravascular coagulation. Blood 1982;60:261-4. 12. Vigano S, Mannucci PM, Solinas S, Botasso B, Mariani G. Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulant therapy. Br J Haematol 1984;57:213-20.
Johanson-Blizzard syndrome and hypopituitarism Kristleifur Kristjansson, MD, William H. Hoffman, MD, David B. Flannery, MD, and Morris J. Cohen, PhD From the Department of Pediatrics, Medical College of Georgia, Augusta
Since J o h a n s o n and Blizzard 1 reported three girls with aplasia of the alae nasi, deafness, hypothyroidism, dwarfism, absent p e r m a n e n t teeth, and malabsorption, 19 additional cases have been reported. 2-17 Subsequent reports have d e m o n s t r a t e d variability of the syndrome, with hypoplasia of the alae nasi being the only consistent finding (Table). W e report a patient with the Johanson-Blizzard syndrome who has hypopituitarism and, at the age of 33 months, has no clinical or laboratory evidence of pancreatic exocrine insufficiency. CASE REPORT A 33-month-old boy had been referred at 10 days of age for evaluation of a low screening thyroxine value and unusual facies. The infant was born by normal spontaneous vaginal delivery to a 27-year-old mother after an uncomplicated 36-week pregnancy. There was no consanguinity. Apgar scores were 1 and 9 at 1 and 5 Submitted for publication April 12, 1988; accepted June 27, 1988. Reprint requests: William H. Hoffman, MD, Section of Pediatric Endocrinology, Department of Pediatrics, Medical College of Georgia, Augusta, GA 30912.
minutes, respectively. Birth weight was 2.4 kg (35th percentile), length 45.5 cm (25th percentile), and head circumference 33 cm (50th percentile). Physical findings included a malformed, lowset, and rotated right ear and an atretic right external canal. There was a branchial cleft sinus inferior to the crus of the helix. The TBG TRH TSH
Thyroxine-binding globulin Thyroid-releasing hormone Thyroid-stimulating hormone
penis measured 1.0 cm in length, with a normal urethral orifice. The testes measured 0.5 • 0.5 Cm. Laboratory studies included a serum thyroxine concentration of 2.7 #g/dl and thyroid-stimuling hormone 10.1 #IU/ml. Thryoxine-binding globulin was 30/zg/ml (normal 11 to 36). A prometaphase karyotype was 46, XY. Sonogram of the kidneys was normal. After initiation of L-thyroxine therapy, the infant had improved muscle tone and feeding. At 9 weeks of age the patient was readmitted because of generalized tonic-clonic seizures associated with recurrence of hypoglycemia. During one of the hypoglycemic episodes (glucose, 20 mg/dl), the plasma cortisol concentration was 6 #g/dl (normal >15) and the growth hormone value was 3.8 ng/ml (normal >7).