Spontaneous Chylothorax

in Noonan

Syndrome

Treatment With Prednisone M. Beth

Goens, MD; David Campbell, MD; James W. Wiggins, MD

Objective.\p=m-\Todescribe a case of spontaneous chylothoin a child with Noonan syndrome successfully treated with prednisone. Design.\p=m-\Casereport. Setting.\p=m-\Apediatric cardiology referral center for the Rocky Mountain region. Patient.\p=m-\An18-month-old girl with Noonan's syndrome, pulmonary stenosis, and hypertrophic cardiomyopathy who presented with spontaneous chylothorax. Interventions.\p=m-\Thechild's chylothorax did not respond to thoracic duct ligation, tetracycline pleurodesis, and pleurectomy during a 2-month period. A low-fat diet was helpful but did not eliminate the problem. Prednisone was started orally at 1 mg/kg per dose twice daily and slowly tapered during 3 months. The chylothorax did not recur during 8 months of follow-up. \s=b\

rax

Conclusions.\p=m-\Prednisonemay be useful in the treatment of chylothorax in Noonan syndrome. A controlled clinical trial would be helpful but would be difficult in such a rare complication of an uncommon syndrome.

(AJDC. 1992;146:1453-1456)

is present in less than 20% of Noonan syndrome.1 It is most com¬ monly manifest by lymphedema of the dorsal aspect of the hands and feet at birth that resolves with age. Rarely, patients with Noonan syndrome have a more severe, generalized dysplasia of the intestinal or pulmonary lymphatics.210 The lymphatic vessels are hypoplastic, causing obstruction, lymphangiectasis, and retrograde flow of lymph into the tissues. Complications of these abnormal lymphatic vessels include chylothorax, chyloperitoneum with a protein-losing enteropathy, malnu¬ trition, and lymphopenia, especially of the T-helper

Lymphati c dysplasia with patients

lymphocytes.1116 Congenital heart disease is seen in 50% of patients with Noonan syndrome.1 The most common cardiac defect is Accepted for publication July 11, From the

1992. Denver with the National Institutes of

University of Colorado School of Medicine,

Children's Hospital. Dr Goens is now Health, National Heart, Lung, and Blood Institute, Laboratory of Molecular Cardiology, Bethesda, Md. Reprint requests to National Institutes of Health, National Heart, Lung, and Blood Institute, Laboratory of Molecular Cardiology, Bldg 10, Rm 8N-202, Bethesda, MD 20892 (Dr Goens).

Fig 1.—Posteroanterior chest roentgenogram showing the reaccumula¬ tion of the left chylothorax after thoracentesis and catheter drainage.

pulmonary stenosis, either valvular or supravalvular. The pulmonary stenosis can be accompanied by atrial septal defect, patent ductus arteriosus, ventricular septal defect, and peripheral pulmonary stenosis. Hypertrophie cardi¬ omyopathy is seen in about 30% of patients with Noonan syndrome.17 This report describes the course of an 18-month-old girl with Noonan syndrome who presented with spontaneous chylothorax. She also had hypertrophie cardiomyopathy, valvular pulmonary stenosis, and a small atrial septal de¬ fect. She did not have pulmonary lymphangiectasis as an¬ ticipated. We will discuss her response to treatment that included a low-fat diet, pleural drainage with tetracycline pleurodesis, thoracic duct ligation, and steroid adminis¬ tration. Treatment of chylothorax with steroids is a new approach that may have a role in difficult cases. REPORT OF A CASE An 18-month-old white girl presented with respiratory distress. Her medical history was significant for polyhydramnios and de¬ creased fetal movement prenatally, a mild oxygen requirement at birth, lasting 3 weeks, and an echocardiographic diagnosis of hy¬ pertrophie cardiomyopathy. On presentation, she was easily fa¬ tigued, tachypneic, and diaphoretic. A chest roentgenogram showed a moderate left pleural effusion. Thoracentesis produced 90 mL of chylous fluid with a lymphocyte count of greater than

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Fig 2.—Summary of hospital course. Total chylous drainage over each 5-day period is plotted. The timing of each therapeutic intervention is indicated. ASD indicates atrial septal defect; PS, pulmonary stenosis; and TPN, total parenteral nutrition. Noonan Source

Patient Age

CHD

Never resolved

30 g fat/d; sion but

PDA

L, spontaneous

7d

ECD, PS

25 d, recurred on 8 wk, recurred on

Low-fat diet, mediumchain triglycéride formula Low-fat diet, then TPN Low-fat diet, TPN, TD ligation; died of sepsis

NR

NR

Surgery to locate leak

Chan and Ho24

Newborn

Stringel

et

4y

Smith

al10 et al3

Baltaxe et al" Cardner et al5

Treatment

Drainage

HCM

11 y

Lannlng

Duration of

NR NR

Fisher et al23

et

Chylothorax

NR NR

ASD, PS

al25

Syndrome With Chylothorax*

Bilateral, postoperative R, 2 yr postoperative R, spontaneous

32 y 11 y

Hernandez et al'

Fig 3.—Posteroanterior chest roentgenogram showing resolution of sig¬ nificant effusions 5 months after hospital discharge.

PS

12 y

SV

8y

PS

L, 15 d postoperative L, 1 y after Fontan proce¬ dure L, spontaneous

3V2 y

ASD

Bilateral, spontaneous

Weeks

1

mo mo

R, postoperative R, spontaneous

2 wk

4

ASD, PS, HCM ASD, PDA

never

3 wk

resolved

R, 11 d R,

persistent effu¬ asymptomatic

unsuccessful; died Low-fat diet Low-fat diet for 10 d then TPN

septal defect; CHD, congenital heart defect; ECD, endocardial cushion defect; HCM, hypertrophie cardiomyopathy; NR, reported; PDA, patent ductus arteriosus; PS, pulmonary stenosis; SV, single ventricle ; TD, thoracic duct; and TPN, total parenteral nutrition. *ASD indicates atria

ÍO.OXIOVL. She was transported to Denver (Colo) Children's Hospital for further evaluation. On physical examination, the patient was a small, acyanotic 18-month-old girl. Her height and weight were both in the 10th percentile for her age. She had dysmorphic features consistent with Noonan syndrome, including hypertelorism, striking blue eyes,18 webbed neck, and nonpitting edema of the dorsal aspect

of the hands and feet. There was no evidence of trauma to the neck or chest. She had decreased breath sounds in the left base. Palpa¬ tion of the chest revealed a right ventricular lift. There was a nor¬ mal Si, a narrowly split S2 with an increased P2, and a prominent gallop at the apex. There was a grade 4/6 systolic ejection mur¬ mur at the middle left sternal border. Her liver was palpable 2 cm below the right costal margin. The electrocardiogram showed a superior, rightward axis of 230°, typical of Noonan syndrome. There was mild right atrial enlargement and right ventricular hypertrophy. An occasional premature ventricular contraction was noted on rhythm strip. A previous 24-hour Holter monitor study had been normal. The chest roentgenogram showed significant reaccumulation of the left pleural effusion and cardiomegaly. An echocardiogram showed right ventricular hypertrophy, a normal pulmonary annulus size, and thick, dysplastic pulmonary valve leaflets with supravalvular pulmonary stenosis and a

not

continuous-wave Doppler gradient of 85 mm Hg. There was asym¬ metric hypertrophy of the interventricular septum and systolic an¬ terior motion of the mitral valve. No aortic stenosis was identified. At catheterization, the patient was sedated with fentanyl citrate and midazolam hydrochloride. The right atrial pressure was nor¬ mal. The right ventricular pressure of 110/6 mm Hg was slightly greater than the left ventricular pressure of 105/12 mm Hg. There was an 85-mm Hg gradient across the pulmonary valve and a 25-mm Hg gradient across the left ventricular outflow tract. There was a small left-to-right shunt at the atrial level. A balloon pul¬ monary valvuloplasty was performed but only decreased the gradient to 50 mm Hg. An additional 170 mL of chylous effusion was removed by thoracentesis from the left side of the patient's chest, and a drainage catheter was left in place; however, the ef¬ fusion quickly reaccumulated (Fig 1). Additional evaluation of the chylous effusion included a mag¬ netic resonance image of the chest, which showed no mass com¬ pressing the thoracic duct. Results of laboratory studies included normal white blood cell and absolute lymphocyte counts, low al¬ bumin (26 g/L) and total protein (56 g/L) levels, and normal re¬ sults of liver function tests. Results of high-resolution chromo¬ some analysis were normal. During the next 4 hospital days, the patient had a total of 2527 mL of chylous drainage from a left-sided chest tube. On her

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sixth hospital day, she was taken to the operating room for place¬ an outflow patch across the supravalvular pulmonary stenosis, a partial pulmonary valvulectomy, and atrial septal de¬ fect closure. Thymus, lung, and pulmonary valve tissues were sent for pathologic analysis. The thymus and lung biopsy spec¬ imens were normal; the pulmonary valve was myxomatous, without inflammation. Relief of the right ventricular outflow tract obstruction did not stop the chylous leak. The postoperative course was complicated by persistent chest tube drainage of 100 to 250 mL/d. While the child was treated with parenteral hyperalimentation and, later, a low-fat diet of medium-chain trigylceride formula (Portagen), the drainage became less chylous but did not decrease in volume. Her total protein and albumin levels returned to normal, and her lymphocyte count remained normal. The chylous effusion failed to respond to treatments that included thoracic duct ligation, two tetracycline pleurodeses, and left pleurectomy. A posterior mediastinal lymph node biopsy specimen showed numerous ectatic lymphatic channels, in contrast to her previous normal lung bi¬ opsy specimen. Figure 2 is a summary of her hospital course. On the 49th hospital day, treatment with prednisone, 1 mg/kg per dose orally twice daily, was started on the basis of a report by Rothman et al.19 The effusion resolved during the next 2 days and did not recur. The patient was discharged on the 72nd day after admission. Her discharge medications were propranolol hydrochloride, 0.5 mg/kg every 6 hours; furosemide, 1 mg/kg three times daily; hydrochlorothiazide, 1 mg/kg twice daily; spironolactone, 1 mg/kg twice daily; prednisone, 1 mg/kg twice daily; and nasal cannula oxygen, one-eighth L/min. She contin¬ ued on a low-fat diet of medium-chain triglycéride formula and some solid foods. A chest roentgenogram showed small bilateral pleural effusions. The patient showed steady improvement after discharge. The steroids were tapered slowly over 3 months. A regular diet was gradually restarted without fat restrictions after 8 weeks, with no evidence of change in her effusions. Five months after her initial presentation, she had gained 2 kg and had no recurrence of the chylothorax. Figure 3 shows her chest roentgenogram 5 months after discharge. ment of

COMMENT Spontaneous chylothorax in Noonan syndrome has been reported at all ages. Prenatal and newborn patients have a history of polyhydramnios and dyspnea at birth.20-21 Childhood and adult patients are asymptomatic or present with dyspnea. These reports are few; spontaneous chy¬ lothorax is a rare manifestation of Noonan syndrome.22 In a review of the literature, we found 12 cases of Noonan syndrome with chylothorax, including our patient (Table).2"5'9,2325 In seven of these patients, the chylothorax was spontaneous. Five cases occurred after surgical repair of pulmonary stenosis and atrial septal defect. In two of these five patients, the chylothorax occurred 1 and 2 years postoperatively. This suggests an inherent abnormality of the lymphatic system in patients with Noonan syndrome. However, pulmonary lymphangiectasis was rare. The chylothorax in Noonan syndrome may be caused by a less generalized pulmonary lymphatic abnormality, as in our patient, in whom only the mediastinal lymph nodes were involved. When chylothorax does complicate Noonan syndrome, the treatment options include drainage by repeated thora¬ centesis, chest tube, or pleuroperitoneal shunt26; reduction of chyle production by a low-fat diet or total parenteral nutrition; and surgical modification of the lymph flow by chemical pleurodesis, thoracic duct ligation, or pleurecto¬ my.27 Most chylothoraxes eventually resolve with drainage and diet modification; however, this took 2 to 9 weeks in

the reported cases.28 The patients whose chylothoraxes re¬ solved in 2 to 3 weeks did well, with few complications. The patients who required longer periods of drainage de¬

veloped weight loss, hypoalbuminemia, lymphopenia, and infectious complications, which could be fatal. Of the 12 cases of Noonan syndrome with chylothorax that we found, five responded to a low-fat diet or total parenteral nutrition, in four patients there was no discussion of treat¬ ment, two died

despite diet and surgical treatment, and patient finally responded to steroid treatment. None of the reports on chylous effusions were helpful in dealing with the patient who fails to respond to both diet and surgical intervention. Our patient underwent thoracic duct ligation, two tetracycline pleurodeses, and pleurecour

tomy, but the effusion recurred. A report by Rothman al19 described two patients with

et

pleural effusions for more than 6 months after a modified Fontan procedure. Both patients had low erythrocyte sedimentation rates; however, their effusions resolved after prednisone ther¬ apy. Both effusions recurred when the prednisone was ta¬ pered over 2 weeks. They both responded to a second course of prednisone and did not have recurrences when the prednisone was tapered over 3 to 6 months. Rothman et al also mentioned two patients in whom chylothorax occurring after a Fontan procedure did not respond to prednisone. One of these patients had a chylous effusion. The authors of that report suggested that prolonged pleu¬ ral effusions may have an inflammatory component. The effect of prednisone on lymph flow is unknown. However, it is known that endogenous glucocorticoids decrease the quantity of protein in most tissues by increas¬ ing the rate of breakdown of extrahepatic proteins. This frees amino acids and allows the liver to synthesize more plasma proteins.29 The increased plasma oncotic pressure causes more fluid to move directly from the interstitium into the blood, decreasing that left for the lymphatics to drain. This effect may be helpful in decreasing lymph flow long enough for normal lymph drainage to be serous

reestablished.

In conclusion, chylous pleural effusion is a rare but se¬ rious complication of Noonan syndrome. The treatment should initially be conservative, with drainage and a lowfat diet or total parenteral nutrition. If these strategies are unsuccessful after a few weeks or if the patient shows signs of malnutrition, chemical pleurodesis or thoracic duct ligation should be considered. Steroid treatment is un¬ proved, and the improvement in our patient and those of Rothman et al19 could be coincidental with eventual self-resolution. A controlled clinical trial would be helpful to decide whether prednisone therapy might be tried be¬ fore surgical intervention or whether all three treatments (diet, thoracic duct ligation, and steroids) are necessary concurrently to treat the most difficult cases. References

HMM, Opitz JM. Noonan syndrome: a review. Am J Med Genet. 1985;21:493-506. 2. Bawle EV, Black V. Nonimmune hydrops fetalis in Noonan's syndrome. AJDC. 1986;140:758-760. 3. Lanning P, Simila S, Suramo I, Paavilainen T. Lymphatic abnormalities in Noonan's syndrome. Pediatr Radiol. 1978;7:106-109. 4. Baltaxe HA, Lee JG, Ehlers KH, Engle MA. Pulmonary lymphangiectasia demonstrated by lymphangiography in 2 patients with Noonan's syndrome. Radiology. 1975;115:149-153. 5. Gardner TW, Domm AC, Brock CE, Pruitt AW. Congenital pulmonary lymphangiectasis: a case complicated by chylothorax. Clin Pediatr. 1983; 1. Mendez

22:75-78. 6. Herzog DB,

Logan R,

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Kooistra JB. The Noonan

syndrome with

intesti-

nal

lymphangiectasia. JPediatr. 1976;88:270-272. HL, Holtzapple PG, Eberlein WR, Yakovac WC, Moshang T, Bongiovanni AM. Noonan syndrome with intestinal lymphangiectasis: a metabolic and anatomic study. J Pediatr. 1972;80:269-274. 8. Hoeffel JC, Juncker P, Remy J. Lymphatic vessel dysplasia in Noonan's syndrome. Am J Radiol. 1980;134:399-401. 9. Hernandez RJ, Stern AM, Rosenthal A. Pulmonary lymphangiectasis in Noonan syndrome. Am J Radiol. 1980;134:75-80. 10. Smith S, Schulman A, Weir EK, Beatty DW, Joffe HS. Lymphatic abnormalities in Noonan syndrome: a case report. S Afr Med J. 1979;56:271-274. 11. Hunter WS, Becroft DMO. Congenital pulmonary lymphangiectasis associated with pleural effusions. Arch Dis Child. 1984;59:278-279. 12. Lester LA, Rothberg RM, Krantman HJ, Shermeta DW. Intestinal lymphangiectasia and bilateral pleural effusions: effect of dietary therapy and surgical intervention on immunologic and pulmonary parameters. J Allergy 7. Vallet

Clin Immunol. 1986;78:891-897. 13. Garty B-Z, Levinson Al, Danon YL, Wilmott R, Douglas SD. Lymphocyte subpopulations in children with abnormal lymphatic circulation. J Allergy Clin Immunol. 1989;84:515-520. 14. Noonan JA, Walters LR, Reeves JT. Congenital pulmonary lymphangiectasis. AJDC. 1970;120:314-319. 15. Van Aerde J, Campbell AN, Smyth JA, Lloyd D, Bryan MH. Spontaneous chylothorax in newborns. AJDC. 1984;138:961-964. 16. Felman AH, Rhatigan RM, Pierson KK. Pulmonary lymphangiectasia: observation in 17 patients and proposed classification. AJR Am J Roentgenol.

1972;116:548-558.

17. Nora JJ, Lortscher RH, Spangler RD. Echocardiographic studies of left ventricular disease in Ullrich-Noonan syndrome. AJDC. 1975;129:1417-1420.

18. Allanson JE, Hall JG, Hughes HE, Preus M, Witt RD. Noonan syndrome: the changing phenotype. Am J Med Genet. 1985;21:507-514. 19. Rothman A, Mayer JE, Freed MD. Treatment of chronic pleural effusions after the Fontan procedure with prednisone. Am J Cardiol. 1987;60: 408-409. 20. Dunkelman

H, Sharief N, Berman L, Ninan, T. Generalised lymphanDis Child. 1989;64:1058-1060. Wilson 21. Kerr RHJ, Duncan A, Hume R, Bain AD. Prenatal pleural efassociated fusion with congenital pulmonary lymphangiectasia. Prenatal Diagn. 1985;5:73-76. Nora Nora 22. JJ, AH, Sinha AK, Spangler RD, Lubs HA. The Ullrich\x=req-\ Noonan syndrome (Turner phenotype). AJDC. 1974;127:48-55. 23. Fisher E, Weiss EB, Michals K, DuBrow IW, Hastrieter AR, Matalon R. Spontaneous chylothorax in Noonan's syndrome. Eur J Pediatr. 1982;138:

giomatosis with chylothorax. Arch

282-284. 24. Chan

DK-L, Ho N-K. Noonan syndrome with spontaneous chylothobirth. Aust Paediatr J. 1989;25:296-298. 25. Stringel G, Mercer S, Bass J. Surgical management of persistent postoperative chylothorax in children. Can J Surg. 1984;27:543-546. 26. Murphy MC, Newman BM, Rodgers BM. Pleuroperitoneal shunts in the management of persistent chylothorax. Ann Thorac Surg. 1989;48:195\x=req-\ rax at

200. 27. Fairfax AJ, McNabb WR,

Spiro SG. Chylothorax: a review of 18 cases. Thorax. 1986;41:880-885. 28. Puntis JWL, Roberts KD, Handy D. How should chylothorax be managed? Arch Dis Child. 1987;62:593-596. 29. Guyton AC. Textbook of Medical Physiology. Philadelphia, Pa: WB Saunders Co; 1991:769.

In Other AMA

Journals

ARCHIVES OF INTERNAL MEDICINE

Physician

Restraints in the Practice of Medicine: Current

Wayland Marks, MD (Arch Intern Med. 1992;152:2203-2206)

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Concepts