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Acrodermatitis enteropathica with immune deficiency
December, 1973 T h e ] o u r n a l o[. P E D I A T R I C S
1007
Acrodermatitis enteropathica with immune deficioccy A male in[ant presented with alopecia, eczematoid dermatitis, chronic diarrhea, and [ailure to thrive. The usual causes o[ chronic malabsorption were ruled out. Acrodermatitis enteropathica was diagnosed. A trial o[ oral Diodoquin and breast milk as the only source o[ nutrition resulted in rapid amelioration o[ symptoms. The patient acquired secondary diarrhea and secondary injections with enteropathogenie Escherichia coli, Candida, and Pseudomonas aeruginosa and subsequently died o[ sepsis. Studies o[ serum and tears revealed a marked deficiency o[ irnmunoglobulins. Necropsy demonstrated a generalized de[eet in his immunopoietic tissues. There were low levels o[ the essential [arty acids in serum. The observations in this case suggest that acrodermatitis enteropathica may in some instances be the clinical expression o[ a primary immune disorder.
Richard Julius, M.D.,* Martin Schulkind, M.D., Terry Sprinkle, M.S., and Owen Rennert, M.D., Gainesville, Fla.
AGRODER2CIATITIS
ENTEROPATI-I-
ICA1 is a rare disease of infancy characterized by diarrhea, alopecia, and an erythematous and vesiculopustular dermatitis primarily localized to the periorificial and acral areas. Children with this disorder may also have stomatitis, glossitis, photophobia, cor-
From the Departments o[ Pediatrics (Divisions o[ Genetics, Endocrinology and Metabolism and Immunology and Infectious Diseases) and Biochemistry, University o[ Florida College o[ Medicine. Supported in part by N I H Training Grant 1 TO1 AM0-5680-01 DM; the Developmental Physiology Training Grant, N I H T1-HDO054; and aided by a grant [rom the National Foundation-Mizrch o[ Dimks. ~Reprint address: Department o] Pediatrics, University oJ Florida College o[ Medicine, Gainesville, Fla. 32610.
neal opacities, blepharitis, conjunctivitis, paronychia, and dystrophy of the nails. In the untreated child death results from overwhelming infection, superimposed on a chronic marasmic state. Treatment has been empirical, consisting of resumption of human milk feedings and oral administration of halogen-substituted 8-hydroxyquinolinesY The cause of this autosomal recessive disease is unknown. Since a number of affected children have indicanuria, Hansson 3 suggested that, as a consequence of defective tryptophan metabolism, accumulation of xanthurenic acid produced the clinical manifestations. Cow's milk was thought to precipitate symptoms since its tryptophan content is three times that of human milk. Vol. 83, No. 6, pp. 1007-1011
1 0 0 8 Julius et al.
The Journal o[ Pediatrics December t973
T a b l e I. Serum fatty acids in P a t i e n t J. K. a n d normal i n f a n t
Lipid class
14:0
Phospholipid Patient J . K . 0.2 8-month-old normal infant 0.2 + 0.1 Cholesterol esters Patient J . K . 0.3 8 month-old normal infant 0.1 -+0.1 Free fatty acids Patient J . K . 1.4 8-month-old normal infant 0.6 + 0.4 Triglyeerides Not analyzed
15:0
Palmitic16:0
} PaImit~ t16:1
Steric 18:0
Serum /atty aci~ OIeic 18:1
0.1 0.2 + 0.3
37.0 19.2 -+4.7
1.0 0.4 -+0.1
8.3 16.3 -+ 1.1
19.9 8.1 +- 1.3
0.4 tr.
22.6 i2.9 -+2.0
3.7 t.4 -+0.6
14.7 1.8 +- 1.2
24.5 16.9 +-3.2
tr.
20.0 18.5 + 2.7
3.1 1.7 -2-__0.6
9.4 9.0 +- 2.6
32.8 29.1 "2-1.6
A diet deficient in the essential fatty acids produces alopecia and a d e r m a t i t i s in experim e n t a l animals similar to the @mptoms of acrodermatitis enteropathica. * C a s h a n d Berger 5 d e m o n s t r a t e d in their p a t i e n t with acrodermatitis e n t e r o p a t h i c a that serum arachidonic acid 20:4~o6) was a b n o r m a l l y low, whereas its precursor linoleic acid (18:20~6) a n d other acids in the linoleic acid group were mildly elevated. T h e y suggested that there m a y be a defect in the absorption of u n s a t u r a t e d fatty acids or a metabolic defect in the synthesis of a r a c h i d o n a t e from its precursors in this disease. A complete absence of serum p r e - b e t a a n d beta lipoprotein as well as low concentrations of cholesterol, triglycerides, a n d phospholipids has also been reported.~ No characteristic pathologic changes have been d e m o n s t r a t e d in this entity. 7 R o d i n a n d G o l d m a n ~ studied a 6-year-old boy who lacked cutaneous deIayed hypersensitivity to antigens of C a n d i d a , Aspergillus, staphylococcus, and streptococcus b u t who h a d n o r m a l h u m o r a l antibodies. A t necropsy the thymus was absent. T h e r e was plasmacytosis in the l y m p h nodes a n d spleen, although germinal centers were absent. T h e r e has aIso been one r e p o r t of acrodermatitis e n t e r o p a t h i c a with an isolated deficiency of serum I g A ) W e studied an infant with the manifestations of acrodermatitis e n t e r o p a t h i c a in w h o m there was a deficiency of a r a c h i d o n i c acid a n d its precursors in association with an imm u n e deficiency.
CASE
REPORT
This first-born Caucasian male infant (J. K.) weighed 3.08 Kg. at birth. He developed a scaling erythematous facial dermatitis within the first week of life. Although breast fed, he received supplemental feedings of Enfamil b e g i n ning at 2 weeks of age. Subsequently, a rash became generalized. At 3 months he was weaned from the breast and given Enfamil as the sole source of milk. He developed loose, foul-smelling stools, and occasional emesis which was not remedied by several changes of proprietary or whole milk formulas. At 8 months of age he was given meat-base formulas and treated as though he had milk intolerance. Stools became less frequent, but he continued to vomit and to lose weight. Various forms of topical therapy including colloid baths and steroid creams did not improve his dermatitis. He was admitted to the Shands Teaching Hospital at the University of Florida at 9 months of age. He was extremely irritable and appeared marasmic. His weight was 4.9 Kg., which was at the fiftieth percentile for an infant of 3 months. There were moist erythematous scaling lesions on the face, ears, trunk, and extremities and in the perianal region. He lacked eyebrows and frontal scalp hair and had fine textured hair over the rest of the scalp. The nails were uninvolved. There was a deficiency of subcutaneous tissue. The liver was palpable 4 cm. below the costal margin. He was mildly acidotic with a serum carbon dioxide concentration of 15 mEq. per liter and a chloride level of 108 mEq. per liter; studies of serum sodium and potassium ions were normal. Total protein was 5.5 Gm. per cent; albumin
Volume 83 Number 6
Acrodermatitis enteropathica
(p_~ercent of fatty acid in each lipid class) Linoleic Linolenic 18:2o:6 18:30:3 20:0
[ I 20:20:6
16.4 26.7•
0.2 0.2•
0.2 0.6•
0.2 0.8•
25.9 55.5•
0.1 0.1•
0.4 0.4•
---
13.8 37.4•
1.8
- -
- -
0.6•
tr.
0.3•
was 3.3 Gm. per cent. Sweat chloride was within the normal range. Stools were watery, with normal pH, trypsin, and fat content, and negative for reducing substances. Stool culture revealed no enteropathogenic bacteria or parasites. Roentgenograms of the gastrointestinal tract did not demonstrate any anatomical abnormality. A diagnosis of aerodermatitis enteropathica was considered, based on the presence of diarrhea of undefined nature associated with milk intolerance, alopecia, and a characteristic dermatitis. Initially, the child was treated with oral Diodoquin, 200 mg. three times a day, and topical applications of Vioform cream. There was some improvement in the skin lesions, but they recurred in 4 days. Therefore, breast milk, as a sole source of nourishment, was added to the regimen. Shortly thereafter he ceased vomiting, had two to three formed stools per day, and the skin lesions gradually improved. At home the dermatitis continued to improve and hair grew on the scalp and eyebrows. Approximately 2 weeks later he was readmitted to the hospital because of recurrence of severe diarrhea and vomiting. Stool and blood cultures grew enteropathogenic Escherichia coli (0119: B14). Sepsis responded to therapy with ampicillin and kanamycin. Blood for serum immunoglobulin determination was obtained prior to the child's release from the hospital. Several days later he was readmitted with vomiting, diarrhea, 5 per cent dehydration, and fever. In the interval he had developed yellow crusted ulcers in the inguinal area and on the abdomen. Physical examination revealed the absense of lymph nodes and tonsillar tissues. Previously he had. a normal.number of granuloeytes; he now had neutropenia and lymphopenia.
Arachidonic 20:40:6
1 009
20:30:6
20:30:9
22:40:6
0.8 4.3•
<0.1 --
0.5 12.6•
0.8 2.0•
- -
- -
4.2
- -
0.5•
0.1•
9.6•
0.I•
2.9 --
---
5.4 0.7•
---
Repeat determinations of immunoglobulins and isohemagglutinins were obtained. Tears were studied for IgA levels. Cultures of the ulcers grew Pseudomonas aeruginosa. Despite therapy he died of overwhehning sepsis. SPECIAL STUDIES AND RESULTS P a p e r c h r o m a t o g r a p h y of the patient's urine d i d not show excessive excretion of t r y p t o p h a n or of its metabolites. Serum a r a c h i d o n i c acid was d e t e r m i n e d as its methyl ester by gas-liquid c h r o m a t o g r a p h y . Levels of a r a c h i d o n i c acid were consistently l o w - - l e s s than 15 per cent of control or p u b lished values. A n analysis of the fatty acids in the several serum lipid classes ( p e r f o r m e d by Dr. R a l p h T. H o l m a n of the H o r m e l Institute, Austin, Minnesota) revealed acids of the linoleic acid group (18:2o6, 20:2o6, 20:3o6) and arachidonic acid to be generally lower t h a n in n o r m a l children (Table I ) . T h e proportions of palmitic, palmitoleic, a n d oleic acids were elevated in o u r patient. Serum immunoglobulins were d e t e r m i n e d on three occasions by s t a n d a r d r a d i a l immunodiffusion. O n all occasions I g A and I g G were absent, and I g A was not detectable in his tears. His blood group was A, but no serum isohemagglutinins were present. N E C R O P S Y
T h e r e was a scaling, m a c u l a r , e r y t h e m a tous rash over the posterior neck, shoulders, a n d anterior chest. A 1 cm. • 2 cm. open, clean ulcer was present in the left inguinal
10 10
The Journal o[ Pediatrics December 1973
Julius et al.
area. Scalp hair was normal in distribution. Eyebrows were present. The thymus weighed 1.2 Gm. Small hemorrhages were present over both pleural surfaces. The parenchyma of the lungs appeared focally congested. The liver contained two acute abscesses, 3 mm. in diameter, in the right lobe. Lesions in the distal 4 to 5 cm. of ileum and the cecum were those of pneumotosis cysto!des intestinalis. Air had dissected into the retroperitoneum around the cecum and into the mesentery near the distal ileum. No "crypt lesions" of the gastrointestinal tract were found. An intussusception had developed at the colonic boundary. T h e heart, appendix, pancreas, spleen, kidneys, and brain were grossly normal. There was a marked deficiency of lymphoid tissue. There were no lymph nodes in the thoracic, axillary, inguinal, and cervical areas. Only two (3 to 4 mm.) para-aortic nodes distal to the renal arteries and one (5 mm.) node near the celiac artery were noted. No tonsil!ar lymphoid tissue was present, and there was no evidence of Peyer's patches. MICROSCOPIC
EXAMINATION
The skin demonstrated focal hyperkeratosis with a nonspecific dermal inflammatory infiltrate of macrophages, neutrophils, and eosinophils. There were areas of fresh hemorrhage in all sections of the lung. Extramedullary hematopoiesis was present in the lungs, liver, spleen, and occasionally, as subcortical loci, in the kidney. The islands of Langerhans appeared disorganized with the cells displaying a cribriform arrangement. The heart, adrenal, thyroid, parathyroids, testis, bladder, and prostate appeared unremarkable. The thymus consisted primarily of the epithelial component, very few "thymocytes," and few Hassall's corpuscles. Scattered submucosal lymphocytes were present in tissue from the tonsillar fossa, but there was no identifiable tonsillar tissue. Lingual tonsils could not be found. There were no Peyer's patches in the ileum; lymphoid aggregates without germinal centers were found in the
appendix. Pathologic findings in the spleen revealed the marginal sinus around the vessels in the "white pulp" to be depleted of lymphocytes; there were no germinal centers. The few lymph nodes found had neither paracortical zones nor germinal centers but did have some aggregates of lymphocytes in the cortex. Generally there was a paucity of lymphocytes in the gastrointestinal tract. Plasma cells were virtually nonexistent, except for an occasional cell in the appendix and the colon. Immunohistologic studies of frozen sections of the spleen, lymph node, and appendix revealed no IgG-staining cells and only a few cells staining with fluorescent conjugated monospecific antibodies for IgA and IgM. Postmortem cultures grew out enteropathic E. coli. DISCUSSION
A great deal of emphasis has been placed on the formation of bullae, the involvement of acral areas, and the development of paronychia in acrodermatitis enteropathica. Pathologic studies demonstrate only a nonspecific dermatitis. 7 Our patient did not have significant involvement of the distal portions of his extremities or his nails; nevertheless, the early onset and eczematoid appearance of the dermatitis, the presence of a malasorptive problem, failure to thrive, and improvement during treatment with breast milk and Diodoquin fit the usual history of acrodermatitis enteropathica. Of primary interest in our patient was the association of essential fatty acid deficiency and a defective immunopoietic system, each of which has been described separately in acrodermatitis enteropathica2, 7 Our patient had a marked deficiency of arachidonic acid before and during treatment. Cash and Berger ~ observed an accumulation of 18: 2~6, 18:30~6, and 20:3o6 and suggested that an enzymatic defect might exist in the conversion of the 20:3o6 to arachidonate. During a remission induced by intravenous administration of fat, the precursors to 20:4~6 disappeared. An important difference is that our
Volume 83 Number 6
p a t i e n t h a d low levels of acids of the linoleic acid g r o u p without treatment. A n o t h e r point at variance is the i~igh level of oleic acid in our p a t i e n t in contrast to to the low levels in their patient. T h e d a t a are difficult to compare because Cash and Berger r e p o r t fatty acids as p e r cent of the total fatty acids in serum. A n unusual observation is the absence of measurable amounts of 20:3o,9 in the phospholipids ( T a b l e I ) . This acid, which is synthesized from oleic acid, is usually elevated in essential f a t t y acid deficiency. 9 Soderhjelm a n d a s s o c i a t e s 1~ a n d H o l m a n 11 r e p o r t t h a t there have been significant differences in the proportions of serum fatty acids a m o n g several patients with the clinical features of acrodermatitis enteropathica. T h e i m m u n o p o i e t i c defect in o u r p a t i e n t was p r o f o u n d a n d suggestive of a congenital i m m u n o l o g i c deficiency disease. T h e antem o r t e m fir~dings were consistent with the diagnosis of d y s g a m m a g l o b u l i n e m i a T y p e I. A l t h o u g h the patient's cell-mediated i m m u n e function h a d not been assayed p r i o r to his death, the necropsy findings showed a deficiency in both T-cell a n d B-cell l y m p h o i d elements a n d were suggestive of a combined i m m u n e deficiency disorder. T h e lack of similarity of the observed proportions of fatty acids in the serum of p a tients with acrodermatitis e n t e r o p a t h i c a suggests t h a t more than one disturbance in fatty acid metabolism m a y exist. T h e clinical manifestations of dermatitis, alopecia, diarrhea, a n d failure to thrive would be c o m m o n to any disturbance leading to significant essential fatty acid deficiency.
Acrodermatitis enteropathica
10 1 1
REFERENCES
1. Margileth, A. M.: Acrodermatitis enteropathica. Case report and "review of literature, Am. J. Dis. Child. 105: 285, 1963. 2. Schulze, R. R., and Winkelmann, R. K.: Acrodermatitis enteropathica: Report of a patient responding to combined therapy with human milk and diiodohydroxyquin, Mayo Clin. Proc. 41: 334, 1966. 3. Hansson, O.: Acrodermatitis enteropathica. Report of two cases with a hypothesis concerning the pathogenesis of the disease, Acta Derm. Venereol. 43: 465, 1963. 4. Holman, R. T.: Essential fatty acid deficiency, in Progress in the chemistry of fats and other lipids, vol. IX, Polyunsaturated acids, part 2, Oxford, 1968, Pergamon Press, Inc., p. 275. 5. Cash, R., and Berger, C. K.: Acrodermatitis enteropathica: Defective metabolism of unsaturated fatty acids, J. PEDIATR. 74: 717, 1969. 6. Zaidman, J. L., Julsary, A., Kook, A. I., Szeinberg, A , Wallis, K., and Azizi, E.: Abetalipoproteinemia in aerodermatitis enteropathica, N. Engl. J. Med. 284: 1387, 1971. 7. Rodin, A. E., and Goldman, A. S.: Autopsy findings in acrodermatitis enteropathica, Am. J. Clin. Pathol. 51: 315, 1969. 8. Beyer, P., Wasmer, A., Peter, M., and Malfroy, M.-L.: Acrodermatitis enteropathica. Observation chez un enfant de 2 ans presentant une carence en beta 2 A globulines, Pediatric 21: 677, I966. 9. Holman, R. T., Caster, W. O., and Wiese, H. F.: The essential fatty acid requirement of infants and the assessment of their dietary intake of linoleate by serum fatty acid analysis, Am. J. Clin. Nutr. 14: 70, 1964. 10. Soderhjelm, L., Wiese, H. F., and Holman, R. T.: The role of polyunsaturated acids in human nutrition and metabolism, in Holman, R. T., editor: Progress in the chemistry of fats and other lipids, vol. IX, Polyunsaturated acids, part 4, Oxford, 1969, Pergamon Press, Inc., pp. 555-585. 11. Holman, R. T.: Personal communication.
1007
Acrodermatitis enteropathica with immune deficioccy A male in[ant presented with alopecia, eczematoid dermatitis, chronic diarrhea, and [ailure to thrive. The usual causes o[ chronic malabsorption were ruled out. Acrodermatitis enteropathica was diagnosed. A trial o[ oral Diodoquin and breast milk as the only source o[ nutrition resulted in rapid amelioration o[ symptoms. The patient acquired secondary diarrhea and secondary injections with enteropathogenie Escherichia coli, Candida, and Pseudomonas aeruginosa and subsequently died o[ sepsis. Studies o[ serum and tears revealed a marked deficiency o[ irnmunoglobulins. Necropsy demonstrated a generalized de[eet in his immunopoietic tissues. There were low levels o[ the essential [arty acids in serum. The observations in this case suggest that acrodermatitis enteropathica may in some instances be the clinical expression o[ a primary immune disorder.
Richard Julius, M.D.,* Martin Schulkind, M.D., Terry Sprinkle, M.S., and Owen Rennert, M.D., Gainesville, Fla.
AGRODER2CIATITIS
ENTEROPATI-I-
ICA1 is a rare disease of infancy characterized by diarrhea, alopecia, and an erythematous and vesiculopustular dermatitis primarily localized to the periorificial and acral areas. Children with this disorder may also have stomatitis, glossitis, photophobia, cor-
From the Departments o[ Pediatrics (Divisions o[ Genetics, Endocrinology and Metabolism and Immunology and Infectious Diseases) and Biochemistry, University o[ Florida College o[ Medicine. Supported in part by N I H Training Grant 1 TO1 AM0-5680-01 DM; the Developmental Physiology Training Grant, N I H T1-HDO054; and aided by a grant [rom the National Foundation-Mizrch o[ Dimks. ~Reprint address: Department o] Pediatrics, University oJ Florida College o[ Medicine, Gainesville, Fla. 32610.
neal opacities, blepharitis, conjunctivitis, paronychia, and dystrophy of the nails. In the untreated child death results from overwhelming infection, superimposed on a chronic marasmic state. Treatment has been empirical, consisting of resumption of human milk feedings and oral administration of halogen-substituted 8-hydroxyquinolinesY The cause of this autosomal recessive disease is unknown. Since a number of affected children have indicanuria, Hansson 3 suggested that, as a consequence of defective tryptophan metabolism, accumulation of xanthurenic acid produced the clinical manifestations. Cow's milk was thought to precipitate symptoms since its tryptophan content is three times that of human milk. Vol. 83, No. 6, pp. 1007-1011
1 0 0 8 Julius et al.
The Journal o[ Pediatrics December t973
T a b l e I. Serum fatty acids in P a t i e n t J. K. a n d normal i n f a n t
Lipid class
14:0
Phospholipid Patient J . K . 0.2 8-month-old normal infant 0.2 + 0.1 Cholesterol esters Patient J . K . 0.3 8 month-old normal infant 0.1 -+0.1 Free fatty acids Patient J . K . 1.4 8-month-old normal infant 0.6 + 0.4 Triglyeerides Not analyzed
15:0
Palmitic16:0
} PaImit~ t16:1
Steric 18:0
Serum /atty aci~ OIeic 18:1
0.1 0.2 + 0.3
37.0 19.2 -+4.7
1.0 0.4 -+0.1
8.3 16.3 -+ 1.1
19.9 8.1 +- 1.3
0.4 tr.
22.6 i2.9 -+2.0
3.7 t.4 -+0.6
14.7 1.8 +- 1.2
24.5 16.9 +-3.2
tr.
20.0 18.5 + 2.7
3.1 1.7 -2-__0.6
9.4 9.0 +- 2.6
32.8 29.1 "2-1.6
A diet deficient in the essential fatty acids produces alopecia and a d e r m a t i t i s in experim e n t a l animals similar to the @mptoms of acrodermatitis enteropathica. * C a s h a n d Berger 5 d e m o n s t r a t e d in their p a t i e n t with acrodermatitis e n t e r o p a t h i c a that serum arachidonic acid 20:4~o6) was a b n o r m a l l y low, whereas its precursor linoleic acid (18:20~6) a n d other acids in the linoleic acid group were mildly elevated. T h e y suggested that there m a y be a defect in the absorption of u n s a t u r a t e d fatty acids or a metabolic defect in the synthesis of a r a c h i d o n a t e from its precursors in this disease. A complete absence of serum p r e - b e t a a n d beta lipoprotein as well as low concentrations of cholesterol, triglycerides, a n d phospholipids has also been reported.~ No characteristic pathologic changes have been d e m o n s t r a t e d in this entity. 7 R o d i n a n d G o l d m a n ~ studied a 6-year-old boy who lacked cutaneous deIayed hypersensitivity to antigens of C a n d i d a , Aspergillus, staphylococcus, and streptococcus b u t who h a d n o r m a l h u m o r a l antibodies. A t necropsy the thymus was absent. T h e r e was plasmacytosis in the l y m p h nodes a n d spleen, although germinal centers were absent. T h e r e has aIso been one r e p o r t of acrodermatitis e n t e r o p a t h i c a with an isolated deficiency of serum I g A ) W e studied an infant with the manifestations of acrodermatitis e n t e r o p a t h i c a in w h o m there was a deficiency of a r a c h i d o n i c acid a n d its precursors in association with an imm u n e deficiency.
CASE
REPORT
This first-born Caucasian male infant (J. K.) weighed 3.08 Kg. at birth. He developed a scaling erythematous facial dermatitis within the first week of life. Although breast fed, he received supplemental feedings of Enfamil b e g i n ning at 2 weeks of age. Subsequently, a rash became generalized. At 3 months he was weaned from the breast and given Enfamil as the sole source of milk. He developed loose, foul-smelling stools, and occasional emesis which was not remedied by several changes of proprietary or whole milk formulas. At 8 months of age he was given meat-base formulas and treated as though he had milk intolerance. Stools became less frequent, but he continued to vomit and to lose weight. Various forms of topical therapy including colloid baths and steroid creams did not improve his dermatitis. He was admitted to the Shands Teaching Hospital at the University of Florida at 9 months of age. He was extremely irritable and appeared marasmic. His weight was 4.9 Kg., which was at the fiftieth percentile for an infant of 3 months. There were moist erythematous scaling lesions on the face, ears, trunk, and extremities and in the perianal region. He lacked eyebrows and frontal scalp hair and had fine textured hair over the rest of the scalp. The nails were uninvolved. There was a deficiency of subcutaneous tissue. The liver was palpable 4 cm. below the costal margin. He was mildly acidotic with a serum carbon dioxide concentration of 15 mEq. per liter and a chloride level of 108 mEq. per liter; studies of serum sodium and potassium ions were normal. Total protein was 5.5 Gm. per cent; albumin
Volume 83 Number 6
Acrodermatitis enteropathica
(p_~ercent of fatty acid in each lipid class) Linoleic Linolenic 18:2o:6 18:30:3 20:0
[ I 20:20:6
16.4 26.7•
0.2 0.2•
0.2 0.6•
0.2 0.8•
25.9 55.5•
0.1 0.1•
0.4 0.4•
---
13.8 37.4•
1.8
- -
- -
0.6•
tr.
0.3•
was 3.3 Gm. per cent. Sweat chloride was within the normal range. Stools were watery, with normal pH, trypsin, and fat content, and negative for reducing substances. Stool culture revealed no enteropathogenic bacteria or parasites. Roentgenograms of the gastrointestinal tract did not demonstrate any anatomical abnormality. A diagnosis of aerodermatitis enteropathica was considered, based on the presence of diarrhea of undefined nature associated with milk intolerance, alopecia, and a characteristic dermatitis. Initially, the child was treated with oral Diodoquin, 200 mg. three times a day, and topical applications of Vioform cream. There was some improvement in the skin lesions, but they recurred in 4 days. Therefore, breast milk, as a sole source of nourishment, was added to the regimen. Shortly thereafter he ceased vomiting, had two to three formed stools per day, and the skin lesions gradually improved. At home the dermatitis continued to improve and hair grew on the scalp and eyebrows. Approximately 2 weeks later he was readmitted to the hospital because of recurrence of severe diarrhea and vomiting. Stool and blood cultures grew enteropathogenic Escherichia coli (0119: B14). Sepsis responded to therapy with ampicillin and kanamycin. Blood for serum immunoglobulin determination was obtained prior to the child's release from the hospital. Several days later he was readmitted with vomiting, diarrhea, 5 per cent dehydration, and fever. In the interval he had developed yellow crusted ulcers in the inguinal area and on the abdomen. Physical examination revealed the absense of lymph nodes and tonsillar tissues. Previously he had. a normal.number of granuloeytes; he now had neutropenia and lymphopenia.
Arachidonic 20:40:6
1 009
20:30:6
20:30:9
22:40:6
0.8 4.3•
<0.1 --
0.5 12.6•
0.8 2.0•
- -
- -
4.2
- -
0.5•
0.1•
9.6•
0.I•
2.9 --
---
5.4 0.7•
---
Repeat determinations of immunoglobulins and isohemagglutinins were obtained. Tears were studied for IgA levels. Cultures of the ulcers grew Pseudomonas aeruginosa. Despite therapy he died of overwhehning sepsis. SPECIAL STUDIES AND RESULTS P a p e r c h r o m a t o g r a p h y of the patient's urine d i d not show excessive excretion of t r y p t o p h a n or of its metabolites. Serum a r a c h i d o n i c acid was d e t e r m i n e d as its methyl ester by gas-liquid c h r o m a t o g r a p h y . Levels of a r a c h i d o n i c acid were consistently l o w - - l e s s than 15 per cent of control or p u b lished values. A n analysis of the fatty acids in the several serum lipid classes ( p e r f o r m e d by Dr. R a l p h T. H o l m a n of the H o r m e l Institute, Austin, Minnesota) revealed acids of the linoleic acid group (18:2o6, 20:2o6, 20:3o6) and arachidonic acid to be generally lower t h a n in n o r m a l children (Table I ) . T h e proportions of palmitic, palmitoleic, a n d oleic acids were elevated in o u r patient. Serum immunoglobulins were d e t e r m i n e d on three occasions by s t a n d a r d r a d i a l immunodiffusion. O n all occasions I g A and I g G were absent, and I g A was not detectable in his tears. His blood group was A, but no serum isohemagglutinins were present. N E C R O P S Y
T h e r e was a scaling, m a c u l a r , e r y t h e m a tous rash over the posterior neck, shoulders, a n d anterior chest. A 1 cm. • 2 cm. open, clean ulcer was present in the left inguinal
10 10
The Journal o[ Pediatrics December 1973
Julius et al.
area. Scalp hair was normal in distribution. Eyebrows were present. The thymus weighed 1.2 Gm. Small hemorrhages were present over both pleural surfaces. The parenchyma of the lungs appeared focally congested. The liver contained two acute abscesses, 3 mm. in diameter, in the right lobe. Lesions in the distal 4 to 5 cm. of ileum and the cecum were those of pneumotosis cysto!des intestinalis. Air had dissected into the retroperitoneum around the cecum and into the mesentery near the distal ileum. No "crypt lesions" of the gastrointestinal tract were found. An intussusception had developed at the colonic boundary. T h e heart, appendix, pancreas, spleen, kidneys, and brain were grossly normal. There was a marked deficiency of lymphoid tissue. There were no lymph nodes in the thoracic, axillary, inguinal, and cervical areas. Only two (3 to 4 mm.) para-aortic nodes distal to the renal arteries and one (5 mm.) node near the celiac artery were noted. No tonsil!ar lymphoid tissue was present, and there was no evidence of Peyer's patches. MICROSCOPIC
EXAMINATION
The skin demonstrated focal hyperkeratosis with a nonspecific dermal inflammatory infiltrate of macrophages, neutrophils, and eosinophils. There were areas of fresh hemorrhage in all sections of the lung. Extramedullary hematopoiesis was present in the lungs, liver, spleen, and occasionally, as subcortical loci, in the kidney. The islands of Langerhans appeared disorganized with the cells displaying a cribriform arrangement. The heart, adrenal, thyroid, parathyroids, testis, bladder, and prostate appeared unremarkable. The thymus consisted primarily of the epithelial component, very few "thymocytes," and few Hassall's corpuscles. Scattered submucosal lymphocytes were present in tissue from the tonsillar fossa, but there was no identifiable tonsillar tissue. Lingual tonsils could not be found. There were no Peyer's patches in the ileum; lymphoid aggregates without germinal centers were found in the
appendix. Pathologic findings in the spleen revealed the marginal sinus around the vessels in the "white pulp" to be depleted of lymphocytes; there were no germinal centers. The few lymph nodes found had neither paracortical zones nor germinal centers but did have some aggregates of lymphocytes in the cortex. Generally there was a paucity of lymphocytes in the gastrointestinal tract. Plasma cells were virtually nonexistent, except for an occasional cell in the appendix and the colon. Immunohistologic studies of frozen sections of the spleen, lymph node, and appendix revealed no IgG-staining cells and only a few cells staining with fluorescent conjugated monospecific antibodies for IgA and IgM. Postmortem cultures grew out enteropathic E. coli. DISCUSSION
A great deal of emphasis has been placed on the formation of bullae, the involvement of acral areas, and the development of paronychia in acrodermatitis enteropathica. Pathologic studies demonstrate only a nonspecific dermatitis. 7 Our patient did not have significant involvement of the distal portions of his extremities or his nails; nevertheless, the early onset and eczematoid appearance of the dermatitis, the presence of a malasorptive problem, failure to thrive, and improvement during treatment with breast milk and Diodoquin fit the usual history of acrodermatitis enteropathica. Of primary interest in our patient was the association of essential fatty acid deficiency and a defective immunopoietic system, each of which has been described separately in acrodermatitis enteropathica2, 7 Our patient had a marked deficiency of arachidonic acid before and during treatment. Cash and Berger ~ observed an accumulation of 18: 2~6, 18:30~6, and 20:3o6 and suggested that an enzymatic defect might exist in the conversion of the 20:3o6 to arachidonate. During a remission induced by intravenous administration of fat, the precursors to 20:4~6 disappeared. An important difference is that our
Volume 83 Number 6
p a t i e n t h a d low levels of acids of the linoleic acid g r o u p without treatment. A n o t h e r point at variance is the i~igh level of oleic acid in our p a t i e n t in contrast to to the low levels in their patient. T h e d a t a are difficult to compare because Cash and Berger r e p o r t fatty acids as p e r cent of the total fatty acids in serum. A n unusual observation is the absence of measurable amounts of 20:3o,9 in the phospholipids ( T a b l e I ) . This acid, which is synthesized from oleic acid, is usually elevated in essential f a t t y acid deficiency. 9 Soderhjelm a n d a s s o c i a t e s 1~ a n d H o l m a n 11 r e p o r t t h a t there have been significant differences in the proportions of serum fatty acids a m o n g several patients with the clinical features of acrodermatitis enteropathica. T h e i m m u n o p o i e t i c defect in o u r p a t i e n t was p r o f o u n d a n d suggestive of a congenital i m m u n o l o g i c deficiency disease. T h e antem o r t e m fir~dings were consistent with the diagnosis of d y s g a m m a g l o b u l i n e m i a T y p e I. A l t h o u g h the patient's cell-mediated i m m u n e function h a d not been assayed p r i o r to his death, the necropsy findings showed a deficiency in both T-cell a n d B-cell l y m p h o i d elements a n d were suggestive of a combined i m m u n e deficiency disorder. T h e lack of similarity of the observed proportions of fatty acids in the serum of p a tients with acrodermatitis e n t e r o p a t h i c a suggests t h a t more than one disturbance in fatty acid metabolism m a y exist. T h e clinical manifestations of dermatitis, alopecia, diarrhea, a n d failure to thrive would be c o m m o n to any disturbance leading to significant essential fatty acid deficiency.
Acrodermatitis enteropathica
10 1 1
REFERENCES
1. Margileth, A. M.: Acrodermatitis enteropathica. Case report and "review of literature, Am. J. Dis. Child. 105: 285, 1963. 2. Schulze, R. R., and Winkelmann, R. K.: Acrodermatitis enteropathica: Report of a patient responding to combined therapy with human milk and diiodohydroxyquin, Mayo Clin. Proc. 41: 334, 1966. 3. Hansson, O.: Acrodermatitis enteropathica. Report of two cases with a hypothesis concerning the pathogenesis of the disease, Acta Derm. Venereol. 43: 465, 1963. 4. Holman, R. T.: Essential fatty acid deficiency, in Progress in the chemistry of fats and other lipids, vol. IX, Polyunsaturated acids, part 2, Oxford, 1968, Pergamon Press, Inc., p. 275. 5. Cash, R., and Berger, C. K.: Acrodermatitis enteropathica: Defective metabolism of unsaturated fatty acids, J. PEDIATR. 74: 717, 1969. 6. Zaidman, J. L., Julsary, A., Kook, A. I., Szeinberg, A , Wallis, K., and Azizi, E.: Abetalipoproteinemia in aerodermatitis enteropathica, N. Engl. J. Med. 284: 1387, 1971. 7. Rodin, A. E., and Goldman, A. S.: Autopsy findings in acrodermatitis enteropathica, Am. J. Clin. Pathol. 51: 315, 1969. 8. Beyer, P., Wasmer, A., Peter, M., and Malfroy, M.-L.: Acrodermatitis enteropathica. Observation chez un enfant de 2 ans presentant une carence en beta 2 A globulines, Pediatric 21: 677, I966. 9. Holman, R. T., Caster, W. O., and Wiese, H. F.: The essential fatty acid requirement of infants and the assessment of their dietary intake of linoleate by serum fatty acid analysis, Am. J. Clin. Nutr. 14: 70, 1964. 10. Soderhjelm, L., Wiese, H. F., and Holman, R. T.: The role of polyunsaturated acids in human nutrition and metabolism, in Holman, R. T., editor: Progress in the chemistry of fats and other lipids, vol. IX, Polyunsaturated acids, part 4, Oxford, 1969, Pergamon Press, Inc., pp. 555-585. 11. Holman, R. T.: Personal communication.