Failure to thrive presenting with an unusual skin rash

CLINICAL CONFERENCE

Failure to thrive presenting with an unusual skin rash Jerry L. Rosenblum, M.D., Janice Schweitzer, M.D., John M. Kissane, M.D., and Thomas W. Cooper, M.D. St. Louis, Missouri

CASE PRESENTATION THIS 7-MONTH-OLD white infant girl was admitted to the hospital because of rash, fever, diarrhea, and vomiting. Her birth weight was 3150 gm. The 23-year-old primigravid mother had had an uncomplicated pregnancy, labor, and delivery; she denied ethanol or cigarette use. Jaundice was noted on the second day of life, and the baby received phototherapy for 1 day; the maximum bilirubin concentration in the first week was 15 mg/dl. The baby's blood type was A positive, and the mother's A negative. The patient was discharged on day 7, taking the breast well and with decreasing jaundice. Cereal was added to her diet at 6 weeks of age, followed by fruit, vegetables, and meat sequentially over the first 5 months of life. The diet was supplemented with a cow milk-based formula beginning at 2 months of age, but the infant continued to breast-feed until the time of admission. The baby had three or four loose green or yellow stools daily. She gained weight slowly, weighing 4520 gm at 3 months of age and 5310 gm at 5 months of age. At 2 months of age the baby had persistent jaundice. At 5 months of age her total serum bilirubin remained elevated at 4 mg/dl, but 1 month later fell to 0.4 mg/dl. One month prior to admission the patient developed a rash over her buttocks and knees, which was described as "red bumps" and was treated with corn starch. Two weeks prior to admission the rash spread to involve the legs, lower arms, abdomen, and back. The rash appeared to be desquamating 12 days prior to admission, and the baby developed fever. Swelling of her hands was also noted. A From the Edward Mallinckrodt Department o f Pediatrics and the Department o f Pathology, Washington University School o f Medicine, and the Division o f Pediatric Gastroenterology and Nutrition, St. Louis Children's Hospital. Reprint requests: J. L. Rosenblum, M.D., Department o f Pediatrics, Washington University School o f Medicine, St. Louis, MO 63178.

potassium hydroxide preparation of the skin rash on the buttocks revealed the presence of yeast. Ketoconazole and topical steroid therapy was begun. The following day the baby developed watery diarrhea and vomiting. On the day prior to admission the infant became less active; axillary temperature was 37.7 ~ C. Family history was positive for "hepatitis" in two maternal aunts. Physical examination revealed an irritable, afebrile infant who weighed 5 k g (<5th percentile). The baby had annular, red lesions 2 cm in diameter on the legs, trunk, arms, and face. The skin of the palms and soles was peeling. Nopustules or bullae were noted. Results of laboratory studies including the following: hemoglobin 10.6 gm/dl, hematocrit 32.2%, WBC 14,700/ mm 3 with a normal differential; platelet count 692,000/ mm 3, mean corpuscular volume 78 ft. The peripheral blood smear was normal, and reticulocyte count was 2.3%. Urinalysis revealed a specific gravity of 1.007; pH 8; negative dipstick for glucose, heme, and protein; and one or two red blood cells and granular casts per high-power field. Serum electrolyte and glucose values were normal, blood urea nitrogen 14 mg/dl, total bilirubin 0.6 mg/dl, serum alkaline phosphatase 54 I U / L (normal 118-354 I U / L ) , serum aspartate transferase (SGOT) 95 I U / L , serum alanine transferase (SGPT) 124 I U / L , total serum protein 3.3 gm/dl, albumin 1.6 gm/dl, zinc 50 tzg/ml (normal 60 to 130 ~g/ml), and copper 19 ug/dl (normal 70 to 155 lzg/dl). Serum immunoglobulin values were normal. Findings on chest radiograph and upper gastrointestinal tract series with small bowel follow-through were interpreted as normal. During the hospitalization the baby was febrile, and coughing was noted. Blood cultures grew group D enterococcus and S t a p h y l o c o c c u s aureus. Treatment with intravenous fluids and antibiotics was begun, and skin biopsy findings were interpreted as showing psoriasiform dermatitis. Orally administered zinc therapy was begun.

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On the fifth day the infant, without warning, was found unresponsive and apneic. Although she was successfully resuscitated initially, pulmonary edema and a massive right-sided tension pneumothorax ensued. The baby was oliguric, hypotensive, and hypothermic, and died. Pseudomonas aeruginosa grew from blood cultures obtained on the day of respiratory arrest. CLINICAL DISCUSSION DR. ROSENBLUM: At 7 months of age this infant was brought for treatment of malnutrition, hypoalbuminemia, protracted jaundice, and rash. Her rate of weight gain was slow during the first 5 months of life; thereafter, she actually lost weight. Her failure to thrive cannot readily be attributed to dysfunction of any single organ, at least as reflected by the available clinical and biochemical data. Specifically, there was no evidence of cardiac or pulmonary disease, and normal electrolyte and BUN levels and urinalysis indicated that renal disease was not responsible for her impaired growth or hypoalbuminemia. The infant's malnourished condition forces us to consider that she may have had inadequate caloric intake or malabsorption. We have little information concerning her caloric intake, because the volume of milk consumed by a breast-fed infant is difficult to estimate. Inadequate supply of milk is a prevalent public health problem in developing countries, often leading t o kwashiorkor or marasmus. Malnutrition in the United States is less commonly the result of an inadequate food supply. Rather, inadequate energy intake is a reason to focus on other possible causes, such as anorexia related to reflux esophagitis or a disturbance in the parent-infant relationship. If we assume that the baby's poor growth was not the result of deficient caloric intake, we then need to consider diseases that impair digestion or absorption of ingested nutrients. During the first year of life, gluten-sensitive enteropathy and cystic fibrosis commonly are associated with growth failure and chronic malabsorption. It is not entirely clear when gluten was introduced into this infant's diet, but cereal as well as other solid food was added after 6 weeks of age. Gluten-induced damage can lead to hypoalbuminemia from excessive enteric protein loss. Hypoalbuminemia usually reflects losses from mucosal damage as well as malabsorption of dietary protein. Findings of contrast studies of this infant's small bowel were interpreted as normal, but such studies are not a sensitive test for gluten-sensitive enteropathy or cystic fibrosis. In order to decide whether small bowel biopsy would be appropriate in this patient, more information about ethnicity and the age that gluten-containing foods were introduced into the diet would be helpful. Gluten-sensitive enteropathy would not, however,

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explain the protracted jaundice observed in this infant. Cystic fibrosis, on the other hand, may be noted in infancy with prolonged obstructive jaundice. Although many patients with cystic fibrosis who are jaundiced in infancy also have meconium ileus, the absence of meconium ileus in an icteric infant should not dissuade the clinician from considering the diagnosis of cystic fibrosis.1 Serum transaminase activities may be normal or only mildly elevated. This patient's rash, however, was apparently too extensive to permit a sweat test to be performed. Although we do not know the conjugated fraction of bilirubin during the early course of this infant's illness, the presence of underlying hemolytic disease is not supported by the normal peripheral smear and hemoglobin electrophoresis. The elevated transaminase values suggest the presence of hepatocellular injury. There are many causes of hepatobiliary disease in infancy, but few are associated with the striking failure to thrive and hyp0albuminemia observed in this patient. Escherichia coli septicemia and jaundice would suggest the diagnosis of galactosemia. 2 The absence of mellituria and the resolution of this infant's jaundice while receiving galactose-containing formula make the diagnosis of galactosemia unlikely. Alphalantitrypsin deficiency, another inherited condition, is accompanied by cholestasis in infancy and can be diagnosed by measuring serum alphaj-antitrypsin activity. The clinical features of cholestatic infants with alpha~-antitrypsin deficiency do not usually include growth failure and hypoproteinemia. 3'4 Extrahepatic biliary atresia primarily affects the liver, and growth impairment is paralleled by deepening jaundice. The rash associated with chronic cholestasis results from severe pruritus, and is usually characterized by scattered excoriations and erythema. This infant apparently had no evidence of pruritus at a time when the dermatitis was extensive. The patient had no physical signs of severe liver disease. Without convincing evidence of impaired protein synthesis, consideration should be given to enteric protein loss. The normal findings of the upper gastrointestinal tract series excluded malrotation with mesenteric lymphatic obstruction and giant gastric rugal hypertrophy. The normal lymphocyte count makes intestinal lymphangiectasia, either primary or secondary, unlikely. Hypoalbuminemia and eczema are seen in Wiskott-Aldrich syndrome, but that rare condition follows an X-linked recessive inheritance pattern and is associated with thrombocytopenia. Patients with cystic fibrosis lose enteric protein primarily from an inability to digest exogenous (dietary) protein as a result of exocrine pancreatic insufficiency. The resulting azotorrhea can limit substrate availability required for protein synthesis and thereby lead to hypoalbuminemia. Provision of a formula containing hydrolyzed protein or,

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alternatively, pancreatic extracts can help to circumvent the protein maldigestion. When hypoproteinemia and failure to thrive are the initial features in infants with cystic fibrosis, this syndrome is associated with high mortality? Could the rash be a possible diagnostic clue to this infant's underlying disease? Essential fatty acid deficiency has been associated with eczematous lesions, and low linoleic acid levels have been reported in the serum of patients with cystic fibrosis. A recent case report describes an infant with cystic fibrosis, acrodermatitis enteropathica, and a low serum linoleic acid concentration. 6 Other specific micronutrient deficiencies may be associated with skin changes. Perifollicular hyperkeratosis may be seen with vitamin A deficiency, but not until after infancy. Vitamin A deficiency is a leading cause of blindness worldwide, but can usually be prevented if treatment is initiated before keratomalacia develops. Riboflavin deficiency may cause chronic scarring at the angles of the mouth, and skin lesions in pellagra primarily involve the areas of the skin exposed to sunlight. Periorbital, splinter, and perifollicular hemorrhages can be seen in patients with scurvy. Malnourished infants with diarrhea may certainly have skin lesions that are not readily attributable to any single nutrient deficiency. In some infants, however, diarrhea associated with dermatitis may be caused by rather than lead to a deficiency of one element, zinc. This condition, acrodermatitis enteropathica, is discussed by Dr. Cooper. DR. COOPER: This patient had a low serum zinc level and clinical features compatible with the diagnosis of acrodermatitis enteropathica, a rare autosomal recessive disorder of infants and young children that is caused by zinc deficiency and is characterized by distinctive acral and periorificial skin eruptions, diarrhea, and mood disturbances. The signs and symptoms of this illness can also be seen in other disorders in which zinc deficiency occurs, including malabsorption syndromes, parenteral feeding lacking trace metals, 7 and rarely in the solely breast-fed infant when human milk lacks zinc? There are case reports of acrodermatitis enteropathica in patients with normal zinc levels. These patients either have a variant of acrodermatitis enteropathica or the zinc levels are artifactually elevated. This patient's serum activity of alkaline phosphatase, a zinc-dependent enzyme, is low, providing further biochemical evidence that the low serum zinc level reflects a zinc-depleted state. Acrodermatitis enteropathica was described by Danbolt a n d C l o s s 9 in 1943 and was attributed to zinc deficiency by Moynihan ~~in 1974. The cause of the disease is unclear. The infant thrives until weaned from human milk, then develops, usually within days to weeks, the signs and symptoms of acrodermatitis enteropathica. The current theory Of pathogenesis is a primary intestinal abnormality

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that leads to defective zinc absorption. This defect is overcome by a factor(s) in human milk that facilitates zinc absorption. Once the infants are weaned, they cannot absorb sufficient zinc from a normal diet such as formula and cereal." Clinical features classically develop during infancy or early childhood. Stools are pale, bulky, and foul smelling. Eczematous skin lesions then develop, mainly around body orifices such as eyes, nose, ears, mouth and on the perineum and paronychial tissue. Chronic lesions appear psoriasiform, with scaly, annular red patches over prominences such as elbows, knees, lower back, and the occiput. Hair loss is common and may progress to total loss of body hair. Patients also frequently have mood disturbance, characterized by irritability, depression, and withdrawn affect. The untreated disease usually follows a progressive course, with an unpredictable pattern of remissions and relapses, which culminates in cachexia and a fatal infection during childhood. ~2 The treatment of acrodermatitis enteropathica consists of zinc replacement, ~3 and is usually followed by full clinical recovery within weeks. 9 PATHOLOGIC

FINDINGS

Cystic fibrosis Acrodermatitis enteropathica P s e u d o m o n a s aeruginosa sepsis DR. KISSANE: The skin lesions at autopsy were sharply marginated, annular, intensely erythematous scaly eruptions. The more advanced lesions were ulcerated, and the less advanced were psoriasiform in appearance. The skin biopsy specimen taken during life showed, as previously described, a nonspecific psoriasiform dermatitis, the features of which include acanthosis, a peglike elongation of rete pegs, moderate, nonspecific, largely perivascular mononuclear infiltrate, absence of the granular cell layer, and preservation of nuclei in the stratum corneum, which is called parakeratosis and accounts for the scaliness appreciated clinically (Fig. 1). A recent paper summarized the features of the skin in acrodermatitis enteropathica; each is nonspecific, but when all are present the diagnosis can be made with some certainty, t~ Those authors described a band of clear cells in the midepidermis, and there was a suggestion of its presence in this patient. It is not clear from that paper whether the characteristic lesions on skin biopsy are present in other forms of zinc deficiency. The lungs were heavy and showed a hemorrhagic bronchopneumonia. There was marked pancreatic aeinar atrophy, dilation of central acinar ducts, and perilobular fibrosis, with inspissation of secretions and preservation of islets, absolutely

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Fig. 1. Skin biopsy specimen showing acanthosis, parakeratosis, and moderate nonspecific perivascular mononuclear infiltrate. (Original magnification • 150.)

Fig. 2. Pancreatic tissue showing acinar atrophy, dilation of central acinar ducts containing inspissated secretions, and perilobular fibrosis. (Original magnification • characteristic of cystic fibrosis 15 (Fig. 2). There was a suggestion in the peribronchial glands of dilation, also a feature of cystic fibrosis. The Brunner glands had a similar lesion in the proximal duodenum. Microscopic sections of lung showed a hemorrhagic bronchopneumonia with colonies of gram-negative bacilli. The liver showed extensive fatty infiltration without prominence of portal triads, fibrosis, or proliferation of bile ducts. This, then, was a child with an acrodermatitis-like eruption as a manifestation of cystic fibrosis.

COMMENT DR. SCHWEITZER: Light microscopy of the small bowel mucosa in autopsy and biopsy specimens from patients with acrodermatitis enteropathica has shown no consistent or specific abnormality? 62~ Ultrastructural examination of biopsy specimens from patients with acrodermatitis enteropathica has revealed abnormal inclusion bodies in Paneth cells. ~9,2~ These have been described as spherical, granulelike inclusions suggestive of altered secretory granules, and rodlike

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inclusions resembling lysosomes in cells with wellpreserved oganelles. 22 Similar ultrastructural Paneth cell changes have been described in the intestines of zincdeficient rats? 3 The ultrastructural abnormality has been said to persist after treatment with diiodohydroxyquin, the standard treatment for acrodermatitis enteropathica before the discovery of the efficacy and safety of orally administered zinc therapy. The morphologic response to zinc is inconclusive. The cellular abnormalities have been said to disappear in a single patient in whom a follow-up biopsy specimen was obtained 4 months after initiation of zinc therapy? 2 In another study of five patients, the ultrastructural abnormality persisted after clinical remission of the disease when repeat biopsy specimens were taken 10 days to 5 months after the initiation of zinc therapy? ~ The inclusion bodies may represent a reversible derangement in Paneth cells as a result of zinc deficiency, which disappears with adequate zinc supplement, although the data reporting the morphologic response to zinc therapy in acrodermatitis enteropathica are thus far limited and contradictory. REFERENCES

1. Lloyd-Still JD: Textbook of cystic fibrosis. Littleton, Mass., 1983, John Wright-PSG, Inc., pp 315-316. 2. Levy HL, Sepe S J, Shih V, et al: Sepsis due to Escheriehia eoli in neonates with galactosemia. N Engl J Med 297:823, !977. 3. Sveger T: Prospective follow-up of children with a~-antitrypsin deficiency: Eight-year-old follow-up. J PEDIATR 104:91, 1984. 4. Alagille D: c~-l-Antitrypsin deficiency. Hepatology 4:115, 1984. 5. Fleisher DS, DiGeorge AM, Barness LA, Cornfeld D: Hypo, proteinemia and edema in infants with cystic fibrosis of the pancreas. J PEDIATR64:341, 1964. 6. Hansen RC, Lemen R, Revsin B: Cystic fibrosis manifesting with acrodermatitis enteropathica-like eruption. Arch Dermatol 119:51, 1983.

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7. Moynihan E J, Grupper C: Acrodermatitis enteropathica and other zinc-deficiency disorders. In Fitzpatrick TB, Eisen AZ, WoLff K, et al, editors: Dermatology in general medicine, ed 2. New York, 1979, McGraw-Hill Book Co, pp 137i-1375. 8. Aggett P J, Atherton DJ, More J, DaVey J, Delves HT, Harries JT: Symptomatic zinc deficiency in a breast-fed preterm infant. Arch Dis Child 55:547, 1980. 9. Danbolt N, Closs K: Acrodermatitis enteropathica. Acta Derm Venereol (Stockh) 23:127, 1943. 10. Moynihan E J: Acrodermatitis enteropathica: A lethal inherited human zinc deficiency disorder. Lancet 2:399, 1974. 11. Hambidge KM, Walravens PA: Disorders of mineral metabolism. Clin Gastroenterol 11:87, 1982. 12. Aggett PJ: Acrodermatitis enteropathica. J Inher Metab Dis 6(Suppl 1):39, 1983. 13. Neldner KH, Hambidge KM, Walravcns PA: Acrodermatitis enteropathlca, lnt J Dermatol 17:380, 1978.. 14. Gonzalez JR, Botet MV, Sanchez JL: The histopathology of acrodermatitis enteropathica. Am J Dermatopathol 4:303, 1982. 15. Oppenheimer EH, Esterly JR: Pathology of cystic fibrosis: A review of the literature and comparison with 146 autopsied cases, perspect Pediatr Pathot 2:241, 1975. 16. Kelly R, Davidson GP, Townley RRW, et al: Reversible intestinal mucosal abnormality in acrodermatitis enteropathica. Arch Dis Child 51:219, 1976. 17. Rodin AE, Goldman AS: Autopsy findings in acrodermatitis enteropathica. Am J Clin Path01 51:315, 1969. 18. Moynahan E J: Acrodermatitis enteropathica. Proc R Soc Med 55:240, 1962. 19. Lombeck I, yon Bassewitz DB, Becket K, et al: Ultrastructural findings in acrodermatitis enteropathica. Pediatr Res 8:82, 1974. 20. Neldner KH, Hagler L, Wise WR, et al: Acrodermatitis enteropathica: A clinical and biochemical survey. Arch Dermatol 110:711, 1974. 21. Polanco I, Nistal M, Guerrero J, et al: Acrodermatitis enteropathica, zinc and ultrastructural lesions in Paneth ceils [letter]. Lancet 1:430, 1976. 22. Bohane TD, Cutz E, Hamilton J R , et al: Acrodermatitis enteropathica, zinc, and the Paneth cell: A case report with family studies. Gastroenterology 73:587, 1977. 23. Otto HF, Weitz H: Elektronenmikroskopische Untcrsuchungen an Paneth-Zellen der Ratte unter Zinkarmer Diat. Beitr Pathol 145:336, 1972.