Iatrogenic isolated isoleucine deficiency as the cause of anacrodermatitis enteropathica-like syndrome

A.M.BOSCH, J.H.SILLEVIS SMITT,* A.H.VAN GENNIP, N.G.G.M.ABELING,R.B.H.SCHUTGENS, H.D.BAKKER AND F.A.WIJBURGDepartments of Paediatrics and *;Dermatology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZAmsterdam, The Netherlands

Accepted for publication 3 April 1998

Summary We present two patients with a suspected inborn error of metabolism. A female newborn presentedwith dysmorphic features and convulsions. Metabolic screening suggested a defect in isoleucinedegradation. Within 2 weeks after the introduction of an isoleucine-restricted diet, she developed asevere acrodermatitis enteropathica-like syndrome. The plasma level of isoleucine was low with anormal leucine/isoleucine ratio. The second patient, a female infant deficient in leucine as a result ofa leucine-restricted diet, did not develop a dermatosis. Isoleucine is essential for normal growth anddifferentiation of keratinocytes and enterocytes. Deficiency of isoleucine, and not leucine or animbalance in the leucine/isoleucine ratio, may result in an acrodermatitis enteropathica-likesyndrome.

Acrodermatitis enteropathica is an autosomal recessivedisorder of zinc metabolism characterized by dermatitis,diarrhoea, alopecia and growth failure. The dermatitisstarts with erythematous lesions around the mouth,nose, ears, eyes and perineum, progressing to vesiculo-bullous lesions, erosions and hyperkeratosis on the face,buttocks and extremities.1 An acrodermatitis entero-pathica-like syndrome has been reported in patientswith zinc deficiency,2 AIDS,3 cystic fibrosis,4 disordersof biotin metabolism5 and arginine deficiency.6 Defi-ciency and imbalance of certain amino acids have alsobeen found to be associated with an acrodermatitisenteropathica-like syndrome.7–10 We present twopatients with a suspected inborn error of metabolism.In one, an iatrogenic isoleucine deficiency and, in theother, an iatrogenic leucine deficiency developed duringdietary restriction of isoleucine and leucine. Only theiatrogenic isoleucine deficiency resulted in a severeacrodermatitis enteropathica-like syndrome.

Case reports

Patient 1

This female infant was born, after an uneventfulpregnancy, by Caesarean section because of fetalheart rate decelerations. She is the first child of

British Journal of Dermatology 1998; 139: 488–491.

488 q 1998 British Association of Dermatologists

Correspondence: F.A.Wijburg.Figure 1. The face of patient 1 showing erythematous papular andfocal pustular lesions partly confluent; scaling is minimal.

healthy, non-consanguineous parents. Apgar scoreswere 0, 4 and 8 after 1, 5 and 10 min, respectively.Examination revealed dysmorphic features: a flattenednasal bridge and hypertrichosis on both ears and theforehead. Six hours after birth, she had several tonicclonic convulsions. Laboratory studies revealed throm-bocytopenia, a normal glucose concentration andnormal serum electrolytes. A magnetic resonancescan of the brain demonstrated hypoplasia of thevermis cerebelli. The convulsions were successfullytreated with phenobarbital and phenytoin. Becausean inborn error of metabolism was suspected, organicacid analysis of the urine was performed by gaschromatography–mass spectroscopy (GC–MS). This

revealed a high level of 2-methylbutyrylglycine, sug-gesting a defect in isoleucine degradation at the level ofthe 2-methyl branched-chain acyl-coenzyme A (CoA)dehydrogenase. Plasma levels of branched-chainamino acids were: valine 236 mmol/L (normal 59–199 mmol/L), isoleucine 70 mmol/L (normal 28–84 mmol/L) and leucine 142 mmol/L (normal 47–167 mmol/L). Breastfeeding was stopped, and an iso-leucine-restricted diet (25 mg/kg per 24 h; normal 79–110 mg/kg per 24 h) was started (total protein intake2·6 g/kg per 24 h).

Four days after the start of the diet, she developed afulminant watery diarrhoea. Bacterial and viral cul-tures were negative. A progressive erythema developedin the nappy area, unresponsive to topical treatmentwith miconazole cream and zinc oxide ointment. On the11th day of the diet, perioral erythema and very brightred lips were noted. There was progression of theerythema to a more erythematodesquamative eruptionof the face and extremities. The oral mucosa wasintensely erythematous and bled easily. Sixteen daysafter the start of the diet, an oral isoleucine loading test

ISOLATED ISOLEUCINE DEFICIENCY 489

q 1998 British Association of Dermatologists, British Journal of Dermatology, 139, 488–491

Figure 2. The right hand of patient 1 showing a dark red eruption withfocal lamellar scaling.

Figure 3. The feet of patient 1 showing acral lamellar scaling leavingan erythematous surface.

Figure 4. The nappy area of patient 1 with perianal ulcerative lesionssurrounded by erythema and adherent slightly lamellar scaling.

(100 mg/kg) for evaluation of the suspected metabolicdisorder was performed. Before the loading test, plasmaamino acid values were: valine 104 mmol/L, isoleucine7·2 mmol/L (severely deficient) and leucine 38 mmol/L.Within 24 h after the loading test, there was a short-lived amelioration of both skin lesions and diarrhoea,followed by a severe worsening 2 days later (Figs 1–4).A skin biopsy showed focal epidermal parakeratosis andsome dyskeratotic keratinocytes in the dermis. A super-ficial inflammatory infiltrate was present. Based on theclinical and histological findings, an acrodermatitisenteropathica-like dermatosis was diagnosed. Theplasma level of zinc on the day before the loading testwas 19·8 mmol/L (normal 11–24 mmol/L). Biotinidaseactivity in the plasma was normal.

Because of the rapid deterioration in the skin lesionsand the suspicion of isoleucine deficiency as the cause ofthe dermatosis in this child, dietary intake of isoleucinewas increased to 50 mg/kg per 24 h. There was a rapidimprovement in both dermatosis and diarrhoea. Sixdays after the dietary increase in isoleucine, plasmavalues of valine, isoleucine and leucine were 124 mmol/L, 43 mmol/L and 80 mmol/L, respectively. As the iso-leucine provocation test could not confirm a disorder ofisoleucine metabolism (no abnormalities were found inGC–MS of the urine samples collected during and afterisoleucine loading), the infant was put on a normal diet.All skin lesions disappeared completely within 8 days.Chromosomal analysis of this patient later revealed alarge chromosome 3 containing a trisomic part ofchromosome 4.

Patient 2

This female infant was born after an uneventful preg-nancy and delivery as the first child of healthy, non-consanguineous parents. She had a good start, andexamination showed no abnormalities. On the secondday of life, she was admitted with symmetric tonic clonicconvulsions. Laboratory studies revealed a non-ketotichypoglycaemia. The hypoglycaemia was controlled byglucose intravenously, and the convulsions were suc-cessfully treated with phenobarbital. Because an inbornerror of metabolism was suspected, organic acid analy-sis of the urine was performed by GC–MS. This revealedthe presence of 3-methylglutaric acid, which raised thesuspicion of 3-hydroxy-3-methylglutamyl-CoA (HMG-CoA) lyase deficiency, an inborn error in leucine degra-dation. At this time, plasma amino acid levels were:leucine 78 mmol/L (normal 47–167 mmol/L), isoleu-cine 25 mmol/L (normal 28–84 mmol/L) and valine

153 mmol/L (normal 59–199 mmol/L). Breastfeedingwas stopped, and a leucine-restricted diet (40 mg/kg per24 h; normal 76–150 mg/kg per /24 h) was started(total protein intake 2·6 g/kg per 24 h). On the 16thday of the diet, plasma amino acid levels were: leucine9·0 mmol/L (severely deficient), isoleucine 279 mmol/Land valine 902 mmol/L. No abnormalities of the skin ordiarrhoea were observed during this period. Extendedresearch showed normal HMG-CoA lyase activity inleucocytes. The infant was put on a normal diet after3 weeks of leucine restriction. No cause for the non-ketotic hypoglycaemic episode could be found.

Discussion

In 1973, Diliberti et al.8 presented an infant with maplesyrup urine disease (MSUD) and an acrodermatitisenteropathica-like rash. They suggested that the der-matosis was caused by a high plasma leucine/isoleucineratio. The rash in their patient was most intense whenthe ratio was 10–20 (normal <6) and disappearedwhen the ratio normalized. Three children withinborn errors of metabolism and an acrodermatitisenteropathica-like dermatosis, all deficient in isoleucine,two also in valine and one in leucine as well, treatedwith dietary restrictions were presented by De Raeve etal.7 They stated that isoleucine deficiency seemed tocause the dermatosis through epidermal dysfunction.Leucine/isoleucine ratios in these patients were 3, 7·5and 15, respectively. Giaccoia and Berry.9 presentedanother child with MSUD and an acrodermatitis entero-pathica-like syndrome. Their patient was deficient inisoleucine and had a plasma leucine/isoleucine ratio of500. They also suggested that isoleucine deficiency incombination with an imbalance in the leucine/isoleu-cine ratio caused the dermatosis.

Our first patient demonstrates that an isolated iso-leucine deficiency can cause an acrodermatitis entero-pathica-like syndrome in the absence of an inborn errorof branched-chain amino acid degradation, and alsoshows that an abnormal plasma leucine/isoleucine ratiois not an essential prerequisite for the development ofthe dermatosis. Furthermore, Northrup et al.5 describedtwo episodes of exfoliative erythroderma on the trunk,arms and face of a child with MSUD with a deficiency ofvaline and leucine during the first episode and a defi-ciency only of valine during the second. No isoleucinedeficiency was found in this patient. A severe leucinedeficiency in our second patient did not result in adermatosis. Therefore, it appears that an acrodermatitisenteropathica-like syndrome can be the result of an

490 A.M.BOSCH et al.

q 1998 British Association of Dermatologists, British Journal of Dermatology, 139, 488–491

isolated deficiency in the branched-chain amino acidsisoleucine and valine and that these amino acids may beessential for the normal growth and differentiation ofkeratinocytes as well as enterocytes. The essential roleof isoleucine is further substantiated by the fact that it isthe most critical in keratinocyte cultures, causinggrowth arrest when depleted.11

References1 Nyhan WL. Inborn errors of biotin metabolism. Arch Dermatol

1987; 123: 1696–8.2 Schneider JR, Fisher H, Feingold M. Picture of the month, acro-

dermatitis enteropathica. AJDC 1991; 145: 211–12.3 Tong TK, Andrew LR, Albert A, Mickel JJ. Childhood acquired

immune deficiency syndrome manifesting as acrodermatitis enter-opathica. J Pediatr 1986; 108: 426–8.

4 Hansen RC, Lemen R, Revsin B. Cystic fibrosis with acrodermatitisenteropathica-like eruption. Arch Dermatol 1983; 119: 51–5.

5 Northrup H, Sigman ES, Hebert AA. Exfoliative erythrodermaresulting from inadequate intake of branched chain amino acidsin infants with maple syrup disease. Arch Dermatol 1993; 129:384–5.

6 Goldblum OM, Brusilow SW, Maldonado YA, Farmer ER. Neonatalcitrullinemia associated with cutaneous manifestations and argi-nine deficiency. J Am Acad Dermatol 1986; 14: 321–6.

7 De Raeve L, De Merleir L, Ramet J et al. Acrodermatitis entero-pathica-like cutaneous lesions in organic aciduria. J Pediatr 1994;124: 416–20.

8 Diliberti JH, DiGeorge AM, Auerbach VH. Abnormal leucine/isoleucine ratio and the etiology of acrodermatitis enteropathica-like rash in maple syrup urine disease (msud). Pediatr Res 1973; 7:382. (Abstr.)

9 Giaccoia GP, Berry GT. Acrodermatitis enteropathica-like syn-drome secondary to isoleucine deficiency during treatment ofmaple syrup disease. AJDC 1993; 147: 954–6.

10 Koopman RJJ, Happle R. Cutaneous manifestations of methylma-lonic acidemia. Arch Dermatol Res 1990; 282: 272–3.

11 Shipley GD, Pittelkow MR. Control of growth and differentiation invitro of human keratinocytes cultured in serum-free medium. ArchDermatol 1987; 123: 1541–4.

ISOLATED ISOLEUCINE DEFICIENCY 491

q 1998 British Association of Dermatologists, British Journal of Dermatology, 139, 488–491