Download Acrodermatitis Acidemica Associated with

Case Report
Acrodermatitis Acidemica Associated with Deficiency of
Branched Chain Amino Acids in Maple Syrup Urine Disease
-A Case Report and Review of the Literature
Ching-Yin Chen1 Tien-Yi Tzung1, 2 Chieh-Shan Wu1 Ya-Hui Chen1
Acrodermatitis acidemica is a form of various enzyme defects involving the metabolism
of branched-chain amino acids (BCAAs) along with cutaneous features reminiscent of acrodermatitis enteropathica. We report a case of acrodermatitis acidemica associated with a deficiency
of BCAAs in maple syrup urine disease. This 2-month-old 4402-gram in weight Paiwanese boy,
an aboriginal Taiwanese, was diagnosed as having maple syrup urine disease by severe diarrhea
being the main determining factor. A special milk formula free from BCAAs was used since diagnosis. Two weeks later, he began to suffer from progressive sharply demarcated erythematous
erosions with weeping surface over his face, neck, anogenital area, bilateral antecubital fossae
and four extremities as well as dry desquamation over the bilateral shoulders. In addition, frequent loose stool passages were noted. Blood examinations revealed that the level of the three
essential BCAAs, including leucine, isoleucine, and valine were all below the normal limits. Improvement of the skin rash was observed after adding the above-mentioned essential BCAAs in
his ordinary diet for 1 week. (Dermatol Sinica 27: 122-127, 2009)
Key words: Acrodermatitis acidemica, Branched chain amino acids, Maple syrup urine disease
INTRODUCTION
Acrodermatitis acidemica, also known
as acrodermatitis enteropathica-like eruption,
is a form of various enzyme defects involving the branched-chain amino acid (BCAA)
metabolism with cutaneous features reminiscent of acrodermatitis enteropathica. It has
been described in patients with branchedchain organic acid disorders (methylmalonic
and propionic aciduria, and maple syrup
urine disease).1-4 Maple syrup urine disease
(MSUD) is an autosomal recessive inheri-
tance disorder caused by a deficiency of the
branched-chain ketoacid dehydrogenase
complex, an enzyme common in the degradative pathway of the three BCAAs: leucine,
isoleucine, and valine. The mainstay treatment is a synthetic formula devoid of the
three BCAAs mentioned above. However,
caution should be addressed to supplement
the BCAAs with adequate dosage and at adequate intervals. Otherwise, acrodermatitis
acidemica ensues. We herein report a case of
a 2-month-old boy of MSUD with the classic
From the Department of Dermatology, Kaohsiung Veterans General Hospital,1 Dr. Tzung Dermatological Clinic2
Corresponding author: Tien-Yi Tzung, Dr. Tzung Dermatological Clinic, No. 77-9, Siwei 3rd
Rd., Lingya District, Kaohsiung City 802, Taiwan
TEL: 886-7-5361100 FAX: 886-7-5362732 E-mail: [email protected]
Funding source: none
Conflict of interest: none declared
Received: October 03, 2008
Revised: October 27, 2008
Accepted: October 31, 2008
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Ching-Yin Chen, et al
Fig. 1
(A, B, C) Progressive sharply demarcated erythematous
erosions with weeping surface over face, neck, anogenital
area, bilateral antecubital fossae and four extremities. (D)
Dry scaly desquamation over bilateral shoulders.
Fig. 2
Resolution of the skin rash appeared 2 weeks after the oral
supplement of three essential BCAAs, including leucine,
isoleucine and valine. (A: face; B: genital area)
signs of acrodermatitis acidemica. Administration of oral essential BCAAs to his ordinary diet resulted in complete resolution of
the dermatitis within 2 weeks.
CASE REPORT
A 2-month-old boy of Paiwanese descent was born full term with adequate birth
weight. He had MSUD diagnosed at birth
and received a BCAA-free milk formula
(MSUD diet powder, Mead Johnson) as his
daily feeding (100cc supplement 5-6 times
per day). Leucine, isoleucine, and valine
were also added in adequate dosages.
The patient gained weight with time
but his family didn’t supplement an adequate
dosage of the essential BCAAs mentioned
above to his regular nutritional regimen at
123
home. Progressive sharply demarcated erythematous erosions with weeping surface
over the face, neck, anogenital area, bilateral
antecubital fossae and four extremities (Fig.
1A, 1B, 1C) along with dry scaly desquamation over the bilateral shoulders (Fig. 1D)
ensued for 3 days. Superficial oral aphthouslike lesions were also observed. Meanwhile,
diarrhea frequenting around 6 times per day
occurred at the same time. A biopsy taken
from the junction of psoriasiform and eczematous plaques on his right shoulder demonstrated mild hyperkeratosis with irregular
acanthosis and mild perivascular mononuclear infiltrate in superficial dermis. Neither
hypogranulosis nor keratinocytes ballooning
change was noted. No fungal element was
found by potassium hydroxide scraping. Abnormal laboratory data included an elevated
total white blood count (12700/mm3) with a
differential of eosinophils: 1%, and normocytic anemia (hemoglobin 10.4g/dl). In addition, inborn error urine screening, including
ferric chloride, 2,4-dinitrophenylhydrazine,
cyanide nitroprusside, acid albumin turbidity and Benidict’s test, was unremarkable.
The serum albumin was 2.3 g/dl (3.7-5.3).
The blood levels of iron, total iron-binding
capacity, and zinc were all within the normal
ranges. However, a deficiency of the three
BCAAs was confirmed with a low serum level of leucine: 83.8 μmol/L (83-180), isoleucine: 24.0 μmol/L (49-108), and valine: 81.7
μmol/L (141-261). Under the impression of
acrodermatitis acidemica associated with
deficiency of BCAAs, oral supplementation
of BCAAs was prescribed to supplement his
ordinary dietary regimen.
The skin rash improved within 1 week,
and cleared in 2 weeks (Fig. 2). With adequate dietary management, there were no
subsequent skin eruptions within the following 6 months.
Dermatol Sinica, Jun 2009
Acrodermatitis Acidemica
DISCUSSION
MSUD, a rare metabolic disease that
was first described by Menkes et al. in
1954,5 is an autosomal recessive inborn error
disorder resulting from the deficiency in a
subunit of the mitochondrial branched-chain
ketoacid dehydrogenase complex. This complex catalyzes the oxidative decarboxylation
of branched-chain ketoacids derived from
the transamination of BCAAs, including leucine, isoleucine, and valine. Accumulations
of BCAAs and branched-chain ketoacids
seemed to induce ketoacidosis, neurological disorder, and developmental disturbance
in patients with MSUD.6 The incidence of
MSUD is 1 in 185,000 births throughout the
world.7 In Taiwan, fewer than 10 MSUD cases without accompanying gene analysis have
been reported since 1986. 8, 9 The incidence
is found to be much higher in the aboriginal
tribes of Taiwan.10, 11 Chi et al. reported that
the E2 gene 4.7kb deletion is not only the
first MSUD genetic mutation identified in
Taiwan but also a founder mutation in the
Paiwan tribe, who are one of the nine groups
of the aboriginal tribes of Taiwan.10
Acrodermatitis acidemica, a nutrition disease occurring among children, was
proposed with a similar cutaneous presentation of acrodermatitis enteropathica owing
to various enzyme defects involving the
metabolism of BCAAs.12 It is seen in a variety of conditions including cystic fibrosis,13
necrolytic migratory erythema, 14 anorexia
nervosa,15 maple syrup urine disease,16 methylmalonic academia, propionic academia, 1
biothinidase deficiency (biotin-responsive
multiple carboxylase deficiency),17 citrullinemia, and essential fatty acid deficiency. Systemic presentations include lethargy, failure
to thrive, vomiting, dehydration, dyspnea,
and hypotonia. Sharply demarcated oozing
erythema with desquamation in the diaper
region, the neck folds, the periorificial areas
(mouth, nose, ears, eyes, and perineum) and
Dermatol Sinica, Jun 2009
the extremities are typical cutaneous manifestations. At first, a vesiculobullous eruption
with erosions occurs, and then progresses to
dry, hyperkeratotic, and psoriasiform in appearance.18 Furthermore, scalp hairs might
be sparse, brittle, or hypopigmented. Histopathological findings show pallor of the
upper part of the epidermis with necrosis of
keratinocytes. A diffuse parakeratosis is seen
overlying the pale epidermal cells. Sometimes a subcorneal vesicle is present above
the area of paleness of the epidermis.1 The
differential diagnosis of acrodermatitis acidemica includes Kwashiorkor, chronic mucocutaneous candidiasis, Langerhans cell histiocytosis, Stevens-Johnson syndrome/toxic
epidermal necrolysis, staphylococcal scaled
skin syndrome and multiple carboxylase
deficiency. As the skin rash and histopathological changes of acrodermatitis acidemica
are quite similar to those of acrodermatitis
enteropathica, the diagnosis is based on laboratory surveys and past history.
Sparker et al. first reported eight infants
with MSUD and acrodermatitis acidemica.19
Those patients all had low plasma levels of
isoleucine and the severity of the dermatitis was correlated with the duration of the
isoleucine abnormality. Giacoia and Berry
described the cutaneous manifestations of
acrodermatitis acidemica, diarrhea and anemia related to isoleucine deficiency. 20 The
deficiency of essential amino acids seems to
result in epidermal dysfunction because the
growth of keratinocytes is arrested, which is
especially evident in isoleucine deficiency.21
As the deficiency becomes more severe,
other tissues with high turnover rate, such
as mucous membranes, intestinal mucosa,
and bone marrow red blood cell progenitors
may all be affected.10 The clinical symptoms
and signs of isoleucine deficiency include
body weight loss, erythematous swelling of
the oral mucosa, desquamation of the skin,
and shivering of the hands. Poor feeding, ir124
Ching-Yin Chen, et al
ritability, body weight loss and lethargy may
occur when a deficiency of leucine or valine
exists. There is a marked improvement in
diarrhea and edema once the proper amount
of BCAAs is supplemented. The main tool
of long-term therapy is a synthetic formula
devoid of leucine, isoleucine, and valine and
adding appropriate amounts of these BCAAs
during proper intervals in the patient’s
regular diet. The suggested supplementation
to the dietary regimen is adding 190 μmol/L
leucine per 7-10 days, 105 μmol/L isoleucine
per 1-3 days and 300 μmol/L valine per 2-4
days.
In conclusion, it is very significant for
dermatologists to recognize the features of
acrodermatitis acidemica and be aware of the
combination in the history of MSUD or other
metabolic diseases so as to treat patients
timely and avoid detrimental consequences.
Surveying the plasma amino acid profile is
necessary when facing patients who are suspicious for acrodermatitis acidemica. Thus,
an early diagnosis and subsequent metabolic
control are the most important determinants
of long-term outcome.
REFERENCES
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1994.
2. Bodemer C, De Prost Y, Bachollet B, et al.: Cutaneous manifestations of methylmalonic and
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deficiency during treatment of maple syrup urine
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4. Koopman RJ, Happle R: Cutaneous manifestations of methylmalonic acidemia. Arch Dermatol
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dysfunction associated with an unusual urinary
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6. Mitsubishi H, Owada M, Endo F: Markers associated with inborn errors of metabolism of
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1565S-1567S, 2005.
7. Scriver CR, Beaudet AL, Sly WS, et al.: The
metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill, 19712005, 2001.
8. Feng KP, Chow KW, Chan YP: Maple syrup
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Taiwanica 43: 281-284, 2002.
10.Chi CS, Tsai CR, Chen CH, et al.: Maple syrup
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Paiwan of Taiwan: a novel DBT (E2) gene 4.7
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recombination between LINE-1 and Alu and
the carrier-frequency determination. Eur J Hum
Genet 11: 931-936, 2003.
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12.Rudolf H: Neurocutaneous diseases. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitapatrick’s Dermatology in General Medicine. 5th ed.
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13.Schmidt CP, Tunnessen W: Cystic fibrosis presenting with periorificial dermatitis. J Am Acad
Dermatol 25: 896-897, 1991.
14.Kasper CS: Necrolytic migratory erythema:
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report and review of the literature. Pediatr Dermatol 9: 268-271, 1992.
16.Tain YL, Huang SC, Hung FC, et al.: Acrodermatitis enteropathica-like eruption during treatment of maple syrup urine disease: Report of one
case. Acta Paed Sin 37: 357-360, 1996.
17.Williams ML, Packman S, Cowan MJ: Alopecia
and periorificial dermatitis in biotin-responsive
multiple carboxylase deficiency. J Am Acad Dermatol 9: 97-103, 1983.
18.Niiyama S, Koelker S, Degen I, et al.: Acrodermatitis acidemica secondary to malnutrition in
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19.Spraker MK, Helminski MA, Elsas LJ: Periorificial dermatitis secondary to diet deficiency
of isoleucine in treated with maple syrup urine
disease. J Invest Dermatol 4: 508, 1986.
20.Giacoia GP, Berry GT: Acrodermatitis enteropathica-like syndrome secondary to isoleucine
Dermatol Sinica, Jun 2009
deficiency during treatment of maple syrup urine
disease. Am J Dis Child 147: 954-956, 1993.
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酸血性肢端皮膚炎合併支鏈氨基酸缺乏
於一楓糖尿症患者
-病例報告暨文獻回顧
陳鏡尹
1
1, 2
1
宗天一
吳介山
1
高雄榮民總醫院膚科
1
陳雅惠
2
宗天一皮膚科診所
酸血性肢端皮膚炎是一種與支鏈胺基酸代謝酵素缺乏有關的疾病，其皮膚表徵與腸病性
肢端皮膚炎相似。我們報告一楓糖尿症患者發生酸血性肢端皮膚炎合併支鏈氨基酸缺乏的病
例。一個兩個月大四千四百零二克排灣族男孩因嚴重腹瀉而被診斷出楓糖尿症。該病患因而
開始餵食不含支鏈胺基酸的配方奶粉。然而在兩週後，他的臉上、頸部、生殖器肛門處、雙
側肘窩及四肢出現漸進性輪廓鮮明紅色糜爛病灶及潮濕表面，而且在雙肩出現乾性皮屑。此
外，也出現經常性軟便。血液檢查結果顯示三種必需支鏈胺基酸包含白胺酸，異白胺酸，頡
胺酸皆低於正常值。在他的平日飲食中添加上述必需支鏈胺基酸，其臨床症狀在一週後逐漸
改善。（中華皮誌：27: 122-127, 2009）
127
Dermatol Sinica, Jun 2009