Acrodermatitis enteropathica-like eruption.

An 18-month-old boy, born from a consanguineous marriage, with a history of failure to thrive developed the following within 3 weeks: generalized tonic-clonic seizures, vomiting, an extensive superficial scaled skin, perioral dermatitis in a U-shaped pattern, and alopecia totalis (Fig 1, Fig 2, Fig 3). Blood investigations revealed anemia (hemoglobin 8.9 g/dL), a white blood cell count of 20 × 103/μg, hyperammonemia (300 μg/dL), and hypoglycemia (35 mg/dL). The level of methylcitric acid in his urine was 47.6 mmol/mol and that of methylmalonic acid was 4712 mmol/mol; his plasma zinc level was normal (70 μg/dL), as was a bacterial culture from his skin. Radiographic examination revealed interstitial pneumonia and dilated cardiomyopathy.

Fig 1

Fig 2

Fig 3

Question 1: What is the best diagnosis?

Staphylococcal scalded skin syndrome

Zinc deficiency

Lyell syndrome

Methylmalonic acidemia (MMA)

Generalized bullous impetigo

Answers:

Staphylococcal scalded skin syndrome – Incorrect. Staphylococcal scalded skin syndrome is caused by the release of 2 exotoxins (epidermolytic toxins A and B). It usually begins with fever within 24 to 48 hours. Large blisters appear, followed by tissue-paper–like wrinkling of the skin. In our case, the patient presented with this condition for 3 weeks, but the skin bacterial culture was negative.

Zinc deficiency – Incorrect. Acrodermatitis enteropathica is a rare, genetic, autosomal recessive disease characterized by typical periorificial dermatitis, alopecia, and diarrhea. Because the patient’s plasma zinc level was normal, this diagnosis was excluded.

Lyell syndrome – Incorrect. Toxic epidermal necrolysis rarely affects children and adolescents (ie, only 20% in the United States). The medications most frequently prescribed for treating toxic epidermal necrolysis are phenobarbital, carbamazepine, piroxicam, aminopenicillins, and allopurinol. Our patient did not take any medication prior to the onset of the disease.

MMA – Correct. MMA is a rare, autosomal recessive, inborn error of metabolism characterized by the accumulation of methylmalonic acid caused by a deficiency of methylmalonyl-coenzyme A (CoA) mutase (MUT) that catalyzes the conversion of methylmalonic-CoA to succinyl-CoA, which requires vitamin B12. The main manifestations include lethargy, hypotonia, vomiting, seizures, and respiratory distress. Patients present with superficial scalded skin over erythematous underlying tissues, stomatitis, cheilitis, and alopecia. These cutaneous manifestations are called acrodermatitis metabolica entheropathica–like syndrome.

Generalized bullous impetigo – Incorrect. The general condition of our patient was altered, which is not the case in patients with generalized bullous impetigo. In fact, these patients have no systemic symptoms and normal laboratory findings (hemogram, liver and renal function tests, and urinalysis).

Question 2: What is the most specific test to confirm the diagnosis?

Skin biopsy

Direct immunofluorescence

Genetic analysis of the MUT gene mutation

Dosage of urine organic acid (methylcitric acid and methylmalonic acid)

Dosages of blood/urine parameters (glucose level, ammonemia, bicarbonate level, and ketone)

Answers:

Skin biopsy – Incorrect. A skin biopsy can be performed to eliminate differential diagnoses such as autoimmune bullous dermatosis (pemphigus and bullous pemphigoid) and toxic epidermal necrolysis. Because the histopathologic findings are not specific (psoriasiform pattern, confluent necrosis of keratinocytes, and intraepidermal vacuolization, etc), a skin biopsy is not recommended.

Direct immunofluorescence – Incorrect. Similar to a skin biopsy, direct immunofluorescence is an invasive technique, especially for newborns and infants. The skin sample can reveal a deposit of IgG or C3, which is not specific to this diagnosis.

Genetic analysis of the MUT gene mutation – Correct. MMA occurs because of a defective conversion of methylmalonyl-CoA to succinyl-CoA in the absence of MUT. The search for the mutation analysis is performed in specialized centers (not available in our country). It is the gold standard diagnosis and can also help in the choice of treatment strategies. It can predict whether a patient will respond to vitamin B12 injections.

Dosage of urine organic acid (methylcitric acid and methylmalonic acid) – Incorrect. The detection of urine organic acid using chromatography or mass spectrometry may lead to the diagnosis. However, because there are 2 types of MMA (cobalamin disorders and MUT deficiencies [non–vitamin B12]), this test is not considered the most specific and definitive laboratory test.

Dosages of blood/urine parameters (glucose level, ammonemia, bicarbonate level, and ketone) – Incorrect. Combined with the clinical history, the dosages of these laboratory markers are suggestive of MMA and other organic metabolic disorders, such as proprionic acidemia.

Question 3: What is the best treatment option in this case?

Extracorporeal detoxification

Intramuscular injection of vitamin B12

Hepatic and renal transplantation

Protein-restricted diet, supplementation with L-carnitine, antibiotics, and vitamin B12 injections

Oral antibiotics only

Answers:

Extracorporeal detoxification – Incorrect. Extracorporeal detoxification is recommended in severe cases of metabolic acidosis with electrolyte imbalances and hyperammonemia (>400-500 μmol/L), which is not the case here.

Intramuscular injection of vitamin B12 – Incorrect. Hydroxocobalamin is a cofactor precursor of MUT. Thus, intramuscular injections are useful to prevent decompensation. Nonetheless, 2 types of vitamin B12–unresponsive MMA have been described (mut0 and mut-), which makes this an adjuvant therapy.

Hepatic and renal transplantation – Incorrect. Hepatic and renal transplantation can improve metabolic decompensation and prevent sequelae. However, some cases of metabolic stroke have been described, even in patients who have undergone liver transplants. Moreover, this therapy is not cost effective and is associated with high morbidity and mortality rates.

Protein-restricted diet, supplementation with L-carnitine, antibiotics, and vitamin B12 injections – Correct. Diet modification is essential in the treatment of patients with MMA. The diet should provide adequate energy (high-calorie regimen) and avoid endogenous protein catabolism through a low or restricted protein (isoleucine, valine, threonine, and methionine) intake. For instance, the diet must exclude foods such as eggs, chicken, beans, and green peas. The long-term management of MMA is based on supplementation with L-carnitine, antibiotics (neomycin or metronidazole), and vitamin B12 injections to prevent optic nerve atrophy.

Oral antibiotics only – Incorrect. The use of oral antibiotics alone is not sufficient. Antibiotics can help to reduce propionate production from intestinal flora. However, their long-term use can induce the development of drug-resistant colonies. The most frequently recommended antibiotics are metronidazole (10-20 mg/kg/d in 2-3 doses), amoxicillin, and cotrimoxazole.

Conflicts of interest

None disclosed.