Widespread erythematous scaly eruption in an infant with phenylketonuria

An 11-month-old girl presented to our clinic with widespread erythema, desquamation, and sparse hair. She had been diagnosed with phenylketonuria (PKU) at birth and was on a strict phenylalanine (Phe)-restricted diet. Her cutaneous symptoms had first appeared at 9 months of age, initially manifesting as symmetric pinpoint brown papules on the lower extremities and the dorsum of the hands. Subsequently, the lesions enlarged with progressive desquamation. She had previously been diagnosed with eczema by several dermatologists and treated with topical corticosteroids and emollients, but showed limited improvement. The patient had no gastrointestinal symptoms such as diarrhea, and her growth parameters were within normal limits for her age. On examination, the patient had pale yellow, sparse hair and eyebrows. Large, irregular erythematous patches with desquamation and partial crusting were noted on the trunk, extremities, head, neck, and genital area, with acral predominance. A perioral eczematous eruption was also evident (Figure 1). The child showed lethargy, photophobia, decreased muscle tone in the extremities, and bilateral lower extremity edema. Your diagnosis? … Diagnosis: Acrodermatitis enteropathica-like eruption secondary to phenylalanine deficiency Given the patient's history of PKU and severe dietary Phe restriction, amino acid deficiency was the primary consideration for the skin lesions. At birth, her blood Phe level was 10.54 mg/dl (normal upper limit for neonates: 2 mg/dl), with a Phe/Tyr ratio of 8.64 (reference range < 1). Genetic testing revealed compound heterozygous variants in the PAH gene [c.922C>T (p.Leu308Phe) and c.728G>A (p.Arg243Gln)], confirming the diagnosis of PKU. According to the parents, the patient had been fed with Phe-free formula since birth, with low-protein complementary foods introduced at 4 months of age. At presentation, the patient's blood Phe level was significantly low at only 0.62 mg/dl (Figure 2), while other amino acids and vitamins were within normal ranges. Isolated Phe deficiency can cause acrodermatitis enteropathica (AE)-like skin lesions accompanied by ocular abnormalities and neuropsychiatric symptoms, as previously reported and experimentally validated.1 However, the differential diagnosis still required consideration of zinc deficiency. Her serum zinc level was mildly reduced at 7.63 µmol/l (reference range 9.2–22.9 µmol/l), while plasma alkaline phosphatase, an indirect marker of zinc status, was normal at 223 U/l. Genetic testing showed no mutations in the SLC39A4 gene, thereby excluding hereditary zinc deficiency.2 Despite only mild zinc reduction, which appeared insufficient to explain her severe clinical phenotype, her serum albumin was markedly decreased at 31 g/l (reference range 40–55 g/l). Because albumin is the major carrier of zinc in blood, an oral zinc supplementation trial was nevertheless considered necessary for this infant.3 Skin lesions should respond rapidly to zinc supplementation therapy within five days. Both a zinc supplementation trial and Phe level monitoring were necessary to determine the primary etiology. Because the parents were concerned about isolated zinc supplementation, treatment was initiated with oral zinc (12.9 mg elemental zinc daily) combined with regular formula feeding for two days, followed by a 1:1 mixture of Phe-free and regular formula as recommended by the genetics department. Although initial improvement was observed after one week, the skin lesions recurred and worsened during the second week despite continued zinc supplementation. Laboratory testing at that time revealed a further decrease in blood Phe level to 0.33 mg/dl. Considering acrodermatitis enteropathica-like skin lesions secondary to severe Phe deficiency, the patient was hospitalized after infection had been excluded. Treatment included intravenous human albumin, electrolyte correction, and continuation of regular formula feeding to restore adequate Phe levels. The skin lesions improved rapidly, with resolution of edema, disappearance of ocular symptoms, and hair regrowth. Follow-up laboratory tests showed normalization of both blood Phe and albumin levels. At the 1-month follow-up after discharge, the patient's growth and development were normal. Acrodermatitis enteropathica is a clinical phenotype of hereditary zinc deficiency caused by mutations in the zinc transporter protein, leading to impaired zinc absorption and characterized by acral and perioral dermatitis, alopecia, and diarrhea. Additionally, acquired zinc deficiency resulting from inadequate intake, increased losses, or elevated requirements can also cause AE-like syndrome.4 Zinc supplementation represents an effective treatment for both hereditary and acquired zinc deficiency. However, recent studies have demonstrated that various metabolic disorders can present with AE-like eruptions that are unresponsive to zinc supplementation,5, 6 suggesting that AE-like manifestations may not solely be attributed to zinc transport defects. These metabolic disorders include maple syrup urine disease (MSUD), methylmalonic acidemia (MMA), propionic acidemia (PA), citrullinemia, cystic fibrosis (CF), ornithine transcarbamylase deficiency (OTC), and PKU. Based on these observations, some authors have proposed the term “acrodermatitis dysmetabolica” to describe AE-like eruptions secondary to metabolic disorders rather than acquired zinc deficiency (Table 1).7 Among metabolic disorders, PKU represents a particularly illustrative example of how overly restrictive dietary management can result in AE-like skin manifestations. In patients with PAH gene mutations, dietary Phe restriction remains the primary therapeutic approach. However, excessive control can lead to iatrogenic complications. Several case reports have documented associations between low plasma Phe levels and a constellation of symptoms including cutaneous eruptions (erythema, desquamation, alopecia), lethargy, hypotonia, gastrointestinal symptoms (poor appetite, diarrhea), growth failure, and in severe cases, ocular involvement and impaired brain development and function.1, 8, 9 Infants younger than 12 months are disproportionately affected by this syndrome, likely reflecting their elevated Phe needs during accelerated development. In all previously reported cases, the cutaneous eruptions showed remarkable response to amino acid supplementation. Regular monitoring of blood amino acid levels and growth parameters is essential for detecting and preventing phenylalanine deficiency. In this case, although the patient's blood Phe concentrations were monitored weekly according to established follow-up guidelines, early recognition and dietary adjustment were not achieved in time to prevent deficiency symptoms. This highlights the need for heightened clinical awareness among healthcare providers to recognize Phe deficiency through dermatological manifestations. In patients with eczematous eruptions unresponsive to corticosteroid therapy, metabolic dermatitis should be considered. None.