Miliarias are a group of eccrine disorders characterized by sweat retention due to the occlusion of eccrine ducts. Miliaria profunda is the rarest form of miliaria and occurs when eccrine ducts are obstructed at the dermal-epidermal junction. A granulomatous variant of centrifugal miliaria profunda classic findings of granulomatous infiltrate on histology and centrifugal expansion of deep nodules or plaques. We report a rare case of the granulomatous variant of centrifugal miliaria in an 8-month-old boy, with associated cardiofaciocutaneous syndrome (CFCS) due to a pathogenic MAP2K1 germline variant.

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The miliarias are a clinically heterogeneous group of diseases which occur when the free flow of eccrine sweat to the skin surface is impeded. Miliaria profunda is a variant with obstruction of the duct at or below the level of dermoepidermal junction. The giant centrifugal variant of miliaria profunda has been described in the past at the sites of occlusive tapes and in febrile patients. Thyroid hormone has a regulatory effect on the skin and its appendages and an association of hypothyroidism with this variant of miliaria profunda has not been described in the past. We report a case of giant centrifugal miliaria profunda in an infant with congenital hypothyroidism.

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Sweat glands are critical for thermoregulation. The single tubular structure of sweat glands has a lower secretory portion and an upper reabsorptive duct leading to the secretory pore in the skin. Genes that determine sweat gland structure and function are largely unidentified. Here we report that a Fox family transcription factor, Foxc1, is obligate for appreciable sweat duct activity in mice. When Foxc1 was specifically ablated in skin, sweat glands appeared mature, but the mice were severely hypohidrotic. Morphologic analysis revealed that sweat ducts were blocked by hyperkeratotic or parakeratotic plugs. Consequently, lumens in ducts and secretory portions were dilated, and blisters and papules formed on the skin surface in the knockout mice. The phenotype was strikingly similar to the human sweat retention disorder miliaria. We further show that Foxc1 deficiency ectopically induces the expression of keratinocyte terminal differentiation markers in the duct luminal cells, which most likely contribute to keratotic plug formation. Among those differentiation markers, we show that Sprr2a transcription is directly repressed by overexpressed Foxc1 in keratinocytes. In summary, Foxc1 regulates sweat duct luminal cell differentiation, and mutant mice mimic miliaria and provide a possible animal model for its study.

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