Linear crusted papules in an infant.

Clinical vignette

An otherwise developmentally normal 3-month-old female infant born at term to a mother with an uncomplicated prenatal history presented with a linear crusted plaque involving the left upper aspect of the chest, which had been present since birth (Fig 1). A punch biopsy of the lesion was obtained (Fig 2). The patient's mother was incidentally found to have small, symmetric, skin-colored to yellow-brown, crusted papules on her face and chest, which she reported had been present since adolescence. Family history was significant for multiple generations of male and female relatives with findings similar to those of the patient's mother.

Fig 1

Fig 2

Question 1: What is the most likely diagnosis?

Inflammatory linear verrucous epidermal nevus

Incontinentia pigmenti

Linear lichen planus

Segmental Darier disease

Mosaic neurofibromatosis type 1

Answers:

Inflammatory linear verrucous epidermal nevus—Incorrect. Although inflammatory linear verrucous epidermal nevus can present in a unilateral distribution along the lines of Blaschko, lesions are typically scaly patches or verrucous papules. In addition, it histologically has a psoriasiform appearance with elongation and thickening of the rete ridges, epidermal hyperplasia, papillomatosis, parakeratosis, and acanthosis.

Incontinentia pigmenti—Incorrect. Incontinentia pigmenti may also present at or shortly after birth, following Blaschko lines; however, streaking, whorled papulovesicular lesions with characteristic hyperpigmentation and female predominance (because of lethality in utero in male patients without XXY genotype or mosaicism) clinically distinguishes incontinentia pigmenti.

Linear lichen planus—Incorrect. Linear lichen planus classically manifests as flat-topped violaceous papules along lines of Blaschko.

Segmental Darier disease—Correct. Histopathology of segmental Darier disease is indistinguishable from that of classic segmental Darier disease, with acantholysis, suprabasal cleavage, and keratin plugs, as well as 2 dyskeratotic cell types, corps ronds and grains. These findings, combined with the clinical presentation of crusted or hyperkeratotic papules or plaques following the lines of Blaschko, sparing nails, palms, soles, and the oral cavity, argue for a diagnosis of segmental Darier disease.2, 3, 4 The differential diagnosis also includes an epidermal nevus with Darier-type acantholysis; however, this was thought to be less likely, given the extensive family history.

Mosaic neurofibromatosis type 1—Incorrect. Although the cutaneous distribution described may resemble mosaic neurofibromatosis type 1, analysis of the lesion and histopathology were indicative of segmental Darier disease.

Question 2: Pathogenic variants of which of the following genes are associated with this disease?

ATP2C1

ATP2A2

KRT10

ABCA12

COL7A1

Answers:

ATP2C1—Incorrect. Pathogenic variants of the ATP2C1 gene result in Hailey-Hailey disease. Like segmental Darier disease, this gene encodes a calcium ATPase pump that, when mutated, results in calcium dysregulation and loss of epidermal cell adhesion. In contrast to segmental Darier disease, the calcium ATPase pump for Hailey-Hailey disease is located in the Golgi apparatus, not the endoplasmic reticulum.,

ATP2A2—Correct. Segmental Darier disease results from pathogenic variants of the ATP2A2 gene. This gene encodes the sarco/endoplasmic reticulum calcium ATPase pump, which transports calcium into the endoplasmic reticulum and is critical to cellular function. In particular, loss of calcium transport by the sarco/endoplasmic reticulum calcium ATPase-b isoform localized to the epithelium results in the acantholysis and cutaneous manifestations of segmental Darier disease.2, 3, 4

KRT10—Incorrect. Pathogenic variants of the KRT10 gene disrupt keratinocyte differentiation, resulting in epidermolytic hyperkeratosis, not segmental Darier disease.

ABCA12—Incorrect. Pathogenic variants of the ABCA12 gene disrupt lipid transporters on epidermal cells, which are critical to cellular structure, resulting in autosomal-recessive congenital ichthyosis, not segmental Darier disease.

COL7A1—Incorrect. The COL7A1 gene encodes type VII collagen, the critical component of anchoring fibrils. Therefore, pathogenic variants COL7A1 gene causes separation of the epidermis from the dermis, resulting in dystrophic epidermolysis bullosa.

Question 3: The cutaneous distribution of these findings is most likely a result of which of the following?

Autosomal-dominant inheritance

Revertant mosaicism

Isodisomy

Lyonization

Forward mosaicism

Answers:

Autosomal-dominant inheritance—Incorrect. Although classic segmental Darier disease follows an autosomal-dominant inheritance pattern, this alone would not account for the linear and segmental findings in this patient.2, 3, 4

Revertant mosaicism—Incorrect. Revertant mosaicism would present with a background of diseased skin with a linear patch of normal skin, the inverse of our patient's presentation.

Isodisomy—Incorrect. Inheritance of 2 identical homologous chromosomes, as observed in isodisomy, would not explain the segmental cutaneous distribution described.

Lyonization—Incorrect. Although lyonization, or X-chromosome inactivation, can lead to skin disease following the lines of Blaschko, this is not the mechanism thought to cause segmental Darier disease.

Forward mosaicism—Correct. Typically, segmental Darier disease is inherited in a type 1 forward mosaic pattern (Fig 3). Although findings of segmental Darier disease usually appear later in life, we postulate that this patient's disease presented at birth because of loss of heterozygosity in a mosaic pattern, and that she may develop more generalized findings of classic segmental Darier disease later in life, thus exemplifying a type 2 forward mosaic pattern of inheritance., Cell lines affected in segmental Darier disease with type 2 forward mosaicism will have ATP2A2 pathogenic variants in both alleles, but neighboring cell lines will have the autosomal dominantly inherited variant in only 1 allele. Clinically, this results in a background of diseased skin with linear areas of more severely diseased skin.

Fig 3