Aplasia cutis congenita of the scalp: Histopathologic features and clinicopathologic correlation in a case series

Aplasia cutis congenita (ACC) is a rare and heterogeneous disorder characterized by congenital absence of skin. The scalp is the most commonly affected site and lesions may overlie deeper ectodermal abnormalities. The exact etiology is still unknown, and histopathologic features are poorly defined.


| INTRODUCTION
Aplasia cutis congenita (ACC) is a rare and heterogenous group of congenital disorders that are characterized by localized or widespread absence of skin. 1 The reported incidence is 1 to 3 in 10,000 live births, and the exact pathogenesis is unknown. 2 Most commonly, ACC presents as small hairless patch on the scalp vertex but can occur anywhere on the body and be associated with other abnormalities.
Frieden classified ACC into nine groups depending on the occurrence of other physical anomalies or malformation syndromes. 1 Only a few cases have been analyzed microscopically as the diagnosis usually rests with the clinician. Microscopic findings are predominantly based on single case reports, and thus, histopathologic characteristics are poorly defined, conflicting, and age-related changes unknown. 3 Clinical differentiation of ACC from other forms of congenital alopecias can be challenging and histopathological analysis is critical in these cases.
In this study, we investigated the histopathologic spectrum of ACC with emphasis on elastic fibers and age-related changes.

| PATIENTS AND METHODS
Dermatopathology reports of the Department of Dermatology of the University Hospital Tübingen between 2005 and 2019 were searched for the keyword ACC. Ten cases from nine patients were identified, and clinical information were retrieved from archived medical files. All cases diagnosed as ACC were present at birth, and patient #6 had three lesions that were excised at two different time points. Formalin-fixed, paraffin-embedded tissue was cut into 2.5 to 5 μm thick sections and stained with hematoxylin and eosin (H&E), anti-S100 (dilution 1:2000, The fragmentation and density of elastic fibers within ACC were graded from 0 to 3 according to Roten et al. 4 :0 = no elastic fibers detected; 1 = thin and focal elastic fibers; 2 = thin and diffuse elastic fibers; and 3 = thick and diffuse elastic fibers.

| Clinical characteristics
Tables 1 and 2 summarize the findings of the study. Patient age at biopsy ranged from 1 day to 39 years (median 57 months) and there was a female predominance. All patients presented with circumscribed hairless areas on the scalp since birth ( Figure 1A,C) and with the clinical impression of scars (6/9 patients), multiple yellowish nodules (1/9), a skincolored plaque (1/9), or ulcer (1/9). ACC was clinically suspected in 6/9 patients whereas the remaining diagnoses included nevus sebaceus, epidermoid cyst, and morphea en coup de sabre. Cranial imaging was documented in 5/9 patients of which one patient (#1) presented with a localized bone defect beneath the affected skin. None of the patients showed further abnormalities, or had a known genodermatosis, malformation syndrome, or associated epidermolysis bullosa.

| Histopathologic characteristics
Histopathological examination demonstrated that all cases resembled scars with a complete loss of all adnexal structures (folliculosebaceous units, arrector pili muscles, sweat glands, and ducts) in one patient (#7) and near-complete loss in all other cases (Figures 1 and 2, Table 1). Scattered hair follicles were found in 8/10 cases but sweat glands and ducts were found in only 2/10 cases. Arrector pili muscles were rarely observed, and if present, they were usually associated with an adjacent hair follicle. The epidermal silhouette was either dome-shaped (6/10) or flat (4/10) and ACC showed a wedge-shaped configuration in all eight cases that also included normal surrounding tissue ( Figure 2D). In 9/10 cases, dermal collagen bundles were compact, showed a more parallel orientation than in normal skin and blood vessels ran perpendicular to the epidermis (EVG stain; Figure 2F).
Patient #1 demonstrated loosely arranged collagen bundles with parallel orientation and ectatic vessels (Figure 2A,). Intralesional elastic fibers were reduced, always more fragmented than in the surrounding normal tissue (Figure 3A-C) and the thickness and density increased with older age ( Figure 3D-F). The subcutis was thinned in one case (#6) or replaced by collagen bundles in 7/8 evaluable cases. None of the patients had a meningocele or cephalocele, and none of the biopsies contained heterotopic brain tissue.
In addition, there were some unexpected findings: Dermal freefloating hair shafts with foreign body giant cells and milia formation were found in patient #2 ( Figure 4A,B). Scar tissue did not always replace the entire dermis but also surrounded hair follicles or overlay them at the periphery of the lesion ( Figure 4C,D  Figure 4E,F). Cutaneous nerves were also identified by H&E and S100 stain in all other cases but they were not increased. Neuroimaging studies (ultrasonography and magnetic resonance imaging) are indicated in patients with the "hair collar sign" and large or membranous lesions of the scalp to exclude underlying bone and neurovascular anomalies. The "hair collar sign" describes a ring of long hair encircling a congenital hairless area on the scalp and is a sign of a potential neural tube defect, such as heterotopic brain tissue, encephalocele,  11 This membranous type is often associated with a "hair collar sign" and has been proposed as a forme fruste of a neural tube defect due to its shared clinical and histopathologic features. 11 As a matter of precaution, imaging with ultrasonography is advisable before biopsy in all scalp lesions suspicious for ACC.

| DISCUSSION
Correct diagnosis of ACC is crucial as it may be associated with other abnormalities and genetic syndromes with autosomal dominant or recessive inheritance. 1 Clinical differentiation from other congenital alopecias can be challenging and histopathologic analysis may be necessary in these cases. Nevus sebaceus is a more common congenital lesion that occurs primarily on the scalp as a hairless plaque. It represents a benign hamartoma of the skin that combines a variety of epidermal and adnexal abnormalities. Samples of nevus sebaceus in children invariably contain primitive hair follicles and often show epidermal alterations such as acanthosis, spongiosis, and papillomatosis. 12 Hyperplastic sebaceous glands occur later in life but ectopic apocrine glands can also be found in children. 12 Rare differential diagnoses of focal congenital hair loss include the benign non-scarring alopecias congenital triangular alopecia and congenital alopecia areata. Congenital triangular alopecia usually affects the frontotemporal region and rarely involves the occipital scalp. 13 Microscopically, terminal hair follicles are replaced by sparse vellus hair follicles but the number of folliculosebaceous units is usually in the normal range. 13 Congenital alopecia areata shows miniaturized anagen follicles and lymphocytic infiltrates around the bulbs but no scarring. 14 Scarring alopecias are exceedingly rare in newborns and young children but potential causes include linear morphea en coup de sabre and trauma. 15,16 Clinically, morphea en coup de sabre commonly involves the frontoparietal area and is characterized by a linear indurated plaque, resembling the stroke of a sword. 17 Early histopathologic changes reveal an edema in the papillary dermis and a superficial and deep perivascular and perineural lymphocytic infiltrate with admixed plasma cells. 18