Aplasia cutis congenita

INTRODUCTION — Aplasia cutis congenita (ACC) is a rare, heterogeneous group of congenital disorders characterized by focal or widespread absence of the skin [1,2]. ACC can occur anywhere on the body, but most cases occur on the scalp. In approximately 15 to 30 percent of cases, the scalp defect is associated with a defect in the underlying bone and dura mater, with exposure of the brain and sagittal sinus, or a cerebrovascular defect. Although in most cases ACC is an isolated finding, it may be associated with several genetic syndromes and congenital anomalies, including abdominal wall defects, limb abnormalities, cleft deformities, and fetus papyraceus.

EPIDEMIOLOGY — ACC is an uncommon disorder. The true incidence is unknown but has been estimated around 0.5 to 3 in 10,000 live births [3,4]. ACC is likely to be underreported, as milder cases often go undetected. Some studies report a slightly higher female predominance [5,6]. Approximately 85 to 96 percent of ACC cases present as isolated scalp lesions [3,7,8].

Most cases of ACC occur sporadically, though familial cases have been reported [9,10]. The mode of transmission can be either autosomal dominant with reduced penetrance (a portion of gene carriers will not manifest clinical signs or symptoms) or autosomal recessive [9].

PATHOGENESIS — The exact pathogenesis of ACC is unknown. Various theories have been proposed, including the incomplete closure of the neural tube or embryonic fusion lines, intrauterine trauma, vascular compromise from placental insufficiency, ischemic or thrombotic event from fetus papyraceus (the demise of a twin fetus in the late first or early second trimester of pregnancy), amniotic membrane adhesions, intrauterine infections, genetic mutations, and teratogens (table 1).

Various drugs have been implicated in the pathogenesis of ACC. These include methimazole [11,12], valproic acid, angiotensin-converting enzyme inhibitors, benzodiazepines, misoprostol, and cocaine.

The only known gene associated with nonsyndromic ACC (MIM #107600) is BMS1, a ribosomal ATPase located on chromosome 10q11 and involved in preribosomal RNA processing, which has been described in one family [13].

CLASSIFICATION — A widely accepted classification of ACC, based upon the location and pattern of the skin defect, presence of associated abnormalities, and mode of inheritance, was proposed in 1986 [14]. This classification identifies nine ACC phenotypes and is summarized in the table (table 2).

CLINICAL PRESENTATION

General features — The clinical presentation of ACC at birth can be extremely variable, depending upon the time of occurrence, tissue layers involved, and degree of healing in utero. Most commonly, ACC presents as a small (≤1 cm), solitary, hairless skin defect on the scalp vertex covered with atrophic tissue or eschar (picture 1); multiple small, grouped defects can also be seen (picture 2).

The shape of the individual lesions can be round, oval, linear, rhomboidal, stellate, or circular with a punched-out appearance. The surface may present with granulation tissue or may be ulcerated, eroded, or scar-like (picture 3). In some cases, ACC presents as a bulla filled with serous fluid and covered by a membrane (picture 4) (see 'Membranous aplasia cutis congenita of the scalp' below). Some defects may present as a scar, as a result of healing in utero. Large (>1 cm), irregular defects (picture 3) are often associated with defects of the underlying bone, dura, and intracranial vasculature. Vertex and midline location and presence of hair collar sign, vascular stains, and nodules may be more suggestive of cranial and cerebrovascular defects [15]. (See 'Nonmembranous (stellate) aplasia cutis congenita of the scalp' below.)

More than 80 percent of scalp ACC are found on or near the midline, between the anterior and posterior fontanelle, but lesions may also occur anterior to the vertex of the scalp, on the lateral parietal scalp, or rarely, on the face, in a line extending from the preauricular region to the angles of the mouth.

Nonscalp defects involving the trunk and/or the limbs, which represent approximately 15 percent of the ACC cases, are often bilateral and symmetric (picture 5) [16]. Combined scalp and trunk/limb defects have also been reported [17]. (See 'Aplasia cutis congenita of the trunk and limbs' below.)

Clinical subtypes

Membranous aplasia cutis congenita of the scalp — Membranous or bullous ACC is an uncommon variant of ACC that presents at birth as a well-marginated, round or oval lesion resembling a cyst or bulla, covered with a thin, glistening epithelium (picture 4) [18,19]. Lesions are in most cases small (≤1 cm) and can be solitary or multiple, with the latter often arranged in a linear pattern (picture 6). Membranous ACC is thought to be a "forme fruste" variant of neural tube defect, based upon its specific histologic pattern, which is similar to meningoceles and encephaloceles [20]. Over time, the lesion transforms into a flat, atrophic scar as the bulla resorbs.

The "hair collar" sign — Unlike other forms of scalp ACC, membranous ACC lesions may have an abnormal surrounding circle of coarse, long hair called the "hair collar" (picture 6). The hair collar has been postulated to result from improper neural migration causing abnormally placed neural ectoderm and is a marker of cranial neural tube defects, such as an encephalocele, meningocele, or heterotopic brain tissue [21].

Histopathology — Membranous ACC has distinctive histopathologic features, which include an atrophic epidermis with small or absent adnexal structures and epithelial stratification and the replacement of the superficial dermis with a loose fibrovascular stroma. In some cases, histopathology reveals a deep-reaching scar with thinned or absent subcutis; fragmented elastic fibers; very few isolated, residual hair follicles; and, rarely, sweat glands and ducts [22]. If a hair collar is present, then the edge of the specimen will have clustered, hypertrophic hair follicles. Membranous ACC appears to be similar to cranial neural tube defects, but there is a lack of meningeal or cranial neural tissue.

Nonmembranous (stellate) aplasia cutis congenita of the scalp — ACC presenting with large, irregular, angulated, or stellate defects (picture 7A-B) can be familial and inherited in an autosomal dominant pattern [23]. However, the size and depth of the defects can vary significantly even in the same family, and it is possible that small scalp defects and alopecic areas go unnoticed in some family members.

Large, irregular, or angulated defects are often associated with defects of the underlying bone, with exposure of the dura, sagittal sinus, and brain. Sometimes, enlarged transcranial veins and arteriovenous malformation can be present [23]. Newborns with large bone defects have a high risk of infection, massive hemorrhage, and sagittal sinus thrombosis.

Aplasia cutis congenita of the trunk and limbs — Extensive truncal and limb defects have been associated with fetus papyraceus (the demise of a twin fetus in the late first or early second trimester of pregnancy). These defects present as large, linear, or angulated erosions involving the lateral aspects of the trunk (picture 5) and extensor surfaces of the extremities (picture 8) [24]. Frequently, they are bilateral and symmetric. It has been hypothesized that these defects result from placental infarction following the death of a twin fetus, which would explain their symmetric distribution. The most affected locations tend to be in "watershed" areas, meaning areas that are located farthest away from an arterial blood supply and are most at risk for ischemic injury. This type of ACC may also be associated with gastrointestinal malformations, such as bowel atresia, which is also thought to be a consequence of ischemia in early pregnancy.

Associated genetic syndromes or congenital anomalies — Although ACC is an isolated finding in most cases, it may be a feature of a variety of genetic syndromes, such as trisomy 13, 4p deletion syndrome, epidermolysis bullosa, ectodermal dysplasias, Adams-Oliver syndrome, amniotic band sequence, and SCALP (sebaceous nevus, central nervous system malformations, aplasia cutis congenita, limbal dermoid, and pigmented [giant melanocytic] nevus) syndrome (table 3) [25]. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome' and "Microdeletion syndromes (chromosomes 1 to 11)", section on '4p deletion syndrome (Wolf-Hirschhorn syndrome)' and "Amniotic band sequence".)

●Bart syndrome (aplasia cutis congenita and epidermolysis bullosa) – The association of ACC and epidermolysis bullosa (Bart syndrome), was first described in 1966 and is characterized by congenital localized absence of the skin, blistering, and nail abnormalities [26]. It is caused by a variant in COL7A1, resulting in glycine-to-arginine substitution within the triple-helical domain of type VII collagen [27]. Subsequently, ACC has been found in association with all clinical forms of inherited epidermolysis bullosa, including dominant and recessive dystrophic epidermolysis bullosa [28,29].

Variants in PLEC, encoding for plectin (a cytoskeleton intrafilament that is important in contributing to the skin structure), have also been associated with epidermolysis bullosa and ACC [30].

●Adams-Oliver syndrome – Adams-Oliver syndrome (MIM #100300) is an extremely rare developmental disorder characterized by the presence of ACC of the scalp vertex and terminal limb-reduction defects, including brachydactyly, oligodactyly, syndactyly, hypoplastic nails, or transverse amputations [31]. The limb defects are usually bilateral and often asymmetric, affect the lower limbs more frequently than the upper limbs, and in most cases consist of terminal reduction defects of the fingers and toes [32]. These patients may also have variable involvement of central nervous, cardiopulmonary, gastrointestinal, and genitourinary systems [33]. Additional anomalies may include central nervous system anomalies, congenital heart defects, vascular anomalies such as cutis marmorata telangiectatica congenita, and gastrointestinal and genitourinary anomalies. Adams-Oliver syndrome is caused by mutations in six genes (EOGT, DOCK6, ARHGAP31, RBP, NOTCH1, and DLL4) and can be transmitted in an autosomal dominant or autosomal recessive fashion. Genotype-phenotype correlations have been described in patients with Adams-Oliver syndrome [34].

●ACC has also been found in association with a number of isolated or multiple congenital anomalies, including abdominal wall defects, limb abnormalities, orofacial clefts, nevus sebaceous, epidermal nevi, and congenital heart defects (table 3) [14,25,35].

Clinical course and complications — The clinical course of ACC varies depending upon the size of the defect and the layers of underlying tissues involved. Small lesions (≤1 cm in diameter), even when involving the bone, usually heal spontaneously over weeks to months by epithelialization and new bone formation from the surrounding healthy tissues. Spontaneous healing results in a smooth, hairless scar amenable to surgical revision at a later time.

Major complications that can occur in large defects of ACC involving the bone and dura include hemorrhage from sagittal sinus or enlarged veins, sagittal sinus thrombosis, local infection, meningitis, and leakage of cerebrospinal fluid. Brain herniation and infarction have also been reported. These complications are associated with a high mortality rate, ranging from 10 to 50 percent of cases [2].

DIAGNOSIS

Clinical — The diagnosis of ACC is in most cases clinical, based upon the characteristic finding of a skin defect usually located on the scalp vertex. A careful complete physical examination should be performed in all cases to assess for additional anomalies and plan appropriate workup.

In patients with large, irregular defects or membranous lesions of the scalp with the hair collar sign, imaging studies are indicated to assess for underlying bone defects, vascular anomalies, or brain malformations. (See 'Additional evaluation' below.)

In some with membranous ACC of the scalp or in those presenting with hypertrophic or cystic lesions, a biopsy for histopathologic evaluation can be performed to confirm the diagnosis. (See 'Histopathology' above.)

Dermoscopy — Dermoscopy and trichoscopy can aid in the diagnosis of ACC. On trichoscopy, ACC lesions show hair bulbs with very dark proximal ends (typical for anagen bulbs) arranged radially through a translucent epidermis along the margins of alopecia [36]. The central parts of the lesions show no follicular openings with prominent vasculature, which corresponds to skin atrophy [36,37]. In individuals with skin of color, some findings may be less evident due to skin pigmentation, but the lack of hair/follicular openings can be consistently noted [38].

Additional evaluation — Newborns presenting with large ACC scalp defects or membranous lesions may require neuroimaging studies, including cranial skull radiographs, color Doppler ultrasonography, transfontanellar ultrasonography, computed tomography, and magnetic resonance imaging, to assess for underlying abnormalities of bone, intracranial vasculature, and brain [21,39].

Additional imaging, laboratory, and genetic studies may be needed for patients with ACC and other anomalies that raise suspicion of a malformation syndrome (table 3).

Prenatal diagnosis — Membranous ACC may occasionally be detected prenatally by ultrasonography. In one report, membranous ACC presented as a protruding, round lesion of the scalp that flattened toward the end of pregnancy [40].

There are several reports documenting an association of truncal or limb ACC due to fetus papyraceus (the demise of a twin fetus in the late first or early second trimester of pregnancy) with high maternal serum and amniotic fluid alpha-fetoprotein (AFP) levels and detectable acetylcholinesterase in the amniotic fluid [24,41]. However, the sensitivity and specificity of these tests for the diagnosis of ACC are not known.

High maternal levels of AFP are associated with neural tube defects and other congenital anomalies. (See "Neural tube defects: Overview of prenatal screening, evaluation, and pregnancy management", section on 'Alpha-fetoprotein'.)

DIFFERENTIAL DIAGNOSIS — ACC should be differentiated from obstetrical trauma from forceps, placement of fetal scalp electrodes, or other potential birth injury. ACC should also be distinguished from congenital Volkmann ischemic contracture, a very rare entity in the newborn characterized by asymmetric, well-demarcated, stellate ulcerations of the extremities with muscular and neurologic impairment [42]. Controversy exists about whether this is truly a distinct entity or a variant of ACC that affects the limbs and is associated with neuromuscular impairment. (See "Supracondylar humeral fractures in children", section on 'Complications'.)

MANAGEMENT

General considerations — There is no consensus or evidence-based guideline for the management of ACC [2,43]. Given the high variability in the clinical presentation and severity of ACC, the approach to treatment must be individualized based upon the size and depth of the defect, presence of associated abnormalities, risk of complications, and clinical experience. Treatment options range from nonintervention, conservative treatments, surgical treatment, or a combination of surgical and nonsurgical interventions [2].

Most small scalp lesions, including those with underlying bone defect, do not require any significant therapy other than wound care and usually close spontaneously over weeks or months. Large defects of the scalp or scalp defects that involve the underlying skull or dura, with exposure of sagittal sinus, large veins, or brain, may require surgical intervention due to the high risk of infection, hemorrhage, or thrombosis. However, due to the high morbidity and mortality risk associated with surgery itself and general anesthesia, estimated to be approximately 14 percent [43], there is no agreement among experts on whether surgery should be performed immediately or delayed after initial conservative management.

Data from retrospective studies reflect a large variability in the approach to the management of newborns with complicated scalp defects:

●In an Australian series of 17 newborns with large ACC without bone involvement, 13 were treated conservatively with nanocrystalline silver dressings changed daily for two weeks and then every two to three days until complete healing was achieved [44]. All underwent later excision with primary closure. Four newborns with a defect involving the bone underwent primary surgical management of the defect with local fasciocutaneous flaps. Two of them experienced complications, including graft failure, partial flap failure, sagittal sinus thrombosis, and seizures.

●In a series of 21 newborns with scalp ACC ranging from 1 to 150 cm², 14 were treated conservatively only (with occlusive dressing and topical antibiotic ointment) and 7 underwent split skin grafting [45]. In five newborns, early autologous split-thickness skin grafting was performed three to four hours after birth. There were three deaths due to incontrollable hemorrhage, none of which occurred among newborns treated with immediate skin grafting.

●In a review of 48 reported cases, 23 were treated surgically with primary closure, skin graft, and/or flap rotation [43]. Complications occurred in five cases treated surgically (flap necrosis, hemorrhage, brain herniation) and in one treated conservatively (hemorrhage). There were two deaths, one from a late hemorrhage during conservative treatment of a large defect involving all layers and one from surgical complications.

Treatment options

Conservative treatment — Conservative treatment of scalp defects involves the use of adhering or nonadhering dressings and emollients, with or without antibacterial agents. Silver-impregnated dressings, dressing impregnated with topical antibiotics, and hydrogel sheet dressings that control the moisture are generally used. In cases in which the defect exposes a large vessel or the sagittal sinus, it is important to keep the wound moist and covered at all times to avoid the risk of desiccation, which may result in the rupture of the dura and fatal hemorrhage [46,47]. (See "Basic principles of wound management", section on 'Wound dressings'.)

A conservative approach has been traditionally used for small scalp defects (≤1 cm in diameter with intact dura, no sagittal sinus involvement, and no large vascular malformation). However, there are several reports of successful conservative management of large scalp defects with or without bone involvement [2,44,48-51]. In lesions involving the bone, if the dura mater is intact, conservative treatment may promote the osteogenic potential of the bone surrounding the defect, although bone defects >5 cm in diameter are unlikely to close spontaneously [2].

Large defects in nonscalp locations are generally amenable to conservative treatment. Defects associated with fetus papyraceus heal well without surgical intervention [52].

Surgical treatment — Surgical treatment options include allogenic skin grafts, full-thickness or split-thickness skin grafts, cultured keratinocyte grafts, free or local flap transfer, and reconstructive cranioplasty [2,53,54]. Grafts and flaps are typically used as initial wound coverage for large defects associated with exposure of intracranial structures. Drawbacks of the surgical approach include donor site morbidity, graft loss, and local flap necrosis due to abnormal vasculature in adjacent tissue. (See "Skin autografting".)

Reconstructive cranioplasty using split-rib grafts or cranial vault splitting is usually performed when the child is two to four years old to allow for spontaneous bone regrowth and reduction of the defect size. However, some experts advocate early composite cranioplasty (a one-time reconstruction of bone and skin defect) with autologous full-thickness or split-thickness bone grafts and scalp flaps, which can be performed before two weeks of age [55-57]. Early cranioplastic with autologous pericranium might also take advantage of the significant osteogenic potential of the dura during the first two years of life [50].

Approach — The choice of treatment for a newborn with ACC must be made in the individual patient, based upon the size, depth, and location of the defect and in consultation with a multidisciplinary team including a pediatrician, pediatric dermatologist, pediatric plastic surgeon, and pediatric neurosurgeon, as needed [58]. A management classification that takes into account the size and depth of the defect, layers of tissue involved, and involvement of scalp veins has been proposed to help in treatment planning (table 4) [45]:

●For small defects of the scalp, measuring ≤1 cm in diameter, wound care measures including emollients, topical antibacterial agents, and nonadherent dressings are generally sufficient. Small defects of the underlying bone usually ossify completely with conservative treatment.

●Most large scalp defects without bone involvement can also heal with conservative management over weeks to months.

●Large scalp and skull defects of the midline that expose the sagittal sinus or brain tissue are associated with a high risk of thrombosis or hemorrhage. There is some agreement among experts that these lesions should undergo surgical intervention with skin grafts or local flaps for coverage of exposed soft tissues [2]. The choice of the surgical technique and the timing of surgery should be made based upon the defect type, presence of associated abnormalities, and experience of the surgeon.

●For large defects involving the skull, reconstructive cranioplasty with split-rib grafts or cranial vault splitting is generally delayed until the child is two to four years old to allow for spontaneous bone growth.

●The hairless scar resulting from the defect healing does not warrant urgent treatment, but surgical revision at a later time should be considered. This may include staged simple excisions with primary closure or the use of serial tissue expander application for large alopecic areas [59].

●Large ACC defects in nonscalp locations, including those associated with fetus papyraceus, can usually be managed with conservative wound care [52,60].

PROGNOSIS — Overall, the prognosis for discrete, small scalp lesions of ACC is excellent. The majority of these defects self-resolve within the first few weeks or months of life. The prognosis is guarded for newborns with large scalp defects that involve the bone and intracranial vascular and nervous structures due to the high risk of infection, hemorrhage, and thrombosis associated with both conservative and surgical treatment. The estimated mortality rate among patients with large ACC ranges from 20 to over 50 percent [2].

In patients with small ACC defects, small residual scars and alopecic patches may go unnoticed. Large defects in scalp and nonscalp locations resulting in hairless patches, permanent scars, or contractures may be disfiguring and require further surgical correction.

SUMMARY AND RECOMMENDATIONS

●Definition and classification – Aplasia cutis congenita (ACC) is a rare congenital disorder characterized by focal or widespread absence of the skin. A widely accepted classification of ACC, based upon location and pattern of the skin defect, presence of associated abnormalities, and mode of inheritance, identifies nine ACC phenotypes (table 2). (See 'Classification' above.)

●Clinical presentation – The clinical presentation of ACC at birth can be extremely variable. Most commonly, ACC presents as a small, solitary, round or oval, hairless skin defect on the scalp vertex covered with atrophic tissue or eschar (picture 1). Large, irregular, angulated or stellate scalp defects (picture 7A) are often associated with defects of the underlying bone and exposure of intracranial vascular structures. (See 'Clinical presentation' above.)

●Diagnosis – The diagnosis of ACC is in most cases clinical, based upon the characteristic finding of a skin defect usually located on the scalp vertex. In patients with large, irregular defects (picture 7A) or membranous lesions (picture 4) of the scalp with the hair collar sign (picture 6), imaging studies are indicated to assess for underlying bone defects, vascular anomalies, or brain malformations. (See 'Diagnosis' above.)

●Management – There is no consensus or evidence-based guideline for the management of ACC. The choice of treatment for a newborn with ACC must be made in the individual patient, based upon the size, depth, and location of the defect and in consultation with a multidisciplinary team including a pediatrician, pediatric dermatologist, pediatric plastic surgeon, and pediatric neurosurgeon, as needed. (See 'Management' above.)

For small defects of the scalp, wound care measures are generally sufficient. Large scalp and skull defects of the midline that expose the sagittal sinus are associated with a high risk of thrombosis or massive hemorrhage. There is some agreement among experts that these lesions should undergo surgical intervention with skin grafts or local flaps for coverage of exposed soft tissues. The choice of the surgical technique and the timing of surgery are made based upon the defect type, presence of associated abnormalities, and experience of the surgeon. (See 'Approach' above.)