Aplasia Cutis Congenita

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Background

Aplasia cutis congenita (ACC)[1, 2] is a heterogenous group of disorders characterized by the absence of a portion of skin in a localized or widespread area at birth. First reported by Cordon in 1767, ACC most commonly manifests as a solitary defect but may sometimes occur as multiple lesions. (See the images below.) Although most commonly seen on the scalp (at least 70% of cases), ACC can affect any part of the body, including the trunk and limbs.



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Aplasia cutis congenita on the scalp (most common location) shortly after birth.



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Triplet areas of aplasia cutis congenita are common in infants with trisomy 13.

ACC lesions are noninflammatory and well-demarcated, varying widely in size. They may be circular, oval, linear, or stellate in configuration. ACC occurring in a blaschkoid distribution has also been reported.[3, 4] At birth, the lesions may have already healed with scarring or may remain superficially eroded to deeply ulcerated, occasionally involving the dura or the meninges. Defects in the skin that form early in gestation may heal before delivery and appear as an atrophic membranous,[5] bullous,[6] or parchmentlike scar with associated alopecia, whereas less mature defects present as ulcerations. The membranous type of ACC is most common.

Most ACC lesions occur on the scalp vertex just lateral to the midline, but defects may also occur on the face, trunk, or limbs, sometimes symmetrically. The defect may involve only the epidermis and upper dermis, resulting in minimal alopecic scarring, or it may extend into the deep dermis, subcutaneous tissue, or (rarely) the periosteum, skull, and dura. Large, irregular ACC lesions are suggestive of extension to deeper structures. 

Although ACC is most often a benign isolated defect, it can be associated with other physical anomalies or malformation syndromes.[7] (See Pathophysiology.)

Pathophysiology

The exact pathophysiology of ACC is unclear. The most commonly accepted theory focuses on the tension that prevents the skin from converging during development in utero. Proposed mechanisms include intrauterine trauma, vascular compromise, infection, and medications. It has been theorized that stellate or angulated lesions in particular result from vascular abnormalities or intrauterine ischemia.

ACC is typically sporadic; however, autosomal dominant and, less commonly, autosomal recessive cases have also been reported. Mutations in the ribosomal GTPase BMS1 have been identified as one cause of autosomal dominant ACC.[8] Familial ACC on the scalp is generally nonmembranous, whereas membranous ACC of the scalp is usually sporadic.[9]

Research has shown that dominant-negative mutations in the genes KCTD1 and KCTD15 cause ACC through loss of function of KCTD1/KCTD15 complexes in cranial neural crest cells.[10] This loss of function hinders formation of normal midline cranial sutures and the overlying skin.

Classification

Frieden[11] created a classification system for ACC that consisted of nine groups, defined on the basis of the number and location of the lesions and the presence or absence of associated malformations.

Group 1

This is ACC of the scalp without multiple anomalies.[12] Nearly 86% of all solitary lesions occur on the scalp. A collar of hair is often seen around the defect, particularly with membranous ACC. It can be autosomal dominant[13] or sporadic.[14]

Group 2

This is ACC of the scalp with limb anomalies.[15] Adams-Oliver syndrome[16, 17, 18]  is a distinct disorder in which distal limb-reduction abnormalities are found in association with solitary midline scalp defects. This syndrome exhibits both autosomal dominant and autosomal recessive patterns of inheritance. Mutations in EOGT and DOCK6 have been identified as causes of autosomal recessive Adams-Oliver syndrome, and mutations in DLL4, ARHGAP31, RBPJ, and NOTCH1 have been observed in autosomal dominant forms of the syndrome.[19, 20, 21, 22, 23, 24]  

In group 2 ACC, the scalp lesions tend to be large. The most common limb malformation is hypoplastic or absent distal phalanges, but the severity of limb anomalies ranges from minor defects (eg, an absent nail or a broad fingertip) to more severe involvement. Limb anomalies are usually asymmetric and more commonly involve the lower extremities.[25]  Other anomalies may include cutis marmorata telangiectatica congenita, hemangiomas, cranial arteriovenous malformation (AVM), congenital heart defects, skin tags, supernumerary nipples, and woolly hair.

Group 3

This is ACC of the scalp with epidermal and sebaceous (organoid) nevi[26, 27]  that also involve the scalp, usually adjacent to the ACC. Some patients have also had ophthalmic and neurologic findings typical of epidermal nevus syndrome, including seizures, intellectual disability, corneal opacities, and eyelid colobomas. The term SCALP syndrome may be used as a label for the constellation of nevus sebaceus, central nervous system (CNS) malformations, ACC, limbal dermoid, and pigmented nevus.[28, 26]  Inheritance is sporadic.

Group 4

This is ACC overlying deeper embryologic malformations[29, 30, 31, 32]  (eg, meningomyelocele, porencephaly, leptomeningeal angiomatosis, cranial stenosis, spinal dysraphism, gastroschisis, and omphalocele). A hair collar is often present in the scalp lesions overlying neural tube defects. Intracranial AVMs and arteriovenous fistulas (AVFs) have also been reported in association with scalp ACC in rare cases.[33]  The inheritance pattern in this group varies with the associated underlying condition. There is often a need for repair of abdominal-wall defects with this type of ACC.[34]

Group 5

This is ACC associated with fetus papyraceus or placental infarct.[35, 36, 37, 38, 39, 40, 41] Fetus papyraceus is found at the time of delivery and results from the death of a twin fetus in the late first or early second trimester. The surviving fetus is affected with extensive truncal and limb ACC in a linear or stellate configuration but is usually otherwise normal.

Group 6

This is ACC associated with epidermolysis bullosa (EB),[42, 43] , also referred to as Bart syndrome. ACC can be seen with any type of EB (simplex, junctional, or dystrophic). Many reports describe ACC in this setting, usually on the lower extremities. A subgroup includes the association of pyloric or duodenal atresia, ureteral stenosis, renal abnormalities, craniofacial abnormalities, nail dystrophy, and ACC.

Group 7

This is ACC localized to the extremities without EB.[44, 45, 46, 47]  At least two families have been reported in which multiple members have had extensive ACC on the pretibial lower extremities and the dorsal aspects of the hands and the feet.

Group 8

This is ACC due to teratogens. A few cases of ACC have been linked to intrauterine infection with herpes simplex virus (HSV) or varicella zoster virus (VZV) or to exposure to methimazole[48, 49, 50]  in the treatment of maternal thyrotoxicosis during pregnancy. Imperforate anus has been associated with methimazole or carbimazole exposure during gestation.

Group 9

This is ACC associated with malformation syndromes.[51, 52]  ACC has been reported as a characteristic in many syndromes,[53, 54, 55, 56]  including the following:

Reticulolinear ACC on the face and neck is a distinctive cutaneous manifestation in several syndromes linked to band Xp22.

Etiology

No single unifying theory can account for all lesions of ACC. Because this condition is the phenotypic result of more than one disease process, it is likely that more than one mechanism is involved. Mechanisms include the following:

Of particular note is the association of fetus papyraceus with bilaterally symmetric ACC.

The proximity of scalp ACC to the scalp hair whorl, which is thought to be the point of maximum tensile force during rapid brain growth, led to the hypothesis that tension-induced disruption of the overlying skin occurs at 10-15 weeks' gestation, when hair direction, patterning, and rapid brain growth occur. This may also explain the increased incidence of ACC on the vertex scalp.

Early rupture of the amniotic membranes, forming amniotic bands, has appeared to be the cause of ACC in several cases.

The bullous or membranous variants of ACC reveal a distinct histologic pattern identical to those noted in encephaloceles and meningoceles. This finding supports the hypothesis that these types of ACC may represent the forme fruste of a neural tube closure defect.

Epidemiology

US and international statistics

ACC is an uncommon anomaly of newborns. Hundreds of cases of ACC have been reported since its initial description, but because of significant underreporting of this generally benign disorder, the precise frequency has not been established. For example, one estimate of incidence cited a figure of approximately three cases in 10,000 births, whereas another cited a figure of 0.3%.[59]  A population-based study using data from 28 EUROCAT registries in 16 European countries reported an overall prevalence of 5.1 per 100,000 for the period from 1998 to 2017.[7]

Age-, sex-, and race-related demographics

ACC lesions are present at birth. Unless associated with an X-linked malformation syndrome, ACC has not been shown to have any sexual predilection. No racial predilection has been established.

Prognosis

The prognosis for patients with ACC is usually excellent. If the defect is small, recovery is uneventful, with gradual epithelialization and formation of a hairless, atrophic scar over several weeks. For patients treated conservatively, the average length of recovery is 27.9 days.[60] Small underlying bony defects usually close spontaneously during the first year of life. Surgical repair of large or multiple scalp defects, either with excision and primary closure (if feasible) or with the use of tissue expanders and rotation of a flap, may be considered. Truncal and limb defects, despite their large size, usually epithelialize and form atrophic scars, which can be revised later if necessary.

When ACC is associated with other anomalies, the prognosis depends on the severity of those anomalies. Underlying or associated defects may significantly affect mortality and morbidity. Full-thickness defects of the scalp, skull, and dura are associated with a mortality exceeding 50%. Even large defects on areas other than the scalp usually heal well with conservative skin care (eg, topical antibiotic ointment). The rare larger scalp defects are prone to hemorrhagic and infectious complications, placing patients at risk for death. Extensive ACC of the scalp may be associated with an increased risk of sagittal sinus thrombosis. For these reasons, surgical intervention may be required for large full-thickness scalp defects.

Patient Education

Genetic counseling is advised for parents of affected individuals if there is a strong family history of ACC or if the affected children have ACC in association with a malformation syndrome.

History

The obstetric history should include a review of maternal medications and infections (eg, varicella zoster virus [VZV] or herpes simplex virus [HSV]) during the pregnancy. An initial multiple pregnancy with death of a fetal twin or any placental anomalies should be determined. Because some forms of aplasia cutis congenita (ACC) are inherited, a thorough family history is also important.

Physical Examination

The diagnosis of ACC is made on the basis of physical findings indicative of a disruption of skin development in utero. Most ACC lesions occur on the scalp lateral to the midline, but they may also occur on the face, trunk, or limbs, sometimes symmetrically. (See the image below.)



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Extensive aplasia cutis congenita on the scalp, extending down to the skull.

The lesions are noninflammatory and well-demarcated. Their appearance varies, depending on when they occur during intrauterine development. Lesions that form early in gestation may heal before delivery and appear as an atrophic membranous parchmentlike or fibrotic alopecic scar, whereas less mature defects may present as an ulceration of variable depth. With only the epidermis and the upper dermis involved, minimal alopecic scarring may result, but deeper defects may extend through the dermis, subcutaneous tissue, and rarely periosteum, skull, or dura.

Distorted hair growth around a scalp lesion, known as the hair collar sign, is commonly seen with membranous ACC and is a marker for underlying defects such as encephaloceles, meningoceles, and heterotopic brain tissue. (See the image below.)



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This area of healed aplasia cutis congenita is located in an area of nevus flammeus. Note the collarette of coarser hair at the margin of the defect.

A rare bullous variant of ACC, manifesting as a tense yellow vesicle or cyst on the scalp, has been reported. However, it is usually seen after the bullae have absorbed, leaving a flat scar. Accordingly, some authors equate bullous ACC and membranous ACC.

A complete physical examination should be performed to search for associated physical anomalies or recognizable malformation syndromes, paying particular attention limb and digit defects. (See the image below.)



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Bilateral involvement of the lower extremities in aplasia cutis congenita associated with fetus papyraceous.

Complications

Major complications of ACC are rare but include hemorrhage, secondary local infection, meningitis, and sagittal sinus thrombosis.

Larger lesions associated with underlying bony defects may result in death secondary to central nervous system (CNS) infection or hemorrhage from the sagittal sinus.

Laboratory Studies

No specific laboratory abnormalities are consistently found in aplasia cutis congenita (ACC). Abnormalities due to associated conditions may be present. Chromosome analysis or genetic testing may be indicated if a pattern of abnormalities suggests a genetic disorder.

Elevated alpha-fetoprotein (AFP) levels in maternal serum and amniotic fluid, as well as elevated acetylcholinesterase in amniotic fluid, have been reported as possible early signs of ACC. However, these tests are neither sensitive nor specific and are not generally used for diagnosis.[61]

Imaging Studies

Imaging studies are seldom required for small circular or oval ACC of the scalp with no apparent associated anomalies.

Atypical or very large scalp defects should be imaged for possible underlying bone, vascular, or soft-tissue defects. In one neonate, a ventricular diverticulum of the posterior horn of the lateral ventricle was associated with ACC of the scalp. It manifested as an expanding bulge of the subdural space.

Magnetic resonance imaging (MRI) of the head is recommended for evaluation of ectopic neural tissue in midline bullous or membranous scalp ACC.[62] Ultrasonography (US) can be used to evaluate for underlying bony defects with larger nonmembranous scalp ACC lesions.[63]

Distal radial epiphyseal dysplasia associated with ACC over the dorsum of the distal forearm has been reported. Although the ACC was diagnosed at birth, the radial dysplasia was not recognized until presentation to an orthopedist at age 5-10 years. In cases of ACC involving the distal forearm, radiographs of the involved extremity should be performed.

Other Tests

Other tests may be indicated for evaluation of any associated conditions that are present.

Histologic Findings

The histologic features of the skin vary according to the depth of ACC and its duration. At birth, ulcerated lesions may show a complete absence of skin. After healing, the epidermis may appear flattened with a proliferation of fibroblasts within the connective-tissue stroma and an absence of adnexal structures. Bullous ACC is a rare clinical subtype with a distinct pattern containing fibrovascular stroma, edematous stroma, or both. Identical histologic findings are found in encephaloceles and meningoceles. The diagnosis of ACC can typically be made without histologic evidence, however. In view of the patient’s age, a biopsy may not be obtained.[64]

Medical Care

The decision to employ medical therapy, surgical therapy, or both in a patient with aplasia cutis congenita (ACC) depends primarily on the size, depth, and location of the cutaneous defect and on any treatment that is indicated for associated defects. The goals of treatment are to restore the mechanical and immunologic integrity of the skin and to limit fluid leakage or organ rupture.[34, 63, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74]

Local therapy includes gentle cleansing and application of a bland ointment or a topical antibiotic ointment to prevent desiccation of the defect.

Antibiotics are indicated only if overt signs of infection are noted.

Further treatment usually is not necessary, because the erosions and ulcerations almost always heal spontaneously.

A variety of specialized dressing materials have been used.[75, 76] Basic fibroblast growth factor (bFGF; also referred to as FGF-2 or FGF-β) has also been used as part of conservative treatment to accelerate healing and has been suggested as a treatment to provide a better epithelium for future reconstruction in giant ACC.[77]

Surgical Care

Surgical repair is not usually indicated for ACC if the defect is small. Recovery is uneventful, with gradual epithelialization and formation of a hairless atrophic scar over several weeks. Small underlying bony defects usually close spontaneously during the first year of life.

Surgical repair of large or multiple scalp defects may require excision with primary closure, if feasible, or the use of tissue expanders[78] and rotation of a flap to fill the defect. Occasionally, skin or bone grafting may be necessary. One instance of large ACC associated with exposed neurologic structures showed surgical success with an acellular dermal matrix–skin graft construct to promote regeneration of soft and bony tissue.[79] Successful use of a synthetic dermal substitute to manage full-thickness scalp ACC without the need for grafting has been described.[80]

Patients with large full-thickness scalp defects may face a treatment dilemma—namely, conservative vs surgical therapy. Complete osseous regeneration of a large skull defect associated with ACC has been obtained with a conservative approach consisting of skin care and topical antibiotics. No surgical treatment of bone or soft-tissue reconstruction was necessary. On the other hand, ACC of the scalp may be complicated by sagittal sinus hemorrhage or thrombosis, and primary closure with scalp flaps may prevent a potentially fatal outcome.

Truncal and limb defects, despite their large size, usually epithelialize and form atrophic scars, which can later be revised if necessary.

Patients should be evaluated for evidence of epidermolysis bullosa (EB) before a surgical endeavor is undertaken.

Consultations

Genetic counseling should be considered if associated anomalies are noted. Consultations based on other findings are appropriate to evaluate these conditions.

What is aplasia cutis congenita (ACC)?How is aplasia cutis congenita (ACC) classified?What are group 1 aplasia cutis congenita (ACC) malformations?What are group 2 aplasia cutis congenita (ACC) malformations?What are group 3 aplasia cutis congenita (ACC) malformations?What are group 4 aplasia cutis congenita (ACC) malformations?What are group 5 aplasia cutis congenita (ACC) malformations?What are group 6 aplasia cutis congenita (ACC) malformations?What are group 7 aplasia cutis congenita (ACC) malformations?What are group 8 aplasia cutis congenita (ACC) malformations?What are group 9 aplasia cutis congenita (ACC) malformations?What is the pathophysiology of aplasia cutis congenita (ACC)?What causes aplasia cutis congenita (ACC)?What is the prevalence of aplasia cutis congenita (ACC)?What are the racial predilections of aplasia cutis congenita (ACC)?What are the sexual predilections of aplasia cutis congenita (ACC)?At what age does aplasia cutis congenita (ACC) present?What is the prognosis of aplasia cutis congenita (ACC)?When is genetic counseling indicated for families of patients with aplasia cutis congenita (ACC)?What is the focus of the clinical history for suspected aplasia cutis congenita (ACC)?Which physical findings are characteristic of aplasia cutis congenita (ACC)?Which physical findings are characteristic of a bullous variant of aplasia cutis congenita (ACC)?What are the possible complications of aplasia cutis congenita (ACC)?Which conditions should be included in the differential diagnoses of aplasia cutis congenita (ACC)?What are the differential diagnoses for Aplasia Cutis Congenita?What is the role of lab testing in the workup of aplasia cutis congenita (ACC)?What is the role of imaging studies in the workup of aplasia cutis congenita (ACC)?Which histologic findings are characteristic of aplasia cutis congenita (ACC)?How is aplasia cutis congenita (ACC) treated?What is the role of surgery in the treatment of aplasia cutis congenita (ACC)?Which specialist consultations are beneficial to patients with aplasia cutis congenita (ACC)?

Author

Chris G Adigun, MD, FAAD, Director and Physician, Dermatology and Laser Center of Chapel Hill; Senior Medical Advisor, Klara

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Sciton; OrthoDermatologics; Lumenis; PhotonMD; Galderma<br/>Received income in an amount equal to or greater than $250 from: Sciton.

Coauthor(s)

Megan E Freeze, MD Candidate, The Brody School of Medicine at East Carolina University

Disclosure: Nothing to disclose.

Specialty Editors

Michael J Wells, MD, FAAD, Dermatologic/Mohs Surgeon, The Surgery Center at Plano Dermatology

Disclosure: Nothing to disclose.

Van Perry, MD, Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

Joy Wan, MD, MSCE, Assistant Professor, Johns Hopkins University School of Medicine

Disclosure: Received research grant from: Pfizer .

Acknowledgements

Mark A Crowe, MD Assistant Clinical Instructor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine

Mark A Crowe, MD is a member of the following medical societies: American Academy of Dermatology and North American Clinical Dermatologic Society

Disclosure: Nothing to disclose.

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Aplasia cutis congenita on the scalp (most common location) shortly after birth.

Triplet areas of aplasia cutis congenita are common in infants with trisomy 13.

Extensive aplasia cutis congenita on the scalp, extending down to the skull.

This area of healed aplasia cutis congenita is located in an area of nevus flammeus. Note the collarette of coarser hair at the margin of the defect.

Bilateral involvement of the lower extremities in aplasia cutis congenita associated with fetus papyraceous.

Aplasia cutis congenita on the scalp (most common location) shortly after birth.

Triplet areas of aplasia cutis congenita are common in infants with trisomy 13.

This area of healed aplasia cutis congenita is located in an area of nevus flammeus. Note the collarette of coarser hair at the margin of the defect.

Extensive aplasia cutis congenita on the scalp, extending down to the skull.

Bilateral involvement of the lower extremities in aplasia cutis congenita associated with fetus papyraceous.