aplasia cutis congenita

What is aplasia

Aplasia means failure of an organ or tissue to develop or to function normally during embryonic life.

Aplasia cutis congenita

Aplasia cutis congenita is a rare disorder where babies are born with the absence of certain layer(s) of skin, most often on the scalp, but also on the trunk, and/or arms and legs, with or without the absence of underlying structures such as bone 1). The affected area is typically covered with a thin, transparent membrane. The skull and/or underlying areas may be visible and be abnormally developed. Aplasia cutis congenita may be the primary disorder or it may occur in association with other underlying disorders.

Aplasia cutis congenita is a rare congenital condition with an incidence of approximately 1 to 3 out of 10,000 births 2). There is no significant gender or cultural predilection that has been reported in the literature 3). Lesions will typically be noticed at birth, although patients may not present to be evaluated for several months as lesions are often asymptomatic.

While most people with aplasia cutis congenita have no other abnormalities, some people have congenital malformations involving the cardiovascular (heart), gastrointestinal, genitourinary, and central nervous systems 4). The cause of aplasia cutis congenita is unclear and appears to be multifactorial (many different factors appear to play a role); contributing factors may include teratogens, genes, trauma, and compromised blood flow to the skin 5).

Aplasia cutis congenita has been classified into 6 subtypes, some of which are associated with congenital dermatologic syndromes 6). Although most lesions are self-healing, certain locations and clinical characteristics should prompt a more thorough workup to screen for underlying soft tissue anomalies that can potentially be life-threatening 7).

A classification for aplasia cutis congenita was proposed in 1986, which is still accepted today, and presented below 8).

  • Group 1: Scalp aplasia cutis congenita without multiple anomalies
  • Group 2: Scalp aplasia cutis congenita with limb abnormalities
  • Group 3: Scalp aplasia cutis congenita with epidermal and organoid nevi
  • Group 4: Aplasia cutis congenita overlying congenital malformations
  • Group 5: Aplasia cutis congenita with associated fetus papyraceus or placental infarct
  • Group 6: Aplasia cutis congenita with epidermolysis bullosa
  • Group 7: Aplasia cutis congenita localized to extremities without blistering
  • Group 8: Aplasia cutis congenita due to specific teratogens
  • Group 9: Aplasia cutis congenita associated with malformation syndromes

Figure 1. Aplasia cutis congenita

Aplasia cutis congenita

Aplasia cutis congenita cause

There is no one cause for all cases of aplasia cutis congenita 9). Aplasia cutis congenita is thought to be multifactorial, which means that several factors likely interact to cause the condition 10). Factors that may contribute include genetic factors; teratogens (exposures during pregnancy that can harm a developing fetus) such as methimazole, carbimazole, misoprostol, and valproic acid; compromised vasculature to the skin; and trauma 11). Some cases may represent an incomplete or unusual form of a neural tube defect 12). Familial cases of aplasia cutis congenita have been reported 13). Cases that appear to be genetic may be inherited in an autosomal dominant or autosomal recessive manner 14).

Until recently, no specific genetic target had been identified, but a recent study showed BMS1 gene to play a possible role 15). Aplasia cutis congenita can also be associated with several genetic syndromes including Adams-Oliver syndrome, Bart syndrome, and Setleis syndrome as described below 16).

  • Adams-Oliver syndrome: aplasia cutis congenita on the scalp plus skull defect plus Cutis marmorata telangiectatica congenital plus limb defects plus cardiac anomalies 17).
  • Bart syndrome: aplasia cutis congenita of lower extremities plus epidermolysis bullosa 18).
  • Setleis syndrome: Bilateral temporal aplasia cutis congenita plus “leonine” facies 19).

Aplasia cutis congenita signs and symptoms

Individuals born with aplasia cutis congenita lack skin (and therefore hair), in localized areas of the body, usually, but not always, on the scalp (70 percent of cases). In some cases, the trunk, arms, and/or legs may also be involved. Sometimes, the underlying bone may be missing as well as the skin. The affected area(s) are usually replaced with a thin transparent membrane. In some cases, these affected structures and other organs may be seen through the transparent membrane.

Most individuals with aplasia cutis congenita exhibit no other abnormalities. However, in some rare cases, they may experience other physical characteristics including abnormalities of the ears, a form of paralysis (palsy) affecting one side of the face, an abnormally large head (macrocephaly), and/or congenital heart anomalies.

Aplasia cutis congenita may also occur as a physical condition characteristic of several other disorders, including Adams-Oliver syndrome, aplasia cutis congenita-gastrointestinal, and Johanson-Blizzard syndrome.

Aplasia cutis congenita can be associated with underlying morphologic abnormalities in approximately 37% of cases according to Mesrati et al. 20) including underlying bony defects, vascular anomalies, or neurologic malformations, so it is prudent for clinicians to evaluate the disease involvement with imaging. A midline vertex scalp lesion, hair collar sign, and vascular stains have all been shown to be strong indicators for cranial or central nervous system (CNS) involvement 21). Small, scalp lesions are less likely associated with underlying defects and typically heal on their own within a couple of months; therefore, monitoring these lesions without further imaging is acceptable 22). For larger, ulcerative lesions, ultrasound provides a relatively inexpensive evaluation while not putting the child through a great deal of discomfort. If there is any concern for underlying defects on ultrasound, further workup with MRI is warranted. MRI is more sensitive and specific for identifying underlying lesions according to a 2017 retrospective multicenter study 23); however, it is more costly than ultrasound and typically requires the child to be sedated for the duration of the procedure, making this a poor choice for initial screening. If the lesion is purulent or surrounded by erythema, a lab workup including complete blood count, blood cultures and wound cultures would be advised 24).

Aplasia cutis congenita treatment

Treatment of aplasia cutis congenita varies depending on the condition of the infant. Conservative treatment is preferred 25). Small areas (less than 4 cm) without additional findings, usually heal on their own over time 26). Gentle cleansing and application of bland ointments or silver sulfadiazine can help prevent infection. Lesions will typically heal within a few weeks to a few months with an atrophic, hairless scar 27). Larger lesions (greater than 4 cm) are more commonly associated with underlying defects and are at increased risk of complications including hemorrhage, venous thrombosis, and infection 28). Early surgical repair is recommended to avoid these complications. Skin grafting or flap techniques are commonly utilized as some lesions can be several centimeters in size 29). If infection occurs, antibiotics can be used 30). Recently, a variety of specialized dressing materials have been developed and used 31). Ultimately, the decision to use medical, surgical, or both forms of therapy depends primarily on the size, depth, and location of the skin defect 32).

Aplasia cutis congenita prognosis

The long-term outlook (prognosis) for people with aplasia cutis congenita is usually excellent. If the condition is associated with other abnormalities or malformations, the prognosis then depends on the nature and severity of the other condition(s) 33).

Major complications of aplasia cutis congenita are rare, but can include hemorrhage, secondary local infection, meningitis, or sagittal sinus thrombosis. Larger affected areas associated with underlying bony defects can cause death due to central nervous system infection, or hemorrhage from the sagittal sinus. Complications can also result from associated abnormalities or malformations, when present 34).

The estimated mortality rate ranges from 20-55% as a result of serious complications 35). The most common life-threatening complication of aplasia cutis congenita is sagittal sinus bleeding, seen with lesions nearby on the scalp 36). Another potential complication of aplasia cutis congenita includes secondary infection of the lesion. Patients are at an increased risk of cutaneous infections given the fact that the skin’s barrier against environmental microbes is absent or impaired. Severe infections can progress to meningitis if not treated appropriately 37). Prompt management of large scalp lesions, commonly with surgery, can help prevent these complications 38).

Pure red cell aplasia

Pure red cell aplasia is an uncommon disorder in which maturation arrest occurs in the formation of red blood cells resulting in the bone marrow making a reduced number of red blood cells (called anemia). As a result, affected people may experience fatigue, lethargy, and pale skin 39). Erythroblasts are virtually absent in bone marrow; however, white blood cell and platelet production are normal 40). The anemia due to pure red cell aplasia is usually normocytic but can be macrocytic. In 1922, Kaznelson recognized that this condition was a different entity from aplastic anemia, which presents as pancytopenia.

The characteristics of pure red cell aplasia include the following:

  • Severe anemia
  • Reticulocyte count <1%
  • The presence of less than 0.5% mature erythroblasts in the bone marrow
  • Normocellular bone marrow in most cases

The cause of pure red cell aplasia is heterogeneous. A rare congenital form of pure red cell aplasia was initially described by Joseph in 1936 and by Diamond and Blackfan in 1938 called Diamond Blackfan syndrome, is an inherited condition that is also associated with other physical abnormalities 41). Congenital pure red cell aplasia is a lifelong disorder and is associated with physical abnormalities.

Pure red cell aplasia can be transient and reversible. Transient erythroblastopenia of childhood can occur after viral infections. Pure red cell aplasia can also be due to medications, infections, pregnancy, renal failure, and conditions such as thymomas, autoimmune disease (such as systemic lupus erythematosus), cancers of the blood, and solid tumors. In many cases, the cause of the condition is unknown (idiopathic) 42). In adults, most cases of chronic pure red cell aplasia are idiopathic.

Secondary pure red cell aplasia occurs in patients with conditions such as the following:

  • Autoimmune disorders
  • Thymomas
  • Systemic lupus erythematosus
  • Hematologic malignancies
  • Solid tumors

Pure red cell aplasia is an uncommon disorder. The idiopathic form is the most common type of pure red cell aplasia. The incidence of transient and reversible pure red cell aplasia that occurs in childhood and in adults secondary to medications and infections is probably underestimated. The reason for this underestimation is the anemia is self-limiting. Acquired secondary pure red cell aplasia is not common. Diamond-Blackfan syndrome is rare.

No racial, age, or sex predilection is reported in pure red cell aplasia. However, females are more likely to have autoimmune disorders.

Therapeutic approaches include the following:

  • Transfusions for severe anemia with cardiorespiratory failure
  • Discontinuation of medications that could cause Pure red cell aplasia
  • Observation of children with pure red cell aplasia, with treatment if indicated
  • Treatment of infections
  • Treatment of underlying conditions
  • Corticosteroids and immunosuppressive agents
  • Plasmapheresis or lymphocytapheresis

The life expectancy of patients with idiopathic pure red cell aplasia is about 1-2 decades 43). The survival of patients with congenital pure red cell aplasia is limited. The lifespan of patients with secondary pure red cell aplasia depends on the course of the underlying disorder.

Pure red cell aplasia pathophysiology

In general, pure red cell aplasia is due to a selective injury, often immunological, that affects the early phase of erythrocyte maturation.

Childhood

Diamond-Blackfan syndrome is a rare congenital pure red cell aplasia that is usually detected at birth, or later during the first 18 months of childhood. Affected individuals usually have a macrocytic anemia. The expression of hemoglobin F and surface “I” antigen in erythrocytes is increased, indicating erythrocyte immaturity.

About one third of these patients have developmental defects, including cleft palates, macroglossia, craniofacial defects, thumb or upper limb abnormalities, cardiac defects, and urogenital malformations. Growth is often retarded 44). A modest increased risk for leukemia and neoplasms is noted.

Diamond-Blackfan syndrome is caused by the deletion of genes for ribosomal protein RPS19 in 25% of patients, leading to defects in ribosome biogenesis. This ribosomopathy and haploinsufficiency may be responsible for impaired mRNA translation and the activation of the tumor suppressor gene TP53 in this disorder 45).

Germ-line mutations in genes encoding components of both the small (RPS24, RPS17, RPS7, RPS10, and RPS26) and large (RPL35A, RPL5, RPL11, and RPL26) ribosomal subunits have also been described in Diamond-Blackfan anemia patients 46). Mutations in the GATA1 gene has been found to cause Diamond-Blackfan anemia in a minority of patients 47). Because GATA1 has been implicated in Diamond-Blackfan anemia, it is possible that non-RP genes may also lead to the characteristic erythroid hypoplasia 48).

De novo cases of Diamond-Blackfan syndrome are believed to be caused by intrauterine damage to early erythroid stem cells 49). A familial history of pure red cell aplasia is evident in approximately 10% of patients.

Transient erythroblastopenia of childhood is a self–limiting, benign disorder. A history of a recent viral infection is usually noted 50). Parvovirus 19 infection should be ruled out.

Adults

Acquired primary (idiopathic) pure red cell aplasia is the most common form of red cell aplasia in adults.

However, pure red cell aplasia can be secondary to underlying disorders. For example, autoimmune disorders (eg, type 1 diabetes, thyroiditis, rheumatoid arthritis, Sjögren syndrome) can be responsible. pure red cell aplasia has been shown to be secondary to T-cell inhibition of marrow erythroid cells. pure red cell aplasia can also be secondary to and is associated with the following:

  • Thymoma (1-15%)
  • Hematological malignancies (eg, B- and T-cell chronic lymphocytic leukemia)
  • T-cell large granular lymphocyte leukemia and solid tumors
  • Infections
  • Drugs
  • Pregnancy 51)
  • Systemic lupus erythematosus (SLE)
  • Renal failure
  • Good syndrome (thymoma with combined B- and T-cell deficiency)

Pure red cell aplasia can occur following ABO-mismatched marrow transplantation 52).

The incidence of pure red cell aplasia has increased in patients with chronic renal disease who have received epoetin therapy. This has been ascribed to the generation of antiepoetin antibodies, which occurs more often with epoetin-alpha than with epoetin-beta. This complication may be avoided by using an erythropoietin-mimicking human antibody, which stimulates erythropoiesis but does not appear to induce antiepoetin antibodies and pure red cell aplasia 53).

Pure red cell aplasia causes

Infections such as the following can cause pure red cell aplasia 54):

  • HIV infection
  • Respiratory tract infections
  • Gastroenteritis
  • Primary atypical pneumonia
  • Infectious mononucleosis
  • Mumps
  • Viral hepatitis

Most cases of acute transient pure red cell aplasia are caused by parvovirus B19 infection 55). Parvovirus B19 can cross the placenta in infected women and can destroy erythroid cells in the fetus and induce spontaneous abortions. Parvovirus 19 infections can persist longer in immunocompromised patients.

A partial list of medications thought to cause pure red cell aplasia is as follows 56):

  • Antiepileptic medications (eg, phenytoin, carbamazepine, sodium valproate)
  • Mycophenolate
  • Azathioprine
  • Chloramphenicol
  • Thiamphenicol
  • Sulfonamides
  • Isoniazid
  • Procainamide
  • Clopidogrel 57)

Originally, thymoma was cited as the primary cause of acquired pure red cell aplasia. However, subsequent studies have revealed that only a small percent of all cases of pure red cell aplasia result from thymomas. Conversely, only 7% of patients with thymomas had pure red cell aplasia.

Pure red cell aplasia signs and symptoms

Presenting symptoms depend on the severity of the anemia. Some patients are virtually asymptomatic, whereas others have an uncompensated anemia, have cardiopulmonary distress, and are transfusion dependent 58).

Patients with aplastic anemia, as opposed to pure red cell aplasia, may have a history of bruising due to thrombocytopenia 59).

Obtaining the history of medications that patients are taking is important. A history of recent infections, such as infectious mononucleosis or viral hepatitis, is important.

Patients who have an underlying hemolytic anemia can become markedly anemic if they develop pure red cell aplasia. This is known as an aplastic crises and is caused by hemolysis that is ongoing while erythrocyte production is impaired. The possibility of an aplastic crisis should be considered in patients with a hemolytic anemia if reticulocyte counts are low and if they have had recent infections. In contrast, the development of anemia in pure red cell aplasia in patients without hemolysis is often gradual and self-limited and, hence, not noticed.

To determine whether the patient has a secondary pure red cell aplasia, ask about the possibility of pregnancy, signs of systemic lupus erythematosus (SLE), signs of a hematological malignancy, and signs of other possible disorders that can cause pure red cell aplasia. A history of miscarriages might suggest SLE.

A history of autoimmune disorders such as type 1 diabetes, thyroiditis, and rheumatoid arthritis should be elicited. Dryness of eyes and mouth occurs in Sjögren syndrome.

Recognize that chronic renal failure and erythropoietin therapy, AB0-incompatible transfusion, and stem cell transplantation are associated with pure red cell aplasia.

Diamond-Blackfan syndrome should be considered in a child with pure red cell aplasia, retarded growth, and developmental defects.

Pure red cell aplasia diagnosis

The classical presentation of pure red cell aplasia is with a normocytic anemia and a reticulocyte count of less than 1%. Bone marrow studies reveal a normocellular marrow with an absence of erythroblasts. Maturation arrest is evidenced by the presence of more immature erythrocyte progenitors.

When the results of those laboratory studies are not consistent with classical pure red cell aplasia, a workup to identify other anemias should be done. If macrocytosis or microcytosis is evident, appropriate diagnostic tests should be indicated. Examination of peripheral smears and bone marrow is important.

Laboratory Studies

The following blood tests should be obtained in suspected pure red cell aplasia:

  • Complete blood cell count (CBC) count
  • Red blood cell (RBC) indices
  • Reticulocyte count
  • White blood cell (WBC) differential analysis of white blood cells

Other studies to consider include the following:

  • Iron studies, especially iron saturation and serum ferritin levels, are used to diagnose hemosiderosis; this possibility should be considered in patients who have received multiple transfusions.
  • Serum vitamin B-12 and folate levels might be indicated in patients with macrocytosis.
  • Lactate dehydrogenase (LDH), indirect bilirubin, and serum haptoglobin levels are used to detect hemolysis.
  • Hemoglobin A 2 and hemoglobin F are used to rule out thalassemia.
  • Flow cytometry is used to diagnose hematological malignancies and T-cell disorders.

Tests to identify infection, including the following, are indicated:

  • Parvovirus B19 infection 60)
  • Hepatitis
  • Infectious mononucleosis

Tests to detect autoimmune disorders should include the following:

  • Antinuclear antibody test
  • C-reactive protein (CRP) level
  • Erythrocyte sedimentation rate (ESR)
  • Quantitative immunoglobulin analysis
  • Direct Coombs test to detect an autoimmune hemolytic anemia
  • Tests for thyroiditis, diabetes mellitus, rheumatoid arthritis, Sjögren syndrome, and systemic lupus erythematosus (SLE) might be indicated.

In addition, the following tests are helpful in diagnosing Diamond-Blackfan syndrome:

  • Hemoglobin F assay
  • “I” antigen on the surface of erythrocytes
  • Adenosine deaminase determination

Peripheral smears demonstrate a normocytic anemia in most cases of pure red cell aplasia. However, macrocytic anemia occurs in Diamond-Blackfan and Good syndromes and in HIV infections. Peripheral smears can be used to screen for infectious mononucleosis, megaloblastosis, and hematological malignancies.

Bone marrow histology

Bone marrow aspiration smears in pure red cell aplasia usually reveal a normocellular marrow. An absence of erythroblasts is noted, whereas more immature erythrocyte progenitors are present (maturation arrest). White blood cells and platelet maturation are normal. Bone marrow can be used to evaluate iron stores and help diagnose megaloblastosis and hematological malignancies.

Imaging studies

Uses of imaging studies include the following:

  • Positron emission tomography (PET) and computed tomography (CT) scans are used to detect thymomas.
  • Spleen size can be determined by ultrasound imaging.
  • Appropriate imaging studies are used to help diagnose and evaluate hematological malignancies.
  • Duel-energy x-ray absorptiometry scans are used to assess osteopenia and osteoporosis due to corticosteroid therapy.

Pure red cell aplasia treatment

The initial treatment plan should include blood transfusions for patients who are severely anemic and have cardiorespiratory failure. Anemia is more severe in patients with pure red cell aplasia who have ongoing hemolysis (aplastic crises).

Medications that could cause pure red cell aplasia should be discontinued.

Children with pure red cell aplasia should be observed and not aggressively treated to avoid corticosteroid-related growth retardation. This caution is feasible since pure red cell aplasia in children is often transient and reversible. However, transfusion should be administered if indicated.

Infections should be treated. High-dose intravenous immunoglobin therapy should be considered for parvovirus B19 infections 61). Pure red cell aplasia due to medication or infections is usually reversible within a few months, if not earlier. However, immunotherapy may be needed to reverse erythropoiesis-stimulating agent (ESA)–related pure red cell aplasia.

Underlying conditions should be treated. These conditions include a thymoma, hematological malignancies such as T-cell large granular lymphocyte leukemia 62), solid tumors, and systemic lupus erythematosus (SLE). Surgery or gamma irradiation of the thymus should be considered in a patient with a thymoma.

pure red cell aplasia considered to be idiopathic and due to autoimmunity should be initially treated with corticosteroids 63). A response is expected within 4-6 weeks in about 45% of patients. Corticosteroids should be judiciously given to children to avoid growth retardation. Immunosuppressive agents have an important role. Immunosuppressive agents used in pure red cell aplasia include cyclophosphamide, 6-mercaptopurine, azathioprine, and cyclosporine A. Rituximab has been reported to be effective in managing pure red cell aplasia 64). Antithymic globulin (ATG) is another therapeutic option. Danazol has been helpful in some cases but is contraindicated in children. Plasmapheresis has been used to remove autoantibodies.

Autologous and nonmyeloablative allogeneic peripheral stem cell transplantation have been used, especially in patients whose disease is refractory to therapy 65).

Several patients have responded to plasmapheresis or lymphocytapheresis 66).

Iron chelation should be considered in patients who have had multiple transfusions and have evidence of iron overload.

Surgical care

Thymectomy might be indicated in patients with a thymoma. However, the procedure should not be performed in patients with a normal-sized thymus. About 30% of patients with thymomas respond to thymectomy.

Although not effective in most cases, splenectomy might be helpful in refractory cases. Splenectomy is indicated to manage pure red cell aplasia complicated by hypersplenism.

Pure red cell aplasia prognosis

Prognosis varies among the different types of pure red cell aplasia.

Transient erythroblastopenia and other pure red cell aplasia disorders in children and adults are benign with an excellent prognosis.

The prognosis of secondary pure red cell aplasia depends on the course of the underlying condition, such as a thymoma or a hematological malignancy. About 30% of pure red cell aplasia cases due to thymomas are reversed by thymectomy.

Most cases of pure red cell aplasia are idiopathic. About 68% respond to intervention. However, relapses are common. The lifespan of these patients is about 1-2 decades.

Most patients with Diamond-Blackfan syndrome respond to corticosteroid therapy but are prone to relapses. Estimating the lifespan of patients with this disorder is difficult because it is rare.

Prognosis is also influenced by the complications of therapy. Hemosiderosis can develop in multitransfused patients. Corticosteroid therapy can lead to osteopenia and osteoporosis and infections. Pure red cell aplasia can evolve into aplastic anemia and acute myelogenous leukemia, which have high morbidity and mortality rates. Infections acquired during blood product transfusions can also affect prognosis.

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