Bowen Hutterite syndrome is a rare genetic lethal autosomal recessive disorder characterized by distinctive malformations of the head and facial (craniofacial) area as well as additional skeletal, genital, kidney (renal), and/or brain abnormalities that are apparent at birth (congenital). Characteristic facial features include a prominent, high-bridged nose and an unusually small jaw (micrognathia) and chin. Affected individuals typically have pinky fingers that are curved toward or away from the ring finger (fifth finger clinodactyly) or permanently flexed (camptodactyly), feet with soles that are rounded outward (rocker-bottom feet), and restricted joint movement.
The disorder is characterized by growth delays before birth (intrauterine growth retardation); failure to grow and gain weight at the expected rate (failure to thrive) during infancy; malformations of the head and facial (craniofacial) area, resulting in a distinctive appearance; and other physical abnormalities. These may include restricted joint movements, abnormal deviation (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers, foot deformities, and/or descended testes (cryptorchidism) in affected males. Some affected infants may also have kidney (renal), brain, and/or other malformations. Bowen Hutterite syndrome is inherited as an autosomal recessive trait.
Symptoms
Bowen Hutterite syndrome is primarily characterized by distinctive malformations of the head and facial (craniofacial) area as well as additional skeletal, genital, kidney (renal), and/or brain abnormalities.
In most instances, there are abnormal growth delays before birth (intrauterine growth retardation), resulting in low birth weight. In addition, in some cases, the fetus may be in a breech presentation, meaning that the buttocks or feet (rather than the head) may present first in the birth canal during delivery. A breech presentation may cause difficulties during labor and an increased risk of complications.
In infants with Bowen Hutterite syndrome, characteristic findings include poor suckling ability, associated feeding difficulties, and failure to grow and gain weight at the expected rate (failure to thrive). In addition, most affected infants have a characteristic appearance strongly resembling that of infants with Trisomy 18 syndrome, a chromosomal disorder. (For further information on this disorder, please see the “Related Disorders” section of this report below.) For example, infants with Bowen Hutterite syndrome tend to have a distinctive facial appearance due to certain craniofacial malformations. These may include an abnormally small head (microcephaly) that appears unusually long and narrow (dolichocephaly); a prominent nose; a small, underdeveloped jaw (micrognathia); and a small chin.
Bowen Hutterite syndrome is also typically associated with malformations of the hands and feet. Affected infants may have abnormal deviation (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers; underdeveloped (hypoplastic) nails; and/or a deformity in which the feet appear shaped like the rocker of a rocking chair (“rocker-bottom feet”) with malformation of the ankle bones (vertical tali). Additional musculoskeletal defects may also be present, such as limited movements of certain joints or malformations of bones in the spinal column (vertebrae).
Other features that occur in some affected individuals include seizures; structural abnormalities of the kidneys, heart, brain, or other organs; and an opening in the lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate). Affected males may have the opening of the urethra on the underside of the penis (hypospadias) or undescended testes (cryptorchidism).
Bowen Hutterite syndrome may also be characterized by genital malformations. In affected males, the testes fail to descend into the scrotum (cryptorchidism). In addition, there may be the abnormal placement of the urinary opening (hypospadias), such as on the underside of the penis. Additional malformations may also be associated with the disorder, such as protrusion of portions of the intestine through an abnormal opening in muscles of the groin (inguinal hernia), joining of the two kidneys at the base, creating a “horseshoe”-like shape (horseshoe kidneys), or other renal defects, and/or structural abnormalities of the heart (congenital heart defects). Infants with Bowen Hutterite syndrome may also be susceptible to respiratory infections, such as pneumonia.
A few cases have been reported of infants with the disorder who also have brain malformations, such as the absence of part of the narrow protrusion or lobe between the two hemispheres of the region of the brain known as the cerebellum.
According to reports in the medical literature, individuals with Bowen-Hutterite syndrome may develop life-threatening complications within the first months or years of life.
Causes
Bowen Hutterite syndrome is transmitted as an autosomal recessive trait. Human traits, including classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
Bowen-Conradi syndrome is caused by a mutation in the EMG1 gene. This gene provides instructions for making a protein that is involved in the production of cellular structures called ribosomes, which process the cell’s genetic instructions to create new proteins. Ribosomes are assembled in a cell compartment called the nucleolus.
The particular EMG1 gene mutation known to cause Bowen-Conradi syndrome is thought to make the protein unstable, resulting in a decrease in the amount of EMG1 protein that is available in the nucleolus. A shortage of this protein in the nucleolus would impair ribosome production, which may reduce cell growth and division (proliferation); however, it is unknown how EMG1 gene mutations lead to the particular signs and symptoms of Bowen-Conradi syndrome.
In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier of the disease but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers of a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal. The risk is the same for each pregnancy.
The parents of most individuals with Bowen Hutterite syndrome have been closely related by blood (consanguineous). In recessive disorders, if both parents carry the same gene for the same disease trait, there is an increased risk that their children may inherit the two genes necessary for the development of the disease.
Topical chemotherapy involves the application of creams applied directly to the lesion. Two common topical medications used to treat Bowen disease are 5-fluorouracil and imiquimod 5%. These treatments may be used alone or in conjunction with other therapies. 5-fluorouracil works by destroying abnormal skin cells. Generally, affected individuals apply the cream once or twice daily for at least two weeks if not much longer.
Imiquimod 5% is generally used for lesions on the lower legs, larger lesions, and the erythroplasia of the Queyrat variant of Bowen disease. The nonconventional therapies such as a combination of oral cyclooxygenase enzyme inhibitor and topical imiquimod, topical tazarotene, topical diclofenac, topical paricalcitol, phenol peel, topical and intralesional bleomycin, oral acitretin, oral isoretinoin with subcutaneous interferon-alpha and ultrasonic surgical aspiration have been useful.[rx,rx]
Topical chemotherapy For Skin Conditions
Imiquimod
This immune response modifier has antitumor activity by stimulating the local production of cytokines.[rx] Imiquimod is a good treatment option for BD lesions of difficult-to-treat areas like the lower leg, shaft, glans penis, and large facial lesions. The clinical efficacy varies between 57% and 86% after 6 weeks in various trials. Imiquimod has been reported to be used in conjunction with 5-fluorouracil and sulindac in immunosuppressed individuals.[rx] Sotiriou et al.[rx] treated a large BD measuring 100 cm2 with a single session of MAL-PDT along with daily topical imiquimod for 6 weeks. The associated inflammatory reaction, erythema, and pigmentation are the commonly reported adverse effects. It has limited efficacy in hyperkeratotic BD.[rx,rx] In a study, 38% (6/16) of the patients discontinued the imiquimod used earlier due to its side effects.[rx]
Fluorouracil
This topical cytotoxic agent is used in the treatment of BD on the skin, and shaft of the penis as a once or twice daily application for 3–4 weeks, to be repeated if needed.[rx,rx] Clinical evidence showed a complete clinical response in 48% to 83% of individuals with daily use for 3–4 weeks.[rx] The efficacy of 5-FU can be increased by application under occlusion, pretreatment with laser, iontophoresis, and with the use of dinitrochlorobenzene as a vehicle.[rx] The pain, erythema, burning sensation, and ulceration at the applied site are the common adverse effects associated with its use.[rx]
Light-based procedures
Photodynamic Therapy
Photodynamic therapy (PDT) for BD involves topical application of Methyl Amino-levulinate (MAL) under occlusion for three hours followed by illumination using red light from a narrowband light-emitting diode source. It is repeated once after 7 days and again 3 months later if needed. The use of fluorescence helps in lesion delineation and recurrence detection with 100% sensitivity and 85% specificity.[rx] It is of immense benefit in large lesions (>3 cm2), leg BD, and in difficult-to-treat sites. Topical PDT is noninvasive, tissue sparing, highly efficacious, and a good esthetic therapeutic modality.[rx,rx] There are case reports of successful treatment of BD with PDT in the setting of radiodermatitis and epidermolysis bullosa.[rx]
Radiotherapy
The various radiotherapy techniques used in the treatment of BD are external beam radiotherapy, radioactive skin patch, and Grenz rays.[rx] In BD, both high and low-dose regimens of radiotherapy are equally efficacious in the treatment.[rx] The advantages of this technique include utilization in difficult-to-treat areas such as the scalp, penile, and perianal BD. The disadvantages include high cost, patient inconvenience, and poor wound healing in the legs.[rx,rx,rx]
Lasers
LASERS are considered for genital and nail lesions.[rx] In a large retrospective study, 44 BD patients were treated with CO2 laser achieving clearance in 86% of patients after one treatment.[rx] Because CO2 laser spares the deeper follicular epithelium, chances of recurrence and treatment failure are high. To overcome this, a diode laser can be used as a final pass following the three passes of the CO2 laser.[rx]
Surgical modalities
Excision
Simple wide excision of the lesion and primary closure is an acceptable method of treating BD of small size, single lesion, and perianal BD. It is helpful by histopathologically ruling out the invasive disease.[rx, RX,rx] The BD is excised with a minimum of 4 mm margin in well-defined tumors of <2 cm in diameter and at least 6 mm margin for larger lesions or less-differentiated tumors or lesions in high-risk locations (e.g., scalp, eyelids, ears, nose, and lips).[rx] Excision with a narrow lateral margin may lead to subclinical lateral spread, which is associated with a higher chance of recurrence.[rx] The recurrence rate varies from 2.8% to 19.4% in various studies. The limitations are prolonged wound healing in certain regions and functional and cosmetic outcomes.[rx,rx,rx]
Moh’s Micrographic Surgery
Moh’s micrographic surgery is very effective in difficult-to-treat areas like periorificial, periungual regions and genital lesions where tissue sparing is the main objective.[rx] It is also useful in incompletely excised and recurrent BD. In a retrospective analysis of 270 cases of BD in the head and neck region treated with Moh’s micrographic surgery, 128 cases were previously treated with modalities such as cryotherapy, curettage and cautery, excision, and radiotherapy.[rx] The recurrence after Moh’s surgery is around 6.3%.[rx]
Destructive Modalities
The involvement of pilosebaceous units by atypical epithelium can lead to failure of treatment when superficial destructive modalities are used.[rx]
Curettage With Cautery
It is a simple, cheap, safe, and one of the most effective treatment modalities suitable in single, small BD.[rx,rx] It is preferred in patients who have large hyperkeratotic lesions, are intolerant to cryotherapy, and cannot apply topical agents for a prolonged period.[rx] However, the results depend on the equipment used and the skill of the operator. The cure rate ranges from 81% for curettage and up to 93% to 98% in case of curettage and cautery.[rx,rx]
Cryotherapy
Cryotherapy is a simple, inexpensive, outpatient modality of treatment of BD. It is used as a treatment modality in the case of single, small BD located at well healing sites.[rx] The efficacy of cryotherapy differs depending on the technique and regimens used. It is avoided in poorly vascularized areas and legs where wound healing is prolonged. The failure rate is around 5%–10%.[rx,rx,rx,rx] Gaitanis et al.[rx] successfully treated four cases of BD in renal transplant recipients with cryotherapy and topical imiquimod for 2 weeks with no recurrence.
Superficial Skin Surgery
Superficial skin surgery refers to shave, curettage and electrosurgery, and is an excellent choice for solitary or few hyperkeratotic lesions. The lesion is sliced off or scraped out; then the base is cauterized. Dressings are applied to the open wound to encourage moist wound healing over the next few weeks.
Fluorouracil cream
5-fluorouracil cream contains a cytotoxic agent and can be applied to multiple lesions. The cream may be used for intraepidermal SCC for four weeks and repeated if necessary. It causes a vigorous skin reaction that may ulcerate.
Imiquimod cream
Imiquimod cream is an immune response modifier used off-license to treat intraepidermal SCC. It is applied 3–5 times weekly for 4–16 weeks and causes an inflammatory reaction.
Summary Of Various Treatment Modalities Of Bowen’s Disease
| Drug | Application | Preferred | Limitations and adverse effects | Outcome |
|---|---|---|---|---|
| Imiquimod 5% cream | Once-daily application for 16 weeks | Large lesions, face, lower leg, the shaft of penis, glans penis | Limited response in hyperkeratotic lesions, erythema, inflammation, crusting, pigmentation | 57%-86% clearance |
| 5-Fluorouracil cream | Once- or twice-daily application for 3-4 weeks, repeated if required | Large lesions, poor healing sites | Cannot be used in immunocompromised patients, pain, erythema, burning sensation, ulceration | 48%-83% clearance |
| Cryotherapy | Freeze of 30 s at least once or 20 s at least twice for one to three sittings | Good healing sites Multiple lesions | Cannot be used in poor wound healing sites, Hypopigmented scarring | 68%-100% clearance 5%-10% failure rate |
| Curettage with cautery | Simple, single-time, safe method | Small/single lesion, facial lesions | Cannot be performed for larger lesions, Success depends on the skills of the operator | 93%-98% cure rate 2%-20% recurrence |
| Excision | Simple, wide excision of the lesion | Small/single lesion with poor healing | Prolonged wound healing, poor functional and cosmetic outcomes | 2.8% to 19.4% recurrence |
| Moh’s micrographic surgery | Individual layers of tissue are removed and examined under a microscope | Tissue sparing sites such as periorificial, genital, and periungual regions | Expensive needs a skilled operator | Recurrence is around 6.3% |
| Photodynamic therapy | Day 0, 7, and repeated after 1 month | For larger lesions and difficult-to-treat areas | Pain | 88%-100% clearance 3 months after one cycle of MAL-PDT |
| Radiotherapy | Both high- and low-dose regimens are equally efficacious | Difficult-to-treat sites such as digits and penis | High-cost, patient inconvenience, poor healing, erythema, edema | Failure to heal in 33% of individuals |
| LASERS | CO2 LASER | Difficult-to-treat sits such as digits and penis | Spares deeper follicular epithelium | Clearance of 86% after one treatment |
Investigational Therapies
Various case reports in the medical literature discuss the use of laser therapy for the treatment of Bowen’s disease. In individual patients, laser therapy has been effective in treating the disorder. However, no clinical trials in large populations have been undertaken. In addition, laser therapy may be expensive and have limited availability. More research is necessary to determine the long-term safety, effectiveness, and viability of laser therapy as a potential treatment for Bowen’s disease.
References
