Birt-Hogg-Dube syndrome is an autosomal dominant inherited disorder based on mutations in the FLCN gene. Patients suffer from multiple skin lesions, lung cysts, and renal tumors. Treatment is limited to symptomatic resection and, if necessary, follow-up of the tumors.
What is Birt-Hogg-Dube syndrome?
Hereditary diseases are conditions caused by mutation(s) in one or more genes that shape genetic dispositions. Some hereditary diseases occur not only in certain hereditary courses, but also spontaneously. Birt-Hogg-Dube syndrome falls into the group of hereditary diseases. The disease is also known as Hornstein-Knickenberg syndrome or fibrofolliculoma with trichodiscomas and acrochordons. The condition is named after its three first describers, Canadian physicians Birt, Dogg, and Dube. It is estimated that the prevalence of Birt-Hogg-Dube syndrome is one to nine cases per 1,000,000 people. In addition to skin lesions, disease symptoms include renal tumors and lung cysts. Usually, the age of manifestation is in adulthood. Although the disease was first described in 1977 and only 100 to 400 family cases have been reported since then, the causes of Birt-Hogg-Dube syndrome are now relatively well understood.
Causes
An autosomal dominant mode of inheritance is observed for BHD. Familial clustering has been documented in more than 100 families. Individual families showed different variants of the syndrome. This observation justifies the suspicion of a family-inherited clinical picture. Various mutations can be considered as genetic causes of BHD. For example, some researchers consider mutations in the FLCN gene at gene locus 17p11.2 to be a possible major cause. This gene encodes folliculin within the DNA. The function of this substance is not yet known. However, speculation suggests that the largely unexplored protein represents part of the mTOR or mammalian target-of-rapamycin signaling chain. In addition to folliculin, other proteins may also be relevant to the syndrome in a relationship to any hamartoma syndromes. However, at least for the development of the symptomatic renal tumors and associated changes, mutations in the 17p11.2 gene locus seem to make sense.
Symptoms, complaints, and signs
Patients with Birt-Hogg-Dube syndrome have skin lesions, lung cysts, and renal tumors. The renal tumors may correspond to benign oncocytomas, malignant chromophobe, and clear cell and papillary renal cell carcinomas. Mixed renal tumors may also be considered as part of the symptomatology. Fibrofolliculomas with circumscribed proliferation of fibroblasts occur on the skin. Accumulations of collagen are observed around the hair follicle. In some cases, basaloid cells extend into the surrounding fibromucinous stroma. Skin lesions such as trichdiscome or acrochordons may also be characteristic. In most cases, the dermatologic symptoms of the syndrome first appear between the third and fourth decades of life and later persist permanently. Often, the renal tumors form later than the skin lesions. The patients’ pulmonary cysts have cystic dilatations of the alveolar spaces and may correspond to microscopic foci as well as assume diameters of several millimeters. The cysts appear thin-walled and are endowed with epithelium. Inhalation pressure can rupture them and cause pneumothorax.
Diagnosis and course
The diagnosis of Birt-Hogg-Dube syndrome is based on the clinically typical manifestation and the findings on histology. A family history may also provide initial clues to the syndrome. A molecular genetic mutation detection in the FLCN gene can confirm the diagnosis and exclude differential diagnoses such as multiple papules. As part of the diagnostic process, a more detailed determination of multiple lesions is performed. Those of epithelial origin are differentiated from changes of mesodermal and mixed origin. The prognosis for patients with Birt-Hogg-Dube syndrome depends primarily on the severity of expression. Involvement of internal organs is prognostically crucial, as is the type of renal tumor.
Complications
Patients with Birt-Hogg-Dube syndrome suffer from renal tumors, lung cysts, and multiple skin lesions. The renal tumors can be benign or malignant.Papillary renal cell carcinoma confined to the mucosa and mixed forms are also possible. Dermatologic symptoms occur in the form of rashes of varying severity. Lung cysts are microscopic to several millimeters in size. They are thin-walled and have a surface-covering cell layer. Due to the pressure that occurs in the lungs during breathing, the cysts can rupture and cause an accumulation of air between the lungs and chest in the form of a pneumothorax. Although the causes of this hereditary disease are comparatively well understood, it still remains unclear what role the genetic defect plays. Therefore, causal therapeutic approaches are not yet available and treatment is symptomatic. Treatment success and prognosis depend on how far Birt-Hogg-Dube syndrome has progressed. There is no specific dermatological treatment for the rashes. Surgical removal of the affected house sites is possible, but there is a high recurrence rate. Because the renal tumors can also spread to surrounding organs, regular monitoring of potentially malignant changes in these areas must be performed. Lung cysts also increase the risk of developing lung cancer. Removal of tumors in the kidney is possible depending on the extent of the diseased tissue. Life expectancy depends on the extent of renal tumors and involvement of internal organs.
When should you see a doctor?
Birt-Hogg-Dube syndrome is an inherited disorder that usually does not manifest until adulthood. Individuals in whose families Birt-Hogg-Dube syndrome has already occurred should familiarize themselves with the symptoms and course of the disease so that they can recognize the first signs as such and discuss them promptly with a physician. Typical for the disease are skin lesions, especially benign skin tumors such as fibrofolliculomas. To the affected person, these skin lesions often appear like red blisters or pustules, which can also be seen in childhood illnesses or a contact allergy. If the Birt-Hogg-Dube syndrome has already occurred in the family, however, all skin changes, even if they initially appear harmless, should be presented to a doctor immediately. It is essential to inform the physician of the hereditary disease. Prompt consultation of a physician is especially important because the skin lesions usually appear before the other typical symptoms, especially lung cysts and kidney tumors, develop. While skin lesions are usually a primarily cosmetic problem that does not necessarily require immediate medical attention, early detection and treatment of malignant tumors can save the patient’s life.
Treatment and therapy
The causes of Birt-Hogg-Dube syndrome are relatively well understood; however, the role of the defective protein remains rather unclear. No causal therapy is available to patients. Because the syndrome is a genetic defect, advances in gene therapy may provide causal treatment approaches in the coming decades. To date, however, gene therapy has not reached the clinical stage. Therefore, at the present time, patients with BHD are treated more or less symptomatically. The individual therapeutic steps thus depend on the severity of the disease and the symptoms present in each individual case. As a supportive step, affected patients are offered genetic counseling, which may include molecular analysis. The dermatological manifestations of the syndrome are treated depending on the individual case. No specific treatment exists for the skin lesions. In some cases, resection is the treatment of choice. Solitary and perifollicular fibromas, for example, must be treated by invasive procedures. These invasive procedures correspond to surgically removing the lesion as completely as possible. In individual cases, applications such as dermabrasion or electrodesiccation may be considered. In many cases, skin lesions are at high risk of recurrence. Therefore, regular monitoring by the dermatologist is recommended. In addition, patients with the syndrome should be checked regularly for any changes in the lungs, kidneys, and gastrointestinal tract. Removal of any renal tumors that may occur usually does not involve removal of the entire kidney.Because those affected have an increased risk of lung cancer, they are strongly discouraged from smoking.
Outlook and prognosis
Birt-Hogg-Dube syndrome has a poor prognostic outlook. It is a genetic disorder that is not curable with current medical and scientific knowledge. Complicating matters is the fact that, due to legal requirements, interfering with human genetics is not permitted. Nevertheless, without seeking medical care, the prospects for symptom relief worsen further. The patient’s well-being and quality of life decline considerably, as the disease is associated with numerous secondary illnesses. The risk of premature death also increases to a significant degree, as most patients develop cancer. In a medical treatment, the individually occurring symptoms are treated. There is a removal of the formed cysts or tumors. In addition, the organism is supported in time in case of deficiency symptoms. This strengthens the immune system and helps in the physical management of the disease and its sequelae. In regular control examinations, skin changes can be detected and diagnosed at an early stage. The treatment enables the patient to improve his or her living conditions and prolongs the likelihood of life. In addition, the emotional and mental stability of the affected person can be promoted in psychotherapy. There, the patient learns to live with the disease and can thus better cope with the challenges of everyday life.
Prevention
To date, Birt-Hogg-Dube syndrome can only be prevented by genetic counseling during the family planning phase. If appropriate findings are made, couples may decide against having their own children and arrange for adoptions instead.
Follow-up
Because Birt-Hogg-Dube syndrome is a hereditary condition, direct follow-up is not usually possible or necessary. The affected person is thus dependent on medical treatment throughout his or her life in order to avoid further complications. However, since Birt-Hogg-Dube syndrome significantly increases the likelihood of tumors occurring, regular examinations are necessary to prevent the tumors from spreading. Likewise, regular visits to a dermatologist are necessary to relieve skin discomfort. In some cases, the skin complaints can be completely cured, so that further treatment is no longer necessary. However, facial examinations for carcinomas are also necessary. Since patients suffering from Birt-Hogg-Dube syndrome have a significantly increased risk of lung cancer, smoking should be completely avoided. In some cases of Birt-Hogg-Dube syndrome, a visit to a psychologist may also be useful to treat or prevent psychological complaints. The patient’s parents and relatives may also seek psychological treatment, as they also suffer from the disease. Causal treatment is not possible in this syndrome. If the patient wishes to continue having children, genetic counseling should be performed to possibly prevent the recurrence of Birt-Hogg-Dube syndrome.
What you can do yourself
Birt-Hogg-Dube syndrome is a genetic inherited disorder. Affected individuals cannot take self-help measures that are causative. Individuals who have a family history of the syndrome should familiarize themselves with the condition and seek qualified medical attention at the first signs. The disease usually does not manifest itself until adulthood. The first symptoms are skin lesions, which medical laypersons may also mistake for an allergic rash or other harmless skin change. The skin lesions themselves are usually harmless, although they often appear disfiguring. Depending on their severity, they can be removed by a dermatologist or simply concealed with cosmetic products. Patients should respond promptly, however, for other reasons. The skin lesions usually appear before other typical symptoms of the disease develop. Characteristic symptoms include cysts and tumors that predominantly affect the kidneys. These tumors can be malignant. The earlier they are detected and treated, the greater the patient’s chances of recovery.The most important contribution to self-help is for those affected by Birt-Hogg-Dube syndrome to know and observe their own bodies well, so that they can respond promptly to pathological changes.
