Birt-Hogg-Dubé Syndrome patients, families, and caregivers are encouraged to join the NIH Rare Lung Diseases Consortium Contact Registry. This is a privacy protected site that provides up-to-date information for individuals interested in the latest scientific news, trials, and treatments related to rare lung diseases.

The disorder has been reported in more than 100 families worldwide, though some sources cite up to 400 families, and it is inherited in an autosomal dominant pattern. It is considered to be under-diagnosed because of the variability in its expression. The pattern of mutations and spectrum of symptoms are heterogeneous between individuals. Less severe skin phenotypes are seen in women and people of both sexes who have a late onset of skin symptoms.

Based on a survey of >800, surgical removal of the entire involved kidney plus the peri-renal fat appeared curative for the majority of all types of mesoblastic nephroma; the patient overall survival rate was 94%. Of the 4% of non-survivors, half were due to surgical or chemotherapeutic treatments. Another 4% of these patients suffered relapses, primarily in the local area of surgery rare cases of relapse due to lung or bone metastasis.. About 60% of these recurrent cases had a complete remission following further treatment. Recurrent disease was treated with a second surgery, radiation, and/or chemotherapy that often vincristine and actinomycin treatment. Removal of the entire afflicted kidney plus the peri-renal fat appears critical to avoiding local recurrences. In general, patients who were older than 3 months of age at diagnosis or had the cellular form of the disease, stage III disease, or involvement of renal lymph nodes had a higher recurrence rate. Among patients with these risk factors, only those with lymph node involvement are recommended for further therapy.

It has been suggested that mesoblastic nephroma patients with lymph node involvement or recurrent disease might benefit by adding the ALK inhibitor, crizotinib, or a tyrosine kinase inhibitor, either larotrectinib or entrectinib, to surgical, radiation, and/or chemotherapy treatment regimens. These drugs inhibit NTRK3's tyrosine kinase activity. Crizotinib has proven useful in treating certain cases of acute lymphoblastic leukemia that are associated with the "ETV6-NTRK3" fusion gene while larotrectinib and entrectinib have been useful in treating various cancers (e.g. a metastatic sarcoma, papillary thyroid cancer, non-small-cell lung carcinoma, gastrointestinal stromal tumor, mammary analog secretory carcinoma, and colorectal cancer) that are driven by mutated, overly active tyrosine kinases. Relevant to this issue, a 16-month-old girl with infantile fibrosarcoma harboring the "ETV6–NTRK3" fusion gene was successfully trated with larotrectinib. The success of these drugs, howwever, will likely depend on the relative malignancy-promoting roles of ETV6-NTRK3 protein's tyrosine kinase activity, the lose of ETV6-related transcription activity accompanying formation of ETV6-NTRK3 protein, and the various trisomy chromosomes that populate mesoblastic nephroma.

Basal-cell cancer is a very common skin cancer. It is much more common in fair-skinned individuals with a family history of basal-cell cancer and increases in incidence closer to the equator or at higher altitude. There are approximately 800,000 new cases yearly in the United States alone. Up to 30% of Caucasians develop basal-cell carcinomas in their lifetime. In Canada, the most common skin cancer is basal cell carcinoma (as much as one third of all cancer diagnoses), affecting 1 in 7 individuals over a lifetime.

In the United States approximately 3 out of 10 caucasians develop a basal cell carcinoma during their lifetime. This tumor accounts for approximately 70% of non-melanoma skin cancers. In 80 percent of all cases, basal cell carcinoma affects the skin of head and neck. Furthermore, there appears to be an increase in the incidence of basal-cell cancer of the trunk in recent years.

Most sporadic BCC arises in small numbers on sun-exposed skin of people over age 50, although younger people may also be affected. The development of multiple basal-cell cancer at an early age could be indicative of nevoid basal-cell carcinoma syndrome, also known as Gorlin's Syndrome.

Basal-cell carcinoma is a common skin cancer and occurs mainly in fair-skinned patients with a family history of this cancer. Sunlight is a factor in about two-thirds of these cancers; therefore, doctors recommend sunscreens with at least SPF 30. One-third occur in non-sun-exposed areas; thus, the pathogenesis is more complex than UV exposure as "the" cause.

The use of a chemotherapeutic agent such as 5-Fluorouracil or imiquimod, can prevent development of skin cancer. It is usually recommended to individuals with extensive sun damage, history of multiple skin cancers, or rudimentary forms of cancer (i.e., solar keratosis). It is often repeated every 2 to 3 years to further decrease the risk of skin cancer.

Congenital mesoblastic nephroma, while rare, is the most common kidney neoplasm diagnosed in the first three months of life and accounts for 3-5% of all childhood renal neoplasms. This neoplasm is generally non-aggressive and amenable to surgical removal. However, a readily identifiable subset of these kidney tumors has a more malignant potential and is capable of causing life-threatening metastases. Congenital mesoblastic nephroma was first named as such in 1967 but was recognized decades before this as fetal renal hamartoma or leiomyomatous renal hamartoma.

The clinical spectrum of the condition is broad. In other words, people with NF II may develop a wide range of distinct problems.

1. Acoustic nerve: 90% of the patients show bilateral acoustic schwannomas on magnetic resonance imaging (MRI).

2. Other cranial nerves and meninges: About 50% of patients develop tumours in other cranial nerves or meningiomas.

3. Spinal cord: About 50% of the patients develop spinal lesions. Only 40% of the spinal lesions are symptomatic. The spinal tumours in NF II are separated in two groups. Intramedullary lesions are located within the spinal tissue and usually belong to the so-called spinal astrocytomas or ependymomas. The extramedullary lesions are located within the small space between the surface of the spinal cord and the bony wall of the spinal canal. These tumours belong to the schwannomas and meningiomas.

4. Skin: If children show neurofibromas, a diagnostic procedure should be performed to decide which form of neurofibromatosis causes the alterations.

5. Eyes: Studies on patients with NF II show that more than 90% of the affected persons suffer eye lesions. The most common alteration in NF II is the juvenile subcapsular cataract (opacity of the lens) in young people.

"Presenting symptoms" (initial concern that brings a patient to a doctor) of a lesion of the nervus vestibulocochlearis due to a tumour in the region of the cerebello-pontine angle are the following: hearing loss (98%), tinnitus (70%), dysequilibrium (67%), headache (32%), facial numbness and weakness (29% and 10% respectively).

"Clinical signs" (alterations that are not regarded by the patient and that can be detected by the doctor in a clinical examination) of the lesion in discussion are: abnormal corneal reflex (33%), nystagmus (26%), facial hypesthesia (26%).

Evaluation (study of the patient with technical methods) shows the enlargement of the porus acousticus internus in the CT scan, enhancing tumours in the region of the cerebello-pontine angle in gadolinium-enhanced MRI scans, hearing loss in audiometric studies and perhaps pathological findings in electronystagmography. Some times there are elevated levels of protein in liquor study.

In NF II, acoustic neuromas usually affect young people, whereas in sporadic forms of acoustic neuromas, the appearance of the tumour is limited to the elderly.

There are two forms of the NF II:

- The "Wishart-Phenotype" is characterized by multiple cerebral and spinal lesions in patients younger than 20 years and with rapid progression of the tumours.

- Patients that develop single central tumours with slow progression after age of 20 are thought to have the "Feiling-Gardner-Phenotype".

Because hearing loss in those with NF-2 almost always occurs after acquisition of verbal language skills, patients do not always integrate well into the Deaf culture and are more likely to resort to auditory assistive technology.

The most sophisticated of these devices is the cochlear implant, which can sometimes restore a high level of auditory function even when natural hearing is totally lost. However, the amount of destruction to the cochlear nerve caused by the typical NF2 schwannoma often precludes the use of such an implant. In these cases, an auditory brainstem implant (ABI) can restore a primitive level of hearing, which, when supplemented by lip reading, can restore a functional understanding of spoken language.

Limited normal functions and movements are caused by osteochondromas growing slowly and inwardly. The majority of osteochondromas are symptomless and are found incidentally. Each individual with osteochondroma may experience symptoms differently and most of the time individuals will experience no symptoms at all. Some of the most common symptoms are a hard immobile painless palpable mass, adjacent muscle soreness, and pressure or irritation with heavy exercising.

Major symptoms arise when complications such as fractures, bone deformity or mechanical joint problems occur. If the occurrence of an osteochondroma is near a nerve or a blood vessel, the affected limb can experience numbness, weakness, loss of pulse or color change. Periodic changes in the blood flow can also take place. Approximately 20% of patients experiencing nerve compression commonly acknowledge vascular compression, arterial thrombosis, aneurysm, and pseudoaneurysm. Formation of pseudoaneurysm and venous thrombosis lead to claudication, pain, acute ischemia, and symptoms of phlebitis. If the tumor is found under a tendon, it can cause pain during movement causing restriction of joint motion. Pain can also occur due to bursal inflammation, swelling or fracture at the base of the tumor stalk. Some of the clinical signs and symptoms of malignant osteochondroma are pain, swelling, and mass enlargement.

Osteochondromas are benign lesions and do not affect life expectancy. Complete excision of osteochondroma is curative and the reoccurrences take place when the removal of tumor is incomplete. Multiple reoccurrences in a well-excised lesion indicate that it may be malignant. The risk of malignant transformation takes place in 1–5% of individuals. If any symptoms of cancerous tumor takes place, then the patient should be evaluated by a bone specialist. No treatment is necessary for Solitary osteochondromas that are asymptomatic. Treatments for solitary osteochondroma are careful observation over time and taking regular x-rays to monitor any changes in the tumor. If the lesion is causing pain with activity, nerve or vessel impingement, or if the bone growth has fully matured and the presence of a large cartilage cap is prominent, then it is advised that the tumor be surgically removed.

Osteochondromas have a low rate of malignancy (<1%) and resection of the tumor is suggested if symptoms such as pain, limitation of movement, or impingement on nerves or vessels occur. Resection of the tumor also takes place when the tumor increases in size and progresses towards malignancy. During surgical resection, the entire lesion along with the cartilaginous cap should be removed to minimize any chances of reoccurrences. Surgical treatment becomes the sole treatment of choice if common complications such as fractures, symptoms of peripheral nerves such as paresthesia, paraplegia, peroneal neuropathy, and upper limb neuropathy take place. A prophylactic resection is suggested if the lesion lies next to a vessel.

Depending on the size and location of the tumor, the time it takes to return to normal daily activities varies between individuals. Limitation on some activities is advised if pain or discomfort persists after surgical excision.

Intake of alcohol during pregnancy has been associated with childhood leukemia. A review published by the National Cancer Institute placed maternal alcohol consumption during pregnancy in the category of "suggestive" but concluded that the risk was not important.

- Acute Lymphocytic Leukemia (ALL)

For ALL in children, maternal alcohol consumption during pregnancy is "unlikely to be an important risk factor for ALL"

- Acute myeloid leukemia (AML)

A study concluded, "In conclusion, even though our study did not show a clear association between alcohol intake and leukemia risk, some of the patterns of the risk estimates (a possible J-shaped dose-response curve between alcohol intake and ALL, AML, and CLL risks, and the positive association between alcohol and CML), may be suggestive."

- Childhood AML

"Three studies have reported an increased risk (approximately 1.5-2 fold) in mothers who drank alcoholic beverages during pregnancy. These associations have been particularly apparent in children diagnosed younger than three years of age.". "Maternal alcohol consumption during pregnancy increases the risk of infant leukemia, especially AML."

- Acute non-lymphocytic leukemia (ANLL)

A study found that intrauterine exposure to alcohol doubled the risk for childhood ANLL.

- Chronic Lymphocytic Leukemia (CLL)

A study concluded, "In conclusion, even though our study did not show a clear association between alcohol intake and leukemia risk, some of the patterns of the risk estimates (a possible J-shaped dose-response curve between alcohol intake and ALL, AML, and CLL risks, and the positive association between alcohol and CML), may be suggestive."

- Chronic myeloid leukemia (CML)

A population-based case-control study in Italy found a non-significant positive association between drinking and CML.

- Hairy cell leukemia

A study concluded, "There was no association found for cigarette smoking, alcohol or coffee consumption and hairy cell leukemia."

Any alcohol intake is associated with the development of malignant melanoma.

There is still some discussion on whether FND is sporadic or genetic. The majority of FND cases are sporadic. Yet, some studies describe families with multiple members with FND. Gene mutations are likely to play an important role in the cause. Unfortunately, the genetic cause for most types of FND remains undetermined.

Parry–Romberg syndrome appears to occur randomly and for unknown reasons. Prevalence is higher in females than males, with a ratio of roughly 3:2. The condition is observed on the left side of the face about as often as on the right side.

The cause of frontorhiny is a mutation in the ALX3 gene. ALX3 is essential for normal facial development. Different mutations can occur in the ALX3 gene, but they all lead to the same effect: severe or complete loss of protein functionality. The ALX3 mutation never occurs in a person without frontorhiny.

Many conditions affect the human integumentary system—the organ system covering the entire surface of the body and composed of skin, hair, nails, and related muscle and glands. The major function of this system is as a barrier against the external environment. The skin weighs an average of four kilograms, covers an area of two square meters, and is made of three distinct layers: the epidermis, dermis, and subcutaneous tissue. The two main types of human skin are: glabrous skin, the hairless skin on the palms and soles (also referred to as the "palmoplantar" surfaces), and hair-bearing skin. Within the latter type, the hairs occur in structures called pilosebaceous units, each with hair follicle, sebaceous gland, and associated arrector pili muscle. In the embryo, the epidermis, hair, and glands form from the ectoderm, which is chemically influenced by the underlying mesoderm that forms the dermis and subcutaneous tissues.

The epidermis is the most superficial layer of skin, a squamous epithelium with several strata: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. Nourishment is provided to these layers by diffusion from the dermis, since the epidermis is without direct blood supply. The epidermis contains four cell types: keratinocytes, melanocytes, Langerhans cells, and Merkel cells. Of these, keratinocytes are the major component, constituting roughly 95 percent of the epidermis. This stratified squamous epithelium is maintained by cell division within the stratum basale, in which differentiating cells slowly displace outwards through the stratum spinosum to the stratum corneum, where cells are continually shed from the surface. In normal skin, the rate of production equals the rate of loss; about two weeks are needed for a cell to migrate from the basal cell layer to the top of the granular cell layer, and an additional two weeks to cross the stratum corneum.

The dermis is the layer of skin between the epidermis and subcutaneous tissue, and comprises two sections, the papillary dermis and the reticular dermis. The superficial papillary dermis with the overlying rete ridges of the epidermis, between which the two layers interact through the basement membrane zone. Structural components of the dermis are collagen, elastic fibers, and ground substance. Within these components are the pilosebaceous units, arrector pili muscles, and the eccrine and apocrine glands. The dermis contains two vascular networks that run parallel to the skin surface—one superficial and one deep plexus—which are connected by vertical communicating vessels. The function of blood vessels within the dermis is fourfold: to supply nutrition, to regulate temperature, to modulate inflammation, and to participate in wound healing.

The subcutaneous tissue is a layer of fat between the dermis and underlying fascia. This tissue may be further divided into two components, the actual fatty layer, or panniculus adiposus, and a deeper vestigial layer of muscle, the panniculus carnosus. The main cellular component of this tissue is the adipocyte, or fat cell. The structure of this tissue is composed of septal (i.e. linear strands) and lobular compartments, which differ in microscopic appearance. Functionally, the subcutaneous fat insulates the body, absorbs trauma, and serves as a reserve energy source.

Conditions of the human integumentary system constitute a broad spectrum of diseases, also known as dermatoses, as well as many nonpathologic states (like, in certain circumstances, melanonychia and racquet nails). While only a small number of skin diseases account for most visits to the physician, thousands of skin conditions have been described. Classification of these conditions often presents many nosological challenges, since underlying etiologies and pathogenetics are often not known. Therefore, most current textbooks present a classification based on location (for example, conditions of the mucous membrane), morphology (chronic blistering conditions), etiology (skin conditions resulting from physical factors), and so on. Clinically, the diagnosis of any particular skin condition is made by gathering pertinent information regarding the presenting skin lesion(s), including the location (such as arms, head, legs), symptoms (pruritus, pain), duration (acute or chronic), arrangement (solitary, generalized, annular, linear), morphology (macules, papules, vesicles), and color (red, blue, brown, black, white, yellow). Diagnosis of many conditions often also requires a skin biopsy which yields histologic information that can be correlated with the clinical presentation and any laboratory data.

The fact that some people affected with this disease have circulating antinuclear antibodies in their serum supports the theory that Parry–Romberg syndrome may be an autoimmune disease, specifically a variant of localized scleroderma. Several instances have been reported where more than one member of a family has been affected, prompting speculation of an autosomal dominant inheritance pattern. However, there has also been at least one report of monozygotic twins in which only one of the twins was affected, casting doubt on this theory. Various other theories about the cause and pathogenesis have been suggested, including alterations in the peripheral sympathetic nervous system (perhaps as a result of trauma or infection involving the cervical plexus or the sympathetic trunk), as the literature reported it following sympathectomy, disorders in migration of cranial neural crest cells, or chronic cell-mediated inflammatory process of the blood vessels. It is likely that the disease results from different mechanisms in different people, with all of these factors potentially being involved.

Fibrochondrogenesis is quite rare. A 1996 study from Spain determined a national minimal prevalence for the disorder at 8 cases out of 1,158,067 live births.

A United Arab Emirates (UAE) University report, from early 2003, evaluated the results of a 5-year study on the occurrence of a broad range of osteochondrodysplasias. Out of 38,048 newborns in Al Ain, over the course of the study period, fibrochondrogenesis was found to be the most common of the recessive forms of osteochondrodysplasia, with a prevalence ratio of 1.05:10,000 births.

While these results represented the most common occurrence within the group studied, they do not dispute the rarity of fibrochondrogenesis. The study also included the high rate of consanguinous marriages as a prevailing factor for these disorders, as well as the extremely low rate of diagnosis-related pregnancy terminations throughout the region.

Exposure of spermatozoa to lifestyle, environmental and/or occupational hazards may increase the risk of aneuploidy. Cigarette smoke is a known aneugen (aneuploidy inducing agent). It is associated with increases in aneuploidy ranging from 1.5 to 3.0-fold. Other studies indicate factors such as alcohol consumption, occupational exposure to benzene, and exposure to the insecticides fenvalerate and carbaryl also increase aneuploidy.

Osteitis fibrosa cystica ( ), is a skeletal disorder resulting in a loss of bone mass, a weakening of the bones as their calcified supporting structures are replaced with fibrous tissue (peritrabecular fibrosis), and the formation of cyst-like brown tumors in and around the bone. Osteitis fibrosis cystica, abbreviated OFC, also known as osteitis fibrosa, osteodystrophia fibrosa, and von Recklinghausen's disease of bone (not to be confused with von Recklinghausen's disease, neurofibromatosis type I), is caused by hyperparathyroidism, which is a surplus of parathyroid hormone from over-active parathyroid glands. This surplus stimulates the activity of osteoclasts, cells that break down bone, in a process known as osteoclastic bone resorption. The hyperparathyroidism can be triggered by a parathyroid adenoma, hereditary factors, parathyroid carcinoma, or renal osteodystrophy. Osteoclastic bone resorption releases minerals, including calcium, from the bone into the bloodstream, causing both elevated blood calcium levels, and the structural changes which weaken the bone. The symptoms of the disease are the consequences of both the general softening of the bones and the excess calcium in the blood, and include bone fractures, kidney stones, nausea, moth-eaten appearance in the bones, appetite loss, and weight loss.

First described in the nineteenth century, OFC is currently detected through a combination of blood testing, X-rays, and tissue sampling. Before 1950, around half of those diagnosed with hyperparathyroidism in the United States saw it progress to OFC, but with early identification techniques and improved treatment methods, instances of OFC in developed countries are increasingly rare. Where treatment is required, it normally involves addressing the underlying hyperparathyroidism before commencing long-term treatment for OFC—depending on its cause and severity, this can range from hydration and exercise to surgical intervention.

Osteitis fibrosa cystica is the result of unchecked hyperparathyroidism, or the overactivity of the parathyroid glands, which results in an overproduction of parathyroid hormone (PTH). PTH causes the release of calcium from the bones into the blood, and the reabsorption of calcium in the kidney. Thus, excess PTH in hyperparathyroidism causes elevated blood calcium levels, or hypercalcemia.

There are four major causes of primary hyperparathyroidism that result in OFC:

- Parathyroid adenoma

The vast majority of cases of hyperparathyroidism are the result of the random formation of benign, but metabolically active, parathyroid adenoma swellings. These instances comprise approximately 80–85% of all documented cases of hyperparathyroidism.

- Hereditary factors

Approximately 1 in 10 documented cases of hyperparathyroidism are a result of hereditary factors. Disorders such as familial hyperparathyroidism, multiple endocrine neoplasia type 1 (MEN Type 1) and hyperparathyroidism-jaw tumor syndrome can, if left unchecked, result in OFC. MEN Type 1 is an autosomal dominant disorder and the most common hereditary form of hyperparathyroidism, affecting about 95% of genetic cases of OFC, and also tends to affect younger patients than other forms. Major mutations which can lead to hyperparathyroidism generally involve the parathyroid hormone receptor, G proteins, or adenylate cyclase. Certain genetic mutations have been linked to a higher rate of parathyroid carcinoma occurrence, specifically mutations to the gene HRPT2, which codes for the protein parafibromin.

- Parathyroid carcinoma

Parathyroid carcinoma (cancer of the parathyroid gland) is the rarest cause of OFC, accounting for about 0.5% of all cases of hyperparathyroidism. OFC onset by parathyroid carcinoma is difficult to diagnose.

- Renal complications

OFC is a common presentation of renal osteodystrophy, which is a term used to refer to the skeletal complications of end stage renal disease (ESRD). OFC occurs in approximately 50% of patients with ESRD. ESRD occurs when the kidneys fail to produce calcitriol, a form of Vitamin D, which assists in the absorption of calcium into the bones. When calcitriol levels decrease, parathyroid hormone levels increase, halting the storage of calcium, and instead triggering its removal from the bones. The concept of renal osteodystrophy is currently included into the broader term chronic kidney disease-mineral and bone disorder (CKD-MBD).

Alopecia mucinosa (also known as "Follicular mucinosis," "Mucinosis follicularis,", "Pinkus’ follicular mucinosis," and "Pinkus’ follicular mucinosis–benign primary form") is a skin disorder that generally presents, but not exclusively, as erythematous plaques or flat patches without hair primarily on the scalp and face. This can also present on the body as a follicular mucinosis and may represent a systemic disease.

Fibrochondrogenesis is inherited in an autosomal recessive pattern. This means that the defective gene responsible for the disorder is located on an autosome, and two copies of the gene — one copy inherited from each parent — are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder each carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. Currently, no specific genetic mutation has been established as the cause of fibrochondrogenesis.

Omphalocele is a congenital feature where the abdominal wall has an opening, partially exposing the abdominal viscera (typically, the organs of the gastrointestinal tract). Fibrochondrogenesis is believed to be related to omphalocele

type III, suggesting a possible genetic association between the two disorders.

Infection-related cutaneous conditions may be caused by bacteria, fungi, yeast, viruses, or parasites.

Mosaicism syndromes can be caused by mitotic nondisjunction in early fetal development. As a consequence, the organism evolves as a mixture of cell lines with differing ploidy (number of chromosomes). Mosaicism may be present in some tissues, but not in others. Affected individuals may have a patchy or assymmetric appearance. Examples of mosaicism syndromes include Pallister-Killian syndrome and Hypomelanosis of Ito.