Birt–Hogg–Dubé Syndrome
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Birt–Hogg–Dubé syndrome (BHD), also Hornstein–Birt–Hogg–Dubé syndrome, Hornstein–Knickenberg syndrome, and fibrofolliculomas with trichodiscomas and acrochordons is a human, adult onset,
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...
caused by a mutation in the folliculin (''FLCN'') gene. It can cause susceptibility to
kidney cancer Kidney cancer, also known as renal cancer, is a group of cancers that starts in the kidney. Symptoms may include blood in the urine, a lump in the abdomen, or back pain. Fever, weight loss, and tiredness may also occur. Complications can include ...
,
renal In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retrop ...
and
pulmonary cyst A focal lung pneumatosis is an enclosed pocket of air or gas in the lung and includes blebs, bullae, pulmonary cysts, and lung cavities. Blebs and bullae can be classified by their wall thickness. * A bleb has a wall thickness of less than 1 mm. ...
s, and noncancerous tumors of the
hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction betwee ...
s, called
fibrofolliculoma Fibrofolliculomas are 2 to 4 mm in diameter, dome-shaped, yellowish or skin-colored papules usually located on the head, neck, and upper trunk. They are characteristically seen in Birt–Hogg–Dubé syndrome.Freedberg, et al. (2003). ''Fitzpa ...
s. The symptoms seen in each family are unique, and can include any combination of the three symptoms. Fibrofolliculomas are the most common manifestation, found on the face and upper trunk in over 80% of people with BHD over the age of 40. Pulmonary cysts are equally common (84%) and 24% of people with BHD eventually experience a collapsed lung (
spontaneous pneumothorax A pneumothorax is collection of air in the pleural space between the lung and the chest wall. Symptoms typically include sudden onset of sharp, one-sided chest pain and shortness of breath. In a minority of cases, a one-way valve is formed by ...
). Kidney tumors, both cancerous and benign, occur in 14–34% of people with BHD; the associated kidney cancers are often rare hybrid tumors. Any of these conditions that occurs in a family can indicate a diagnosis of Birt–Hogg–Dubé syndrome, though it is only confirmed by a
genetic test Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
for a mutation in the ''FLCN'' gene, which codes for the protein folliculin. Though its function is not fully understood, it appears to be a
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
gene that restricts cell growth and division. Versions of ''FLCN'' have been found in other animals, including fruit flies,
German Shepherd The German Shepherd, also known in Britain as an Alsatian, is a German Dog breed, breed of working dog of medium to large size. The breed was developed by Max von Stephanitz using various Old German herding dogs, traditional German herding dog ...
s,
rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include '' Neotoma'' (pack rats), '' Bandicota'' (bandicoo ...
s, and
mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
. The disease was discovered in 1977, but the connection with ''FLCN'' was not elucidated until 2002, after kidney cancer, collapsed lungs, and pulmonary cysts were all definitively connected to BHD. Birt–Hogg–Dubé syndrome can manifest similarly to other diseases, which must be ruled out when making a diagnosis. These include
tuberous sclerosis Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combinatio ...
, which causes skin lesions similar to fibrofolliculomas, and
Von Hippel–Lindau disease Von Hippel–Lindau disease (VHL), also known as Von Hippel–Lindau syndrome, is a rare disease, rare genetic disorder with multisystem involvement. It is characterized by visceral cysts and benign tumors with potential for subsequent malignant t ...
, which causes hereditary kidney cancers. Once diagnosed, people with BHD are treated preventatively, with monitoring of kidneys and lungs using
medical imaging Medical imaging is the technique and process of imaging the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to revea ...
. Fibrofolliculomas can be removed surgically and pneumothorax and kidney cancer are treated according to the normal standard of care. Dermatologic examinations, neck ultrasounds and colonoscopies should be considered as well.


Signs and symptoms


Skin

Birt–Hogg–Dubé syndrome affects the skin and increases the risk of tumors in the kidneys and lungs. The condition is characterized by multiple noncancerous, dome-shaped tumors of the
hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction betwee ...
s (
fibrofolliculoma Fibrofolliculomas are 2 to 4 mm in diameter, dome-shaped, yellowish or skin-colored papules usually located on the head, neck, and upper trunk. They are characteristically seen in Birt–Hogg–Dubé syndrome.Freedberg, et al. (2003). ''Fitzpa ...
s), particularly on the face, neck, and more rarely, the upper chest. The fibrofolliculomas are generally described as having an opaque white color or a yellowish tone and have a waxy, smooth texture. The tumors are always found on and around the nose and on and behind the
outer ear The outer ear, external ear, or auris externa is the external part of the ear, which consists of the auricle (also pinna) and the ear canal. It gathers sound energy and focuses it on the eardrum ( tympanic membrane). Structure Auricle The ...
. Typically, they first appear in a person's 20s or 30s, and are found in more than 80% of people with the syndrome above the age of 40. The tumors become larger and more numerous over time. Tumors differ between individuals; they may appear merged in plaques, look similar to a
comedo A comedo (plural comedones) is a clogged hair follicle (pore) in the skin. Keratin (skin debris) combines with oil to block the follicle. A comedo can be open (blackhead) or closed by skin (whitehead) and occur with or without acne. The word ''com ...
with a plug of
keratin Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. It is the key structural material making up Scale (anatomy), scales, hair, Nail (anatomy), nails, feathers, horn (anatomy), horns, claws, Hoof, hoove ...
, or include
epidermoid cyst An epidermoid cyst or epidermal inclusion cyst is a benign cyst usually found on the skin. The cyst develops out of ectodermal tissue. Histologically, it is made of a thin layer of squamous epithelium. Signs and symptoms The epidermoid cyst may ...
s. A large number of tumors on the face can be associated with hyperseborrhea (abnormally elevated
sebum A sebaceous gland or oil gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur ...
production). The presence of fibrofolliculomas on a person's face can cause significant
psychological distress Mental distress or psychological distress encompasses the symptoms and experiences of a person's internal life that are commonly held to be troubling, confusing or out of the ordinary. Mental distress can potentially lead to a change of behavior, ...
. Other tumors can include
trichodiscoma A trichodiscoma is a cutaneous condition, a benign, usually skin-colored tumor most often affecting the face and upper trunk. See also * Birt–Hogg–Dubé syndrome * Fibrofolliculoma * List of cutaneous conditions * List of cutaneous neoplasms ...
s (tumors of the
hair disc The hair disc is a receptor complex found in hairy skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal cov ...
, which may be identical to fibrofolliculomas),
angiofibroma Angiofibroma (AGF) is a descriptive term for a wide range of benign skin or mucous membrane (i.e. the outer membrane lining body cavities such as the mouth and nose) lesions in which individuals have: # benign papules, i.e. pinhead-sized elevatio ...
s, and
perifollicular fibroma Perifollicular fibroma is a cutaneous condition, a benign tumor usually skin colored, most often affecting the face and upper trunk. See also * Birt–Hogg–Dubé syndrome * List of skin conditions Many skin conditions affect the human int ...
s. However, angiofibromas are more common in tuberous sclerosis. Along with the tumors, other skin conditions are seen in people with Birt–Hogg–Dubé syndrome. About 40% of people or families with the disease have
papules A papule is a small, well-defined bump in the skin. It may have a rounded, pointed or flat top, and may have a dip. It can appear with a stalk, be thread-like or look warty. It can be soft or firm and its surface may be rough or smooth. Some ...
in their mouths, which can be located on the cheeks (
buccal mucosa The oral mucosa is the mucous membrane lining the inside of the mouth. It comprises stratified squamous epithelium, termed "oral epithelium", and an underlying connective tissue termed ''lamina propria''. The oral cavity has sometimes been describ ...
), tongue, gums, or lips. Either white or mucosa-colored, they are discrete, small, and soft, and consist of fibrous tissue covered in thickened
epithelium Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
. Collagenomas of the skin are also found in some families. Many people with BHD have skin lesions that appear to be
acrochordon A skin tag, or acrochordon (: acrochorda), is a small benign tumor that forms primarily in areas where the skin forms creases (or rubs together), such as the neck, armpit and groin. They may also occur on the face, usually on the eyelids. Thoug ...
s (skin tags), but may instead be fibrofolliculomas. These lesions are usually found in the
armpit The axilla (: axillae or axillas; also known as the armpit, underarm or oxter) is the area on the human body directly under the shoulder joint. It includes the axillary space, an anatomical space within the shoulder girdle between the arm an ...
, on the
eyelid An eyelid ( ) is a thin fold of skin that covers and protects an eye. The levator palpebrae superioris muscle retracts the eyelid, exposing the cornea to the outside, giving vision. This can be either voluntarily or involuntarily. "Palpebral ...
s, and in folds of skin. Not all individuals develop the facial tumors; some families with the mutation that causes BHD develop only kidney tumors or spontaneous pneumothorax.


Kidneys

People over 20 years of age with BHD have an increased risk of developing slow-growing
kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
tumors ( chromophobe renal carcinoma and
renal oncocytoma A renal oncocytoma is a tumour of the kidney made up of oncocytes, epithelial cells with an excess amount of mitochondria. Signs and symptoms Renal oncocytomas are often asymptomatic and are frequently discovered by chance on a CT or ultrasoun ...
), kidney cysts, and possibly tumors in other organs and tissues. These tumors often occur in both kidneys and in multiple locations in each kidney. The average number of kidney tumors found in a person with BHD is 5.3, though up to 28 tumors have been found. Hybrid oncocytoma/chromophobe carcinoma, found in 50% of cases, is the most commonly found cancer, followed by chromophobe renal carcinoma, clear cell renal carcinoma, renal oncocytoma, and
papillary renal cell carcinoma Papillary renal cell carcinoma (PRCC) is a malignant, heterogeneous tumor originating from renal tubular epithelial cells of the kidney, which comprises approximately 10-15% of all kidney neoplasms. Based on its morphological features, PRCC can be ...
. People over 40 years old and men are more likely to develop kidney tumors, which are diagnosed at a median age of 48. Kidney cancer associated with BHD have been diagnosed in people at ages as young as 20. In general, people with this syndrome are at roughly at seven times the risk of kidney cancer compared to the unaffected population. Estimates of the incidence among people with the disease range from 14 to 34%. Rarely, it is associated with
clear cell renal cell carcinoma Clear-cell renal-cell carcinoma (CCRCC) is a type of renal-cell carcinoma. Genetics Cytogenetics * Alterations of chromosome 3p segments occurs in 70–90% of CCRCCs * Inactivation of von Hippel–Lindau disease ( VHL) gene by gene mutation a ...
and
papillary renal cell carcinoma Papillary renal cell carcinoma (PRCC) is a malignant, heterogeneous tumor originating from renal tubular epithelial cells of the kidney, which comprises approximately 10-15% of all kidney neoplasms. Based on its morphological features, PRCC can be ...
. If it develops in someone with BHD, renal cell carcinoma occurs later in life and has a poor prognosis. Though the types of tumors typically associated with BHD are considered less aggressive, cases of advanced or metastatic kidney cancer have been observed in people with the syndrome. Both benign and cancerous tumors can reduce
kidney function Assessment of kidney function occurs in different ways, using the presence of symptoms and medical sign, signs, as well as measurements using urine tests, blood tests, and medical imaging. Renal physiology, Functions of a healthy kidney include ...
over time as they grow larger.


Lungs

Along with fibrofolliculomas and kidney tumors, affected individuals frequently develop
cyst A cyst is a closed sac, having a distinct envelope and division compared with the nearby tissue. Hence, it is a cluster of cells that have grouped together to form a sac (like the manner in which water molecules group together to form a bubb ...
s ( blebs or bullae) in the sub
pleura The pleurae (: pleura) are the two flattened closed sacs filled with pleural fluid, each ensheathing each lung and lining their surrounding tissues, locally appearing as two opposing layers of serous membrane separating the lungs from the med ...
l
lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
base or intraparenchymal space that may rupture and cause an abnormal collection of air in the chest cavity (
pneumothorax A pneumothorax is collection of air in the pleural space between the lung and the chest wall. Symptoms typically include sudden onset of sharp, one-sided chest pain and dyspnea, shortness of breath. In a minority of cases, a one-way valve is ...
), which could result in the collapse of a lung. The cysts do not cause other symptoms and
lung function The lungs are the primary organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the backbone on either side of the heart. Their function in the respiratory system ...
is usually normal. More than 83% of people with BHD have cysts, but the syndrome does not cause conditions like progressive
chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory s ...
or generalized
respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a r ...
, though it does cause
emphysema Emphysema is any air-filled enlargement in the body's tissues. Most commonly emphysema refers to the permanent enlargement of air spaces (alveoli) in the lungs, and is also known as pulmonary emphysema. Emphysema is a lower respiratory tract di ...
. Spontaneous, sometimes recurrent, pneumothorax occurs far more often and at a younger age with BHD than in the unaffected population. Around 24% of people with the disease have at least one spontaneous pneumothorax, 30 times the occurrence in unaffected people. Though pneumothorax caused by BHD often occurs in middle age, at a median age of 38, 17% of affected people have a spontaneous pneumothorax before turning 40. Pneumothoraces have been seen in people as young as 7 and 16 years of age. Some families have a form of BHD that only affects the lungs.


Other organs

Thyroid nodules Thyroid nodules are nodules (raised areas of tissue or fluid) which commonly arise within an otherwise normal thyroid gland. They may be hyperplastic or tumorous, but only a small percentage of thyroid tumors are malignant. Small, asymptomatic ...
have been associated with the Birt–Hogg–Dubé phenotype, present in 65% of individuals and 90% of families with the syndrome. However, a connection between BHD and thyroid cancer has not been substantiated. Other conditions have been reported to be associated, but may not be caused by the mutation in ''FLCN'' or may not be related at all. These include
multinodular goiter A goitre (British English), or goiter (American English), is a swelling in the neck resulting from an enlarged thyroid gland. A goitre can be associated with a thyroid that is not functioning properly. Worldwide, over 90% of goitre cases are ca ...
,
medullary thyroid carcinoma Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells (C cells), which produce the hormone calcitonin.Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP"Thyroid and Parathyroid Cancers"in Pazdur R, ...
, parotid oncocytoma, colonic polyposis, connective tissue nevus,
lipoma A lipoma is a benign tumor made of adipose tissue, fat tissue. They are generally soft to the touch, movable, and painless. They usually occur just under the skin, but occasionally may be deeper. Most are less than in size. Common locations inc ...
s,
angiolipoma Angiolipoma is a subcutaneous nodule with vascular structure, having all other features of a typical lipoma. They are commonly painful.James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. ( ...
s,
parathyroid adenoma A parathyroid adenoma is a benign tumor of the parathyroid gland. It generally causes hyperparathyroidism; there are very few reports of parathyroid adenomas that were not associated with hyperparathyroidism. A human being usually has four parath ...
s, flecked chorioretinopathy,
neurothekeoma A Neurothekeoma (NT) is a type of rare benign cutaneous tumor that usually develops on the head and neck. They often occur in the second and early third decades of life and tend to afflict women more frequently than men. First described by Richard ...
,
meningioma Meningioma, also known as meningeal tumor, is typically a slow-growing tumor that forms from the meninges, the membranous layers surrounding the brain and spinal cord. Symptoms depend on the location and occur as a result of the tumor pressing ...
s,
angiofibroma Angiofibroma (AGF) is a descriptive term for a wide range of benign skin or mucous membrane (i.e. the outer membrane lining body cavities such as the mouth and nose) lesions in which individuals have: # benign papules, i.e. pinhead-sized elevatio ...
s of the face,
trichoblastoma Trichoblastomas are a Human skin, skin condition characterized by benign neoplasms of the Hair follicle, follicular germinative cells known as ''trichoblasts''. ''Trichoblastic fibroma'' is a term used to describe small Nodule (medicine), nodular ...
s, cutaneous focal mucinosis, cutaneous leiomyoma, breast cancer, tonsillar cancer,
colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the Colon (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...
,
sarcoma A sarcoma is a rare type of cancer that arises from cells of mesenchymal origin. Originating from mesenchymal cells means that sarcomas are cancers of connective tissues such as bone, cartilage, muscle, fat, or vascular tissues. Sarcom ...
of the leg, lung cancer,
melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...
,
dermatofibrosarcoma protuberans Dermatofibrosarcoma protuberans (DFSP) is a rare locally aggressive malignant cutaneous soft-tissue sarcoma. DFSP develops in the connective tissue cells in the middle layer of the skin (dermis). Estimates of the overall occurrence of DFSP in the U ...
,
basal cell carcinoma Basal-cell carcinoma (BCC), also known as basal-cell cancer, basalioma, or rodent ulcer, is the most common type of skin cancer. It often appears as a painless, raised area of skin, which may be shiny with Telangiectasia, small blood vessels ru ...
, cutaneous leiomyosarcoma, and
squamous cell carcinoma Squamous-cell carcinoma (SCC), also known as epidermoid carcinoma, comprises a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
.


Pathophysiology


Genetics

An association with the folliculin (''FLCN'') gene was first reported in 2002. This 14-
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
gene is located on the short arm of
chromosome 17 Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 84 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total DN ...
(17p11.2) and has a
cytosine Cytosine () (symbol C or Cyt) is one of the four nucleotide bases found in DNA and RNA, along with adenine, guanine, and thymine ( uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attac ...
-rich region in exon 11 particularly susceptible to mutation. The most common mutation in this region is the insertion or deletion of a cytosine residue, found in 53% of BHD-affected families. No significant difference has been found in the symptoms experienced by families with an insertion at that location compared to those who have a deletion, but mutations in ''FLCN'' associated with BHD syndrome are heterogeneous, and are often
nonsense mutation In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a ''nonsense codon'', or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. No ...
s or
frameshift mutation A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet natur ...
s that cause early truncation of the protein product at the
carboxy terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...
. Very rarely,
missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...
s are observed. The mutations in the FLCN gene that cause Birt–Hogg–Dubé syndrome are
germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and Egg cell, ova). Mutations in these cells are the only mutations that can be passed on to offspring, when e ...
s, which means that they occur in every cell of the body and can be passed down to future generations. These mutations are often passed from one generation to the next in an autosomal dominant fashion, but can occur as a new mutation in an individual with no prior family history (a ''de novo'' mutation). The children of an affected parent each has a 50% chance of having the disease. BHD has very high
penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the pr ...
. A correlation between different ''FLCN'' genotypes and phenotypes has not been discovered.


Function

''FLCN'' creates a protein, folliculin, that has two
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
s. It appears to act as a
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell (biology), cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results ...
, and is expressed strongly in the skin, distal
nephron The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structu ...
s, and
type I pneumocyte A pulmonary alveolus (; ), also called an air sac or air space, is one of millions of hollow, distensible cup-shaped cavities in the lungs where pulmonary gas exchange takes place. Oxygen is exchanged for carbon dioxide at the blood–air barr ...
s. It has also been found in the
parotid gland The parotid gland is a major salivary gland in many animals. In humans, the two parotid glands are present on either side of the mouth and in front of both ears. They are the largest of the salivary glands. Each parotid is wrapped around the m ...
, brain,
breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
,
pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...
,
prostate The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
, and
ovaries The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endocr ...
. Tumor suppressors normally prevent cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the ''FLCN'' gene may interfere with the ability of folliculin to restrain cell growth and division, leading to the formation of noncancerous and cancerous tumors. Recent studies suggest that folliculin accomplishes this function through its involvement with
cellular metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
, possibly through modulation of the
mTOR The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...
(mammalian target of
rapamycin Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ rejection, organ transplant rejection, treat a rare lung disease called lymphang ...
) pathway and/or
oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...
in
mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
. Folliculin interacts with FNIP1 and FNIP2 (FLCN-interacting protein) to form a
complex Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...
with
AMP-activated protein kinase 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cell ...
. Folliculin's participation in the mTOR pathway may explain the similarity in phenotype between BHD syndrome, Cowden syndrome, tuberous sclerosis, and
Peutz–Jeghers syndrome Peutz–Jeghers syndrome (often abbreviated PJS) is an dominance (genetics), autosomal dominant genetic disorder characterized by the development of benign hamartomatous Polyp (medicine), polyps in the human gastrointestinal tract, gastrointestinal ...
. Most of the cancer-causing mutations cause the protein to be truncated at the carboxy terminus. The C-terminal end of folliculin has shown to be the domain through which it interacts with FNIP1, and thereby possibly the mTOR pathway. ''FLCN'' is highly conserved in vertebrates—it is very similar between many vertebrate species. The 508th
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
, normally
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...
, is affected by a missense mutation in some people with BHD. The lysine at this position is found to be conserved between invertebrate and vertebrate
ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...
s of folliculin, indicating that it is important to the protein's function. People with BHD are born with one mutated copy of the ''FLCN'' gene in each cell.
Haploinsufficiency Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type ...
—only having one functional copy of the ''FLCN'' gene—is enough to cause the fibrofolliculomas and pulmonary cysts, though one copy of the gene is enough to keep kidney cells in check. During a person's lifetime, random mutations might inactivate the normal copy of the gene in a subset of cells. When this occurs, the result is that these cells have no functional copies of the ''FLCN ''gene, allowing the cells grow out of control. This
loss of heterozygosity In genetics, loss of heterozygosity (LOH) is a type of genetic abnormality in diploid organisms in which one copy of an entire gene and its surrounding chromosomal region are lost. Since diploid cells have two copies of their genes, one from each ...
is a common mechanism in cancer, and it is frequently detected in the renal cancers associated with BHD. The molecular genetic defects in renal tumors of people with BHD are different from two other similar kidney tumors,
chromophobe A chromophobe cell is a cell that does not stain readily, and thus appears relatively pale under the microscope. It is contrasted with a chromophil cell that does stain easily. Chromophobe cells are one of three cell stain types present in the a ...
renal cell carcinoma and renal
oncocytoma An oncocytoma is a tumor made up of oncocytes, epithelial cell (biology), cells characterized by an excessive amount of mitochondria, resulting in an abundant acidophilic, granular cytoplasm. The cells and the tumor that they compose are often be ...
. BHD-associated
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abn ...
differs between the kidney, where loss of ''FLCN'' heterozygosity is responsible for cancers, and the skin, where ''FLCN'' is strongly expressed in heterozygotes. ''FLCN'' has been found to be overexpressed in fibrofolliculoma tissue, and to have very low levels of expression in affected kidneys. Furthermore, the mTOR pathway is shown to be activated in tumor tissue from both humans and mice. Renal cystogenesis and tumorigenesis in BHD have been shown to be driven by the constitutive activation of TFEB.


Diagnosis

BHD can be suggested by clinical findings but is definitively diagnosed by molecular
genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
to detect mutations in the ''FLCN'' gene. The classical clinical triad includes benign growths of the hair follicles, pulmonary cysts and spontaneous pneumothorax, and bilateral, multifocal renal tumors.


Clinical triad

The cutaneous manifestations of BHD were originally described as fibrofolliculomas (abnormal growths of a hair follicle), trichodiscomas (hamartomatous lesions with a hair follicle at the periphery, often found on the face), and acrochordons (skin tags). Cutaneous manifestations are confirmed by
histology Histology, also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...
. Most individuals (89%) with BHD are found to have multiple cysts in both lungs, and 24% have had one or more episodes of pneumothorax. The cysts can be detected by chest
CT scan A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...
. Renal tumors can manifest as multiple types of renal cell carcinoma, but certain pathological subtypes (including
chromophobe A chromophobe cell is a cell that does not stain readily, and thus appears relatively pale under the microscope. It is contrasted with a chromophil cell that does stain easily. Chromophobe cells are one of three cell stain types present in the a ...
,
oncocytoma An oncocytoma is a tumor made up of oncocytes, epithelial cell (biology), cells characterized by an excessive amount of mitochondria, resulting in an abundant acidophilic, granular cytoplasm. The cells and the tumor that they compose are often be ...
, and oncocytic hybrid tumors) are more commonly seen. Although the original syndrome was discovered on the basis of cutaneous findings, individuals with BHD may only manifest the pulmonary and/or renal findings, without any skin lesions. Though these signs indicate BHD, it is only confirmed with a genetic test for ''FLCN'' mutations.


Genetic testing

''FLCN'' mutations are detected by
sequencing In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which succ ...
in 88% of
proband In medical genetics and other medical fields, a proband, propositus (male proband), or proposita (female proband) is a particular subject (human or other animal) being studied or reported on. On pedigrees, the proband is noted with a square (male) ...
s with this syndrome. This means that some people with the clinical diagnosis have mutations that are not detectable by current technology, or that mutations in another currently unknown gene could be responsible for a minority of cases. In addition, amplifications and deletions in
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
ic regions are also tested. Genetic testing can be useful to confirm the clinical diagnosis and to provide a means of determining other at-risk individuals in a family even if they have not yet developed BHD symptoms.


Differential diagnosis

BHD can be difficult to diagnose from symptoms alone, because hereditary renal cancers, pneumothorax, and cutaneous tumors occur with other syndromes. Hereditary bilateral, multifocal kidney tumors similar to those seen in BHD can occur with
von Hippel–Lindau disease Von Hippel–Lindau disease (VHL), also known as Von Hippel–Lindau syndrome, is a rare disease, rare genetic disorder with multisystem involvement. It is characterized by visceral cysts and benign tumors with potential for subsequent malignant t ...
(clear cell renal cell carcinoma), hereditary papillary renal cancer (papillary renal cell carcinoma), and hereditary leiomyomatosis and renal cell cancer syndrome. They are differentiated with examination of the tumors' histology. Hereditary recurrent pneumothorax or pulmonary cysts are associated with
Marfan syndrome Marfan syndrome (MFS) is a multi-systemic genetic disorder that affects the connective tissue. Those with the condition tend to be tall and thin, with dolichostenomelia, long arms, legs, Arachnodactyly, fingers, and toes. They also typically ha ...
,
Ehlers–Danlos syndrome Ehlers–Danlos syndromes (EDS) is a group of 14 genetic connective-tissue disorders. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Co ...
,
tuberous sclerosis complex Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combinatio ...
, alpha1-antitrypsin deficiency, and
cystic fibrosis Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...
. Nonhereditary recurrent pneumothorax and/or pulmonary cysts can occur with
Langerhans cell histiocytosis Langerhans cell histiocytosis (LCH) is an abnormal clonal proliferation of Langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes. Symptoms range from isolated bone lesions to multisystem d ...
and
lymphangioleiomyomatosis Lymphangioleiomyomatosis (LAM) is a rare, progressive and systemic disease that typically results in cystic lung destruction. It predominantly affects women, especially during childbearing years. The term sporadic LAM is used for patients with LA ...
. These conditions are differentiated from BHD through examining the patient history and performing a physical examination. In women suspected to have the disease, ruling out pulmonary or thoracic
endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...
may be necessary. Though fibrofolliculomas are unique to BHD, they may present with an ambiguous appearance and must be confirmed histologically. Other diseases can mimic the dermatologic manifestations of BHD, including tuberous sclerosis complex,
Cowden syndrome Cowden syndrome (also known as Cowden's disease) is an autosomal dominant inherited condition characterized by benign overgrowths called hamartomas as well as an increased lifetime risk of breast, thyroid, uterine, and other cancers. It is also k ...
, familial trichoepitheliomas, and
multiple endocrine neoplasia type 1 Multiple endocrine neoplasia type 1 (MEN-1 aka Wermer Syndrome) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pa ...
. Tuberous sclerosis must be distinguished because both disorders can present with angiofibromas on the face, though they are more common in tuberous sclerosis.


Management

The different manifestations of BHD are controlled in different ways. The fibrofolliculomas can be removed surgically, through
curettage Curettage ( or ), in medical procedures, is the use of a curette (French, meaning "scoop" Mosby's Medical, Nursing & Allied Health Dictionary, Fourth Edition, Mosby-Year Book 1994, p. 422) to remove tissue by scraping or scooping. Curettages ...
, shave excision, skin resurfacing, or
laser ablation Laser ablation or photoablation (also called laser blasting) is the process of removing material from a solid (or occasionally liquid) surface by irradiating it with a laser beam. At low laser flux, the material is heated by the absorbed laser ...
; this is not a permanent solution, though, as the tumors often recur. Dermatologic examination is recommended every 6-12 months due to risk of melanoma. Thyroid/parotid ultrasound should be considered annually and colonoscopies should be considered also. The renal and pulmonary symptoms are generally managed preventatively: CT scans,
ultrasounds Ultrasound is sound with frequencies greater than 20 kilohertz. This frequency is the approximate upper audible limit of human hearing in healthy young adults. The physical principles of acoustic waves apply to any frequency range, includi ...
, or
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
s of the kidneys are recommended regularly, and family members are advised not to smoke. However, surgical interventions such as video assisted thoracoscopy (VATS) and mechanical or chemical pleurodesis should be considered in case of recurrent pneumothorax. MRIs are the preferred method for surveillance of the kidneys in people with BHD because they do not carry the same risk of
radiation In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or a material medium. This includes: * ''electromagnetic radiation'' consisting of photons, such as radio waves, microwaves, infr ...
complications as CT scans, and are more sensitive than ultrasounds. Smokers with Birt–Hogg–Dubé have more severe pulmonary symptoms than non-smokers. Though
nephrectomy A nephrectomy is the surgical removal of a kidney, performed to treat a number of kidney diseases including kidney cancer. It is also done to remove a normal healthy kidney from a living or deceased donor, which is part of a kidney transplant pro ...
is sometimes indicated, kidney tumors in cases of BHD are often removed without taking the whole kidney, in a partial nephrectomy.
Knockout mouse A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
studies have shown that administration of
rapamycin Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ rejection, organ transplant rejection, treat a rare lung disease called lymphang ...
may mitigate the effects of ''FLCN'' mutations on kidneys and improve renal cancer prognoses because of folliculin's interaction with the mTOR pathway.


Epidemiology

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 Homogeneity and heterogeneity are concepts relating to the uniformity of a substance, process or image. A homogeneous feature is uniform in composition or character (i.e., color, shape, size, weight, height, distribution, texture, language, i ...
between individuals. Less severe skin phenotypes are seen in women and people of both sexes who have a late onset of skin symptoms.


Patient registry

Birt-Hogg-Dubé Syndrome patients, families, and caregivers are encouraged to join th
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.


History

The syndrome was first well described in 1977, by three Canadian physicians, Arthur R. Birt, Georgina R. Hogg, and William J. Dubé. The earliest case of possible BHD in the medical literature was published by Burnier and Rejsek in 1927, who described a case of
perifollicular fibroma Perifollicular fibroma is a cutaneous condition, a benign tumor usually skin colored, most often affecting the face and upper trunk. See also * Birt–Hogg–Dubé syndrome * List of skin conditions Many skin conditions affect the human int ...
s on a 56-year-old woman's face. Trichodiscomas were first described in 1974 by H. S. Zackheim and H. Pinkus, but were not associated with BHD until Birt, Hogg, and Dubé. The first case of BHD with the systemic symptoms was described by Hornstein and Knickenberg and found in two siblings and their father, all of whom exhibited colon polyps and the characteristic fibrofolliculomas. Though the siblings did not have renal or pulmonary symptoms, their father had cysts in his lungs and kidneys. Hornstein-Knickenberg syndrome is a now-deprecated name for the inherited fibrofolliculomas inherent to BHD. Birt, Hogg, and Dubé examined a family with a hereditary thyroid cancer, and discovered that many of the members had fibrofolliculomas, trichodiscomas, and acrochordons, which became defined as the classical symptoms of the eponymous disease. The first case of spontaneous pneumothorax associated with BHD was discovered in 1986; the first case of renal cancer followed in 1993, and the presence of lung cysts in people with BHD was confirmed in 1999. People with BHD were once thought to be at higher risk for
colorectal polyps A colorectal polyp is a polyp (fleshy growth) occurring on the lining of the colon or rectum. Untreated colorectal polyps can develop into colorectal cancer. Colorectal polyps are often classified by their behaviour (i.e. benign vs. malignant) ...
and
neoplasm A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s, but this has been disproven. The BHD Foundation supports research into the syndrome and holds regular symposia in BHD and related disorders for researchers, clinicians, and family members.


Other animals

Genes related to ''FLCN'' and diseases similar to BHD have been found in dogs, fruit flies, rats, and mice. In German Shepherd dogs, missense mutations in the canine
ortholog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a speci ...
of ''FLCN'' cause a similar phenotype to human BHD—kidney cancers (in this case, multifocal renal
cystadenocarcinoma Cystadenocarcinoma is a malignant tumor that arises from glandular epithelial cells and forms cystic structures. It is most commonly found in the ovaries and pancreas, but it can also develop in other organs. The exact cause of cystadenocarcinoma is ...
) and skin tumors (
nodular dermatofibrosis Nodule may refer to: *Nodule (geology), a small rock or mineral cluster *Manganese nodule, a metallic concretion found on the seafloor *Nodule (medicine), a small aggregation of cells *Root nodule Root nodules are found on the roots of plants, p ...
). They had a similar pattern of tumorigenesis to human BHD in that the skin lesions were heterozygous for the'' FLCN ''mutation, and the renal tumors were likely caused by loss of heterozygosity. Female German Shepherds with a ''FLCN'' mutation are also prone to
uterine leiomyoma Uterine fibroids, also known as uterine leiomyomas, fibromyoma or fibroids, are benign smooth muscle tumors of the uterus, part of the female reproductive system. Most people with fibroids have no symptoms while others may have painful or h ...
s. A homolog of ''FLCN'' called'' DBHD ''has been discovered in the common fruit fly, ''
Drosophila melanogaster ''Drosophila melanogaster'' is a species of fly (an insect of the Order (biology), order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly", "pomace fly" ...
''. Decrease expression of the DBHD results in loss of male germline stem cells (GSC), which suggest that DBHD is required for male GSC maintenance in the fly testis.Singh SR, Zhen W, Zheng Z, Wang H, Oh SW, Liu W, Zbar B, Schmidt LS, Hou SX. The Drosophila homolog of the human tumor suppressor gene BHD interacts with the JAK-STAT and Dpp signaling pathways in regulating male germline stem cell maintenance. Oncogene. 2006 Sep 28;25(44):5933-41. Further, ''DBHD'' regulates GSC maintenance downstream or in parallel of the JAK/STAT and Dpp signal-transduction pathways, which suggest that BHD regulates tumorigenesis by controlling stem cells in human A line of rats with hereditary kidney cancer were developed by Japanese researchers. They have a mutation in the ''FLCN'' homolog that produces a truncated protein, though they do not develop the cutaneous or pulmonary symptoms seen in humans. Heterozygotes have renal abnormalities seen very early in life that develop into clear-cell and hybrid tumors, significantly shortening the animals' lifespans; they also are prone to
endometrial The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...
and
salivary gland The salivary glands in many vertebrates including mammals are exocrine glands that produce saliva through a system of ducts. Humans have three paired major salivary glands ( parotid, submandibular, and sublingual), as well as hundreds of min ...
clear-cell hyperplasia as well as
rhabdomyolysis Rhabdomyolysis (shortened as rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some o ...
. Homozygotes do not survive to birth. When a wild-type ''FLCN'' gene was added, the phenotype was rescued.
Knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
have been created for a kidney-cancer causing mutation of BHD; heterozygotes develop kidney cysts and tumors that lead to renal failure within three weeks of birth. In these mice, the mTOR pathway was inappropriately activated, indicating that the mouse homolog of ''FLCN'' plays a regulatory role in this pathway. Rapamycin partially rescued the phenotype by regulating mTOR. Homozygotes die ''in utero''.


References

Citations Bibliography * * * * * * * * * * * * * * * * * * * * * * * *


External links


BHDSyndrome.org

Cancer.Net: Birt-Hogg-Dubé Syndrome
{{DEFAULTSORT:Birt-Hogg-Dube syndrome Epidermal nevi, neoplasms, and cysts Autosomal dominant disorders Syndromes with tumors Syndromes affecting the lung Rare syndromes