Reed's syndrome is a rare inherited condition characterised by
multiple cutaneous leiomyoma
Multiple cutaneous leiomyomas, also known as Pilar leiomyomas, arise from the arrectores pilorum muscles, and are made up of a poorly circumscribed proliferation of haphazardly arranged smooth muscle fibers located in the dermis that appear to infi ...
s and, in women,
uterine leiomyoma
Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women with fibroids have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bl ...
s. It predisposes for
renal cell cancer
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, res ...
, an association denominated hereditary leiomyomatosis and renal cell cancer,
and it is also associated with increased risk of uterine
leiomyosarcoma
Leiomyosarcoma is a malignant (cancerous) smooth muscle tumor. A benign tumor originating from the same tissue is termed leiomyoma. While leiomyosarcomas are not thought to arise from leiomyomas, some leiomyoma variants' classification is evolv ...
.
[ The syndrome is caused by a mutation in the fumarate hydratase gene, which leads to an accumulation of fumarate. The inheritance pattern is autosomal dominant.
]
Signs and symptoms
Almost all women present with uterine fibroids, approximately 76% with dermal manifestations and 10–16% with renal tumors.[
The uterine fibroids tend to occur at younger age and larger and more numerous than in general population. They may be distinguishable from sporadic fibroids by special histological features such as prominent nucleoli with perinucleolar halos.][
The skin presentation is of asymmetrical, reddish-brown nodules or papules with a firm consistency, predominantly located on the limbs (]multiple cutaneous leiomyoma
Multiple cutaneous leiomyomas, also known as Pilar leiomyomas, arise from the arrectores pilorum muscles, and are made up of a poorly circumscribed proliferation of haphazardly arranged smooth muscle fibers located in the dermis that appear to infi ...
), although they may occur anywhere, including the face. The lesions, which are typically painful and most often present during the third decade of life, are piloleiomyomata—a benign smooth muscle tumour arising from the arrectores pilorum
The arrector pili muscles, also known as hair erector muscles, are small muscles attached to hair follicles in mammals. Contraction of these muscles causes the hairs to stand on end, known colloquially as goose bumps (piloerection).
Structure
E ...
muscles of the skin. These tumours may also arise in the tunica dartos of the scrotum
The scrotum or scrotal sac is an anatomical male reproductive structure located at the base of the penis that consists of a suspended dual-chambered sac of skin and smooth muscle. It is present in most terrestrial male mammals. The scrotum co ...
and the mammillary muscle of the nipple ( genital leiomyoma), the smooth muscle of blood vessels (angioleiomyoma
Angioleiomyoma (vascular leiomyoma, angiomyoma) of the skin is thought to arise from vascular smooth muscle, and is generally acquired.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). Page 1033. McGraw-Hill. ...
) and the lung ( pulmonary lymphangioleiomyomatosis). A pseudo-Darier sign
Darier's sign is a change observed after stroking lesions on the skin of a person with systemic mastocytosis or urticaria pigmentosa.
In general, the skin becomes swollen, itchy and red. This is a result of compression of mast cells, which a ...
may be present.
The renal cell carcinoma tends to be of the papillary (type 2) form and tends to occur more commonly in women than men with this syndrome. These cancers present earlier than is usual for renal cell carcinomas (typically in the twenties and thirties) and to be at relatively advanced stages at presentation. Tumours have rarely been reported in children. These tumours occur in ~20% of those with this mutation suggesting that other factors are involved in the pathogenesis.
Associated conditions
Other relatively rare conditions have been reported in association with this disease. It is not yet known if these associations are fortuitous or manifestations of the condition itself.
Cerebral cavernomas and massive, macronodular adrenocortical disease have also been reported in association with this syndrome. A case of cutis verticis gyrata
Cutis verticis gyrata is a medical condition usually associated with thickening of the scalp. The condition is identified by excessive thickening of the soft tissues of the scalp and characterized by ridges and furrows, which give the scalp a cer ...
, disseminated collagenoma and Charcot–Marie–Tooth disease
Charcot–Marie–Tooth disease (CMT) is a hereditary motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. This disease is the most ...
in association with a mutation in the fumarate hydratase gene has also been reported. Two cases of ovarian mucinous cystadenoma have also been reported with this mutation.
Cause
The fumarate hydratase gene, located on the long arm of chromosome 1
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...
(1q42.3-43), spans 22 kilobases and has 10 exons. The first exon codes for a signal peptide.
Pathogenesis
While the pathogenetic mechanisms underlying the lesions remain unclear, it has been suggested that the accumulation of fumarate may lead to overexpression of the aldo-keto reductase
The aldo-keto reductase family is a family of proteins that are subdivided into 16 categories; these include a number of related monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase, aldose reductase, prostaglandin F synthase, xy ...
enzyme, AKR1B10
Aldo-keto reductase family 1 member B10 is an enzyme that in humans is encoded by the ''AKR1B10'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ...
. It has also been found that fumarate is present in the mitochondria and in the cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
. The cytoplasmic form appears to have a role in the protection of DNA from molecular injury.
Fumarate has been shown to be a competitive inhibitor of prolyl hydroxylase
Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mec ...
. This inhibition leads to the stabilisation of a number of hypoxia-inducible factors
Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They are only present in parahoxozoan animals.
Discovery
The HIF transcriptional complex w ...
which are thought to predispose to tumorigenesis.
An alternative pathway for the metabolism of fumarate in the presence of these mutations has been described. Other genes involved affected by this mutation are Keap1
Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the ''Keap1'' gene.
Structure
Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 res ...
, Nrf2
Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may reg ...
and HMOX1
''HMOX1'' (heme oxygenase 1 gene) is a human gene that encodes for the enzyme heme oxygenase 1 (). Heme oxygenase (abbreviated HMOX or HO) mediates the first step of heme catabolism, it cleaves heme to form biliverdin.
The ''HMOX'' gene is locat ...
.
Diagnosis
The diagnosis is made either by testing of the fumarate hydratase activity in cultured skin fibroblasts or lymphoblastoid cells and demonstrating reduced activity (≤60%) or by molecular genetic testing. Special histologic features of fibroids may allow an early diagnosis in absence of other symptoms.
Histology
The skin lesions may be difficult to diagnose clinically but a punch biopsy will usually reveal a Grenz zonebr>
separating the tumour from the overlying skin. Histological examination shows dense dermal nodules composed of elongated cells with abundant eosinophilic cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
arranged in Nerve fascicle, fascicles (spindle cell
Von Economo neurons (VENs), also called spindle neurons, are a specific class of mammalian cortical neurons characterized by a large spindle-shaped soma (or body) gradually tapering into a single apical axon (the ramification that ''transmits ...
s). The nuclei are uniform, blunt-ended and cigar-shaped with only occasional mitoses
In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maintai ...
. Special stains that may be of use in the diagnosis include Masson's trichrome, Van Gieson's stain
Van Gieson's stain is a mixture of picric acid and acid fuchsin. It is the simplest method of differential staining of collagen and other connective tissue. It was introduced to histology by American neuropsychiatrist and pathologist Ira Van ...
and phosphotungstic acid
Phosphotungstic acid (PTA) or tungstophosphoric acid (TPA), is a heteropoly acid with the chemical formula . It forms hydrates . It is normally isolated as the ''n'' = 24 hydrate but can be desiccated to the hexahydrate (''n'' = 6). EPTA is the na ...
–haematoxylin
Haematoxylin or hematoxylin (), also called natural black 1 or C.I. 75290, is a compound extracted from heartwood of the logwood tree (''Haematoxylum campechianum'') with a chemical formula of . This naturally derived dye has been used as a ...
.
The renal cell carcinomas have prominent eosinophilic nucleoli
The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of s ...
surrounded by a clear halo.
Differential diagnosis
Differential diagnosis of this condition includes the Birt–Hogg–Dubé syndrome
Birt–Hogg–Dubé syndrome (BHD), also Hornstein–Birt–Hogg–Dubé syndrome, Hornstein–Knickenberg syndrome, and fibrofolliculomas with trichodiscomas and acrochordons is a human autosomal dominant genetic disorder that can cause suscept ...
and tuberous sclerosis. As the skin lesions are typically painful, it is also often necessary to exclude other painful tumors of the skin (including blue rubber bleb nevus, leiomyoma, eccrine spiradenoma, neuroma
A neuroma (; plural: neuromata or neuromas) is a growth or tumor of nerve tissue. Neuromas tend to be benign (i.e. not cancerous); many nerve tumors, including those that are commonly malignant, are nowadays referred to by other terms.
Neuroma ...
, dermatofibroma
A dermatofibroma, or benign fibrous histiocytomas, is a benign nodule in the skin, typically on the legs, elbows or chest of an adult. It is usually painless.
It usually ranges from 0.2cm to 2cm in size but larger examples have been reported. It ...
, 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''. ( ...
, neurilemmoma, endometrioma
Endometrioma is the presence of tissue similar to, but distinct from, the endometrium in and sometimes on the ovary. It is the most common form of endometriosis. Endometrioma is found in 17–44% patients with endometriosis. More broadly, endometr ...
, glomus tumor
:''Glomus tumor was also the name formerly (and incorrectly) used for a tumor now called a paraganglioma.''
A glomus tumor (also known as a "solitary glomus tumor," "solid glomus tumor,") is a rare neoplasm arising from the glomus body and mainl ...
and granular cell tumor
Granular cell tumor is a tumor that can develop on any skin or mucosal surface, but occurs on the tongue 40% of the time.
It is also known as Abrikossoff's tumor, granular cell myoblastoma, granular cell nerve sheath tumor, and granular cell schw ...
; the mnemonic "BLEND-AN-EGG" may be helpful). Other skin lesions that may need to be considered include cylindroma, lipoma
A lipoma is a benign tumor made of 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 include upper back, ...
, poroma
Poromas are rare, benign, cutaneous adnexal tumors. Cutaneous adnexal tumors are a group of skin tumors consisting of tissues that have differentiated (i.e. matured from stem cells) towards one or more of the four primary adnexal structures fo ...
and trichoepithelioma
Trichoepithelioma is a neoplasm of the adnexa of the skin. Its appearance is similar to basal cell carcinoma.
One form has been mapped to chromosome 9p21.
Types
Trichoepitheliomas may be divided into the following types:
:* Multiple familial ...
; these tend to be painless and have other useful distinguishing features.
Treatment
Uterine fibroid
Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women with fibroids have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bl ...
s can be treated with the same methods like sporadic uterine fibroids including antihormonal treatment, surgery or embolisation
Embolization refers to the passage and lodging of an embolus within the circulatory system, bloodstream. It may be of natural origin (pathological), in which word sense, sense it is also called embolism, for example a pulmonary embolism; or i ...
. Substantially elevated risk of progression to or independent development of uterine leiomyosarcoma has been reported which may influence treatment methods.[
The predisposition to renal cell cancer calls for screening and, if necessary, ]urological
Urology (from Greek οὖρον ''ouron'' "urine" and ''-logia'' "study of"), also known as genitourinary surgery, is the branch of medicine that focuses on surgical and medical diseases of the urinary-tract system and the reproductive organ ...
management.
The skin lesions may be difficult to treat as they tend to recur after excision or destructive treatment. Drugs which affect smooth muscle contraction, such as doxazosin
Doxazosin, sold under the brand names Cardura among others, is a medication used to treat symptoms of benign prostatic hyperplasia (enlarged prostate) and hypertension (high blood pressure). For high blood pressure, it is a less preferred option ...
, nitroglycerine
Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating ...
, nifedipine
Nifedipine (3,5-dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate), sold under the brand name Adalat and Procardia, among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Ra ...
and phenoxybenzamine
Phenoxybenzamine (marketed under the trade names Dibenzyline and Dibenyline) is a non-selective, irreversible alpha blocker.
Uses
It is used in the treatment of hypertension, and specifically that caused by pheochromocytoma. It has a slower ons ...
, may provide pain relief.
Topical lidocaine patches have been reported to decrease in severity and frequency of pain cutaneous leiomyomas.
Prognosis
A 2006 review stated that RS often leads renal cancer between ages 30–50. Renal cancer kills about 1 in 3 people, but 5-year survival rates improved between 1974–1976 and 1995–2000, from 52% to 64%.
History
The syndrome was first described by Reed ''et al'' in 1973. The link with the fumarate hydratase gene was uncovered in 2002.
Notes
A database of the mutations of the fumarate hydratase gene is available. Autosomal recessive mutations cause a serious neurological disease known as fumarase deficiency, which is associated with a variety of congenital lesions in the brain.
References
External links
{{Medical resources
, ICD10 =
, ICD9 =
, OMIM = 150800
, OMIM_mult = {{OMIM, 136850, , none
, MedlinePlus =
, eMedicineSubj =
, eMedicineTopic =
, DiseasesDB = 34278
, MeshID = C537112
Reed syndrome
an
Hereditary leiomyomatosis and renal cell cancer
at the Genetic and Rare Diseases Information Center (GARD)
Dermal and subcutaneous growths
Gynaecological neoplasia
Syndromes
Gynaecology
Uterine tumour