A rare, capillary-venous malformations characterized by closely clustered irregular dilated capillaries that can be asymptomatic or that can cause variable neurological manifestations such as seizures, non-specific headaches, progressive or transient focal neurologic deficits, and/or cerebral hemorrhages. Epidemiology The overall prevalence of all CCMs has been estimated at 1/200 to 1/1,000 individuals. Familial cerebral cavernous malformation (FCCM) represents about 20% of all CCM cases with an estimated prevalence of 1/5,000 -1/10,000 and is therefore rare, contrarily to sporadic CCMs which are not. A strong founder effect has been found in Hispanic-American CCM families. Clinical description Close to 60% of FCCM patients are symptomatic. FCCM usually manifests between 20 to 30 years of age, but clinical manifestations can occur at any age.

A number sign (#) is used with this entry because of evidence that this form of cerebral cavernous malformations (CCM2) can be caused by mutation in the CCM2/malcavernin gene (607929). Evidence suggests that a 2-hit mechanism involving biallelic germline and somatic mutations is responsible for CCM2 pathogenesis, see PATHOGENESIS and MOLECULAR GENETICS sections. For a phenotypic description and discussion of genetic heterogeneity of cerebral cavernous malformations, see CCM1 (116860). Clinical Features Ahdab et al. (2008) reported 2 sibs with CCM2 confirmed by genetic analysis. The 57-year-old proband presented with generalized tonic-clonic seizures and status epilepticus.

A number sign (#) is used with this entry because of evidence that this form of cerebral cavernous malformations (CCM3) can be caused by mutation in the PDCD10 gene (609118). Evidence suggests that a 2-hit mechanism involving biallelic germline and somatic mutations is responsible for CCM3 pathogenesis, see PATHOGENESIS and MOLECULAR GENETICS sections. For a phenotypic description and discussion of genetic heterogeneity of cerebral cavernous malformations, see CCM1 (116860). Clinical Features Denier et al. (2006) compared the clinical features of mutation carriers from 86 families with CCM1, 25 families with CCM2 (603284), and 17 families with CCM3, ascertained from academic medical centers in France. Of the 3 groups, CCM3 families had the lowest number of affected individuals per family, and the highest proportion of patients with onset of symptoms before age 15 years.

However, in a study of 168 pregnancies (64 women), 28 with sporadic CCM and 36 with FCCM, only five symptomatic cerebral hemorrhages were reported, most commonly manifesting as seizures.

Complex regional pain syndrome (CRPS) is a rare neurologic disease painful progressive condition that corresponds to a group of disorders characterized by a disproportionate spontaneous or stimulus-induced pain, accompanied by a variably mixed myriad of autonomic and motor disorders including symptoms such as swelling, allodynia, skin blood supply and trophic disturbances. CRPS most often affects one of the arms, legs, hands, or feet and usually occurs after an injury or trauma to that limb.

Complex regional pain syndrome (CRPS) is a chronic pain condition that mainly affects the arms, legs, hands, and feet, but may involve the entire body. CRPS symptoms often begin after surgery or an injury. The main feature of CRPS is continuous, intense pain that is out of proportion to the severity of the injury. The pain gets worse over time and often spreads throughout the entire affected area. Other symptoms may include color and temperature changes of the skin over the affected area; skin sensitivity; sweating; and swelling. The underlying cause of CRPS is often not known. Two classifications of CRPS have been recognized based on causalgia.

Overview Complex regional pain syndrome (CRPS) is a form of chronic pain that usually affects an arm or a leg. complex regional pain syndrome (CRPS) typically develops after an injury, a surgery, a stroke or a heart attack. The pain is out of proportion to the severity of the initial injury. CRPS is uncommon, and its cause isn't clearly understood. Treatment is most effective when started early. In such cases, improvement and even remission are possible. Symptoms Signs and symptoms of CRPS include: Continuous burning or throbbing pain, usually in the arm, leg, hand or foot Sensitivity to touch or cold Swelling of the painful area Changes in skin temperature — alternating between sweaty and cold Changes in skin color, ranging from white and blotchy to red or blue Changes in skin texture, which may become tender, thin or shiny in the affected area Changes in hair and nail growth Joint stiffness, swelling and damage Muscle spasms, tremors and weakness (atrophy) Decreased ability to move the affected body part Symptoms may change over time and vary from person to person. Pain, swelling, redness, noticeable changes in temperature and hypersensitivity (particularly to cold and touch) usually occur first.

Rare hereditary hemochromatosis comprises the rare forms of hereditary hemochromatosis (HH), a group of diseases characterized by excessive tissue iron deposition. These rare forms are hemochromatosis type 2 (juvenile), type 3 (TFR2-related), and type 4 (ferroportin disease) (see these terms). Hemochromatosis type 1 (also called classic hemochromatosis; see this term) is not a rare disease. Epidemiology The rare forms of HH have a broad geographical distribution with few cases described. Clinical description Hemochromatosis causes chronic fatigue and bronzed skin pigmentation, with severe tissue damage in the liver, pancreas, joints, bone, endocrine glands, or heart, which results in various complications usually in adulthood including liver fibrosis (cirrhosis with the risk of hepatocellular carcinoma), diabetes mellitus, arthropathy, osteoporosis, hypogonadotropic hypogonadism, and cardiac failure.

Overview Hemochromatosis (he-moe-kroe-muh-TOE-sis) causes your body to absorb too much iron from the food you eat. Excess iron is stored in your organs, especially your liver, heart and pancreas. Too much iron can lead to life-threatening conditions, such as liver disease, heart problems and diabetes. There are a few types of hemochromatosis, but the most common type is caused by a gene change passed down through families. Only a few people who have the genes ever develop serious problems. Symptoms usually appear in midlife.

Li-Fraumeni syndrome (LFS) is an inherited condition that is characterized by an increased risk for certain types of cancer. Affected people often develop cancer at an earlier age than expected and may be diagnosed with more than one cancer during their lifetime. LFS is primarily associated with sarcomas (cancers of muscle, bone or connective tissue ), breast cancer, brain tumors, leukemia and adrenocortical carcinoma ; however, many other types of cancer have been reported in people with this condition. It is caused by changes (mutations) in the TP53 gene and is inherited in an autosomal dominant manner. Management may include high-risk cancer screening and/or prophylactic surgeries.

A rare, inherited, cancer predisposition syndrome characterized by the early-onset of multiple primary cancers including breast cancer, soft tissue and bone sarcomas, brain tumors, adrenal cortical carcinoma (ACC), leukemias, and other cancers. Epidemiology More than 400 families with Li-Fraumeni (LFS) have been reported in the literature. The estimated prevalence of pathogenic and likely pathogenic germline TP53 mutations is not well defined but has been estimated to range between 1/3,555-5,476. Clinical description The core cancers in Li-Fraumeni syndrome (LFS) are early-onset breast cancer, ACC, soft tissue sarcomas, osteosarcomas, and brain tumors. Also seen in LFS are leukemias, lymphomas, colorectal cancer, and many other cancers.

In one series, the average onset of first cancer for men with LFS was age 17 years; the average onset of first cancer for women was age 28 years when including breast cancer and age 13 years when excluding breast cancer [Bougeard et al 2015].

Li–Fraumeni syndrome Other names Sarcoma family syndrome of Li and Fraumeni Li–Fraumeni syndrome is inherited via an autosomal dominant manner Specialty Oncology , medical genetics , neurology Li–Fraumeni syndrome is a rare, autosomal dominant , hereditary disorder [1] that predisposes carriers to cancer development. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni, Jr. , who first recognized the syndrome after reviewing the medical records and death certificates of 648 childhood rhabdomyosarcoma patients. [2] This syndrome is also known as the sarcoma, breast, leukaemia and adrenal gland ( SBLA ) syndrome . The syndrome is linked to germline mutations of the p53 tumor suppressor gene , [3] which encodes a transcription factor (p53) that normally regulates the cell cycle and prevents genomic mutations. The mutations can be inherited , or can arise from mutations early in embryogenesis , or in one of the parent's germ cells .

A number sign (#) is used with this entry because Li-Fraumeni syndrome-2 is caused by heterozygous mutation in the CHEK2 gene (604373) on chromosome 22q12. For a general phenotypic description and a discussion of genetic heterogeneity of Li-Fraumeni syndrome (LFS), see LFS1 (151623). Clinical Features In affected members of 3 unrelated families, 1 family with classic LFS and 2 with LFS-variant, without mutations in the TP53 gene (191170), Bell et al. (1999) identified heterozygous germline mutations in the CHK2 gene (see, e.g., 604373.0001 and 604373.0002). They defined LFS-variant as the occurrence in an individual of 3 separate primary cancers, with the first cancer diagnosed under age 45 years, or the combination of a proband with childhood cancer or LFS component tumor diagnosed under age 45 years, a first- or second-degree relative with LFS component tumor diagnosed at any age, and a first- or second-degree relative with any cancer diagnosed under age 60 years. CHK2 is a homolog of Saccharomyces cerevisiae RAD53 and Schizosaccharomyces pombe cds1+, protein kinases required for DNA damage and replication checkpoints.

Polycystic kidney disease is a disorder that affects the kidneys and other organs. Clusters of fluid-filled sacs, called cysts, develop in the kidneys and interfere with their ability to filter waste products from the blood. The growth of cysts causes the kidneys to become enlarged and can lead to kidney failure. Cysts may also develop in other organs, particularly the liver. Frequent complications of polycystic kidney disease include dangerously high blood pressure (hypertension), pain in the back or sides, blood in the urine (hematuria), recurrent urinary tract infections, kidney stones, and heart valve abnormalities. Additionally, people with polycystic kidney disease have an increased risk of an abnormal bulging (an aneurysm ) in a large blood vessel called the aorta or in blood vessels at the base of the brain.

A rare, genetic, renal tubular disease characterized by progressive outgrowths of fluid-filled cysts from the renal epithelium, which can manifest with hematuria, urinary tract infections, hypertension, and abdominal or flank pain. The slowly progressive loss of kidney function may evolve to end stage kidney disease (ESKD). Epidemiology Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease, with estimated prevalence of 1/2,500 in Europe. Clinical description Symptoms typically manifests in adulthood; however, approximately 2-5% of cases present before 15 years of age. The renal phenotype ranges from patients in advanced age with preserved kidney function to rare cases of enlarged kidneys that are detected in utero.

A number sign (#) is used with this entry because this form of disordered steroidogenesis is caused by homozygous or compound heterozygous mutations in the POR gene (124015), which encodes cytochrome p450 oxidoreductase, on chromosome 7q11.2. Mutations in this gene also result in a form of Antley-Bixler syndrome (ABS1; 201750). Description This rare variant of congenital adrenal hyperplasia, caused by mutations in the POR gene, results in apparent combined deficiency of P450C17 (609300) and P450C21 (613815) and accumulation of steroid metabolites. The most striking phenotypic feature is that affected girls are born with ambiguous genitalia, indicating intrauterine androgen excess. After birth, however, virilization does not progress and amounts of circulating androgens are low or normal.

Congenital adrenal hyperplasia (CAH) is an inherited endocrine disorder caused by a steroidogenic enzyme deficiency that is characterized by adrenal insufficiency and variable degrees of hyper or hypo androgeny manifestations, depending of the type and the severity of the disease. Epidemiology The estimated prevalence is 1/10,000 and annual incidence ranges from 1/5,000 to 1/15,000. Clinical description The most frequent form of CAH is classical CAH due to a 21-hydroxylase deficiency which can further be divided into simple virilizing, salt wasting or non-classical types (see these terms). Girls present at birth with ambiguous genitalia and variable levels of virilization. They have a normal uterus but abnormal vaginal development. The external genitalia in boys are normal.

Overview Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders that affect the adrenal glands, a pair of walnut-sized organs above the kidneys. The adrenal glands produce important hormones, including: Cortisol, which regulates the body's response to illness or stress Mineralocorticoids, such as aldosterone, which regulate sodium and potassium levels Androgens, such as testosterone, which are male sex hormones required for growth and development in both males and females In people who have CAH , a gene change (mutation) results in a lack of one of the enzymes needed to make these hormones. The two major types of congenital adrenal hyperplasia are: Classic CAH . This rarer, more-severe form is usually detected at birth or in early infancy. Nonclassic CAH . This form is milder and more common. It may not be identified until childhood or early adulthood.

A number sign (#) is used with this entry because of evidence that congenital adrenal hyperplasia (CAH) due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency is caused by homozygous or compound heterozygous mutation in the HSD3B2 gene (613890) on chromosome 1p12. Description Classic 3-beta-hydroxysteroid dehydrogenase deficiency is an autosomal recessive form of CAH characterized by a severe impairment of steroid biosynthesis in both the adrenals and the gonads, resulting in decreased excretion of cortisol and aldosterone and of progesterone, androgens, and estrogens by these tissues. Affected newborns exhibit signs and symptoms of glucocorticoid and mineralocorticoid deficiencies, which may be fatal if not diagnosed and treated early, especially in the severe salt-wasting form. Moreover, male newborns exhibit pseudohermaphroditism with incomplete masculinization of the external genitalia due to an impairment of androgen biosynthesis in the testis. In contrast, affected females exhibit normal sexual differentiation or partial virilization (summary by Rheaume et al., 1992).

A number sign (#) is used with this entry because of evidence that lipoid congenital adrenal hyperplasia (LCAH) is caused by homozygous or compound heterozygous mutation in the gene encoding steroidogenic acute regulatory protein (STAR; 600617) on chromosome 8p11. Description Lipoid congenital adrenal hyperplasia, the most severe disorder of steroid hormone biosynthesis, is caused by a defect in the conversion of cholesterol to pregnenolone, the first step in adrenal and gonadal steroidogenesis. All affected individuals are phenotypic females with a severe salt-losing syndrome that is fatal if not treated in early infancy (summary by Lin et al., 1991 and Bose et al., 1996). Clinical Features Affected individuals may have a severe deficiency of adrenal or gonadal steroids. All affected individuals are phenotypic females irrespective of gonadal sex, and frequently die in infancy if mineralocorticoid and glucocorticoid replacement are not instituted.

Congenital adrenal hyperplasia (CAH) refers to a group of genetic conditions that affect the adrenal glands. These glands sit on top of the kidneys and are responsible for releasing various types of hormones that the body needs to function. Affected people lack an enzyme the adrenal glands need to make one or more of these hormones and often overproduce androgens (male hormones such as testosterone). The signs and symptoms present in each person depend on many factors including the type of CAH, the age of diagnosis, and the sex of the affected person. For example, females with a severe form of the condition may have ambiguous genitalia at birth and if not properly diagnosed, develop dehydration, poor feeding, diarrhea, vomiting and other health problems soon after.

21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia (CAH) . CAH is a group of disorders that affect how the adrenal glands work. In 21-hydroxylase deficiency, a missing enzyme leads to overproduction of specific hormones made by the adrenal glands. There are three types of 21-hydroxylase deficiency that vary by the severity of symptoms. Infants with the more severe forms can experience excessive loss of salt in their urine, which can be life-threatening. Female infants may be born with genitalia that doesn't look male or female ( ambiguous genitalia ).

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (classic 21-OHD CAH) affects the adrenal glands which are responsible for producing specific hormones. There are two types of classic 21-OHD CAH, the salt-wasting form and the simple-virilizing form. Symptoms include abnormal development of the external sex organs in females ( ambiguous genitalia ), early puberty, and short stature. The salt-wasting form also may include the inability to retain salt and water. This can lead to dehydration, low blood pressure, and a life-threatening adrenal crisis.

21-hydroxylase deficiency is an inherited disorder that affects the adrenal glands. The adrenal glands are located on top of the kidneys and produce a variety of hormones that regulate many essential functions in the body. In people with 21-hydroxylase deficiency, the adrenal glands produce excess androgens, which are male sex hormones. There are three types of 21-hydroxylase deficiency. Two types are classic forms, known as the salt-wasting and simple virilizing types. The third type is called the non-classic type. The salt-wasting type is the most severe, the simple virilizing type is less severe, and the non-classic type is the least severe form.

A disorder that is the most common form of congenital adrenal hyperplasia (CAH), characterized by simple virilizing or salt wasting forms that can manifest with genital ambiguity in females and with adrenal insufficiency (in both sexes), and that presents with dehydration, hypoglycemia in the neonatal period (that can be lethal if untreated), and hyperandrogenia. Epidemiology The prevalence is about 1/14,000. Clinical description Classic 21-OHD CAH can be divided into 2 clinical groups: simple-virilizing or salt wasting (see these terms). Clinical signs of classic 21-OHD CAH are observed prenatally or at birth. Girls present with ambiguous genitalia (clitoromegaly, partially fused labia majora with rugae, common urogenital sinus) and the extent of virilization can vary from a nearly male appearance to minimal clitoromegaly. A normal uterus and various degrees of abnormal vaginal development are seen.

Japanese encephalitis is an arboviral disease ( i.e. a disease due to a virus transmitted by an arthropod). Epidemiology The estimated annual incidence of the disease is 1/160 000 but it is 20 times higher in endemic areas. It mainly occurs in rural areas of China, Korea and Japan, in sub-tropical regions of Asia, and in some regions of Oceania. Imported cases are exceptional. The disease is symptomatic in 1-20/1000 infections, and children and young adults are predominantly affected. Clinical description After an incubation period of four to 14 days, infected individuals present with signs ranging from moderate with a headache and low-grade fever to more severe infection with high fever, meningeal syndrome (neck stiffness, vomiting), disorientation and sometimes tremors or coma.

In 1987, HPbCD was used in a medical case involving a boy suffering from severe hypervitaminosis A . [28] On May 17, 2010, the FDA granted Hydroxypropyl-beta-cyclodextrin orphan drug status and designated HPbCD cyclodextrin as a potential treatment for Niemann–Pick type C disease.

Summary Clinical characteristics. Niemann-Pick disease type C (NPC) is a slowly progressive lysosomal disorder whose principal manifestations are age dependent. The manifestations in the perinatal period and infancy are predominantly visceral, with hepatosplenomegaly, jaundice, and (in some instances) pulmonary infiltrates. From late infancy onward, the presentation is dominated by neurologic manifestations. The youngest children may present with hypotonia and developmental delay, with the subsequent emergence of ataxia, dysarthria, dysphagia, and, in some individuals, epileptic seizures, dystonia, and gelastic cataplexy. Although cognitive impairment may be subtle at first, it eventually becomes apparent that affected individuals have a progressive dementia.

A number sign (#) is used with this entry because Niemann-Pick disease type C2 (NPC2) is caused by homozygous mutation in the NPC2 gene (601015) on chromosome 14q24. Description Niemann-Pick type C (NPC) disease is an autosomal recessive lipid storage disorder characterized by progressive neurodegeneration. Approximately 95% of cases are caused by mutations in the NPC1 gene (607623), referred to as type C1 (257220); 5% are caused by mutations in the NPC2 gene (601015), referred to as type C2. The clinical manifestations of types C1 (257220) and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes (summary by Vance, 2006). Clinical Features Vanier et al. (1996) reported 5 patients with NPC2.

Niemann-Pick disease type C (NP-C) is a lysosomal lipid storage disease (see this term) characterized by variable clinical signs, depending on the age of onset, such as prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly, and progressive, often severe neurological symptoms such as cognitive decline, cerebellar ataxia, vertical supranuclear gaze palsy (VSPG), dysarthria, dysphagia, dystonia, seizures, gelastic cataplexy, and psychiatric disorders.

A number sign (#) is used with this entry because of evidence that metachromatic leukodystrophy due to saposin B deficiency is caused by homozygous or compound heterozygous mutation in the prosaposin gene (PSAP; 176801) on chromosome 10q22. This disorder is genetically distinct from metachromatic leukodystrophy (MLD; 250100) due to deficiency of arylsulfatase A (ARSA; 607574). Clinical Features Shapiro et al. (1979) and Hahn et al. (1982) described 3 patients from 2 families with metachromatic leukodystrophy and normal arylsulfatase A activity. Stevens et al. (1981) defined this biochemically distinct form of metachromatic leukodystrophy in 2 sibs of consanguineous Mexican-American parents. The clinical picture was that of juvenile MLD. Instead of the expected profound deficiency of arylsulfatase A, their enzyme levels were about half-normal, and the enzyme from fibroblasts had properties identical to those of normal fibroblasts.

Metachromatic leukodystrophy is an inherited condition characterized by the accumulation of fats called sulfatides in cells, especially cells of the nervous system. This accumulation results in progressive destruction of white matter of the brain , which consists of nerve fibers covered by myelin. Affected individuals experience progressive deterioration of intellectual functions and motor skills, such as the ability to walk. They also develop loss of sensation in the extremities, incontinence , seizures, paralysis , inability to speak, blindness, and hearing loss. Eventually they lose awareness of their surroundings and become unresponsive.

Overview Metachromatic leukodystrophy is a rare hereditary (genetic) disorder that causes fatty substances (lipids) to build up in cells, particularly in the brain, spinal cord and peripheral nerves. This buildup is caused by a deficiency of an enzyme that helps break down lipids called sulfatides. The brain and nervous system progressively lose function because the substance that covers and protects the nerve cells (myelin) is damaged. There are three forms of metachromatic leukodystrophy, which involve different age ranges: late infantile form, juvenile form and adult form. Signs and symptoms can vary. The infantile form is the most common and progresses more rapidly than the other forms.

A rare lysosomal disease characterized by accumulation of sulfatides in the central and peripheral nervous system due to deficiency of the enzyme arylsulfatase A, leading to demyelination. Three clinical subtypes can be distinguished based on the age of onset: late infantile, juvenile, and adult. Lead symptoms are deterioration in motor or cognitive function or behavioral problems, depending on the subtype, all eventually culminating in a decerebrated state and death after a highly variable disease course and duration. Mode of inheritance is autosomal recessive.

In 10 members of 4 generations with several instances of male-to-male transmission, Wright et al. (1988) described an apparent variant of adult-onset metachromatic leukodystrophy. Arylsulfatase A levels were normal, yet the histologic findings in the autopsy in 1 case were those of metachromatic leukodystrophy, and thin-layer chromatography confirmed an excess of sulfatides in the white matter of the brain. The adrenals were unaffected. Disabling hypotension was a striking feature in 2 brothers studied in detail. Because adrenal function was normal, autonomic neuropathy was considered the cause of this feature. The index case, a 55-year-old white male, presented to hospital 3 months before his death with a 2 to 3 year history of progressive difficulty walking.

A number sign (#) is used with this entry because this form of peroxisomal biogenesis disorder (PBD9B) is caused by homozygous or compound heterozygous mutation in the PEX7 gene (601757) on chromosome 6q23. Description While most patients of PBD complementation group 11 manifest rhizomelic chondrodysplasia punctata (RCDP1; 215100), a few have been reported with unusually mild phenotypes with longer survival, less neurologic involvement, normal or near-normal growth, and absence of rhizomelia (Braverman et al., 2002). In some cases this phenotype was indistinguishable from that of classic Refsum disease (266500) and patients carried this diagnosis. Individuals with PBDs of complementation group 11 (CG11, equivalent to CGR) have mutations in the PEX7 gene. For information on the history of PBD complementation groups, see 214100.

A number sign (#) is used with this entry because classic Refsum disease is caused by mutation in the gene encoding phytanoyl-CoA hydroxylase (PHYH, or PAHX; 602026) on chromosome 10. Description Refsum disease is an autosomal recessive inborn error of lipid metabolism classically characterized by a tetrad of clinical abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells. However, not all patients show all these features. All patients have accumulation of an unusual branched-chain fatty acid, phytanic acid, in blood and tissues. Other variable features include cardiac dysfunction, nerve deafness, ichthyosis, and multiple epiphyseal dysplasia (review by Skjeldal et al., 1987). Increased levels of phytanic acid can also be found in peroxisomal biogenesis disorders; see Zellweger syndrome (see 214100) (Skjeldal et al., 1987).

Refsum disease is an inherited condition that causes vision loss, absence of the sense of smell (anosmia), and a variety of other signs and symptoms. The vision loss associated with Refsum disease is caused by an eye disorder called retinitis pigmentosa. This disorder affects the retina , the light-sensitive layer at the back of the eye. Vision loss occurs as the light-sensing cells of the retina gradually deteriorate. The first sign of retinitis pigmentosa is usually a loss of night vision, which often becomes apparent in childhood.

A metabolic disease characterized by anosmia, cataract, early-onset retinitis pigmentosa and possible neurological manifestations, including peripheral neuropathy and cerebellar ataxia. Other features can be deafness, ichthyosis, skeletal abnormalities, and cardiac arrhythmia. It is characterized biochemically by accumulation of phytanic acid in plasma and tissues. Epidemiology About 60 cases of Refsum disease (RD) have been reported worldwide. Prevalence rates are not known but the disorder may be underdiagnosed.

Refsum disease is an inherited condition that causes vision loss, loss of smell (anosmia), and a variety of other signs and symptoms. The vision loss associated with Refsum disease is caused by an eye disorder called retinitis pigmentosa . Other features can include bone abnormalities of the hands and feet; progressive muscle weakness and wasting; poor balance and coordination (ataxia); hearing loss; arrhythmias and heart abnormalities; and dry, scaly skin (ichthyosis). Refsum disease can result from mutations in the PHYH gene or the PEX7 gene and is inherited in an autosomal recessive pattern.

A number sign (#) is used with this entry because orthostatic hypotension-1 (ORTHYP1) due to congenital dopamine beta-hydroxylase deficiency is caused by homozygous or compound heterozygous mutation in the DBH gene (609312) on chromosome 9q34. Genetic Heterogeneity of Orthostatic Hypotension See also ORTHYP2 (618182), caused by mutation in the CYB561 gene (600019) on chromosome 17q11. Clinical Features Robertson et al. (1986) reported a 33-year-old woman of Scottish-Irish descent with isolated failure of autonomic noradrenergic neurotransmission caused by a defect in the beta-hydroxylation of dopamine in peripheral nerves. Clinical features included orthostatic hypotension, ptosis, nasal stuffiness, and a neonatal history of delayed eye opening. From age 2 years, she had had episodes of syncope, especially after exercise, and marked ptosis.

This article may contain indiscriminate , excessive , or irrelevant examples . Please improve the article by adding more descriptive text and removing less pertinent examples . See Wikipedia's guide to writing better articles for further suggestions. ( August 2020 ) This article's text uses more words than are necessary . Please help improve this article by using fewer words whilst keeping the content of the article. ( August 2020 ) Dopamine beta hydroxylase deficiency Other names DβH deficiency Dopamine beta hydroxylase is the enzyme responsible for converting dopamine (pictured) to norepinephrine . Dopamine beta (β)-hydroxylase deficiency is a condition involving inadequate dopamine beta-hydroxylase .

Dopamine beta hydroxylase deficiency is a disease which affects the body’s ability to regulate blood pressure and body temperature. Symptoms typically begin in late childhood and include vomiting, dehydration, low blood pressure, especially upon standing ( orthostatic hypotension ), and low blood sugar levels ( hypoglycemia ). Low blood pressure can also cause dizziness, blurred vision, and difficulty exercising. Other symptoms may include drooping eyelids (ptosis), nasal congestion, muscle pain, and weakness. Dopamine beta hydroxylase deficiency is caused by mutation in the DBH gene and is inherited in an autosomal recessive manner.

Dopamine beta (β)-hydroxylase deficiency is a condition that affects the autonomic nervous system, which controls involuntary body processes such as the regulation of blood pressure and body temperature. Problems related to this disorder can first appear during infancy. Early signs and symptoms may include episodes of vomiting, dehydration, decreased blood pressure (hypotension), difficulty maintaining body temperature, and low blood sugar (hypoglycemia). Individuals with dopamine β-hydroxylase deficiency typically experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting. This sudden drop in blood pressure is usually more severe when getting out of bed in the morning, during hot weather, and as a person gets older. People with dopamine β-hydroxylase deficiency experience extreme fatigue during exercise (exercise intolerance) due to their problems maintaining a normal blood pressure.

Dopamine beta-hydroxylase deficiency is an extremely rare genetic metabolic disorder characterized by autonomic dysregulation leading mainly to orthostatic hypotension.

Overview Bullous pemphigoid (BUL-us PEM-fih-goid) is a rare skin condition that causes large, fluid-filled blisters. They develop on areas of skin that often flex — such as the lower abdomen, upper thighs or armpits. Bullous pemphigoid is most common in older adults. Bullous pemphigoid occurs when your immune system attacks a thin layer of tissue below your outer layer of skin. The reason for this abnormal immune response is unknown, although it sometimes can be triggered by taking certain medications. Bullous pemphigoid often goes away on its own in a few months, but may take as many as five years to resolve.

Autoimmune disease of skin and connective tissue characterized by large blisters Bullous pemphigoid A photo of legs covered in popped blisters caused by bullous pemphigoid. The blisters cover his entire body. Specialty Dermatology Bullous pemphigoid is an autoimmune pruritic skin disease preferentially in older people, aged over 60, that may involve the formation of blisters ( bullae ) in the space between the epidermal and dermal skin layers . The disorder is a type of pemphigoid . It is classified as a type II hypersensitivity reaction, with the formation of anti- hemidesmosome antibodies. Contents 1 Signs and symptoms 2 Causes 3 Pathophysiology 4 Diagnosis 5 Treatment 6 Prognosis 7 Epidemiology 8 Research 9 See also 10 References 11 Further reading 12 External links Signs and symptoms [ edit ] Clinically, the earliest lesions may appear as a hives -like red raised rash, but could also appear dermatitic, targetoid , lichenoid , nodular, or even without a rash ( essential pruritus ). [1] Tense bullae eventually erupt, most commonly at the inner thighs and upper arms, but the trunk and extremities are frequently both involved. Any part of the skin surface can be involved. Oral lesions are present in a minority of cases. [2] The disease may be acute, but can last from months to years with periods of exacerbation and remission. [3] Several other skin diseases may have similar symptoms.

Bullous pemphigoid is a skin disorder characterized by large blisters. The blisters are usually located on the arms, legs, or middle of the body. In some people, the mouth or genitals are also affected. The blisters may break open and form ulcers or open sores. Bullous pemphigoid usually occurs in older persons and is rare in young people. Symptoms may come and go. In most patients, the condition goes away after several years.

A rare autoimmune bullous skin disease characterized by acquired, subepidermal tense bullae occurring on normal of inflamed skin and that is typically widespread (occurring in the flexor regions of the proximal arms and legs, in the armpits, groin and the abdomen) and often associated with pruritus. The evolution is typically chronic with spontaneous exacerbations and remission. Epidemiology Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. It has an estimated prevalence of 1/4,000 in Europe. The incidence is reported to be increasing but currently ranges between 2-22/1,000,000 worldwide. Clinical description BP predominantly affects the elderly with an average age of 80 years and is significantly associated with neurological disorders.

Epidermolysis bullosa simplex (EBS) is one of the major forms of epidermolysis bullosa , a group of genetic conditions that cause the skin to be very fragile and to blister easily. EBS is classified into two groups of subtypes by the layer of skin at which the peeling originates. The basal subtypes cause skin peeling at the lower layers of the epidermis. The most common basal subtypes include EBS localized , Dowling Meara EBS , Generalized other EBS and EBS with muscular dystrophy . More rarely seen basal subtypes include EBS with mottled pigmentation , EBS with pyloic atreseia , EBS Ogna , and EBS circinate migratory .

Epidermolysis bullosa simplex Epidermolysis bullosa simplex Specialty Medical genetics Epidermolysis bullosa simplex ( EBS ), is a disorder resulting from mutations in the genes encoding keratin 5 or keratin 14 . [1] : 598 [2] Blister formation of EBS occurs at the dermoepidermal junction . Sometimes EBS is called epidermolytic . [ citation needed ] Contents 1 Cause 2 Diagnosis 2.1 Classification 3 Management 4 See also 5 References 6 Further reading 7 External links Cause [ edit ] Absence of keratin-5,14 since birth. [ citation needed ] Diagnosis [ edit ] Classification [ edit ] Epidermolysis bullosa simplex may be divided into multiple types: Type Locus & Gene OMIM Epidermolysis bullosa simplex with migratory circinate erythema 12q13 ( KRT5 ) 609352 Epidermolysis bullosa simplex with mottled pigmentation. Associated with a recurrent mutation in KRT14. [3] : 557 [4] [5] 12q13 ( KRT5 ) 131960 Epidermolysis bullosa simplex, autosomal recessive 17q12-q21 ( KRT14 ) 601001 Generalized epidermolysis bullosa simplex Also known as "Koebner variant of generalized epidermolysis bullosa simplex", presents at birth to early infancy with a predilection for the hands, feet, and extremities, and palmar-plantar hyperkeratosis and erosions may be present. [1] : 598 [3] : 556 17q12-q21 ( KRT5 ), 12q13 ( KRT14 ) 131900 Localized epidermolysis bullosa simplex Also known as "Weber–Cockayne syndrome", [5] : 460 and "Weber–Cockayne variant of generalized epidermolysis bullosa simplex", is characterized by onset in childhood or later in life, and is the most common variant of epidermolysis bullosa simplex. [1] : 598 [3] : 557 17q12-q21 ( KRT5 ), 17q11-qter, 12q13 ( KRT14 ) 131800 Epidermolysis bullosa herpetiformis Also known as "Dowling-Meara epidermolysis bullosa simplex", presents at birth with a generalized distribution, often with oral mucosa involvement and variable lesions in infancy. [1] : 598 [3] : 557 17q12-q21 ( KRT5 ), 12q13 ( KRT14 ) 131760 Epidermolysis bullosa simplex with muscular dystrophy A rare clinical entity, and is the only epidermolytic epidermolysis bullosa described that is not caused by a keratin mutation, presenting as a generalized intraepidermal blistering similar to the Koebner variant of generalized epidermolysis bullosa simplex , but also associated with adult onset muscular dystrophy. [1] : 598 [3] : 557 [5] 8q24 ( PLEC1 ) 226670 Epidermolysis bullosa simplex with pyloric atresia 8q24 ( PLEC1 ) 612138 Epidermolysis bullosa simplex of Ogna Has onset in infancy, presenting with seasonal blistering on acral areas during summer months. [1] : 598 [3] : 557 [5] 8q24 ( PLEC1 ) 131950 Management [ edit ] No cure for EB Treat symptoms Protect skin, stop blister formation, promote healing Prevent complications Necessary treatment: use oral and topical steroid for healing and prevent complication Maintain cool environment, avoid overheating and decreases friction See also [ edit ] Epidermolysis bullosa List of cutaneous conditions caused by mutations in keratins References [ edit ] ^ a b c d e f Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine . (6th ed.). McGraw-Hill. ISBN 0-07-138076-0 . ^ Bardhan, Ajoy; Bruckner-Tuderman, Leena; Chapple, Iain L.

Epidermolysis bullosa simplex (EBS) is a group of hereditary epidermolysis bullosa (HEB) disorders characterized by skin fragility resulting in intraepidermal blisters and erosions that occur either spontaneously or after physical trauma. Epidemiology Reported prevalence ranges from 1/215,000 in the USA to 1/35,000 in Scotland. Clinical description Onset is usually at or shortly after birth, although blistering in localized EBS may not develop until late childhood or early adulthood. Along with localized or generalized blistering and erosions, sometimes showing characteristic patterns (herpetiform grouping), cutaneous features may include nail shedding and dystrophy, and, rarely, milia formation. Scarring is mostly absent or minimal (mild atrophic wrinkling and dyspigmentation).

Hoyeraal–Hreidarsson syndrome Other names Progressive pancytopenia-immunodeficiency-cerebellar hypoplasia syndrome [1] This condition is inherited in an X-linked recessive manner. Specialty Medical genetics Hoyeraal–Hreidasson syndrome [2] ) is a very rare multisystem X-linked recessive disorder characterized by excessively short telomeres and is considered a severe form of dyskeratosis congenita . [2] [3] Being an X-linked disorder, Hoyeraal–Hreidasson syndrome primarily affects males. Patients typically present in early childhood with cerebellar hypoplasia , immunodeficiency , progressive bone marrow failure , and intrauterine growth restriction . [2] The primary cause of death in Hoyeraal–Hreidasson syndrome is bone marrow failure, but mortality from cancer and pulmonary fibrosis is also significant. [4] [5] [6] Contents 1 Presentation 1.1 Overlap with dyskeratosis congenita 2 Pathogenesis 3 Diagnosis 4 Treatment 5 See also 6 References 7 External links Presentation [ edit ] The currently recognized features are cerebellar hypoplasia , immunodeficiency , progressive bone marrow failure , and intrauterine growth restriction . Patients also commonly exhibit symptoms such as microcephaly , aplastic anemia , and intellectual disability . [3] Overlap with dyskeratosis congenita [ edit ] Patients with Hoyeraal–Hreidasson syndrome frequently present with the mucocutaneous triad of nail dysplasia , lacy skin pigmentation , and oral leukoplakia . [ citation needed ] Pathogenesis [ edit ] Although the pathogenesis remains unknown, it is strongly suspected that the clinical sequelae of Hoyeraal–Hreidasson syndrome arise from the accelerated telomere shortening. [2] It has been associated with mutations in the poly(A)-specific ribonuclease poly(A)-specific ribonuclease gene. [7] Diagnosis [ edit ] Neuroimaging – cerebellar hypoplasia /atrophy, small brainstem, thin corpus callosum and cerebral calcifications Molecular genetic testing – for confirmation Treatment [ edit ] Current treatment is supportive: [ citation needed ] The aplastic anemia and immunodeficiency can be treated by bone marrow transplantation. Supportive treatment for gastrointestinal complications and infections.

A number sign (#) is used with this entry because of evidence that autosomal dominant dyskeratosis congenita-6 (DKCA6) and autosomal recessive dyskeratosis congenita-7 (DKCB7) are caused by heterozygous and compound heterozygous mutation, respectively, in the ACD gene (609377) on chromosome 16q22. One family with each disorder has been reported. Description Dyskeratosis congenita is a multisystem disorder caused by defective telomere maintenance. Features are variable and include bone marrow failure, nail dysplasia, oral leukoplakia, and increased risk of cancer (summary by Kocak et al., 2014). For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550). Clinical Features Guo et al. (2014) reported a white family in which 3 women in 3 subsequent generations had progressive bone marrow failure.

A number sign (#) is used with this entry because of evidence that autosomal recessive dyskeratosis congenita-6 (DKCB6) is caused by homozygous or compound heterozygous mutation in the PARN gene (604212) on chromosome 16p13. Description Autosomal recessive dyskeratosis congenita-6 is a bone marrow failure disorder associated with abnormal skin pigmentation, nail dystrophy, oral leukoplakia, microcephaly, and developmental delay (summary by Tummala et al., 2015). For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550). Clinical Features Tummala et al. (2015) reported 4 children from 3 unrelated families with dyskeratosis congenita. Two of the families were of Pakistani origin. Clinical features included abnormal skin pigmentation, leukoplakia, nail dystrophy, bone marrow failure, intrauterine growth retardation, developmental delay, microcephaly, and cerebellar hypoplasia.

A number sign (#) is used with this entry because autosomal dominant dyskeratosis congenita-3 (DKCA3) is caused by heterozygous mutation in the TINF2 gene (604319) on chromosome 14q12. Description Dyskeratosis congenita is an inherited bone marrow failure syndrome classically characterized by the triad of mucosal leukoplakia, nail dysplasia, and abnormal skin pigmentation. Affected individuals have an increased risk of aplastic anemia and malignancy. Less common features include epiphora, premature gray hair, microcephaly, developmental delay, and pulmonary fibrosis, among others. The phenotype is highly variable. All affected individuals have shortened telomeres due to a defect in telomere maintenance (summary by Savage et al., 2008).

An X-linked syndromic intellectual disability considered to be a severe variant of dyskeratosis congenita characterized by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, progressive combined immune deficiency and aplastic anemia. Epidemiology Hoyeraal-Hreidarsson syndrome (HHS) prevalence is unknown. The syndrome may be underdiagnosed due to high mortality rates. Clinical description The disease generally presents in early childhood and primarily affects males. Growth retardation is usually of prenatal onset. Other clinical manifestations include microcephaly, mucocutaneous lesions (hyperpigmentation, nail dystrophy, premalignant leukoplakia affecting oral and gastrointestinal mucosa), early onset bone marrow failure, immunodeficiency and pancytopenia. Cancer predisposition is also reported. Etiology HSS is caused by mutations in the DKC1 gene (Xq28), encoding the nucleolar protein dyskerin which interacts with the human telomerase RNA complex.

A number sign (#) is used with this entry because autosomal recessive dyskeratosis congenita-5 (DKCB5) is caused by homozygous or compound heterozygous mutation in the RTEL1 gene (608833) on chromosome 20q13. Heterozygous mutation in the RTEL1 gene can cause autosomal dominant dyskeratosis congenita-4 (DKCA4). Description Dyskeratosis congenita (DKC) is a bone marrow failure syndrome characterized by severely shortened telomeres and diverse clinical symptoms. The classic presentation of DKC includes nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is a severe clinical variant of DKC that is characterized by intrauterine growth failure, microcephaly, developmental delay, immunodeficiency, bone marrow failure, and cerebellar hypoplasia.

A number sign (#) is used with this entry because autosomal dominant dyskeratosis congenita-2 (DKCA2) and autosomal recessive dyskeratosis congenita-4 (DKCB4) are caused by heterozygous and homozygous or compound heterozygous mutation, respectively, in the TERT gene (187270) on chromosome 5p15. Description Dyskeratosis congenita is a multisystem disorder caused by defective telomere maintenance. Features are variable and include bone marrow failure, pulmonary and liver fibrosis, and premature graying of the hair (summary by Armanios et al., 2005). For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550). Clinical Features Armanios et al. (2005) reported a 3-generation family in which at least 6 members had autosomal dominant dyskeratosis congenita without skin manifestations.

Silver-Russell syndrome is characterized by growth retardation with antenatal onset, characteristic facies and limb asymmetry. Epidemiology The incidence is evaluated at 1-30/100 000 cases and about 400 cases have been reported in the literature. Clinical description Weight is often more affected than size, with little subcutaneous fat tissue. Bone maturation is delayed, in accordance with small stature. The fontanelle may be late to close. The skull has a normal circumference, which may contrast with the rest of the body and confers a pseudohydrocephalic appearance.

A number sign (#) is used with this entry because of evidence that severe growth restriction with distinctive facies (GRDF) is caused by heterozygosity for a paternally inherited mutation in the IGF2 gene (147470) on chromosome 11p15. One such family has been reported. Silver-Russell syndrome (SRS; 180860), which has overlapping features, is caused by epigenetic alteration in the chromosome 11p15 region. Clinical Features Begemann et al. (2015) reported a 4-generation family in which 4 affected individuals had severe prenatal and postnatal growth restriction and a distinctive triangular face with prominent forehead and low-set ears. The proband was a 26-year-old man born with hypotrophy and relative macrocephaly, who also exhibited right ulnar ray defect (missing digits 3-5) and contracture of the right elbow with pterygium. He had severe feeding problems that necessitated a nasogastric tube for the first 3 years of life.

The possibility of an X-linked form was raised by Partington (1985) on the basis of the following observations: 2 brothers, aged 7 and 4, had prenatal growth retardation, triangular facies and cafe-au-lait (CAL) spots. Both had asthma. The mother was 160 cm tall and had CAL spots. Her 4 brothers were tall with no spots. Of her 5 sisters, 3 were over 168 cm tall and had no spots; 2 were 156 cm tall and had CAL spots. Partington (1985) suggested that this may represent X-linked inheritance with severe expression in males and mild expression in females. In the full report with illustrations (Partington, 1986), the pigmentary anomaly was presented as quite different from cafe-au-lait spots.

A number sign (#) is used with this entry because 20 to 60% of cases of Silver-Russell syndrome (SRS) are caused by the epigenetic changes of DNA hypomethylation at the H19/IGF2-imprinting control region (ICR1; 616186) on chromosome 11p15.5. ICR1 regulates the imprinted expression of H19 (103280) and IGF2 (147470). About 10% of SRS cases are due to maternal uniparental disomy of chromosome 7 (summary by Penaherrera et al., 2010). Description Silver-Russell syndrome is a clinically heterogeneous condition characterized by severe intrauterine growth retardation, poor postnatal growth, craniofacial features such as a triangular shaped face and a broad forehead, body asymmetry, and a variety of minor malformations. The phenotypic expression changes during childhood and adolescence, with the facial features and asymmetry usually becoming more subtle with age.

Russell-Silver syndrome (RSS) is a rare condition associated with poor growth both before and after birth. Signs and symptoms vary and may include low birth weight, short stature, characteristic facial features, large head in relation to body size, body asymmetry, and feeding difficulties. Other features may include poor appetite, clinodactyly (curved finger), digestive system abnormalities, delayed development, and/or learning disabilities. The genetic causes of RSS are complex and relate to certain genes that control growth. Sometimes, the genetic cause cannot be identified. Most cases are not inherited from a parent and occur sporadically .

Russell-Silver syndrome is a growth disorder characterized by slow growth before and after birth. Babies with this condition have a low birth weight and often fail to grow and gain weight at the expected rate (failure to thrive). Head growth is normal, however, so the head may appear unusually large compared to the rest of the body. Affected children are thin and have poor appetites, and some develop recurrent episodes of low blood sugar (hypoglycemia) as a result of feeding difficulties. Adults with Russell-Silver syndrome are short; the average height for affected men is about 151 centimeters (4 feet, 11 inches) and the average height for affected women is about 140 centimeters (4 feet, 7 inches).

Silver-Russell syndrome Other names Silver–Russell dwarfism A somewhat triangular head and delicate facial features are typical characteristics of Silver-Russell syndrome. Specialty Medical genetics Silver–Russell syndrome ( SRS ), also called Silver–Russell dwarfism , is a rare congenital growth disorder . In the United States it is usually referred to as Russell–Silver syndrome ( RSS ), and Silver–Russell syndrome elsewhere. It is one of 200 types of dwarfism and one of five types of primordial dwarfism . Silver–Russell syndrome occurs in approximately one out of every 50,000 to 100,000 births.

A number sign (#) is used with this entry because of evidence that mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) is caused by compound heterozygous mutation in the ECHS1 gene (602292) on chromosome 10q26. Description Mitochondrial short-chain enoyl-CoA hydratase-1 deficiency is an autosomal recessive inborn error of metabolism characterized by severely delayed psychomotor development, neurodegeneration, increased lactic acid, and brain lesions in the basal ganglia (summary by Peters et al., 2014). Clinical Features Peters et al. (2014) reported 2 sibs, born of unrelated parents of Greek ancestry, with a severe neurologic disorder resulting in death from cardiorespiratory failure at ages 4 and 8 months. Both patients presented at birth with hypotonia, poor suck, and episodic apnea. One of the patients also had vertical nystagmus as well as cardiac abnormalities, including ventricular septal defect and severe progressive hypertrophic obstructive cardiomyopathy.

Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency is an inborn error of metabolism characterized by delayed psychomotor development, neurological degeneration, increased lactic acid , and brain lesions in structures of the brain known as the basal ganglia . It is one subtype of Leigh-Like syndrome . Only a few cases have being reported. Symptoms may include delayed motor and speech development, hearing problems, poor muscle tone (hypotonia), poor suck, and sporadic lack of breath (apnea). Other symptoms reported include abnormal eye movements (nystagmus), heart defects, brain anomalies, and abnormal movements. This condition is caused by mutations in the ECHS1 gene. It is inherited in an autosomal recessive pattern.