Cicatricial Alopecia

Cicatricial alopecias are classified as primary or secondary. This discussion is confined to the primary cicatricial alopecias, in which the hair follicle is the target of a destructive inflammatory process. In secondary cicatricial alopecias, destruction of the hair follicle is incidental to a non-follicle-directed process or external injury, such as severe infections, burns, radiation, or tumors.

Affected areas of the scalp may have redness, scaling, increased or decreased pigmentation, pustules, or draining sinuses. Other cases may show little signs of inflammation. The inflammation that destroys the follicle is below the skin surface and there is usually no scar seen on the scalp, although the affected scalp is usually left bare and smooth without hair and without the usual pore markings.

The cause of the various cicatricial alopecias is not well understood. However, all types of cicatricial alopecias involve inflammation directed at the upper part of the hair follicle where the stem cells and sebaceous gland (oil gland) are located. If the stem cells and sebaceous gland are destroyed, there is no possibility for regeneration of the hair follicle, leading to permanent hair loss. Cicatricial alopecias are not contagious.

Cicatricial alopecias affect healthy men and women of all ages, although primary cicatricial alopecia is not usually seen in children. Cicatricial alopecias occur worldwide. Epidemiologic studies have not been performed to determine the incidence of cicatricial alopecias. In general, they are not common.

Symptoms of the following disorder can be similar to those of cicatricial alopecia. Comparisons may be useful for a differential diagnosis:

Chronic cutaneous lupus erythematosus (CCLE) is predominantly a cutaneous disease with few systemic complications. Scarring and disfiguring changes in the skin (discoid lesons) are commonly seen in this disease. It occurs more frequently in females than males and more commonly in adults than children.

Primary cicatricial alopecias are classified by the predominant type of inflammatory cells that attack the hair follicles (i.e., lymphocytes, neutrophils, or mixed inflammatory cells), and treatment strategies are different for each subtype and each patient.


Citrullinemia type I

Citrullinemia type I (CTLN1) is a rare autosomal recessive genetic disorder that includes a neonatal acute (classic) form, a milder late-onset form, a form that begins during or after pregnancy and an asymptomatic form.

The severity of CTLN1 varies from patient to patient. The classic form, characterized by profound lack of ASS enzyme activity, displays symptoms shortly after birth (neonatal period). A milder form of the disorder, which is characterized by partial lack of the ASS enzyme, affects some infants later during infancy or childhood.

CTLN1 is caused by changes (mutations or pathogenic variants) in the ASS1 gene that is responsible for production of the argininosuccinate synthetase (ASS) enzyme. The symptoms of CTLN1 develop due to deficiency of this enzyme, which is needed to detoxify ammonia in the body. Failure to properly remove ammonia via synthesis of urea leads to the abnormal accumulation of ammonia in the blood (hyperammonemia).

CTLN1 occurs in approximately 1/57,000 births.

Symptoms of the following disorders may be similar to those of citrullinemia type 1. Comparisons may be useful for a differential diagnosis:

The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which waste nitrogen is converted into urea and removed from the body through the urine. Ammonia is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, intolerance to protein and/or coma. The liver may be abnormally enlarged (hepatomegaly) in some patients. In severe cases, life-threatening complications often result. In addition to citrullinemia, the other urea cycle disorders are: carbamyl phosphate synthetase (CPS) deficiency; argininosuccinic acid lyase deficiency; ornithine transcarbamylase (OTC) deficiency; arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency. (For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)


Classic Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) is a general term for several rare genetic disorders that are characterized by the accumulation of iron in various organs of the body such as the liver, heart and pancreas. The abnormally stored iron can damage affected organs, potentially causing a variety of different symptoms. The most common form of hemochromatosis is known by several different names including hemochromatosis type I, HFE-related hemochromatosis, hereditary hemochromatosis and classic hereditary hemochromatosis. Iron accumulation in classic hereditary hemochromatosis occurs slowly over many years. Eventually, iron accumulation causes tissue damage and impaired functioning of affected organs. In many affected individuals, symptoms may not become apparent until some point between 40-60 years of age. Onset is usually earlier for men compared to women. Common symptoms include abdominal pain, weakness, lethargy, and unintended weight loss. Without treatment, classic hereditary hemochromatosis can progress to cause serious, life-threatening complications including failure of affected organs.

The symptoms of classic hereditary hemochromatosis develop gradually over many years because of the excess accumulation of iron in the body. Symptoms usually become apparent at some point between 40-60 years of age, but may develop early or later. Symptoms rarely develop before 20 years of age. The specific symptoms that occur may vary depending upon the specific organs affected. The severity of the disorder may also vary. Some individuals may have mild, undetected cases, while others have serious complications including organ failure.

Classic hereditary hemochromatosis is caused by changes (mutations) of the HFE gene. This mutation is inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

The exact prevalence of classic hereditary hemochromatosis is unknown. The disorder is thought to be the most common autosomal recessive disorder in Caucasian populations. In individuals of Northern European descent, the prevalence is estimated to be as high as 1 in 227 individuals in the general population. Approximately 10 percent of the Caucasian population is estimated to be a carrier for classic hereditary hemochromatosis (i.e., has one mutation of the HFE gene). Some individuals who have genetic mutations that cause classic hereditary hemochromatosis do not develop symptoms of the disorder, making it difficult to determine the true frequency of classic hereditary hemochromatosis in the general population.

Symptoms of the following disorders can be similar to those of classic hereditary hemochromatosis. Comparisons may be useful for a differential diagnosis.

A diagnosis of classic hereditary hemochromatosis is made based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.


Classic Infantile CLN1 Disease

婴儿神经元蜡样质脂褐质沉积症

The signs and symptoms of classic infantile CLN1 disease usually become apparent between 2 and 24 months of age. Infants will develop normally initially, but then become to regress. Their mental and motor development levels off and then begins to decline. Many infants are never able to speak or walk. However, some children do not become ill until later because they still have residual enzyme activity.

Classic infantile CLN1 disease is caused by an alteration in the PPT1 gene (designated CLN1). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

Classic infantile CLN1 disease affects males and females in equal numbers. In the United States, classic infantile CLN1 disease along with other forms of neuronal ceroid lipofuscinosis occurs in approximately three in 100,000 live births. Classic infantile CLN1 disease occurs with greater frequency in Finland where its prevalence is estimated to be 1 in 190,000.

Symptoms of the following disorders can be similar to those of classic infantile CLN1 disease. Comparisons may be useful for a differential diagnosis.

A diagnosis of classic infantile CLN1 disease may be based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic physical findings, and a variety of specialized tests including enzyme assays and molecular genetic testing.

The treatment of classic infantile CLN1 disease is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, specialists who diagnose and treat eye disorders (ophthalmologists), specialists who diagnose and treat disorders of the central nervous system (neurologists), speech pathologists, a medical geneticist, a psychiatrist and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Psychosocial support for the entire family is essential as well. Genetic counseling is of benefit for affected individuals and their families.


Cleidocranial dysplasia

Cleidocranial dysplasia is a rare genetic disorder characterized by abnormal bone formation commonly affecting the skull, teeth and long bones. As a result, short stature, distinctive facial features and narrow, sloping shoulders caused by abnormally developed or absent collarbones (clavicles) may be present in affected individuals. Major features may include premature closing of the soft spot on the head (coronal), delayed closure of the space between the bones of the skull (fontanels), narrow and abnormally shaped pelvic and pubic bones and abnormalities in development of the chest (thoracic region). If not diagnosed at birth, clinical presentation of remarkable features may be most notable in early childhood or adolescence. Additionally, a high arched palate, failure of the lower jaw joints to unite, delayed eruption of teeth and fingers that are irregular in length may also be present. Cleidocranial dysplasia is inherited as an autosomal dominant genetic condition. Approximately 1,000 cases of this disorder have been reported in the medical literature.

Because affected individuals can present with an array of features related to cleidocranial dysplasia, it is not always diagnosed at birth. The most prominent feature of cleidocranial dysplasia is the absence of collarbones or narrow, drooping shoulders caused by complete or partial absence of the collarbones. There may be abnormalities of the muscles in the area of the collarbones associated with an irregularly wide range of shoulder movement in affected individuals with collarbone abnormalities. Another prominent feature is atypical skull formation or skull abnormalities, which may include a premature closure of the two soft spots on the head (fontanels) and the fibrous joints where bones of the skull meet (sutures) causing abnormal development of the skull. Distinct facial features typically include a prominent forehead, unusually wide face, prominent chin, small upper jaw (maxillary hypoplasia) and bulging of the skull cap. Most individuals with cleidocranial dysplasia have some but not necessarily all features listed above and are diagnosed between birth and adolescence as the child develops and abnormalities may become more noticeable over time (irregular growth of long bones or pelvis, atypical facial feature development, abnormal tooth or jaw formation, etc.).

Cleidocranial dysplasia is caused by changes (mutations or pathogenic variants) in the RUNX2 gene (originally called the CBFA1 gene). This gene codes for a protein that affects bone development and the proliferation of healthy osteoblasts. Osteoblasts are the specific cell type that make up bones and contribute to proper bone formation in the body. RUNX2 is a transcription factor or regulator of osteoblast generation in the body termed osteogenesis. About 20-30% of individuals with cleidocranial dysplasia do not have a pathogenic variant in the RUNX2 gene. This suggests that there are other genetic causes of this condition.

Cleidocranial dysplasia is a very rare disorder that is apparent at birth and affects males and females in equal numbers. Approximately 1,000 cases of this disorder have been reported in the medical literature. The birth prevalence is approximately 1 in 1 million.

Symptoms of the following disorders can be similar to those of cleidocranial dysplasia. Comparisons may be useful for a differential diagnosis:

Mandibuloacral dysplasia is a rare disorder that may be characterized by a limitation in joint movement, slowed growth of the jaw, atrophic skin, underdeveloped fingers, a wide space between the bones of the skull, limited joint movement, absent or underdeveloped collarbone and/or a hip defect in which the thigh bone angles out to the side of the body (coxa valga). Mandibuloacral dysplasia is thought to affect males and females equally. Although these features may overlap with those present in individuals with cleidocranial dysplasia, mandibuloacral dysplasia is inherited in an autosomal recessive manner.


CLOVES syndrome

先天性脂肪瘤样增生，血管畸形和表皮痣综合征

CLOVES syndrome belongs to the spectrum of overgrowth syndromes with complex vascular anomalies caused by mosaic mutations in the PIK3CA gene. CLOVES syndrome may affect the soft tissue, blood vessels, bone and internal organs. The manifestations are very variable ranging from mild to severe anomalies. These abnormalities are typically present at birth.

CLOVES syndrome is a nonhereditary disorder caused by a somatic (body cell) mutation in a gene known as PIK3CA. Mutations in this growth regulatory gene result in two sets of cells within the body (mosaic status): those with the mutation and those without the mutation. The mutated cells give rise to the abnormal tissue.

CLOVES syndrome is rare and evident at birth. It affects males and females equally regardless of their race or ethnicity. Many of the patients with CLOVES syndrome are misdiagnosed as having other syndromes such as Klippel-Trenaunay syndrome or Proteus syndrome.

PIK3CA-related overgrowth syndromes (PROS) refers to a group of disorders caused by PIK3CA gene mutations such as CLOVES and Klippel-Trenaunay syndrome.

The diagnosis is evident at birth based on physical signs and symptoms. Confirmation of diagnosis can be done with molecular genetic testing for the PIK3CA gene mutation. Imaging studies include plain x-rays (radiography), magnetic resonance imaging (MRI) of the chest, abdomen, pelvis, spine and limbs and ultrasound for vascular anomalies and kidneys. Prenatal diagnosis with imaging tools is feasible.


Coats disease

Coats disease was first described in 1908 and is a rare disorder characterized by abnormal development of the blood vessels in the retina. The retina is a nerve-rich tissue lining the back of the eye that transmits light images to the brain, which allows a person to see. Therefore, affected individuals may experience loss of vision due to changes in the retina and, in severe cases, retinal detachment. In almost all people with Coats disease, only one eye is affected. Rarely, both eyes may be exhibit symptoms, however, one eye is often affected more than the other. The specific cause of Coats disease is not known.

Coats disease affects males more often than females in a ratio of 3:1. The disorder may occur at any age, but the majority of patients are diagnosed in the first two decades of life. Individuals affected with Coats disease may display few or no symptoms while others may have severe involvement. The most common features at presentation of Coats disease include loss of vision, misalignment of the eyes (strabismus), and/or the development of a white reflex rather than the normal red or orange color in the pupil when light is flashed into the pupil so that the pupil appears white (leukocoria).

The specific cause of Coats disease is not known. One theory is that a mutation of the Norrie disease protein (NDP) gene leads to Coats disease. This gene is an attractive candidate because it has been shown to play a vital role in retinal blood vessel development. One study showed some promise for involvement of the NDP gene in Coats disease, however further studies have not been able to verify this hypothesis. In general, Coats disease is considered a non-genetic, non-heritable condition.

It is estimated that about 69% of those affected are male. The average age at diagnosis is 8-16 years, although the disease has been diagnosed in patients as young as 4 months. About two-thirds of juvenile cases present before age 10. Approximately one-third of patients are 30 years or older before symptoms begin.

Signs of the following disorders can be similar to those of Coats disease.

A diagnosis of Coats disease is made based upon a thorough clinical ophthalmic evaluation, a detailed patient history, and specialized tests, including retinal fluorescein angiography, diagnostic echography, and in some cases computed tomography imaging of the orbits.


Cockayne Syndrome

Cockayne Syndrome (CS) is a rare genetic disorder characterized by short stature, an abnormally small head (microcephaly) and neurologic abnormalities that can lead to intellectual disability. Affected children may also have skin that is sensitive to light (photosensitivity); inflammation of peripheral nerves and destruction of the fatty covering (myelin sheath) of nerve fibers; vision abnormalities including cataracts; hearing loss; dental abnormalities and a face with a sunken appearance of the eyes.

CS type I, the classical form, is characterized by a normal appearing newborn with symptoms that become apparent in the first wo years of life. Vision, hearing and nervous system functioning gets worse over time, resulting in severe disability.

Cockayne syndrome is caused by changes (pathogenic variants) in the ERCC6 and ERCC8 genes. Pathogenic variants in ERCC6 account for about 65% of cases and pathogenic variants in ERCC8 cause about 35% of cases. These genes are involved in the normal repair of DNA that occurs after damage from ultraviolet light, which is the body’s natural defense against sunburn. Exposure to the ultraviolet component of sunlight damages DNA and because the cells are no longer able to repair the damaged DNA, it accumulates in the cells.

Cockayne syndrome affects males and females in equal numbers and has been diagnosed in children from many different ethnic backgrounds. The incidence of CS has been estimated to be 2.7 per 1,000,000 births in western Europe, but it is probably underdiagnosed.

Many different disorders have symptoms similar to those of Cockayne syndrome. Conditions that might be included in a differential diagnosis include Pelizaeus-Merzbacher disease; Cornelia deLange syndrome; Dubowitz syndrome; Hallerman-Streiff syndrome; Rubinstein-Taybi syndrome; Silver-Russell syndrome; Seckel syndrome; Wiedemann-Rautenstrauch syndrome; xeroderma pigmentosum, Bloom syndrome; Hutchinson-Gilford progeria syndrome; Werner syndrome; Rothmund-Thompson syndrome; Warburg micro syndrome; disorders of calcium and phosphate metabolism; and congenital infections (rubella, toxoplasmosis).

Cockayne syndrome is diagnosed by molecular genetic (DNA) testing for pathogenic variants in the ERCC6 or ERCC8 genes. If pathogenic variants in these genes are not found, a DNA repair assay on skin cells can be done to look for sensitivity to ultraviolet radiation.


Coffin Lowry Syndrome

Coffin-Lowry syndrome (CLS) is a rare genetic disorder characterized by intellectual disability; abnormalities of the head and facial (craniofacial) area; large, soft hands with short, thin (tapered) fingers; short stature; and/or various skeletal abnormalities. Characteristic facial features may include an underdeveloped upper jawbone (maxillary hypoplasia), an abnormally prominent brow, downslanting eyelid folds (palpebral fissures), widely spaced eyes (hypertelorism), large ears, and/or unusually thick eyebrows. Skeletal abnormalities may include abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and unusual prominence of the breastbone (sternum) (pectus carinatum). Coffin-Lowry syndrome is caused by changes (mutations) in the RPS6KA3 gene and is inherited in an X-linked dominant pattern. Males are usually more severely affected than females.

The symptoms of Coffin-Lowry syndrome tend to be more severe in males, although symptoms in affected females can range from none to the same severity seen in males. The characteristic facial features seen in affected males become more easily identifiable in late childhood and adulthood. The face is characterized by a prominent forehead and eyebrows, narrowing of both temples, scarce hair on the scalp, thickened eyebrow ridges, downslanting eyelid slits, wide-set eyes, thickened upper eyelids, a broad nasal bridge with a thick dividing cartilage (septum), thick prominent lips, an open mouth, prominent chin and ears.

Coffin-Lowry syndrome is caused by changes (mutations) in the RPS6KA3 gene on the X chromosome. Some individuals with Coffin-Lowry syndrome do not have a detectable mutation in the RPS6KA3 gene.

Coffin-Lowry syndrome affects as many males as females. However, symptoms may be more severe in males.

Symptoms of the following disorder can be similar to those of Coffin-Lowry syndrome. Comparisons may be useful for a differential diagnosis:

Borjeson syndrome is a rare genetic disorder primarily characterized by an unusual facial appearance, intellectual disability, obesity, seizures, delayed sexual development, and/or poor muscle tone (hypotonia). The disorder is follows X-linked recessive inheritance and therefore is usually fully expressed in males only. However, females who carry a single copy of the disease gene may manifest certain, usually more variable features of the disorder. (For more information on this disorder, choose Borjeson as your search term in the Rare Disease Database.)


Coffin-Siris syndrome

Coffin-Siris syndrome (CSS) is a rare genetic disorder that may be evident at birth (congenital). The disorder may be characterized by abnormalities of the head and facial (craniofacial) area, resulting in a coarse facial appearance. Craniofacial malformations may include an abnormally small head (microcephaly) or large head (macrocephaly); a wide nose with a low nasal bridge; a wide mouth with thick, prominent lips; thick eyebrows and eyelashes or excess hair growth in unusual places such as the back (hypertrichosis); and sparse scalp hair. In addition, affected infants and children may have short fifth fingers (pinkies) and toes with underdeveloped (hypoplastic) or absent nails; other malformations of the fingers and toes and eye abnormalities. Feeding difficulties and frequent respiratory infections during infancy, diminished muscle tone (hypotonia), abnormal looseness (laxity) of the joints, delayed bone age, developmental delays, hearing loss, and intellectual disability may also be present. The specific symptoms and severity can vary among affected individuals. Treatment is directed towards the symptoms that are present in an individual with CSS.

CSS is characterized by distinctive abnormalities of the head and facial (craniofacial) region with affected individuals often described as having coarse facial features that become more prominent with age. Affected individuals may have an unusually small or large head (micro- or macrocephaly); a wide mouth with full, prominent lips; a broad nasal tip; a low nasal bridge and an abnormally long vertical groove between the nose and the upper lip (philtrum). Additional features may include thick eyebrows, long eyelashes and generalized excessive hair growth (hypertrichosis) with the exception of the scalp hair, which tends to be relatively sparse (scalp hypotrichosis). Reports suggest that sparse scalp hair improves with age.

CSS is thus far known to be caused by pathogenic gene variants (mutations) in one of the following genes: ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1, SMARCC2, DPF2, SOX4 and SOX11. Genes provide instructions for creating proteins that play a critical role in many functions of the body. The ARID and SMARC genes linked to CSS provide the instructions to make several different protein complexes that are known as BRG-1 associated factor (BAF) complex in humans. SOX11 is involved with transcriptional regulation of the BAF complex. These protein complexes regulate gene activity by altering how tightly regions of DNA are packaged, which can affect gene expression. Subsequently, the BAF complex is involved in a variety of processes including cell growth, division, and differentiation and the replication and repairing of DNA. It is still unclear how these mutations affect the BAF complex, but researchers believe they alter DNA packaging, which can disrupt gene activity and cellular processes and lead to the symptoms of CSS.

CSS occurs worldwide with no ethnic predisposition. Since the disorder was originally described in 1970 (G.S. Coffin), there are likely several thousand individuals with known CSS, however there are more individuals with CSS who have not yet undergone molecular testing or who have not come to medical attention.

Symptoms of the following disorders may be similar to those of Coffin-Siris syndrome. Comparisons may be useful for a differential diagnosis:

Mosaic trisomy 9 is a rare chromosomal disorder in which there are three copies (trisomy) of chromosome number 9 rather than twice in some cells of the body. The term mosaic indicates that some cells contain the extra chromosome 9, while others have the normal chromosomal pair. Associated symptoms and findings may vary greatly in range and severity, depending on the percentage of cells with the extra chromosome. However, common features include growth deficiency before birth (intrauterine growth retardation); intellectual disability; structural malformations of the heart that are present at birth (congenital heart defects) and/or distinctive abnormalities of the skull and facial (craniofacial) region, such as a sloping forehead, a bulbous nose, short eyelid folds (palpebral fissures), deeply set eyes and/or low-set, malformed ears. The syndrome may also be characterized by musculoskeletal, genital, kidney (renal) and/or additional physical abnormalities. Mosaic trisomy 9 may be caused by errors during the division of a parent’s reproductive cells or during the division of body tissue cells early in the development of the embryo. (For further information, choose mosaic trisomy 9 as your search term in the Rare Disease Database.)


Cogan Reese Syndrome

Cogan-Reese syndrome is an extremely rare eye disorder characterized by a matted or smudged appearance to the surface of the iris; the development of small colored lumps on the iris (nodular iris nevi); the attachment of portions of the iris to the cornea (peripheral anterior synechiae); and/or increased pressure in the eye (glaucoma). Secondary glaucoma may lead to vision loss. This disorder most frequently appears in young and middle-aged females, usually affecting only one eye (unilateral) and developing slowly over time.

Major characteristics of Cogan-Reese syndrome include a matted or smudged appearance to the surface of the iris (nevus), yellow or brown lumps or nodules on the iris (nodular iris nevi), the attachment of portions of the iris to the cornea (peripheral anterior synechiae), and increased pressure in the eye (glaucoma). The development of Cogan-Reese syndrome is gradual, and may be preceded by symptoms of essential iris atrophy and/or Chandler’s syndrome. The matted appearance of the iris and development of nodules on the iris distinguish Cogan-Reese syndrome from the other iridocorneal endothelial syndromes.

The cause of Cogan-Reese syndrome is not known. Some researchers suspect that inflammation or chronic infection may be the cause of the disease. Others suggest that the primary disorder involves the cells that line the cornea (corneal endothelium), with the impact on the iris as a secondary or associated disorder. Some scientists suggest that the three iridocorneal (ICE) syndromes may represent different stages of one disease process.

Cogan-Reese syndrome is a very rare disorder that predominantly affects females in the middle adult years, although cases have been reported in children. Most affected individuals are white. The male to female ratio ranges from 1:2 to 1:5. A family history usually shows no other affected family members.

Symptoms of the following disorders can be similar to those of Cogan-Reese syndrome. Comparisons may be useful for a differential diagnosis:

Chandler’s syndrome (CS) is a rare eye disorder in which the endothelium, the single layer of cells lining the inner surface of the cornea, proliferates causing corneal edema, distortion of the iris, and unusually high pressure in the eye (glaucoma). CS is one of three syndromes affecting the eyes (progressive iris atrophy and Cogan-Reese syndrome are the other two) that make up the iridocorneal endothelial syndrome (ICE syndrome). The spectrum is an acquired, unilateral disorder, which typically occurs in early to middle adulthood and predominantly affects women. Chandler’s syndrome is the most commonly encountered clinical variant of this spectrum. (For more information on this disorder, choose Chandler as your search term in the Rare Disease Database.)


Cohen Syndrome

Cohen syndrome is a variable genetic disorder characterized by diminished muscle tone (hypotonia), abnormalities of the head, face, hands and feet, eye abnormalities, and non-progressive intellectual disability. Affected individuals usually have microcephaly, a condition that indicates that head circumference is smaller than would be expected for an infant’s age and sex. In many older patients, obesity is present, especially around the torso and is associated with slender arms and legs. A lowered level of certain white blood cells known as neutrophils (neutropenia) is present from birth in some affected individuals. Cohen syndrome is an autosomal recessive genetic disease caused by changes (variants or mutations) in the VPS13B/COH1 gene.

The signs and symptoms of Cohen syndrome may vary from one individual to another. Although researchers have been able to establish a clear syndrome with characteristic or core features, much about the disorder is not fully understood. Several factors including the small number of identified cases and the lack of large clinical studies, prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.

Cohen syndrome is caused by changes (variants or mutations) in the COH1 gene. This gene is also known as the VPS13B gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When an alteration of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.

Cohen syndrome affects males and females in about equal numbers. It appears to occur more frequently in people of Finnish, Amish, Greek/Mediterranean and Irish ancestry. More than 150 cases have been reported in the medical literature and an estimated over 1,000 individuals have been diagnosed with the disorder worldwide. However, instances of Cohen syndrome often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of the disorder in the general population.

Symptoms of the following disorders can be similar to those of Cohen syndrome. Comparisons may be useful for a differential diagnosis:

Prader-Willi syndrome (PWS) is a genetic multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), feeding difficulties and poor weight gain. In childhood, features of this disorder include short stature, small genitals and an excessive appetite because affected individuals do not feel satisfied after completing a meal (satiety). Without intervention, this can lead to overeating and the gradual onset of obesity. Food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to alterations affecting certain genes in a specific region of chromosome 15. These abnormalities usually result from random (sporadic) errors in development but are sometimes inherited. (For more information on this disorder, choose Prader-Willi as your search term in the Rare Disease Database.)

The treatment of Cohen syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, orthopedists, ophthalmologists, psychiatrists, speech pathologists and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is recommended for affected individuals and their families.


Cohen-Gibson syndrome

Cohen-Gibson Syndrome is a neurodevelopmental disorder caused by disease-causing changes (pathogenic variants) in the EED gene. Affected children typically have developmental delays or intellectual disability, tall stature for age, large head size, large hands and feet and facial features that are unusual for their family background.

Developmental Delay and Intellectual Disability

Cohen-Gibson syndrome is caused by likely pathogenic or pathogenic variants (disease-causing changes) in a gene called EED (embryonic ectoderm development). The EED protein cooperates with several other proteins, including EZH2 and SUZ12, to form a protein bundle called PRC2 (polycomb repressive complex 2). The job of the PRC2 complex is to help cells put away genes that they don’t need to use – a process called chromatin compaction. Essentially, when the body’s stem cells need to convert into a specific organ, they need to put away all their stem cell genes, as well as all the genes they would use if they were turning into a different organ. In this way, muscle cells would put away all the not-muscle genes (such as genes specific to fat tissue, the eyes, bone, etc.) and leave the muscle-only genes turned on. Bone cells would put away all the not-bone genes (including the genes that self-renew stem cells) and leave the bone-only genes turned on. The PRC2 complex adds a modification to histone proteins in the nucleus of the cell to help these histone proteins pack themselves (and the DNA that is wrapped around them) together more tightly. If the PRC2 complex is not working at full efficiency, such as when a pathogenic variant is present in the EED gene, some genes remain turned on for longer, and this affects how the body tissues develop.

Cohen-Gibson syndrome is very rare, and the true incidence and prevalence of the condition is unknown. As of 2024, fewer than 10 patients with this disorder have been reported in the medical literature. There does not seem to be a specific global superpopulation or subpopulation that is affected more frequently than others. Because the features of Cohen-Gibson syndrome overlap with those seen in Weaver syndrome, Imagawa-Matsumoto syndrome and other overgrowth conditions (see below), the diagnosis is best confirmed by finding a variant in EED that is classified by a genetic testing lab as likely pathogenic or pathogenic. Large DNA sequencing studies that have aggregated data from hundreds of thousands of healthy people and people with a variety of diseases have found that about 1 in 500 people have a detectable rare variant of unknown significance (VUS) in EED; since the prevalence of Cohen-Gibson syndrome cannot plausibly be 2 persons per 1,000 population, most variants in EED will not cause Cohen-Gibson syndrome.

Several rare overgrowth disorders have clinical features that can overlap with Cohen-Gibson syndrome. Weaver syndrome and Imagawa-Matsumoto syndrome are caused by likely pathogenic and pathogenic variants in EZH2 and SUZ12, respectively. Both disorders resemble Cohen-Gibson syndrome and include neurodevelopmental delays, unusual facial features and childhood-onset overgrowth. Sotos syndrome is caused by likely pathogenic and pathogenic variants in NSD1. There are many other syndromes that feature childhood overgrowth. Importantly, the overgrowth in Cohen-Gibson syndrome is symmetrical (affecting both sides of the body). The presence of asymmetrical overgrowth, where one side of the body grows larger than the other, should suggest a different subset of overgrowth disorders including Beckwith-Wiedemann syndrome.

Confident diagnosis of Cohen-Gibson syndrome requires clinical examination by a physician as well as clinical-grade DNA testing that identifies a likely pathogenic or pathogenic variant in the EED gene that affects the EED protein. Testing results from labs that are not accredited to provide clinical-grade testing should not be used for diagnosis, since both false positive and false negative results would result in an incorrect diagnosis.

There is currently no cure for Cohen-Gibson syndrome and there are no licensed medications that target the cause at the level of the EED protein. Supportive care remains the cornerstone of management. Multiple specialist visits in the early years are often required.


Cold agglutinin disease

Cold agglutinin disease (CAD) is a rare autoimmune disorder characterized by the premature destruction of red blood cells (hemolysis). Autoimmune diseases occur when one’s own immune system attacks healthy tissue. More specifically, CAD is a subtype of autoimmune hemolytic anemia. In this type of disorder, red blood cells are tagged by antibodies and are then destroyed by other types of immune cells. The disease is termed cold because the antibodies are active and cause hemolysis at cold temperatures, usually 3 to 4oC (37 to 39oF), which is not necessarily the case in other types of autoimmune hemolytic anemia. CAD affects about one person per million every year, and mostly develops between the ages of 40 and 80 years. Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In individuals with CAD, the red blood cells are destroyed prematurely and the rate of production of new cells in the bone marrow can no longer compensate for their loss. A decreased number of red blood cells (anemia) may cause fatigue, weakness, a pale skin color (pallor), dizziness, palpitations, and shortness of breath (dyspnea). Hemolysis leads to an increased release from red blood cells of hemoglobin, a protein responsible for carrying oxygen in the blood. Degradation of hemoglobin into bilirubin can result in yellowing of the skin and whites of the eyes (jaundice). Hemoglobin can also pass in the urine and give it a dark brown color. Other symptoms that can be triggered by exposure to cold include sweating and coldness of the fingers and/or toes (digits) and painful bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud sign). Treatment of CAD includes avoidance of cold temperatures, treating anemia and hemolysis (if needed) and medications that modulate the immune system to decrease the production of antibodies against red blood cells. If applicable, the underlying disease that caused CAD should be treated.

CAD typically develops in individuals between the age of 40 and 80, and is more common in elderly individuals. The symptoms associated with the disease are mostly the result of either hemolysis or circulatory symptoms, both of which are triggered by exposure to cold temperatures. Some individuals, especially those with mild hemolysis and a gradual onset of anemia, may not have any obvious symptoms (asymptomatic). Symptoms of anemia include paleness of the skin (pallor), fatigue, shortness of breath (dyspnea), dizziness and palpitations. In cases of brisk and severe hemolysis, chest pain, decreased alertness (lethargy), confusion, transient loss of consciousness  (syncope), and deregulation of heart rate and blood pressure (hemodynamic instability) might occur. Hemolysis also leads to increased release of hemoglobin (an oxygen-carrying protein) in the blood and urine, which can result in darkly pigmented urine. Hemoglobin is degraded into a yellow compound called bilirubin, which can accumulate and lead to yellowing of the skin and whites of the eyes (jaundice). Circulatory symptoms seen in CAD include coldness of the fingers and/or toes (digits) and painful bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud phenomenon). In severe cases, ulcers may develop on the extremities of digits. There is a possibility that people living with CAD are at a higher risk of developing blood clots, although more studies are needed to clarify this potential association. CAD can be a long-standing (chronic) disease, but can be self-limited and clinically silent, especially when associated with infectious diseases (see below); although it can be caused by severe diseases, CAD itself does not seem to be associated with a significantly decreased life expectancy.

CAD occurs when antibodies produced by the immune system bind to red blood cells and identify them as targets. Antibodies are specialized proteins that bind to invading organisms and contribute to their destruction. There are five main classes of antibodies -IgA, IgD, IgE, IgG, and IgM. Most cases of CAD are due to IgM antibodies. When antibodies attack healthy tissue, they may be referred to as autoantibodies. In the case of CAD, these autoantibodies are active and can trigger hemolysis when they are exposed to cold temperatures. Once red blood cells are tagged by a cold-induced antibody, they can clump (agglutinate) and are then bound by another component of the immune system known as complements. Once red blood cells are bound to complements, they are attacked and destroyed by different types of immune cells, such as macrophages.

CAD most commonly affects people between the ages of 40 and 80. The median age at symptom onset is around 65 years, meaning that half of affected individuals develop symptoms before this age, and the other half after this age. The disease is present in about 16 people per million (prevalence), and develops in one person per million every year (incidence). The disease is almost twice as common in women compared to men. Those living with conditions associated with CAD (see causes section above) are more likely to develop the disease. CAD is also potentially more common, or at least more recognized, in colder climates.

Symptoms of the following disorders can be similar to those of CAD. Comparisons may be useful for a differential diagnosis:

Paroxysmal cold hemoglobinuria (PCH) is a type of cold-induced autoimmune hemolytic anemia. The hemolysis is usually brisk and can be associated with severe pain in the back and legs, headache, vomiting, diarrhea and passage of dark brown urine (hemoglobinuria). There may be temporary enlargement of the liver and spleen. This disorder is frequently associated with viral infections such as chickenpox and mumps. (For more information on this disorder, choose paroxysmal cold hemoglobinuria as your search term in the Rare Disease Database.)


Colorado Tick Fever

Colorado Tick Fever is a rare viral disease transmitted by ticks that commonly inhabit the western United States. Major symptoms may include fever, headaches, muscle aches, and/or generalized discomfort (myalgia). The symptoms usually last for about a week and resolve on their own.

Colorado Tick Fever typically has a sudden onset about five days after a tick bite.  It usually occurs at moderate altitudes during spring or early summer. The symptoms are flu-like and may include chills, headache, increased sensitivity to light (photophobia), fatigue, nausea, vomiting, and a lack of appetite.  Muscle pain occurs, especially in the legs and back.  There may be a slight, reddish rash, and the spleen can become enlarged (splenomegaly). Fever may rise sharply for two or three days and then subside only to return after a day or two (biphasic fever).  The second fever typically subsides after 2 to 4 days.

Colorado Tick Fever is a rare viral disease caused by a virus belonging to the Coltivirus family.  It is transmitted to humans through the bite of the wood tick (Dermacentor andersoni).

Colorado Tick Fever is a rare viral disease that affects males and females in equal numbers.  Most reported cases have occurred in the Rocky Mountain area of the United States and the western provinces of Canada.  Several hundred cases of this disease are reported each year in these areas where the wood tick lives (endemic).  However, it is possible that many additional cases are misdiagnosed or undiagnosed.

Symptoms of the following disorders can be similar to those of Colorado Tick Fever.  Comparisons may be useful for a differential diagnosis:

Lyme Disease is an infectious inflammatory disease transmitted by a tick (Borrelia burgdorferi).  The early symptoms may include a characteristic red, round skin lesion (bull-eye rash), fever, muscle pain, chills, headache, nausea, and/or vomiting.  Swollen and/or painful joints may also occur. Neurological abnormalities may develop (e.g., meningitis, facial paralysis, involuntary muscle movements) but usually resolve completely without treatment.  (For more information on this disorder, choose Lyme as your search term in the Rare Disease Database.)

The diagnosis of Colorado Tick Fever is confirmed by isolation of the virus from the blood. Treatment for Colorado Tick Fever is symptomatic and may include acetaminophen to relieve headaches and muscle pain.


Common Variable Immune Deficiency

Common variable immune deficiency (CVID) is a type of primary immunodeficiency, which is defined as an immune system dysfunction typically caused by a mutation in a gene or genes. The World Health Organization (WHO) recognizes more than 400 primary immunodeficiencies ranging from relatively common to quite rare.

The clinical course and symptoms of CVID vary widely from mild to severe. The immunoglobulins affected also vary. For example, some patients have a deficiency in all three major types of immunoglobulins: immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM) while others have a shortage of just IgG and IgA. The diagnosis is made by finding that functional antibodies are very low or absent.

The cause of CVID is unknown for most patients but a genetic cause has been identified in about 20%. Autosomal dominant (mostly) and autosomal recessive inheritance has been reported in CVID. More commonly, sporadic cases, with no apparent history of the disorder in their family, may still be caused by either rare autosomal defects or complex interactions of environmental and genetic causes (multifactorial inheritance). Mutations in genes that are involved in the development and function of B cells are only a small part of the genes that lead to CVID, as most the causal genes identified are those that are involved in regulation of immune responses.

CVID equally affects males and females. The prevalence of CVID is approximately 1 in 30,000 people. The diagnosis of CVID is not made in children under the age of 4, because until that time, it may be confused with other genetic defects that must be excluded. In addition, it can be confused with physiologic immaturity. However, most patients have symptoms later and are not diagnosed until ages 20-40.

Symptoms of the following disorders may be similar to those of common variable immunodeficiency. Comparisons may be useful for a differential diagnosis:

Agammaglobulinemia is a group of inherited immune deficiencies characterized by a low concentration of antibodies in the blood due to the lack of particular lymphocytes (B cells) in the blood and lymph. The types of agammaglobulinemia are: X-linked agammaglobulinemia (XLA), the much rarer X-linked agammaglobulinemia with growth hormone deficiency (about 10 cases reported), and autosomal recessive agammaglobulinemia. All of these disorders are characterized by a weakened immune system that must be strengthened by the administration of gammaglobulin in order to fight off infections. (For more information on this disorder, choose agammaglobulinemia as your search term in the Rare Disease Database.)


Complex Regional Pain Syndrome

The most common and prominent symptom of CRPS is the pain that affected individuals will feel. The pain is often deep inside the limbs with a burning, stinging or tearing sensation. Sensory changes are also common, and may include increased sensitivity to painful stimuli, feeling pain from stimuli that are usually non-painful and, in some instances, sensory loss (e.g., numbness).

The exact causes of CRPS are unclear, but it is likely that there are multiple factors that contribute to its development.

CRPS occurs 3 to 4 times more often in women than men. Although CRPS can occur at any age, it is rare in children and adolescents. In the pediatric population, the onset of CRPS usually occurs in early adolescence with the lower end of the range falling between 7 to 9 years. In adults, the age of onset is highly variable from 37 to 70 years of age. CRPS occurs most frequently in people of European ancestry (in about 66 to 80 percent of cases). In a study done in the United States, it was found that CRPS type I developed in 5.46 persons out of every 100,000 per year. It is estimated that CRPS affects nearly 200,000 patients annually in the United States.

Symptoms of some disorders may be similar to CRPS, and it is important to be able to be able to recognize them during the process of diagnosing CRPS.

Diagnosis of CRPS is suspected when a patient’s symptoms develop 4 to 6 weeks after limb trauma, symptoms cannot be fully explained by the initial trauma and the symptoms are regional (affecting an entire limb). Actual diagnosis of CRPS is made solely based on a history and physical examination to determine whether a patient meets CRPS diagnostic criteria (often called the Budapest criteria).


Progressive cone dystrophy

The symptoms of cone dystrophy may vary from one person to another, even among individuals with the same form of the disorder. The age of onset, specific symptoms, severity and progression (if any) can vary greatly. The amount of vision loss varies and is difficult to predict. Affected individuals should talk to their physician and medical team about their specific case and associated symptoms.

Many cases of cone dystrophy occur randomly for no identifiable reason (sporadically). Some forms are inherited in an autosomal dominant, autosomal recessive or X-linked pattern. Inherited forms of cone dystrophy are due to changes (mutations) in one of several genes that have been linked to cone dystrophy. These genes contain instructions for making proteins that play vital roles in the development, function and overall health of cone cells. The exact underlying mechanisms that cause cone dystrophy are not fully understood.

Cone dystrophy affects males and females in equal numbers when it occurs sporadically or is inherited in an autosomal dominant or recessive pattern. The X-linked form of cone dystrophy only affects males fully, although some females may have mild symptoms of the disorder. The exact incidence of cone dystrophy is unknown. Most sources estimate that the condition affects 1 in 30,000 individuals in the general population.

Symptoms of the following disorders can be similar to those of cone dystrophy. Comparisons may be useful for a differential diagnosis.

A diagnosis of cone dystrophy is made based on identification of characteristic symptoms, a detailed family history, and a thorough clinical evaluation involving ophthalmological exams that measure visual acuity, the ability to perceive color and field of vision. An electroretinogram (ERG) is used to confirm the diagnosis of cone dystrophy.


Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is a group of rare inherited autosomal recessive disorders characterized by a deficiency of one of the enzymes needed to make specific hormones. CAH affects the adrenal glands located at the top of each kidney. Normally, the adrenal glands are responsible for producing three different hormones: corticosteroids, which gauge the body’s response to illness or injury; mineralocorticoids, which regulate salt and water levels; and androgens, which are male sex hormones. An enzyme deficiency will make the body unable to produce one or more of these hormones, which in turn will result in the overproduction of another type of hormone precursor in order to compensate for the loss. The most common cause of CAH is the absence of the enzyme 21-hydroxylase. Different variants in the gene responsible for 21-hydroxylase result in different levels of the enzyme, producing a spectrum of effects. CAH due to 21-hydroxylase deficiency is responsible for 95% of all cases of CAH and is broken down further into two subcategories: classical CAH, which can be sub-divided into the salt-losing form or the simple-virilizing form, and non-classical CAH. Classical CAH is by far the more severe form and can result in adrenal crisis and death if not detected and treated. Non-classical CAH is milder and may or may not present symptoms. Since the absence of 21-hydroxylase makes these individuals unable to make the hormone cortisol and, in the case of salt-losing CAH, aldosterone, the body produces more androgens which cause a variety of symptoms such as atypical genital development in infant girls. There are other much rarer forms of CAH as well, including 11-Beta hydroxylase deficiency, 17a- hydroxylase deficiency, 3-Beta-hydroxysteroid dehydrogenase deficiency, congenital lipoid adrenal hyperplasia and p450 oxidoreductase deficiency which all present different symptoms. Although CAH is not curable, patients can go on to lead normal lives if they receive adequate care and treatment.

Many individuals with CAH present with abnormally enlarged adrenal glands (hyperplastic adrenomegaly) that produce excessive amounts of androgens (male steroid hormones) leading to abnormal sexual development in females affected with the disease. Females with severe or classic virilizing CAH due to 21-hydroxylase deficiency will most likely have ambiguous or atypical external genitalia (masculinization or virilization), although they are genetically female and will have normal internal reproductive organs. Males with this type of CAH will not have ambiguous genitalia. Both genders can experience other symptoms such as early onset of puberty, fast body growth and premature completion of growth leading to short stature, if they are not diagnosed and treated in early life. About 75% of people with classical CAH due to 21-hydroxylase deficiency also have a deficiency of the hormone aldosterone, leading to the inability to retain salt and water (salt wasting). This results in excessive loss of water (dehydration), low circulating blood volume (hypovolemia) and abnormally low blood pressure (hypotension and shock). Without treatment, this severe form of CAH can lead to profound weakness, vomiting, diarrhea and circulatory collapse due to adrenal crisis. The remaining 25% are referred to as simple-virilizers and do not have a problem regulating salt and water levels. Fortunately, in the United States, and in many other developed countries, there is universal newborn screening for CAH due to 21-hydroxylase deficiency, and the vast majority of children are diagnosed and treated early to avoid these complications. The mild form of 21-hydroxylase deficiency (non-classical CAH) is not life-threatening and is due to a more common genetic variant. This mild form is not usually detected in our newborn screening programs, and it seldom requires early treatment. Symptoms in later childhood may include premature body hair or acne development. In adolescent females, the most common problems include excessive facial or body hair, menstrual irregularities, and pustular acne. Both genders have normal genitals. A small proportion of the non-classical CAH population has sub-fertility. Patients with CAH may or may not require treatment to improve their quality of life.

Deletions and changes (mutations or variants) in the CYP21A2 gene account for all cases of the 21-hydroxylase deficiency form of CAH. Variants in the CYP11B1, CYP17A1, HSD3B2, CYP11A1, STAR and CYPOR genes are responsible, respectively, for 11-hydroxylase, 17-hydroxylase, 3-beta-hydroxysteroid dehydrogenase deficiencies, lipoid adrenal hyperplasia, and PORD, the other rarer forms of CAH.

The most common form of CAH, 21 hydroxylase deficiency, affects approximately 1:10,000 to 1:15,000 people in the United States and Europe. Among Yupik Eskimos, the occurrence of the salt-wasting form of this disorder may be as high as 1 in 282 individuals. Other forms of CAH are much rarer. In contrast, non-classical CAH affects approximately 1 in 100 to 1 in 200 individuals in the general population.

Symptoms of the following disorders can be similar to those of congenital adrenal hyperplasia. Comparisons may be useful for a differential diagnosis:

All newborns in the United States are screened for classic 21-hydroxylase deficiency. Non-classic CAH is frequently not detected in the newborn test and therefore, may not be diagnosed until childhood or early adulthood when the patient first starts showing symptoms. Genetic testing for the gene variants associated with the various forms of CAH is available but is most often performed when pre-pregnancy genetic counseling is indicated, after an endocrinologist confirms the diagnosis through blood hormone tests, or if results of hormone tests are not definitive.

Treatment of CAH varies greatly depending on the type and severity. CAH cannot be cured, but it can be effectively treated. Treatment of classical CAH starts soon after birth and is needed throughout the patient’s life. People with classical CAH should have a team of healthcare providers, including specialists in pediatric endocrinology, uro-gynecologic surgery (for girls), psychology and genetics. People with classical CAH can have normal, fulfilling lives. Patients with non-classical CAH may not need any treatment, depending on their symptoms. Treatment must be individualized by doctors who have experience with this condition. The primary goal of treating classical CAH is to reduce the excess androgen production and replace the deficient hormones. Proper treatment with the correct dosage of these medications is crucial to preventing adrenal crisis and virilization. Daily tablets including glucocorticoids (usually as hydrocortisone to replace cortisol), mineralocorticoids (fludrocortisone to replace aldosterone) and salt supplements may be prescribed, the latter particularly in infancy. During times of high stress or illness adrenal glands are normally much more active. Therefore, when ill or after major surgery or stressful event, CAH patients must be closely monitored because their bodies will require more hormones to help the body recover and meet increased demands. Hormone levels need to be adjusted and monitored throughout the patient’s life. The dose of glucocorticoids should be adjusted to avoid development of Cushing’s syndrome, a disorder characterized by a variety of symptoms and physical abnormalities including weight gain; skin, muscle and bone changes. High dose mineralocorticoid supplements or salt should be avoided to prevent high blood pressure.


Congenital Afibrinogenemia

The absence of fibrinogen in the circulating blood of individuals with congenital afibrinogenemia makes them unable to effectively coagulate their blood, leading to prolonged bleeding. Bleeding episodes can be spontaneous or due to minor trauma and can happen anywhere in the body, including the skin, nose, oral cavity, gastrointestinal tract, liver, genital and urinary tract and central nervous system. Symptoms begin to show at birth with umbilical cord bleeding in around 85% of individuals. Bleeding might also be noticed in the stools or vomit of newborns.

Absence of fibrinogen in the blood is caused by changes (pathogenic variants or mutations) in one of three genes, known as the fibrinogen alpha-chain (FGA), beta-chain (FGB), and gamma-chain (FGG).

Congenital afibrinogenemia is a very rare disorder that affects approximately one in a million people. Males and females are equally affected. There doesn’t seem to be any ethnic predisposition to this disease. However, as it is an autosomal recessive disorder, children whose parents are blood relatives (consanguineous) are more at risk. Indeed, individuals from the same family are more likely to have the same rare gene variant and can have an affected child if they inherit the pathogenic variant from both parents. Therefore, the disease is more common in areas with high rates of consanguineous marriage, such as the Middle East and Southern India.

Symptoms of the following blood clotting disorders can be similar to those of congenital afibrinogenemia. Comparisons may be useful for a differential diagnosis:

Factor XIII deficiency is a very rare inherited disorder that prevents the blood from clotting normally. The lack of clotting factor XIII can cause slow, oozing internal bleeding which may begin several days after even a mild trauma, such as a bump or bruise. The bleeding may persist so that large cysts form in the tissue spaces, destroying the surrounding bone and causing peripheral nerve damage. This typically occurs in the thigh and buttocks area. (For more information on this disorder, choose Factor XIII Deficiency as your search term in the Rare Disease Database.)


Congenital central hypoventilation syndrome

Congenital Central Hypoventilation Syndrome

The underlying cause of CCHS is a change (mutation) in the PHOX2B gene, a key player in the prenatal development of the nervous system. The majority of individuals with CCHS (~90%) have mutations in exon 3 of the PHOX2B gene that normally has a repeat of 20 alanines. These mutations cause an increase in the number of these alanine repeats from the normal 20 alanines to a range of 24 to 33 alanines and are called poly-alanine repeat expansion mutations (PARMs). The remaining individuals with CCHS have different mutations in the PHOX2B gene not related to PARMs including missense, nonsense, frameshift, or stop codon mutations. These are non-poly-alanine repeat expansion mutations (NPARMs). Both PARMs and NPARMs lead to impaired function of the PHOX2B protein, and the variations in these mutations result in the broad range of symptoms and differing degrees of severity encountered among individuals with CCHS.

CCHS is a rare disorder that affects females and males in equal numbers. Though the mutation is already present before birth, in milder cases the diagnosis may be missed until after the newborn period. Some affected individuals will not be identified until after receiving sedation, anesthesia, or anti-seizure medications, making it especially important to educate health care personnel about CCHS and to have a high index of suspicion for considering a diagnosis of CCHS. As of 2013, more than 1,000 cases are known worldwide. The birth prevalence of CCHS has been extrapolated from incidence figures and general birth rates, but the true prevalence is unknown as culturally diverse large population based studies have not been reported. Because the milder cases of CCHS may go unrecognized or misdiagnosed, it is difficult to estimate the true frequency of CCHS in the general population, though the anticipation is far greater than the current estimate.

The following disorders might be considered in the differential diagnosis of CCHS:

Along with early recognition of the clinical features of CCHS, the gold standard test to diagnose CCHS is genetic testing to identify mutations in the PHOX2B gene, including PARMs, NPARMs, or deletions and duplications.

A multidisciplinary team approach to the management of CCHS is essential to ensuring proper ventilation and development of children with CCHS. Local children’s hospitals may be sufficient in the management of CCHS. In complex cases, CCHS specialists (listed below) can be found throughout the world and can be consulted, or seen for management of CCHS. Primary team members who play an active role in patient management should include: the primary caregivers (parents or family members), pulmonologists, cardiologists, ENT physicians, gastroenterologists, endocrinologists, neurologists, ophthalmologists, social workers, and speech/language pathologists (SLPs).


Cholangiocarcinoma

Congenital contractural arachnodactyly (CCA) is an extremely rare genetic disorder characterized by a Marfan-like body habitus (tall, slender), the permanent fixation of certain joints (e.g., fingers, elbows, knees, and hips) in a flexed position (contractures); abnormally long, slender fingers and toes (arachnodactyly); permanently flexed fingers (camptodactyly); and/or differently shaped ears resulting in a crumpled appearance. In addition, affected individuals may exhibit front-to-back and side-to-side curvature of the spine (kyphoscoliosis); feet that are differently positioned (talipes equinovarus or clubfoot); outward displacement of the fingers (ulnar deviation of the fingers); a short neck. Rarely, affected individuals may have a slight deformity of the valve on the left side of the heart (mitral valve prolapse). CCA is inherited in an autosomal dominant pattern.

CCA encompasses a broad range of symptoms. The specific symptoms that develop in each individual case and the severity of symptoms often vary. Most individuals have permanent fixation of certain joints in a flexed position (contractures) that is present a birth (congenital). The joints of the fingers, elbows, knees and hips are most often affected. In most cases, contractures improve with age.

CCA occurs due to changes (variants or mutations) to the fibrillin-2 (FBN2) gene.

CCA affects males and females in equal numbers. The prevalence of CCA is unknown. For years, researchers speculated that the Marfan syndrome (another rare connective tissue disorder) and CCA may be the same disorder because of the overlap of clinical symptoms. However, investigators have determined these disorders are caused by variants in different genes confirming that CCA is a distinct disorder.

Symptoms of the following disorders can be similar to those of CCA. Comparisons may be useful for a differential diagnosis:

Arthrogryposis multiplex congenita is a rare congenital disease characterized by reduced mobility of multiple joints at birth due to proliferation of fibrous tissue. Symptoms of this disorder may be a fixed range of motion of joints; shoulders that are bent inward and internally rotated; wrists and fingers that are bent and muscles that are underdeveloped. (For more information on this disorder, choose arthrogryposis multiplex congenita as your search term in the Rare Disease Database.)


Congenital disorder of glycosylation

CDG encompass a wide variety of disorders and symptoms. Their severity and prognosis vary greatly depending upon the specific type of CDG, even among individuals with the same type or from the same family. In addition, most types of CDG have only been reported in a handful of individuals, which makes it difficult for physicians to have an accurate picture of associated symptoms and prognosis. In most cases, these disorders become apparent in infancy. It is important to note that affected individuals will not always have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

As discussed above, CDG are caused by a deficiency or lack of specific enzymes or other proteins involved in the formation of sugar trees (glycans) and their binding to other proteins or lipids (glycosylation). Glycosylation is an extensive and complex process that modifies 1000’s of proteins. Hundreds of different genes and unique enzymes are involved in glycosylation. These genes contain instructions for creating (encoding) these enzymes. An individual with a CDG lacks functional levels of one of these enzymes because of a mutation in the corresponding gene. Due to lack of or diminished levels of these enzymes, glycosylation is impaired. Improper glycosylation is the underlying problem in individuals with CDG. The specific organs affected and the various symptoms that develop depend, in part, upon the specific gene and protein product involved. Not all CDG types are caused by mutations in enzymes. Sometimes they result from mutations in proteins that transport, organize or direct other molecules within cells.

Congenital disorders of glycosylation affect males and females in equal numbers. The exact incidence or prevalence of these disorders is the general population is unknown. Researchers believe that many cases go unrecognized or misdiagnosed, making it difficult to determine their true frequency. As these disorders become better known and more types are identified, more cases should be recognized. The most common type (PMM2-CDG) has been reported in more than 1,000 individuals, but the real frequency is probably much higher.

Numerous different metabolic disorders share similar signs and symptoms to CDG, and comparisons may be useful for a differential diagnosis. Such disorders include congenital muscle disorders (myopathies), urea cycle disorders, inborn errors of bile metabolism, fatty acid oxidation disorders, organic acidurias, peroxisome biogenesis disorders and sphingolipidoses. Additional disorders that have similar signs and symptoms include cerebral palsy, Prader-Willi syndrome, congenital coagulation disorders, ataxia-telangiectasia and other hereditary ataxias. (For more information on these disorders, choose the specific disorder or umbrella group name as your search term in the Rare Disease Database.)

A diagnosis of a CDG may be suspected based upon the identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. A variety of specialized tests may be necessary to confirm a diagnosis of CDG and/or to determine the specific subtype. CDG should be considered and ruled out in any unexplained syndrome.


Congenital erythropoietic porphyria

先天性红细胞生成性卟啉病

Congenital erythropoietic porphyria (CEP) is a very rare inherited metabolic disorder resulting from the deficient function of the enzyme uroporphyrinogen III synthase (UROS), the fourth enzyme in the heme biosynthetic pathway. Due to the impaired function of this enzyme, excessive amounts of particular porphyrins accumulate, particularly in the bone marrow, plasma, red blood cells, urine, teeth, and bones. The major symptom of this disorder is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the photo-activated porphyrins in the skin cause bullae (blistering) and the fluid-filled sacs rupture, and the lesions often get infected. These infected lesions can lead to scarring, bone loss, and deformities. The hands, arms, and face are the most commonly affected areas. CEP is inherited as an autosomal recessive genetic disorder. Typically, there is no family history of the disease. Neither parent has symptoms of CEP, but each carries a defective gene that they can pass to their children. Affected offspring have two copies of the defective gene, one inherited from each parent.

The most common symptom of CEP is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with blistering of the skin occurring after exposure. Affected individuals may also exhibit abnormal accumulations of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema). Affected areas of the skin may develop sac-like lesions (vesicles or bullae), scar, and/or become discolored (hyperpigmentation) if exposure to sunlight is prolonged. These affected areas of skin may become abnormally thick. In addition, in some cases, affected individuals may also have loss of nails and end digits of the fingers due to infection of the underlying bone. Loss of sun exposed facial features such as lips, parts of the ears, and nose can also occur. The severity and degree of photosensitivity differ depending on the severity of the patient’s gene lesions which correlate with the deficient enzyme activity. Photosensitivity is seen from birth; however, in some cases, it may not occur until childhood, adolescence or adulthood. Patients also often have brownish discolored teeth (erythrodontia) which fluoresce under ultraviolet light as well as increased hair growth (hypertrichosis).

Congenital erythropoietic porphyria is inherited as an autosomal recessive genetic condition. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, and usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

CEP is a very rare genetic disorder that affects males and females in equal numbers. Over 200 cases have been reported worldwide.

Symptoms of the following disorders can be similar to those of CEP. Comparisons may be useful for a differential diagnosis:

CEP is one of a group of disorders known as the porphyrias. The porphyrias are all characterized by abnormally high levels of particular porphyrins in the body due to deficiencies of specific enzymes essential to the synthesis of heme for hemoglobin and other hemo-proteins. The symptoms associated with the various types of porphyria differ, depending upon which of the eight enzymes in the heme biosynthesis pathway is deficient. There are two major types of porphyria: The cutaneous porphyrias which present with skin involvement, and the acute porphyrias which are usually characterized by abdominal pain and neurological symptoms.


Congenital Fiber Type Disproportion

The symptoms of CFTD are similar to other types of congenital myopathy and may vary from person to person. Onset of symptoms occurs at birth or in early infancy. The severity of symptoms is highly variable, ranging from mild deficits to severe weakness that may result in death in early childhood. In many patients with CFTD, the health problems are less severe than those of other classic congenital myopathies.

The clinical features of CFTD arise at least in part from abnormalities in the relative size and distribution of certain types of muscle fibers, most notably fiber types I and II. Muscle fibers are the highly organized, specialized, contractile cells of skeletal or cardiac muscle tissue. Type I fibers are considered slow twitch and participate in longer, more-sustained periods of contraction, whereas type II fibers are considered fast twitch and participate in faster bursts of activity. Ordinarily, type I fibers are slightly larger than type II fibers. In individuals with CFTD, type I fibers are abnormally, uniformly small (hypotrophy) and are usually (but not always) present in increased numbers.

CFTD affects males and females in equal numbers. In a meta-analysis examining CFTD prevalence across European, North American and Asian populations, a pooled prevalence of the disorder for all-age population was estimated to be between 0.23 per 100,000 and between 0.25 per 100,000 for a pediatric population. Based on these prevalence estimates, CFTD is considered a rare disease.

Symptoms of the following disorders can resemble those of CFTD. Comparisons may be useful for a differential diagnosis.

The diagnosis of CFTD may be suspected based on a thorough clinical evaluation and identification of characteristic findings (i.e., hypotonia and muscle weakness). However, clinical presentation alone is not enough to diagnose CFTD because symptoms are similar to other types of congenital myopathies. A diagnosis of CFTD is confirmed if type I muscle fibers are, on average, significantly (12-40%) smaller in diameter than type II muscle fibers on muscle biopsy.


先天性广泛眼外肌纤维化综合征

Congenital fibrosis of extraocular muscles

Congenital Fibrosis of the Extraocular Muscles

Congenital fibrosis of the extraocular muscles (CFEOM) includes at least five rare genetic eye movement disorders present at birth that are characterized by incomitant strabismus. Specifically, there is an inability to move the eyes in certain directions (opthalmoplegia), droopy eyelids (ptosis) and eyes that are fixed in an abnormal position. The oculomotor nucleus and nerve (cranial nerve III) and the muscles it serves and, in some cases the trochlear nucleus and nerve (cranial nerve IV) and/or the abducens nucleus and nerve (cranial nerve VI) and the muscles they serve are affected.

Affected individuals have limited ability to move their eyes vertically (upward and downward) and can have variable limitations in moving their eyes horizontally. CFEOM is also frequently associated with droopy eyelids (ptosis) and eyes that are fixed in an abnormal position. Individuals with CFEOM often have their eyes fixed in a downward position, and elevate the chin so they can see. These disorders have been classified as CFEOM1, CFEOM2, and CFEOM3 based on ophthalmologic findings and molecular genetic testing. CFEOM3 can be characterized by additional involvement of the peripheral and central nervous system in addition to the eye findings. Tukel syndrome is characterized by missing and webbed fingers and toes in addition to the eye findings. These disorders do not worsen over time.

CFEOM 1 and CFEOM 3 are inherited as autosomal dominant genetic conditions. CFEOM 2 and Tukel syndrome are inherited as autosomal recessive genetic conditions.

CFEOM are rare disorders that have been seen in a range of diverse ethnic populations and affect males and females. A minimum prevalence has been estimated to be 1 in 230,000.

Strabismus is a common group of eye movement disorders in which the eyes are not properly yoked together and one or both eyes are misaligned and cannot be voluntarily controlled. Strabismus is either concomitant or incomitant. Concomitant strabismus occurs when the misalignment, or the angle of deviation between the two eyes, remains constant and independent of the direction of gaze. Strabismus is incomitant when the misalignment varies with gaze direction. Congenital cranial dysinnervation disorders include the various forms of incomitant strabismus such as CFEOM, Duane syndrome, Moebius syndrome, and Brown syndrome. Strabismus may be an isolated finding or found in association with other birth defects.

The diagnosis of CFEOM is made by a thorough eye examination, with special attention to the presence of other eye or systemic malformations. Measurements of the ocular (eye) misalignment, ocular range of motion, head turn, glove (eyeball) retraction, palpebral fissure (eye opening) size, and upward and downward movement of the eye are taken. Forced duction (the rotation of the eye by its extraocular muscles) and vision tests are also recommended.


Congenital generalized lipodystrophy

Infants with all forms of CGL have a near total absence of body fat at birth or soon thereafter. They also have an extremely muscular appearance and may display prominent superficial veins. During early childhood, most children grow at an accelerated rate and have slightly enlarged hands, feet, and jaws (acromegaloid features). Infants and children have a markedly increased appetite and have been described as voracious eaters.

CGL is caused by variants (mutations) of specific genes. Four genes that cause CGL have been identified including the AGPAT2 gene, which causes CGL type 1; the BSCL2 gene, which causes CGL type 2; the CAV1 gene, which causes CGL type 3; and the CAVIN1 gene, which causes CGL type 4. Some individuals with CGL do not have a mutation in any of these genes, suggesting that additional, as yet unidentified genes can cause the disorder.

Approximately 500-600 patients with CGL have been reported in the medical literature. The estimated worldwide prevalence ranges from 1 in a million to 1 in 10 million individuals in the general population. The disorder has been reported in individuals of every ethnic group.

Symptoms of the following disorders can be similar to those of CGL. Comparisons may be useful for a differential diagnosis.

A diagnosis of CGL is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A lipodystrophy diagnosis should be suspected in individuals who are lean or non-obese and who present with early diabetes, severe hypertriglyceridemia, hepatic steatosis, hepatosplenomegaly, acanthosis nigricans and/or polycystic ovarian syndrome.


Congenital heart block

Congenital heart block (CHB), or atrioventricular block (AVB), is characterized by interference of the transfer of the electrical nerve impulses (conduction) that regulate the normal and rhythmic pumping action of the heart muscle. The severity of such conduction abnormalities varies among affected individuals.

The presentation of congenital heart block varies with age of onset, underlying etiology, and type of heart block.

Over half the cases of congenital heart block (60-90 percent) are associated with an autoimmune disorder in the affected individual’s mother such as systemic lupus erythematosus or Sjogren’s syndrome. This results in a passively acquired autoimmune disease in the child termed neonatal lupus. Autoimmune disorders occur when the body’s natural defenses against foreign or invading organisms (antibodies) begin to attack healthy tissue for unknown reasons. Congenital heart block may result when maternal antibodies cross the placenta, enter the fetus, and attack the fetal cardiac conduction system. The antibodies that were originally produced by the mother’s body to fight infections recognize parts of the conduction system in the fetal heart as foreign and abnormally attack and damage the tissues, resulting in inflammation and scarring which leads to faulty conduction. Neonatal lupus may present with other symptoms such as cutaneous lupus lesions and liver abnormalities, though these symptoms normally resolve after a few months of age when the maternal antibodies have been cleared. The heart conduction system abnormalities, on the other hand, are irreversible. Autoimmune heart block is typically of the third degree and begins in utero, while heart block due to other causes tends to present after birth and may be first, second, or third degree. In fact, up to 40 percent of AV block cases do not present until later in childhood, out of which only around 5 percent are of autoimmune origin. (For information on neonatal lupus, choose lupus as your search term in the Rare Disease Database.)

Congenital heart block is a rare disorder that appears to affect males and females in equal numbers. In the general population, the incidence varies between 1 in 15,000 to 1 in 22,000 live births. The incidence of complete (third degree) congenital heart block is one in approximately 20,000 to 25,000 live births.

Symptoms of bundle branch block, another disorder affecting the heart’s electrical activity, can be similar to those of congenital heart block. Comparison may be useful for a differential diagnosis.

The prenatal diagnosis of congenital heart block is more common as cardiac imaging techniques are improving. A growing number of autoimmune cases are being diagnosed between 18 and 24 weeks of pregnancy, leading to a better prognosis. Diagnosis depends on the results of one or more cardiac imaging tests such as fetal electrocardiography (ECG) and fetal echocardiography. This may help determine the type of heart block and may rule out any structural heart anomalies.


Congenital Hepatic Fibrosis

Congenital hepatic fibrosis (CHF) is a rare disease that is present at birth (congenital) and affects the liver. CHF rarely occurs as an isolated problem, and is usually associated with ciliopathies that affect the kidneys, called hepatorenal fibrocystic diseases (FCD). These include polycystic kidney disease (PKD), nephronophthisis (NPHP) chronic tubulointerstitial disease, and others. Typical liver abnormalities include an enlarged liver (hepatomegaly), increased pressure in the venous system that carries blood from different organs to the liver (portal hypertension), and fiber-like connective tissue that spreads over and through the liver (hepatic fibrosis). Gastrointestinal (stomach and intestine) bleeding, splenomegaly (enlarged spleen) and hypersplenism (decreased platelet and other blood counts due to enlarged spleen) may be early signs of this condition.

The more obvious symptoms are a swollen abdomen, a firm, slightly enlarged and abnormally shaped liver and vomiting blood (hematemesis) due to bleeding from the enlarged blood vessels (varices) under the inner lining of the esophagus, stomach, and intestines. There is an increased risk for inflamed bile ducts (cholangitis) as well. The main findings in this disorder are identified through diagnostic testing. Many of the following signs are present in affected individuals with this disorder:

CHF is caused by abnormal development of the portal veins and bile ducts that begins with a malformation in the embryonic structure called the ductal plate. CHF rarely occurs as an isolated problem, and is usually associated with ciliopathies that are associated with kidney disease, called hepatorenal fibrocystic diseases (FCD). These include polycystic kidney disease (PKD), nephronophthisis (NPHP) chronic tubulointerstitial disease, and others.  FCDs are caused by defects in proteins on the primary (immotile) cilia that interfere with receiving signals from other cells or fluids nearby.  FCDs can be inherited as autosomal recessive, autosomal dominant or X-linked disorders.  Mutations in many different genes are associated with the various FCDs. No specific genes have been associated with isolated CHF.

The frequency of CHF is not known. The prevalence has been estimated to be 1/10,000 -20,000 based on the prevalence of ciliopathies that are associated with CHF.

Symptoms of the following disorders can be similar to those of CHF. Comparisons may be useful for a differential diagnosis.

CHF is diagnosed by ultrasound exam and magnetic resonance imaging of the liver and kidneys, and rarely, by liver biopsy. CHF and Caroli’s syndrome are often associated with cystic disease of the kidneys. Family history, physical exam, and various tests including kidney ultrasound exam, kidney function tests, X-rays, eye exam, brain MRI, and molecular genetic testing can help to determine the underlying FCD syndrome.


Congenital Hyperinsulinism

先天性孤立型高胰岛素血症

Congenital hyperinsulinism (HI) is the most frequent cause of severe, persistent hypoglycemia in newborn babies, infants, and children. In most countries it occurs in approximately 1/25,000 to 1/50,000 births. About 60% of babies with HI are diagnosed during the first month of life. An additional 30% will be diagnosed later in the first year and the remainder after that. With early treatment and aggressive prevention of hypoglycemia, brain damage can be prevented. However, brain damage can occur in children with HI if the condition is not recognized or if treatment is ineffective in the prevention of hypoglycemia.

It is often difficult to identify symptoms of HI because they are often confused with typical behaviors of newborns and infants. Common symptoms include irritability, sleepiness, lethargy, excessive hunger and rapid heart rate. More severe symptoms, such as seizures and coma, can occur with a prolonged or extremely low blood sugar level. Common symptoms of low blood sugar in older children and adults include feelings of shakiness, weakness, or tiredness, confusion and rapid pulse. More severe symptoms include seizures or coma.

A number of causes exist. Some forms will resolve and are considered transient. Others arise from genetic defects and persist for life. These genetic forms of HI do not go away, but in some cases, may become easier to treat as the child gets much older.

HI affects both males and females and has been reported in many countries. In most countries it occurs in approximately 1/25,000 to 1/50,000 births.

Due to the similarity in names people often confuse hyperinsulinemia with hyperinsulinism. Hyperinsulinemia is something completely different but over production of insulin is also involved and the names are similar.

The diagnosis of HI may be quite difficult if one relies on demonstrating a detectable blood insulin concentration at the time of hypoglycemia because insulin levels fluctuate widely over time in patients with HI. Other signs and chemical markers must be used to provide clues to excess insulin action and are often easier to demonstrate.


Congenital Lactic Acidosis

Lactate is a chemical compound normally produced by all cells and plays important roles in several chemical processes in the body. Lactic acidosis occurs when lactate and other molecules, called protons, accumulate in bodily tissues and fluids faster than the body can remove them. Consequently, tissues and fluids may become acidic and impair the normal functioning of cells. Lactic acidosis can have many different causes and is often present in severely ill patients hospitalized in intensive care units.

The enzyme deficiencies that give rise to congenital lactic acidosis can potentially affect many different organ systems of the body and, therefore, lead to a wide variety of symptoms and signs. Whereas some individuals may have persistently elevated levels of lactic acid in blood, cerebrospinal fluid and urine, other people may have only occasional increases in lactic acid that are brought on by another illness, such as an infection, a seizure or an asthmatic attack.

Most cases of congenital lactic acidosis are caused by one or more inherited mutations of genes in DNA located in the nucleus (nDNA) or in genes in the mitochondria (mtDNA) of cells. Genes carry the genetic instructions for cells. A mutation (also called a pathogenic variant) is a change in a gene located in nuclear or mitochondrial DNA that may cause disease. Mutations in nDNA, which occur in cellular chromosomes, can be inherited in different patterns, including autosomal recessive, autosomal dominant or X-linked recessive inheritance.

Congenital lactic acidosis affects males and females in equal numbers. The exact incidence of congenital lactic acidosis is unknown. One estimate is that the incidence is 250-300 live births per 1,000 per year in the United States. However, it is likely that many cases go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of congenital lactic acidosis in the general population.

A diagnosis of congenital lactic acidosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood and cerebrospinal fluid tests can reveal certain findings associated with congenital lactic acidosis such as elevated levels of lactate. An enzyme deficiency may be diagnosed by tests conducted on white blood cells or on skin or muscle cells obtained by biopsy. Genetic testing can be used to determine the molecular cause (pathogenic variants or mutations) of congenital lactic acidosis in many patients.


Congenital Leptin Deficiency

先天性瘦素缺乏所致肥胖症

obesity due to congenital leptin deficiency

Most babies with CLD have a normal weight at birth. The earliest symptoms of CLD are constant hunger and excessive eating leading to rapid weight gain and obesity before one year of age. People with CLD always feel hungry even after eating a full meal and often have abnormal behaviors related to food. Many have low levels of sex hormones (hypogonadotropic hypogonadism) causing delayed or absent puberty and infertility. Other symptoms include low energy levels, low blood pressure and insulin resistance, which can lead to type 2 diabetes. Children with CLD are often prone to infections, due to an immune system that doesn’t work correctly. Excessive weight gain can lead to other symptoms such as abnormal bone growth, liver disease and difficultly walking.

CLD is caused by pathogenic variants (mutations) in the LEP gene. The LEP gene is responsible for making the protein, leptin.  Leptin is made by fat cells and helps regulate energy storage in the body by balancing how much fat is made and how much is burned for energy. Without leptin, the body doesn’t recognize when the body has enough energy and it’s time to stop eating.

Congenital leptin deficiency is a very rare disorder. It has been estimated that 1 in 4.4 million people may have this condition. Many come from parts of the world where it is customary for relatives to marry.

CLD is one of several rare inherited conditions that include early-onset extreme obesity with few or no other signs or symptoms. These conditions are due to variants in one of the genes that normally work together to help regulate hunger and growth of body fat. These conditions may be difficult to diagnose based solely on clinical examination and sometimes genetic testing is the only way to tell the difference between them.

Congenital leptin deficiency is diagnosed based on a clinical examination, symptoms and the results of laboratory and genetic testing. Because there are several inherited conditions that include excessive hunger and early-onset obesity, genetic testing may be done to help make a specific diagnosis. This testing often involves using a gene panel, allowing the lab to look for genetic variants in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations.

Congenital leptin deficiency is treatable with leptin replacement using recombinant human leptin, also known as metreleptin. Treatment results in a decreased appetite and significant weight and fat loss.  In addition, leptin replacement leads to normal sexual development, decreased insulin levels and restores the immune system.


Congenital muscular dystrophy

The onset, specific symptoms, and severity of CMD varies considerably even among affected members of the same family. Several different methods of classifying the CMDs have been proposed. One classification separates these disorders based upon the primary genetic defect. This classification has three main categories: CMDs caused by defective genes that produce structural proteins of the basement membrane or the extracellular matrix, a complex structure that surrounds and supports cells; CMDs caused by defective genes that produce proteins essential for the normal attachment or binding (glycosylation) of sugar molecules to dystroglycan, a protein found on the membrane (sarcolemma) of muscle cells; or CMDs caused by a defective selenoprotein 1 (SEPN1) gene, which produces a protein without a currently known function. Recently, defective genes that produce proteins of the nuclear envelope, the double-layered membrane that covers the nucleus of certain cells, have also been linked to CMD.

Most of the congenital muscular dystrophies are inherited as autosomal recessive conditions.

CMD affects males and females in equal numbers. The exact incidence and prevalence of CMD is unknown. One estimate based upon findings within an Italian population place the incidence at 1 in 125,000. Another study placed the incidence in western Sweden at 1 in 16,000. However, these findings may not be applicable in other parts of the world. The muscular dystrophies as a whole are estimated to affect approximately 250,000 people in the United States.

Symptoms of the following disorders can be similar to those of congenital muscular dystrophy. Comparisons may be useful for a differential diagnosis.

A diagnosis of CMD is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and a variety of specialized tests including surgical removal and microscopic examination (biopsy) of affected muscle tissue that may reveal characteristic changes to muscle fibers; a test that assesses the health of muscles and the nerves that control muscles (electromyography); specialized blood tests; tests that evaluate the presence and number of certain muscle proteins (immunohistochemistry); magnetic resonance imaging (MRI), and molecular genetic testing.