Glucose-galactose malabsorption

葡葡糖-半乳糖吸收不良症

Symptoms usually begin in the first days of life, when a newborn drinks milk. Milk is broken down into simple sugars. Symptoms include severe diarrhea which can lead to life-threatening dehydration and difficulties gaining weight. The diarrhea and dehydration are fatal if left untreated. Once symptoms are managed, affected children typically have a normal lifespan. The symptoms may become less severe as patients age, which can allow for some sugars to be introduced back into their diet.

Normally, the SCL5A1 gene creates a protein that transports glucose and galactose into the intestines and kidneys. These simple sugars are used throughout the body and removed through urination.

GGM is an extremely rare disorder. There are around 300 cases worldwide. It appears to be more common in females. Most cases are seen in families where the parents are related by blood because they are more likely to carry the same harmful gene change.

The following disorders may appear with similar symptoms to GGM.

GGM can be diagnosed by testing the SLC5A1 gene to look for harmful changes. Diagnosis may also be confirmed through restricting dietary sugars (glucose, galactose, sucrose and lactose) to see if the symptoms stop. Genetic testing is replacing the glucose hydrogen breath test which is now less frequently used.


Glutaryl-CoA dehydrogenase deficiency

戊二酰-辅酶A脱氢酶缺乏

Babies with GA1 are born healthy and may only have unspecific signs like macrocephaly or muscular hypotonia at birth. Macrocephaly is one of the earliest signs of GA1 so newborns with an enlarged head circumference should be evaluated for GA1. Especially during the age of 3 months to 3 years, most affected untreated babies develop an acute encephalopathic crisis which is triggered by catabolic conditions such as febrile infections, febrile reactions to vaccinations or surgery. These crises result in striatal injury and a complex, mostly dystonic, irreversible and severe movement disorder which is associated with high morbidity and mortality. These babies can experience several symptoms resembling those of cerebral palsy, such as frequently assuming odd positions due to disordered muscle tone (dystonia), involuntary and ceaseless slow, sinuous, writhing (athetotic) or jerky (choreic) movements of the trunk and limbs. Controlling the movement of hands, arms, feet, legs, head and neck may become very hard and muscle spasms may occur. Repeated stress on the body (such as infection and fever) can cause symptoms to worsen, but in some children, brain damage will occur without a triggering fever.

GA1 is caused by pathogenic variants in the GCDH gene that leads to deficiency of the enzyme, glutaryl-CoA dehydrogenase or GCDH. This enzyme is responsible for metabolizing the amino acids lysine, hydroxylysine and tryptophan. Pathogenic variants in GCDH prevent production of the enzyme resulting in abnormal levels of glutaric, 3-hydroxyglutaric and (to a lesser extent) glutaconic acids These products accumulate and cause damage to an area of the brain called the basal ganglia that regulates motor movement.

GA1 is a rare inborn error of metabolism that affects males as often as females. It has been estimated that there are about 140 patients with this type of organic aciduria in the United States. GA1 occurs in approximately 1 of every 100,000 births. Five genetic isolates are known with a high carrier frequency (up to 1:10) and incidence (up to 1:250 newborns): the Old Order Amish Community in Lancaster County, Pennsylvania, United States, the Oji-Cree First Nations in Manitoba and Western Ontario, Canada, the Irish Travelers in the Republic of Ireland and United Kingdom, the Lumbee in North Carolina, United States and the Xhosa in South Africa.

There are many rare disorders caused by enzyme deficiencies, so misdiagnosis is common for a GA1 patient. Differential diagnosis includes encephalitis, Reye’s syndrome, familial infantile bilateral striatal necrosis, familial megalocephaly, post encephalitic parkinsonism, dystonic cerebral palsy, battered child syndrome with chronic subdural effusions, sudden infant death syndrome and vaccine induced brain-injury. Increased levels of 3‐OH‐GA, typical in GA1 patients, have been found in patients with short‐chain 3‐hydroxyacyl CoA dehydrogenase (SCAD) deficiency, patients with renal insufficiency, in patients with disorders of long‐chain fatty acid oxidation and mitochondrial disorders, and in ketotic patients.

GA1 Is diagnosed by the characteristic metabolites GA, 3-OH-GA, glutaconic acid and glutarylcarnitine (C5DC) detected in body fluids (urine, plasma, CSF) and tissues using gas chromatography/mass spectrometry (GC/MS) or electrospray-ionization tandem mass spectrometry (MS/MS). As neonatal diagnosis and start of treatment significantly improves neurologic outcome, GA1 has been included in MS/MS based NBS disease panels in many countries worldwide.


Glutaric Aciduria Type II

electron transfer flavoprotein, deficiency of

Glutaric aciduria type II (GAII) is one of the conditions termed organic acidemias. Individuals with these conditions have a deficiency or absence of an enzyme that prevents the breakdown of certain chemicals (proteins and fats) in the body, resulting in the accumulation of several organic acids in the blood and urine. Two enzymes that may be deficient in GAII are electron transfer flavoprotein (ETF) and ETF-dehydrogenase (ETFDH). The severity of GAll varies widely among affected individuals. A complete enzyme deficiency causes a severe form of the disorder termed neonatal GAll that is associated with a short life span and, sometimes, with specific physical birth defects. Individuals with this form may be born with physical abnormalities including brain malformations, enlarged liver, kidney malformations, unusual facial features, and genital abnormalities. They may also emit an odor resembling sweaty feet. The less severe form of the disorder is termed late onset GAll, which may appear in infancy, childhood, or even adulthood. Most often, GAll first appears in infancy or early childhood as a sudden episode of a metabolic crisis, that can cause weakness, behavior changes (such as poor feeding and decreased activity) nausea, vomiting and low blood sugar (hypoglycemia). GAII is an autosomal recessive genetic disorder caused by mutations in the ETFA, ETFB, or ETFDH genes. Treatment varies depending on the severity and symptoms but often includes a low fat, low protein, and high carbohydrate diet.

Signs and symptoms of GAII vary greatly depending on the age of onset and severity of the condition in each affected individual.

Glutaric aciduria type II is an autosomal recessive disease caused by changes (mutations) in the ETF-A (subunit alpha), ETF-B (subunit beta) or ETFDH genes. The mutations result in deficient or complete absence of activity of multiple acyl-CoA dehydrogenase (MADD) enzymes needed to break down fats and proteins that the body uses for energy. This results in the accumulation of several organic acids in the blood and urine. Mutations in ETFA and ETFB generally cause the neonatal forms of this disorder and the ETFDH gene mutation is found in many late onset forms of GAII. Dysfunction of either ETF or ETFDH flavoproteins leads to compromised fatty acid oxidation and amino acid degradation that alters energy production as well as production of other molecules needed for fuel storage and use.

Prevalence is estimated to be 1/200,000 and GAll affects both males and females. Prevalence in ethnicities is not known.

Glutaric aciduria type I is a rare hereditary metabolic disorder caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase. Patients are usually well at birth but present during early infancy/childhood with an acute event of vomiting, seizures & reduced consciousness often in association with an infection such as a bad cold or gastroenteritis. The patient may have involuntary movements of the trunk and limbs (dystonia or athetosis), and intellectual disability may occur. (For more information on this disorder, choose glutaric aciduria I as your search term in the Rare Disease Database.)

The diagnosis of GAll begins with examining urine organic acids. The characteristic pattern for glutaric aciduria is an elevation of a range of organic acids which may include glutaric, lactic, ethylmalonic, isovaleric, adipic,butyric, isobutyric, suberic & sebacic acids with a number of characteristic acylglycines. Blood acylcarnitine analysis by tandem mass spectrometry will show increases in a wide range of acylcarnitines from C4-C18. Some mildly affected individuals may not have an abnormal pattern of urine organic acids except when they are ill. Diagnosis of GAll can also be made by demonstrating reduced fatty acid oxidation in cultured fibroblasts obtained from a skin biopsy or by molecular genetic testing.


Glutathione synthetase deficiency

Glutathione synthetase deficiency is an extremely rare disorder characterized by a deficiency of the enzyme glutathione synthetase. This enzyme is part of the chemical process by which the body creates glutathione, a protein molecule that plays a role in many cell processes. Glutathione synthetase deficiency is often classified as mild, moderate or severe. Consequently, the specific symptoms and severity can vary greatly from one person to another. Generally, the mild form only affects red blood cells (erythrocytes). The severe form is widespread (generalized) affecting many types of cells of the body. The moderate form falls in between these two extremes. Glutathione synthetase deficiency is caused by alterations (mutations) in the GSS gene and is inherited in an autosomal recessive manner.

Glutathione synthetase deficiency may be best thought of as a spectrum of disease ranging from mild to moderate to severe expression of the disorder. Although researchers have been able to establish a clear syndrome with characteristic or core symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder 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 and that each individual is unique. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.

Glutathione synthetase deficiency is caused by alterations in the GSS gene. 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.

Glutathione synthetase deficiency affects males and females in equal numbers. More than 70 individuals from 50 families have been described in the medical literature. The exact incidence and prevalence are unknown. Because individuals may be misdiagnosed or go undiagnosed, determining the true frequency in the general population is difficult.

Symptoms of the following disorders may be similar to those of glutathione synthetase deficiency. Comparisons may be useful for a differential diagnosis:

There are numerous other conditions that cause elevated levels of 5-oxoproline in the urine (5-oxoprolinuria) including severe burns, Stevens-Johnson syndrome, nephropathic cystinosis, and various inborn errors of metabolism including 5-oxoprolinase deficiency, urea cycle disorders, tyrosinemia and homocystinuria. In some individuals, the use of certain drugs may cause 5-oxoprolinuria. Such drugs include paracetamol, vigabatrin, and certain antibiotics. Hemolytic anemia can occur in many different conditions including other disorders of glutathione metabolism including gamma-glutamylcysteine synthetase deficiency and glucose-6-phosphate dehydrogenase deficiency. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)

The treatment of glutathione synthetase deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment will include sodium bicarbonate to correct the metabolic acidosis. Initially, this may require parenteral (e.g. intravenous) therapy. Eventually, affected individuals can be treated with sodium bicarbonate or citrate, delivered through the mouth (orally). Supplemental therapy with vitamins E and C, which have antioxidant properties, may also be given.


Glycogen Storage Disease Type 7

肌磷酸果糖激酶缺乏所致糖原贮积病

GSD7 is caused by harmful changes (mutations) in the gene for muscle phosphofructokinase (PFKM). This leads to problems with the function of phosphofructokinase enzyme, the protein that breaks down glycogen to glucose. This lowered enzyme activity results in a decreased amount of energy for muscles to use during exercise. This leads to muscle pain and cramps.

GSD7 is a rare disease that is seen more often in individuals of Japanese and Ashkenazi (Eastern European) Jewish ancestry. GSD7 affects males and females in equal numbers. The condition is estimated to occur is less than 1/1,000,000 people.

Glycogen storage disease type 5 (McArdle disease or GSD5) is an inherited or genetic glycogen storage disease. In GSD5, symptoms are caused by a missing muscle enzyme called myophosphorylase. This enzyme is needed for the breakdown of glycogen (the body’s form of stored energy) into sugar (glucose) in muscle. Autosomal recessive GSD5 symptoms can start in childhood or in adulthood. There is also a much rarer autosomal dominant form of GSD5. Symptoms of GSD5 are exercise intolerance, muscle cramping and dark, reddish brown-colored urine (myoglobinuria)

GSD7 is diagnosed by measuring the amount of the phosphofructokinase enzyme in a sample of muscle tissue taken from a muscle biopsy. It can also be diagnosed by measuring the phosphofructokinase enzyme level in red blood cells.


Glycogen Storage Disease Type I

葡萄糖-6-磷酸酶缺乏所致肝糖原贮积症

Glycogen storage diseases are a group of disorders in which stored glycogen cannot be metabolized into glucose to supply energy and to maintain steady blood glucose levels for the body. Type I glycogen storage disease is inherited as an autosomal recessive genetic disorder. Glycogen storage disease type I (GSDI) is characterized by accumulation of excessive glycogen and fat in the liver and kidneys that can result in an enlarged liver and kidneys and growth retardation leading to short stature. GSDI is associated with abnormalities (mutations) in the G6PC gene (GSDIA) or SLC37A4 gene (GSDIB). These mutations result in enzyme deficiencies that block glycogen breakdown in affected organs causing excess amounts of glycogen and fat accumulation in the body tissues and low levels of circulating glucose in the blood. The enzyme deficiency also results in an imbalance or excessive accumulation of other metabolites, especially lactates, uric acid and fats like lipids and triglycerides.

The primary symptom of GSDI in infancy is a low blood sugar level (hypoglycemia). Symptoms of GSDI usually begin at three to four months of age and include enlargement of the liver (hepatomegaly), kidney (nephromegaly), elevated levels of lactate, uric acid and lipids (both total lipids and triglycerides), and possible seizures caused due to repeated episodes of hypoglycemia. Continued low blood sugar can lead to delayed growth and development and muscle weakness. Affected children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen.

Type I glycogen storage disease is associated with abnormalities in two genes. Mutations in the G6PC gene result in a deficiency in the glucose-6-phosphatase (G6Pase) enzyme and account for approximately 80% of GSDI. This type of GSDI is termed glycogen storage disease type Ia. Mutations in the SLC37A4 gene result in a deficiency in the glucose-6-phosphatase translocase enzyme (transporter deficiency) and account for approximately 20% of GSDI. This type of GSDI is termed glycogen storage disease type Ib. Both these enzyme deficiencies cause excess amounts of glycogen along with fats to be stored in the body tissues.

Type I glycogen storage disease occurs in approximately 1 in 100,000 births. The prevalence of GSDI in Ashkenazi Jews is approximately 1 in 20,000. This condition affects males and females in equal numbers in any given population group.

Symptoms of the following disorders can be similar to those of glycogen storage disease type I. Detailed evaluations may be useful for a differential diagnosis:

Forbes or Cori disease (GSD-III) is one of several glycogen storage disorders that are inherited as autosomal recessive traits. Symptoms are caused by a lack of the enzyme amylo-1,6 glucosidase (debrancher enzyme). This enzyme deficiency causes excessive amounts of an abnormally digested glycogen (the stored form of energy that comes from carbohydrates) to be deposited in the liver, muscles and, in some cases, the heart. Symptoms become evident during the first years of life with hepatomegaly and/or myopathy, and elevated liver enzymes. In the first few months some symptoms may overlap with GSDI (elevated lipids, hepatomegaly, low glucose).


糖原脱支酶缺乏所致糖原贮积病

Glycogen storage disease due to glycogen debranching enzyme deficiency

The median age at the first clinical presentations is in the first year of life. Most common presenting symptoms are enlarged liver (hepatomegaly) (98%), low blood sugar (hypoglycemia) (53%), failure to thrive (49%) and recurrent illness and/or infections (17%). Symptoms and signs of GSD-III, at least during the first 4 to 6 years of life, may be indistinguishable from GSD type I. The amount of glycogen in the liver and muscles is abnormally high, the liver is enlarged, and the abdomen protrudes. The muscles tend to be flaccid or weak.

GSD-III is an inborn error of metabolism caused by mutations in the AGL gene that is located on chromosome 1p21. The AGL gene is responsible for the production of the debranching enzyme.

All glycogen storage diseases together affect fewer than 1 in 40,000 persons in the United States. GSD-III has an incidence of about 1 in 100,000. The incidence of GSD-III is higher in North African Jews (± 1 in 5,400), Faroese (± 1 in 3,100) and the Inuit population in Nunavik, Canada (± 1 in 2,500).

The following diseases are similar to GSD-III. Comparisons may be useful for a differential diagnosis. Several GSD subtypes can be considered:

An enlarged liver and low blood sugar with high levels of ketones, transaminases, lipids and creatine kinase is indicative of GSD-III. Uric acid and fasting lactic acid levels are usually normal. In GSD-IIIb creatine kinase can be normal. Molecular genetic testing for mutations in the AGL gene can be used to confirm the diagnosis. Nowadays, liver and muscle biopsies are uncommon. In many countries besides the United States, studies in blood cells and skin fibroblasts are clinically available to confirm GDE deficiency.


磷酸化酶激酶缺乏所致糖原贮积病

Glycogen storage disease due to phosphorylase kinase deficiency

GSD-IX is caused by deficiency of the enzyme phosphorylase kinase. The specific symptoms present, severity and prognosis can vary depending upon the subtype and the areas of the body affected. The symptoms and severity can vary even among individuals with the same mutation. In addition, some subtypes have only been reported in a handful of individuals, which prevents 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. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Individuals with the liver form of GSD-IX have a wide range of clinical symptoms ranging from less severe to more severe hepatic manifestations of the disease. Natural history studies are necessary to understand completely the long-term course and prognosis of GSD IX.

Glycogen storage disease type IX is caused by mutations in the PHKA1, the PHKA2, the PHKB, or the PHKG2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation is present in a gene, 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. For GSD-IX, these mutations can be inherited in either an autosomal recessive or X-linked manner.

The autosomal recessive forms of glycogen storage disease IX affect males and females in equal numbers. The X-linked forms primarily affect males, although females can have symptoms, such as enlargement of the liver and, more rarely, females can have symptoms similar to those seen in males. GSD-IX types A, B and C are estimated to affect 1 in 100,000 individuals in the general population. These disorders account for approximately 25% of all glycogen storage disorders making GSD-IX one of the most common forms of these disorders. Because some affected individuals go undiagnosed or misdiagnosed, it is difficult to determine the true frequency of GSD-IX in the general population. GSD-IXd is extremely rare and its prevalence is unknown.

Symptoms of the following disorders can be similar to those of glycogen storage disease type IX. Comparisons may be useful for a differential diagnosis.

A diagnosis of glycogen storage disease type IX is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.


肌糖原磷酸化酶缺乏所致糖原贮积病

Glycogen storage disease due to muscle glycogen phosphorylase deficiency

Glycogen storage disease type V (GSD-V or McArdle disease) is the most common disorder of skeletal muscle carbohydrate metabolism and one of most frequent genetic myopathies (prevalence ~1:100000). Twelve different types of glycogen storage disease have been described (type 0, I-VII, IX, XI-XIII), which result from defects in glycogen synthesis and breakdown principally in the muscle and liver, although other tissues can also be affected. GSD-V is caused by the lack of the muscle glycogen phosphorylase (myophosphorylase) enzyme. Although symptoms typically begin during the first ten years of life, the age of diagnosis can vary significantly. The characteristic symptoms of GSD-V are exercise intolerance, myalgia (muscle pain), muscle stiffness and contractures, quick fatigue as well as hyperCKemia and myoglobinuria (dark, burgundy-colored urine due to the presence of myoglobin, a protein found in heart and muscles). These symptoms are usually caused by isometric or uninterrupted aerobic exercise. Currently, there is no cure for GSD-V.  To manage GSD-V, medical professionals suggest that people affected avoid intense exercise and a completely inactive lifestyle, but do engage in consistent, reasonable aerobic exercise.

GSD-V is characterized by exercise intolerance. This typically consists in acute crises of early fatigue and muscle stiffness and contractures, especially at the start of the exercise, that usually disappear if exercise is stopped or the intensity is reduced. Symptoms usually present within the first ten years of life, but there is a wide range of clinical onset and severity. Some GSD-V patients have mild symptoms while another form progresses quickly and is apparent shortly after the person is born.  Progressively weak muscles, in some individuals, do not manifest until the age of sixty to seventy years old.

GSD-V is caused by mutations in the PYGM (glycogen phosphorylase, muscle form) gene that codes for the myophosphorylase enzyme.  The PYGM gene is located on chromosome 11 at 11q13.

GSD-V is very rare with only a few hundred cases reported in the medical literature. Some researchers believe that it is probably under-diagnosed because of the mildness of the symptoms. The neonatal, early-onset and very late-onset forms are even rarer. The prevalence of GSD-V in the Dallas-Fort Worth, TX area has been estimated at 1:100,000 and the prevalence in Spain has been reported at 1:170,000.

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

Pompe Disease (GSD-II) is a rare multisystem genetic disorder that is characterized by absence or deficiency of the lysosomal enzyme alpha-glucosidase (GAA). The infantile form is characterized by severe muscle weakness and abnormally diminished muscle tone (hypotonia) without muscle wasting, and usually manifests within the first few months of life. Additional abnormalities may include enlargement of the heart (cardiomegaly), the liver (hepatomegaly), and/or the tongue (macroglossia). Without treatment, progressive cardiac failure usually causes life-threatening complications by the age of 12 to 18 months. Pompe disease can also present in childhood, adolescence or adulthood, collectively known as late-onset Pompe disease. The extent of organ involvement may vary among affected individuals; however, skeletal muscle weakness is usually present with minimal cardiac involvement. Initial symptoms of late-onset Pompe disease may be subtle and may go unrecognized for years. Pompe disease is inherited as an autosomal recessive trait.


肝糖原磷酸化酶缺乏所致糖原贮积病

Glycogen storage disease due to liver glycogen phosphorylase deficiency

Symptoms vary from person to person, and people with GSD6 may not have all the symptoms listed. GSD6 is usually a relatively mild disorder, although rare cases with more severe symptoms have been reported.

GSD6 is caused by harmful changes (mutations) in the PYGL gene. This gene is responsible for telling the body how to make an enzyme called liver glycogen phosphorylase. This enzyme is responsible for breaking down glycogen. Glycogen is a form of energy that comes from carbohydrates and is stored in the liver. When the body needs more energy, glycogen in the liver is broken down by the PYGL gene product, glycogen phosphorylase.

Males and females are affected in equal numbers due to the autosomal recessive inheritance of GSD6. The incidence of all glycogen storage diseases is estimated to be between 1 in 20,000 and 1 in 25,000 persons in the United States. However, GSD6 is estimated to affect only 1 in 1,000,000 individuals in the general population. Because some affected individuals go undiagnosed or are misdiagnosed, it is difficult to determine the exact frequency of GSD6 in the general population. A higher occurrence of GSD6 has been seen in the Mennonite population, about 1 in 1,000 live births. There is a specific PYGL gene mutation that is present in about 3% of the Mennonite population which accounts for this higher incidence.

Symptoms of the following disorders can be similar to those of GSD6. Comparisons may be useful for a differential diagnosis:

GSD6 is diagnosed based on signs and symptoms of the disease, such as an enlarged liver, growth delay and hypoglycemia. The diagnosis can be confirmed by genetic testing of the PYGL gene. A liver biopsy that tests the function of liver glycogen phosphorylase may be necessary if the results of the genetic testing are not clear.


GNB1-Related Disorder

全球发育迟缓-神经-眼异常-癫痫发作-智力障碍综合征

global developmental delay-neuro-ophthalmological abnormalities-seizures-intellectual disability syndrome

The most common signs and symptoms of GNB1-related disorder are developmental delays and intellectual disabilities, which can range from mild to severe. Intellectual disability is the most common characteristic, but it may not be recognized until the child attends school. Some people with GNB1-related disorder can talk and walk independently and others cannot.

GNB1-related disorder is caused by a disease-causing variant or a likely disease-causing variant in the GNB1 gene.

There are over 60 individuals reported in the world with GNB1-related disorder. The condition is not currently known to be more common in any specific population or ethnic group.

There are many different genetic conditions that have symptoms such as seizures and developmental delay that are present in children with GNB1-related disorder. Distinguishing this condition from other conditions based on signs and symptoms can be challenging.

Many genetic conditions are associated with developmental delays and seizures, so individuals with GNB1-related disorder are usually diagnosed with broad genetic tests such as whole exome sequencing or whole genome sequencing that look for variants in thousands of different genes. Gene panel tests that look for variants in a number or genes or analysis of the GNB1 gene only can also confirm the diagnosis, but these tests are ordered less frequently.

There is currently no cure for GNB1-related disorder. Treatment is based on managing the symptoms that are present in the patient with therapies that are known to be effective for those symptoms. Treatment should include developmental therapies, seizure medications as needed and early intervention services if needed. There is no specific anti-seizure medication recommended for individuals with GNB1-related disorder.


GNE myopathy

GNE myopathy manifests between the second and third decade of life and is characterized by progressive muscle wasting often accompanied by severe incapacitation within 10 to 20 years after onset. Even at early stages of the disease, GNE myopathy patients exhibit a characteristic bilateral foot drop which is caused by weakness of the tibialis anterior muscle (one of the frontal muscles that is connected to the knee and the foot). Early stage muscle weakness in GNE myopathy patients can include disturbed gait and decreased stability, frequent falls, difficulty in climbing stairs, running and getting up from a seated position. Most patients end up wheelchair-bound within 10-20 years of disease onset. Lower limb muscles are affected first with the exception of the quadriceps which appears to be relatively spared. As the disease progresses, 5 to 10 years after the onset of symptoms, the majority of patients experience progressive weakness and loss of the upper limb muscles. In advanced stages of the disease, neck muscles can also be affected. 1, 10, 11 Ultimately, disease progression may result in complete loss of skeletal muscle function and dependence on caregivers 1, 12, 13

GNE myopathy is caused by mutations in the GNE gene. This gene is responsible for the production of an enzyme needed to make SA. Patients consistently express lower levels of SA as clearly demonstrated by analyses performed on muscle biopsies. It is believed that the loss of SA is one of the main contributors in the typical muscle wasting observed in patients, although further studies are required to determine the specific mechanisms of action of the GNE enzyme in muscle. Mutations in GNE can occur anywhere along the sequence of the gene. The majority of mutations reported are so-called missense mutations. These are alterations of the genetic code that only produce a small change in the genetic sequence but affect the function of the GNE enzyme.

Mutations in the GNE gene have been reported worldwide in approximately 4,000 patients although the incidence of the disease has been estimated to be 1-9/100,000 individuals (Orphanet; https://www.orpha.net/). This suggests that the vast majority (approximately 40,000) of GNE myopathy patients still remain undiagnosed. 1

Clinically, the diagnosis may be confused with other conditions, such as other distal myopathies, limb girdle muscular dystrophy, spinal muscular atrophy or Charcot-Marie-Tooth disease. As such, referral to a neuromuscular specialist is highly recommended.

Patients presenting with foot drop (young adults) and distal extremity muscle weakness (in individuals at more advance stages of the disease) are good candidates for GNE myopathy testing.


Goblet cell carcinoma

At the time of diagnosis, GCAs can be either localized to the appendix or have spread to other parts of the body – particularly the abdomen. For GCAs that are localized, the most common signs and symptoms are those of acute appendicitis – namely right lower abdominal pain. For GCAs that have already spread away from the appendix, the most common presenting signs and symptoms are abdominal pain and a mass. Finding GCAs that have already spread at the time of diagnosis is more common in females and 15-30% are initially diagnosed as having an ovarian cancer. There is a clear attraction of GCAs to the ovary for a reason that is not yet known but it is under investigation.

The exact cause of GCAs are unknown. One study has suggested a possible connection between schistosomiasis (a parasitic infection found in certain tropical and subtropical countries) and GCAs, however a causal relationship has not been established and the vast majority of GCAs occur in the absence of schistosomiasis. Recent studies have shown that GCAs do have a unique genomic profile distinct from adenocarcinomas and neuroendocrine tumors of the appendix, which may offer future targetable pathways for treatment. There are no genetic, familial or environmental factors known to cause this disorder. It does not run in families.

GCAs are very rare with approximately 1 case per 2 million individuals. The average age at the time of diagnosis is most frequently reported between 50-60. While most studies have reported that males and females are affected in equal numbers, a few have suggested a slightly increased frequency in females (2-3:1). Advanced GCAs tend to present more frequently in females and 15-30% of females are initially diagnosed with an ovarian cancer. Less than 1% of GCAs are accurately diagnosed prior to surgery.

GCAs are a subtype of neoplasms (cancers and tumors) that can occur in the appendix. The general topic of appendiceal cancer and tumors is discussed in a separate Rare Disease Report.

Because there are no unique features of GCAs on imaging studies such as ultrasound, CT scan, PET scan or MRI, the diagnosis of GCA cannot be made until a tumor specimen is examined by a pathologist. This is frequently accomplished at the time of appendectomy for appendicitis, surgery for an intestinal blockage or presumed ovarian cancer. It can also be diagnosed during a tumor biopsy performed for an abnormal clinical or radiographic finding, such as a palpable tumor or tumors seen on an imaging study. GCAs tend to be easier to identify because of the unique combination of neuroendocrine and epithelial cells, although the presence of neuroendocrine cells is not required.

Once the diagnosis is established, a staging work-up including imaging studies (most commonly a CT scan of the chest, abdomen and pelvis) and tumor marker blood tests (CEA, CA 19-9 and CA 125) should be performed. (Tumor markers are proteins related to the cancer cells that can be measured in the blood.) Treatment recommendations depend on both the histology of the GCAs (the microscopic structure of the tumor cells) and whether it is localized or disseminated. Most of the larger and more recent studies of GCAs recommend surgical removal of the right side of the colon (right hemicolectomy) to ensure that all the disease has been removed and to test the regional lymph nodes for any cancer cells. Some also recommend removal of the ovaries in post-menopausal females given the affinity of these tumors for the ovaries. In very rare instances, when the tumor is localized to the appendix, low grade, and removed completely with an appendectomy, some may consider appendectomy alone, but this remains controversial.


Anti-glomerular basement membrane disease

Goodpasture syndrome is a rare autoimmune disorder characterized by inflammation of the filtering structures (glomeruli) of the kidneys (glomerulonephritis) and excessive bleeding into the lungs (pulmonary hemorrhaging). Autoimmune syndromes occur when the body’s natural defenses (antibodies) against invading or foreign organisms begin to attack the body’s own tissue, often for unknown reasons. Symptoms of Goodpasture syndrome include recurrent episodes of coughing up of blood (hemoptysis), difficulty breathing (dyspnea), fatigue, chest pain, and/or abnormally low levels of circulating red blood cells (anemia). In many cases, Goodpasture syndrome may result in an inability of the kidneys to process waste products from the blood and excrete them in the urine (acute renal failure). In some cases of Goodpasture syndrome, affected individuals have had an upper respiratory tract infection before the development of the disorder. The exact cause of Goodpasture syndrome is not known.

The major symptoms of Goodpasture syndrome are excessive bleeding into the lungs (pulmonary hemorrhaging) and inflammation of the filtering structures (glomeruli) or the kidneys (glomerulonephritis). In some cases, an upper respiratory tract infection may precede the development of the disorder. General symptoms associated with Goodpasture syndrome may include fever, nausea, and fatigue.

Goodpasture syndrome develops due to unknown causes. Environmental factors such as hydrocarbon chemical exposure, cigarette smoke, or infections such as influenza may play a role in the development of the disorder. It is not known why simple infections can progress to Goodpasture syndrome in some people. When infection occurs, the body’s natural defenses (antibodies) fight the invading organisms (e.g., viruses or bacteria). In autoimmune disorders, antibodies attack healthy tissue for no apparent reason. Pulmonary hemorrhage has been frequently associated with smoking in individuals with Goodpasture syndrome.

Goodpasture syndrome is a rare autoimmune disorder that appears to affect males more frequently than females. Age of onset is usually between 20 and 30, but individuals at any age may be affected.

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

Wegener’s granulomatosis is an uncommon disorder characterized by inflammation of blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some cases, kidney abnormalities may progress to kidney failure, a serious complication. If the lungs are affected, a cough, expectoration of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the inside of the lung may be present. The exact cause of Wegener’s granulomatosis is not known. (For more information on this disorder, choose Wegener’s as your search term in the Rare Disease Database.)


Gordon syndrome

arthrogryposis multiplex congenita, distal, type IIA

Gordon syndrome is characterized by stiffness and impaired mobility of certain joints of the arms and legs (distal arthrogryposis) including the knees, elbows, wrists, and/or ankles. In most infants with this disorder, several fingers may be permanently fixed in a flexed position (camptodactyly), which may result in limitations in range of motion and manual dexterity. In addition, affected infants may exhibit abnormal bending inward of the foot (clubfoot or talipes). In severe instances, infants with Gordon syndrome may experience delays in walking.

Gordon syndrome is caused by an alteration (mutation) in the PIEZO2 gene. 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.

Gordon syndrome affects males and females in equal numbers. More than 40 people in five families (kindreds) have been reported in the medical literature. In most people, physical features associated with Gordon syndrome are obvious at birth (congenital).

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

In most people, Gordon syndrome is diagnosed at birth by a thorough clinical evaluation and the identification of characteristic physical findings. Many of the physical features associated with Gordon syndrome (e.g., camptodactyly, clubfoot, and/or cleft palate) are obvious at birth (congenital).

The treatment of Gordon 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, surgeons, speech pathologists, physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.


Gorham-Stout disease

The symptoms of GSD depend upon the specific bones involved. The ribs, spine, pelvis, skull, collarbone (clavicle), and jaw are the most commonly affect bones in GSD. In some cases, affected individuals may rapidly develop pain and swelling in the affected area. In other cases, affected individuals may experience a dull pain or ache or generalized weakness that builds over time. Trauma is often a trigger of the initial presentation of the disease. Bones affected by GSD are prone to pathological fractures.

The exact cause of GSD is unknown. No environmental, immunological or genetic risk factors have been identified. Most cases occur randomly for no known reason (sporadically).

GSD usually affects children and young adults under the age of 40. However, the disorder has been reported in an infant less than one month old and an adult more than 70, suggesting GSD can potentially affect individuals of any age. Some medical sources state that males are affected more often than females. Other medical sources state that the ratio is even (1:1). More than 300 affected individuals have been reported in the medical literature. Because GSD is so rare, many cases go undiagnosed or misdiagnosed making it difficult to determine the disorder’s true frequency in the general population.

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

There is no specific test or procedure that definitively diagnoses GSD, which is partly a diagnosis of exclusion. A diagnosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including biopsies and specialized imaging techniques.


Gorlin-Chaudhry-Moss syndrome

Craniofacial Dysostosis-PD Arteriosus-Hypertrichosis-Hypoplasia of Labia

Gorlin-Chaudhry-Moss syndrome is an extremely rare inherited disorder characterized by premature closure of the fibrous joints (sutures) between certain bones in the skull (craniosynostosis), unusually small eyes (microphthalmia), absence of some teeth (hypodontia), and/or excessive amounts of hair (hypertrichosis) on most areas of the body. Affected individuals may also exhibit a mild delay in physical development (growth retardation); short fingers and/or toes; and/or underdevelopment (hypoplasia) of the two long folds of skin on either side of the vaginal opening (labia majora) in females. In addition, there may be an abnormal opening between the two large blood vessels that carry blood away from the heart (pulmonary artery and aorta), causing inappropriate recirculation of some blood through the lungs, rather than throughout the rest of the body (patent ductus arteriosus). In some cases, mild mental retardation may also be present. It is believed that Gorlin-Chaudhry-Moss syndrome may be inherited as an autosomal recessive trait.

Gorlin-Chaudhry-Moss syndrome is characterized by a mild delay in physical development (growth retardation), short stature, mild mental retardation, and several physical abnormalities.

It is believed that Gorlin-Chaudhry-Moss syndrome may be inherited as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

Gorlin-Chaudhry-Moss syndrome is an extremely rare inherited disorder that is apparent at birth (congenital). Approximately four cases have been reported in the medical literature. Although all reported cases have involved females, the true ratio of affected females to males is not known. The first case of Gorlin-Chaudhry-Moss syndrome was reported in the medical literature in 1960.

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

Weill-Marchesani syndrome is a rare inherited disorder of the connective tissue. It is characterized by an abnormally short head (brachycephaly), round face, and pug nose; short fingers (brachydactyly); joint stiffness with limited extension; and short stature with a muscular, stocky build. In most cases, several eye abnormalities are present, including abnormally small, round lenses (microspherophakia) that tend to dislocate (ectopia lentis); loss of transparency of the lenses (cataracts); nearsightedness (myopia); and/or abnormally increased pressure in the fluid of the eye (glaucoma). It is believed that Weill-Marchesani syndrome may be inherited as an autosomal dominant or recessive genetic trait. (For more information on this disorder, choose Weill-Marchesani as your search term in the Rare Disease Database.)


Acrogeria

The signs and symptoms of Gottron syndrome vary somewhat from one person to another. Because this condition is so rare, it is difficult to get a complete picture of the core features that define the syndrome.

Gottron syndrome is a rare disorder that for which the mode of inheritance is still not well understood. There is evidence for both autosomal recessive and autosomal dominant inheritance patterns. Most often, a child with Gottron syndrome is the only affected person in the family.

It is believed that Gottron syndrome may affect more females than males. While about 50 affected individuals have been reported in the medical literature, the exact number of people with this condition is unknown.

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

De Barsy syndrome is a rare genetic disorder characterized by a prematurely-aged appearance (progeroid) as well as skin that is loose and lacking elasticity (cutis laxa).The appearance of the infant appears prematurely aged-due to the underdevelopment of the skin and structures of the face (facial hypoplasia) which is further enhanced by wrinkled and saggy skin. Other notable facial features include a prominent forehead, thin lips, and large ears. This is often accompanied by eye abnormalities, intellectual disability as well as growth delays. Affected infants may also have diminished muscle tone (hypotonia). Signs and symptoms of de Barsy syndrome are usually evident in early infancy if not at birth. (For more information on this disorder, choose De Barsy syndrome as your search term in the Rare Disease Database.)


GPT2 Deficiency

出生后小头畸形-小儿肌张力低下-痉挛性截瘫-构音障碍-智力障碍综合征

alanine transaminase 2 (ALT2) deficiency

GPT2 deficiency (glutamate pyruvate transaminase 2 deficiency) is a genetic, neurological and metabolic disorder that results in intellectual disability and progressive motor dysfunction. This deficiency disrupts important biological processes necessary for proper brain growth. The developing brain relies on the creation and reinforcement of synapses, or connections, between neurons. This disease compromises those connections, resulting in fewer synapses and weaker brain circuits. GPT2 deficiency ultimately hinders brain development, causes metabolic abnormalities including deficiencies in metabolites that protect the nervous system, so patients tend to become more severely affected over time (neurodegenerative course).

Individuals with GPT2 deficiency have been reported to have varying levels of intellectual disability. Most affected infants have low muscle tone (hypotonia) at birth and too much muscle tone (hypertonia) later in childhood. Most individuals experience progressive coordination and movement problems, including spastic paraplegia or diplegia around 8-10 years of age. Below is a list of reported and researched symptoms:

GPT2 deficiency is caused by loss-of-function variants (mutations) in the GPT2 gene. This gene codes for the important mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2). Loss-of-function mutations reduce the capacity of important enzymes and proteins to carry out normal operation, sometimes with total inactivation. The GPT2 gene is expressed in the brain and helps regulate levels of metabolites central to proper development. Metabolites are tiny molecules that are responsible for proper cell growth, defense and function.

GPT2 deficiency seems to affect males and females equally. Individuals with this condition are from a variety of countries across the globe and from many different ethnic backgrounds. GPT2 deficiency is currently considered an ultra-rare disease with a very small number of individuals reported with the mutations and it is often unrecognized or misdiagnosed. As genetic testing, specifically whole exome sequencing (WES), becomes more accessible, it will be possible to gain more information about affected populations.

GPT2 deficiency may appear in a differential diagnosis with other disorders that may be defined by intellectual and developmental disability, postnatal microcephaly and spastic paraplegia. This includes several different genetic forms of intellectual disability or complex spastic paraplegias.

Diagnosis of GPT2 deficiency must be confirmed through genetic testing. The GPT2 gene is included in certain genetic diagnostic panels and whole exome sequencing.


Graft versus host disease

Graft versus Host Disease (GVHD) is a rare disorder that can strike persons whose immune system is deficient or suppressed and who have received a bone marrow transplant or a nonirradiated blood transfusion. Symptoms may include skin rash, intestinal problems and liver dysfunction.

GVHD occurs most frequently after allogeneic bone marrow transplant and initially leads to dermatitis (a skin rash), gastrointestinal problems and liver dysfunction. In its chronic form involvement of mucosa (mouth and eyes) resembling sicca syndrome, lungs (resembling bronchiolitis obliterans) and the muskuloskeletal system (resembling myositis) is observed. GVHD affects about 60% of all bone marrow transplant but usually is limited and mild.

GVHD is caused by donor T cells recognizing foreign antigens (histocompatibility or human leucocyte antigens) on the recipient’s cells and reacting to them. Prior to allogeneic bone marrow transplants recipients usually undergo myeloablative treatment with radiation or chemotherapy to destroy their own diseased bone marrow and weaken their immune system. When receiving the bone marrow or stem cell transplant, immunocompetent donor lymphocytes recognize foreign minor locus histocompatibility antigens on the recipient’s cells resulting in GVHD.

GVHD affects males and females of all ages who have been immunosuppressed before being given a bone marrow transplant or a nonirradiated blood transfusion containing allogeneic lymphocytes. The risk of GVHD usually increases with the recipient’s age and with the degree of HLA differences between donor and recipient unless fully T-cell depleted.

Symptoms of the following disorders can be similar to those of Graft versus Host Disease. Comparisons may be useful for a differential diagnosis.


Granulomatosis with polyangiitis

Granulomatosis with polyangiitis (GPA) is a rare disorder characterized by inflammation of small- and medium-sized blood vessels (vasculitis) that results in damage to various organ systems of the body, most often the respiratory tract and kidneys. Symptoms may include ulcerations of the mucous membranes in the nose with secondary bacterial infection, a persistent runny nose, sinus pain, and chronic middle ear infection (otitis media) potentially resulting in hearing loss. In some individuals, kidney abnormalities may progress to kidney failure, a serious complication that requires dialysis or a kidney transplant. If the lungs are affected, a cough, coughing up of blood (hemoptysis), and inflammation of the thin membrane lining the outside of the lungs and the tissues inside of the lung may be present. Other symptoms can occur depending on which organ systems are affected in an individual.

The specific symptoms and severity of the symptoms associated with granulomatosis with polyangiitis vary greatly from one person to another. Indeed, granulomatosis with polyangiitis has been described affecting almost all organ systems of the body.

The exact cause of granulomatosis with polyangiitis is not fully understood. Because of the characteristic tissue changes seen in affected tissues, and increased immune response of the body, an abnormal immune reaction has been suggested as a possible basis for the disorder. Many researchers consider the disorder an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses against foreign or invading organisms begin to attack healthy tissue for unknown reasons.

Granulomatosis with polyangiitis is a rare disorder that affects males and females in equal numbers. In most people, onset is after the fourth or fifth decade of life; however, the disorder can occur at any age. There are some studies that suggest that girls are affected more often than boys when the disorder occurs in childhood. There are also studies that suggest that males are more likely to have severe disease, while females are more likely to have localized disease.

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

Microscopic polyangiitis (MPA), formerly known as microscopic polyarteritis, is another form of antineutrophil cytoplasmic antibodies-associated (ANCA-associated) vasculitis. MPA overlaps with granulomatosis with polyangiitis and the two disorders are often discussed together in the medical literature. Individuals with MPA have inflammation of small blood vessels in various organs of the body.


Graves’ Disease

Graves’ disease is a disease affecting the thyroid and often the skin and eyes. The thyroid is a gland and is part of the endocrine system, the network of glands that secrete hormones that regulate the chemical processes (metabolism) that influence the body’s activities as well as regulating the heart rate, body temperature, and blood pressure. Hormones are secreted directly into the bloodstream where they travel to various areas of the body. Graves’ disease is characterized by abnormal enlargement of the thyroid (goiter) and increased secretion of thyroid hormone (hyperthyroidism). Thyroid hormones are involved with many different systems of the body and, consequently, the specific symptoms and signs of Graves’ disease can vary widely from one person to another. Common symptoms include unintended weight loss, an abnormal intolerance of heat, muscle weakness, fatigue and protrusion or bulging of the eyeballs from their sockets. Graves’ disease is an autoimmune disease.

Onset of the symptoms associated with Graves’ disease is usually gradual, often taking several weeks or months to develop. Symptoms may include behavioral changes such as nervousness, irritability, anxiousness, restlessness and difficulty sleeping (insomnia). Additional symptoms include unintended weight loss, muscle weakness, an abnormal intolerance to heat, increased sweating, a rapid, irregular heartbeat (tachycardia) and fatigue

Graves’ disease is considered to be an autoimmune disorder, but other factors may contribute to its development, including genetic, environmental, and/or other factors.

Graves’ disease affects females more often than males by a ratio of 5-10 to 1. The disorder usually develops during middle age with a peak incidence of 40-60, but can also affect children, adolescents and the elderly. Graves’ disease occurs in almost any part of the world. Graves’ disease is estimated to affect 2%-3% of the general population. Graves’ disease is the most common cause of hyperthyroidism.

Individuals with Graves’ disease often have a history of other family members with thyroid or autoimmune problems. Some relatives may have had hyperthyroidism or an underactive thyroid; others may have other autoimmune diseases including premature graying of the hair (beginning in their 20s). Similarly, there may be a history of related immune problems in the family, including juvenile diabetes, pernicious anemia (due to lack of vitamin B12) or painless white patches on the skin known as vitiligo.

A diagnosis of Graves’ disease is made based upon a detailed patient and family history, a thorough clinical evaluation, identification of characteristic findings, and specialized tests such as blood tests that measure the levels of thyroid hormone and thyroid-stimulating hormone. Blood tests to detect the presence of specific antibodies that cause Graves’ disease can be performed to confirm a diagnosis, but are usually not necessary.


Greig cephalopolysyndactyly syndrome

Greig头多指（趾）综合征

Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. Characteristic digital features may include extra (supernumerary) fingers and/or toes (polydactyly), webbing and/or fusion of the fingers and/or toes (cutaneous or osseous syndactyly), and/or additional abnormalities. Craniofacial malformations associated with this disorder may include a large and/or unusually shaped skull; metopic synostosis; a high, prominent forehead (frontal bossing); an abnormally broad nasal bridge; widely spaced eyes (ocular hypertelorism); and/or other physical abnormalities. The range and severity of symptoms may vary greatly among affected individuals. In most individuals, GCPS is inherited in an autosomal dominant pattern.

GCPS, a rare genetic disorder that is present at birth (congenital), is characterized by abnormalities of the fingers and toes (digits) and the head and facial (craniofacial) area. The range and severity of symptoms vary from individual to individual, with the facial characteristics, in particular, being quite subtle in some individuals.

GCPS is caused by abnormal variants in the GLI3 gene. Most of the variants in GLI3 that cause the disorder are single nucleotide changes, deletions or insertions. Less commonly, affected individuals have larger insertions or deletions of the gene. Patients who have very large deletions that include GLI3, and neighboring genes are diagnosed with the Greig cephalopolysyndactyly contiguous gene syndrome. A few patients have the disorder because of a balanced chromosomal translocation. Regardless of the specific variant type, it is deletion and/or reduced expression of the GLI3 gene that leads to GCPS.

GCPS affects males and females in equal numbers. There have been over 200 patients with this disorder reported in the medical literature. However, because some affected individuals may exhibit few and/or mild symptoms, they may never be diagnosed with the disorder. Therefore, it is difficult to determine the true frequency of GCPS in the general population.

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

GCPS is usually diagnosed at birth based upon a thorough clinical evaluation; identification of characteristic physical findings; and specialized imaging procedures, including X-rays and computed tomography (CT) scanning. In pregnancies at 50% risk, GCPS may be detected before birth by observing extra fingers or toes (polydactyly) and an enlarged skull (macrocephaly) during ultrasound imaging. During ultrasonography, reflected sound waves create images of the developing fetus. There are other prenatal testing methods available, such as analyzing the fetal cells.


Growth Hormone Deficiency

非获得性孤立型生长激素缺乏症

Growth hormone deficiency (GHD) is a rare disorder characterized by the inadequate secretion of growth hormone (GH) from the anterior pituitary gland, a small gland located at the base of the brain that is responsible for the production of several hormones. GHD can be present from birth (congenital), resulting from genetic mutations or from structural defects in the brain. It can also be acquired later in life as a result of trauma, infection, radiation therapy, or tumor growth within the brain. A third category has no known or diagnosable cause (idiopathic). Childhood-onset GHD may be all three: congenital, acquired, or idiopathic. It results in growth retardation, short stature, and maturation delays reflected by the delay of lengthening of the bones of the extremities that is inappropriate to the chronological age of the child. Adult-onset GHD is most often is acquired from a pituitary tumor or trauma to the brain but may also be idiopathic. It is characterized by a number of variable symptoms including reduced energy levels, altered body composition, osteoporosis (reduced bone mineral density), reduced muscle strength, lipid abnormalities such as increased LDL cholesterol, insulin resistance, and impaired cardiac function. Treatment for GHD requires daily injections of recombinant human growth hormone (rHGH). Patients with GHD that have no known cause are diagnosed as having idiopathic GHD. Genetic tests may reveal a congenital anomaly, but are often considered unnecessary after confirmation of GHD since they will have no effect on treatment. However, it is recommended that children be retested for GHD when they transition from pediatric to adult care since GH levels may normalize upon reaching adulthood. The level of GH considered normal for an adult is much lower than that for a child, especially one undergoing the pubertal growth spurt.

A child with GHD is usually of normal size at birth. A few children may become hypoglycemic (low blood sugar) during the newborn period. Males may have a small penis (micropenis). Later, children with GHD may present with delayed rates of development of facial bones, slow tooth eruption, delayed lengthening of long bones, fine hair, and poor nail growth. They may also demonstrate truncal obesity, a high pitched voice, and delayed closure of the sutures of the skull, causing delayed closure of the fontanelles.

Congenital GHD results from genetic error, and may be associated with brain structure defects or with midline facial defects such as a cleft palate or single central incisor.

Prevalence and incidence data vary widely due to the lack of standard diagnostic criteria. While congenital GHD and most cases of idiopathic GHD are thought to be present from birth, diagnosis is often delayed until the patient’s short stature is noticed in relation to their peers. Diagnosis most often occurs during two age ranges. The first is around 5 years of age when children begin school. The second is around 10-13 years old in girls and 12-16 years in boys associated with the delay in the pubertal growth spurt.

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

Small for gestational age (SGA) generally describes any infant whose birth weight and/or length was less than the 3rd percentile (adjusted for prematurity). Children with SGA are shorter and thinner than his or her peers. Typical characteristics for these children include low birth weight, short birth length, inadequate catch-up growth in first two years, persistently low weight-for-height proportion, and lack of muscle mass and/or poor muscle tone. The FDA has approved growth hormone therapy as long-term treatment of children who were born SGA and who have not achieved catch-up growth by two years of age.


Growth Hormone Insensitivity

There is a wide range of effects depending on the gene mutations involved (see Causes section). The very few individuals with IGF-I gene mutation have severe intellectual disability and intrauterine growth failure, with deafness and micrognathia. GHRD results in severe growth failure without deleterious effects on intrauterine growth or brain development, and the mutation of STAT5b, responsible for an important activator protein, has similar growth effects but is also associated with severe impairment of immunocompetence. The IGFALS mutation, affecting an important stabilizing component of the circulating IGF-I, while associated with very low circulating IGF levels, has only modest effects on growth.

GHI is inherited as an autosomal recessive genetic disorder and caused by mutation of the GHR gene or mutations in the genes involved in the action pathway within the cell after GH binds to its receptor, including STAT5b, IGF-1, and IGFALS.

Worldwide, only about 300 cases of GHI due to GHRD have been reported. The ethnic background for most (90%) of the reported cases is known. About 65% of patients have Middle Eastern ancestry and a group of Ecuadorian conversos. (Conversos are Jews who converted to Christianity in Spain during the Inquisition, some of whom migrated to the New World) Subsequently, marriage among close relatives made the disorder more common among the descendants of these groups. STAT5b, IGF-1 and IGFALS mutations have been reported in only a few families.

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

In addition to the genetic forms of GHI, failure to have a normal growth response despite adequate GH production is characteristic of a number of conditions including chronic illness, undernutrition, kidney disease, liver disease, and congenital syndromes. These conditions are often referred to as secondary GHI.


The severity of GAMT varies from patient to patient. Global developmental delays affect all individuals with this disorder and may be the first sign, appearing before other symptoms. Most individuals with GAMT deficiency have intellectual disabilities, seizure disorders, muscle weakness, behavior disorders and movement disorders. People with GAMT may have weak muscle tone and delayed development of motor skills such as sitting or walking. Severely affected patients may lose previously acquired skills such as the ability to support their head or to sit unsupported.

GAMT deficiency is a caused by changes (called variants or mutations) in the GAMT gene that makes the enzyme that creates creatine, resulting in a shortage of creatine. It is the most severe of the three CCDS due to the elevation of guanidinoacetate (which is neurotoxic) in addition to creatine deficiency. Affected individuals may demonstrate cerebral creatine deficiency on MR spectroscopy and high GAA in plasma.

The prevalence of GAMT deficiency has been estimated to be from 1 out of 250,000 to 1 out of 550,000 patients being diagnosed. As of 2015, there have only been 110 individuals with GAMT deficiency diagnosed worldwide.

GAMT deficiency patients are frequently misdiagnosed with cerebral palsy as infants and toddlers. Children are often misdiagnosed with autism or global developmental delays.

Testing in both urine and plasma is recommended by measuring the concentration of creatine (Cr), guanidinoacetate (GAA), and creatinine (Crn). A positive screen for GAMT is based on plasma GAA that is elevated with creatine being low and urine GAA that is elevated and creatine being low to normal. Urine testing might be normal in young children, for which plasma testing is recommended.


Guillain-Barré syndrome

Weakness usually begins in the legs and spreads to the arms and body. Sometimes it spreads to the face, throat and breathing muscles. In up to a quarter of people with GBS, the breathing muscles become so weak that a breathing machine (respirator) is needed. Tingling feelings, pins and needles, and numbness (loss of feeling) are common. These are due to damage to the sensory nerves that signal feeling from the skin and joints. The abnormal feelings are usually worst in the feet and hands. The tingling may be painful, and the muscles may hurt. The symptoms usually worsen for the first two weeks, but progression may last as little as one day or as long as four weeks. Symptoms usually affect both sides of the body equally.

The cause of GBS is inflammation of the peripheral nerves. These nerves normally take messages to and from the skin and muscles to the brain and spinal cord. There is strong evidence that the cause is autoimmune. The immune system produces an immune response to an infection which cross-reacts with the nerves. It usually reacts with and damages the outer coating sheath of the nerve fibers, called myelin. In more severely affected people, this damage also affects the central conducting core of the nerve, called the axon. In some people, the axon is itself the main target of the autoimmune response.

Some people have a similar illness but lack some characteristic features or have additional features. For instance, Miller Fisher syndrome has three main features:

Guillain-Barré syndrome is only one of many causes of acute weakness and numbness. The diagnosis requires recognition of the characteristic symptoms and signs. Because the disease is rare, diagnosis may be difficult for the non-specialist and referral to a neurologist is usually appropriate. Clinical examination shows loss of tendon reflexes and supports the diagnosis of peripheral nerve disease. Two tests are commonly used to support the diagnosis:

The most important parts of treatment are general medical and nursing care, physiotherapy and rehabilitation. Because of the risks of breathing failure and heart-beat instability in the acute stage, people with severe disease need to be monitored for pulse and breathing. If breathing becomes difficult, mechanical ventilation with a breathing machine in an intensive care unit becomes necessary. For this, a special plastic tube, called an endotracheal tube, connects the person to the breathing machine via the mouth or nose. If mechanical ventilation lasts more than a few days, it is more comfortable to put the tube in the throat by making a small opening in the windpipe for this purpose (an operation called a tracheostomy). After recovery, the tube is removed and the opening gradually closes on its own. Difficulty swallowing requires insertion of a thin plastic tube through the nose into the stomach for feeding and drinking. Medicines and nursing measures treat pain and reduce the risk of veins clotting, bed sores and constipation. Physical therapy helps muscle strength and function and prevents muscle shortening and joint stiffness. When people become medically stable, they often move to a rehabilitation center for physical and occupational therapy. Psychological support is important throughout the illness.


Hailey-Hailey disease

The symptoms and severity of Hailey-Hailey disease varies from one person to another, even among members of the same family. In most cases, there is a family history of the disorder.

Hailey-Hailey disease is caused by a change (variant or mutation) in the ATP2C1 gene. The ATP2C1 gene contains instructions for creating (encoding) a protein that acts as a calcium and magnesium pump in the cells. This protein pumps calcium or magnesium ions into a specialized organelle in the cell known as the Golgi apparatus. Calcium ions play an essential role in cell-to-cell adhesion and, when the calcium pump does not function properly, the affected cells will not stick together, damaging the skin (acantholysis). The exact process by which loss or improper function of the protein product of the ATP2C1 gene causes Hailey-Hailey disease is not fully understood, although recent studies suggest that Hailey-Hailey disease and the related diseases, Darier’s disease (see below) and Grover’s disease share defects in a central structural system of actin organization. The ATP2C1 protein is most active in keratinocytes, the main cell type of the outermost layer of skin (epidermis). Failure of keratinocytes to stick together results in the blistering seen in the disease.

Hailey-Hailey disease affects males and females in equal numbers. According to one estimate, the disorder affects 1 in 50,000 people in the general population. Hailey-Hailey disease often goes misdiagnosed or undiagnosed, making it difficult to determine its true frequency in the general population.

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

A diagnosis of Hailey-Hailey disease is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests including the surgical removal and microscopic examination (biopsy) of affected skin tissue. A biopsy may reveal abnormal formation of keratin tissue (keratinization) and failure of cell-to-cell adhesion (acantholysis). Blood tests in individuals with Hailey-Hailey disease will fail to detect antibodies, which rules out autoimmune disorders such as pemphigus.


Haim-Munk syndrome

Haim-Munk syndrome is a rare genetic disorder characterized by the development of red, scaly thickened patches of skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis), frequent pus-producing (pyogenic) skin infections, overgrowth (hypertrophy) of the fingernails and toenails (onychogryposis), and degeneration of the structures that surround and support the teeth (periodontosis). Periodontosis usually results in the premature loss of teeth. Additional features associated with the disorder may include flat feet (pes planus); abnormally long, slender fingers and toes (arachnodactyly); loss of bone tissue at the ends of the fingers and/or toes (acroosteolysis); and/or other physical findings. Haim-Munk syndrome is inherited as an autosomal recessive trait.

Haim-Munk syndrome is a rare inherited disorder characterized by the development of dry scaly patches of skin that are abnormally red and thickened on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis). Such patches may appear around the age of one to five years. However, in some cases, hyperkeratosis may be present at birth (congenital). These reddened patches are usually confined to the undersides of the hands and feet, but may eventually spread to the knees and elbows. In some rare cases, the upper portions of the hands and feet, the eyelids, the lips, and the cheeks may also be affected. Affected individuals also may have frequently recurring, pus-producing (pyogenic) skin infections.

Haim-Munk syndrome is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Haim-Munk syndrome is a rare genetic disorder that affects males and females in equal numbers. The disorder is named after the investigators (Haim S, Munk J) who originally reported the disease entity in 1965 among members of an extended Jewish family (kindred) from Cochin, India. Since then, the disorder has been described in over 50 individuals in several multigenerational Jewish families in Cochin. It has sometimes been referred to as Cochin Jewish disorder.

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

The diagnosis of Haim-Munk syndrome may be confirmed by a thorough clinical evaluation that includes a detailed patient history and identification of characteristic physical findings. In some cases, skin abnormalities, including characteristic red, scaly thick patches of skin (hyperkeratosis) on the palms of the hands and the soles of the feet, may be apparent at birth (congenital) or during infancy. In most cases, Haim-Munk syndrome may not be firmly distinguished from other disorders with similar skin abnormalities until the inflammation and degeneration of the tissues surrounding and supporting the teeth (periodontium) becomes apparent. This usually occurs between the third and fifth year of life, when the infant teeth (deciduous) begin to erupt.


Hairy Cell Leukemia

Onset of hairy cell leukemia is usually gradual. Symptoms are nonspecific and may include a general feeling of ill health (malaise), fatigue, weakness, fever, night sweats, and/or weight loss. In addition, affected individuals may experience abdominal pain and a feeling of abdominal fullness due to an abnormally enlarged spleen (splenomegaly).

The exact cause of hairy cell leukemia is unknown.

Hairy cell leukemia is a rare disorder that affects males four times more often than females (M4:F1). Hairy cell leukemia affects about 6,000 persons in the United States. Approximately 600-800 new cases are diagnosed each year. Most of the affected individuals are males 50 years of age or older. However, the disorder may occur in individuals between 20 to 80 years of age.

Leukemia is a form of cancer affecting the bone marrow and blood. It is characterized by the uncontrolled accumulation of cancerous blood cells. Acute forms of leukemia often result in low levels of red and white blood cells and platelets (pancytopenia). (For more information, choose leukemia as your search term in the Rare Disease Database.)

Until recently, treatment of hairy cell leukemia consisted of surgically removing the spleen (splenectomy). In rare cases, in which individuals do not respond to drug treatments, a splenectomy may still be performed. Chemotherapy drugs, specifically purine analogs such as cladribine and pentostatin, are now the initial treatment option for most individuals with hairy cell leukemia. Those who do not have any symptoms may not need treatment right away.


Hajdu Cheney Syndrome

The signs and symptoms of Hajdu-Cheney syndrome can vary greatly among affected individuals. The disorder is present at birth (congenital), but in some individuals the signs and symptoms may be more apparent during adolescence and adulthood.

Hajdu-Cheney syndrome is associated with a change (variant or mutation) in the NOTCH2 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant of a gene occurs, the protein product may be faulty, inefficient, absent or have increased function. When there is increased function, this is called a gain-of-function variant. In Hajdu-Cheney syndrome there is a gain of NOTCH2 protein function and increased activity of the protein. Depending upon the functions of the protein, and where the protein is made can affect many organ systems of the body.

Hajdu-Cheney syndrome is an extremely rare disorder. More than 80 affected individuals have been described in the medical literature. The exact prevalence or incidence of the disorder is unknown. Rare disorders often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.

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

A diagnosis of Hajdu-Cheney syndrome is based upon the identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized imaging tests.


Hallermann-Streiff syndrome

Associated symptoms and signs vary greatly in range and severity from case to case. The principal features of Hallermann-Streiff syndrome include abnormalities of the skull (cranium) and certain bones of the face (known as dyscephaly); distinctive facial features; ocular defects; dental anomalies; and/or proportionate short stature. In many cases, additional abnormalities are also present.

In almost all reported cases, Hallermann-Streiff syndrome has occurred randomly for unknown reasons (sporadically), most likely due to a new spontaneous dominant genetic change (mutation). There have been reports of patients with this disorder reproducing successfully and bearing multiple normal children. From families with an affected child, there is little evidence for this being a recessively inherited disorder in which both parents are carriers (normal looking but carry the mutation). Therefore, the mode of inheritance of this disorder remains elusive making it difficult to determine the exact recurrent risk.

Hallermann-Streiff syndrome appears to affect males and females in relatively equal numbers. More than 150 cases have been reported in the medical literature.

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

Hutchinson-Gilford progeria syndrome is a very rare progressive disorder of childhood characterized by premature aging (progeria); growth delays occurring in the first year of life resulting in short stature and low weight; deterioration of the layer of fatty tissue beneath the skin (subcutaneous lipodystrophy); and characteristic craniofacial abnormalities including an abnormally small face, underdeveloped jaw (micrognathia), unusually prominent eyes, and/or a small, beak-like nose. In addition, during the first year or two of life, scalp hair, eyebrows, and eyelashes may become sparse, and veins of the scalp may become unusually prominent. Additional symptoms and physical findings may include joint stiffness, repeated non-healing fractures, a progressive aged appearance, delays in tooth eruption (dentition), and/or malformation and crowding of the teeth. Individuals with the disorder typically have normal intelligence. In most cases, affected individuals develop premature, widespread thickening and loss of elasticity of arterial walls (arteriosclerosis), potentially resulting in life-threatening complications. Hutchinson-Gilford progeria syndrome is due to a de novo heterozygous mutation in the lamin A gene (LMNA) on chromosome 1q22. (For more information on this disorder, choose Hutchinson Gilford as your search term in the Rare Disease Database) Other disorders with less severe, but overlapping features include mandibuloacral dysplasia, an autosomal recessive disorder, which is caused by different mutations in the LMNA gene or the ZMPSTE24 gene, and Werner syndrome, an autosomal recessive progeroid syndrome caused by autosomal recessive mutations in the RECQL2 gene.


Hypoglossia-hypodactyly syndrome

The craniofacial abnormalities in children with Hanhart syndrome can include a small mouth (microstomia); small jaw and deeply receding jaw (micrognathia); shorty, incompletely developed tongue (hypoglossia); cleft palate; cleft tongue; broad nose; increased distance between the inner corners of the eyelids (telecanthus); lower eyelid defects; facial asymmetry; and partial absence of the jaw (mandibular hypodontia).

The exact cause of Hanhart syndrome is not known. Cases tend to occur randomly, with no apparent cause (sporadic). Some researchers believe that the disorder, which has been reported in the children of blood relatives (consanguinity) in a number of cases, may be inherited in an autosomal recessive pattern.

Hanhart syndrome is a very rare developmental disorder that affects males and females in equal numbers. Fewer than 1 in 20,000 children are affected with this disorder. Approximately 30 cases of Hanhart syndrome were reported in the medical literature from 1932 to 1991.

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

Oromandibular-limb hypogenesis syndrome is the name sometimes used to describe a group of rare disorders that are all characterized by underdevelopment (hypogenesis) of the mouth and jaw (oromandibular) areas, the limb buds, and possibly other areas in the developing embryo. This group of disorders includes Hanhart syndrome, ankyloglossum superiorsyndrome, Charlie M syndrome, and Moebius syndrome. Some researchers believe that these are overlapping disorders or disease variants representing a spectrum of malformations caused by environmental or other factors.


Hantavirus Pulmonary Syndrome

HCPS (hantavirus cardiopulmonary syndrome)

Hantavirus pulmonary syndrome (HPS) is an infectious disease caused by hantaviruses (Sin Nombre hantavirus in most of the US). Transmission occurs when direct or indirect (airborne) contact is made with the saliva or waste products of rodents that carry the virus, most commonly the deer mouse (Peromyscus maniculatus). Initial symptoms may include fever, muscle aches (myalgias), headache, cough, and/or difficulty breathing. Symptoms progress rapidly, and abnormally low blood pressure (hypotension), shock, and/or respiratory failure may occur.

The initial symptoms of HPS most commonly include fever, muscle aches (myalgias), headache, and/or cough. Chills, abdominal pain, diarrhea, and/or a sense of overall discomfort (malaise) may be present. Other symptoms usually include shortness of breath, rapid breathing (tachypnea), rapid heartbeat (tachycardia), dizziness, and sometimes joint pain (arthralgia), back and/or chest pain, and/or sweating.

HPS in the US is mostly caused by Sin Nombre Hantavirus, a newly identified virus within the Bunyaviridae family. The virus is carried by the deer mouse (Peromyscus maniculatus). The deer mouse can be found in most parts of the United States, except the southeast. Not all deer mice are infected with Sin Nombre hantavirus, and those that do carry the virus do not appear to be affected by any associated disease.

HPS appears to affect males and females in equal numbers. Approximately half of the cases reported in the medical literature have affected Native Americans, and the majority of the remaining reported cases affected Caucasians. The population affected by HPS appears to be related to geographic location and exposure to rodent droppings as opposed to ethnic background. Because many of the documented cases have occurred in the southwestern United States, a high percentage of the initially affected individuals were Native Americans. As the virus was found in others parts of the US, many others of varied ethnic backgrounds have been affected throughout the United States.

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

There are many types of pneumonia that can be caused by bacteria or virus. In general the symptoms of pneumonia are similar to those of Hantavirus Pulmonary Syndrome. Only laboratory testing can determine which disease is affecting an individual.

It is important to avoid areas where deer mice leave their droppings, such as storage sheds, basements, and wood piles. When exposed to mouse droppings, an individual should wear a face mask that covers both nose and mouth, as well as rubber gloves. The area should be sanitized with disinfectant to avoid aerosolization of potentially infected dust. People who exhibit flu-like symptoms after exposure to mouse droppings should be taken to a hospital immediately, because this disorder progresses over a matter of hours, and every hour is crucial.


Harlequin ichthyosis

Harlequin ichthyosis is a rare genetic skin disorder. The newborn infant is covered with plates of thick skin that crack and split apart. The thick plates can pull at and distort facial features and can restrict breathing and eating. Harlequin infants need to be cared for in the neonatal intensive care unit immediately. Harlequin ichthyosis is inherited in an autosomal recessive pattern.

Infants with Harlequin ichthyosis are covered in thick plate-like scales of skin. The tightness of the skin pulls around the eyes and the mouth, forcing the eyelids and lips to turn inside out, revealing the red inner linings. The chest and abdomen of the infant may be severely restricted by the tightness of the skin, making breathing and eating difficult. The hands and feet may be small and swollen, and partially flexed. The ears may appear to be misshapen or missing, but are really fused to the head by the thick skin. Infants born with harlequin ichthyosis may also have a flat nose (depressed nasal bridge), abnormal hearing, frequent respiratory infections, and decreased joint mobility.

Harlequin ichthyosis is caused by changes (mutations) in the ABCA12 gene, which gives instructions for making a protein that is necessary for skin cells to develop normally. It plays a key role in the transport of fats (lipids) to most superficial layer of the skin (epidermis), creating an effective skin barrier. When this gene is mutated, the skin barrier is disrupted.

Harlequin ichthyosis affects males and females in equal numbers. This condition affects approximately one in 500,000 persons or about seven births annually in the United States.

Symptoms of the following disorder may be similar to harlequin ichthyosis.

Harlequin ichthyosis is diagnosed at birth based on the child’s physical appearance. Prenatal testing may be possible by testing fetal DNA for mutations in the ABCA12 gene. In addition, some of the features of harlequin ichthyosis maybe seen on ultrasound during the second trimester and onward.

A multi-disciplinary team is involved in the care of infants with harlequin ichthyosis as soon as they are born. This has been shown to improve outcomes and reduce complications such as respiratory distress, dehydration, electrolyte imbalances, impaired thermoregulation, systemic bacterial infections, and feeding difficulties. Early treatment with oral retinoids is also thought to improve outcomes. However, they are only used in severe cases due to their known toxicity and side effects.


Hartnup disease

Hartnup disease is a rare genetic disorder that involves an inborn error of amino acid metabolism. The disorder is characterized by a distinctive skin rash and in a few reported patients was accompanied by episodes of neurological involvement including an inability to coordinate voluntary movements (ataxia), vision problems and cognitive delays. The symptoms associated with this disorder may be triggered by fever, drugs or situations when an affected individual is under emotional or physical stress such as during an illness. Generally, the frequency of such episodes usually diminishes with age. Hartnup disease is caused by changes (variants or mutations) in the SLC6A19 gene and is inherited in an autosomal recessive pattern.

The symptoms of Hartnup disease vary greatly from one person to another. Most affected individuals do not have any apparent symptoms (asymptomatic). When symptoms do develop, they most often occur between the ages of 3-9. In rare instances, symptoms first appear in adulthood.

Hartnup disease is caused by disease-causing variants in the SLC6A19 gene. 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 protein, this can affect many organ systems of the body.

Hartnup disease affects both males and females in equal numbers. The disorder usually begins in childhood and continues into adulthood. The number of people affected by Hartnup disease is unknown. It has been estimated to occur at a frequency of approximately one in 30,000 individuals based upon newborn screening results in the United States and Australia.

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

Loss of collectrin, which is required for transportation and activation of SLC6A19 in the kidney has been reported in two patients with symptoms that are very similar to Hartnup disease. Both presented with neuropsychiatric symptoms including autistic features, anxiety, depression, compulsions and motor tics. Due to amino acids appearing in urine, both were initially diagnosed with Hartnup disease.


Hereditary elliptocytosis

遗传性椭圆形红细胞增多症

Hashimoto encephalopathy is a rare disorder characterized by impaired brain function (encephalopathy). The exact cause is unknown, but it is believed to be an immune-mediated disorder or a disorder in which there is inflammation resulting from abnormal functioning of the immune system. Affected individuals have the presence of antithyroid antibodies in their body. Antibodies are part of the immune system; they are specialized proteins that target foreign or invading organisms. Antithyroid antibodies are ones that mistakenly target thyroid tissue. However, it is unclear whether these antibodies play any role in the development of Hashimoto encephalopathy or are a coincidental finding. The main signs and symptoms are related to the encephalopathy. The onset of impaired brain function is rapid (acute), while other times it can develop slowly over many years. The specific symptoms, severity, and course of the disorder can vary greatly among affected individuals. The disorder often responds to therapy with corticosteroids.

The most important symptom is impaired brain function (encephalopathy), namely, altered mental status. It is impairment of the cognition, attention, orientation, sleep-wake cycle and consciousness.

The exact cause of Hashimoto encephalopathy is unknown. However, some clinical researchers believe that the disorder is most likely the result of an abnormal immune system response to an infection or other trigger. Many researchers suggest that the disorder may represent, in part, an abnormal immune reaction directed against the body’s own tissues (autoimmune disorder). In autoimmune disorders, the body’s natural defenses (e.g. antibodies, lymphocytes) against substances that are perceived as foreign (antigens) inappropriately begin to attack healthy tissues for unknown reasons. When antibodies mistakenly target healthy tissue, they may be referred to as autoantibodies.

Hashimoto encephalopathy is a rare disease that affects women more often than men. The disorder is estimated to affect 2.1 per 100,000 individuals in the general population. It can affect children, but only approximately 60 affected children have been described in the medical literature. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population.

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

A diagnosis of Hashimoto encephalopathy is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. By definition, Hashimoto encephalopathy must have detectable levels of antithyroid antibodies in the body. However, there is no correlation between the amount of antibody levels and the presence or severity of symptoms. Antithyroid antibodies are relatively common in the general population, so this finding must occur in individuals with the characteristic findings associated with Hashimoto encephalopathy and in whom other potential diagnoses have been ruled out.


Hemimegalencephaly

Hemimegalencephaly (HME) is a rare neurological condition in which one-half of the brain, or one side of the brain, is abnormally larger than the other. The structure of the brain on the affected side may be markedly abnormal or show only subtle changes. In either case, as a consequence of this size and structural differences, the enlarged brain tissue causes frequent seizures, often associated with cognitive or behavioral disabilities. Seizures in association with HME often begin in early infant life including an association with infantile spasms. Hemimegalencephaly may occur as an isolated or sporadic brain malformation or it may be associated with other neurodevelopmental syndromes. Thus, when detected, HME should prompt a search for other syndromic diagnoses.

HME typically is identified in the neonatal period when the baby develops presents seizures. The seizures usually do not decline in severity or number with medical treatment and in some cases they may exceed 50 or more per day. On physical examination, a child with HME may presents with enlarged head circumference or an asymmetrical head shape.  There may be movement or motor deficits on the side opposite to the HME. When these signs are present, the neurologist may suspect the presence of HME and order magnetic resonance imaging (MRI) examination.

The basic cause(s) of HME is not well understood. The disorder occurs because the cells of one hemisphere of the brain grow much more rapidly than do the corresponding cells of the other half of the brain (hamartomatous overgrowth of one hemisphere). It is widely believed that a single or multiple gene mutations contribute to this process. As might be expected, the cortex of the enlarged brain is malformed (dysplastic) and the white matter is abnormal. One of the common, empty spaces of the brain (lateral ventricle) in the enlarged hemisphere is enlarged in proportion to the lateral ventricle of the smaller hemisphere.

Hemimegalencephaly is a very rare disorder for which prevalence estimates are not available.

Hydrocephalus is a condition in which abnormally widened (dilated) cerebral spaces in the brain (ventricles) inhibit the normal flow of cerebrospinal fluid (CSF). The cerebrospinal fluid accumulates in the skull and puts pressure on the brain tissue. An enlarged head in infants and increased cerebrospinal fluid pressure are frequent findings but are not necessary for the diagnosis of hydrocephalus. There are several different forms of hydrocephalus: communicating hydrocephalus, non-communicating hydrocephalus or obstructive hydrocephalus, internal hydrocephalus, normal pressure hydrocephalus, and benign hydrocephalus.

Examination by MRI is usually sufficient to confirm a suspected case of HME. Thus, an MRI examination should be performed as soon as HME is suspected. Seizures are diagnosed and defined by electroencephalography (EEG).