Ovarian cancer

Ovarian cancer refers to cancer that arises in the almond-shaped reproductive organs in women in which eggs, or ova, are produced (ovaries), in either of the two tubes through which eggs travel from the ovaries to the uterus (fallopian tubes), or in the membrane that lines the pelvis and the abdominal cavity and covers all of the abdominal organs (peritoneum). There are usually no symptoms (asymptomatic) during the early stages. As a result, ovarian cancer is usually not diagnosed until an advanced stage. Common symptoms that can develop include abdominal swelling or bloating, unintended weight loss, or changes in the bowel habits including constipation. The cause of ovarian cancer is multifactorial, which means that multiple factors that occur together are necessary for the cancer to develop. These factors include genetic, immunologic and environmental factors. About 20% of all women with ovarian cancer have a variation in one of two genes called BRCA1 or BRCA2. BRCA-associated ovarian cancer is not specifically discussed in this report. NORD has a separate report on ovarian cancer caused by variations in these two genes that is titled Hereditary Breast and Ovarian Cancer (HBOC) Syndrome.

The specific symptoms and physical findings of ovarian cancer can vary from one person to another, depending upon the extent and region(s) of involvement and other factors. Ovarian cancer usually does not cause any symptoms in the early stages. Symptoms may be described as acute (developing rapidly and severely) or subacute (having a slower onset and slower progression).

The exact, underlying cause of ovarian cancer is not fully understood. The reason why cancer develops is a complex question and researchers speculate that multiple factors are involved in the development of ovarian cancer. These factors can include genetic, environmental and immunologic factors.

In 2017, more than 22,400 women were diagnosed with ovarian cancer in the United States. It affects about 1 in 70 women in the U.S and is the second most common gynecological cancer behind only endometrial cancer. The average age at diagnosis is 63. Worldwide about 240,000 women are diagnosed each year with ovarian cancer. The incidence, which is the number of people with a disease over a given period of time such as one year, is greater in developed countries.

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

A diagnosis of ovarian cancer is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. There is no screening test that can be run that detects ovarian cancer in all women. Ovarian cancer does not cause many symptoms during the early stages of development, and symptoms tend to be nonspecific (common to many diseases). Consequently, ovarian cancer is often undiagnosed until it has spread to the abdomen and pelvis.


46,XX 卵睾两性畸形

Ovotesticular Disorder of Sex Developmen

Ovotesticular disorder of sex development (ovotesticular DSD) is a very rare disorder in which an infant is born with the internal reproductive organs (gonads) of both sexes (female ovaries and male testes). The gonads can be any combination of ovary, testes or combined ovary and testes (ovotestes). The external genitalia are usually ambiguous but can range from normal male to normal female.

Ovotesticular DSD is characterized by the presence of both ovarian and testicular tissue in the same individual. An ovotestis is present in approximately 2/3 of affected individuals.

The exact cause of ovotesticular DSD is known only in a small percentage of patients. Most affected individuals have a 46, XX chromosomal make-up (karyotype), which normally results in female sexual development. In about 10% of patients, testicular tissue in an individual with a 46, XX karyotype is present as a result of a translocation of the SRY gene on the Y chromosome to the X chromosome or another chromosome. In patients with 46, XX, there have been a small number of cases reported with genetic variations of other genes such as, duplication of SOX9, mutations in RSPO1, and a specific mutation in the NR5A1 gene. In the more rare individuals with ovotesticular DSD who have a Y chromosome (which normally results in male sexual development), deletions of DMRT1, mutations of SRY and mutations of MAP3K1 have been reported, as well as a karyotype that shows some cells with XY chromosomes and others with XX chromosomes (XX/XY mosaicism).

Ovotesticular DSD is the rarest disorder of sex development in humans and has an approximate incidence of less than 1/20,000. At least 500 affected individuals have been reported.

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

Klinefelter syndrome is a group of chromosomal disorders in males in which one or more extra X chromosomes are present. Males with the classic form of the disorder have one extra X chromosome. Males with variant forms of Klinefelter syndrome have additional X and/or Y chromosomes. The extra X and/or Y chromosome can effect physical and intellectual development. Common physical features may include small testes (hypogonadism), delayed pubertal development, and breast development (gynecomastia) in late puberty. These features may be associated with low testosterone level and elevated gonadotropin levels. (For more information on this disorder, choose Klinefelter as your search term in the Rare Disease Database.)


Pachydermoperiostosis

Pachydermoperiostosis, also called primary hypertrophic osteoarthropathy (PHO) is a rare genetic condition. The three main features are large finger tips (clubbing), thickening of the skin of the face (pachydermia) and extra sweating (hyperhidrosis). It typically starts during childhood or adolescence, often around the time of puberty, and progresses slowly for about ten years.

PHO is characterized by problems with the growth of skin and bones. People with PHO usually have coarse facial features with oily, thick, grooved skin on the face, joint pain, large tips of the fingers and toes (clubbing) and extra sweating of the hands and feet (hyperhidrosis).

For most individuals, the diagnosis of PHO is based on the clinical features. It is recognized more often in males than females, as males have more noticeable and severe features. PHO can be inherited, but a non-genetic form has also been described.

PHO is a rare disorder that affects males more than females with a ratio of 7:1. This means that for about every 7 males that are diagnosed with this condition, 1 female is diagnosed. However, since females tend to have milder symptoms than males, females may go undiagnosed.

Symptoms of the following disorders can be similar to those of pachydermoperiostosis. Comparing features can be useful to make the correct diagnosis:

Acromegaly is a rare, slowly progressive, acquired disorder that affects adults. It is a condition where extra growth hormone causes different tissues to be become larger than normal and the individual to be taller. The arms, legs, jaws and face are most often affected. Enlargement of soft tissues, especially within the heart, is a serious feature of this condition. (For more information on this disorder choose acromegaly as your search term in the Rare Disease Database.)


Pachyonychia congenita

The symptoms and severity of pachyonychia congenita can vary widely, even among individuals in the same family or among individuals with the same disease-causing gene mutation.

Pachyonychia congenita is caused by a mutation in one of five keratin genes, KRT6A, KRT6B, KRT6C, KRT16 or KRT17. These mutations are inherited in an autosomal dominant manner, although approximately 30-40% of cases are the result of new spontaneous mutations with no previous family history. In an autosomal dominant disorder, only one copy of an abnormal gene is necessary to produce clinical symptoms. The risk of an affected individual passing the abnormal gene to offspring is 50 percent for each pregnancy. For unaffected parents of a child with PC there is a very low risk of having subsequent affected children; germline mosaicism is extremely rare, with as of Jan 2018, only one out of 792 cases reported in the IPCRR.

PC affects both males and females. No ethnic differences have been reported. Prevalence is estimated at between 5,000 and 10,000 worldwide.

Another autosomal dominantly inherited disorder, Clouston syndrome, can mimic PC due to the overlapping clinical characteristics; occasionally this can lead to misdiagnosis of patients. The features of Clouston sydrome are thick nails (hypertrophic nail dystrophy), partial or total hair loss (alopecia) and palmoplantar hyperkeratosis. Alopecia (partial to total) does not typically occur in PC but is relatively common in Clouson syndrome. Clouston syndrome is caused by mutations in the gap junction protein connexin 30 (GJB6) gene.

PC is normally diagnosed by clinical examination, which can now be confirmed at the molecular level. Molecular diagnosis (from a blood sample or saliva sample), of PC patients is available to identify the exact gene defect (mutation) in KRT6A, KRT6B, KRT6C, KRT16 or KRT17 and to confirm the clinical diagnosis. See the Pachyonychia Congenita Project website (www.pachyonychia.org) for details about genetic testing which is offered free of charge for patients that enroll in the IPCRR (https://www.pachyonychia.org/patient-registry/).


Paget disease of the nipple

Paget’s disease of the breast is a malignant (cancerous) condition that initially appears as chronic, inflammatory, eczema-like changes of the nipple and adjacent areas.

Two main theories have been proposed to explain the development of Paget’s disease of the breast. One theory suggests that distinctive cancer cells called Paget’s cells break off from an underlying tumor or malignancy within the breast and travel through the milk ducts to the nipples. Supportive evidence includes laboratory studies demonstrating that Paget cells and the underlying breast cancer share certain characteristics, thus appearing to originate from the same cell population. In addition, malignant cells have been shown to extend along breast ductal tissue from the underlying breast tumor to the nipple. Accordingly, many researchers have concluded that Paget cells appear to be derived from the lining (epithelium) of the milk ducts, invading and multiplying (proliferating) within the surface tissue (epidermis) of the nipple and adjacent areas of the areola. This theory explains why most individuals with Paget’s disease of the breast have an underlying form of cancer.

Paget’s disease of the breast is a rare form of breast cancer that almost exclusively affects women. However, there have been rare cases in which the disorder has occurred in men. Paget’s disease of the breast most commonly affects middle-aged individuals, primarily occurring between 50 to 60 years of age, although it has been reported in individuals in their 20s. It is thought to represent less than 5 percent of all breast cancer clinical presentations. The exact prevalence and incidence of Paget’s disease of the breast in the general population is unknown.

Symptoms of the following disorders may be similar to those of Paget’s disease of the breast. Comparisons may be useful for a differential diagnosis:

Extramammary Paget’s disease (EMPD) is characterized by the development of a reddish, scaling lesion that resembles that seen in Paget’s disease of the breast but does not occur on the breasts. The term extramammary refers to regions other than or outside of the breasts. In those with EMPD, additional symptoms and findings may include itching, burning, pain, and/or bleeding of the affected area. EMPD often involves the female or male external genitals (e.g., vulva, glans penis) and/or the region around the anus (perianal region). EMPD of the vulva is associated with an underlying cancer (carcinoma) in about 30 percent of patients; involvement of the perianal area is associated with a distant or underlying carcinoma in up to approximately 73 percent of individuals.


Paget Disease

Paget’s disease of bone is a chronic, slowly progressive skeletal condition of abnormally rapid bone destruction (osteolytic) and reformation (osteoblastic). The new bone may occur in one or more regions of the body and is structurally abnormal, dense and fragile. This abnormal development may cause bone pain, arthritis, deformities and fractures. The bones most frequently affected are in the spine, skull, pelvis and lower legs. The exact cause of Paget’s disease is not known.

Early symptoms of Paget’s disease include bone pain, joint pain (especially in the back, hips and knees), and headache. Physical signs include enlargement and bowing of the thighs (femurs) and lower legs (tibias), and enlargement of the skull in the area of the forehead. Most individuals with Paget’s disease do not have any symptoms (asymptomatic) or only develop mild symptoms.

The exact cause of Paget’s disease is unknown. Researchers speculate that the cause of the disorder may be multifactorial (e.g. caused by the interaction of certain genetic and environmental factors). In most cases, no specific cause for Paget’s disease can be identified (sporadic).

Paget’s disease is rarely diagnosed in people under the age of 40 years but may occur in up to three percent of the population over the age of 60 years. Paget’s disease affects individuals of all ethnic and racial groups. However, it affects individuals of Asian descent less frequently. Both men and women can be affected with a slight male predominance. The prevalence of Paget’s disease in the United States is estimated to be 1-2 percent of the general population.

Symptoms of the following disorders can be similar to those of Paget’s disease. Comparisons may be useful for a differential diagnosis.

Osteoarthritis is a prevalent form of arthritis that involves degeneration of joints in the body. Osteoarthritis is characterized by a gradual deterioration of the cartilage between bones of the joints. Later, bones may become deformed and the condition becomes painful. This is the most common form of arthritis and it commonly occurs in older people. Symptoms may include pain and joint stiffness particularly in the morning or after exercise or prolonged rest.


Pallister Killian Mosaic Syndrome

chromosome 12, Isochromosome 12p syndrome

Individuals with Pallister-Killian mosaic syndrome typically have low muscle tone at birth (hypotonia), sparse scalp hair, a high forehead, a coarse face, an abnormally wide space between the eyes, a broad nasal bridge, a highly arched palate, a fold of the skin over the inner corner of the eyes, and large ears with lobes that are thick and protrude outward.

Pallister-Killian mosaic syndrome is caused by the presence of four copies of the short arm of chromosome 12 instead of the normal two. The extra two copies of the short arm of chromosome 12 (12p) usually appear as a single chromosome (isochromosome) and are sometimes present in some but not all cells examined (mosaicism). The chromosome abnormality in Pallister-Killian mosaic syndrome is limited to specific cell types. The mechanism and parental origin of the isochromosome 12p can usually not be determined. The extra genetic material disrupts the normal course of development and results in the signs and symptoms of this disorder.

Pallister-Killian mosaic syndrome is a very rare disorder that affects males and females in equal numbers. The exact prevalence is unknown; this disorder may be underdiagnosed because it is difficult to detect in patients with mild symptoms. Currently, more than 150 people with this disorder have been reported in the medical literature.

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

Hypomelanosis of Ito is a rare disorder in which the main characteristic is lesions of the skin. A whorl-like lack of pigmentation of the skin may occur on any part of the body except the soles, palms, and scalp. Over half of the patients with this disorder may have seizures, intellectual disability, crossed eyes, nearsightedness, a cleft along the edge of the eyeball (coloboma), an abnormally small head and/or an abnormal overgrowth of brain tissue (megalencephaly). Autosomal dominant inheritance has been suggested in some cases. For more information on this disorder, choose Hypomelanosis of Ito as your search term in the Rare Disease Database.)


Pallister W Syndrome

Pallister W syndrome is a rare genetic disorder characterized by unusual facial features such as clefting of the palate and the upper lip, a broad flat nose, widely spaced slanted eyes, and/or downslanting eyelid folds (palpebral fissures). Other symptoms may include mental retardation, speech problems, bone deformities of the arms and legs, and/or seizures. The exact cause of Pallister W syndrome is not known.

Pallister W syndrome is apparent at birth.  It is characterized by widely spaced eyes (hypertelorism) with downward slanting eyelid folds (palpebral fissures), a broad flat nasal bridge, a broad tip of the nose, a broad flat jaw, central clefting of the palate or upper lip, seizures, and mental retardation.  There may also be bone abnormalities in the arms and legs such as abnormal deviation of the elbow away from the body when the arm is extended (cubitus valgus).  Other symptoms may include hair that does not lie flat on the head (cowlick), missing teeth (partial adontia), broad uvula, and a high broad forehead.  Additional findings may include tremor and/or involuntary muscle contractions (i.e., spasticity).

The exact cause of Pallister W syndrome is not known.  The disorder is thought to be inherited as a X-linked genetic trait.  Geneticists interested in this disorder cannot agree about whether genetic transmission follows the rules of dominant or recessive inheritance patterns.

Pallister W syndrome is a very rare disorder.  As of  the year 2000, only six cases had been reported in the medical literature.  More than half involved male infants but the numbers are not large enough to draw any conclusions regarding whether it affects one sex more than the other.

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

Oto-Palato-Digital Syndrome, Types I and II, characteristically affect males more severely than females.  Clefting of the palate, slanting of the eyes, abnormalities of the face, fingers and toes, and speech problems occur. (For more information on this disorder, choose Oto-Palato-Digital as your search term in the Rare Disease Database.)


Pallister-Hall syndrome

CAVE (cerebro-acro-visceral early lethality) complex

Symptoms and findings in individuals with PHS may vary greatly in range and severity from patient to patient. Whereas some affected individuals may have only a few characteristic abnormalities, others may have most symptoms and physical features associated with the disorder.

PHS is typically inherited in an autosomal dominant pattern with wide variability in expression and is caused by pathogenic variants in the GLI3 gene, termed GLI3-related PHS. In affected families, most individuals with the familial GLI3 gene variant will have symptoms and findings associated with the disorder (high penetrance). However, in such instances, the characteristics may vary in range and severity from patient to patient. The variability within a particular family appears to be less than the variability in affected members of different families. GLI3 is the associated gene in 95% of affected individuals with PHS. A few patients have been found to have two variants in the SMO gene, termed SMO-related PHS. This rare form of PHS is inherited in an autosomal recessive pattern.

PHS is an extremely rare disorder that is typically apparent at birth (congenital), appears to affect males and females equally. Approximately 100 patients have been reported in the medical literature, including affected individuals from several large families (kindreds) and single occurrences in which a positive family history has not been found. The range and severity of associated symptoms and findings may vary greatly from one affected individual to the next (variable expressivity). Because PHS is extremely variable and therefore may be under- or misdiagnosed, it may be difficult to determine the true frequency of the disorder in the general population.

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

There are several related disorders characterized by pathogenic variants in the GLI3 gene. This group of disorders includes Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, postaxial polydactyly type A, preaxial polydactyly type IV, oral-facial-digital syndrome, acrocallosal syndrome, and a novel disorder with polydactyly associated with biallelic variants in GLI3. These disorders occur due to distinct variants of the GLI3 gene (allelic disorders) and share some similar characteristics. Despite similarities, these disorders are considered distinct clinical entities.


Pustulosis palmaris et plantaris

Palmoplantar pustulosis (PPP) is a rare, recurrent inflammatory disorder. Affected individuals develop small to large sterile blisters filled with a yellow turbid liquid (pustules) on the palms of the hands and/or soles of the feet. The pustules may be painful and cause a burning feeling. The condition primarily affects women between 40 and 69 years of age, and predominantly smokers. The exact cause of PPP is not known. Researchers have determined that possible causes include smoking, bacterial infections (acute or chronic tonsillitis, dental infection, chronic sinusitis), contact allergies (mainly metals) and certain medications. Genetics may play a role for patients who have a family history of the disorder. PPP is strongly related to psoriasis vulgaris, some patients have both PPP and plaque psoriasis or PPP and psoriatic arthritis. Psoriatic nail involvement is frequently seen in PPP and a family history of psoriasis is recorded in 10-42% of patients affected by PPP. Depending on the cause, there are many treatments available including certain moisturizers, medications (topical steroids and/or retinoids), light therapy and systemic therapies for severe cases with retinoids, conventional immunosuppressants (methotrexate, cyclosporine) and/or biological therapies.

PPP causes recurrent crops of sterile pustules to form on the palms of the hands and/or the soles of the feet  The pustules often coalesce in an erythematous background where infiltrated and scaly plaques tends to form after several days with the onset of painful fissures. Itching and/or pain are often present. Patients may also feel like their hands and/or feet are burning. Due to these symptoms, patients may have difficulty walking and performing other daily tasks with the hands and feet.

The exact cause of PPP is not known. Researchers have found some possible causes including smoking, infections, certain medications and genetics.

PPP mostly affects women between 40 and 69 years of age and smokers, but this condition may affect people of any age.

Some researchers suggest that PPP is a type of psoriasis, while others suggest that it is a separate disorder. Psoriasis is a skin condition that causes skin cells to multiply too quickly after inflammation. Symptoms of psoriasis include itchy, scaly skin and dry, red patches which may be painful.

A doctor will look at the affected skin and skin swabs might be indicated to confirm the sterile nature (without bacteria or fungi) inside the pustules. In some patients, a skin biopsy will be needed. If a biopsy is necessary, the doctor will take a piece of skin from the affected area to test it for histopathology.

Although there is no definitive cure for PPP but there are different treatment options available.


Pancreatic Neuroendocrine Neoplasms (pNENs)

The pancreas is a gland located between the stomach, spleen, duodenum and colon transversum. It contains specialized exocrine cells that secrete enzymes that travel to the intestines and aid in digestion as well as endocrine cells, so called islet cells. Pancreatic neuroendocrine neoplasms (pNENs) are an increasingly common group of malignancies that arise within the endocrine tissue of the pancreas. Endocrine tissue is specialized tissue that contains hormone-secreting cells (e.g. α-cells, ß-cells). These cells secrete several different hormones into the blood (endocrine) or to local cells (paracrine, autocrine). These hormones have a variety of functions within the body (e.g. glucose-metabolism). Neoplasms that arise from endocrine tissue may also secrete hormones, resulting in excessive levels of these hormones in the body and potentially a wide variety of symptoms. There are several different subtypes of functioning pNENs distinguished by the specific type of hormone that they secrete. Insulinomas and gastrinomas are the most common types of hormone secreting pNENs.

The symptoms, severity and rate of progression of pNENs can vary greatly from one person to another, even among individuals with the same type of malignancy.

The exact cause of pancreatic neuroendocrine neoplasms is unknown. Most pNENs occur randomly for no apparent reason (sporadically). Some individuals may have a genetic predisposition to developing pNENs. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but the disorder may not be expressed unless it is triggered or activated under certain circumstances, such as due to certain environmental factors. The genetic or environmental factors associated with pNENs are unknown. More research is necessary to determine what specific factors may play a role in the development of pNENs.

PNENs seem to affect women slightly more often than men. Individuals of any ethnic or racial group may develop a pNEN. Affected individuals usually develop sporadic pNENs between the ages of 30-60. When pNENs occur as part of a genetic syndrome, they tend to occur during childhood or young adulthood. PNENs affect approximately ~1 in 100,000 individuals in the general population per year. They account for approximately 2-4 percent of all pancreatic neoplasms.

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

A diagnosis of a pancreatic neuroendocrine neoplasms is made based upon identification of characteristic symptoms (if present), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including advanced imaging techniques (octrotide-scintigraphy, CT, MRI, PET-CT, PET-MRI), blood tests (Chromogranin A, NETest), biochemical tests, and also biopsies.


大脑铁沉积型神经退行性病变1型

The common feature among all individuals with PKAN is iron accumulation in the brain, in a pattern called the ‘eye of the tiger sign,’ along with a progressive movement disorder. Symptoms may vary greatly from case to case. In most cases, progression of the disease extends over several years, leading to death in childhood or early adulthood in classic cases. Some patients experience rapid deterioration and die within 1-2 years. Others have a slower progression or can plateau for long periods of time and continue to function into the third decade of life. Atypical individuals often retain a high level of function into later adulthood and some are known to be living in their sixties to seventies.

Individuals with PKAN have abnormal accumulation of iron in certain areas of the brain. This is especially seen in regions of the basal ganglia called the globus pallidus and the substantia nigra. The basal ganglia is a collection of structures deep within the base of the brain that assist in regulating movements. The exact relationship between iron accumulation and the symptoms of PKAN is not fully understood.

PKAN affects males and females in equal numbers. The symptoms typically develop during childhood, although occasionally they begin during late adolescence or adulthood. Cases in infancy and of adult onset have also been reported.

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

The diagnosis of PKAN is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. PKAN is typically suspected when the characteristic brain MRI finding called the eye-of-the-tiger sign, which is a dark area indicating accumulation of iron with a bright spot in the center, is observed on T2-weighted MRI. This MRI finding is not seen in other forms of NBIA.


Papillon-Lefèvre syndrome

keratoris palmoplantaris with periodontopathia

Papillon-Lefèvre syndrome (PLS) is an extremely rare genetic disorder that typically becomes apparent from approximately one to five years of age. PLS is characterized by the development of dry scaly patches on the skin of the palms and the soles (palmar-plantar hyperkeratosis) in association with severe inflammation and degeneration of the structures surrounding and supporting the teeth (periodontium). The primary (deciduous) teeth frequently become loose and fall out by about age five. Without treatment, most of the secondary (permanent) teeth may also be lost by approximately age 17. Additional symptoms and findings associated with PLS may include frequent pus-producing (pyogenic) skin infections, abnormalities of the nails (nail dystrophy), and excessive perspiration (hyperhidrosis). Papillon-Lefèvre syndrome is inherited in an autosomal recessive pattern. It results from changes (alterations) of the CTSC gene that regulates production of an enzyme known as cathepsin C.

Papillon-Lefèvre syndrome is characterized by the development of dry scaly patches of skin (hyperkeratosis) usually around the age of one to five years. These patches are usually confined to the undersides of the hands and feet, but may spread to the knees and elbows. Rarely, the upper portions of the hands and feet, the eyelids, the lips, the cheeks, and/or other areas of the body may also be affected. Affected skin may be unusually red and thick, but can vary in color and texture. Skin lesions may worsen in the cold and walking may be painful. In rare instances, cysts may form on the eyelids later in life.

Papillon-Lefèvre syndrome is caused by changes (alterations) in CTSC (Cathepsin C) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a gene is altered, 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.

Papillon-Lefèvre syndrome is an extremely rare disorder that affects males and females in equal numbers and is found in all ethnic groups. More than 200 cases have been reported in the medical literature. In the general population, the disorder occurs in approximately one to four individuals per million. However, determining the incidence or prevalence of rare disorder is extremely difficult. Skin abnormalities associated with this disorder may be present at birth (congenital) or by the age of five. Other symptoms usually become apparent between the third and fifth year of life.

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

Haim-Munk syndrome, also known as keratosis palmoplantaris with periodontopathia and onychogryphosis is a rare inherited disorder. It is characterized by reddening and overgrowth of skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis) and overgrowth of the fingernails and toenails (onychogryphosis). Affected individuals may also have flat feet (pes planus); abnormally long, slender fingers and toes (arachnodactyly); and/or a heightened sensitivity to cold temperatures and loss of bone tissue in the fingers and toes (acroosteolysis). Degeneration of the structures that surround and support the teeth may also be present. Haim-Munk syndrome is inherited as an autosomal recessive genetic trait. Some researchers believe the disorder may be a variant of Papillon-Lefèvre syndrome. (For more information, choose Haim Munk as your search term in the Rare Disease Database.)

Treatment 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, physicians who evaluate and treat skin problems (dermatologists), dentist, dental surgical team, which includes a pediatric dentist, a specialist in treating disorders affecting the area supporting and surrounding the teeth (periodontist), and a specialist in the restoration and replacement of teeth (prosthodontist), and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support is recommended for the entire family as well.


Paracoccidioidomycosis

Paracoccidioidomycosis (PCM) is a chronic infectious tropical disease caused by the fungus Paracoccidioides brasiliensis. The initial infection usually occurs in the lungs, but may also spread to the skin, mucous membranes, and other parts of the body. Specialized cells that line the walls of blood and lymphatic vessels and dispose of cellular waste (reticuloendothelial system) may also be affected by paracoccidioidomycosis. If the patient does not receive treatment, life-threatening complications can occur. Most cases of this disease occur in South and Central America.

The symptoms of paracoccidioidomycosis generally occur from several weeks or months to years after the initial exposure to the fungus.  The symptoms vary according to which areas of the body are infected.

Paracoccidioidomycosis is caused by infection with a fungus known as Paracoccidioides brasiliensis.  Many cases of this disease occur years after airborne fungal spores are inhaled, although the period of latency is not always this long.

Paracoccidioidomycosis is a rare fungal disease.  For reasons that are not clearly understood, its chronic adult form affects males 15 times more frequently than it does females.  Most affected people are between the ages of 20 and 50 years.  The subacute juvenile form of the disorder affects males and females equally.

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

Blastomycosis or North American Blastomycosis is a systemic fungal infection caused by Blastomyces dermatitidis.  It occurs primarily in the southeastern and Mississippi valley areas of the United States.  Symptoms initially include fever, chills, cough, heavy sweating, and/or difficulty breathing (dyspnea).  Other symptoms may develop later and involve the lungs, skin, bones, joints, kidneys, and/or central nervous system.  Chronic infection of the lungs may lead to pneumonia.  If left untreated, Blastomycosis can have life-threatening complications.   (For more information on this disorder, choose Blastomycosis as your search term in the Rare Disease Database.)


Paramyotonia congenita of Von Eulenburg

Muscle stiffness in PMC is the inability for the muscles to relax in a timely manner after contracting (myotonia). The muscles most commonly affected are located in the face, neck and upper extremities, although it can affect the muscles used for breathing and swallowing, as well as muscles in the lower back. PMC is usually apparent during infancy and always presents by teenage years. Symptoms do not progress with age. Individuals with this disorder do not have wasting of muscles (atrophy) but often have an increase of muscle bulk (hypertrophy).

PMC is an autosomal dominant genetic condition caused by a change (mutation) in the SCN4A gene which codes for a sodium channel specific for skeletal muscles.

PMC is a very rare disorder that affects males and females in equal numbers. The symptoms can begin during infancy, and are always apparent by the teenage years. It is estimated to affect fewer than 1 in 100,000 people.

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

When PMC is suspected, a test is administered to test the capacity of muscles to conduct electricity (electromyography). During the test, the muscles are chilled and electrical signals are recorded before and after the muscle is cooled. The electromyography (EMG) will show rapid repetitive electrical discharges. EMG cannot always diagnose PMC definitively, and further testing may be necessary.


Paraneoplastic neurologic syndrome

Paraneoplastic neurologic syndromes (PNS) are a group of conditions that affect the nervous system (brain, spinal cord, nerves and/or muscles) in patients with cancer. The term paraneoplastic means that the neurological syndrome is not caused by the tumor itself, but by the immunological reactions that the tumor produces. It is believed that the body’s normal immunological system interprets the tumor as an invasion. When this occurs, the immunological system mounts an immune response, utilizing antibodies and lymphocytes to fight the tumor. The end result is that the patient’s own immune system can cause collateral damage to the nervous system, which can sometimes be severe. In many patients, the immune response can cause nervous system damage that far exceeds the damage done to the tumor. The effects of PNS can remit entirely, although there can also be permanent effects.

Paraneoplastic neurologic syndromes can manifest themselves in different ways, such as encephalitis (inflammation of the brain), ataxia (loss of balance), neuropathy (progressive numbness/ weakness of feet and hands), myoclonus/opsoclonus (body jerks and irregular rapid eye movements), psychiatric disturbances, or myasthenia gravis (a neuromuscular disorder that causes extreme weakness of several muscle groups, including those that control breathing). It is the presence of specific paraneoplastic antibodies that often leads to the diagnosis of a paraneoplastic neurologic syndrome.

The specific cause of PNS is unknown. The findings in the serum or cerebrospinal fluid (CSF) of antibodies (onconeural antibodies) to specific malignant tumors suggest that the cause of some PNS is the immune response against the tumor being misdirected against the nervous system.

In general, PNS are considered rare disorders. However, some PNS such as the paraneoplastic neuropathies are relatively frequent, affecting approximately 10% of patients with some cancers of the immunological system. In many instances, PNS are not recognized and the patients’ complaints attributed to other more common problems.

Patients with a suspected paraneoplastic syndrome should receive a complete panel of laboratory studies, including blood, urine, and CSF. In addition, the use of an MRI, EEG (electroencephalogram), and EMG (electromyogram) can further display abnormalities that help to diagnose PNS.


Paroxysmal cold hemoglobinuria

The typical presentation is that of a child who during the preceding 1-2 weeks had suffered from what appeared to be an undefined or flu-like illness. Usually the onset of hemolysis is signaled by a recurrence of fever and then the passage of red-brown urine. This urine contains the iron bearing, oxygen transporting,  protein pigment of blood called hemoglobin, which is released when red blood cells are prematurely destroyed. The presence of hemoglobin in the urine (hemoglobinuria) causes the dark brown color of the urine. Hemoglobinuria, hemoglobinemia (hemoglobin in the plasma), jaundice and pallor are common clinical findings in acute PCH and, of particular significance is that hemoglobinuria is found in almost all acute cases in childhood.

In most affected children, PCH occurs as an acute hemolytic anemia, following an infection and spontaneously resolves once the infection subsides. Usually, PCH does not recur (self-limited) in children, but recurrent cases have been reported in the medical literature. In most adults the cause of PCH is unknown (idiopathic) and is usually a chronic disease. With the dramatic decline in the prevalence of syphilis, PCH in adults has declined, and the current understanding of the adult form of the disease is less clear.

Autoimmune hemolytic anemias as a group are estimated to affect 1-3 people per 100,000 in the general population.  Both the syphilitic and non-syphilitic forms of chronic PCH are exceedingly rare.  The prevalence and incidence rates are unknown.   Anyone may acquire PCH, but it is more common among children than among adults. An individual with a viral infection is at higher risk of contracting the disorder. No known genetic, sex, or racial risk factors exist, although the disease has been reported in families.

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

A diagnosis of PCH may be suspected in some individuals with anemia. In particular, the diagnosis should be suspected in any acutely ill child with hemoglobinuria. A diagnosis is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of specialized tests such as a direct antiglobulin test (Coombs) test, which is used to detect certain antibodies that act against red blood cells. A diagnosis of PCH is confirmed by the results of a Donath-Landsteiner test, which can distinguish PCH from other forms of hemolytic anemia. The test consists of incubating a sample of the patient’s serum with normal red blood cells (RBCs) in the cold for 30 minutes and then warming the mixture to body temperature (37C). Hemolysis of the RBCs in this bi-phasic test indicates a diagnosis of PCH.


Paroxysmal nocturnal hemoglobinuria

阵发性睡眠性血红蛋白尿症

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder in which red blood cells break apart prematurely. It is an acquired hematopoietic stem cell disorder. Hematopoietic stem cells are created in the bone marrow, the spongy center of the long bones of the body. These cells grow and eventually develop into red blood cells, white blood cells and platelets. Some hematopoietic stem cells in individuals with PNH are defective and consequently produce defective blood cells. These defective red blood cells of PNH are extremely susceptible to premature destruction by a particular part of a person’s own immune system called the complement system. The destruction of red blood cells (hemolysis) by complement leads to episodes of hemoglobin in the urine (hemoglobinuria). Hemoglobin is the red, iron-rich, oxygen-containing pigment of the blood. Individuals with hemoglobinuria may exhibit dark-colored or blood colored urine. This finding is most prominent in the morning, after the urine has concentrated overnight during sleep. However, hemolysis in individuals with PNH is a constant process (i.e., it does not occur only at night). Hemoglobin in the urine may not always be visible. In addition to hemolysis, individuals with PNH are also susceptible to developing repeated, potentially life-threatening blood clots (thromboses). Affected individuals also have some degree of underlying bone marrow dysfunction. Severe bone marrow dysfunction results in low levels of red and white blood cells and platelets (pancytopenia). The specific symptoms of PNH vary greatly from one person to another and affected individuals usually do not exhibit all the symptoms associated with the disorder.

The symptoms of PNH occur because of the production of defective blood cells and because the bone marrow does not produce enough blood cells. The specific symptoms and progression of the disorder vary greatly from one person to another. Some individuals may have mild symptoms that remain stable for many years; others may have serious symptoms that can progress to cause life-threatening complications.

Two factors are necessary for the development of PNH: an acquired somatic mutation of the PIGA gene, which affects one or more hematopoietic stem cells creating defective PNH blood cells, and a process that leads to the multiplication and expansion of these defective stem cells. Most likely, PNH arises in the setting of autoimmune bone marrow failure, as occurs in most cases of acquired aplastic anemia. Researchers believe that defective PNH stem cells survive the misguided attack by the immune system and multiply, while healthy stem cells are destroyed, resulting in the development of PNH. The reason that defective cells survive while healthy cells are destroyed is incompletely understood but appears to be due to properties of the PNH cell that provide a survival advantage in the setting of immune-mediated attack on the bone marrow.

PNH is believed to affect males and females in equal numbers, although some studies show a slightly more females affected. The prevalence is estimated to be between 0.5-1.5 per million people in the general population. The disorder has been described in people of many ethnic backgrounds and has been identified in all areas of the world. The disorder may occur with greater frequency in individuals from Southeast Asia or the Far East who experience greater rates of aplastic anemia. The disorder can affect any age group. The median age at diagnosis is during the 30s.

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

Budd-Chiari syndrome is a rare disorder characterized by narrowing and obstruction (occlusion) of the veins of the liver (hepatic veins). In individuals with PNH, blood clots (thromboses) block the hepatic veins. Symptoms associated with Budd Chiari syndrome include pain in the upper right part of the abdomen, an abnormally large liver (hepatomegaly) and/or accumulation of fluid (ascites) in the space between the two layers of the membrane that lines the stomach (peritoneal cavity). Additional findings that may be associated with the disorder include nausea, vomiting and/or an abnormally large spleen (splenomegaly). The severity of the disorder varies from person to person, depending upon the site and number of affected veins. In some cases, if the major hepatic veins are involved, high blood pressure in the veins carrying blood from the gastrointestinal (GI) tract back to the heart through the liver (portal hypertension) may be present. (For more information on this disorder, choose Budd-Chiari as your search term in the Rare Disease Database.)


Progressive hemifacial atrophy

Parry-Romberg syndrome is a rare, acquired disorder characterized by slowly progressive shrinkage (atrophy) of the skin and soft tissues of half of the face (hemifacial atrophy). In rare cases, both sides of the face are affected. In some people, atrophy may also affect the limbs, usually on the same side of the body as the facial atrophy.

The symptoms, progression and severity of Parry-Romberg syndrome are highly variable from one person to another and range from mild to severe. It is important to note that affected individuals will not have all the symptoms discussed below. It seems likely that individuals with milder symptoms are much more common than severely affected individuals. Affected individuals should talk to their physician and medical team about their specific case and associated symptoms.

The cause of Parry-Romberg syndrome is unknown and appears to occur randomly for unknown reasons (sporadically). Different theories have been proposed to explain the development of the disorder including abnormal development or inflammation of the sympathetic nervous system; viral infections; inflammation of the brain and membranes (meninges) covering the brain (meningoencephalitis); trauma; abnormalities of blood vessel formation (angiogenesis); or autoimmunity.

Parry-Romberg syndrome is a rare disorder. The true incidence is unknown. Because the disorder often goes undiagnosed or misdiagnosed, determining the true frequency of Parry-Romberg syndrome in the general population is difficult. Researchers have estimated that Parry-Romberg may affect as many as 1 in 250,000 people in the general population. Parry-Romberg syndrome appears to affect females slightly more often than males, but proper studies of the population are lacking. Parry-Romberg syndrome typically becomes apparent during the first or early during the second decade of life, with most affected individuals experiencing symptoms before the age of 20 years. However, the disorder has been described in infants and individuals more than 50 years of age. Parry-Romberg syndrome was originally described in the medical literature in 1825 (C.H. Parry) and 1846 (E. Henoch and H.M. Romberg). There are anecdotal reports of Parry-Romberg syndrome worsening in some pregnant women, either during pregnancy or shortly after childbirth.

Symptoms of the following disorders can be similar to those of Parry-Romberg syndrome. Comparisons may be useful for a differential diagnosis, although the clinical features of Parry Romberg syndrome are quite distinct to a doctor familiar with the condition.

A diagnosis of Parry-Romberg syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.


Pars Planitis

Although pars planitis is generally benign, there can be significant vision loss in extreme cases. It is an immunological disorder of the eye characterized by inflammation of a part of the uvea, the layer of tissue between the sclera and the retina, the membranes protecting the eyeball. The uvea, in turn, is made up of three portions: the iris, the ciliary body, and the choroid. In addition, the uvea contains many of the blood vessels that supply the eye.

The symptoms of pars planitis include blurred vision and dark floating spots that intrude upon clarity of eyesight. Swelling can occur inside the eye, particularly on the peripheral retina or macula that may lead to decreased vision. Glaucoma may occur as well.

Pars planitis is thought to be an autoimmune disorder. An autoimmune reaction causes the inflammation that is thought to cause symptoms of this disorder.

Pars planitis is an uncommon ocular disorder of children and young adults that affects males slightly more frequently than females.

The following disorders may be associated with pars planitis as secondary characteristics.  They are not necessary for a differential diagnosis:

Pars planitis is usually diagnosed by means of a thorough physical evaluation, detailed patient history, and specialized eye examination.


Parsonage Turner Syndrome

The hallmark finding of PTS is the abrupt onset of pain in one of the shoulders (unilateral pain). In rare cases, both shoulders can be affected (bilateral). Onset may be rapid in some people, while in others pain onset is gradual and subtle (insidious), followed by a rapid increase in both intensity and severity. Pain has been described as sharp, aching, burning or stabbing. Pain may also affect the neck and the arm and hand on the same side as the affected shoulder.

The exact, underlying cause of PTS is not fully understood. Different factors, including immunological, environmental and genetic ones, are thought to play a role in the development of the disorder.

PTS affects males more often than females. The incidence of the disorder is based upon available population studies and is estimated to be approximately 1.64 to 3 people per every 100,000 individuals in the general population per year. However, cases of PTS may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. The condition develops most often in young to middle-aged adults but has been reported in young children and the elderly.

Additional conditions or disorders that can cause symptoms similar to those seen in PTS include bursitis, rotator cuff injury or disease, calcific tendonitis, impingement syndromes, Guillain-Barre syndrome, cervical disc disease, cervical radiculopathy, mononeuritis monoplex, amyotrophic lateral sclerosis (Lou Gehrig’s disease), chronic inflammatory demyelinating polyneuropathy, polymyalgica rheumatica, thoracic outlet syndrome and brachial plexus injury secondary to cancer (neoplastic brachial plexopathy). Adhesive capsulitis, which can develop as a complication of PTS, can develop for other reasons as well. NORD has individual reports on some of these disorders. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)

A diagnosis of PTS is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.


Partial androgen insensitivity syndrome

部分性雄激素不敏感综合征

Characteristics of partial androgen sensitivity syndrome vary from person. Each person with PAIS is unique and may not have the same features.

Partial androgen insensitivity syndrome is a genetic condition that is inherited in an X-linked recessive pattern. The gene related to partial androgen sensitivity syndrome is the AR gene, which is located on the X chromosome. When people have a change in the AR gene, their bodies may have issues producing androgen receptors, which are structures in cells that allow the body to properly respond to androgens (male sex hormones). Because of problems with the androgen receptors, people with changes in the AR gene have the characteristics of partial androgen sensitivity syndrome.

Partial androgen sensitivity syndrome is very rare in the general population. 1 in 99,000 male infants are born with one of the several androgen sensitivity syndrome types, including PAIS. PAIS only affects males, but females can be carriers for this genetic condition.

Symptoms of the following disorders can be similar to those of partial androgen insensitivity syndrome. Comparisons may be useful for a differential diagnosis.

Because features of partial androgen insensitivity syndrome vary from person to person, there are no standard diagnostic procedures for PAIS. PAIS may be suspected based on clinical features such as female-appearing genitals, absence of female sex organs (ovaries and the uterus), and issues with sperm production. Some laboratory results can help with the diagnosis. For example, if the patient has some physical features of PAIS and is confirmed through genetic testing to have XY chromosomes, it would further support the possibility of PAIS. Some other lab results that could help with diagnosis include having normal or high levels of testosterone (produced by testes) and luteinizing hormone (produced by pituitary gland).


激酶原转化酶1缺乏所致肥胖症

Obesity due to prohormone convertase I deficiency

obesity due to prohormone convertase deficiency

The symptoms of PCSK1 deficiency are due to abnormalities of the endocrine glands. The endocrine glands make hormones that affect growth, sexual development, blood pressure and the way the body makes and uses energy. Babies with PCSK1 deficiency develop severe diarrhea and digestive problems in the first few months of life. Symptoms may last for several months and lead to poor growth and weight gain. Sometimes, the diarrhea is severe enough to lead to hospitalization. These symptoms eventually get better and other symptoms related to endocrine gland abnormalities develop. These include uncontrollable hunger and early-onset obesity which continues through adulthood. Other symptoms include the inability to absorb salt and water, causing extreme thirst (polydipsia) and frequent urination (polyuria). Other endocrine problems include low levels of sex hormones, thyroid gland insufficiency and growth hormone deficiency. Puberty may be delayed or absent. Adults with PCSK1 deficiency are shorter than average and obese.

PCSK1 deficiency is caused by pathogenic variants (mutations) in the PCSK1 gene. This gene makes a protein that plays an important role in processing many of the endocrine gland hormones involved in energy, metabolism and appetite regulation. When the PCSK1 gene is not working, these hormones don’t work correctly.

PCSK1 deficiency is very rare and has been reported in less than 50 people. Many of the people that have been diagnosed with this condition are from Turkey and the Middle East. It has been diagnosed more often in populations where marriage between relatives is customary.

PCSK1 deficiency is one of several rare inherited conditions that lead to early-onset obesity. These conditions are due to variants in one of the genes that normally work together to help regulate hunger and energy production. These conditions may be difficult to diagnose based solely on clinical examination. Severe diarrhea in infancy may set PCSK1 deficiency apart from other early-onset obesity conditions, but often genetic testing is the only way to tell the difference between them. Some (but not all) of these conditions include:

PCSK1 deficiency is diagnosed based on a clinical examination, symptoms and the results of blood and genetic testing. Severe malabsorptive diarrhea is one of the first symptoms of PCSK1 deficiency, but has many other, more common causes. Because of that, PCSK1 deficiency is often not diagnosed until the other symptoms, especially early-onset obesity become apparent.

In early childhood, treatments for obesity may include weight management through diet and behavioral therapies. Gastric bypass surgery has been tried in at least one patient. Several medications are available for treating obesity, although all have limited effectiveness and may have side effects. Most of these treatments do not result in permanent weight loss.


Pediatric Crohn Disease

The signs and symptoms can vary from one person to another. Symptoms can appear suddenly, or they may build slowly over time. Symptoms may be triggered by trauma, illness or stress. Sometimes, symptoms occur with no identifiable triggering event.

The exact cause of pediatric Crohn’s disease is not fully understood. Most likely, pediatric Crohn’s disease is a multifactorial disorder, which means that multiple factors must occur together for the disorder to develop. These factors can include genetic, immunological and environmental factors.

Crohn’s disease is a common disorder, affecting as many as 780,000 people in the United States. The disorder is most common in individuals between 15-35, with approximately 25% diagnosed by age 20. There is another increase in frequency among individuals between 60-80 years of age.

Symptoms of the following disorders can be similar to those of pediatric Crohn’s disease. Comparisons may be useful for a differential diagnosis.

A diagnosis of pediatric Crohn’s disease is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Pediatric Crohn’s disease may be suspected in children or adolescents with chronic abdominal pain, diarrhea, weight loss and anemia.


Peeling skin syndrome

Peeling skin syndrome (PSS) is a group of rare inherited skin disorders in which the normal gradual process of invisible shedding of the outermost skin layers is hastened and/or aggravated. PSS is characterized by painless, continual, spontaneous skin peeling (exfoliation) due to a separation of the outermost layer of the epidermis (stratum corneum) from the underlying layers. Other findings may include blistering and/or reddening of the skin (erythema) and itching (pruritus). Symptoms may be present from birth or appear in early childhood and are often exacerbated by friction, heat or other external factors. Based on the extent of skin involvement, PSS may involve the skin of the entire body (generalized form), or is limited to the extremities, mostly hands and feet (localized form). Generalized PSS can be distinguished into an inflammatory type which is associated with erythema, involves other organ systems and is more severe, and a milder, non-inflammatory type. PSS may be caused by disease-causing variants in multiple genes encoding proteins with crucial functions for cell-cell adhesion: structural proteins forming cell-cell adhesion points (desmosomes, corneodesmosomes) and inhibitors of epidermal proteases that control skin shedding.

Peeling skin syndrome belongs to the groups of congenital ichthyosis and skin fragility disorders with autosomal recessive inheritance. Most forms of PSS manifest at birth or during infancy with shedding or peeling of the outermost layer of the skin (horny layer, aka stratum corneum). Skin peeling occurs spontaneous, is painless, and may persist lifelong with gradual improvements. Often, affected individuals and/or their caregivers can remove sheets of skin manually, comparable to skin peeling after a severe sunburn.

To date, genetic changes in several distinct genes have been reported to cause PSS.  These genes encode either structural proteins of corneocytes, the cells of the outermost skin layer (CDSN; DSG1; FLG2; DSC3; JUP) or inhibitors of epidermal proteases (SPINK5, CSTA; CAST; SERINB8), which are crucial regulators for the degradation of corneodesmosomes and shedding of corneocytes.

Peeling skin syndrome is a rare inherited disorder that, in theory, affects males and females in equal numbers. More than 100 cases have been reported in the medical literature from different population groups. Peeling skin syndrome due to variants in the CHST8 and CSTA genes were reported in consanguineous Pakistani and in Bedouin families, respectively. In Japanese individuals, a particularly common deletion involving CDSN has been reported. In Europeans, acral PSS due to TMG5 variants is more common.

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

Exfoliative dermatitis refers to a scaling skin disorder accompanied by distinct reddening (erythematous dermatitis) involving 90% or more of the skin surface. It is characterized by erythema and scaling involving the skin’s surface that often obscures the primary lesions. It is frequently difficult for clinicians to find the cause of exfoliative dermatitis even though the history of illness prior to erythema and scaling is obtained. Often, biopsies and blood studies are required. The term red man syndrome is reserved for idiopathic exfoliative dermatitis in which no primary cause can be found, notwithstanding a variety of examinations and tests. This form of the disorder is characterized by marked hardening of the skin of the palms and soles, swelling (lymphadenopathy), and raised levels of immunoglobulin E.


Pelizaeus-Merzbacher disease

The signs of PMD may vary widely from person to person. The signs of the classical form of PMD usually begin during early infancy, typically before 2 months of age. Initially, affected infants may fail to develop normal control of the head and eyes, specifically abnormal head bobbing and rapid, involuntary, jerky eye movements (nystagmus). Abnormally slow growth may also be an early sign. As affected infants and children age, additional signs may become apparent, including muscle tremors, weakness, facial grimacing, lack of muscle tone (hypotonia), impaired ability to coordinate voluntary movements (ataxia), and/or impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation) including delays in reaching developmental milestones such as sitting, standing, and walking. Affected individuals may also develop involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs and potentially partial paralysis of the arms and legs (spastic quadriparesis); abnormal, permanent fixation of certain joints (contractures); progressive degeneration of the nerves that lead to the eyes (optic atrophy); and/or difficulty speaking (dysarthria). As some affected children age, nystagmus may disappear. Some children may also develop skeletal deformities secondary to the severe spasticity that typically develops over time.

PMD is inherited as an X-linked recessive genetic disorder that affects mostly males. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females that have a disease gene present on one of their two X chromosomes are carriers for that disorder. Female carriers usually do not display symptoms because one of their two X chromosomes is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother, and if a male inherits an X chromosome that contains a disease gene, he will develop the disease.

The classical and connatal forms of PMD affect males far more often than females. In rare cases, heterozygous females will exhibit some of the signs associated with the disorder. However, in the milder forms of PMD and the allelic SPG2 and HEMS, carrier females may be affected.

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

A diagnosis of PMD may be suspected based upon a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests such as magnetic resonance imaging (MRI) to detect deficiency of white matter. Recognition of early myelination defects, such as lack of myelination in the cerebellum and brainstem, may aide in early diagnosis of the severe forms of PMD. Molecular genetic testing for the PLP1 gene is available to confirm the diagnosis.


Pemphigus and Pemphigoid

Pemphigus and pemphigoid are rare autoimmune blistering diseases of the skin and/or mucous membranes. Pemphigus affects the outer layer of the skin (epidermis) and causes lesions and blisters that easily rupture. Pemphigoid affects a lower layer of the skin, between the epidermis and the dermis, creating tense blisters that do not break easily. Sometimes pemphigoid may look like hives or eczema without blisters.

There are several different types of pemphigus.

Pemphigus and pemphigoid are not inherited but there can be a genetic predisposition to develop the disease. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or activated under certain circumstances, such as due to particular environmental factors. It is not currently possible to predict who may get these diseases.

Males and females are equally affected. The conditions are known to affect people from all racial and cultural backgrounds. However, there are certain groups of people (Ashkenazi Jews, people of Mediterranean, North Indian and Persian decent) who have a higher incidence of pemphigus.

Pemphigus and pemphigoid are diagnosed through special testing and clinical presentation. Types of testing include:


Pendred syndrome

The most common symptoms of Pendred syndrome include:

Pendred syndrome is caused by changes (mutations) in three genes (SLC26A4, FOXI1, or KCNJ10) in about 50% of patients, and the other half are due to unknown causes.  Mutations in SLC26A4 (also known as PDS), which encodes the protein pendrin, are the most common identifiable causes of Pendred syndrome. Pendrin is found in the inner ear (responsible for hearing and balance), the thyroid (a butterfly-shaped organ in the lower neck which is responsible for controlling metabolism) and kidneys (responsible for filtering waste and controlling salt levels). Pendrin pumps chloride and iodide to maintain their ion balance in the inner ear, thyroid and kidney. Mutations in these genes result in a lack of pendrin, so the ion levels become unbalanced and cause hearing and balance issues, a swollen thyroid and less commonly electrolyte imbalances.

Pendred syndrome affects approximately 2-3 per 1,000 children. This condition is not known to occur more often in people with different racial/ethnic backgrounds.

Congenital cytomegaloviral infection (cCMV) – may also cause hearing loss at birth due to a viral infection during pregnancy

Hearing loss at birth or during childhood is usually the first sign of this disease. An MRI scan of the inner ear may show an enlarged vestibular aqueduct or an abnormal cochlea. Genetic testing for the pendrin gene is the most common test leading to a diagnosis of Pendred syndrome.


Penta X Syndrome

Penta X syndrome is an extremely rare chromosomal disorder in which females have three extra X chromosomes. Typically, females have only two X chromosomes, resulting in a 46,XX karyotype. However, in those with penta X syndrome, there are a total of five X chromosomes, resulting in a karyotype of 49,XXXXX. The condition is typically characterized by moderate to severe intellectual disability, short stature, upslanting eyelid folds (palpebral fissures), a flat nasal bridge, malformed ears, and a short neck with a low hairline. Penta X syndrome may also be characterized by mild angulation of the fifth finger (pinky) toward the fourth finger (ring finger) (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers, heart and/or kidney defects, and deficient development of the ovaries and uterus. The disorder results from random errors during the division of reproductive cells in one of the parents. While the exact incidence of this disorder is unknown, researchers believe it occurs in close to one in 85,000 live births, comparable to the male equivalence (49,XXXXY).

Penta X syndrome is characteristically associated with growth delays before birth (prenatal growth deficiency), failure to grow and gain weight at the expected rate after birth (failure to thrive), and short stature. In addition, infants and children with penta X syndrome typically have delays in the acquisition of skills requiring the coordination of mental and physical activities (psychomotor deficits) and are affected by moderate to severe intellectual disability.

Penta X syndrome is a chromosomal disorder characterized by the presence of three extra X chromosomes in females. Chromosomes are found in the nucleus of all body cells and carry the genetic characteristics of each individual. There are 46 human chromosomes arranged into 23 pairs, with the 23rd pair determining the sex of the individual. Females with a normal chromosomal make-up (karyotype) have two X chromosomes (46,XX karyotype), receiving one chromosome from the mother and one from the father in each of the 23 pairs.

Penta X syndrome is a rare chromosomal disorder that affects only females. Since the syndrome was originally described in 1963 by Kesaree and Wooley, only approximately 40 cases have been reported in the medical literature. The exact incidence of 49,XXXXX is still unknown, however, researchers believe it is close to that of 49,XXXXY (1:85,000).

Certain symptoms of the following disorders may be similar to those of penta X syndrome. Comparisons may be useful for a differential diagnosis.

Penta X syndrome may be suspected upon thorough clinical examination and the detection of characteristic physical findings. However, a diagnosis may be confirmed by chromosomal analysis performed on blood samples that can reveal the presence of three extra X chromosomes in body cells.


Pentalogy of Cantrell

Pentalogy of Cantrell is a rare disorder that is present at birth (congenital). Pentalogy of Cantrell is characterized by a combination of birth defects. These birth defects can potentially involve the breastbone (sternum), the muscle that separates the chest cavity from the abdomen and aids in breathing (diaphragm), the thin membrane that lines the heart (pericardium), the abdominal wall, and the heart. Pentalogy of Cantrell occurs with varying degrees of severity, potentially causing severe, life-threatening complications. Most infants do not develop all of the potential defects, which may be referred to as incomplete pentalogy of Cantrell. When all five defects are present, this is referred to as complete pentalogy of Cantrell. The variability of the disorder from one individual to another can be significant. The exact cause of pentalogy of Cantrell is unknown. Most cases are believed to occur sporadically.

The specific symptoms and severity of pentalogy of Cantrell can vary dramatically from one person to another. Some infants may have mild defects with incomplete expression of the disorder. Other infants may have serious, life-threatening complications. It is important to note that affected individuals will not necessarily have all of the symptoms discussed below. Parents of caregivers of individuals with this condition should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.

The exact cause of pentalogy of Cantrell is unknown. Most cases occur randomly for no apparent reason (sporadically). One theory suggests that the symptoms of pentalogy of Cantrell occur due to an abnormality in the development of midline embryonic tissue fourteen to eighteen days after conception. Several familial cases have been reported, and some researchers have suggested that genetic factors may play a role in the development of the disorder. More research is necessary to determine the exact, underlying cause(s) of pentalogy of Cantrell.

Pentalogy of Cantrell affects males and females in equal numbers. The exact prevalence is unknown, but estimated to be 5.5 in 1 million live births. The symptoms of pentalogy of Cantrell are present at birth (congenital).

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

A diagnosis of pentalogy of Cantrell can often be made before birth (prenatally) sometimes using a fetal ultrasound. An ultrasound is an exam that uses high-frequency sound waves to produce an image of the developing fetus. A fetal ultrasound can detect some of the defects associated with pentalogy of Cantrell. An echocardiography is usually performed to evaluate the extent of the involvement of the heart. An echocardiography is an exam that uses sound waves to produce images of the heart


磷酸烯醇式丙酮酸羧激酶缺乏症

PEPCK deficiency is an extremely rare disorder characterized by episodes of low blood sugar (hypoglycemia). It is a disorder of carbohydrate metabolism caused by a deficiency in the enzyme called phosphoenolpyruvate carboxykinase or PEPCK. This enzyme normally converts proteins and fats to glucose during times of fasting, in a process called gluconeogenesis. The glucose is used as a source of energy by the body. PEPCK deficiency is inherited in an autosomal recessive pattern.

There are two forms of PEPCK deficiency: PEPCK1 deficiency (cytosolic) and PEPCK2 deficiency (mitochondrial).Both forms represent an inherited deficiency of the PEPCK enzymes. These enzymes are part of a process of converting proteins and fat to glucose (gluconeogenesis) that occurs primarily in the liver. This process is activated when dietary intake of glucose is insufficient, such as fasting or when extra energy is needed, such as during periods of intense exercise. Glucose is essential as the body’s source of energy, and for the functioning of many organs and systems in the body, especially the brain.

Changes (variants or mutations) in the PCK1 gene cause the cytosolic (soluble) form of PEPCK deficiency (PEPCK1) and variants in the PCK2 gene cause the mitochondrial form of PEPCK deficiency (PEPCK2). Variants in these genes result in a reduced amount or absence of the PEPCK enzyme.  Researchers think that the severity of disease is based on the amount of residual enzyme activity that remains.

PEPCK deficiency is extremely rare. Prior to 2007, only 10 cases were reported in the medical literature. Since then, there have been at least 6 new cases reported for a total of 16 cases of PEPCK deficiency. Males and females are equally affected..

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

Patients with fatty acid oxidation disorders such as medium chain acyl-coA dehydrogenase deficiency (MCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD) and glycogen storage disorders can present with hypoglycemia during fasting, and may have abnormal metabolites in urine. (For more information on these disorders, search the Rare Disease Database.)

The mainstay of treatment for PEPCK deficiency is avoidance of fasting. Individuals with this disorder may consume extra carbohydrate such as cornstarch to lower the occurrence of symptoms. This is especially important in the evenings before an overnight fast.


Perivascular epithelioid cell neoplasm

Signs and symptoms of PEComas vary quite a bit between patients and depend on tumor location. Some PEComas cause no symptoms and are found when patients undergo imaging for other reasons.

The cause of sporadic cases of PEComas is not known. PEComas may be associated with the genetic condition tuberous sclerosis complex (TSC), an autosomal dominant genetic disorder.

PEComas have been found in people of all ages, from children to older adults. Although they often occur in children with TSC, they also occur sporadically in people with no known risk factors.

PEComas can be mistaken for other tumors, some of which can be malignant. Different tumors on imaging can appear similar to one another, so a PEComa in one organ may be difficult to distinguish from another tumor that can occur in the same organ.

PEComas may be detected by imaging with X-ray, CT scan or MRI. Once a tumor is detected, biopsy is needed to examine the cellular make-up and distinguish it from other types of tumors.

Surgery to remove a localized PEComa that has not spread is currently the recommended form of treatment. Surgery may be curative for patients with benign PEComas, although tumor regrowth can occur. If regrowth occurs, surgery is again recommended to remove the regrowth. Surgery is not usually recommended to remove tumors that have spread (metastasized) to other parts of the body. Instead, medical treatment is usually recommended.


Perrault syndrome

gonadal dysgenesis, XX type, with deafness

Perrault syndrome is a rare genetic disorder which causes sensorineural hearing loss in both males and females and ovarian dysfunction in females. Only about 100 cases have been reported, mostly in females. Hearing loss is present at birth or early childhood and may be progressive, but the disease is usually diagnosed in females in early adulthood due to a late puberty. In females, the ovaries do not function normally to begin puberty despite having an otherwise normal set of chromosomes (46,XX karyotype). Male fertility is normal, but females may not be able to conceive naturally, depending on the severity. A diagnosis is usually made after imaging shows a uterus but no functional ovaries and the karyotype of 46,XX.

The most common symptoms of Perrault syndrome include:

Perrault syndrome is caused by changes (mutations) in six genes: CLPP, ERAL1, HARS2, HSD17B4, LARS2, or TWNK. Mutations in one of these genes have been identified in about 40% of patients. The cause is unknown in the other 60% of patients.

Fewer than 100 cases of Perrault syndrome have been diagnosed, making it extremely rare (<1 in 1 million). A family history of this disease is the greatest known risk, particularly if the genetic mutation is identified.

Turner syndrome – also causes ovarian dysfunction but affected females have a 45,XO karyotype

The diagnosis of Perrault syndrome is based on the early hearing loss and ovarian dysfunction in females with a normal 46,XX set of chromosomes. Genetic testing for mutations in the six known causative genes can help to confirm the diagnosis, but more commonly the exact cause will be unknown. Since males with Perrault syndrome tend to only experience hearing loss, they may not receive a diagnosis unless they also have a sister with Perrault syndrome.

There is no cure for Perrault syndrome and treatment focuses on remedying the symptoms of hearing loss, hormone imbalance and infertility. Depending on the severity of hearing loss, an audiologist or ENT physician may recommend hearing aids, cochlear implants or vibrotactile devices. Routine hearing checks are important to determine if the hearing loss is getting worse.


Whooping cough

Pertussis is a highly contagious acute respiratory disease caused by the bacteria Bordetella pertussis. This disease has 3 stages: catarrhal, paroxysmal, and convalescent. The symptoms of the catarrhal stage are mild and may go unnoticed. The paroxysmal stage of Pertussis is characterized by episodes of coughing with a distinctive whooping sound when breathing in (inspiration). This characteristic cough gives the disease its common name, Whooping Cough. During the convalescent stage, episodes of coughing are less frequent and symptoms improve. The incidence of Pertussis has diminished greatly with widespread use of the DPT vaccine (Diphtheria Pertussis Tetanus), but in certain areas of the United States outbreaks have occurred periodically in recent years.

Pertussis is a highly contagious disease that typically lasts for approximately 6 to 10 weeks. The symptoms are more severe in infants or in individuals who have never been immunized against the disease. There are three recognized stages of the disease: catarrhal, paroxysmal, and convalescent.

Pertussis is an infectious disease caused by the gram-negative coccobacillus, Bordetella pertussis. Pertussis is a highly contagious disease via droplets in the air from the respiratory tract of infected individuals. Transmission occurs during the catarrhal stage and during the first 2 to 3 weeks of the paroxysmal phase.

Pertussis occurs most frequently and severely in young children. Adolescents and adults tend to experience much less severe symptoms, and sometimes the disease may not even be recognized as Pertussis. For reasons that are not fully understood, slightly more females than males are affected.

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

Acute Bronchitis is a common respiratory disease characterized by inflammation of the bronchi and bronchial tubes. Symptoms may include a persistent cough accompanied by abundant mucous discharge (sputum), fever, and/or back pain. Bronchitis is caused by the spread of an upper respiratory infection into the bronchi and may occur along with other diseases such as measles, pertussis, and/or diphtheria.


Peutz-Jeghers syndrome

PJS is characterized by the growth of multiple benign polyps called hamartomas on the mucous lining of the gastrointestinal system and spots of dark blue to dark brown skin freckling (melanocytic macules) around the mouth, eyes, nostrils, fingers, oral mucosa and anus (perianal). These melanocytic macules can appear as early as the first year of life and are present in most affected children under five years of age. They tend to fade away with age and might completely disappear in puberty or adulthood, although they tend to persist in the oral mucosa. Polyps also begin to grow within the first years of life, but associated symptoms typically arise between 10 to 30 years of age. Around half of patients with PJS have to undergo surgery by age 18 because of polyps-related complication. Polyps most often tend to develop in the small intestine (in the jejunum, specifically) but can also arise in the stomach and large intestine. Rarely, polyps can grow outside the gastrointestinal tract and affect the ureters, bladder, lungs, bronchi, and gallbladder. Gastrointestinal polyps can cause abdominal pain, vomiting, diarrhea, intestinal obstruction and rectal bleeding, which can lead to anemia. They can also provoke folding of the intestine into itself (intussusception), which can lead to severe abdominal pain and emergency surgery.

Peutz Jeghers syndrome is an autosomal dominant genetic condition caused by mutations in the STK11/LKB1 gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (de novo) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

Peutz Jeghers syndrome is a rare disorder that affects males and females in equal numbers and can occur in any racial or ethnic group. The birth prevalence of PJS is estimated to be between 1/50,000 and 1/200,000. Limited evidence shows that the disease might be more prevalent in certain countries such as the Netherlands and China. Women are at a higher risk of developing cancer compared to men, as PJS increases the likelihood of developing breast, ovarian, cervical, and uterine cancer.

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

A clinical diagnosis of Peutz Jeghers syndrome can be made when any one of the following criteria is present:


Pfeiffer syndrome

Pfeiffer syndrome is a rare genetic disorder characterized by premature fusion of certain skull bones (craniosynostosis) and broad and medially deviated thumbs and great toes. Most affected individuals also have differences to their midface (protruding eyes) and conductive hearing loss. Three forms of Pfeiffer syndrome are recognized, of which types II and III are the more serious.

Infants with Pfeiffer syndrome type I have craniosynostosis that causes the head to appear short and tall (turribrachycephaly). Additional features may include a high, full forehead; underdeveloped midfacial regions (midface hypoplasia); widely spaced eyes (ocular hypertelorism); an underdeveloped upper jaw (hypoplastic maxilla), with a prominent lower jaw; and dental abnormalities. Intelligence is usually normal. There is usually some degree of hearing loss, which is more commonly conductive rather than sensorineural.

Pfeiffer syndrome type I is associated with variants in FGFR1 and FGFR2. Pfeiffer syndrome type II and type III are associated with variants in FGFR2.

The incidence of all types of Pfeiffer syndrome is approximately 1/100,000.

Apert syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by distinctive malformations of the head that lead to distinctive facial features. In addition, the hands and/or feet may be webbed (syndactyly) and in some cases, intellectual disability may also be present. Babies born with Apert syndrome have fibrous joints between bones of the skull (sutures) that close prematurely (craniosynostosis). The pressure of continued brain growth distorts various bones of the skull and the face. The skull is forced into one of several characteristic shapes. Often the head appears abnormally pointed at the top (acrocephaly). The distortion of the skull plates creates changes in the facial bones leading to characteristic facial abnormalities, such as widely spaced eyes (ocular hypertelorism), abnormal protrusion of the eyes (exophthalmos), underdevelopment of midfacial regions (midface hypoplasia), and/or a narrow roof of the mouth (palate). Malformations of the hands and feet may include unusually broad thumbs and great toes, short fingers, and/or partial to complete fusion (syndactyly) of certain fingers and toes (digits). Most commonly, there is complete fusion of bones within the second to the fourth fingers and the presence of a single common nail (mitten-like syndactyly). Apert syndrome is an autosomal dominant genetic condition associated with variants in FGFR2. (For more information on this disorder, choose Apert as your search term in the Rare Disease Database.)

The diagnosis of Pfeiffer syndrome is based on clinical findings. Molecular genetic testing for FGFR1 and FGFR2 gene variants is available if the diagnosis is uncertain.


PHACE syndrome

Although researchers have been able to establish diagnostic criteria with characteristic or core symptoms, much about the disorder is not fully understood. Several factors including the relatively small number of identified cases, the lack of large clinical studies, and the possibility of multiple genes influencing the phenotype prevent physicians from developing a one size fits all description of PHACE and its prognosis. Therefore, it is important to note that every person is unique and that most affected individuals will not have all of the symptoms discussed below.

The exact cause of PHACE syndrome is unknown. It appears to occur randomly (sporadically) for no known reason. There have not been reports of the disorder occurring in multiple members of the same family.

PHACE syndrome affects more females than it does males, although researchers are not exactly sure why this is the case. It has been described affecting many different ethnic groups. The exact incidence or prevalence of the disorder is unknown. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population.

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

A diagnosis of PHACE syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. There are consensus-based diagnostic criteria that have been established by medical experts for PHACE syndrome. These were first published in 2009 (Garzon et al.) and updated in 2016 (Metry et al.). These diagnostic guidelines break down the symptoms of PHACE syndrome into major and minor criteria. A diagnosis is based on the presence of a hemangioma of the head or scalp that is greater than 5 centimeters in diameter (about 2 inches) that occurs along with one major or two minor criteria or the presence of a hemangioma of the neck, upper trunk or trunk and proximal upper extremity plus two major criteria.


2p21 microdeletion syndrome

Phelan-McDermid syndrome (PMS) is a rare genetic condition caused by a deletion or other structural change of the terminal end of chromosome 22 in the 22q13 region or a disease-causing (pathogenic) variant of the SHANK3 gene.

Most infants with PMS exhibit normal growth before birth (intrauterine growth) with normal growth after birth (postnatally). The first physical sign associated with PMS is neonatal hypotonia (low muscle tone) which is often accompanied by feeding difficulties, weak cry and poor head control. Children also experience a significant delay in reaching early developmental milestones, such as rolling over, sitting, crawling and walking; this delay is likely associated with low muscle tone. These are often the first noticeable symptoms that prompt families to start their diagnostic journey.

PMS is caused by the deletion or disruption of the segment of the long arm (q) of chromosome 22 that is identified as 22q13. Chromosomes are found in the nucleus of all body cells. They carry the genetic information for the growth and development of each individual. Pairs of human chromosomes include the autosomes, numbered from 1 to 22, and the sex chromosomes, X and Y. Females have two X chromosomes while males have one X and one Y chromosome. Each chromosome has a short arm designated as p and a long arm identified by the letter q. Chromosomes are further subdivided into numbered bands. Therefore, chromosome 22q13 refers to band 13 on the long arm (q) of chromosome 22.

Deletion of 22q13 was initially described in the medical literature in 1985. Since that time, increased understanding through scientific research, advances in genetic testing and advocacy have led to approximately 3,000 members in the Phelan-McDermid Syndrome Foundation as of 2022. Males and females are equally likely to be affected. Based on limited statistical analysis, the occurrence rate has been estimated to fall in the range of 2.5-10 per million births, although this is likely to be a gross underestimate. Due to the subtle appearance of the deletion of chromosome 22 and the relatively mild physical features of affected individuals, diagnosis of PMS is often difficult. Prior to the advent of CMA testing, over 30% of individuals with this deletion required two or more chromosome studies before the deletion was detected. It is likely that there are many older individuals who had normal chromosome studies at an earlier age but who actually carry this subtle chromosome abnormality or pathogenic variant of SHANK3. Unless these individuals are studied by CMA testing or NGS, their diagnosis will remain a mystery.

Autism spectrum disorders (ASD) refer to a wide range of conditions characterized by impaired social interaction and communication. Individuals with ASD may or may not have intellectual disability (ID). Genetic testing for ASD often consists of a CMA and/or a targeted gene panel that includes SHANK3. This testing will distinguish most cases of PMS from non-syndromic autism.

The diagnosis of PMS is based on genetic testing for the identification of a deletion or disruption of the chromosome region 22q13. The first tier of genetic testing for individuals with intellectual disability or developmental delay includes chromosomal microarray analysis (CMA) and next generation sequencing (NGS).


Phenylketonuria

Phenylketonuria (PKU) is an inborn error of metabolism that can be diagnosed during the first days of life with routine newborn screening. PKU is characterized by absence or deficiency of an enzyme called phenylalanine hydroxylase (PAH), responsible for processing the amino acid phenylalanine. Amino acids are the chemical building blocks of proteins and are essential for proper growth and development. With normal PAH activity, phenylalanine is converted to another amino acid, tyrosine. However, when PAH is absent or deficient, phenylalanine accumulates and is toxic to the brain. Without treatment, most people with PKU would develop severe intellectual disability. To prevent intellectual disability, treatment consists of a carefully controlled, phenylalanine-restricted diet beginning during the first days or weeks of life.

Infants with PKU typically appear normal at birth. With early screening and dietary treatment, affected individuals may never show symptoms of PKU. However, untreated newborns not diagnosed in the first days of life may be weak and feed poorly. Other symptoms may include vomiting, irritability and/or a red skin rash with small pimples. Developmental delay may be obvious at several months of age. The average IQ of untreated children is usually less than 50. Intellectual disability in PKU is a direct result of elevated levels of phenylalanine in the brain which causes the destruction of the fatty covering (myelin) of individual nerve fibers. It can also cause depression by reducing brain levels of dopamine and serotonin (neurotransmitters).

PKU is caused by changes (variants) in the PKU gene. More than 300 different disease-causing variants in the PKU gene have been identified. Because the different variants result in varying degrees of PAH enzyme activity, and therefore varying degrees of phenylalanine elevation in blood, the diet of each child must be adjusted to the individual’s specific phenylalanine tolerance.

The reported incidence of PKU from newborn screening programs ranges from one in 13,500 to 19,000 newborns in the United States. PKU affects people from most ethnic backgrounds, although it is rare in Americans of African descent and Jews of Ashkenazi ancestry.

Phenylalanine hydroxylase (PAH) deficiency is the term used to describe a disease spectrum. The most severe condition in the spectrum is classic PKU. Hyperphenylalaninemia is the term used to describe people who have phenylalanine levels on an unrestricted diet that are above normal but below 1,200 μmol/L (20 mg/dL). These people have a much lower risk for intellectual disability without treatment.

PKU can be diagnosed with routine newborn screening by measuring an elevated level of phenylalanine (concentrations above 1,200 μmol/L (20 mg/dL) on a blood spot. PKU can also be diagnosed with molecular genetic testing that shows two disease-causing variants in the PKU gene.