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Interstitial lung disease (ILD) comprises a heterogeneous group of rare diseases affecting the distal part of the lung and characterized by a progressive remodeling of the alveolar interstitium. The manifestations form a spectrum ranging from idiopathic interstitial pneumonia (IIP) or pneumonitis to the more severe idiopathic pulmonary fibrosis (IPF). IPF is associated with an increased risk of developing lung cancer, which occurs in a subset of patients with ILD. Clinical features of ILD include dyspnea, clubbing of the fingers, and restrictive lung capacity. Imaging typically shows ground glass opacities and inter- and intraseptal thickening, while histologic studies usually show a pattern consistent with 'usual interstitial pneumonia' (UIP) (review by Gross and Hunninghake, 2001; summary by Legendre et al., 2020). Idiopathic pulmonary fibrosis is one of a family of idiopathic pneumonias sharing clinical features of shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees in inflammation, fibrosis, or both on lung biopsy. In some cases, the disorder can be rapidly progressive and characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. Although older studies included several forms of interstitial pneumonia under the term 'idiopathic pulmonary fibrosis,' the clinical label of 'idiopathic pulmonary fibrosis' should be reserved for patients with a specific form of fibrosing interstitial pneumonia referred to as usual interstitial pneumonia (Gross and Hunninghake, 2001). It is estimated that 0.5 to 2.2% of cases of idiopathic pulmonary fibrosis are familial (Marshall et al., 2000). Gross and Hunninghake (2001) reviewed idiopathic pulmonary fibrosis, emphasizing definition, pathogenesis, diagnosis, natural history, and therapy. Antoniou et al. (2004) provided a 'top ten list' of references pertaining to etiopathogenesis, prognosis, diagnosis, therapy, and other aspects of idiopathic pulmonary fibrosis. For a discussion of genetic heterogeneity of ILD, see ILD1 (619611). Pulmonary fibrosis can also be a feature in patients with mutations in the TERT (187270) or the TERC (602322) gene; see PFBMFT1 (614742) and PFBMFT2 (614743). Some patients with surfactant protein C deficiency (610913) who survive to adulthood manifest features of pulmonary fibrosis. [from OMIM]

17 alpha(a)-hydroxylase/17,20-lyase deficiency is a condition that affects the function of certain hormone-producing glands called the gonads (ovaries in females and testes in males) and the adrenal glands. The gonads direct sexual development before birth and during puberty and are important for reproduction. The adrenal glands, which are located on top of the kidneys, regulate the production of certain hormones, including those that control salt levels in the body. People with 17a-hydroxylase/17,20-lyase deficiency have an imbalance of many of the hormones that are made in these glands. 17a-hydroxylase/17,20-lyase deficiency is one of a group of disorders, known as congenital adrenal hyperplasias, that impair hormone production and disrupt sexual development and maturation.

Hormone imbalances lead to the characteristic signs and symptoms of 17a-hydroxylase/17,20-lyase deficiency, which include high blood pressure (hypertension), low levels of potassium in the blood (hypokalemia), and abnormal sexual development. The severity of the features varies. Two forms of the condition are recognized: complete 17a-hydroxylase/17,20-lyase deficiency, which is more severe, and partial 17a-hydroxylase/17,20-lyase deficiency, which is typically less so.

Males and females are affected by disruptions to sexual development differently. Females (who have two X chromosomes) with 17a-hydroxylase/17,20-lyase deficiency are born with normal external female genitalia; however, the internal reproductive organs, including the uterus and ovaries, may be underdeveloped. Women with complete 17a-hydroxylase/17,20-lyase deficiency do not develop secondary sex characteristics, such as breasts and pubic hair, and do not menstruate (amenorrhea). Women with partial 17a-hydroxylase/17,20-lyase deficiency may develop some secondary sex characteristics; menstruation is typically irregular or absent. Either form of the disorder results in an inability to conceive a baby (infertility).

In affected individuals who are chromosomally male (having an X and a Y chromosome), problems with sexual development lead to abnormalities of the external genitalia. The most severely affected are born with characteristically female external genitalia and are generally raised as females. However, because they do not have female internal reproductive organs, these individuals have amenorrhea and do not develop female secondary sex characteristics. These individuals have testes, but they are abnormally located in the abdomen (undescended). Sometimes, complete 17a-hydroxylase/17,20-lyase deficiency leads to external genitalia that do not look clearly male or clearly female. Males with partial 17a-hydroxylase/17,20-lyase deficiency may have a small penis (micropenis), the opening of the urethra on the underside of the penis (hypospadias), or a scrotum divided into two lobes (bifid scrotum). Males with either complete or partial 17a-hydroxylase/17,20-lyase deficiency are also infertile. [from MedlinePlus Genetics]

Li-Fraumeni syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults.

A very similar condition called Li-Fraumeni-like syndrome shares many of the features of classic Li-Fraumeni syndrome. Both conditions significantly increase the chances of developing multiple cancers beginning in childhood; however, the pattern of specific cancers seen in affected family members is different.

The cancers most often associated with Li-Fraumeni syndrome include breast cancer, a form of bone cancer called osteosarcoma, and cancers of soft tissues (such as muscle) called soft tissue sarcomas. Other cancers commonly seen in this syndrome include brain tumors, cancers of blood-forming tissues (leukemias), and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands (small hormone-producing glands on top of each kidney). Several other types of cancer also occur more frequently in people with Li-Fraumeni syndrome. [from MedlinePlus Genetics]

Preeclampsia, which along with chronic hypertension and gestational hypertension comprise the hypertensive disorders of pregnancy, is characterized by new hypertension (blood pressure 140/90 or greater) presenting after 20 weeks' gestation with clinically relevant proteinuria. Preeclampsia is 1 of the top 4 causes of maternal mortality and morbidity worldwide (summary by Payne et al., 2011). Preeclampsia is otherwise known as gestational proteinuric hypertension (Davey and MacGillivray, 1988). A high proportion of patients with preeclampsia have glomerular endotheliosis, the unique histopathologic feature of the condition (Fisher et al., 1981). A distinct form of severe preeclampsia is characterized by hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) (Brown et al., 2000). Genetic Heterogeneity of Preeclampsia/Eclampsia Susceptibility loci for preeclampsia/eclampsia include PEE1 on chromosome 2p13, PEE2 (609402) on chromosome 2p25, and PEE3 (609403) on chromosome 9p13. PEE4 (609404) is caused by mutation in the STOX1 gene (609397) on chromosome 10q22. PEE5 (614595) is caused by mutation in the CORIN gene (605236) on chromosome 4p12. An association with PEE has been found with the EPHX1 gene (132810) on chromosome 1q. [from OMIM]

Triple A syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima. Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that carries food from the throat to the stomach. It can lead to severe feeding difficulties and low blood glucose (hypoglycemia). Addison disease, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of Addison disease include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of triple A syndrome is a reduced or absent ability to secrete tears (alacrima). Most people with triple A syndrome have all three of these features, although some have only two.

Many of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. This part of the nervous system controls involuntary body processes such as digestion, blood pressure, and body temperature. People with triple A syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia).

People with this condition may have other neurological abnormalities, such as developmental delay, intellectual disability, speech problems (dysarthria), and a small head size (microcephaly). In addition, affected individuals commonly experience muscle weakness, movement problems, and nerve abnormalities in their extremities (peripheral neuropathy). Some develop optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain. Many of the neurological symptoms of triple A syndrome worsen over time.

People with triple A syndrome frequently develop a thickening of the outer layer of skin (hyperkeratosis) on the palms of their hands and the soles of their feet. Other skin abnormalities may also be present in people with this condition.

Alacrima is usually the first noticeable sign of triple A syndrome, as it becomes apparent early in life that affected children produce little or no tears while crying. They develop Addison disease and achalasia during childhood or adolescence, and most of the neurologic features of triple A syndrome begin during adulthood. The signs and symptoms of this condition vary among affected individuals, even among members of the same family. [from MedlinePlus Genetics]

Increased top to bottom height of vertebral bodies. [from HPO]

Life expectancy of affected individuals depends on the severity of the malformations and whether or not surgical intervention can improve associated health problems, such as breathing and feeding problems caused by the facial clefts.

Frontonasal dysplasia is a condition that results from abnormal development of the head and face before birth. People with frontonasal dysplasia have at least two of the following features: widely spaced eyes (ocular hypertelorism); a broad nose; a slit (cleft) in one or both sides of the nose; no nasal tip; a central cleft involving the nose, upper lip, or roof of the mouth (palate); incomplete formation of the front of the skull with skin covering the head where bone should be (anterior cranium bifidum occultum); or a widow's peak hairline.

Other features of frontonasal dysplasia can include additional facial malformations, absence or malformation of the tissue that connects the left and right halves of the brain (the corpus callosum), and intellectual disability.

There are at least three types of frontonasal dysplasia that are distinguished by their genetic causes and their signs and symptoms. In addition to the features previously described, each type of frontonasal dysplasia is associated with other distinctive features. Individuals with frontonasal dysplasia type 1 typically have abnormalities of the nose, a long area between the nose and upper lip (philtrum), and droopy upper eyelids (ptosis). Individuals with frontonasal dysplasia type 2 can have hair loss (alopecia) and an enlarged opening in the two bones that make up much of the top and sides of the skull (enlarged parietal foramina). Males with this form of the condition often have genital abnormalities. Features of frontonasal dysplasia type 3 include eyes that are missing (anophthalmia) or very small (microphthalmia) and low-set ears that are rotated backward. Frontonasal dysplasia type 3 is typically associated with the most severe facial abnormalities, but the severity of the condition varies widely, even among individuals with the same type. [from MedlinePlus Genetics]

Limitation of the extension of the hip, i.e., decreased ability to straighten the hip joint and thereby increase the angle between torso and thigh; moving the thigh or top of the pelvis backward. [from HPO]

Pyramidal skinfold extending from the base to the top of the nails is a rare and distinctive anomaly seen in popliteal pterygia syndrome. [from HPO]

In some affected individuals, the patches have characteristics of both lichen and macular amyloidosis. These cases are called biphasic amyloidosis.

Nodular amyloidosis is characterized by firm, raised bumps (nodules) that are pink, red, or brown. These nodules often occur on the face, torso, limbs, or genitals and are typically not itchy.

In macular amyloidosis, the patches are flat and dark brown. The coloring can have a lacy (reticulated) or rippled appearance, although it is often uniform. Macular amyloidosis patches are most commonly found on the upper back, but they can also occur on other parts of the torso or on the limbs. These patches are mildly itchy.

Lichen amyloidosis is characterized by severely itchy patches of thickened skin with multiple small bumps. The patches are scaly and reddish brown in color. These patches usually occur on the shins but can also occur on the forearms, other parts of the legs, and elsewhere on the body.

In all forms of PLCA, the abnormal patches of skin usually arise in mid-adulthood. They can remain for months to years and may recur after disappearing, either at the same location or elsewhere. Very rarely, nodular amyloidosis progresses to a life-threatening condition called systemic amyloidosis, in which amyloid deposits accumulate in tissues and organs throughout the body.

Primary localized cutaneous amyloidosis (PLCA) is a condition in which clumps of abnormal proteins called amyloids build up in the skin, specifically in the wave-like projections (dermal papillae) between the top two layers of skin (the dermis and the epidermis). The primary feature of PLCA is patches of skin with abnormal texture or color. The appearance of these patches defines three forms of the condition: lichen amyloidosis, macular amyloidosis, and nodular amyloidosis. [from MedlinePlus Genetics]

Preeclampsia, which along with chronic hypertension and gestational hypertension comprise the hypertensive disorders of pregnancy, is characterized by new hypertension (blood pressure 140/90 or greater) presenting after 20 weeks' gestation with clinically relevant proteinuria. Preeclampsia is 1 of the top 4 causes of maternal mortality and morbidity worldwide (summary by Payne et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of preeclampsia/eclampsia, see PEE1 (189800). [from OMIM]

The odontoid process, or dens, is a bony projection from the axis (C2) upward into the ring of the atlas (C1) at the top of the spine. During embryogenesis, the body of the odontoid derives from the centrum of the atlas and separates from the atlas, fusing with the superior portion of the axis. If the odontoid is hypoplastic or absent, the attachments for the apical and alar ligaments are missing, allowing for excessive rotation of the atlas, craniocervical instability, and possibly cord compression (summary by Stevens et al., 2009). [from OMIM]

Elevated ratio between the upper and the lower segment of the body, where the lower segment is defined as the length between the top of pubic symphysis to floor, and the upper segment is defined as the top of head to top of pubic symphysis. [from HPO]

Decreased ratio between the upper and the lower segment of the body, where the lower segment is defined as the length between the top of pubic symphysis to floor, and the upper segment is defined as the top of head to top of pubic symphysis. Consider the term Disproportionate tall stature (HP:0001519) if tall stature is also present. [from HPO]

There are two forms of enlarged parietal foramina, called type 1 and type 2, which differ in their genetic cause.

The enlarged parietal foramina are soft to the touch due to the lack of bone at those areas of the skull. People with enlarged parietal foramina usually do not have any related health problems; however, scalp defects, seizures, and structural brain abnormalities have been noted in a small percentage of affected people. Pressure applied to the openings can lead to severe headaches, and individuals with this condition have an increased risk of brain damage or skull fractures if any trauma is experienced in the area of the openings.

Enlarged parietal foramina is an inherited condition of impaired skull development. It is characterized by enlarged openings (foramina) in the parietal bones, which are the two bones that form the top and sides of the skull. This condition is due to incomplete bone formation (ossification) within the parietal bones. The openings are symmetrical and circular in shape, ranging in size from a few millimeters to several centimeters wide. Parietal foramina are a normal feature of fetal development, but typically they close before the baby is born, usually by the fifth month of pregnancy. However, in people with this condition, the parietal foramina remain open throughout life. [from MedlinePlus Genetics]

An aldosterone-producing adenoma is a noncancerous (benign) tumor that develops in an adrenal gland, which is a small hormone-producing gland located on top of each kidney. In most cases, individuals develop a single tumor in one of the adrenal glands. The adrenal tumor produces too much of the hormone aldosterone, which is a condition known as primary hyperaldosteronism. Aldosterone helps regulate the body's fluid levels and blood pressure by controlling the amount of salt retained by the kidneys. Excess aldosterone causes the kidneys to retain more salt than normal, which increases the body's fluid levels and blood pressure. People with an aldosterone-producing adenoma may develop severe high blood pressure (hypertension), and they have an increased risk of heart attack, stroke, or an irregular heart beat (atrial fibrillation). [from MedlinePlus Genetics]

Autoimmune problems affecting non-endocrine tissues can lead to a variety of additional signs and symptoms in people with APECED. These features occur more often in North American populations than in European populations. Rashes that resemble hives (urticarial eruptions) are common and often occur in infancy and early childhood. Other early signs and symptoms may include thin enamel on the teeth (enamel hypoplasia) and chronic diarrhea or constipation associated with difficulty in absorbing nutrients from food. Additional features that occur in people with APECED, many of which can lead to permanent organ and tissue damage if left untreated, include stomach irritation (gastritis), liver inflammation (hepatitis), lung irritation (pneumonitis), dry mouth and dry eyes (Sjogren-like syndrome), inflammation of the eyes (keratitis), kidney problems (nephritis), vitamin B12 deficiency, hair loss (alopecia), loss of skin color in blotches (vitiligo), high blood pressure (hypertension), or a small (atrophic) or absent spleen (asplenia).

Damage to the small hormone-producing glands on top of each kidney (adrenal glands) results in a third major feature of APECED, adrenal gland insufficiency (autoimmune Addison disease). Reduced hormone production by the adrenal glands leads to signs and symptoms that can include fatigue, muscle weakness, loss of appetite, weight loss, low blood pressure, and changes in skin coloring. Other endocrine problems that can occur in APECED include type 1 diabetes resulting from impaired production of the hormone insulin; a shortage of growth hormone leading to short stature; problems affecting the internal reproductive organs (ovaries or testes) that can cause inability to conceive children (infertility); and dysfunction of the thyroid gland (a butterfly-shaped tissue in the lower neck), which can result in many symptoms including weight gain and fatigue.

Other features of APECED result from the body's immune system attacking the network of hormone-producing glands (the endocrine system). The second characteristic feature of the disorder is hypoparathyroidism, which is a malfunction of the parathyroid glands. These glands secrete a hormone that regulates the body's use of calcium and phosphorus. Damage to the parathyroid glands leads to reduced parathyroid hormone production (hypoparathyroidism). Hypoparathyroidism can cause a tingling sensation in the lips, fingers, and toes; muscle pain and cramping; weakness; and fatigue. Serious effects of hypoparathyroidism, such spasms of the voicebox (larynx) leading to breathing problems and seizures, can be life-threatening.

CMC is a tendency to develop infections of the skin, the nails, and the moist lining of body cavities (mucous membranes) caused by a type of fungus called Candida. These infections, which are commonly known as yeast infections, are chronic, which means they recur and can last a long time. CMC is usually the first of the three characteristic features of APECED to become apparent in people with this disorder. Almost all affected individuals develop infections of the oral cavity (known as thrush). Infections of the tube that carries food from the mouth to the stomach (the esophagus) are also common, while the skin and nails are affected less often. In women, vaginal infections frequently occur.

In most cases, the signs and symptoms of APECED begin in childhood or adolescence. This condition commonly involves three characteristic features: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal gland insufficiency. Affected individuals typically have at least two of these features, and many have all three.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inherited condition that affects many of the body's organs. It is one of many autoimmune diseases, which are disorders that occur when the immune system malfunctions and attacks the body's own tissues and organs by mistake. [from MedlinePlus Genetics]

21-hydroxylase deficiency is an inherited disorder that affects the adrenal glands. The adrenal glands are located on top of the kidneys and produce a variety of hormones that regulate many essential functions in the body. In people with 21-hydroxylase deficiency, the adrenal glands produce excess androgens, which are male sex hormones.

There are three types of 21-hydroxylase deficiency. Two types are classic forms, known as the salt-wasting and simple virilizing types. The third type is called the non-classic type. The salt-wasting type is the most severe, the simple virilizing type is less severe, and the non-classic type is the least severe form.

Males and females with either classic form of 21-hydroxylase deficiency tend to have an early growth spurt, but their final adult height is usually shorter than others in their family. Additionally, affected individuals may have a reduced ability to have biological children (decreased fertility). Females may also develop excessive body hair growth (hirsutism), male pattern baldness, and irregular menstruation.

Approximately 75 percent of individuals with classic 21-hydroxylase deficiency have the salt-wasting type. Hormone production is extremely low in this form of the disorder. Affected individuals lose large amounts of sodium in their urine, which can be life-threatening in early infancy. Babies with the salt-wasting type can experience poor feeding, weight loss, dehydration, and vomiting. Individuals with the simple virilizing form do not experience salt loss.

In both the salt-wasting and simple virilizing forms of this disorder, females typically have external genitalia that do not look clearly male or female. Males usually have male-typical genitalia but the testes may be small.

Females with the non-classic type of 21-hydroxylase deficiency have female-typical genitalia. As affected females get older, they may experience hirsutism, male pattern baldness, irregular menstruation, and decreased fertility. Males with the non-classic type may have early beard growth and small testes. Some individuals with this type of 21-hydroxylase deficiency have no symptoms of the disorder. [from MedlinePlus Genetics]

An abnormality of head shape characterized by the presence of a short, wide head as well as a pointy or conical form of the top of the head owing to premature closure of the coronal and lambdoid sutures. [from HPO]

A name applied to several itchy skin eruptions of unknown cause. The characteristic course is the formation of a dome-shaped papule with a small transient vesicle on top, followed by crusting over or lichenification. (From Dorland, 27th ed) [from MONDO]