The cause of the disease is unknown. It was originally thought that the epidermal changes were secondary to profound malnutrition as a result of protein-losing enteropathy. Recent findings have called this hypothesis into question; specifically, the hair and nail changes may not improve with improved nutrition.

Other conditions consisting of multiple hamartomatous polyps of the digestive tract include Peutz-Jeghers syndrome, juvenile polyposis, and Cowden disease. Related polyposis conditions are familial adenomatous polyposis, attenuated familial adenomatous polyposis, Birt–Hogg–Dubé syndrome and MUTYH.

Cronkhite–Canada syndrome is a rare syndrome characterized by multiple polyps of the digestive tract. It is sporadic (i.e. it does not seem to be a hereditary disease), and it is currently considered acquired and idiopathic (i.e. cause remains unknown).

About two-thirds of patients are of Japanese descent and the male to female ratio is 2:1. It was characterized in 1955.

The prevalence rate has been estimated to be less than 1/1,000,000 worldwide. However, it is much more common in the French-Canadian population of the Saguenay and Lac-St-Jean regions of Quebec, Canada, where it has a frequency of about 1 in 2100 in live births, and a carrier rate of 1 in 23.

The prognosis is poor. Patients are usually wheelchair bound by their 20s and die by their 30s.

Research has revealed that a number of genetic disorders, not previously thought to be related, may indeed be related as to their root cause. Joubert syndrome is one such disease. It is a member of an emerging class of diseases called ciliopathies.

The underlying cause of the ciliopathies may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles which are present in many cellular types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases.

Currently recognized ciliopathies include Joubert syndrome, primary ciliary dyskinesia (also known as Kartagener Syndrome), Bardet-Biedl syndrome, polycystic kidney disease and polycystic liver disease, nephronophthisis, Alstrom syndrome, Meckel-Gruber syndrome and some forms of retinal degeneration.

Joubert syndrome type 2 is disproportionately frequent among people of Jewish descent.

Rare diseases are usually genetic and are therefore chronic. EURORDIS estimates that at least 80% of them have identified genetic origins. Other rare diseases are the result of infections and allergies or due to degenerative and proliferative causes.

Symptoms of some rare diseases may appear at birth or in childhood, whereas others only appear once adulthood is reached.

Research publications emphasize rare diseases that are chronic or incurable, although many short-term medical conditions are also rare diseases.

Swyer–James syndrome (SJS, also called Swyer–James–Macleod's syndrome) is a rare lung disorder found by English chest physician William Mathiseon Macleod, and (simultaneously) by physician Paul Robert Swyer and radiologist George James in the 1950s in Canada.

Swyer–James syndrome is a manifestation of postinfectious obliterative bronchiolitis. In SJS, the involved lung or portion of the lung does not grow normally and is slightly smaller than the opposite lung. The characteristic radiographic appearance is that of pulmonary hyperlucency, caused by overdistention of the alveoli in conjunction with diminished arterial flow. and has been linked to adenovirus type 21.

In appearance Swyer–James normally leaves shadowing in a CT scan in the upper lobar regions of one or (rarely) both lungs. Patients with the illness operate in much the same way as patients with mild bronchiectasis. As a result, the illness can go undiagnosed for some time. With current pharmaceutical developments, the prognosis is good for sufferers of the illness to lead normal and healthy lives.

In a sample of 19 children, a 1997 study found that 3 died before the age of 3, and 2 never learned to walk. The children had various levels of delayed development with developmental quotients from 60 to 85.

Prevalence (number of people living with a disease at a given moment), rather than incidence (number of new diagnoses in a given year), is used to describe the impact of rare diseases. The Global Genes Project estimates some 300 million people worldwide are affected by a rare disease.

The European Organization for Rare Diseases (EURORDIS) estimates that as many as 5,000 to 7,000 distinct rare diseases exist, and as much as 6% to 8% of the population of the European Union is affected by one. Only about 400 rare diseases have therapies and about 80% have a genetic component according to Rare Genomics Institute.

Rare diseases can vary in prevalence between populations, so a disease that is rare in some populations may be common in others. This is especially true of genetic diseases and infectious diseases. An example is cystic fibrosis, a genetic disease: it is rare in most parts of Asia but relatively common in Europe and in populations of European descent. In smaller communities, the founder effect can result in a disease that is very rare worldwide being prevalent within the smaller community. Many infectious diseases are prevalent in a given geographic area but rare everywhere else. Other diseases, such as many rare forms of cancer, have no apparent pattern of distribution but are simply rare. The classification of other conditions depends in part on the population being studied: All forms of cancer in children are generally considered rare, because so few children develop cancer, but the same cancer in adults may be more common.

About 40 rare diseases have a far higher prevalence in Finland; these are known collectively as Finnish heritage disease.

Leber's congenital amaurosis (LCA) is a rare inherited eye disease that appears at birth or in the first few months of life.

One form of LCA was successfully treated with gene therapy in 2008.

It affects about 1 in 40,000 newborns. LCA was first described by Theodor Leber in the 19th century. It should not be confused with Leber's hereditary optic neuropathy, which is a different disease also described by Theodor Leber.

X-linked myopathy with excessive autophagy (XMEA) is a rare childhood onset disease characterized by slow progressive vacuolation and atrophy of skeletal muscle. There is no known cardiac or intellectual involvement.

Lipoprotein lipase deficiency (also known as "familial chylomicronemia syndrome", "chylomicronemia", "chylomicronemia syndrome" and "hyperlipoproteinemia type Ia") is a rare autosomal recessive lipid disorder caused by a mutation in the gene which codes lipoprotein lipase. As a result, afflicted individuals lack the ability to produce lipoprotein lipase enzymes necessary for effective breakdown of triglycerides.

Genetic tests and related research are currently being performed at Centogene AG in Rostock, Germany; John and Marcia Carver Nonprofit Genetic Testing Laboratory in Iowa City, IA; GENESIS Center for Medical Genetics in Poznan, Poland; Miraca Genetics Laboratories in Houston, TX; Asper Biotech in Tartu, Estonia; CGC Genetics in Porto, Portugal; CEN4GEN Institute for Genomics and Molecular Diagnostics in Edmonton, Canada; and Reference Laboratory Genetics - Barcelona, Spain.

North American Indian childhood cirrhosis (NAIC) is a disease in humans that can affect Ojibway-Cree children in northwestern Quebec, Canada. The disease is due to an autosomal recessive abnormality of the "CIRH1A" gene, which codes for cirhin.

NAIC is a ribosomopathy. An R565W mutation of "CIRH1A" leads to partial impairment of cirhin interaction with NOL11.

Initial transient neonatal jaundice advances over time to biliary cirrhosis with severe liver fibrosis. Eventually, liver failure occurs, and requires liver transplantation.

X-linked dystonia parkinsonism is thought to result from a mutation of the TAF1 (TATA-binding protein-associated factor 1) gene at Xq13.1. It has an X-linked, recessive pattern of inheritance. Genetic analysis suggests that the responsible mutation was introduced into the Ilongo ethnic group of the Panay Island over 2000 years ago.

This disorder is inherited in a recessive X linked fashion. As a result males are much more commonly affected than females.

It is due to a mutation in VMA21 gene - the human homolog of the yeast Vma21p protein. This gene is located on the long arm of chromosome X (Xq28). It is an essential assembly chaperone of the vacuolar ATPase - the principal mammalian proton pump complex. Mutations in this gene increase lysosomal pH. This in turn reduces lysosomal degradative ability and blocks autophagy.

The disorder affects about 1 out of 1,000,000 people, however epidemiological data are limited and there are regional differences due to cofounder effect (e.g. in Canada) or intermarriage.

X-linked dystonia parkinsonism (XDP), also known as Lubag Syndrome or X-linked Dystonia of Panay, is a rare x-linked progressive movement disorder with high penetrance found almost exclusively in males from the Panay, Philippines. It is characterized by dystonic movements first typically occurring in the 3rd and 4th decade of life. The dystonic movements often either coexist or develop into parkinsonism within 10 years of disease onset.

A 2014 review stated that 25% and 30% of identified suffers die in the first two decades of life, mainly due to lack of treatment.

Sertoli cell-only syndrome (a.k.a. Del Castillo syndrome and germ cell aplasia ) is a disorder characterized by male sterility without sexual abnormality. It describes a condition of the testes in which only Sertoli cells line the seminiferous tubules.

Hyperpigmentation can be caused by sun damage, inflammation, or other skin injuries, including those related to acne vulgaris. People with darker skin tones are more prone to hyperpigmentation, especially with excess sun exposure.

Many forms of hyperpigmentation are caused by an excess production of melanin. Hyperpigmentation can be diffuse or focal, affecting such areas as the face and the back of the hands. Melanin is produced by melanocytes at the lower layer of the epidermis. Melanin is a class of pigment responsible for producing colour in the body in places such as the eyes, skin, and hair. As the body ages, melanocyte distribution becomes less diffuse and its regulation less controlled by the body. UV light stimulates melanocyte activity, and where concentration of the cells is greater, hyperpigmentation occurs. Another form of hyperpigmentation is post inflammatory hyperpigmentation. These are dark and discoloured spots that appear on the skin following acne that has healed.

Hyperpigmentation is associated with a number of diseases or conditions, including the following:

- Addison's disease and other sources of adrenal insufficiency, in which hormones that stimulate melanin synthesis, such as melanocyte-stimulating hormone (MSH), are frequently elevated.

- Cushing's disease or other excessive adrenocorticotropic hormone (ACTH) production, because MSH production is a byproduct of ACTH synthesis from proopiomelanocortin (POMC).

- Acanthosis nigricans—hyperpigmentation of intertriginous areas associated with insulin resistance.

- Melasma, also known as "chloasma"—patchy hyperpigmentation

- Acne scarring from post-inflammatary hyperpigmentation

- Linea nigra—a hyperpigmented line found on the abdomen during pregnancy.

- Peutz-Jeghers syndrome—an autosomal dominant disorder characterized by hyperpigmented macules on the lips and oral mucosa and gastrointestinal polyps.

- Exposure to certain chemicals such as salicylic acid, bleomycin, and cisplatin.

- Smoker's melanosis

- Coeliac disease

- Cronkite-Canada syndrome

- Porphyria

- Tinea fungal infections such as ringworm

- Haemochromatosis—a common but debilitating genetic disorder characterized by the chronic accumulation of iron in the body.

- Mercury poisoning—particularly cases of cutaneous exposure resulting from the topical application of mercurial ointments or skin-whitening creams.

- Aromatase deficiency

- Nelson's syndrome

- Grave's disease

- As a result of tinea cruris.

Hyperpigmentation can sometimes be induced by dermatological laser procedures.

Epidemiologically speaking, nephronophthisis, occurs equally in both sexes, and has an estimate 9 in about 8 million rate in individuals. Nephronophthisis is the leading monogenic cause of end-stage renal disease.

3-Methylglutaconic aciduria, seems to be most prevalent amongst the Jewish population of Iraq. However, a high concentration of one type is found in the Saguenay-Lac-Saint-Jean region of Canada. This tends to show that the disease is more frequent in insular areas where there is more chance that both parents be carriers, a higher birth rate, and higher number of congenital marriages. As all types of 3-Methylglutaconic aciduria are known to be genetic diseases and show a recessive pattern it is likely that congenital marriages where both partners are carriers increase the chance to have a baby with the condition.

Sucrose intolerance, also called sucrase-isomaltase deficiency, congenital sucrase-isomaltase deficiency (CSID), or genetic sucrase-isomaltase deficiency (GSID), is the condition in which sucrase-isomaltase, an enzyme needed for proper metabolism of sucrose (sugar) and starch (i.e., grains and rice), is not produced or the enzyme produced is either partially functional or non-functional in the small intestine. All GSID patients lack fully functional sucrase, while the isomaltase activity can vary from minimal functionality to almost normal activity. The presence of residual isomaltase activity may explain why some GSID patients are better able to tolerate starch in their diet than others with GSID.

The highest prevalence rates are seen in the Inuit populations of Greenland (5–10%), Alaska (3–7%) and Canada (about 3%). European descent prevalence ranges from 0.2% to 0.05%. There is a lower prevalence reported in African Americans and Hispanics compared to Caucasians.

The prevalence of diverticulosis progressively increases with age. Approximately 50% of people over the age of 60 and 70% of people over the age of 80 have diverticulosis. This disease is common in the U.S., Britain, Australia, Canada, and is uncommon in Asia and Africa. Large-mouth diverticula are associated with scleroderma. Diverticular disease is more common in collagen disorders such as Ehlers Danlos Syndrome.