For unknown reasons, children born with FOP have deformed big toes, possibly missing a joint or simply presenting with a notable lump at the minor joint. The first "flare-up" that leads to the formation of FOP bones usually occurs before the age of 10. The bone growth progresses from the top downward, just as bones grow in fetuses. A child with FOP will typically develop bones starting at the neck, then on the shoulders, arms, chest area and finally on the feet.

Specifically, ossification is typically first seen in the dorsal, axial, cranial and proximal regions of the body. Later the disease progresses in the ventral, appendicular, caudal and distal regions of the body. However, it does not necessarily occur in this order due to injury-caused flare-ups. Often, the tumor-like lumps that characterize the disease appear suddenly. This condition causes loss of mobility to affected joints, including inability to fully open the mouth limiting speech and eating. Extra bone formation around the rib cage restricts the expansion of lungs and diaphragm causing breathing complications.

Since the disease is so rare, the symptoms are often misdiagnosed as cancer or fibrosis. This leads physicians to order biopsies, which can exacerbate the growth of these lumps. However, those born with FOP tend to have malformed toes or thumbs which help distinguish this disorder from other skeletal problems.

The median age of survival is 40 years with proper management. However, delayed diagnosis, trauma and infections can decrease life expectancy.

Opsismodysplasia can be characterized by a delay in bone maturation, which refers to "bone aging", an expected sequence of developmental changes in the skeleton corresponding to the chronological age of a person. Factors such as gender and ethnicity also play a role in bone age assessment. The only indicator of physical development that can be applied from birth through mature adulthood is bone age. Specifically, the age and maturity of bone can be determined by its state of ossification, the age-related process whereby certain cartilaginous and soft tissue structures are transformed into bone. The condition of epiphyseal plates (growth plates) at the ends of the long bones (which includes those of the arms, hands, legs and feet) is another measurement of bone age. The evaluation of both ossification and the state of growth plates in children is often reached through radiography (X-rays) of the carpals (bones of the hand and wrist). In opsismodysplasia, the process of ossification in long bones can be disrupted by a failure of ossification centers (a center of organization in long bones, where cartilage cells designated to await and undergo ossification gather and align in rows) to form. This was observed in a 16-month-old boy with the disorder, who had no apparent ossification centers in the carpals (bones of the hand and wrist) or tarsals (bones of the foot). This was associated with an absence of ossification in these bones, as well as disfigurement of the hands and feet at age two. The boy also had no ossification occurring in the lower femur (thigh bone) and upper tibia (the shin bone).

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare connective tissue disease. The disease is caused by a mutation of the body's repair mechanism, which causes fibrous tissue (including muscle, tendon, and ligament) to be ossified spontaneously or when damaged. In many cases, injuries can cause joints to become permanently frozen in place. Surgical removal of the extra bone growths has been shown to cause the body to "repair" the affected area with even more bone.

Opsismodysplasia is a type of skeletal dysplasia (a bone disease that interferes with bone development) first described by Zonana and associates in 1977, and designated under its current name by Maroteaux (1984). Derived from the Greek "opsismos" ("late"), the name "opsismodysplasia" describes a delay in bone maturation. In addition to this delay, the disorder is characterized by (short or undersized bones), particularly of the hands and feet, delay of ossification (bone cell formation), platyspondyly (flattened vertebrae), irregular metaphyses, an array of facial aberrations and respiratory distress related to chronic infection. Opsismodysplasia is congenital, being apparent at birth. It has a variable mortality, with some affected individuals living to adulthood. The disorder is rare, with an incidence of less than 1 per 1,000,000 worldwide. It is inherited in an autosomal recessive pattern, which means the defective (mutated) gene that causes the disorder is located on an autosome, and the disorder occurs when two copies of this defective gene are inherited. No specific gene has been found to be associated with the disorder. It is similar to spondylometaphyseal dysplasia, Sedaghatian type.

The clinical presentation is variable but includes

- developmental and growth delay

- athletic muscular built

- skeletal anomalies

- joint stiffness

- characteristic facial appearance

- deafness

- variable cognitive deficits

- tracheal stenosis

- aortic stenosis

- pyloric stenosis

The facial abnormalities include:

- blepharophimosis (an abnormally narrow gap between the upper and lower eyelids)

- maxillary hypoplasia (underdevelopment of the upper jaw)

- prognathism (prominent lower jaw)

The skeletal abnormalities include:

- short stature

- square body shape

- broad ribs

- iliac hypoplasia

- brachydactyly

- flattened vertebrae

- thickened calvaria

Congenital heart disease and undescended testes have also been reported in association with this syndrome.

The following are symptoms characteristic with individuals having the disorder. Individuals may display some, most, or all of these symptoms throughout the course of their life, though symptoms may vary with each patient.

- Abnormal hair (coarse, thick, brittle)

- Calvarial hypomineralization (soft skull)

- Y-shaped cataracts by 1–2 years of age

- Skeletal defects

- Hypertelorism (wide-set eyes)

- Facial dysmorphisms

- Late-closing fontanels

- Abnormal accumulation of proteins in the endoplasmic reticulum

- Scoliosis

- Broad forehead, nose

- Missing, small teeth or abnormal teeth positioning

- Poor skull calcification

- Flat foot

- Motor delay

- Abnormal vertebrae

- Prominent forehead and brow

- High nose bridge

- Capillary hemangioma

- Delayed tooth eruption

- Long upper lip groove

- Large mouth

- High arched palate

- Narrow hips and rib cage

- Thin lips

- Narrow and sloping shoulders

- Hyperpigmentation

- Hyperextensible joints

Onset of the disease is in neonatal development and infancy, and symptoms tend to become evident soon after birth.

Cleidocranial dysostosis is a general skeletal condition so named from the collarbone (cleido-) and cranium deformities which people with it often have.

People with the condition usually present with a painless swelling in the area of the clavicles at 2–3 years of age. Common features are:

- Clavicles (collarbones) can be partly missing leaving only the medial part of the bone. In 10% cases, they are completely missing. If the collarbones are completely missing or reduced to small vestiges, this allows hypermobility of the shoulders including ability to touch the shoulders together in front of the chest. The defect is bilateral 80% of the time. Partial collarbones may cause nerve damage symptoms and therefore have to be removed by surgery.

- The mandible is prognathic due to hypoplasia of maxilla (micrognathism) and other facial bones.

- A soft spot or larger soft area in the top of the head where the fontanelle failed to close, or the fontanelle closes late.

- Bones and joints are underdeveloped. People are shorter and their frames are smaller than their siblings who do not have the condition.

- The permanent teeth include supernumerary teeth. Unless these supernumeraries are removed they will crowd the adult teeth in what already may be an underdeveloped jaw. If so, the supernumeraries will probably need to be removed to make space for the adult teeth. Up to 13 supernumarary teeth have been observed. Teeth may also be displaced. Cementum formation may be deficient.

- Failure of eruption of permanent teeth.

- Bossing (bulging) of the forehead.

- Open skull sutures, large fontanelles.

- Hypertelorism.

- Delayed ossification of bones forming symphysis pubis, producing a widened symphysis.

- Coxa vara can occur, limiting abduction and causing Trendelenburg gait.

- Short middle fifth phalanges, sometimes causing short and wide fingers.

- Vertebral abnormalities.

- On rare occasions, brachial plexus irritation can occur.

- Scoliosis, spina bifida and syringomyelia have also been described.

Other features are: parietal bossing, basilar invagination (atlantoaxial impaction), persistent metopic suture, abnormal ear structures with hearing loss, supernumerary ribs, hemivertebrae with spondylosis, small and high scapulae, hypoplasia of illiac bones, absence of the pubic bone, short / absent fibular bones, short / absent radial bones, hypoplastic terminal phalanges.

Myhre syndrome is a rare genetic disorder inherited in an autosomal dominant fashion. It is caused by mutation in SMAD4 gene.

Symptoms of Winchester syndrome begin with the deterioration of bone within the hands and feet. This loss of bone causes pain and limited mobility. The abnormalities of the bone spread to other areas of the body, mostly the joints. This causes arthropathy: stiffening of the joints (contractures) and swollen joints. Many people develop osteopenia and osteoporosis throughout their entire body. Due to the damage to the bones, many affected individuals suffer from short stature and bone fractures.

Many individuals experience leathery skin where the skin appears dark and thick. Excessive hair growth is known to be found in these darker areas of the skin (hypertrichosis). The eyes may develop a white or clear covering the cornea (corneal opacities) which can cause problems with vision.

The tibia is the most commonly involved bone, accounting for 85% of cases. It is usually painless, although there may be localized pain or fracture, and presents as a localized firm swelling of the tibia in children less than two decades old (median age for males 10, females 13). Several authors have related this non-neoplastic lesion to adamantinoma - a tumor involving subcutaneous long bones - stating the common cause to be fibrovascular defect. However, the latter is distinguished from an osteofibrous dysplasia by the presence of soft tissue extension, intramedullary extension, periosteal reaction and presence of hyperchromic epithelial cells under the microscope.

Osteofibrous dysplasia may also be mistaken for fibrous dysplasia of bone, although osteofibrous dysplasia is more likely to show an immunohistochemical reaction to osteonectin, neurofibromin, and S-100 protein.

Cranio–lenticulo–sutural dysplasia (CLSD, or Boyadjiev-Jabs syndrome) is a neonatal/infancy disease caused by a disorder in the 14th chromosome. It is an autosomal recessive disorder, meaning that both recessive genes must be inherited from each parent in order for the disease to manifest itself. The disease causes a significant dilation of the endoplasmic reticulum in fibroblasts of the host with CLSD. Due to the distension of the endoplasmic reticulum, export of proteins (such as collagen) from the cell is disrupted.

The production of SEC23A protein is involved in the pathway of exporting collagen (the COPII pathway), but a missense mutation causes and underproduction of SEC23A which inhibits the pathway, affecting collagen secretion. This decrease in collagen secretion can lead to the bone defects that are also characteristic of the disease, such as skeletal dysplasia and under-ossification. Decreased collagen in CLSD-affected individuals contributes to improper bone formation, because collagen is a major protein in the extracellular matrix and contributes to its proper mineralization in bones. It has also been hypothesized that there are other defects in the genetic code besides SEC23A that contribute to the disorder.

Osteofibrous dysplasia (also known as ossifying fibroma) is a rare, benign non-neoplastic condition with no known cause. It is considered a fibrovascular defect. Campanacci described this condition in two leg bones, the tibia and fibula, and coined the term. This condition should be differentiated from Nonossifying fibroma and fibrous dysplasia of bone.

Other abnormalities, affecting the scalp, head, face, jaw and teeth may be found with JBS. These include: ectodermal mid-line scalp defects with sparse, oddly-patterned hair growth; aplasia cutis (underdeveloped, very thin skin) over the head, an enlarged fontanelle ("soft spot" on the head of young infants), microcephaly (undersized skull), prominent forehead, absence of eyebrows and eyelashes, mongoloidal eye shape, nasolacrimo-cutaneous fistulae (this refers to the formation of an abnormal secondary passageway from either the tear duct or lacrimal sac to the facial skin surface, possibly discharging fluid), flattened ears, micrognathism of the maxilla and mandible (underdevelopment of the upper and lower jaw, respectively), with the maxilla more prominently affected in some cases; congenital clefting of bones surrounding the optical orbit (eye socket), such as the frontal and lacrimal bone; and maldeveloped deciduous teeth ("baby teeth"), with an absence of permanent teeth.

The following is a list of conditions and complications associated with NF-1, and, where available, age range of onset and progressive development, occurrence percentage of NF-1 population, method of earliest diagnosis, and treatments and related medical specialties. The progression of the condition is roughly as follows:

1. Congenital musculoskeletal disorders may or may not be present

2. Cutaneous conditions may be observed in early infancy

3. Small tumors may arise in the retina which can eventually lead to blindness. Also, Lisch Nodules may grow on the iris, but these are harmless.

4. Learning disabilities may arise in preschool children

5. Neurofibromas may occur and can sometimes cause many dependent neurological conditions and cutaneous and skeletal disfigurement.

6. Depression and social anxiety may occur as a result of disabilities caused by the condition

7. Neurofibromas may, in rare and extreme cases, transition into cancer, which can be fatal

The NF Clinical Program at St. Louis Children's Hospital maintains a comprehensive list of current NF research studies.

Findings with the inner ear in JBS give explanation to the presence of bilateral sensorineural hearing loss in most patients affected by the disorder. The formation of cystic tissue in both the cochlea and vestibule, with resulting (widening) and malformation of these delicate structures has been implicated. Congenital deformations of the temporal bone and associated adverse anatomical effects on innervation and development of the inner ear also contribute to this type of hearing loss.

Cleidocranial dysostosis (CCD), also called cleidocranial dysplasia, is a birth defect that mostly affects the bones and teeth. The collarbones are typically either poorly developed or absent, which allows the shoulders to be brought close together. The front of the skull often does not close until later, and those affected are often shorter than average. Other symptoms may include a prominent forehead, wide set eyes, abnormal teeth, and a flat nose. Symptoms vary among people; however, intelligence is typically normal.

The condition is either inherited from a person's parents or occurs as a new mutation. It is inherited in an autosomal dominant manner. It is due to a defect in the RUNX2 gene which is involved in bone formation. Diagnosis is suspected based on symptoms and X-rays with confirmation by genetic testing. Other conditions that can produce similar symptoms include mandibuloacral dysplasia, pyknodysostosis, osteogenesis imperfecta, and Hajdu-Cheney syndrome.

Treatment includes supportive measures such as a device to protect the skull and dental care. Surgery may be performed to fix certain bone abnormalities. Life expectancy is generally normal.

It affects about one per million people. Males and females are equally commonly affected. Modern descriptions of the condition date to at least 1896. The term is from "cleido" meaning collarbone, "cranial" meaning head, and "dysostosis" meaning formation of abnormal bone.

Musculoskeletal abnormalities affecting the skull include Sphenoid bone dysplasia, Congenital Hydrocephalus and associated neurologic impairment. These abnormalities are non-progressive and may be diagnosed in the fetus or at birth.

Disorders affecting the spine include:

- In NF-1, there can be a generalized abnormality of the soft tissues in the fetus, which is referred to as mesodermal dysplasia, resulting in maldevelopment of skeletal structures.

- Meningoceles and formation of cystic diverticula of the dura of the spine, unrelated to Spina bifida

- Radiographically, Dural ectasia can lead to scalloping of the posterior vertebral bodies and to the formation of cystic diverticula of the dura of the spine (termed meningoceles. This meningocele is not related to spina bifida).

- Focal scoliosis and/or kyphosis are the most common skeletal manifestation of NF-1, occurring in 20% of affected patients. Approximately 25% of patients will require corrective surgery.

Skeletal muscle weakness and motor control deficits

Deficits in motor function in NF-1 have been long recognised and have been historically attributed to nerve dysfunction. In recent years however, studies suggest NF-1 is associated with a primary problem in muscle function (myopathy).

Clinical findings in people with NF-1 include:

- Reduced skeletal muscle size

- Reduced exercise capacity

- Muscle weakness (The most recent study reports between 30–50% reduced upper and lower limb muscle strength in NF-1 children compare with matched controls ).

Studies in genetically modified mice have thus far confirmed that the NF1 gene is vital for normal muscle development and metabolism. Knockout of the NF1 gene in muscle results in deregulated lipid metabolism and muscle weakness.

It is interesting to note that NF-1 is a disease in the RASopathy family of diseases, which include Costello Syndrome, Noonan Syndrome, and Cardiofaciocutaneous syndrome. The RASopathies also present with skeletal muscle weakness. It is likely that impaired muscle function in these disorders is linked to altered Ras/MAPK signalling, however, the precise molecular mechanisms remain unknown.

The specific problems produced differ according to the particular abnormal synthesis involved. Common manifestations include ataxia; seizures; retinopathy; liver fibrosis; coagulopathies; failure to thrive; dysmorphic features ("e.g.," inverted nipples and subcutaneous fat pads; and strabismus. If an MRI is obtained, cerebellar atrophy and hypoplasia is a common finding.

Ocular abnormalities of CDG-Ia include: myopia, infantile esotropia, delayed visual maturation, low vision, optic disc pallor, and reduced rod function on electroretinography.

Three subtypes of CDG I (a,b,d) can cause congenital hyperinsulinism with hyperinsulinemic hypoglycemia in infancy.

Patients with black bone disease are asymptomatic as children or young adults, but their urine may turn brown or even inky black if collected and left exposed to open air. Pigmentation may be noted in the cartilage of the ear as well as other cartilage, and the sclera and corneal limbus of the eye.

After the age of thirty people begin to develop pain in the weight-bearing joints of the spine, hips and knees. The pain can be severe to the point that interferes with activities of daily living and may affect ability to work. Joint replacement surgery (hip and shoulder) is often necessary at a relatively young age. In the longer term, the involvement of the spinal joints leads to reduced movement of the rib cage and can affect breathing. Bone mineral density may be affected, increasing the risk of bone fractures, and rupture of tendons and muscles may occur.

Valvular heart disease, mainly calcification and regurgitation of the aortic and mitral valves, may occur, and in severe and progressive cases valve replacement may be necessary. Irregularities in the heart rhythm and heart failure affect a significant proportion of people with alkaptonuria (40% and 10% respectively). Hearing loss affects 40% of people. There is also a propensity to developing kidney stones, and eventually also gallstones and stones in the prostate and salivary glands (sialolithiasis).

Winchester syndrome is a rare congenital connective tissue disease described in 1969, of which the main characteristics are short stature, marked contractures of joints, opacities in the cornea, coarse facial features, dissolution of the carpal and tarsal bones (in the hands and feet, respectively), and osteoporosis. Winchester syndrome was once considered to be related to a similar condition, multicentric osteolysis, nodulosis, and arthropathy (MONA). However, it was discovered that the two are caused by mutations found in different genes; they are now thought of as two separate disorders. Appearances resemble rheumatoid arthritis. Increased uronic acid is demonstrated in cultured fibroblasts from the skin and to a lesser degree in both parents. Despite initial tests not showing increased mucopolysaccharide excretion, the disease was regarded as a mucopolysaccharidosis. Winchester syndrome is thought to be inherited as an autosomal recessive trait.

People with Aarskog-Scott syndrome often have distinctive facial features, such as widely spaced eyes (hypertelorism), a small nose, a long area between the nose and mouth (philtrum), and a widow's peak hairline. They frequently have mild to moderate short stature during childhood, but their growth usually catches up with that of their peers during puberty. Hand abnormalities are common in this syndrome and include short fingers (brachydactyly), curved pinky fingers (fifth finger clinodactyly), webbing of the skin between some fingers (cutaneous syndactyly), and a single crease across the palm. Other abnormalities in people with Aarskog-Scott syndrome include heart defects and a split in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate).

Most males with Aarskog-Scott syndrome have a shawl scrotum, in which the scrotum surrounds the penis instead of hanging below. Less often, they have undescended testes (cryptorchidism) or a soft out-pouching around the belly-button (umbilical hernia) or in the lower abdomen (inguinal hernia).

The intellectual development of people with Aarskog-Scott syndrome varies widely. Some may have mild learning and behavior problems, while others have normal intelligence. In rare cases, severe intellectual disability has been reported.

Mutations in several genes have been associated with the traditional clinical syndromes, termed muscular dystrophy-dystroglycanopathies (MDDG). A new nomenclature based on clinical severity and genetic cause was recently proposed by OMIM. The severity classifications are A (severe), B (intermediate), and C (mild). The subtypes are numbered one to six according to the genetic cause, in the following order: (1) POMT1, (2) POMT2, (3) POMGNT1, (4) FKTN, (5) FKRP, and (6) LARGE.

Most common severe types include:

Alkaptonuria is a rare inherited genetic disorder in which the body cannot process the amino acids phenylalanine and tyrosine, which occur in protein. It is caused by a mutation in the "HGD" gene for the enzyme homogentisate 1,2-dioxygenase (); if a person inherits abnormal copies from each parent (it is a recessive condition) the body accumulates an intermediate substance called homogentisic acid in the blood and tissues. Homogentisic acid and its oxidized form "alkapton" are excreted in the urine, giving it an unusually dark color. The accumulating homogentisic acid causes damage to cartilage (ochronosis, leading to osteoarthritis) and heart valves as well as precipitating as kidney stones and stones in other organs. Symptoms usually develop in people over thirty years old, although the dark discoloration of the urine is present from birth.

Apart from treatment of the complications (such as pain relief and joint replacement for the cartilage damage), the drug nitisinone has been found to suppress homogentisic acid production, and research is ongoing as to whether it can improve symptoms. Alkaptonuria is a rare disease; it occurs in one in 250,000 people, but is more common in Slovakia and the Dominican Republic.

Trichothiodystrophy (TTD) is an autosomal recessive inherited disorder characterised by brittle hair and intellectual impairment. The word breaks down into "tricho" – "hair", "thio" – "sulphur", and "dystrophy" – "wasting away" or literally "bad nourishment". TTD is associated with a range of symptoms connected with organs of the ectoderm and neuroectoderm. TTD may be subclassified into four syndromes: Approximately half of all patients with trichothiodystrophy have photosensitivity, which divides the classification into syndromes with or without photosensitivity; BIDS and PBIDS, and IBIDS and PIBIDS. Modern covering usage is TTD-P (photosensitive), and TTD.

Aarskog–Scott syndrome is a rare disease inherited as X-linked and characterized by short stature, facial abnormalities, skeletal and genital anomalies. This condition mainly affects males, although females may have mild features of the syndrome.

The Aarskog–Scott syndrome (AAS) is also known as the Aarskog syndrome, faciodigitogenital syndrome, shawl scrotum syndrome and faciogenital dysplasia.