Acromesomelic dysplasia is a rare

skeletal disorder A skeleton is the structural frame that supports the body of an animal. There are several types of skeletons, including the exoskeleton, which is the stable outer shell of an organism, the endoskeleton, which forms the support structure inside ...

that causes abnormal bone and

cartilage Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck an ...

development, leading to shortening of the forearms, lower legs, hands, feet, fingers, and toes. Five different

genetic mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mit ...

have been implicated in the disorder. Treatment is individualized but is generally aimed at palliating symptoms, for example, treatment of

kyphosis Kyphosis is an abnormally excessive convex curvature of the spine as it occurs in the thoracic and sacral regions. Abnormal inward concave ''lordotic'' curving of the cervical and lumbar regions of the spine is called lordosis. It can result fr ...

and

lumbar hyperlordosis Lordosis is historically defined as an ''abnormal'' inward curvature of the lumbar spine. However, the terms ''lordosis'' and ''lordotic'' are also used to refer to the normal inward curvature of the lumbar and cervical regions of the human spin ...

Signs and Symptoms

Acromesomelic dysplasia (AMD) is characterized by the inhibition of growth of certain long bones such as the forearms and lower legs. This disease typically becomes apparent during the first years of life. Forearms, lower legs, hands and feet do not grow proportionally with the rest of the body. Over time, individuals can have a hard time fully extending their arms, rotating the arms inwards towards the body with palms facing down and rotating the arms outward with the palms facing upward. Abnormalities of cartilage and bone development may also cause the bones within the fingers, toes, hands and feet to become sufficiently shorter and broader. During early childhood, individuals may experience progressive, abnormal curvature of the spine. Common symptoms include: *

Short stature Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called '' ...

* Progressive degeneration * Stiffness * Tenderness *

Osteoarthritis Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...

* Abnormal bone shape Infants with AMD typically have a normal birth weight, but can have other characteristic facial abnormalities. *

Macrocephaly Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to ...

Frontal bossing Skull bossing is a descriptive term in medical physical examination indicating a protuberance of the skull, most often in the frontal bones of the forehead ("frontal bossing"). Although prominence of the skull bones may be normal, skull bossing m ...

* Occipital prominence * Slightly flattened midface * Abnormally small, pug nose

Causes

AMD is extremely rare and is inherited as an autosomal recessive genetic trait.

Autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

means that two copies of an abnormal gene must be present in order for the disease to develop. This can be inherited from the parents or the gene can mutate in the person who has AMD.

Pathophysiology

Genetic studies indicate that the mutation a
chromosome 9p13-12
for AMD Maroteaux, is a gene that codes for a protein that affects bone development, natriuretic peptide receptor B (Npr2). This is a receptor for the hormone

C-type natriuretic peptide Natriuretic peptide precursor C, also known as NPPC, is a protein that in humans is encoded by the ''NPPC'' gene. The precursor NPPC protein is cleaved to the 22 amino acid peptide C-type natriuretic peptide (''CNP''). Function Natriuretic pe ...

which is a hormone that is essential for bone growth. AMD Grebe dysplasia has a gene located a
chromosome 20q11.2
This chromosome codes for a protein known as growth and development factor-5 (

GDF5 Growth/differentiation factor 5 is a protein that in humans is encoded by the ''GDF5'' gene. The protein encoded by this gene is closely related to the bone morphogenetic protein (BMP) family and is a member of the TGF-beta superfamily. This grou ...

). AMD with genital anomalies has a gene located a
chromosome 4q23-24
this codes for a protein known as a bone morphogenetic protein receptor, type 1B.

Genetic diseases A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

are determined by the combination of genes for a certain trait that is on the chromosomes received from the mother and father. Dominant genetic disorders happen when a single copy of an abnormal gene is needed to cause a certain disease. The abnormal gene can be inherited from either parent or result from a gene mutation.

Diagnosis

The diagnosis is based on a clinical presentation
molecular analysis

electropherogram An electropherogram, or electrophoregram, can also be referred to as an EPG or e-gram. It is a record or chart produced when electrophoresis is used in an analytical technique, primarily in the fields of forensic biology, molecular biology and ...

an
radiograph
This disease is diagnosed within the first few years of life. Identification of the main characteristics is the key factor in diagnosis. Molecular analysis is used to examine the DNA of the affected person and their parents. For this, a blood sample is needed and the DNA will be extracted with an automatic DNA extractor. The results will show the mutated chromosome and identify if this chromosome was passed on from a parent. A

radiograph Radiography is an imaging technique using X-rays, gamma rays, or similar ionizing radiation and non-ionizing radiation to view the internal form of an object. Applications of radiography include medical radiography ("diagnostic" and "therapeut ...

will show abnormal growth plates and misshapen bones in the limbs. This can confirm the abnormal development and premature fusion of the regions where the

diaphyses The diaphysis is the main or midsection (shaft) of a long bone. It is made up of cortical bone and usually contains bone marrow and adipose tissue (fat). It is a middle tubular part composed of compact bone which surrounds a central marrow cavity ...

, of certain long bones, meet their

epiphyses The epiphysis () is the rounded end of a long bone, at its joint with adjacent bone(s). Between the epiphysis and diaphysis (the long midsection of the long bone) lies the metaphysis, including the epiphyseal plate (growth plate). At the join ...

Electropherogram An electropherogram, or electrophoregram, can also be referred to as an EPG or e-gram. It is a record or chart produced when electrophoresis is used in an analytical technique, primarily in the fields of forensic biology, molecular biology and ...

is used to identify

genotyping Genotyping is the process of determining differences in the genetic make-up ( genotype) of an individual by examining the individual's DNA sequence using biological assays and comparing it to another individual's sequence or a reference sequence. ...

. These results can be used to compare to a normal sequence and relatives sequences. 814 Radiograph of Hand

It is important to have a detailed patient history, including the parents or other relatives. Typically, the parent that carries the chromosome for AMD, seems to be shorter than average. Monitoring the weight and height of the person affected with AMD is important. Based on the person's age, they should be meeting a certain percentile to identify any issues that may be causing a stunt in growth. There are five types of AMD: # Osebold-Remondini # Maroteaux # Grebe dysplasia # Du Pan syndrome # Acromesomelic dysplasia with genital anomalies Osebold-Remondini causes shortness of limbs and

hypoplasia Hypoplasia (from Ancient Greek ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.second phalanges with fusion to the remaining phalanges,

carpal The carpal bones are the eight small bones that make up the wrist (or carpus) that connects the hand to the forearm. The term "carpus" is derived from the Latin carpus and the Greek καρπός (karpós), meaning "wrist". In human anatomy, th ...

and

tarsal coalition Tarsal coalition is an abnormal connecting bridge of tissue between two normally-separate tarsal bones. The term 'coalition' means a coming together of two or more entities to merge into one mass. The tissue connecting the bones, often referred ...

s. Maroteaux type causes severe

dwarfism Dwarfism is a condition wherein an organism is exceptionally small, and mostly occurs in the animal kingdom. In humans, it is sometimes defined as an adult height of less than , regardless of sex; the average adult height among people with dw ...

with a height below 120 cm. This type also causes shortening of the middle and distal segments of the limbs. Grebe dysplasia causes extreme abnormalities of the limb joints and limbs. In this type of AMD, the hands and feet are affected the most. This type primarily affects the joints in the hands and feet causing a lack of articulation. Grebe dysplasia does not have any major effects on the

stature Stature may refer to: * Human stature, the distance from the bottom of the feet to the top of the head in a human body, standing erect * Reputation, social opinion about an entity * Respect Respect, also called esteem, is a positive feeli ...

. Du Pan syndrome causes underdevelopment of the tissues in the

fibula The fibula or calf bone is a leg bone on the lateral side of the tibia, to which it is connected above and below. It is the smaller of the two bones and, in proportion to its length, the most slender of all the long bones. Its upper extremity is ...

e, feet and hands. Acromesomelic dysplasia with genital anomalies causes shortness of limbs and stature with

congenital malformations A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can r ...

of the female

genital tract The female reproductive system is made up of the internal and external sex organs that function in the reproduction of new offspring. In humans, the female reproductive system is immature at birth and develops to maturity at puberty to be abl ...

and

male reproductive system The male reproductive system consists of a number of sex organs that play a role in the process of human reproduction. These organs are located on the outside of the body and within the pelvis. The main male sex organs are the penis and the tes ...

. All five types of AMD are caused by a gene mutation or receiving it from their parents. The differences between the types are the different genes that are affected. The mutated gene for each type is listed in the

pathophysiology Pathophysiology ( physiopathology) – a convergence of pathology with physiology – is the study of the disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is the ...

section.

Treatment

There are a few treatment plans for AMD and each person's results vary. Depending on the type of AMD and the symptoms the person has, their therapy may differ.

Physical therapy Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, patient ...

is aimed to help specific symptoms. For example, abnormal curvature of the spine may be treated by exercises, braces, casts and in severe cases, corrective surgery. It is important to start physical therapy as early as possible to ensure that people with AMD can reach their full potential. One treatment that can help a person who is affected with AMD is recombinant human growth hormone (rhGH). Recombinant human growth hormones are produced in the

pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...

and can help spur growth in children and adolescents. It is used in AMD patients to help muscle and bone growth. This treatment is long-term and will not cure this disease, it will only help the patient grow a couple of centimeters. A case study showed a growth velocity of 3.6-4.2 cm/year during this first year of treatment. As well as height improving from 1.2 to 1.8 SD over 5 years of treatment. Another case study was conducted that showed within a year, a patient had an increase of 7.0 cm/year. With this treatment, it is important to start it during the puberty stage. Some patients that have received this treatment, have seen no difference or increase in height. There is no prevention with AMD and not many options for managing the symptoms.

Kyphosis Kyphosis is an abnormally excessive convex curvature of the spine as it occurs in the thoracic and sacral regions. Abnormal inward concave ''lordotic'' curving of the cervical and lumbar regions of the spine is called lordosis. It can result fr ...

is an excessive outward curvature of the spine resulting in a hunch back. Treatment for this disease includes taking pain relievers and

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...

medications. Medication for

helps strengthen the bones to help prevent any spinal fractures.

Lumbar hyperlordosis Lordosis is historically defined as an ''abnormal'' inward curvature of the lumbar spine. However, the terms ''lordosis'' and ''lordotic'' are also used to refer to the normal inward curvature of the lumbar and cervical regions of the human spin ...

is a condition that occurs when the lower back region experiences stress or extra weight. This causes the lower back to become arched and creates muscle spasms or pain. Treatment focuses on stretching the lower back, quads, hip flexors and strengthening the hamstrings, glutes and abdominal muscles. Braces may be used to help relieve some stress or pressure on the lower back. Risk factors from taking

rhGH Growth hormone therapy refers to the use of growth hormone (GH) as a prescription medication—it is one form of hormone therapy. Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates Cell growth, growth and cell (b ...

include: # Nerve, muscle or joint pain #

Edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...

Carpal tunnel syndrome Carpal tunnel syndrome (CTS) is the collection of symptoms and signs associated with median neuropathy at the carpal tunnel. Most CTS is related to idiopathic compression of the median nerve as it travels through the wrist at the carpal tunn ...

# Numbness and tingling of the skin #

High cholesterol Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), ...

# Increase the risk of

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

Other risk factors that increase the risk of having AMD include a family history of having this condition or a child born from parents who are close blood relatives.

Prognosis

A person diagnosed with AMD will have a normal life expectancy. With this disease, there are no chances of full recovery; it is something that the person will have for their entire life. Abnormal cartilage and bone development can affect many bones in the body. Long term effects include

joint pain Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...

arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...

, abnormal curvature of the spine and short stature of limbs and height.

Epidemiology

The prevalence for AMD is <1/1000000. Nearly ten million people in the world carry the NPR2 mutated gene (Maroteaux type); only 3500 people in the entire world are affected with AMD. AMD is rare and there are less than 100 reported cases. AMD can be classified as

skeletal dysplasia Osteochondrodysplasia is a general term for a disorder of the development (dysplasia) of bone ("osteo") and cartilage ("chondro"). Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia. Non ...

, which approximately occurs in 1 out of 5000 births. This disease affects both males and females as well as any racial or ethnic group. The majority of the case studies involve patients that live in Pakistan, Morocco, or Karnataka. AMD does primarily begin in the first few years of life or as early as the

neonatal An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...

phase, but it can affect anyone at any age.

Current Research

There has been a recent research study that established a new type of AMD. In the case study, an exome sequence was performed on two girls that had

short stature Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called '' ...

due to acromesomelic limb shortening. The researchers wanted to determine if

protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...

br>cGMP-dependent type II gene
( PRKG2) had any effect on longitudinal growth in bones. The results showed two homozygous PRKG2 variants: nonsense and a frameshift. These variants alter the downstream

mitogen activated protein kinase A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a ...

signaling pathway by failing to phosphorylate c-Raf 1 at Ser43 and reduce activation in response to fibroblast growth factor 2. Another research study was conducted on mice to find a new treatment for people with AMD (Maroteaux type). The results showed that

Npr2 Natriuretic peptide receptor B/guanylate cyclase B (atrionatriuretic peptide receptor B), also known as NPR2, is an atrial natriuretic peptide receptor. In humans it is encoded by the NPR2 gene. A mutation of the NPR2 gene can result in dispropo ...

is expressed in

osteoblast Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...

s and

chondrocyte Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...

s; leading to the conclusion that the disruptions in the

growth plate The epiphyseal plate (or epiphysial plate, physis, or growth plate) is a hyaline cartilage plate in the metaphysis at each end of a long bone. It is the part of a long bone where new bone growth takes place; that is, the whole bone is alive, wi ...

from

, can be a leading cause for AMD. They also found that

stops the activation of a signaling pathway for MEK/ERK, which is a pathway in the

growth plates The epiphyseal plate (or epiphysial plate, physis, or growth plate) is a hyaline cartilage plate in the metaphysis at each end of a long bone. It is the part of a long bone where new bone growth takes place; that is, the whole bone is alive, with ...

. The data showed that treatment of a pharmacological inhibitor of MEK/ERK pathway might improve bone growth. The data for this treatment produced promising results. It showed that the drug effectively inhibited MEK/ERK activation. This study was only conducted on mice, but it could potentially be a treatment to help people diagnosed with AMD. There are research studies being conducted to see the effect of

. As stated in the treatment section, results may vary per person. Some patients seem to have an overall positive effect of these hormones and it helps them grow a few more centimeters each year. No other clinical trials are going on for AMD. There is a lack of knowledge or medication that can treat or reverse this disease.

References

External links

{{Medical resources , ICD10 = , ICD9 = , ICDO = , OMIM = , DiseasesDB = , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeSH = C535658 , GeneReviewsNBK = , GeneReviewsName = , Orphanet = 93437 Skeletal disorders Rare diseases Genetic diseases and disorders