Neonatal onset multisystem inflammatory disease
Encyclopedia
Neonatal onset multisystem inflammatory disease (abbreviated NOMID, also known as chronic infantile neurologic cutaneous and articular syndrome, or CINCA) is a rare
genetic periodic fever syndrome
which causes uncontrolled inflammation in multiple parts of the body starting in the newborn period. Symptoms include skin rashes, severe arthritis
, and chronic meningitis
leading to neurologic damage. It is one of the cryopyrin-associated periodic syndrome
s.
NOMID can result from a mutation in the CIAS1
gene (also known as NLRP3 gene), which helps control inflammation. Mutations in this gene also cause familial cold urticaria
and Muckle-Wells syndrome
. NOMID has been successfully treated with the drug anakinra
.
This syndrome is also known as the Prieur-Griscelli syndrome as it was first described by these authors in 1981.
s are born preterm (1/3 cases) and dysmature. The babies are frequently small for dates. The placenta
may be abnormal with non specific inflammation on histology. Umbilical cord
anomalies have been occasionally been reported. In severe cases signs in the brain
may be detected on prenatal ultrasound
.
The presentation is peliomorphic making the diagnosis difficult but the most common features of this disease involve the skin
, joint
s and central nervous system
.
All have a maculopapular urticaria
l skin rash and is often present at birth (75% cases). It is probably more correctly described as an urticarial-like rash. The presence of the rash varies with time and biopsy of these skin lesions shows a perivascular inflammatory infiltrate including granulocytes.
In about 35-65% of cases arthritis
occurs. Joint signs are variably expressed and can lead to transient swelling without sequelae between crises or to unpredictable anomalies of growth cartilage
and long bones epiphyses suggestive of a pseudo-tumour. Biopsies reveal hypertrophic cartilage
without inflammatory cells. This most commonly affects the large joints (knee
s, ankle
s, elbow
s, wrist
s) but may also involve the small joints of the hands and feet. It is usually bilateral and painful. A common and characteristic feature is are giant kneecaps. Severe cases may result in contractures (joint deformities).
Most patients eventually have neurological problems. These manifest themselves in three principal ways: chronic meningitis
, involvement of the both the optic tract and eye
and sensineural deafness. The chronic meningitis presents with the features of chronically raised intracranial pressure: chronic headaches, vomiting, ventriculomegaly, hydrocephalus, macromegaly, cerebral atrophy and optic atrophy. Some of these features may be evidence on prenatal ultrasound. In 50% intellectual deficit occurs. Seizures occur in 25% but other manifestations are rare. Histological examination shows infiltration of the meninges with polymorph
s.
Ocular manifestations occur in 80% and include uveitis
(70%), papillary involvement, conjunctivitis
and optical neuritis. If untreated these may result in blindness (25%). The sensorineural hearing loss occurs in 75% and tends to be progressive leading to deafness in 20%.
Almost all the children are remarkably short and have growth delay. Fever is extremely common but inconstant and is most often mild. Anaemia is frequent. Other findings that have been reported include macrocephaly (95%), large fontanelle, prominent forehead, flattening of the nasal bridge (saddleback nose), short thick extremities and finger clubbing. The liver
and/or spleen
may be enlarged. Lymph node
enlargement may also be present.
Later in life secondary amyloidosis
may occur. Delayed puberty
and secondary amenorrhoea
is not uncommon. Hoarseness due to inflammation of the laryngeal cartilage has also been reported.
and elevated concentrations of C reactive protein are typically all the abnormalities found. Lumbar puncture shows elevated levels of polymorphs (20-70% of cases) and occasionally raised eosinophil counts (0-30% of cases). CSF neopterin
may be elevated.
The X ray changes are unique and charactistic of this syndrome. These changes include bony overgrowth due to premature ossification of the patella and the long bone epiphyses in very young children and bowing of long bones with widening and shortening periosteal reaction in older ones.
Audiometry shows an progressive sensineural deafness. Visual examination shows optic atropy and an increase in the blind spot. CT is usually normal but may show enlargement of the ventricles. MRI with contrast may show enhancement of leptomeninges and cochlea consistent with chronic meningitis. EEG shows is non specific with slow waves and spike discharges.
Polymorphs tend to show increased expression of CD10.
and familial cold urticaria
. In many patients, the parents do not have the same mutation, indicating the problem was not inherited, even though it is a genetic disease.
CIAS1 is involved in controlling the immune system, which is why the mutation leads to out-of-control inflammation.
Still's disease does not affect children under 6 months old.
Hyperimmunoglobulin D syndrome in 50% of cases is associated with mevalonate kinase
deficiency which can be measured in the leukocytes.
, colchicine
and canakinumab
, have been tried with some success. Otherwise, the treatment is supportive, or aimed solely at controlling symptoms and maximizing function.
, which can lead to kidney failure and other problems. The neurologic problems are most troubling. The finding that other diseases are related and a better understanding of where the disease comes from may lead to more effective treatments.
Rare disease
A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear...
genetic periodic fever syndrome
Periodic fever syndrome
The periodic fever syndromes are a set of disorders, many of which are genetic disorders in which the mechanisms which initiate and control inflammation are disturbed, leading to uncontrolled inflammation throughout the body...
which causes uncontrolled inflammation in multiple parts of the body starting in the newborn period. Symptoms include skin rashes, severe arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
, and chronic meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
leading to neurologic damage. It is one of the cryopyrin-associated periodic syndrome
Cryopyrin-associated periodic syndrome
Cryopyrin-associated periodic syndrome is a spectrum of autoinflammatory syndromes including familial cold autoinflammatory syndrome , the Muckle-Wells syndrome , and neonatal-onset multisystem inflammatory disease...
s.
NOMID can result from a mutation in the CIAS1
CIAS1
NACHT, LRR and PYD domains-containing protein 3 or cryopyrin is a protein that in humans is encoded by the NLRP3 gene. The gene is also called cold induced autoinflammatory syndrome 1 and is located on the long arm of chromosome 1...
gene (also known as NLRP3 gene), which helps control inflammation. Mutations in this gene also cause familial cold urticaria
Familial cold urticaria
Familial cold urticaria is an autosomal dominant condition characterized by rash, conjunctivitis, fever/chills and arthralgias elicited by exposure to cold - sometimes temperatures below 22°C .It has been mapped to CIAS1 and is a slightly milder member of the disease family including Muckle–Wells...
and Muckle-Wells syndrome
Muckle-Wells syndrome
Muckle–Wells syndrome , also known as , is a rare autosomal dominant disease which causes sensorineural deafness, recurrent hives, and can lead to amyloidosis. Individuals with MWS often have episodic fever, chills, and painful joints. As a result, MWS is considered a type of periodic fever syndrome...
. NOMID has been successfully treated with the drug anakinra
Anakinra
Anakinra is a drug used to treat rheumatoid arthritis.-Mechanism:Anakinra is an interleukin-1 receptor antagonist...
.
This syndrome is also known as the Prieur-Griscelli syndrome as it was first described by these authors in 1981.
Epidemiology
This is a rare condition with an incidence estimated to be less that 1 in a million live births. About 100 cases have been reported worldwide. The bulk of cases are sporadic but familial forms with autosomal dominant transmission have also been described.Signs and symptoms
The age of onset is almost always before 3 months of age. Many infantInfant
A newborn or baby is the very young offspring of a human or other mammal. A newborn is an infant who is within hours, days, or up to a few weeks from birth. In medical contexts, newborn or neonate refers to an infant in the first 28 days after birth...
s are born preterm (1/3 cases) and dysmature. The babies are frequently small for dates. The placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
may be abnormal with non specific inflammation on histology. Umbilical cord
Umbilical cord
In placental mammals, the umbilical cord is the connecting cord from the developing embryo or fetus to the placenta...
anomalies have been occasionally been reported. In severe cases signs in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
may be detected on prenatal ultrasound
Ultrasound
Ultrasound is cyclic sound pressure with a frequency greater than the upper limit of human hearing. Ultrasound is thus not separated from "normal" sound based on differences in physical properties, only the fact that humans cannot hear it. Although this limit varies from person to person, it is...
.
The presentation is peliomorphic making the diagnosis difficult but the most common features of this disease involve the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, joint
Joint
A joint is the location at which two or more bones make contact. They are constructed to allow movement and provide mechanical support, and are classified structurally and functionally.-Classification:...
s and central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
.
All have a maculopapular urticaria
Urticaria
Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...
l skin rash and is often present at birth (75% cases). It is probably more correctly described as an urticarial-like rash. The presence of the rash varies with time and biopsy of these skin lesions shows a perivascular inflammatory infiltrate including granulocytes.
In about 35-65% of cases arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
occurs. Joint signs are variably expressed and can lead to transient swelling without sequelae between crises or to unpredictable anomalies of growth cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
and long bones epiphyses suggestive of a pseudo-tumour. Biopsies reveal hypertrophic cartilage
Cartilage
Cartilage is a flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs...
without inflammatory cells. This most commonly affects the large joints (knee
Knee
The knee joint joins the thigh with the leg and consists of two articulations: one between the fibula and tibia, and one between the femur and patella. It is the largest joint in the human body and is very complicated. The knee is a mobile trocho-ginglymus , which permits flexion and extension as...
s, ankle
Ankle
The ankle joint is formed where the foot and the leg meet. The ankle, or talocrural joint, is a synovial hinge joint that connects the distal ends of the tibia and fibula in the lower limb with the proximal end of the talus bone in the foot...
s, elbow
Elbow
The human elbow is the region surrounding the elbow-joint—the ginglymus or hinge joint in the middle of the arm. Three bones form the elbow joint: the humerus of the upper arm, and the paired radius and ulna of the forearm....
s, wrist
Wrist
In human anatomy, the wrist is variously defined as 1) the carpus or carpal bones, the complex of eight bones forming the proximal skeletal segment of the hand;...
s) but may also involve the small joints of the hands and feet. It is usually bilateral and painful. A common and characteristic feature is are giant kneecaps. Severe cases may result in contractures (joint deformities).
Most patients eventually have neurological problems. These manifest themselves in three principal ways: chronic meningitis
Meningitis
Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs...
, involvement of the both the optic tract and eye
Eye
Eyes are organs that detect light and convert it into electro-chemical impulses in neurons. The simplest photoreceptors in conscious vision connect light to movement...
and sensineural deafness. The chronic meningitis presents with the features of chronically raised intracranial pressure: chronic headaches, vomiting, ventriculomegaly, hydrocephalus, macromegaly, cerebral atrophy and optic atrophy. Some of these features may be evidence on prenatal ultrasound. In 50% intellectual deficit occurs. Seizures occur in 25% but other manifestations are rare. Histological examination shows infiltration of the meninges with polymorph
Polymorph
-Science:* Polymorphonuclear leukocyte or granulocyte, a type of white blood cell* Polymorph, a trade name for the low melting-temperature polymer, Polycaprolactone * Dreissena polymorpha, the species commonly known as the Zebra mussel...
s.
Ocular manifestations occur in 80% and include uveitis
Uveitis
Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye....
(70%), papillary involvement, conjunctivitis
Conjunctivitis
Conjunctivitis refers to inflammation of the conjunctiva...
and optical neuritis. If untreated these may result in blindness (25%). The sensorineural hearing loss occurs in 75% and tends to be progressive leading to deafness in 20%.
Almost all the children are remarkably short and have growth delay. Fever is extremely common but inconstant and is most often mild. Anaemia is frequent. Other findings that have been reported include macrocephaly (95%), large fontanelle, prominent forehead, flattening of the nasal bridge (saddleback nose), short thick extremities and finger clubbing. The liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and/or spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
may be enlarged. Lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
enlargement may also be present.
Later in life secondary amyloidosis
Amyloidosis
In medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...
may occur. Delayed puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
and secondary amenorrhoea
Amenorrhoea
Amenorrhoea , amenorrhea , or amenorrhœa, is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen during pregnancy and lactation , the latter also forming the basis of a form of contraception known as the lactational amenorrhoea method...
is not uncommon. Hoarseness due to inflammation of the laryngeal cartilage has also been reported.
Investigations
Routine laboratory investigations are non specific: anaemia, increased numbers of polymorphs, an elevated erythrocyte sedimentation rateErythrocyte sedimentation rate
The erythrocyte sedimentation rate , also called a sedimentation rate or Biernacki Reaction, is the rate at which red blood cells sediment in a period of 1 hour...
and elevated concentrations of C reactive protein are typically all the abnormalities found. Lumbar puncture shows elevated levels of polymorphs (20-70% of cases) and occasionally raised eosinophil counts (0-30% of cases). CSF neopterin
Neopterin
Neopterin is a catabolic product of guanosine triphosphate , a purine nucleotide.Neopterin belongs to the chemical group known as pteridines. It is synthesised by macrophages upon stimulation with the cytokine interferon-gamma and is indicative of a pro-inflammatory immune status...
may be elevated.
The X ray changes are unique and charactistic of this syndrome. These changes include bony overgrowth due to premature ossification of the patella and the long bone epiphyses in very young children and bowing of long bones with widening and shortening periosteal reaction in older ones.
Audiometry shows an progressive sensineural deafness. Visual examination shows optic atropy and an increase in the blind spot. CT is usually normal but may show enlargement of the ventricles. MRI with contrast may show enhancement of leptomeninges and cochlea consistent with chronic meningitis. EEG shows is non specific with slow waves and spike discharges.
Polymorphs tend to show increased expression of CD10.
Possible causes
The disease is caused in 60% of cases by a mutated gene called CIAS1 that is known to be involved in other syndromes that appear somewhat similar, such as Muckle-Wells syndromeMuckle-Wells syndrome
Muckle–Wells syndrome , also known as , is a rare autosomal dominant disease which causes sensorineural deafness, recurrent hives, and can lead to amyloidosis. Individuals with MWS often have episodic fever, chills, and painful joints. As a result, MWS is considered a type of periodic fever syndrome...
and familial cold urticaria
Familial cold urticaria
Familial cold urticaria is an autosomal dominant condition characterized by rash, conjunctivitis, fever/chills and arthralgias elicited by exposure to cold - sometimes temperatures below 22°C .It has been mapped to CIAS1 and is a slightly milder member of the disease family including Muckle–Wells...
. In many patients, the parents do not have the same mutation, indicating the problem was not inherited, even though it is a genetic disease.
CIAS1 is involved in controlling the immune system, which is why the mutation leads to out-of-control inflammation.
Diagnosis
The diagnosis is based on observing the patient and finding the constellation of symptoms and signs described above. A few blood tests help, by showing signs of long standing inflammation. There is no specific test for the disease, though now that the gene that causes the disease is known, that may change.Differential diagnosis
- Aicardi-Goutières syndromeAicardi-Goutieres syndromeAicardi–Goutières syndrome is a rare genetic disorder. It is also known as Cree encephalitis and pseudo-TORCH syndrome, both of which were once considered separate disorders. It is a type of leukodystrophy and is usually fatal within the first few years...
- Still's diseaseStill's diseaseStill's disease can refer to:* Juvenile idiopathic arthritis* Adult-onset Still's disease...
- Schnitzler syndromeSchnitzler syndromeSchnitzler syndrome is a rare disease characterised by chronic hives and periodic fever, bone pain and joint pain , weight loss, malaise, fatigue, swollen lymph glands and enlarged spleen and liver....
- Hyperimmunoglobulin D syndrome
- Familial Mediterranean FeverFamilial Mediterranean feverFamilial Mediterranean fever is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in MEFV, a gene which encodes a 781–amino acid protein denoted pyrin....
- Marshall's syndrome
- Castleman's diseaseCastleman's diseaseCastleman's disease is an uncommon lymphoproliferative disorder that can involve single lymph node stations or...
Still's disease does not affect children under 6 months old.
Hyperimmunoglobulin D syndrome in 50% of cases is associated with mevalonate kinase
Mevalonate kinase
Mevalonate kinase is an enzyme that in humans is encoded by the MVK gene. Mevalonate kinases are found in a wide variety of organisms from bacteria to mammals...
deficiency which can be measured in the leukocytes.
Treatment
There have been attempts to control the inflammation using drugs that work in other conditions where inflammation is a problem. The most successful of these are steroids, but they have side effects when used long term. Other medications, including methotrexateMethotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
, colchicine
Colchicine
Colchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...
and canakinumab
Canakinumab
Canakinumab is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha....
, have been tried with some success. Otherwise, the treatment is supportive, or aimed solely at controlling symptoms and maximizing function.
Prognosis
Overall, the prognosis for patients with NOMID is not good, though many (80%) live into adulthood, and a few appear to do relatively well. They are at risk for leukemia, infections, and some develop deposits of protein aggregated called amyloidAmyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
, which can lead to kidney failure and other problems. The neurologic problems are most troubling. The finding that other diseases are related and a better understanding of where the disease comes from may lead to more effective treatments.
See also
- Deficiency of the interleukin-1–receptor antagonistDeficiency of the interleukin-1–receptor antagonistDeficiency of the interleukin-1–receptor antagonist is a rare, autosomal recessive, genetic autoinflammatory syndrome resulting from mutations in IL1RN, the gene encoding the interleukin 1 receptor antagonist....
(DIRA) - Familial cold urticariaFamilial cold urticariaFamilial cold urticaria is an autosomal dominant condition characterized by rash, conjunctivitis, fever/chills and arthralgias elicited by exposure to cold - sometimes temperatures below 22°C .It has been mapped to CIAS1 and is a slightly milder member of the disease family including Muckle–Wells...
, a similar disease - List of cutaneous conditions
- Muckle-Wells syndromeMuckle-Wells syndromeMuckle–Wells syndrome , also known as , is a rare autosomal dominant disease which causes sensorineural deafness, recurrent hives, and can lead to amyloidosis. Individuals with MWS often have episodic fever, chills, and painful joints. As a result, MWS is considered a type of periodic fever syndrome...
, a similar disease
External links
- NOMID Alliance -- Non-profit charity devoted to CAPS diseases