Neonatal-onset multisystem inflammatory disease is a rare genetic

periodic fever syndrome Periodic fever syndromes are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of t ...

which causes uncontrolled inflammation in multiple parts of the body starting in the newborn period. Symptoms include skin rashes, severe

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 ...

, and chronic

meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...

leading to neurologic damage. It is one of the

cryopyrin-associated periodic syndrome Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by Interleukin 1 beta, interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervo ...

s. NOMID can result from a mutation in the ''

CIAS1 NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1. NLRP3 is ...

'' gene (also known as ''NLRP3'' gene), which helps control inflammation. Mutations in this gene also cause

familial cold urticaria Cold urticaria (essentially meaning cold hives) is a disorder in large red welts called hives (''urticaria'') form on the skin after exposure to a cold stimulus. The hives are usually itchy and often the hands and feet will become itchy and swolle ...

and

Muckle–Wells syndrome Muckle–Wells syndrome (MWS) is a rare autosomal dominant disease which causes sensorineural deafness and recurrent hives, and can lead to amyloidosis. Individuals with MWS often have episodic fever, chills, and joint pain. As a result, MWS is ...

. NOMID has been successfully treated with the drug

anakinra Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a recombinant and slightly modifi ...

. This syndrome is also known as the Prieur–Griscelli syndrome as it was first described by these authors in 1981.Prieur AM, Griscelli C (1981) Arthropathy with rash, chronic meningitis, eye lesions, and mental retardation. J. Pediat 99:79-83

Signs and symptoms

The age of onset is almost always before 3 months of age. Many

infant 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 ...

s are born preterm (1/3 cases) and dysmature. The babies are frequently small for dates. The

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mater ...

may be abnormal with non-specific inflammation on histology.

Umbilical cord In placental mammals, the umbilical cord (also called the navel string, birth cord or ''funiculus umbilicalis'') is a conduit between the developing embryo or fetus and the placenta. During prenatal development, the umbilical cord is physiologic ...

anomalies have occasionally been reported. In severe cases, signs in the

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

may be detected on prenatal

ultrasound Ultrasound is sound waves with frequency, frequencies higher than the upper audible limit of human hearing range, hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hea ...

. The disease manifests in many forms, making the diagnosis difficult, but the most common features of this disease involve the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...

joint A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw ...

s, and

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

. All have a maculopapular

urticaria Hives, also known as urticaria, is a kind of skin rash with red, raised, itchy bumps. Hives may burn or sting. The patches of rash may appear on different body parts, with variable duration from minutes to days, and does not leave any long-lasti ...

l skin rash that 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 Mural cells are the vascular smooth muscle cells (vSMCs), and pericytes, of the microcirculation. Both types are in close contact with the endothelial cells lining the capillaries, and are important for vascular development and stability. Mural cel ...

inflammatory infiltrate including

granulocytes Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They hav ...

. In about 35-65% of cases,

occurs. Joint signs are variably expressed and can lead to transient swelling without

sequelae A sequela (, ; usually used in the plural, sequelae ) is a pathological condition resulting from a disease, injury, therapy, or other trauma. Derived from the Latin word, meaning “sequel”, it is used in the medical field to mean a complication ...

between crises, or to unpredictable anomalies of growth

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 ...

and long bones

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 ...

suggestive of a pseudo-tumour. Biopsies reveal

hypertrophic Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J ...

without inflammatory cells. This most commonly affects the large joints (

knee In humans and other primates, the knee joins the thigh with the leg and consists of two joints: one between the femur and tibia (tibiofemoral joint), and one between the femur and patella (patellofemoral joint). It is the largest joint in the hu ...

ankle The ankle, or the talocrural region, or the jumping bone (informal) is the area where the foot and the leg meet. The ankle includes three joints: the ankle joint proper or talocrural joint, the subtalar joint, and the inferior tibiofibular join ...

elbow The elbow is the region between the arm and the forearm that surrounds the elbow joint. The elbow includes prominent landmarks such as the olecranon, the cubital fossa (also called the chelidon, or the elbow pit), and the lateral and the media ...

s, and

wrist In human anatomy, the wrist is variously defined as (1) the Carpal bones, carpus or carpal bones, the complex of eight bones forming the proximal skeletal segment of the hand; "The wrist contains eight bones, roughly aligned in two rows, known ...

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 giant

kneecap The patella, also known as the kneecap, is a flat, rounded triangular bone which articulates with the femur (thigh bone) and covers and protects the anterior articular surface of the knee joint. The patella is found in many tetrapods, such as m ...

s. Severe cases may result in

contractures In pathology, a contracture is a permanent shortening of a muscle or joint. It is usually in response to prolonged hypertonic spasticity in a concentrated muscle area, such as is seen in the tightest muscles of people with conditions like spasti ...

(joint deformities). Most patients eventually have neurological problems. These manifest themselves in three principal ways: chronic

, involvement of both the optic tract and eye, and

sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear or sensory organ (cochlea and associated structures) or the vestibulocochlear nerve (cranial nerve VIII). SNHL accounts for about 90% of rep ...

. The chronic meningitis presents with the features of chronically raised intracranial pressure: headaches, vomiting,

ventriculomegaly Ventriculomegaly is a brain condition that mainly occurs in the fetus when the lateral ventricles become dilated. The most common definition uses a width of the atrium of the lateral ventricle of greater than 10 mm. This occurs in around 1 ...

hydrocephalus Hydrocephalus is a condition in which an accumulation of cerebrospinal fluid (CSF) occurs within the brain. This typically causes increased intracranial pressure, pressure inside the skull. Older people may have headaches, double vision, poor ...

, macromegaly,

cerebral atrophy Cerebral atrophy is a common feature of many of the diseases that affect the brain. Atrophy of any tissue means a decrement in the size of the cell, which can be due to progressive loss of cytoplasmic proteins. In brain tissue, atrophy describes ...

, and

optic atrophy Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. Damage and death of these nerve cells, or neurons, leads to characteristic featu ...

. Some of these features may be evidenced on prenatal ultrasound. In 50% of cases, intellectual deficit occurs.

Seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...

occur in 25% of cases, but other manifestations are rare. Histological examination shows infiltration of the

meninges In anatomy, the meninges (, ''singular:'' meninx ( or ), ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in th ...

with polymorphs. Ocular manifestations occur in 80% of cases and include

uveitis Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and ...

(70%), papillary involvement,

conjunctivitis Conjunctivitis, also known as pink eye, is inflammation of the conjunctiva, outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may ...

, 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% of cases. Almost all children are remarkably short and have growth delay. Fever is extremely common but inconstant and is most often mild.

Anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...

is frequent. Other findings that have been reported include

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 ...

(95%), large

fontanelle A fontanelle (or fontanel) (colloquially, soft spot) is an anatomical feature of the infant human skull comprising soft membranous gaps ( sutures) between the cranial bones that make up the calvaria of a fetus or an infant. Fontanelles allow f ...

, prominent forehead, flattening of the nasal bridge (saddleback nose), short and thick extremities, and finger clubbing. The

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

and/or

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

may be enlarged.

Lymph node A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...

enlargement may also be present. Later in life, secondary

amyloidosis Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight ...

may occur. Delayed

puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a boy. ...

and secondary

amenorrhoea Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Physiological states of amenorrhoea are seen, most commonly, during pregnancy and lactation (breastfeeding). Outside the reproductive years, there is absence of menses ...

are not uncommon. Hoarseness due to inflammation of the laryngeal cartilage has also been reported.

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

and

. 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. Routine laboratory investigations are non specific: anaemia, increased numbers of polymorphs, an elevated

erythrocyte sedimentation rate The erythrocyte sedimentation rate (ESR or sed rate) is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour. It is a common hematology test, and is a non-specific measure of ...

and elevated concentrations of

C-reactive protein C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 ...

are typically all the abnormalities found. Lumbar puncture shows elevated levels of polymorphs (20-70% of cases) and occasionally raised

eosinophil Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...

counts (0-30% of cases). CSF

neopterin Neopterin is a catabolic product of guanosine triphosphate (GTP), a purine nucleotide. Neopterin belongs to the chemical group known as pteridines. It is synthesised by human macrophages upon stimulation with the cytokine interferon-gamma and is i ...

may be elevated. The X ray abnormalities are unique and characteristic 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 a progressive sensineural deafness. Visual examination shows optic atrophy 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 a non-specific pattern with slow waves and spike discharges. Polymorphs tend to show increased expression of

CD10 Neprilysin (), also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzyme that in humans is encoded by the ''MME'' ge ...

Differential diagnosis

Aicardi–Goutières syndrome Aicardi–Goutières syndrome (AGS), which is completely distinct from the similarly named Aicardi syndrome, is a rare, usually early onset childhood, inflammatory disorder most typically affecting the brain and the skin (neurodevelopmental disord ...

* Still's disease *

Schnitzler syndrome There have been several people named Schnitzler ( he, שניצלר): * Arthur Schnitzler (born 1862), an Austrian playwright and author, son of Johann * Barbara Schnitzler (born 1953, Berlin), a German actress (de) * Claude Schnitzler (born 1949 ...

Hyperimmunoglobulin D syndrome Mevalonate kinase deficiency (MKD) is an autosome, autosomal Dominance (genetics), recessive metabolic disorder that disrupts the biosynthesis of cholesterol and isoprenoids. It is a Rare genetic disease, very rare genetic disease. It is charact ...

Familial Mediterranean fever Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in Mediterranean fever gene, which encodes a 781–amino acid protein called pyrin. While all ethnic groups are su ...

Marshall syndrome Marshall syndrome is a genetic disorder of the connective tissue which can cause hearing loss. The three most common areas to be affected are the eyes which are uncommonly large, joints and the mouth and facial structures. Marshall syndrome and ...

Castleman's disease Castleman disease (CD) describes a group of rare lymphoproliferative disorders that involve enlarged lymph nodes, and a broad range of inflammatory symptoms and laboratory abnormalities. Whether Castleman disease should be considered an autoimmu ...

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 is an enzyme (specifically a kinase) that in humans is encoded by the ''MVK'' gene. Mevalonate kinases are found in a wide variety of organisms from bacteria to mammals. This enzyme catalyzes the following reaction: . Funct ...

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

methotrexate Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...

colchicine Colchicine is a medication used to treat gout and Behçet's disease. In gout, it is less preferred to NSAIDs or steroids. Other uses for colchicine include the management of pericarditis and familial Mediterranean fever. Colchicine is taken ...

and

canakinumab Canakinumab (International Nonproprietary Name, INN), sold under the brand name Ilaris, is a medication for the treatment of systemic juvenile idiopathic arthritis (SJIA) and active Still's disease, including adult-onset Still's disease (AOSD). ...

, 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

amyloid Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a beta sheet (β-sheet) Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Staining, ...

, 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.

Epidemiology

This is a rare condition with an incidence estimated to be less than 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.

References

Notes

* * Goldbach-Mansky, R. et al. ''Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1 Inhibition'' N Engl J Med 2006 355: 581–592.

External links

{{Medical resources , DiseasesDB = 32178 , ICD10 = G03.1 G44.8 L50.8 M08.9 , ICD9 = , ICDO = , OMIM = 607115 , MedlinePlus = , eMedicineSubj = , eMedicineTopic = , MeshID = D056587 Rheumatology Neonatology Rare diseases