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 ...

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

arthritis Arthritis is a general medical term used to describe a disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, Joint effusion, swelling, and decreased range of motion of ...

, 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, intense headache, vomiting and neck stiffness and occasion ...

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 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and ey ...

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 i ...

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

. 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 slightly modified recombin ...

. 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 In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to juveniles of ...

s are born

preterm Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is betwee ...

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

placenta The placenta (: placentas or placentae) 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 ...

may be abnormal with non-specific inflammation on histology.

Umbilical cord In Placentalia, 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 i ...

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

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

may be detected on prenatal

ultrasound Ultrasound is sound with frequency, frequencies greater than 20 Hertz, kilohertz. This frequency is the approximate upper audible hearing range, limit of human hearing in healthy young adults. The physical principles of acoustic waves apply ...

. 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 animal coverings, such as the arthropod exoskeleton, have different ...

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, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. All have a maculopapular

urticaria Hives, also known as urticaria, is a kind of skin rash with red or flesh-colored, 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 typically ...

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 generalized name of cell population in the microcirculation that is comprised of vascular smooth muscle cells (vSMCs), and pericytes. Both types are in close contact with the endothelial cells lining the capillaries, and are i ...

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, that ...

. 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 or c ...

between crises, or to unpredictable anomalies of growth

cartilage Cartilage is a resilient and smooth type of connective tissue. Semi-transparent and non-porous, it is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints ...

and long bones

epiphyses An epiphysis (; : epiphyses) is one of the rounded ends or tips of a long bone that ossify from one or more secondary centers of ossification. Between the epiphysis and diaphysis (the long midsection of the long bone) lies the metaphysis, inc ...

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. Although hypertro ...

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, 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 joint. The ...

elbow The elbow is the region between the upper 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 t ...

s, and

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; "The wrist contains eight bones, roughly aligned in two rows, known as the carpal ...

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 (: patellae or patellas), 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 m ...

s. Severe cases may result in

contractures In pathology, a contracture is a shortening of muscles, tendons, skin, and nearby soft tissues that causes the joints to shorten and become very stiff, preventing normal movement. A contracture is usually permanent, but less commonly can be temp ...

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

, involvement of both the optic tract and

eye An eye is a sensory organ that allows an organism to perceive visual information. It detects light and converts it into electro-chemical impulses in neurons (neurones). It is part of an organism's visual system. In higher organisms, the ey ...

, and

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

. 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 cerebrospinal fluid (CSF) builds up within the brain, which can cause pressure to increase in the skull. Symptoms may vary according to age. Headaches and double vision are common. Elderly adults with n ...

, 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 A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

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

meninges In anatomy, the meninges (; meninx ; ) 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 the subarachnoid spac ...

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 or Madras eye, is inflammation of the conjunctiva, the thin, clear layer that covers the white surface of the eye and the inner eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness ...

, 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 (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...

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 Heredity, familial genetic characteristic. People diagnosed with macrocephaly will receive further medical ...

(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 ...

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

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and

spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...

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 includ ...

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, weigh ...

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 female, the testicles i ...

and secondary

amenorrhoea Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...

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 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.

Diagnosis

The diagnosis is based on observing the patient and finding the constellation of symptoms and signs described above. A few

blood test A blood test is a medical laboratory, laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose ...

s 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 Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availab ...

, 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 in ...

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 ...

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 and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...

counts (0–30% of cases). CSF

neopterin Neopterin is an organic compound belonging to the pteridine class of heterocyclic compounds. Neopterin belongs to the chemical group known as pteridines. It is synthesised by human macrophages upon stimulation with the cytokine interferon-gamma an ...

may be elevated. The X ray abnormalities are unique and characteristic of this syndrome. These changes include bony overgrowth due to premature

ossification Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in t ...

of the patella and the long bone

in very young children and bowing of long bones with widening and shortening

periosteal reaction A periosteal reaction is the formation of new bone in response to injury or other stimuli of the periosteum surrounding the bone. It is most often identified on X-ray films of the bones. Cause A periosteal reaction can result from a large number ...

in older ones.

Audiometry Audiometry () is a branch of audiology and the science of measuring hearing acuity for variations in sound intensity and pitch and for tonal purity, involving thresholds and differing frequencies. Typically, audiometric tests determine a subje ...

shows a progressive sensineural

deafness Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is writte ...

. Visual examination shows optic atrophy and an increase in the blind spot. CT is usually normal but may show enlargement of the ventricles.

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...

with contrast may show enhancement of

leptomeninges In anatomy, the meninges (; meninx ; ) 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 the subarachnoid spa ...

and

cochlea The cochlea is the part of the inner ear involved in hearing. It is a spiral-shaped cavity in the bony labyrinth, in humans making 2.75 turns around its axis, the modiolus (cochlea), modiolus. A core component of the cochlea is the organ of Cort ...

consistent with chronic meningitis.

EEG Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The bio signals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neoc ...

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 * Still's disease *

Schnitzler syndrome Schnitzler syndrome or Schnitzler's syndrome is a rare disease characterised by onset around middle age of chronic hives (urticaria) and periodic fever, bone and joint pain (sometimes with joint inflammation), weight loss, malaise, fatigue, swol ...

* Hyperimmunoglobulin D syndrome *

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

Marshall syndrome Marshall syndrome is a genetic disorder of the connective tissue that 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 St ...

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 In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotid ...

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, formerly known as amethopterin, is a chemotherapy agent and immunosuppressive drug, immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancy, ectopic pregnancies. Types of cancers it is u ...

colchicine Colchicine is a medication used to prevent and treat gout, to treat familial Mediterranean fever and Behçet's disease, and to reduce the risk of myocardial infarction. The American College of Rheumatology recommends colchicine, nonstero ...

and canakinumab, 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 Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

, infections, and some develop deposits of protein aggregated called

amyloid Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure (known as cross-β) and ability to be stained by particular dyes, such as Congo red. In the human ...

, which can lead to

kidney failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

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.

Notes

References

* * 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