Immunodeficiency due to interleukin-1 receptor-associated kinase-4 deficiency

Interleukin-1 receptor-associated kinase-4 (IRAK-4) deficiency is an immunodeficiency associated with increased susceptibility to invasive infections caused by pyogenic bacteria.

Summary:
Epidemiology
It has been described in less than 15 patients from eight families with onset occurring during childhood.
Clinical description
The most common recurrent infections in these patients were caused by Streptococcus pneumoniae or Staphylococcus aureus, leading to a range of clinical manifestations such as pneumonia, septic arthritis, cellulitis, osteomyelitis, otitis media, meningitis and sinusitis. In contrast, the patients appeared to be resistant to infection caused by most other bacteria, parasites and viruses but fungal infections have been reported. Although routine immunological evaluations generally gave normal results, the patients displayed reduced inflammatory responses and neutropenia during infectious episodes.
Etiology
IRAK-4 deficiency is caused by mutations in the IRAK-4 gene (chromosome 12q12). IRAK-4 is a member of the IRAK protein kinase family and is involved in the toll-interleukin 1 (TIR) signalling pathway.
Diagnostic methods
IRAK-4 deficiency should be suspected in patients with a failure to sustain antibody responses and recurrent pyogenic bacterial infections. Diagnosis can be confirmed by detection of IRAK-4 gene mutations and through characterisation of the reduced response of blood cells and fibroblasts to stimulation with a large range of interleukin-1 receptor (IL-1R) and toll-like receptor (TLR) ligands and whole bacteria (S. aureus, Escherichia coli and Mycobacterium tuberculosis).
Management and treatment
Intravenous immunoglobulin therapy (IVIG), antibiotic prophylaxis and administration of the heptavalent pneumococcal-conjugated vaccine have provided successful results in some cases.
Prognosis
The prognosis for most patients is good, with infections becoming less frequent with age. However, bacterial meningitis has lead to death in a few cases, particularly when it occurred during infancy.

                            Last update:
                            November 2006

                            - Expert reviewer(s):
                            Pr Alain FISCHER


Immunodeficiency due to MASP-2 deficiency is a rare, genetic immunodeficiency due to a complement cascade protein anomaly characterized by low serum levels of MASP-2 and a variable susceptibility to bacterial infections (e.g. pulmonary tuberculosis, pneumococcal pneumonia, skin abscesses and sepsis), and autoimmune diseases (e.g. inflammatory lung disease, cystic fibrosis, systemic lupus erythematosus). In many cases it remains asymptomatic.


Immunodeficiency due to selective anti-polysaccharide antibody deficiency

A rare primary immunodeficiency characterized by normal immunoglobulin levels (including IgG sub-classes) but impaired polysaccharide responsiveness.

Summary:
Epidemiology
Although the prevalence is not really known, >100 cases have been reported in the literature. The frequency ranges from 11-60% in selected patients with unexplained bacterial infections.
Clinical description
This condition can affect children > 2 years-old or adults, although most of the published cases are adults. Patients suffer from recurrent bacterial infections, mostly of the respiratory tract, such as bronchopulmonary infections (with or without bronchiectasis), recurrent bacterial sinusitis, or chronic rhinosinusitis. Sepsis and meningitis occur less frequently. Offending bacteria possess a polysaccharide capsule, such as pneumococci, Haemophilus influenzae (serotype b), meningococci and group B streptococci. Allergic manifestations are observed in half of the patients.
Etiology
This immunodeficiency is likely heterogeneous with multiple causes. Higher prevalence in certain ethnic populations and familial cases suggest genetic factors are involved. Several hypotheses have been proposed concerning the cause of the disease, but the most likely is a defect in splenic marginal zone B cells (MZB), which is supported by the observed impaired polysaccharide antibody response in splenectomized patients.
Diagnostic methods
The diagnosis is established by identifying deficient antibody response to polysaccharide antigens (usually unconjugated Streptococcus pneumoniae vaccine) contrasting with normal immunoglobulin (including the IgG subclasses) levels and unaffected antibody production to protein antigens (tetanus toxoid, diphtheria) and conjugate polysaccharides. The response to pneumococcal capsular polysaccharide is tested using the third-generation enzyme-linked immunosorbent assay adopted by the WHO. The results must be interpreted according to the guidelines issued in 2012 by the American Academy of Allergy, Asthma & Immunology (AAAAI) Working Group. A single serotype is considered to have normal response if the post-immunization antibody titer is > 1.3 μg/mL (considered to be protective) and/or achieves a 4-fold increase (relative to the preimmunization value). A 2-fold increase is considered acceptable if the initial titer was already > 1.3 μg/mL. A good immunization is defined if a normal response is observed for at least 50% (for children) to 70% (for adults) of the evaluated serotypes. As most children < 2 years old have a physiological defect in response to polysaccharide antigens, the diagnosis cannot be made before this age. Additionally, some patients also appear to be poor responders to conjugate polysaccharides. Anti-polysaccharide response cannot be evaluated in patients treated with steroids or immunosuppressants.
Differential diagnosis
Practicians should exclude other primary immunodeficiencies also characterized by a defective response to polysaccharide antigens, mostly common variable immunodeficiency (CVID), the IgG2 and IgG3 deficiencies. A defect in antibody production to polysaccharides may also be associated with Wiskott-Aldrich syndrome.
Management and treatment
Antibiotics should be given to both control and prevent infections as a prophylactic treatment when they are too frequent. Immunoglobulin substitution could also be of benefit whenever prophylactic antibiotherapy fails. Vaccinations with the conjugate antipneumococcal, antimeningococcal and anti-Haemophilus serotype b vaccines are also required.
Prognosis
Under treatment, infections are generally well controlled. However, patients should be carefully followed-up since this condition could evolve into a more severe immunodeficiency (IgG subclass deficiency or CVID), particularly if the diagnosis is made during childhood.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                            Dr Guillaume LEFEVRE


A rare, genetic, primary immunodeficiency disease characterized by increased susceptibility to recurrent, usually severe, infections (particularly by  Neisseria meningitidis, Escherichia coli, and Haemophilus influenzae), renal impairment and/or autoimmune diseases, typically manifesting with otitis media, bronchitis, meningitis, and/or septicemia, as well as hematuria/proteinuria, asthma, nephrotic syndrome, hemolytic uremic syndrome, glomerulonephritis, and/or systemic lupus erythematosus. Laboratory serum analysis reveals, in addition to factor H deficiency, decreased complement factor B, properdin, complement C3 and terminal complement components.


A rare, genetic, primary immunodeficiency disease characterized by increased susceptibility to recurrent, usually severe, infections (particularly by Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae), typically manifesting as otitis, sinusitis, bronchitis, pneumonia, and/or meningitis. Autoimmune disease (e.g. systemic lupus erythematosus, glomerulonephritis) and atypical hemolytic uremic syndrome may be associated. Laboratory serum analysis reveals, in addition to diminished or undetectable complement factor I, variably decreased complement C3, complement factor B and complement factor H.


A rare glomerular disease, histologically characterized by glomerular mesangial deposits of IgA, often accompanied by IgG and complement C3 as well as mesangioproliferative changes, clinically mostly manifesting as oligosymptomatic glomerulonephritis, possibly infection-triggered macrohematuria and a variable course ranging from spontaneous remission to slow or rarely rapid progression to kidney failure.

Summary:
Epidemiology
In Europe, the annual incidence of IgA nephropathy (IgAN) is approximately 1/131,578, with a point prevalence of 1/3952. Higher prevalences are observed in Asia and lower prevalences in Africa. The male to female ratio is about 2:1 in Europeans. IgAN is rare in children younger than 10-12 years.
Clinical description
IgAN typically runs an oligosymptomatic course with microscopic hematuria, variable degrees of proteinuria (but usually not the nephrotic syndrome), hypertension and slowly progressive decline of glomerular filtration rate (GFR). Consequently, the disease is often diagnosed by chance in younger adults undergoing medical work-up. Sometimes macrohematuria occurs within 1-2 days after the onset of an upper respiratory tract infection. If diagnosed very early, IgAN may spontaneously remit in up to 30% of the cases, whereas 25% slowly loose GFR. Of the patients coming to medical attention at later chronic kidney disease (CKD) stages, up to 100% progress to kidney failure over 20-30 years.
Etiology
IgAN is characterized by the deposition of IgA1 with a particular undergalactosylation pattern in the IgA1 hinge region (gd-IgA1). Deposition of gd-IgA1 with or without IgG directed at gd-IgA1 leads to complement activation, mesangial and other glomerular cell injury, followed by glomerulosclerosis and tubulointerstitial fibrosis. The origin of the B-cells producing undergalactosylated IgA1 may be the intestinal muscosa, pointing to the existence of a gut-kidney axis in IgAN, which is supported by genome-wide association studies.
Diagnostic methods
A diagnosis of IgAN can only be made by kidney biopsy. Findings include mesangial hypercellularity and matrix expansion, endocapillary proliferative changes, glomerulosclerosis and tubulointerstitial fibrosis. Glomerular crescents occur in up to 20% of all biopsies but are rarely extensive. The later very rare cases are characterized by kidney failure occurring within months to a few years.
Differential diagnosis
Secondary causes of IgAN should be excluded. These include rheumatologic, celiac, and chronic inflammatory bowel disease, and infections (hepatitis B, hepatitis C). Other associations may be coincidental since glomerular IgA deposits can be frequently detected in autopsies even in patients with no known disease.
Management and treatment
All patients should receive optimized conservative therapy, targeting blood pressure, proteinuria, and life style (stop smoking, normalize body weight, dietary sodium and protein restrictions). Use of an ACE-inhibitor or angiotensin receptor blocker with systematic uptitration to the maximum allowed or tolerated dose is mandatory in patients with a proteinuria above 0.5 g/d. Patients should also receive a sodium-glucose cotransporter-2 (SGLT2) inhibitor. The value of high dose corticosteroids tapered over 6 months is controversial with some studies (in particular in Asian patients) reporting a delay of kidney failure by about 2.5 years, whereas recent European studies noted no benefit. All randomized trials noted a significant increase in serious adverse events with high dose corticosteroids, including infection-related mortality. In 2022 an enteric coated preparation of budesonide (nefecon) was licensed for IgAN. In 2023 this was followed by sparsentan, a dual angiotensin-II receptor and endothelin receptor-A blocker. Drugs in clinical testing include selective endothelin receptor-A blockers, B-cell proliferation and differentiation inhibitors (targeting APRIL and/or BAFF) and drugs targeting the complement system.
Prognosis
The prognosis over 5-6 years can be estimated using the International IgAN Prediction Tool. Major prognostic parameters include the degree of proteinuria, GFR impairment at baseline, hypertension, nicotine consumption and obesity. However, in particular in younger adults with IgAN even low levels of proteinuria (i.e. <1 g/d) carry a high life-time risk of kidney failure.

                            Last update:
                            December 2023

                            - Expert reviewer(s):
                            Dr Jürgen FLOEGE | ERKNet*

                                * European Reference Network


A rare, small-vessel vasculitis characterized by skin purpura, arthritis, abdominal and/or renal involvement, IgA tissue deposits (arterioles, capillaries, and venules) and circulating IgA immune complexes.

Summary:
Epidemiology
The disease usually affects children and is rare in adults. Annual incidence in children is estimated at between 1/4,880 and 1/6,660, whereas it is estimated at around 1/1,000,000 in adults. The male-to-female ratio is 1.5:1.
Clinical description
Patients present with vascular purpura that is usually symmetrical and primarily localized to the buttocks and legs. In adults it is more frequently complicated by necrotic or hemorrhagic bullous lesions. The lesions progressively regress, disappear after a few days and, in 80% of cases, never reappear. Patients also present with arthralgia, predominantly involving the knees and ankles. Abdominal pain is common and may be associated with life-threatening gastrointestinal bleeding. Renal involvement is more severe and frequent in adults. It usually consists of microscopic hematuria with varying degrees of proteinuria. Nephrotic syndrome, renal failure, and hypertension may also occur. Other manifestations are rare but may include headaches, seizures, paresis, orchiepididymitis, uretritis, pancreatitis, myositis, episcleritis, pulmonary bleeding and myocarditis.
Etiology
The disease is associated with deposition of IgA-dominant immune complexes in arterioles, capillaries, and venules, but the exact etiology remains unknown. Several different viral or bacterial organisms, drugs, foods, and insect bites have been implicated as the initiating factors of the disease.
Diagnostic methods
The diagnosis is based on clinical and histopathological findings. Examination of skin and kidney biopsies reveals tissue deposition of IgA with circulating IgA immune complexes.
Differential diagnosis
Differential diagnoses include other causes of purpura such as thrombopenia, hemopathy or infectious diseases. In adults, ANCA associated vasculitis, systemic lupus erythematosus, and mixed cryoglobulinemia should also be considered in the differential diagnosis.
Management and treatment
The treatment is symptomatic. The use of steroids and/or immunosuppressors is controversial but may be considered in case of severe gastrointestinal or renal manifestations. Renin-angiotensin-system blockers should be started as soon as the proteinuria/creatinine ratio is greater than 50 mg/mmol.
Prognosis
Gastrointestinal or pulmonary bleeding can be life-threatening. The long term prognosis depends on the extent of the renal involvement. Long term follow-up studies of adult series show that end-stage renal failure may occur in up to one-third of patients.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Dr Evangeline PILLEBOUT


A primary form of membranoproliferative glomerulonephritis (MPGN) characterized by deposition in the renal glomeruli of immunoglobulin with complement fractions, especially C3. Clinical presentation may range from nephrotic syndrome and acute kidney injury to asymptomatic proteinuria and hematuria.

Summary:
Epidemiology
It is amongst the rarest forms of glomerular disease; the annual incidence is unknown. Distribution between males and females tends to be equal, and presents at all ages, starting from early childhood.
Clinical description
Clinical features and severity are heterogenous, ranging from asymptomatic proteinuria which is noticed on routine urinalysis, to typical nephritic syndrome with mild proteinuria and hematuria, to a more acute presentation with nephrotic syndrome (edema, oligoanuria), hypertension and possibly acute renal failure. An infectious trigger, typically but not exclusively an upper respiratory tract infection, is frequently described, particularly in children presenting with macroscopic hematuria. Circulating complement evaluation shows frequently reduced C3, while C4 is usually normal.
Etiology
When a clear underlying etiology cannot be identified despite a thorough evaluation, Ig-mediated MPGN is considered primary or idiopathic. Variants in genes encoding for complement alternative pathway proteins and C3 nephritic factor are detected in 10%-25% and in 40%-54% of patients respectively.
Diagnostic methods
Diagnosis relies on renal biopsy, which shows features of MPGN with deposition of both immunoglobulins (IgG, IgA, IgM) and of complement (mainly C3, but also C1q, C4d). Upon histological diagnosis, secondary forms need to be excluded by screening for infection (mainly hepatitis B and C), autoimmune conditions (mainly systemic lupus erythematosus) and monoclonal gammopathies (especially in adults > 50 years of age). In primary forms, especially if circulating C3 is persistently reduced, screening for alternative pathway of complement dysregulation, both genetic and serological, should be performed in expert centers.
Differential diagnosis
At onset, this glomerular disease may resemble acute post-infectious glomerulonephritis, especially in children, which is a more frequent and self-limiting form of glomerulonephritis. Forms presenting with intra or post-infectious macrohematuria and proteinuria may resemble IgA nephropathy clinically, but the renal biopsy will give a different picture. The histological picture can also be found in secondary forms of MPGN, mostly due to infections, autoimmune conditions or monoclonal gammopathies.
Genetic counseling
The forms of immunoglobulin-mediated MPGN with genetic mutations identified in genes encoding for alternative pathway regulator proteins are very rarely familial and disease pathogenesis is multifactorial. Therefore, genetic counseling may be useful but is not essential.
Management and treatment
Management is based on the severity of the presenting features. Due to the rarity of these conditions, expert advice should be sought both for appropriate treatment and for genetic and serological work-up. All patients with proteinuria should receive optimal conservative treatment with low-salt diet, renin-angiotensin system inhibitors and, when appropriate, lipid lowering agents. Although evidence is limited, immunosuppressive treatment is usually used when proteinuria and glomerular inflammation are present, using oral glucocorticoids and mycophenolate mofetil. Response is not always optimal. In the presence of intense inflammation with extracapillary proliferation or acute renal failure, more intense immunosuppression is attempted with anti-proliferative agents such as cyclophosphamide and intravenous boli of methylprednisolone. In patients with evidence of alternative pathway of complement dysregulation, particularly if the above approach has not been successful, the use of complement inhibitory agents may be reasonable. Treatment with these agents, particularly with eculizumab, has only proven effective in approximately one-third of patients. Further agents acting upstream, at the C3 convertase level, need to be investigated in clinical trials.
Prognosis
Though this disease is very heterogenous and can be extremely subtle with low-grade relapsing proteinuria, long-term prognosis in forms which do not respond to treatment is poor, leading not only to terminal renal failure but also to a consistent risk of relapse post-renal transplantation.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Dr Erica DAINA | ERKNet* - Dr Marina VIVARELLI | ERKNet*

                                * European Reference Network


Immunotactoid glomerulopathy (ITG) is a very rare condition characterized by glomerular accumulation of microtubules in the mesangium and the glomerular basement membrane, that mainly presents with proteinuria, micro-hematuria, nephrotic syndrome, renal insufficiency and hematologic malignancy. ITG and non-amyloid fibrillary glomerulopathy (non-amyloid FGP, see this term) are often grouped together as pathogenetically related diseases.

Summary:
Epidemiology
In native renal biopsies, ITG comprises an estimated incidence of 0.06% of adult GN. The disease mainly affect Caucasian population and patients over 50 years old. Men are slightly more affected than women.
Clinical description
ITG may manifest with proteinuria (usually nephrotic), hematuria, renal insufficiency and hypertension. Patients present with edema, ascites, pleural effusion and have an elevated risk of blood clots and infection. ITG patients manifest at a high frequency with hypocomplementemia, dysproteinemia, monoclonal gammopathy, cryoglobulinemia and lymphoproliferative disorders (mainly B-cell lymphocytic leukemia or small lymphocytic non-Hodgkin's lymphoma).
Etiology
Etiopathology of ITG is unknown. It may arise spontaneously or be associated with lymphoproliferative disorders, hepatitis C virus infection, leukocytoclastic vasculitis and hypocomplementemia.
Diagnostic methods
Diagnosis of ITG is based on renal biopsy. Common histological patterns include those of membranoproliferative, diffuse proliferative or membranous glomerulopathy. The diagnosis is also based on the absence of reactivity with Congo red and other agents typically used for the histochemical demonstration of amyloid tissues (e.g. thioflavin T), as well as observation on light, fluorescence and electron microscopy. At the ultrastructural level, deposits consist of usually parallel, hollow microtubular structures (10-90 nm in diameter, often >30 nm), mainly composed of monoclonal immunoglobulin G and complement component 3 (C3). Other laboratory findings may include low serum albumin and an increase in creatinine and in blood cholesterol.
Differential diagnosis
Differential diagnosis of ITG includes simple cryoglobulinemia, systemic lupus erythematosus, amyloidosis and non-amyloid FGP (see these terms).
Management and treatment
No proven effective therapy has been reported for ITG so far. Diuretics (e.g. furosemide) and dietary/fluid restrictions may be recommended in order to reduce fluid retention and prevent the accumulation of salt in the blood. An angiotensin-converting enzyme inhibitor may be prescribed in case of mild renal damage and low levels of protein loss. A statin and blood-thinning medication may be required to reduce cholesterol and the risk of blood clotting respectively, in case of a heavier protein leak. In case of rapidly progressive GN, cyclophosphamide and high doses of steroids may be indicated. Finally, when the disease is associated with an underlying condition, effective therapy directed at this underlying disorder may have some beneficial effect on the renal disease.
Prognosis
The overall course of ITG is usually slowly progressive, with about half of the patients developing end-stage renal disease over 2-4 years, requiring dialysis or renal transplantation. ITG recurrence in the transplanted kidney has been reported. A more extensive glomerular involvement or the presence of systemic involvement renders ITG prognosis poorer.

                            Last update:
                            March 2016

                            - Expert reviewer(s):
                            Dr Laure Hélène NOEL


Immunotactoid or fibrillary glomerulopathy is a group of very rare glomerular diseases, composed of immunotactoid glomerulopathy (ITG) and non-amyloid fibrillary glomerulopathy (non-amyloid FGP) (see these terms), that are characterized by mesangial deposition of monoclonal microtubular or polyclonal fibrillar deposits. Both present clinically with nephrotic range proteinuria, hematuria and renal insufficiency leading to renal failure in many cases. ITG is more likely to manifest with underlying lymphoproliferative disease, hypocomplementemia, dysproteinemia, monoclonal gammopathy or occult cryoglobulinemia. Non-amyloid FGP is 10 times more frequent than ITG.


Imperforate oropharynx-costovertebral anomalies syndrome is a dysostosis with predominant vertebral and costal involvement characterized by oropharyngeal atresia, mild mandibulofacial dysostosis, auricular malformations, and costovertebral anomalies (hemivertebrae, block vertebra, partial fusion of the ribs, absent ribs). There have been no further descriptions in the literature since 1989.


Incessant infant ventricular tachycardia is a rare type of ventricular tachycardia (VT) characterized by the presence of tachycardia originating from the ventricles, observed for more than 10% of a 24 hour monitoring period. Patients are either asymptomatic or present congestive heart failure.

Summary:
Epidemiology
The incidence of incessant infant VT is estimated to be 1/333,300 live births in the United Kingdom. Males are more commonly affected than females.
Clinical description
This type of VT is diagnosed in infancy or early childhood, usually presenting at between 3 and 30 months of age. The rate of VT ranges from 170 to 440 (mean 260) beats/min occurring more than 10% of the day. The most common clinical presentation is VT with congestive heart failure.
Etiology
The physiopathology of this type of VT is unknown but it has been suggested that microscopic tumors such as myocardial hamartomas, also known as histiocytoid cardiomyopathy (see this term), are responsible.
Diagnostic methods
The electrocardiogram (ECG) usually shows a type of right bundle branch block morphology and a superior axis, predicting a tachycardia origin in the posterior or inferior left ventricle. There is usually clear evidence of ventriculo-atrial block with dissociated P waves, or capture beats or fusion beats. The finding of wide QRS tachycardia with retrograde block confirms the diagnosis of ventricular tachycardia. No structural abnormalities are found on the echocardiogram but there is often poor ventricular function at presentation.
Differential diagnosis
The differential diagnosis includes other types of ventricular tachycardia and supraventricular tachycardia with a wide QRS.
Management and treatment
Immediate treatment involves control of tachycardia and general support or resuscitation as required. Intravenous lidocaine (1-2 mg/kg) will usually slow or stop the tachycardia leading to rapid symptomatic improvement. Intravenous amiodarone is an alternative. Direct current (DC) cardioversion is usually ineffective. Once sinus rhythm has been restored, drugs such as amiodarone and flecainide are usually effective in suppressing the arrhythmia, sometimes in combination with a beta-blocker. Digoxin and verapamil are best avoided as they may worsen the tachycardia and lead to cardiovascular collapse.
Prognosis
Tachycardia usually resolves before the age of five years and drug treatment can be withdrawn. Late recurrence is unusual.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christopher WREN


Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is a multisystem degenerative genetic disorder characterized by adult-onset proximal and distal muscle weakness (clinically resembling limb-girdle muscular dystrophy; see this term); early-onset Paget disease of bone (see this term), manifesting with bone pain, deformity and enlargement of the long-bones; and premature frontotemporal dementia (see this term), manifesting first with dysnomia, dyscalculia and comprehension deficits followed by progressive aphasia, alexia, and agraphia. As the disease progresses, muscle weakness begins to affect the other limbs and respiratory muscles, ultimately resulting in respiratory or cardiac failure.


A rare degenerative inflammatory disorder of skeletal muscles characterized by late onset weakness, starting in either the quadriceps or finger flexors and slowly progressing to include other groups of limb muscles. Distinctive histopathological features include inflammatory and degenerative features.

Summary:
Epidemiology
Inclusion body myositis (IBM) has a highly variable prevalence according to geographic, ethnic and age criteria. Prevalence in the general population ranges from 1/14,000-1,000,000 but a three-fold increase is observed when considering only a population over 50 years. Underdiagnosis may be an explanation for the high ethno-geographic variation. Male-to-female ratio is 2:1 on average (but varies between 0.5 to 6.5:1).
Clinical description
IBM onset is over 50 years but the disease may also occur earlier, in the 4th decade. Compared to other idiopathic inflammatory myopathies, the clinical phenotype is characteristic with distal and asymmetrical muscle involvement, amyotrophy, and no extramuscular manifestations. First signs are weakness or even atrophy of the quadriceps or of the finger flexors, leading to difficulties in rising from chairs or ground, climbing stairs, gripping, lifting and using tools, and thereby provoking falls. Flexor digitorum profundus and flexor pollicis longus are more severely involved than the forearm extensor muscles, especially during early stages of the disease. With disease progression, other groups of muscles are also involved, such as the elbow flexors, the hip, knee or neck flexors, and the ankle dorsiflexors, leading to footdrop. Patients frequently have a mild weakness of facial muscles, except for the extraocular muscles. Dysphagia may occur in approximately 66% of patients in advanced stages of the disease and can be severe in some cases.
Etiology
Etiology of IBM is poorly understood. No causal gene has been identified but genes encoding the major histocompatibility complex (MHC), HLA-DR3 and 8.1 ancestral haplotypes (HLA-A1, B8, DRB1*0301), have been shown to correlate with IBM susceptibility. Ageing and environmental factors are also surmised to play a triggering role. Whether IBM is primarily an immuno-inflammatory disorder leading to muscle degeneration or a degenerative disorder leading to muscle inflammation is still under debate. The pathogenic role of anti-cN1A, which is detected in 30-50% of patients, is also debated as it is not specific to IBM and may be found in patients with other autoimmune diseases as well as in healthy controls.
Diagnostic methods
Diagnosis is based on physical examination (especially the detection of finger flexor weakness), age of presentation and a duration of symptoms over 6 months. Muscle biopsy identifies the inflammatory (diffuse MHC class I sarcolemmal overexpression, endomysial inflammatory infiltrates including CD8+ T cells, T cell invasion of non-necrotic muscle fibers) and degenerative features (rimmed vacuoles, P62 and/or TDP43 aggregates and, occasionally, an abnormally elevated number of COX-negative fibers). Laboratory findings are not specific as serum creatine kinase is only slightly raised in some cases. Electromyography only helps in confirming the myopathic origin of the weakness or atrophy. Magnetic resonance imaging (MRI) helps delineating the characteristic pattern of muscle involvement.
Differential diagnosis
Differential diagnosis may include other idiopathic inflammatory myopathies and, in early stages of the disease, arthritis or any motor neuron disease.
Management and treatment
There is no curative treatment for IBM, and patients usually do not respond to anti-inflammatory or immunosuppressant therapies. The standard of care involves symptomatic treatments including exercise therapy, ergotherapy, and orthotic appliance. However, clinical trials are ongoing for new therapeutic strategies, of note for sirolimus, an inhibitor of mTOR.
Prognosis
No change in mean life expectancy has been observed. IBM patients present a progressive and continuous loss of muscle strength between 3.5-16.8% per year. There is a major impact of the disease on the daily activity. After 5 years, most patients require a walking aid and after 10, a wheelchair.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Dr Céline ANQUETIL  - Pr Olivier BENVENISTE


A histopathological form of portosinusoidal vascular disease characterized by the presence of incomplete, thin, perforated, or blind-ended septa, which intermittently delimit rudimentary nodules, although complete cirrhotic-type regenerative nodules are not seen. Isolated collagen bundles can also be observed within the parenchyma.


An X-linked syndromic muti-systemic ectodermal dysplasia presenting neonatally in females with a bullous rash along Blaschko's lines (BL) followed by verrucous plaques and hyperpigmented swirling patterns. It is further characterized by teeth abnormalities, alopecia, nail dystrophy and can affect the retinal and the central nervous system (CNS) microvasculature. It may have other aspects of ectodermal dysplasia such as sweat gland abnormalities. Germline pathogenic variants in males result in embryonic lethality.

Summary:
Epidemiology
The birth prevalence is approximately 1/ 143,000. The female to male ratio is 20:1.
Clinical description
The disorder cutaneous findings typically present perinatally with an erythematous vesicular rash (bullous stage I) following BL: linear on extremities, swirled on trunk and head. Classically, Stage I evolves to a verrucous stage II characterized by wart-like plaques then to Stage III hyperpigmentation along BL that can persist to adulthood. This evolution varies and some adults report persistence of Stages I and II, usually with febrile illness, well into adulthood. These three stages are not sequential, as stage I rash can recur during febrile illness. The so-called Stage IV findings have hypopigmented, hairless regions following BL mostly evident on the lower extremities; however, it is possible that these areas of skin dysplasia may be present from an earlier age, but not visible until the growth of adult body hair. About 50% of IP symptoms are extracutaneous. Delayed dentition, missing, and/or malformed cone shaped teeth occur in most cases. Other manifestations include onycodystrophy, alopecia and a wide range of ophthalmologic abnormalities from primary microphthalmia, to reactive retinal neovascularization (RNV) conferring risk of retinal detachment. CNS abnormalities may comprise microcephaly and neonatal stroke that can result in seizures, neurocognitive and motor impairments. The majority (>60%) of patients are neurologically normal.
Etiology
IP is caused by familial (10-25%) or sporadic de novo (>50%) mutations of the NF-kappaB essential modulator gene IKBKG (formerly NEMO). In females, a common exon 4-10 deletion underlies 65% of cases, 8.6% have a sequence variant, and about 4% have a gene deletion.
Diagnostic methods
Typical skin lesions and genetic testing are sufficient for diagnosis. Leukocytosis and eosinophilia may be noted. Skin histology shows eosinophilic spongisostic bulles (stage I); hyperkeratotic and acanthotic epidermis with dyskeratotic keratinocytes (stage II) and loose dermal melanine deposits (stage III).
Differential diagnosis
Stage I may be misdiagnosed as bullous impetigo, inherited epidermolysis bullosa, herpes, or varicella. Differential diagnosis of stage II includes warts, molluscum contagiosum, and epidermal nevus syndrome. Any condition with 'linear and swirled' pigmentation overlaps with stage III. Stage IV resembles scarring, vitiligo, or other hypopigmentations with localized alopecia. Note that chromosomal mosaicism can manifest swirled and linear pigmentation abnormalities in both males and females. Additional reported differential diagnoses are Naegeli-Franceschetti-Jadassohn syndrome and Norrie's disease.
Antenatal diagnosis
Fertility is normal except for the miscarriage of affected males. Genetic prenatal diagnosis is available.
Genetic counseling
IP is inherited X-linked dominantly. An affected woman has a 50% risk of having affected children. Live-born affected males should be checked for a 47,XXY karyotype.
Management and treatment
Treatment is symptomatic, including standard management of blisters (not opening them and avoidance of trauma), topical treatment (medication, oatmeal baths) and addressing infections (as in cellulitis). Dental abnormalities should be managed by a pedodontist in combination with speech therapy and a pediatric nutritional program as needed. Appropriate specialists are required for RNV monitoring and treatment (cryotherapy and laser photocoagulation) and regular procedures should be followed if retinal detachment occurs. Early retinal angiograms may be indicated. Neurological involvement necessitates a pediatric neurologist, whereas developmental screening and additional complementary therapy may be recommended in cases with developmental delay.
Prognosis
Life expectancy is normal. Those without neonatal CNS abnormalities typically have normal physical and cognitive development.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Dr Angela SCHEUERLE


A rare neoplastic disease characterized by multiple, and on occasion single, asymptomatic, smooth, red-brown papulonodules located on the face, neck, trunk and/or extremities which present a nonepidermotrophic histiocytic infiltrate with immunohistochemical features of both Langerhans and non-Langerhans cells (i.e. immunopositive for S100 protein and CD1a in the absence of Birbeck granules and langerin expression).


A rare, usually benign, chronic, form of systemic mastocytosis (SM) characterized by an abnormal accumulation of neoplastic mast cells (MCs) mainly in the bone marrow (BM) but also in other organs or tissues such as preferably the skin.

Summary:
Epidemiology
Indolent SM (ISM) represents 90% of all cases of SM for which the prevalence in Europe is estimated between 1/7,700 and 1/10,400.
Clinical description
ISM mainly affects adults and typically presents with skin lesions (ISM+), usually in the form of urticaria pigmentosa (UP), while only a few patients have no skin lesions (ISM-). In addition, ISM patients frequently suffer from MC mediator-related symptoms, including pruritus, flushing, syncope, headache and gastro-intestinal (GI) events (vomiting, diarrhea, abdominal pain). Isolated BM mastocytosis (BMM) is a provisional subcategory of ISM typically characterized by absence of cutaneous lesions of ISM and normal to slightly elevated basal tryptase levels. In most patients with BMM, the KIT D816V allele burden in the peripheral blood is low. A BM smear typically reveals small-sized clusters and aggregates of MCs. In both ISM and BMM, patients have a high risk to develop severe anaphylactic reactions to various exogenous substances (triggers/allergens) such as insect bites. Presentation of severe osteoporosis or even spontaneous fractures is also possible.
Etiology
Although the etiology of ISM is not fully understood, an activating mutation of KIT, usually KIT D816V, is found in the MCs of virtually all ISM cases. This mutation probably accounts for the abnormal accumulation of MCs in organ(s)/tissue(s). In some cases, the mutation is found primarily in the neoplastic MC compartment; in other cases, the mutation may be detected in other mature BM and peripheral blood cells such as basophils, eosinophils, neutrophils, as well as B- and T-lymphocytes. Furthermore, precursors of erythroid and myeloid cells as well as CD34+ progenitors may carry the KIT D816V mutation, suggesting the involvement of a pluripotent stem cell.
Diagnostic methods
SM diagnosis is established using the WHO consensus criteria and is subsequently categorized according to the presence of B-findings and C-findings. In ISM and BMM there are neither B-findings, nor C-findings.
Differential diagnosis
Differential diagnoses include all the other forms of SM as well as other causes of MC activation syndromes (MCAS): primary (clonal, but not fulfilling SM diagnostic criteria) MCAS; secondary MCAS where an IgE-dependent allergy or another reactive inflammatory disease process is present; and idiopathic MCAS where neither clonal MC nor an IgE-dependent allergy or another underlying condition/disease can be documented. Additional differential diagnoses include other forms of mastocytosis (pure cutaneous mastocytosis, mast cell sarcoma), endocrine disorders (adrenal tumors, VIPoma, gastrinoma), some gastrointestinal pathologies. In ISM-, the differential diagnosis is BMM. It should also be possible to distinguish Waldenström disease.
Management and treatment
Indolent SM patients, as well as those with BMM, usually only require symptomatic treatments. The main objective is to reduce the symptoms of MC activation, such as pruritus, flushes and gastrointestinal cramps. In case of pruritus or skin manifestations, antihistamines H1 (anti-H1) are used. For GI tract manifestations, anti-H2 are effective and can be combined with anti-H1, with di-sodium cromoglycate or with leukotriene inhibitors. Corticoids can suppress antihistamines recalcitrant symptoms. Epinephrine is indicated for hypotension, which may be spontaneous or observed after an insect bite. Patients should be trained to self-administer injectable epinephrine. Of note, some SM patients may suffer from bee or wasp venom allergy. In these patients, specific immunotherapy should be administered lifelong to ensure protection. For patients with SM and osteoporosis, biphosphonates are recommended with adequate supplementation of calcium and vitamin D.
Prognosis
The evolution of ISM and of BMM is slow and benign. The prognosis is generally good and life expectancy is similar to that of the general population. However, some of these patients may finally progress to SSM, SM-AHN, ASM or even MCL; multilineage KIT D816V involvement is probably the most important prognostic criterion for progression of ISM to more advanced SM subtypes.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Michel AROCK


Indomethacin embryofetopathy refers to the manifestations that may be observed in a fetus or newborn when the mother has taken indomethacin, a potent prostaglandin inhibitor and tocolytic agent that can cross placenta, during pregnancy. Reported adverse fetal/neonatal effects include decreased renal function resulting in oligohydramnios, closure of the ductus arteriosus, and delayed cardiovascular adaptation at birth. These effects are usually transient and reversible. Indomethacin may also be a risk factor for cerebral injury (periventricular leukomalacia) and necrotizing enterocolitisin preterm infants.


A rare form of botulism, a rare acquired neuromuscular junction disease with descending flaccid paralysis caused by botulinum neurotoxins (BoNTs). It is due to intestinal colonization by Clostridium botulinum leading to toxin-mediated infection with toxemia.

Summary:
Epidemiology
Prevalence is unknown. So far, at least 3,350 cases of infant botulism have been reported worldwide, except in Africa, and it is the most frequently occurring form of botulism in the USA and Argentina.
Clinical description
The disease affects infants between one and 52 weeks of age. Incubation is estimated between three and 30 days from the time of exposure to spores, although a case presenting after 38 hours has been reported. Clinical manifestations are similar to other forms of botulism (symmetrical cranial nerve palsy, followed by symmetrical descending flaccid motor paralysis), but infant botulism presentation is characterized by hypotonia, constipation, inability to suck and swallow, weak cry, ptosis, and poor head control. Fever is absent. The onset is subacute to acute and the disease may progress to generalized hypotonia (``floppy babies'') and respiratory failure. Cases of sudden infant death syndrome (SIDS) have been related to infant botulism. An initial presentation mimicking acute abdomen has also been reported.
Etiology
The disease is due to temporary intestinal colonization by spores of C. botulinum type A, B, E, or very rarely by neurotoxigenic strains of C. baratii type F and C. butyricum type E, and in situ toxin production. The spores can reach the intestinal tract by inhalation, or via food. Environmental dust and honey have been identified as the vehicle of spores. Intestinal colonization by Clostridia is believed to occur because normal competitive microflora has not been fully established. After spore germination and toxinogenesis, the BoNT is absorbed into the blood stream and distributed throughout the body, causing the typical manifestations of botulism.
Diagnostic methods
Diagnosis is based on clinical presentation; the electromyography (EMG) pattern is characterized by brief, small, abundant motor-unit action potentials (BSAPs). Diagnosis is confirmed by detection of BoNTs in stools or serum or, more frequently, by isolation of BoNT-producing Clostridia in stools.
Differential diagnosis
Differential diagnosis includes sepsis, dehydration, electrolyte imbalance, intoxication and encephalitis; it also includes metabolic disorders, myopathies, Guillain-Barré syndrome (Miller-Fisher syndrome), infantile spinal muscular atrophy (SMA1), congenital myasthenic syndromes and poliomyelitis (see these terms).
Management and treatment
Management consists mostly of supportive care, such as respiratory and nutritional support, in an intensive care unit (ICU). Antitoxin therapy with a human-derived Botulinum Immune Globulin (BIG-IV, anti A, B) is available for infants. Antibiotics are not effective and not recommended as they may lead to lysis of vegetative cells of BoNT-producing Clostridia, increasing the amount of free toxin. Complications include respiratory arrest with resultant hypoxic encephalopathy and irreversible brain damage or death, cardiac arrest, inappropriate antidiuretic hormone secretion syndrome with hyponatremia, serum hyposmolality and urinary hyperosmolality, and acute otitis media related to Eustachian tube dysfunction.
Prognosis
Prognosis is good in the absence of complications and, with appropriate intensive care, the survival rate is nearly 100% with or without antitoxin therapy.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Dr Lucia FENICIA


Infantile apnea is a cessation of respiratory air flow that may affect newborns or older children because of neurological impairment of the respiratory rhythm or obstruction of air flow through the air passages. The symptoms include cyanosis, pallor or bradycardia and snoring in case of obstructive apnea.


Infantile bilateral striatal necrosis (IBSN) comprises several syndromes of bilateral symmetric spongy degeneration of the caudate nucleaus, putamen and globus pallidus characterized by developmental regression, choreoathetosis and dystonia progressing to spastic quadriparesis. IBSN can be familial or sporadic (see these terms).

Summary:
Epidemiology
The prevalence of the sporadic form has been estimated at 1-9/1,000,000 and prevalence of the familial form has been estimated at less than 1/1,000,000.
Clinical description
The age of onset of familial IBSN varies between 7 months and 15 months, whereas sporadic IBSN can occur any time from the neonatal period through childhood and even in adolescence. Clinical features include choreoathetosis, dystonia, rigidity, spasticity, dysphagia, optic atrophy, intellectual deficit, developmental regression of motor and verbal skills, failure to thrive, myoclonus, quadriparesis, cerebellar ataxia and nystagmus. The familial form has an insidious onset and a slowly progressive downhill course, while the sporadic form is associated with abrupt neurologic dysfunction following an acute systemic febrile illness such as a mycoplasma, measles or streptococcus infection.
Etiology
Autosomal recessive IBSN is caused by mutation in the NUP62 gene (19q13.33) and mitochondrial IBSN is caused by mutation in the ATP synthase-6 gene (MTATP6).
Diagnostic methods
Diagnosis is based on clinical observation of choreoathetoid movements of the face, trunk and extremities and evidence of basal ganglia degeneration on CT and MRI images.
Differential diagnosis
Differential diagnoses include Wilson's disease, acute disseminated encephalomyelitis, neurodegeneration with brain iron accumulation, Leigh disease, juvenile Huntington chorea, methylmalonic aciduria, guanidinoacetate methyltransferase deficiency, glutaric acidemia I (see these terms), carbon monoxide intoxication, small vessel arteritis and trauma.
Antenatal diagnosis
Antenatal diagnosis and genetic counseling is offered to families of affected patients.
Genetic counseling
Familial IBSN can be inherited as an autosomal recessive or mitochondrial disorder.
Management and treatment
There is no standard therapy for familial IBSN. Treatment with oral biotin has been observed to slow disease progress initially. Treatment for the sporadic form is based on treatment of the causal infection.
Prognosis
Prognosis for the familial form is usually poor with patients progressing to spastic quadriparesis followed by death, usually due to infection. For the sporadic form, prognosis is variable, with either gradual improvement in symptoms and complete recovery, observed after recovery from the infection, or severe neurological sequelae.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Rachel STRAUSSBERG


A rare, neurodegenerative disorder characterized by an early onset of truncal hypotonia, variable forms of seizures, athetosis, severe global developmental delay, intellectual disability and various ophthalmologic abnormalities, including strabismus, nystagmus, optic atrophy and retinal degeneration.


Infantile cerebral and cerebellar atrophy with postnatal progressive microcephaly is a rare, central nervous system malformation syndrome characterized by progressive microcephaly with profound motor delay and intellectual disability, associated with hypertonia, spasticity, clonus, and seizures, with brain imaging revealing severe cerebral and cerebellar atrophy, and poor myelination.


Infantile choroidocerebral calcification syndrome

A rare syndromic intellectual disability characterized by severe intellectual disability and calcification of the choroid plexus, associated with elevated cerebrospinal fluid protein concentration. Additional signs and symptoms include strabismus, increased deep tendon reflexes, and foot deformities, among others. There have been no further descriptions in the literature since 1993.


Infantile convulsions and choreoathetosis

Infantile Convulsions and paroxysmal ChoreoAthetosis (ICCA) syndrome is a neurological condition characterized by the occurrence of seizures during the first year of life (Benign familial infantile epilepsy ; see this term) and choreoathetotic dyskinetic attacks during childhood or adolescence.

Summary:
Epidemiology
This disorder is rare but the exact prevalence is unknown.
Clinical description
Benign familial infantile epilepsy begins at 3 to 12 months of age with a family history of the same type of seizures. Seizures are afebrile, partial or sometimes generalized, and normally disappear after the first year of life. During childhood or adolescence, affected individuals present with paroxysmal kinesigenic dyskinesia with frequent and recurrent episodic choreathetotic or dystonic movements that last less than 1 minute. The attacks are triggered by the initiation of voluntary movements or startle. The association with other paroxysmal disorders such as migraine, with or without aura, hemiplegic migraine, episodic ataxia and tics has also been described. Psychomotor development is normal.
Etiology
The genetic loci of ICCA syndrome have been described on chromosomes 16p11.2-q12.1, 16q13-q22.1 and 3q29-29. Mutations in the Proline-rich transmembrane protein 2 (PRRT2) gene, located on 16p11.2, have recently been found in families affected by ICCA syndrome. This gene encodes a membrane protein that interacts with the presynaptic protein SNAP-25 but the mechanism leading to the disease remains unknown.
Diagnostic methods
The diagnosis is mainly clinical, based on the appearance of infantile convulsions with benign evolution followed by kinesigenic dyskinesia attacks later on. Genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnosis includes other paroxysmal dystonias such as paroxysmal exertion-induced dyskinesia and paroxysmal non-kinesigenic dyskinesia (see these terms) triggered by drugs or food intake (such as caffeine and alcohol).
Genetic counseling
ICCA syndrome can present as sporadic or familial; in the latter case, it is transmitted as an autosomal dominant trait that can be variably expressed within the same family.
Management and treatment
Antiepileptic drugs, mainly phenytoin or carbamazepine, are effective in controlling seizures and dyskinesia during the active phase of the disorder.
Prognosis
ICCA has a good outcome. Without treatment, dyskinetic attacks tend to disappear during adulthood.

                            Last update:
                            July 2013

                            - Expert reviewer(s):
                            Pr Federico VIGEVANO


A rare, benign, superficial fibromatosis characterized by firm, pinkish to flesh-colored, solitary or multiple nodular growths, typically less than 2 cm in size. They occur on the dorsal or lateral aspect of fingers and toes and have a tendency to recur. Histology reveals bland intradermal spindle cells with spherical perinuclear inclusion bodies.


Infantile dystonia-parkinsonism (IPD) is an extremely rare inherited neurological syndrome that presents in early infancy with hypokinetic parkinsonism and dystonia and that can be fatal.

Summary:
Epidemiology
The prevalence is unknown. Only eight cases have been reported to date.
Clinical description
The disease presents soon after birth with irritability and feeding difficulties, followed by progressive parkinsonism (manifesting with resting tremor and bradykinesia), dystonia, axial hypotonia, limb hypertonicity and pyramidal tract signs. Clinically it can resemble cerebral palsy. Global developmental delay and impaired motor development occur during childhood, and patients can have trouble communicating. Treatment with L-dopa is ineffective, and death was reported in one case.
Etiology
IPD is caused by mutations in the SLC6A3 gene (5p15.33), which encodes a human dopamine transporter mediating the active reuptake of extracelluar dopamine. Mutations in this gene lead to a reduction in the level of mature dopamine transporter and therefore an impairment in dopaminergic neurotransmission.
Genetic counseling
IPD is inherited in an autosomal recessive manner. Genetic counseling is possible and is recommended.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christoph KAMM


A rare epilepsy syndrome characterized by onset of epileptic spasms in infants between 2 and 12 months of age, and rarely up to 24 months. Infants may have no antecedent history, or a history reflecting the underlying cause. The classical triad of epileptic spasms, hypsarrhythmia and developmental stagnation or regression is historically referred to as West syndrome.

Summary:
Epidemiology
The estimated birth prevalence is between 1/1,650-20,000. Both sexes are affected, with a higher incidence in males.
Clinical description
Epileptic spasms are the typical type of seizures observed. They consist of brief tonic contractions of axial muscles, each typically lasting less than 3 seconds, which may be flexor, extensor or mixed. These usually occur in series or clusters, with increasing prominence of the motor features through the cluster, often over a period of minutes (though clusters may last 30 minutes or longer) and are often seen on awakening. Spasms may be symmetric or asymmetric and some might be subtle, with minor head nods, eye or chin movements. Prior to onset of spasms, development can be normal or abnormal depending on etiology. Developmental delay, arrest or regression is typically seen with the onset of spasms. Isolated regression in visual attention or altered social responsiveness may occur in the days or weeks preceding onset of spasms. Developmental plateauing and regression typically worsen without rapid, effective treatment. Infantile spasms syndrome may have different etiologies and can be a feature of other syndromes such as Down syndrome, tuberous sclerosis complex, inverted duplicated chromosome 15 syndrome, and rarely metabolic diseases.
Etiology
Pathogenic variants in genes and chromosomal abnormalities have been associated with infantile spasms syndrome; amongst syndromes frequently featuring infantile spasms, they include STXBP1, TSC1, TSC2 and trisomy 21. Other common genetic etiologies include ARX, CDKL5, SPTAN1. Structural abnormalities include acquired antenatal and perinatal lesions and malformations of cortical development.
Diagnostic methods
Diagnosis is based on the presence of epileptic spasms, which may be witnessed in person or observed in home video and should be confirmed by electroencephalography (EEG) /video-EEG with electromyography (EMG). Interictal EEG shows either hypsarrhythmia that is observed in the awake and/or sleep recording, or focal and multifocal epileptic anomalies with a less disorganized background. The ictal recording is characterized by a fast activity that might precede a high amplitude, generalized sharp or slow wave followed or super-imposed by low amplitude. EMG helps to distinguish epileptic spasms from myoclonic seizures and tonic seizures. Neuroimaging is useful to determine the syndrome etiology: MRI is abnormal in half to two-thirds of children and can show either acquired or congenital focal, multifocal or diffuse lesions. Metabolic investigations exclude metabolic diseases. Genetic studies may include chromosomal microarray, gene panels or exomes and should be considered in all patients mainly those without a known acquired structural etiology.
Differential diagnosis
Brief paroxysmal events which occur in clusters, both epileptic and non-epileptic, should be differentiated from epileptic spasms. These include myoclonic epilepsy in infancy, hyperekplexia, shuddering, infantile self-stimulation and gastro-esophageal reflux (Sandifer syndrome).
Genetic counseling
Counseling is important for subsequent pregnancies when a genetic etiology is identified. The pattern of inheritance depends on the etiology.
Management and treatment
First line pharmacological treatment is vigabatrin or a combination of corticosteroids and vigabatrin. Treatment should be introduced as early as possible when the diagnosis is established. Early referral to a tertiary epilepsy center should be considered in order to identify candidates suitable for surgery.
Prognosis
Infantile Spasms syndrome may evolve to other epilepsy types or syndromes, including Lennox-Gastaut syndrome, or drug-resistant focal epilepsies. The majority of infants have a poor developmental outcome, regardless of seizure outcome. Severity of developmental delay relates predominantly to etiology and time to treatment from spasm onset. In a small subgroup, patients can have a full recovery with freedom from spasms and no cognitive impact.

                            Last update:
                            April 2022

                            - Expert reviewer(s):
                            Pr Rima NABBOUT | EpiCARE*

                                * European Reference Network


A rare monogenic disease with epilepsy characterized by developmental delay and infantile spasms in the first months of life, followed by chorea and generalized dystonia and progressing to quadriplegic dyskinesia, recurrent status dystonicus, intractable focal epilepsy and severe intellectual disability.


Infantile glycine encephalopathy is a mild to severe form of glycine encephalopathy (GE; see this term), characterized by early hypotonia, developmental delay and seizures.

Summary:
Epidemiology
The prevalence of infantile glycine encephalopathy is not known. Infantile cases are less frequent than the classical neonatal form of GE (neonatal GE; see this term).
Clinical description
Patients present with infantile-onset seizures and variable psychomotor delay after initially normal development, and often have a relatively long history of hypotonia. Seizures of any type are found in less than half of patients and some develop choreoathetosis. Developmental delay mostly affects language and behavioral problems are sometimes found including temper tantrums, irritability, aggressiveness and rage. Attention deficit-hyperactivity disorder (AD-HD) is also sometimes found. Patients do not have lethargy or coma in the neonatal period, unlike those with neonatal GE. The course may be mild or severe (50% of patients in each case).
Etiology
Mutations in two genes are known to cause glycine encephalopathy: GLDC (9p22) and AMT (3p21.2-p21.1).
Genetic counseling
Infantile GE is inherited in an autosomal recessive manner.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                             Shigeo KURE


Infantile hypertrophic cardiomyopathy due to MRPL44 deficiency

A rare mitochondrial oxidative phosphorylation disorder with complex I and IV deficiency characterized by hypertrophic cardiomyopathy, hepatic steatosis with elevated liver transaminases, exercise intolerance and muscle weakness. Neuro-opthalmological features (hemiplegic migraine, Leigh-like lesions on brain MRI, pigmentary retinopathy) have been reported later in life.


A rare, severe, genetic form of hypophosphatasia (HPP) characterized by infantile rickets without elevated serum alkaline phosphatase (ALP) activity and a wide range of clinical manifestations due to hypomineralization.

Summary:
Epidemiology
The prevalence is not known. About 160 cases have been reported to date.
Clinical description
Individuals with infantile-HPP may be normal at birth. Clinical signs resembling rickets are generally found between birth and six months of age. Initial manifestations may include irritability, poor feeding, failure to thrive, hypotonia, and more rarely seizures. Other clinical features include growth failure, short stature, blue sclerae, bone hypomineralization (softening or thinning of the skull, rachitic ribs, scoliosis, thickening of wrists and ankles and bowing of long bones), craniosynostosis (possibly with increased intracranial pressure), lax ligaments, and hypercalciuria/hypercalcemia. Some patients have premature loss of deciduous teeth. Kidney damage (nephrocalcinosis due to hypercalciuria) is reported in some older infants. Severity is variable but many affected patients are at risk of respiratory failure due to rachitic deformities of the chest within the first year of life. There may be some clinical overlap with the moderate form, classed as childhood-onset HPP.
Etiology
Loss-of-function mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. Most patients with the infantile form have two ALPL mutations.
Diagnostic methods
Diagnosis is based on clinical examination, alkaline phosphatase assay and genetic testing.
Differential diagnosis
The main differential diagnosis is osteogenesis imperfecta.
Antenatal diagnosis
Although not typically picked up in ultrasound, there is evidence to suggest affected individuals may present prenatally with radiographic findings of limb bowing, limb shortening and/or skeletal hypomineralization. Genetic prenatal diagnosis may be offered to at risk pregnancies where the genetic mutation has been previously identified in an affected family member.
Genetic counseling
An autosomal recessive pattern of inheritance is mostly reported. Few cases may be dominantly inherited. Genetic counseling should be offered to affected families. Currently, there is no identified geno-phenotype relationship and individuals inheriting a pathogenic mutation may express any form of HPP (perinatal lethal to odontoHPP).
Management and treatment
Asfotase alfa is approved (Europe and USA) for enzyme replacement therapy (ERT) in patients with pediatric-onset hypophosphatasia and is associated with healing of the skeletal manifestations of hypophosphatasia as well as improved respiratory and motor function.
Prognosis
Prognosis depends on the organs affected and timely intervention. Currently there is no data on the long term prognosis when treated with ERT.

                            Last update:
                            February 2020

                            - Expert reviewer(s):
                            Dr Severine BACROT  - Dr Etienne MORNET


Infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome

A rare genetic neurological disorder characterized by infantile hypotonia, congenital ophthalmic anomalies (including strabismus, esotropia, nystagmus, and central visual impairment), global developmental delay and intellectual disability, behavioral abnormalities, and movement disorder (such as dystonia, chorea, hyperkinesia, stereotypies). Mild facial dysmorphism and skeletal deformities have also been reported. EEG testing shows marked abnormalities in the absence of overt epileptic seizures.


Infantile inflammatory bowel disease with neurological involvement

A rare genetic disease characterized by infantile onset of severe inflammatory bowel disease manifesting with bloody diarrhea and failure to thrive, and central nervous system disease with global developmental delay and regression, impaired speech, hypotonia, hyperreflexia, and epilepsy. Brain imaging shows global cerebral atrophy, thin corpus callosum, delayed myelination, and posterior leukoencephalopathy. Cases with recurrent infections and impaired T-cell responses to stimulation, as well as decreased T-cell subsets, have been reported.


Infantile LAD-like disease due to RAC2 deficiency

Neutrophil immunodeficiency syndrome is a primary immunodeficiency characterized by neutrophilia with severe neutrophil dysfunction, leukocytosis, a predisposition to bacterial infections and poor wound healing, including an absence of pus in infected areas.

Summary:
Epidemiology
Prevalence is unknown but, to date, two cases have been reported.
Clinical description
Neutrophil immunodeficiency syndrome presents as similar to leukocyte-adhesion deficiency (LAD; see this term), however there is no evidence of deficiency in the CD11b/CD18 complex.
Etiology
The disease is due to a point dominant negative mutation in the RAC2 gene causing decreased Rac2 protein expression and a defect in a signaling pathway controlling shape change/motility of neutrophils as well as assembly and activation of NADPH oxidase.
Genetic counseling
The mode of transmission is unknown.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Daniel AMBRUSO


Infantile mercury poisoning is a rare intoxication affecting children, most commonly characterized by erythema of the hands, feet and nose, edematous, painful, pink to red, desquamating fingers and toes, bluish, cold and wet extremities, excessive sweating, irritability, photophobia, muscle weakness, diffuse hypotonia, paresthesia, hypertension and tachycardia, due to elemental, organic or inorganic mercury exposure. Additional manifestations include alopecia, loss of appetite, excessive salivation with red and swollen gums, tooth and nail loss and insomnia.


Infantile multisystem neurologic-endocrine-pancreatic disease

A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability characterized by global developmental delay, postnatal microcephaly, intellectual disability, ataxia, sensorineural hearing loss, and exocrine pancreatic insufficiency. More variable manifestations include hypotonia, growth retardation, peripheral demyelinating neuropathy, dysmorphic facial features, and additional endocrine abnormalities. Brain imaging may show progressive cerebellar atrophy in some patients.


A rare benign soft tissue tumor characterized by the development of nodules in the skin, striated muscles, bones, and in exceptional cases, visceral organs, leading to a broad spectrum of clinical symptoms. It contains myofibroblasts.

Summary:
Epidemiology
The estimated prevalence is 1/150,000 live births.
Clinical description
Infantile myofibromatosis (IM) presents at birth or develops shortly thereafter, with 90% of cases occurring before the age of 2 years. IM is characterized by solitary or multiple nodules that are firm, flesh-colored to purple (''myofibroma''), and usually painless (except in case of compression of adjacent nerves). Tumors are located in the skin, subcutaneous tissue, striated muscles and in exceptional cases, visceral organs or bones. There are 4 patterns of clinical presentation: solitary (single lesion affecting the skin and/or muscles in the head, neck, or trunk (75% cases)); congenital multiple (multicentric limited to skin and muscles); congenital multiple with single visceral involvement; and congenital multiple with multiple visceral involvement (multiple lesions of skin and/or muscles, bones, lungs, heart and gastrointestinal tract). Rarely, prenatal diagnosis could be evoked.
Etiology
Most of these tumors are sporadic and isolated. Rare familial cases of IM have been described and 2 genes have been identified as disease causing:  PDGFRB and NOTCH3 which encode PDGFRB and NOTCH3 respectively. PDGFRB is a tyrosine kinase receptor for platelet derived growth factors which are mitogens for cells of mesenchymal origin. PDGFRB expression is up regulated by NOTCH3. This suggests that genetic defects in the 2 genes are involved in the same mechanism.
Diagnostic methods
Diagnosis is evoked partly on family history and physical examination at this age. Myofibromas are identified through ultrasound (mass with an anechoic center), MRI (low signal on T1-weighted imaging and high or low signal intensity areas on T2-weighted imaging) and less frequently CT (mass with peripheral enhancement and calcifications). Histopathology remains the gold standard for the diagnosis of IM. Biopsy reveals interlacing fascicles of spindle cells (myofibroblasts) in the periphery. Immunochemistry reveals vimentin and smooth muscle actin expression while vascular markers (S100 and CD34) are negative. In some cases, molecular tumor analysis could found a PDGFRB gene mutation.
Differential diagnosis
Differential diagnosis in case of solitary lesion includes hemangioma, lymphangioma, neurofibroma, infantile fibrosarcoma, Langerhans cell histiocytosis, inflammatory myofibroblastic tumor, desmoid tumors and dermoid or epidermoid tumors.
Antenatal diagnosis
Prenatal diagnosis is achieved by ultrasound examination and confirm by fetal MRI.
Genetic counseling
IM is mostly isolated and sporadic. In cases of familial and multifocal lesions, IM can be inherited as an autosomal recessive or dominant trait (incomplete penetrance and variable expressivity).
Management and treatment
Due to the benignity of the lesion, therapies without long term effects are preferred. For lesions affecting the skin and/or muscles, treatment is not recommended and a wait-and-see policy is proposed (tendency towards spontaneous regression). Radical surgical excision is required if: vital organs are involved, lesions are in threatening sites, or lesions are symptomatic. In cases of incomplete resection, re-excision can be proposed later. Standard therapy is low dose weekly methotrexate and vinblastine and is indicated for multifocal progressive life threatening lesions. Other treatments such as conventional chemotherapy (vincristine, D-actinomycin, and cyclophosphamide) should be kept for patients with rapid symptomatic progression because of the long-term risks of secondary malignancy development. PDGFRB inhibitors have not already been studied in such disease.
Prognosis
In the majority of cases, which lack visceral involvement, prognosis is excellent and spontaneous regression is often observed. On the other hand, the presence of visceral lesions is associated with a significantly poor outcome and a mortality rate of up to 70%, in the absence of therapy. Death is generally related to organ compression and cardiopulmonary and gastrointestinal involvement.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Pr Christine BODEMER  - Dr Daniel ORBACH


A rare clinical variant of hereditary nephronophthisis characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before 3 years of age.

Summary:
Epidemiology
The prevalence of the infantile form is unknown. This rare kidney disorder affects both male and female; there is no difference in risk between ethnic groups.
Clinical description
Infantile nephronophthisis can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with reduced kidney function beginning within 1 year after birth and progressing to ESRD before 3 years of age. The disease is characterized by severe hypertension, anemia, skeletal abnormalities and increased thirst and urination. Extra renal involvement may include hepatic fibrosis, recurrent bronchial infections, situs inversus and valvular or ventricular septal defects. Renal ultrasound findings include hyperechogenic kidneys with size ranging from reduced to enlarged. Histological findings include diffuse interstitial fibrosis, tubular atrophy, renal cortical microcysts, dilatation of proximal tubules and Bowman space, and absence of a thickened tubular basement membrane.
Etiology
Monogenic causal mutations have been identified in several genes involved in the Inversin compartment, which is localized at the proximal segment of the cilia. The most common pathogenic variants are found in the genes INVS (9q31.1) encoding Inversin, a protein that has a role in kidney development, and NPHP3 (3q22.1) encoding nephrocystin-3. Other pathogenic variants include NEK8  (17q11.2), TTC21B (2q24.3), ZNF423 (16q12.1), and CEP83 (12q22).
Diagnostic methods
The diagnosis is either by renal biopsy or genetic testing. Investigational work-up may include blood tests for anemia, electrolyte imbalances and metabolic panel, and renal or abdominal ultrasound. Involvement of other organs should be investigated and may include an eye examination, neuroimaging, and a neurological examination.
Differential diagnosis
Differential diagnosis includes autosomal recessive polycystic kidney disease, early-onset autosomal dominant polycystic kidney disease, and renal hypodysplasia.
Antenatal diagnosis
Antenatal diagnosis is possible where a pathogenic variant has been identified in a family.
Genetic counseling
Inheritance is autosomal recessive. Homozygous or compound heterozygous mutations can be present in the patient. The parents are obligate heterozygotes (carriers) for a pathogenic variation and are asymptomatic with no risk of developing the disorder. Each sib of an affected individual has 50% risk to be an asymptomatic carrier, 25% to be affected, and 25% to be unaffected and not a carrier. Doubtless the offspring of affected individuals will be obligate carriers for a nephronophthisis-related pathogenic variant.
Management and treatment
There is no specific therapy. The management is supportive to maintain fluid and metabolic balance including correction of water and electrolyte imbalances as well as anemia, hypertension and proteinuria treatment if necessary. The management of patients includes growth hormone therapy in children who meet the criteria for treatment. For the ESRD management, dialysis, and isolated kidney/combined liver-kidney transplant is necessary.
Prognosis
Patients progress to ESRD before the age of 3 years. Despite the risk of complications, transplant outcomes are excellent with no recurrence of tubular injury

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Dr Davide MENEGHESSO | ERKNet* - Dr Luisa MURER | ERKNet* - Dr Susanna NEGRISOLO | ERKNet*

                                * European Reference Network


A subtype of cystinosis characterized by an accumulation of cystine in the organs and tissues, particularly in the kidneys and eyes, and that clinically manifests from infancy with renal Fanconi syndrome, photophobia, hypothyroidism, impaired growth and rickets, in addition to various other systemic effects. Progressive extra-renal manifestations include hypothyroidism, hypogonadism and male infertility, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension, muscle involvement with distal muscle weakness and atrophy, pharyngeal and oral dysfunction, swallowing difficulties, cerebral involvement with hypotonia, speech and walking difficulties, and cerebellar syndrome.


Infantile neuroaxonal dystrophy/atypical neuroaxonal dystrophy (INAD/atypical NAD) is a type of neurodegeneration with brain iron accumulation (NBIA; see this term) characterized by psychomotor delay and regression, increasing neurological involvement with symmetrical pyramidal tract signs and spastic tetraplegia. INAD may be classic or atypical and patients present with symptoms anywhere along a continuum between the two.

Summary:
Epidemiology
Prevalence is unknown, but more than 150 cases have been described, of which the majority are classic INAD.
Clinical description
Classic INAD usually presents between ages six months and three years with psychomotor delay and regression, delayed walking or gait disturbance. It is characterized by early truncal hypotonia progressing to tetraparesis (usually spastic but can be areflexic) and dementia. Visual signs, including strabismus, pendular nystagmus, uncoordinated eye movements, optic atrophy and failing vision are generally early and prominent. Seizures occur in a minority. Onset of atypical NAD is usually in early childhood but can be as late as the late teens and progression is slower. As a result of slower progression patients may present with speech delay and neurobehavioral disturbances including impulsivity, poor attention span and emotional lability. Tetraparesis occurs late in the disease and is not necessarily preceded by truncal hypotonia and patients are more likely to have progressive dystonia and dysarthria. Optic atrophy, nystagmus and seizures occur as in classic INAD.
Etiology
INAD is caused by mutations in the PLA2G6 gene (22q13.1). The mutations alter phospholipid metabolism and often lead to abnormal iron accumulation in the basal ganglia.
Diagnostic methods
The majority of patients with INAD and atypical NAD develop cerebellar atrophy appreciable on MRI at a relatively early age. This, in the presence of high brain iron or optic atrophy, suggests the diagnosis. Genetic testing confirms the diagnosis.
Differential diagnosis
Differential diagnoses include infantile neuronal ceroid-lipofuscinosis, ataxia-telangectasia, and hereditary ataxia (see these terms), although cerebellar atrophy usually presents later for these disorders, other forms of NBIA, including pantothenate kinase-associated neurodegeneration (PKAN; see this term) which is characterized by an ``eye of the tiger'' sign not observed in INAD, infantile GM2 gangliosidosis, Niemann-Pick disease type C, autism and Menkes disease (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible if the disease causing mutations in the family are known.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment is palliative and includes pharmacologic treatment of spasticity and seizures, oral or intrathecal baclofen for those with significant dystonia, physiotherapeutic treatment of spasticity and measures such as gastric feeding tube or tracheostomy to prevent aspiration pneumonia. Iron chelation therapy is not currently recommended.
Prognosis
The progression of classic INAD is usually rapid and many children never learn to walk. Severe spasticity, progressive cognitive decline and visual impairment can result in a vegetative state. Many affected patients do not survive beyond their first decade, but some survive into their teens or later. The life span of atypical NAD is not known but is expected to be longer than that observed in classic INAD.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Allison GREGORY  - Pr Susan HAYFLICK


Infantile neurovisceral acid sphingomyelinase deficiency

A rare, autosomal recessive, acid sphingomyelinase deficiency characterized clinically by onset in infancy or early childhood with failure to thrive, hepatosplenomegaly, interstitial lung disease and rapidly progressive neurodegenerative disorders.

Summary:
Epidemiology
The birth prevalence of acid sphingomyelinase deficiency (combined both Niemann-Pick disease (NPD) types A and B) is estimated between 1/167,000-250,000 in Europe. Niemann-Pick disease type A (NPD-A) is more prevalent in the Ashkenazi Jewish population, where the estimated birth rate is estimated at 1/33,000.
Clinical description
The first symptom in NPD-A is hepatosplenomegaly, usually noted in the first few months of life. Other non-neurological findings include feeding problems, failure to thrive, gastrointestinal complaints (e.g., constipation, diarrhea, and vomiting), recurrent respiratory infections, persistently elevated transaminases, and irritability. Early neurological manifestations include muscular hypotonia, weakness and feeding difficulties. Affected infants have decreased linear growth and body weight. By 6 months of age, global development delay becomes evident and regression of developmental milestones is noted. With advancing age, the loss of motor function and the deterioration of intellectual capabilities are progressively debilitating. A classic cherry-red spot of the macula of the retina is eventually present in all affected children after 6 months of age. Interstitial lung disease results in frequent respiratory infections and often respiratory failure. Osteoporosis is common, presumably due to infiltration and poor nutrition.
Etiology
NPDA is caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene (locus 11p15.4), leading to decreased activity of acid sphingomyelinase (ASM), which results in lysosomal accumulation of sphingomyelin (SM) and secondary increases in the concentrations of cholesterol and other lipids.
Diagnostic methods
The diagnosis of NPD-A is established by detection of biallelic pathogenic variants in SMPD1 and/or residual acid sphingomyelinase enzyme activity (in peripheral blood lymphocytes, cultured skin fibroblasts or dry blood spots (DBS)). The de-acylated form of sphingomyelin (lyso-SPM) is increased in NPD-A and could be measured in plasma and DBS. Bone marrow examination reveals the histochemical characteristic, ''Niemann-Pick'' foam cells.
Differential diagnosis
Differential diagnoses include other lysosomal storage diseases such as Gaucher disease, GM1-and GM2-gangliosidosis, Niemann-Pick disease type C, lysosomal acid lipase deficiency, hematologic malignancy, and primary hepatic disease (e.g., fatty liver, autoimmune, chronic hepatitis B-related, cryptogenic cirrhosis).
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk is possible by testing of ASM enzyme activity or by DNA analysis if both SMPD1 pathogenic variants in the family are known.
Genetic counseling
NPD-A is inherited in an autosomal recessive manner. Genetic counseling should be offered to at-risk couples informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Currently, only supportive care is available for patients with NPD-A. The disease is best managed by an interprofessional team that includes a gastroenterologist, endocrinologist, neurologist, and geneticist. Also, family care, nursing support, and social support are an integral part of the management.
Prognosis
The clinical course is characterized by a brief period of normal development followed by a severe neurodegenerative course and death in the first 5 years of life.

                            Last update:
                            April 2021

                            - Expert reviewer(s):
                            Dr Ekaterina ZAKHAROVA


Infantile onset panniculitis with uveitis and systemic granulomatosis

A rare granulomatous autoinflammatroy syndrome characterized by infantile-onset, widespread, chronic, recurrent, progressive, lobular panniculitis associated with panuveitis, arthritis and severe systemic granulomatous inflammation.


Infantile osteopetrosis with neuroaxonal dysplasia

This syndrome is characterized by osteopetrosis, agenesis of the corpus callosum, cerebral atrophy and a small hippocampus.

Summary:
Epidemiology
It has been described in a brother and a sister born to nonconsanguineous Caucasian parents.
Clinical description
The children died at the ages of 1 and 9 months, respectively. Several additional cases combining axonal dystrophy and osteopetrosis have been described.
Etiology
The etiology remains unclear.
Genetic counseling
Autosomal recessive inheritance has been suggested.

                            Last update:
                            March 2009


Infantile Refsum disease (IRD) is the mildest variant of the peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD- ZSS; see this term), characterized by hypotonia, retinitis pigmentosa, developmental delay, sensorineural hearing loss and liver dysfunction. Phenotypic overlap is seen between IRD and neonatal adrenoleukodystrophy (NALD) (see this term).

Summary:
Epidemiology
The birth prevalence of PBD-ZSS is estimated to be around 1/50,000 in North America and 1/500,000 in Japan. More than ½ of patients with PBD-ZSS have the NALD-IRD forms.
Clinical description
IRD has an onset at birth or early infancy but manifestations may be subtle enough that diagnosis is not until adulthood. In infancy, symptoms may include nystagmus, hypotonia, sensorineural hearing loss, growth retardation, mild facial dysmorphism, and hepatomegaly. Hepatic dysfunction is first displayed in infants with jaundice and later in some with episodes of intracranial bleeding due to coagulopathy. In childhood, progressive retinitis pigmentosa, developmental deficits and hypotonia are seen. Most achieve motor milestones, though delayed, and communicate in a few words or signs. Osteoporosis and fractures can occur in the less mobile. Adrenal insufficiency and renal calcium oxalate stones can present in older children. Leukodystrophy with loss of previously acquired skills can occur at any age and may stabilize, or progress and be fatal. Atypical presentations (visual and hearing loss with preservation of intellect and cerebellar ataxia with/without peripheral neuropathy) have been described.
Etiology
PBD-ZSS is caused by mutations in one of 13 PEX genes encoding peroxins. Mutations in these genes lead to abnormal peroxisome biogenesis.
Diagnostic methods
IRD is suspected on physical exam and definitively confirmed with biochemical evaluation. Plasma very-long-chain fatty acid (VLCFA) levels indicate defects in peroxisomal fatty acid metabolism with elevated plasma concentrations of C26:0 and C26:1 and elevated ratios of C24/C22 and C26/C22. Erythrocyte membrane concentrations of plasmalogens C16 and C18 are usually reduced, but can be normal. Plasma pipecolic acid levels and bile acid intermediates (THCH and DHCA) are increased. Occasionally, VLCFA levels and enzymatic assays in fibroblasts can be within the normal range, requiring additional assessment in expert laboratories. Sequence analysis of the 13 PEX genes can be performed. MRI can be used to identify myelin changes.
Differential diagnosis
The main differential diagnoses include Usher syndrome I and II, other PBD-ZSS disorders (see these terms), single enzyme defects in peroxisome fatty acid beta-oxidation, and disorders that feature severe hypotonia, neonatal seizures, liver dysfunction or leukodystrophy. IRD should not be confused with adult Refsum disease (see this term).
Antenatal diagnosis
Prenatal screening of cultured amniocytes and chorionic villus sampling for VLCFA and plasmalogen synthesis is possible. If both disease causing alleles in parents have been identified, prenatal diagnosis can be performed as well as preimplantation genetic diagnosis.
Genetic counseling
IRD is inherited autosomal recessively, so genetic counseling is possible.
Management and treatment
There is no cure for IRD. Cataracts should be removed in early infancy and glasses used. Hearing aids should be provided to those with hearing impairment and cochlear implants considered when hearing loss is profound. Hepatic coagulopathy can be treated with vitamin K supplementation and liver function may improve with primary bile acid therapy. A gastrostomy tube may be necessary to allow for adequate calorie intake. Foods rich in phytanic acid (such as cow's milk) should be restricted. Standard epileptic drugs are used for seizures. Lifelong follow up monitors changes in hearing, vision and liver function.
Prognosis
Great variation is seen with respect to life expectancy, medical complications and preservation of neurological function. Many patients survive childhood, and survival to adulthood is possible.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Nancy BRAVERMAN


Infantile spasms-broad thumbs syndrome is a rare neurologic disorder characterized by profound developmental delay, facial dysmorphism (i.e. microcephaly, large anterior fontanel, hypertelorism, downslanting palpebral fissures, beaked nose, micrognathia), broad thumbs and flexion and/or extension spasms. Bilateral cataracts, hypertrophic cardiomyopathy and hydrocele have also been reported. EEG shows hypsarrhythmic features and MRI may reveal partial agenesis of the corpus callosum, mild brain atrophy and/or ventriculomegaly. There have been no further descriptions in the literature since 1990.


Infantile spasms-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome

A rare, genetic disorder of thiamine metabolism and transport characterized by infantile spasms progressing to symptomatic generalized or partial seizures, severe global developmental delay, progressive brain atrophy, and bilateral thalamic and basal ganglia lesions.


Infantile systemic hyalinosis (ISH) is a very rare disorder belonging to the heterogeneous group of genetic fibromatoses and is characterized by progressive joint contractures, skin abnormalities, severe chronic pain and widespread deposition of hyaline material in many tissues such as the skin, skeletal muscle, cardiac muscle, gastrointestinal tract, lymph nodes, spleen, thyroid, and adrenal glands.

Summary:
Epidemiology
Less than 20 cases have been described in the literature so far.
Clinical description
The clinical features are evident either at birth or within the first six months of life. Intrauterine growth retardation and reduced fetal movements have been described in some ISH patients. The main clinical features are painful swollen joint contractures, significant discomfort on handling and reduction of spontaneous movement. Dermal abnormalities include diminished skin elasticity, generalized skin thickening with hyperpigmentation over prominences, small pearly papules (predominantly on the face, scalp, and neck), massive gingival hypertrophy, and fleshy nodules in the perianal region. Susceptibility to infections and intractable diarrhea are common findings. Failure to thrive is characteristic. Osteopenia is often present and results in increased susceptibility to bone fractures. Children with ISH are intellectually normal.
Etiology
ISH is caused by mutations in anthrax toxin receptor 2 gene (ANTRX2) on chromosome 4q21. Mutations in the same gene cause juvenile hyaline fibromatosis, a similar but milder disease (see this term).
Diagnostic methods
Diagnosis is clinical and can be further supported by histological evidence of deposition of amorphous hyaline material in the skin or mucosae.
Differential diagnosis
Juvenile hyaline fibromatosis, Winchester syndrome, lipoid proteinosis (Urbach-Wiethe disease) and mucopolysaccharidosis type II (Hunter's syndrome) should be considered in the differential diagnosis (see these terms).
Genetic counseling
ISH is transmitted as an autosomal recessive trait.
Management and treatment
There is no specific treatment for ISH. Physical therapy and nutritional support improve the quality of life of the patients.
Prognosis
ISH has a progressive course that may lead to death within the first two years of life, mostly due to recurrent respiratory infections and severe diarrhea. In patients that live until adulthood, mobility remains severely restricted by joint contractures.

                            Last update:
                            June 2008

                            - Expert reviewer(s):
                            Dr Luciano MERLINI


Infantile-onset ascending hereditary spastic paralysis (IAHSP) is a very rare motor neuron disease characterized by severe spasticity of the lower limbs in early life, progression of spasticity to the upper limbs in late childhood, and dysarthria.

Summary:
Epidemiology
The prevalence and incidence of IAHSP are not known. 17 families accounting for at least 30 cases have been reported to date. The disorder has been described in various ethnic groups.
Clinical description
Affected patients are normal at birth and early development is mostly unremarkable. They then develop spastic paraplegia, increased reflexes and sustained lower limb stiffness in the first two years of life. By 7 to 8 years of age they also develop progressive weakness and spasticity extending to the upper limbs. Other signs include dysarthria, dysphagia (sometimes with drooling), and slow eye movements. Most become wheel-chair bound by late childhood or early adolescence and some patients have feeding difficulties (swallowing liquids) starting in the second decade. Subsequently, the disease progresses to severe spastic tetraparesis and a pseudobulbar syndrome may be observed. Cognitive function is generally preserved.
Etiology
IAHSP appears to be caused by mutations in the ALS2 gene (2q33-q35) encoding alsin, a protein that is abundant in motor neurons. Mutations in this gene are not found in all families with members affected by the disease. Other genes or loci have not been identified to date.
Diagnostic methods
Diagnosis is based on the characteristic features of the disorder and on ascending progression. Electrophysiological studies show severe dysfunction of motor evoked potentials. Somatosensory evoked potentials, electromyography and nerve conduction velocities are normal. Magnetic resonance imaging (MRI) is normal in affected children but brain changes are found in older patients. The diagnosis can be confirmed by molecular genetic testing.
Differential diagnosis
Differential diagnoses include the allelic disorders juvenile primary lateral sclerosis and juvenile amyotrophic lateral sclerosis (see these terms).
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies is possible if the disease-causing mutations have been identified in the family.
Genetic counseling
IAHSP is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes and are therefore asymptomatic carriers. Genetic counseling should be provided to affected families.
Management and treatment
There is currently no specific treatment. Management primarily involves physical and occupational therapy to promote mobility and independence.
Prognosis
The vital prognosis is good with long-term survival in most cases. Quality of life, however, is affected by progressive neurological manifestations and loss of independence.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Pr Enrico BERTINI


Infantile-onset autosomal recessive nonprogressive cerebellar ataxia

A rare, genetic, autosomal recessive cerebellar ataxia disease characterized by nonprogressive cerebellar ataxia, with onset in infancy, manifesting with delayed motor and speech development, gait ataxia, dysmetria, hypotonia, increased deep tendon reflexes, and dysarthria. Additional variable manifestations include moderate nystagmus on lateral gaze, mild spasticity, intention tremor, short stature and pes planus. Brain imaging reveals cerebellar vermis atrophy.


Infantile-onset axonal motor and sensory neuropathy-optic atrophy-neurodegenerative syndrome

A rare neurologic disease characterized by axonal sensorimotor neuropathy, progressive optic atrophy, cognitive deficit, bulbar dysfunction, seizures, and early hypotonia and feeding difficulties. Additional possible features include dystonia, scoliosis, joint contractures, ocular anomalies, and urogenital anomalies. Brain MRI reveals variable degrees of cerebral atrophy. The disease is fatal in childhood due to respiratory failure.


Infantile-onset generalized dyskinesia with orofacial involvement

A rare hyperkinetic movement disorder characterized by delayed motor development and infantile onset of axial hypotonia and a generalized hyperkinetic movement disorder, principally with dyskinesia of the limbs and trunk, and facial involvement including orolingual dyskinesia, drooling, and dysarthria. Variable hyperkinetic movements may include a jerky quality, intermittent chorea and ballismus. Brain imaging is normal and cognitive performance is typically preserved.