Infantile-onset mesial temporal lobe epilepsy with severe cognitive regression is a rare monogenic disease with infantile-onset pharmacoresistant focal seizures of mesial temporal lobe onset manifesting with unresponsiveness, hypertonia and automatisms and cognitive regression soon after seizure onset leading to severe intellectual disability with behavioral abnormalities.


Infantile-onset periodic fever-panniculitis-dermatosis syndrome

A rare genetic autoinflammatory syndrome characterized by early-onset of repeated episodes of fever, nodular neutrophil-rich panniculitis, arthralgia, and lipodystrophy. Additional reported features include diarrhea, failure to thrive, lymphadenopathy, and vasculitis. Laboratory examination may reveal elevated serum C-reactive protein and leukocytosis with neutrophilia in the absence of infection.


Infantile-onset pulmonary alveolar proteinosis-hypogammaglobulinemia

A rare genetic respiratory disease characterized by infantile onset of pulmonary alveolar proteinosis with hypogammaglobulinemia. Patients have normal respiratory function at birth, but subsequently develop recurrent, mainly viral, infections and progressive respiratory failure, often leading to death in infancy or early childhood. Additional reported features include leukocytosis and splenomegaly.


Infantile-onset spinocerebellar ataxia (IOSCA) is a hereditary neurological disorder with early and severe involvement of both the peripheral and central nervous systems. It has only been described in Finnish families.

Summary:
Epidemiology
So far, 24 cases have been reported. In Finland, IOSCA has a population carrier frequency of more than 1:230.
Clinical description
IOSCA is characterized by very early ataxia, athetosis and reduced tendon reflexes (between 9 and 18 months of age). Ophthalmoplegia and sensorineural hearing loss are diagnosed in childhood. Other features, such as optic atrophy and sensory neuropathy with progressive loss of myelinated fibers in the sural nerve, appear later in the disease course. Hypogonadism may occur in females. Some patients show intellectual deficit. Epilepsy is a late manifestation and seizures may be life-threatening.
Etiology
IOSCA is caused by mutations in the C10orf2 gene (10q24) encoding the mitochondrial helicase Twinkle. The c.1523A>G (p.Y508C) causative mutation has been postulated to be a founder mutation. Twenty-one of the reported patients were homozygous for this mutation, and three were compound heterozygotes: c.952G>A/c.1523A>G (two patients) and c.1523A>G/c.1287C>T (one patient). The mutations lead to mtDNA depletion in the brain and the liver, but not in the muscle.
Diagnostic methods
The diagnosis is based on clinical and pathological findings. Studies of sural nerve biopsies reveal an early and rapidly progressive axonal neuropathy. Neuroimaging studies revealing cerebellar atrophy and genetic testing for the c.1523A>G mutation may also help to confirm the diagnosis.
Differential diagnosis
Differential diagnoses include early-onset cerebellar ataxias with sensory axonal neuropathy and epileptic encephalopathy, mitochondrial disorders with axonal neuropathy (such as Friedreich ataxia), progressive external ophthalmoplegia (PEO), juvenile- or adult-onset mitochondrial recessive ataxia syndrome (MIRAS), and POLG-related disorders (see theseterms).
Antenatal diagnosis
Prenatal testing may be available for families in which the disease-causing mutations have already been identified.
Genetic counseling
IOSCA is inherited in an autosomal recessive manner. Genetic counseling is an important clinical tool for preventing new cases, especially for couples with an affected first child: the risk of having an affected child in further pregnancies is 25%.
Management and treatment
IOSCA patients are often managed by a multidisciplinary team, involving a pediatrician, neurologist, psychiatrist, orthopedic surgeon, physical and occupational therapists, genetic counselor, and social worker. Treatment is symptomatic and may include: (1) hearing aids, speech therapy and sign language for deafness; (2) physical therapy, orthotic devices and orthopedic surgery for sensory axonal neuropathy; (3) walking aids, a wheelchair, physiotherapy and occupational therapy for ataxia; (4) antiepileptic drugs for seizures and (5) antipsychotics and antidepressants for psychiatric symptoms.
Prognosis
Prognosis is unfavorable. Patients are wheelchair-bound by adolescence. Early death is common due to severe seizures. The clinical course seems to be more rapid and severe (with death during infancy) in c.952G>A/ c.1523A>G compound heterozygotes.

                            Last update:
                            April 2009

                            - Expert reviewer(s):
                            Dr Carmen ESPINÓS  - Pr Francesc PALAU


Infantile-onset X-linked spinal muscular atrophy

A rare form of spinal muscular atrophy characterized by the neonatal onset of severe hypotonia, areflexia, profound weakness, multiple congenital contractures, facial dysmorphic features (myopathic face with open, tent-shaped mouth), cryptorchidism, and mild skeletal abnormalities (i.e. kyphosis, scoliosis), that is often preceded by polyhydramnios and reduced fetal movements in utero and followed by bone fractures shortly after birth. Muscle weakness is progressive and chest muscle involvement eventually leads to ventilatory insufficiency and respiratory failure.


Infection-related hemolytic uremic syndrome

A rare type of hemolytic uremic syndrome (HUS) characterized by the triad of hemolytic anemia due to generalized thrombotic microangiopathy, thrombocytopenia, and acute kidney injury, and most commonly occurring after acute gastroenteritis due to Shiga toxin-producing enterohemorrhagic Escherichia coli or Shigella dysenteriae. Other infectious causes of HUS include Streptococcus pneumoniae, HIV, Mycoplasma pneumoniae, Histoplasmosis, and Coxsackie virus.


A rare ophthalmic disorder characterized by inflammation primarily of the anterior part of the uvea (iris and ciliary body), due to an infectious etiology. Clinical symptoms are pain, redness, photophobia, and variable visual loss. Signs on examination include presence of inflammatory cells in the anterior chamber and anterior vitreous, keratic precipitates, hypopyon, iris nodules, posterior synechiae, and miosis, among others.


Infectious epithelial keratitis is a rare, potentially sight-threatening, acquired ocular disease chracterized by corneal epithelium inflammation resulting from viral (mainly Herpes Simplex virus), bacterial, fungic or protist infection, manifesting with variable symptoms, such as conjunctival hyperemia, lacrimation, rapid onset of pain, blurred vision and/or photophobia, depending on the causative agent.


A rare ophthalmic disorder characterized by generalized inflammation of all parts of the uveal tract (iris, ciliary body, and choroid), simultaneously involving adjacent vitreous and retina, without any predominant site of inflammation, due to viral, bacterial, fungal, or parasitic infections. Clinical symptoms include pain, photophobia, redness, blurring of vision, and floaters. Signs on examination are lid edema, ciliary injection, chemosis, keratic precipitates, cells in the anterior chamber, hypopyon, iris nodules and neovascularization, posterior synechiae, macular edema, vitreous and retinal hemorrhage, and retinal detachment, among others. Complications may result in visual loss.


A rare ophthalmic disorder characterized by inflammation of the posterior uveal tract (retina and choroid), due to an infectious etiology. Presenting symptoms are decreased visual acuity, visual field defects, floaters, photopsia, photophobia, and occasionally pain. Signs on examination include conjunctival injection, keratic precipitates, retrolental cells, inflammatory infiltrates on the retina, macular edema, and peripheral retinal neovascularization, among others. Complications (such as cataracts, band keratopathy, glaucoma, cystoid macula edema, and retinal detachment) may lead to permanent vision loss.


Infective dermatitis associated with HTLV-1 is a rare and severe chronic disease characterized by recurrent chronic eczema (with erythematous, scaly and crusted lesions) mainly affecting seborrheic areas (e.g. scalp, forehead, eyelids, paranasal and periauricular skin, neck, axillae, and groin), a generalized fine papular rash, chronic nasal discharge with crusting of the anterior nares, and non-virulent Staphylococcus aureus or beta-hemolytic Streptococcus infections, thought to be a result of HTLV-1-induced immunosuppression. Lymphadenopathy, anemia, mild to moderate pruritus and increased incidence of other infections (e.g. crusted scabies) have also been reported in some patients. Patients may subsequently develop other HTLV-1 associated conditions such as adult T-cell leukemia/lymphoma and tropical spastic paraparesis (see these terms).


A rare bacterial infectious disease characterized by infection of a native or prosthetic heart valve, the endocardial surface, or an indwelling cardiac device. Main causative agents are Gram-positive bacteria, most commonly Staphylococcus and Streptococcus species. Signs and symptoms include high fever or prolonged subfebrile state, excessive sweating, malaise, asthenia, arthralgia, myalgia, weight loss, headache, nausea, dyspnea, cough, heart murmurs, and petechiae of the skin. The most common complications are embolism in different organs and ischemic stroke, sepsis, heart failure, and renal failure.


Inferior vena cava interruption without azygos continuation

A rare congenital anomaly of the inferior vena cava characterized by complete interruption of the vessel in which no direct continuity exists between the inferior vena cava and the azygos/hemiazygos system. Clinical manifestations depend on the variant drainage patterns or collaterals and include lower extremity deep vein thrombosis, thromboembolic attacks, leg swelling and pain, lower extremity varices, abdominal pain, intraabdominal varices, and hematochezia, among others. Additional venous abnormalities or cardiac malformations are frequently present.


Inflammatory bowel disease-recurrent sinopulmonary infections syndrome

A rare genetic immune disease characterized by recurrent sinopulmonary infections and autoimmune enterocolopathy, manifesting as frequent episodes of intractable diarrhea with abdominal pain and fever, accompanied by eczematous rashes, due to deficits in components of innate and adaptive immunity. Immunologic abnormalities include IgG subclass deficiency, impaired antigen-induced lymphocyte proliferation, reduced cytokine production by CD8+ T lymphocytes, and decreased numbers of natural killer cells.


Inflammatory myofibroblastic tumor is a rare neoplastic lesion of the submucosal stroma, which can develop in any organ, often occurring in the lung, mesentery, omentum and the retroperitoneal region. It is histologically heterogenous, composed of spindle-shaped cells, myofibroblasts and inflammatory cells. It is usually benign, however local invasion, recurrence, malignant transformation with vascular invasion and metastases may occur. The presentation is nonspecific and depends on the organ involved. Some patients may present with paraneoplastic syndrome (fever, malaise, weight loss, anemia, thrombocytosis) or symptoms related to compression of adjacent organs, such as bowel obstruction.


Inflammatory myopathy with abundant macrophages

A rare idiopathic inflammatory myopathy characterized by diffuse destructive infiltration of CD68+ macrophages into the fascia rather than muscle fibers in muscle biopsies, proximal muscle weakness and myalgia with or without scaly dermatomyositis-like or atypical non-dermatomyositis-like skin lesions, elevation of creatine kinase levels and thickening of muscle fascia in muscle MRI.


A rare benign liver tumor characterized by a prominent inflammatory infiltrate and often mimicking a malignant liver neoplasm. The tumor is frequently solitary with a predilection for the right lobe; however, multiple lesions are possible. There are two clinicopathological subtypes: fibrohistiocytic inflammatory pseudotumor of the liver and lymphoplasmacytic inflammatory pseudotumor of the liver. Patients present with non-specific clinical symptoms such as abdominal pain or discomfort, fever, and weight loss. The condition may be associated with other chronic inflammatory or autoimmune diseases.


A type of primary hypophysitis characterized by an inflammation of the posterior pituitary and the stalk. The major clinical manifestation is diabetes insipidus with polyuria and polydipsia. Less frequent symptoms are headaches, adrenal insufficiency, hyperprolactinemia and hypogonadism.


Inhalational anthrax is a rare acute systemic infection caused by the inhalation of Bacillus anthracis spores (e.g. through infected animal products, bioterrorism) and characterized by an initial stage where patients present with non specific symptoms (fever, cough, chills, fatigue) that is followed by an acute phase during which hemorrhagic mediastinitis occurs that can progress into meningitis, gastrointestinal involvement, and refractory shock, that can be fatal, if left untreated.


Inhalational botulism is a man-made form of botulism (see this term), a rare acquired neuromuscular junction disease with descending flaccid paralysis caused by botulinum neurotoxins (BoNTs).

Summary:
Epidemiology
Prevalence is unknown. So far, nearly 10 cases have been reported worldwide.
Clinical description
Clinical manifestations are similar to other forms of botulism, with symmetrical cranial nerve palsies followed by descending, symmetric flaccid paralysis of voluntary muscles, which may progress to respiratory compromise and death.
Etiology
The disease results from accidental or intentional release of aerosolized BoNTs. After inhalation, the toxin is absorbed into the blood stream and distributed throughout the body, causing the typical manifestations of botulism. The time to onset of inhalational botulism cannot be stated with certainty as few cases are known or because of repeated exposure. Accidental cases were initially reported in three laboratory workers and more recently in illicit drug users after intranasal use of cocaine, through sinusitis and possible sinus colonization and toxicogenesis, or through direct absorption by the nasal mucosa of preformed toxin in contaminated street cocaine. Deliberate dissemination of BoNTs by aerosol could produce an outbreak of inhalational botulism in a large number of simultaneous cases with a common geographic factor, but without common dietary exposure and, possibly, with an unusual BoNT type (e.g. type C, D, F, G). All cases of botulism should be reported to the appropriate government agency.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Dr Michel POPOFF


Inherited acute myeloid leukemia (AML) is a rare, malignant hematopologic disease characterized by clonal proliferation of myeloid blasts, primarily involving the bone marrow, in association with congenital disorders (e.g. Fanconi anemia, dyskeratosis congenita, Bloom syndrome, Down syndrome, congenital neutropenia, neurofibromatosis, etc.) and genetic defects predisposing to AML. Patients present with signs and symptoms related to ineffective hematopoesis (fatigue, bleeding and bruising, recurrent infections, bone pain) and/or extramedullary site involvement (gingivitis, splenomegaly, etc.). Depending on the underlying genetic defect, there may be additional cancer risks and other health problems present.


A heart muscle disease that consists in progressive dystrophy of primarily the right ventricular myocardium with fibro-fatty replacement and ventricular dilation, and that is clinically characterized by ventricular arrhythmias and a risk of sudden cardiac death.

Summary:
Epidemiology
Arrhythmogenic right ventricular cardiomyopathy (ARVC) has a reported prevalence of 1/2,500 to 1/5,000.
Clinical description
ARVC has a variable clinical picture. ARVC can be asymptomatic, or present, usually during adolescence, with ventricular arrhythmias with palpitations, chest pain, dizziness, fatigue, or syncope. All patients are at risk of sudden death, particularly during exertion. Although predominantly a disease of the right ventricle, ARVC may also involve the left ventricle (ARVC left dominant form) or both (ARVC biventricular form), the latter leading in later stages to progressive biventricular failure. ARVC can be associated with palmoplantar keratoderma and woolly hair, the so-called cardio cutaneous syndromes (Naxos disease and Carvajal syndromes, see these terms).
Etiology
ARVC results from a fibro-fatty replacement of myocardium. It is believed to be a disease of desmosomes with impaired cell-to-cell contact and signaling Mutations have been observed in genes encoding for proteins of the cardiac desmosomes (JUP;  DSP;  PKP2;  DSG2; and  DSC2). However, in a minority of patients, mutations in non-desmosomal genes (TGFβ3;  TMEM43/LUMA; DES; CTNNA3; PLN; LMNA; TTN) have also been detected. Variable penetrance is found, suggesting a role for additional genetic or environmental modifiers. Compound/digenic heterozygosity is identified in up to 25% of mutation carriers and seems an additional risk factor. Recent investigations point to a role of the canonical Wnt signaling pathway in the pathogenesis of ARVC.
Diagnostic methods
Diagnosis is based on a scoring system taking into account right ventricle structural and functional abnormalities (dilatation, akinesia, dyskinesia, aneurysms) detected by echocardiography, MRI and angiography; electrocardiographic features (inverted T waves in right precordial leads, epsilon waves and late potentials by signal averaged ECG (SAECG), left bundle branch block ventricular tachycardia, >500 ventricular extrasystoles per 24 h); tissue characterization at endomyocardial biopsy (fibro-fatty replacement of myocardium); and family history. Contrast enhanced MRI substantially enhances the diagnostic sensitivity, particularly in left ventricle variants, while electroanatomic mapping is superior in detecting early RV involvement.
Differential diagnosis
Differential diagnosis includes idiopathic RV outflow tract tachycardia, myocarditis, sarcoidosis and congenital heart diseases (see these terms).
Antenatal diagnosis
Although prenatal diagnosis through amniocentesis is feasible, it is subject to ethical and legal considerations.
Genetic counseling
In more than half of the patients, the disease is familial, primarily autosomal dominant with variable penetrance and polymorphic expressivity. Naxos disease and Carvajal syndrome show an autosomal recessive mode of inheritance. The success rate of genotyping depends on several factors (such as cohort location and ethnicity) and hence requires specialized counseling.
Management and treatment
Risk stratification remains largely empiric and therapeutic interventions include antiarrhythmic drugs like beta-blockers, sotalol and amiodarone, catheter ablation, implantable cardioverter-defibrillator. In refractory congestive heart failure or untreatable ventricular arrhythmias, heart transplantation can be also considered. Since effort is a trigger for disease progression and arrhythmias, competitive sport and moderate to high intense physical activity should be avoided.
Prognosis
The disease progression is variable. Risk factors for sudden death include a history of aborted sudden death, syncope, young age, decreased left ventricular function, and marked decrease in right ventricular function.

                            Last update:
                            December 2015

                            - Expert reviewer(s):
                            Pr Cristina BASSO  - Dr Domenico CORRADO  - Pr Kalliopi PILICHOU  - Pr Gaetano THIENE


Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations is a rare cancer-predisposing syndrome, associated with the D1 subgroup of Fanconi anemia (FA), characterized by progressive bone marrow failure, cardiac, brain, intestinal or skeletal abnormalities and predisposition to various malignancies. Bone marrow suppression and the incidence of developmental abnormalities are less frequent than in other FA, but cancer risk is very high with the spectrum of childhood cancers including Wilms tumor, brain tumor (often medulloblastoma) and ALL/AML.


Inherited congenital spastic tetraplegia is a rare, genetic, neurological disease characterized by non-progressive, variable spastic quadriparesis in multiple members of a family, in the absence of additional factors complicating pregnancy or birth (e.g. perinatal asphyxia, congenital infection). Additional clinical features include congenital hypotonia, intellectual disability, and developmental delay. Dysphagia, dysarthria, exotropia, nystagmus, seizures and brain atrophy with ventriculomegaly may be also present.


A rare form of genetic prion disease characterized by typical CJD features (rapidly progressive dementia, personality/behavioral changes, psychiatric disorders, myoclonus, and ataxia) with a genetic cause and sometimes a family history of dementia.


Epidermodysplasia verruciformis (EV) is a rare inherited genodermatosis characterized by chronic infection with human papillomavirus (HPV) leading to polymorphous cutaneous lesions and high risk of developing non melanoma skin cancer.

Summary:
Epidemiology
The exact prevalence of EV is unknown; more than 200 cases have been reported in the literature so far.
Clinical description
The disease usually manifests during infancy (7.5% of cases), childhood (61.5% of cases) or puberty (22% of cases) with a progressive development of hyperpigmented or hypopigmented flat wart-like papules, irregular reddish brown plaques, seborrheic keratosis-like lesions and pityriasis versicolor-like macules on the trunk, neck, face, dorsal hands and feet (sun-exposed skin). Various HPV subtypes (HPV5 and HPV8 are found in 80% of cases) can be detected in the cutaneous lesions. Thirty to 60% of patients develop non-melanoma skin cancers, especially squamous cell carcinomas (SCC), during the fourth or fifth decades of life, mainly on sun-exposed areas. Black-skinned patients have a much lower incidence of skin cancer. Most SCC remain local; metastases are uncommon.
Etiology
EV can be caused by loss-of-function mutations in either of the 2 adjacent genes EVER1/TMC6 or EVER2/TMC8 (17q25.3) coding for membrane proteins that form a complex with the Zinc transporter protein ZnT-1 in the endoplasmic reticulum (ER) membrane of keratinocytes. The mutations in these genes lead to susceptibility to infection with specific HPV subtypes belonging to the beta genus, including HPV5, 8, 9, 12, 14, 15, 17, 19-25, 36-38, 47 and 49, which are ubiquitous and harmless to healthy individuals.
Diagnostic methods
Diagnosis is based on clinical and histological findings. Skin biopsy shows verruca plana-like lesions with mild hyperkeratosis, hypergranulosis and acanthosis of the epidermis. Keratinocytes of the upper epidermal layers are enlarged with perinuclear vacuolization and a typical blue-gray pallor. HPVs can be detected in keratinocytes using in situ hybridization or immunohistochemistry with anti-HPV antibodies.
Differential diagnosis
Differential diagnosis includes squamous cell carcinoma, acrokeratosis verruciformis (see these terms), tinea versicolor, and generalized verrucosis of other origin. In addition, an acquired epidermodysplasia verruciformis-like syndrome has been described in patients with impaired cell-mediated immunity, mainly HIV-infected subjects.
Genetic counseling
In most cases, transmission is autosomal recessive but sex-linked and autosomal dominant inheritance patterns have also been reported.
Management and treatment
Although permanent cure of EV cannot be achieved by any therapy at present, described treatment modalities include cryotherapy, topical imiquimod and 5-fluorouracil, systemic retinoids, interferon alpha, and 5-aminolevulinic acid photodynamic therapy. Surgical excision is the treatment of choice for SCC. Preventive measures, in particular sun exposure avoidance and photoprotection, are crucial for proper management.
Prognosis
Prognosis is favorable since skin tumors appear progressively and metastases are uncommon.

                            Last update:
                            February 2010

                            - Expert reviewer(s):
                            Pr Giovanna ZAMBRUNO


Inherited epidermolysis bullosa (EB) encompasses a number of disorders characterized by recurrent blister formation as the result of structural fragility within the skin and selected other tissues.

Summary:
Epidemiology
All types and subtypes of EB are rare; the overall incidence and prevalence of the disease in the United States are approximately 1/53,000 live births and 1/125,000, respectively, and similar estimates have been obtained in some European countries. EB affects individuals from all ethnic origins and there is no gender predilection.
Clinical description
Clinical manifestations range widely, from localized blistering of the hands and feet to generalized blistering of the skin and oral cavity, and injury to many internal organs. Four major types of inherited EB have been defined: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), each with numerous subtypes, and Kindler syndrome (see these terms). These forms differ not only phenotypically and genotypically but more importantly by the site of ultrastructural disruption or cleavage.
Etiology
Each EB subtype is known to arise from mutations within the genes coding for several different proteins, each of which is intimately involved in the maintenance of keratinocyte structural stability or adhesion of the keratinocyte to the underlying dermis.
Diagnostic methods
EB is best diagnosed and subclassified by the collective findings obtained via detailed personal and family history, in concert with the results of immunofluorescence antigenic mapping, transmission electron microscopy, and in some cases, by DNA analysis.
Differential diagnosis
Extensive differential diagnosis is not usually required in EB.
Antenatal diagnosis
Molecular prenatal diagnosis may be available if the disease-causing mutation in the family has been identified.
Genetic counseling
EB is inherited in either an autosomal dominant or autosomal recessive manner, depending on the EB type and subtype. Genetic counseling should be offered to affected families.
Management and treatment
Optimal patient management requires a multidisciplinary approach, and revolves around the protection of susceptible tissues against trauma, use of sophisticated wound care dressings, aggressive nutritional support, and early medical or surgical interventions to correct the extracutaneous complications, whenever possible.
Prognosis
Prognosis varies considerably and is based on both EB subtype and the overall health of the patient.

                            Last update:
                            June 2011

                            - Expert reviewer(s):
                            Pr Jo-David FINE


Inherited isolated adrenal insufficiency due to partial CYP11A1 deficiency is a rare, genetic, chronic, primary adrenal insufficiency disorder, due to partial loss-of-function CYP11A1 mutations, characterized by early-onset adrenal insufficiency without associated abnormal external male genitalia. Patients present with signs of adrenal crisis, including electrolite abnormalities, severe weakness, recurrent vomiting and seizures. Ultrasound reveals absent (or very small) adrenal glands.


Inherited isolated arrhythmogenic cardiomyopathy

Familial isolated arrhythmogenic right ventricular dysplasia (ARVC) is the familial autosomal dominant form of ARVC (see this term), a heart muscle disease characterized by life-threatening ventricular arrhythmias with left bundle branch block configuration that may manifest with palpitations, ventricular tachycardia, syncope and sudden fatal attacks, and that is due to dystrophy and fibro-fatty replacement of the right ventricular myocardium that may lead to right ventricular aneurysms.


Iniencephaly is a rare form of neural tube defect in which a malformation of the cervico-occipital junction is associated with a malformation of the central nervous system.

Summary:
Epidemiology
Incidence is estimated at between 1/1,000 and 1/100,000 live births, depending on the geographical area, and more female infants are affected (male:female sex ratio: 1:3 to 1:9).
Clinical description
The cardinal features are occipital bone defect, partial or total absence of cervicothoracic vertebrae, fetal retroflexion of the head and characteristic absence of the neck. It is associated with malformations of the central nervous (spina bifida and/or anencephaly), gastrointestinal (omphalocele) and cardiovascular systems.
Etiology
As with other neural tube defects, it is thought to be of multifactorial origin.
Antenatal diagnosis
Antenatal diagnosis is possible by ultrasonographic monitoring.
Prognosis
Prognosis is poor and iniencephaly is almost always lethal.

                            Last update:
                            January 2010


A rare endocrine disease characterized by hyperinsulinemic hypoglycemia associated with the presence of autoantibodies to endogenous insulin without previous exposure to exogenous insulin. Patients usually present in adulthood with postprandial, fasting-, or exercise-induced hypoglycemia, often with pronounced neuroglycopenic symptoms. Laboratory investigations reveal markedly elevated serum insulin, as well as increased C-peptide and proinsulin. The condition may be associated with other autoimmune diseases, monoclonal gammopathy, and/or recent exposure to certain medications.


Type A insulin-resistance syndrome belongs to the group of extreme insulin-resistance syndromes (which includes leprechaunism, the lipodystrophies, Rabson-Mendenhall syndrome and type B insulin resistance syndrome; see these terms) and is characterized by the triad of hyperinsulinemia, acanthosis nigricans (skin lesions associated with insulin resistance), and signs of hyperandrogenism in females without lipodystrophy and who are not overweight.

Summary:
Epidemiology
It is a rare disorder of unknown prevalence.
Clinical description
It is generally diagnosed in young women with marked signs of hyperandrogenism, but insulin resistance and acanthosis nigricans may be observed in men and in childhood. Acromegaloid facies or muscular cramps are sometimes associated. Hyperinsulinemia, a biological marker for insulin resistance, is often associated with glucose tolerance defects over the course of the disease, and diabetes progressively sets in. Hyperandrogenism (associated with polycystic ovarian syndrome (see this term) or ovarian hyperthecoses) leads to fertility problems.
Etiology
In some cases, the syndrome is caused by heterozygous mutations in the insulin receptor gene (INSR; 19p13.3-p13.2), affecting the region encoding the tyrosine kinase domain. Cases associated with homozygous mutations affecting the insulin-binding domain of the receptor have also been reported. However, only 15 to 20% of female patients with hyperandrogenism, insulin resistance and acanthosis nigricans present mutations in the insulin receptor gene. When such mutations are not found, the disease is of unknown cause and may be considered as an HAIR-AN syndrome (see this term).
Differential diagnosis
The differential diagnosis includes the other forms of extreme insulin-resistance, in particular the lipodystrophy syndromes (see these terms), in which the reparation anomaly of the adipose tissue may be clinically minor. The differential diagnosis with type B insulin resistance syndrome is based on the lack of insulin anti-receptor auto-antibodies in patients with the type A syndrome.
Genetic counseling
Transmission is autosomal dominant.
Management and treatment
The treatment consists of dietary changes and/or drugs (metformin, glitazones, or other antidiabetic drugs) to reduce the insulin resistance and treat the diabetes.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Pr Corinne VIGOUROUX


A rare genetic disease that belongs to the group of extreme insulin-resistance syndromes and is due to autoantibodies directed against insulin receptor.

Summary:
Epidemiology
Insulin-resistance syndrome type B is a rare disorder that mainly affects middle-aged adults, predominantly females. The prevalence is unknown.
Clinical description
The disease may occur in the context of other autoimmune phenomena or well-characterized autoimmune diseases (mainly systemic lupus erythematosus). The onset of the disease is usually characterized by the appearance of a rapidly progressive, severely insulin-resistant diabetes with acanthosis nigricans (the typical skin lesion associated with insulin resistance), weight loss, and hirsutism in females. Hypoglycemia can occur during the course of the disease, or, more rarely, can be the only metabolic manifestation, and may be extremely severe. Unlike most insulin resistance syndromes, type B insulin resistance is not associated with hypertriglyceridemia.
Etiology
The syndrome is associated with the presence of serum auto-antibodies directed against the insulin receptor.
Diagnostic methods
The diagnosis is based on the clinical picture and results of laboratory tests. The detection of anti-insulin receptor auto-antibodies in the serum is rarely performed for routine diagnosis, so that the diagnosis is usually based on probabilistic arguments.
Differential diagnosis
The differential diagnosis include other insulin resistance syndromes and/or hypoglycemia due to other causes.
Management and treatment
Immunosuppressive combination therapies including rituximab were shown effective to induce remission in most cases and should be followed by maintenance immunosuppressive therapy. Non specific therapies should be associated to reverse the hypercatabolic state and treat hyperglycemia (large amount of insulin) and/or hypoglycemia (diet, adaptation of insulin therapy, steroids).
Prognosis
Prognosis depends on the course of the underlying autoimmune disease, and is unfavorable in cases with hypoglycemia (reported to lead to death in 50% of cases).

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Pr Corinne VIGOUROUX


A form of functioning pancreatic neuroendocrine tumor characterized most commonly by a solitary, small pancreatic lesion that causes hyperinsulinemic hypoglycemia.

Summary:
Epidemiology
The incidence in the general population is 1/250,000-1,000,000 (but higher in autopsy studies). There is a slight female predominance. It is the most common endogenous cause of hyperinsulinemic hypoglycemia. Malignant insulinoma has an incidence 0.01/100,000 in Europe.
Clinical description
Insulinoma can present at any age but the median age of diagnosis is in the fifth decade of life. It manifests with various autonomic and neuroglycopenic symptoms such as tremor, palpitations, weakness, diaphoresis, hyperphagia, visual disturbances, confusion, behavioral and personality changes, seizures and coma. Symptoms occur more often during times of fasting, exercise or with a delay in meals. 20-40% of patients are overweight. Insulinomas are malignant in only 7-10% of cases and the most common sites of metastasis are the liver and lymph nodes. Extra-pancreatic insulinoma is most commonly found in the duodenal wall but is extremely rare. The tumor can also rarely be non-functioning.
Etiology
The etiology is unknown in most sporadic cases but somatic YY1 (14q32.2) variants are associated with insulinoma in some cases. Insulinoma originates in the islet beta cells that are equally distributed throughout the pancreas. When functioning, the tumor manifests with hypersecretion of insulin and consequently causes hypoglycemia.
Diagnostic methods
Diagnosis is suspected on the presence of Whipple's triad (hypoglycemia with blood glucose levels of < 50 mg/dL, neuroglycopenic symptoms, and immediate relief of symptoms following the administration of glucose) and confirmed by biological testing, including a 72 hour fasting test (measuring levels of insulin, C-peptide and proinsulin during hypoglycemia). The insulin/C-peptide ratio is > 1.0 in patients with insulinoma. Localization of insulinoma can be achieved by imaging techniques such as transabdominal ultrasound, computed tomography and magnetic resonance imaging, as well as by endoscopic ultrasonography (EUS), angiography, and arterial stimulation venous sampling. Occult insulinoma can be located by dotatate or Glucagon-like peptide-1 analog positron emission tomography.
Differential diagnosis
Malignant insulinomas can be associated with multiple endocrine neoplasia type 1 (MEN1). Other differential diagnoses include other causes of hypoglycemia such as diffuse hepatic disease, Addison disease, and alcoholism, but insulin is not elevated in these conditions. Type B insulin resistance and insulin autoimmune syndrome also need to be considered.
Genetic counseling
With the exception of insulinoma in MEN1, insulinoma is not hereditary.
Management and treatment
Surgical resection is the standard treatment for a benign insulinoma and is often curative. Enucleation, partial or middle pancreatomy, laparoscopic resection and radical resection are all options for benign insulinomas. Octreotide, a somatostatin analogue, can be given pre-operatively as it may be successful in controlling blood glucose levels (not necessary in most cases). Malignant insulinomas require aggressive surgical resection (extended pancreatic and liver resection) along with aggressive secondary treatments (i.e. chemoembolization, radiofrequency ablation). In those with unresectable tumors, octreotide should be administered and glucose monitored regularly, and mammalian target of rapamycin (mTOR) inhibitors are particularly effective in controlling hypoglycemia. Sunitinib malate can be used for malignant insulinomas.
Prognosis
In most cases, insulinomas are benign, and surgical resection is curative. The reported 10-year survival rate of those with a malignant insulinoma, however, is 29%.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Dr Run YU


Intellectual disability, Birk-Barel type is a rare, genetic, syndromic intellectual disability characterized by congenital central hypotonia, developmental delay, moderate to severe intellectual disability and subtle dysmorphic features which evolve over time (dolichocephaly, myopathic facies, ptosis, short and broad philtrum, tented upper lip vermillion, palatal anomalies, mild micro- and/or retrognathia). Patients present reduced facial movements, lethargy, weak cry, transient neonatal hypoglycemia, severe feeding difficulties and failure to thrive. Dysphagia, particularly of solid food, asthenic body build, joint contractures and scoliosis are additional features.


Intellectual disability, Buenos-Aires type is a rare intellectual disability syndrome characterized by growth retardation, microcephaly, characteristic facial features (including narrow forehead, bushy eyebrows, hypertelorism, small, downward-slanting palpebral fissures with blepharoptosis, malformed and low-set ears, broad straight nose, thin upper lip, and a wide, tented mouth), developmental delay, intellectual disability, speech disorder, and multiple organ malformations (e.g. ventricular septal defect, megaloureter, dilated renal pelvis). Additional manifestations reported include neurocutaneous lesions (including palmoplantar hyperkeratosis), internal hydrocephalus, and bilateral partial soft-tissue syndactyly of second and third toe.


Intellectual disability, Wolff type is a rare intellectual disability syndrome characterized by severe intellectual disability, characteristic facial features (low anterior hairline, upward slanting palpebral fissures, ocular hypertelorism, broad, bulbous nose, large ears with helix incompletely developed, thick lips, and micrognathia) and additional anomalies including peripheral joint contractures, delayed skeletal maturation, bilateral cleft lip and palate, strabismus, terminal hypoplasia of fingers, hypospadias, and bilateral inguinal hernias.


Intellectual disability-alacrima-achalasia syndrome is a rare, genetic intellectual disability syndrome characterized by delayed motor and cognitive development, absence or severe delay in speech development, intellectual disability, and alacrima. Achalasia/dysphagia and mild autonomic dysfunction (i.e. anisocoria) have also been reported in some patients. The phenotype is similar to the one observed in autosomal recessive Triple A syndrome, but differs by the presence of intellectual disability in all affected individuals.


Intellectual disability-autism-speech apraxia-craniofacial dysmorphism syndrome

A rare, syndromic intellectual disability characterized by developmental delay, speech apraxia, autism with stereotypies, intellectual disability and unspecific dysmorphic facial features. Seizures or isolated EEG abnormalities may also be associated.


Intellectual disability-balding-patella luxation-acromicria syndrome is characterised by severe intellectual deficit, patella luxations, acromicria, hypogonadism, facial dysmorphism (including midface hypoplasia and premature frontotemporal balding). It has been described in three unrelated males.


Intellectual disability-brachydactyly-Pierre Robin syndrome is a rare developmental defect during embryogenesis syndrome characterized by mild to moderate intellectual disability and phsychomotor delay, Robin sequence (incl. severe micrognathia and soft palate cleft) and distinct dysmorphic facial features (e.g. synophris, short palpebral fissures, hypertelorism, small, low-set, and posteriorly angulated ears, bulbous nose, long/flat philtrum, and bow-shaped upper lip). Skeletal anomalies, such as brachydactyly, clinodactyly, small hands and feet, and oral manifestations (e.g. bifid, short tongue, oligodontia) are also associated. Additional features reported include microcephaly, capillary hemangiomas on face and scalp, ventricular septal defect, corneal clouding, nystagmus and profound sensorineural deafness.


Intellectual disability-cardiac anomalies-short stature-joint laxity syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by intrauterine and postnatal growth restriction, global developmental delay, intellectual disability, and dysmorphic facial features (such as broad nasal root, anteverted nares, long philtrum, low-set and posteriorly rotated ears, and short neck). Additional reported manifestations are microcephaly, short stature, vertebral abnormalities, joint laxity, ocular, cardiac, and renal defects, and minor limb anomalies. Brain imaging may show hypoplastic corpus callosum, delayed myelination, and cerebral atrophy.


Intellectual disability-cataracts-calcified pinnae-myopathy syndrome is a rare, genetic intellectual disability syndrome characterized by macrocephaly, hypotonia, dysmorphic facial features (wide forehead, ptosis, downslanting palpebral fissures, enlarged and calcified external ears, large jaw), sparse body hair, tall stature, and intellectual disability. Hearing loss, insulin-resistant diabetes, and progressive distal muscle wasting (leading to joint contractures) have also been reported in adulthood. Rare manifestations include behavioral abnormalities (aggression and restlessness), hypothyroidism, cerebral calcification, ataxia, and peripheral neuropathy.


Intellectual disability-coarse face-macrocephaly-cerebellar hypotrophy syndrome

A rare, genetic, central nervous system malformation syndrome characterized by early-onset, progressive, severe cerebellar ataxia associated with progressive, moderate to severe intellectual disability, global developmental delay, progressively coarsening facial features, relative macrocephaly and absence of seizures. Sensorineural hearing loss may be associated. Neuroimaging reveals cerebellar atrophy/hypoplasia.


Intellectual disability-developmental delay-contractures syndrome, formerly known as Wieacker-Wolff syndrome, is a severe X-linked recessive neurodevelopmental disorder characterized by severe contractures (arthrogryposis; see this term) and intellectual disability.

Summary:
Epidemiology
Prevalence and incidence rates are not known. The syndrome has been reported in 5 families to date, with fewer than 30 affected individuals described. Affected patients are male, while carrier females are often asymptomatic. Cases have been reported from Germany, France, the Netherlands, Australia, and the United States.
Clinical description
The syndrome is characterized by an association of arthrogryposis multiplexa congenita and intellectual disability. Affected patients are born with severe contractures (arthrogryposis) and muscle weakness causing respiratory distress. Intellectual disability and delayed motor development are found in all patients. Facial weakness (ptosis) and bulbar weakness (feeding difficulty), characteristic dysmorphic facial features (possibly including long flat philtrum, low-set ears, high-arched palate, and carp-shaped mouth), and skeletal abnormalities (camptodactyly, hip dislocation, scoliosis, kyphosis, lordosis and pes equinovarus) have been reported. Other neurological signs may include spasticity and seizures. Heterozygous female carriers may also be affected, but to a lesser degree (intellectual disability, distal muscle weakness, camptodactyly, joint contractures, and pes equinovarus).
Etiology
Intellectual disability-developmental delay-contractures syndrome is caused by mutations in the ZC4H2 gene (Xq11.1) that is presumed to play a role in neuronal function during fetal growth.
Genetic counseling
The disorder follows an X-linked recessive pattern on inheritance. Simplex cases are also found. Genetic counseling should be provided to affected families.

                            Last update:
                            January 2015


Intellectual disability-dysmorphism-hypogonadism-diabetes mellitus syndrome

A rare, genetic, syndromic intellectual disability disorder characterized by mild to moderate intellectual disability, facial dysmorphism (including a long face, deep-set eyes, narrow-based, broad nose with nostril colobomata, mandibular prognathism), hypergonadotrophic hypogonadism, eunuchoid habitus, diabetes mellitus type 1, and epilepsy. There have been no further descriptions in the literature since 1990.


A rare genetic neurological disorder characterized by hypotonia, delayed motor development, dyskinesia of the limbs, intellectual disability with impaired speech development, seizures, autistic features, stereotypic movements, and sleep disturbance. Onset of symptoms is in infancy. Bilateral abnormalities in the putamen on brain MRI have been reported in some patients.


Intellectual disability-expressive aphasia-facial dysmorphism syndrome

A rare genetic syndromic intellectual disability characterized by moderate to severe intellectual deficiency, language deficit (completely absent or significantly impaired speech), and distinctive facial dysmorphism (long face, straight eyebrows, and, less frequently, low-set ears and café-au-lait spots). Additional, variably observed features include motor delays, behavioral difficulties, and seizures.


Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency

A rare, syndromic intellectual disability characterized by intellectual disability of various severity, hypotonia, feeding difficulties, dysmorphic features, autism and behavioral issues. Growth retardation, congenital heart anomalies, gastrointestinal and genitourinary defects have been rarely associated.


Intellectual disability-facial dysmorphism-hand anomalies syndrome is a rare syndromic intellectual disability disorder characterized by moderate intellectual disability, variable hand abnormalities (including brachydactyly, cutaneous and osseous syndactyly), and facial dysmorphism that includes short palpebral fissures, bulbous nasal tip, thin upper and lower vermilion and broad, pointed chin. Other features, including obesity, microcephaly, short stature and a grimacing smile may be observed.


Intellectual disability-hyperkinetic movement-truncal ataxia syndrome

A rare, genetic, syndromic intellectual disability disease characterized by global developmental delay, microcephaly, mild to moderate intellectual disability, truncal ataxia, trunk and limb, or generalized, choreiform movements, and elevated serum creatine kinase levels. Variably associated features include mild cerebral atrophy, muscular weakness or hypotonia in early childhood, and/or seizures. Ocular abnormalities (e.g. exophoria, anisometropia, amblyopia) have been reported.


Intellectual disability-hypoplastic corpus callosum-preauricular tag syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by psychomotor and growth delay, severe intellectual disability, microcephaly, and hypoplastic corpus callosum. Additional reported manifestations include increased muscle tonus, seizures, cardiac anomalies, recurrent bronchopneumonia, camptodactyly, preauricular skin tag, and dysmorphic facial features (such as broad forehead, hypertelorism, flat nasal bridge, anteverted nostrils, and prominent ears), among others.


Intellectual disability-hypotonia-brachycephaly-pyloric stenosis-cryptorchidism syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by craniofacial dysmorphism (brachycephaly resulting from craniosynostosis, frontal bossing, downslanting palpebral fissures, large and low-set ears, depressed nasal bridge, high-arched, wide palate, thin upper lip), impaired neurological development with intellectual disability, hypotonia, pyloric stenosis, pectus excavatum, bilateral cryptorchidism and short stature.


Intellectual disability-macrocephaly-hypotonia-behavioral abnormalities syndrome

A rare, syndromic intellectual disability characterized by hypotonia, global developmental delay, limited or absent speech, intellectual disability, macrocephaly, mild dysmorphic features, seizures and autism spectrum disorder. Associated ophthalmologic, heart, skeletal and central nervous system anomalies have been reported.


Intellectual disability-muscle weakness-short stature-facial dysmorphism syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, developmental delay, delayed bone age, short stature, generalized muscle weakness, and dysmorphic facial features (such as high arched eyebrows, downslanting palpebral fissures, prominent nose, and narrow palate and mouth). Additional reported manifestations include blue sclerae, ophthalmoplegia, and intention tremor. Brain imaging may show white matter abnormalities.


Intellectual disability-myopathy-short stature-endocrine defect syndrome is a rare congenital myopathy syndrome characterized by nonprogressive myopathy (manifesting with mild facial and generalized weakness, bilateral ptosis, and severe lumbar lordosis), severe intellectual disability, short stature, and sexual infantilism (due to hypogonadotropic hypogonadism). The presence of a small pituitary fossa was also noted. There have been no further descriptions in the literature since 1985.


Intellectual disability-obesity-brain malformations-facial dysmorphism syndrome is a rare, syndromic intellectual disability primarily characterized by moderate to severe intellectual disability, true-to-relative microcephaly and brain abnormalities including a thin corpus callosum, cerebellar hypoplasia, cerebral white matter hypoplasia and multi-focal hyperintensity of cerebral white matter on MRI. Obesity and distinctive craniofacial dysmorphism (including brachycephaly, round face, straight eyebrows, synophrys, hypertelorism, epicanthus, wide and depressed nasal bridge, protruding ears with uplifted lobe, downslanting corners of the mouth) are additional features.


Intellectual disability-obesity-prognathism-eye and skin anomalies syndrome is a rare, genetic, syndromic intellectual disability disorder characterized by mild to profound intellectual disability, delayed speech, obesity, ocular anomalies (blepharophimosis, blepharoptosis, hyperopic astigmatism, decreased visual acuity, strabismus, abducens nerve palsy, and/or accommodative esotropia), and dermal manifestations, such as chronic atopic dermatitis. Associated craniofacial dysmorphism includes macrocephaly, maxillary hypoplasia, mandibular prognathism, and crowding of teeth.


Intellectual disability-polydactyly-uncombable hair syndrome is a multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, postaxial polydactyly, phalangeal hypoplasia, 2-3 toe syndactyly, uncombable hair and facial dysmorphism (including frontal bossing, hypotelorism, narrow palpebral fissures, nasal bridge and lips, prominent nasal root, large abnormal ears with prominent antihelix, poorly folded helix, underdeveloped lobule and antitragus, and micrognathia evolving into prognatism). Cryptorchidism, conductive hearing loss and progressive thoracic kyphosis were also reported.


Intellectual disability-seizures-abnormal gait-facial dysmorphism syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay, intellectual disability, seizures, abnormal gait, and craniofacial dysmorphism (including coarse features, depressed nasal bridge, anteverted nares, broad nasal tip, prominent maxilla and upper lip, wide mouth, abnormal gingiva, and widely spaced teeth). Additional reported manifestations are ocular anomalies, cardiac defects, gastrointestinal problems, and autistic features. Brain imaging may show thin corpus callosum, white matter abnormalities, or dilated ventricles.


Intellectual disability-seizures-hypophosphatasia-ophthalmic-skeletal anomalies syndrome

A rare congenital disorder of glycosylation characterized by neonatal hypotonia, global development delay, developmental regress and severe to profound intellectual disability, infantile onset seizures that are initially associated with febrile episodes with subsequent transition to unprovoked seizures, impaired vision with esotropia and nystagmus, progressive cerebral and cerebellar atrophy, skeletal abnormalities (including brachycephaly, scoliosis, slender long bones, delayed bone age, pectus excavatum and osteopenia), inverted nipples and dysmorphic features including high and narrow forehead, frontal bossing, short nose, depressed nasal bridge, anteverted nares, high palate and wide open mouth consistent with facial hypotonia. Other features may include cardiac abnormalities (such as patent ductus arteriosus, atrial septal defects), urogenital abnormalities (such as nephrocalcinosis, urolithiasis), and low plasma concentration of alkaline phosphatase.


Intellectual disability-seizures-macrocephaly-obesity syndrome is a rare syndromic obesity due to complex chromosomal rearrangement characterized by development delay and intellectual disability, childhood-onset obesity, seizures, poor coordination and broad-based gait, macrocephaly and mild dysmorphic features (such as narrow palpebral fissures, malar hypoplasia and thin upper lips), eczema, ocular abnormalities and a social personality.


Intellectual disability-short stature-hypertelorism syndrome is a rare genetic syndromic intellectual disability characterized by short stature, mild to moderate intellectual disability, craniofacial dysmorphism (prominent broad 'square' forehead, hypertelorism, depressed nasal bridge, broad nasal tip and anteverted nares) and early hypotonia, typically present until infancy. There have been no further descriptions in the literature since 1991.


Intellectual disability-spasticity-ectrodactyly syndrome is a rare intellectual disability syndrome characterized by severe intellectual disability, spastic paraplegia (with wasting of the lower limbs) and distal transverse defects of the limbs (e.g. ectrodactyly, syndactyly, clinodactyly of the hands and/or feet).


A rare, genetic, syndromic intellectual disability disorder characterized by moderate to severe intellectual disability and esotropia. Other associated features may include growth failure (underweight, failure to thrive, short stature), microcephaly, tone abnormalities (hypotonia, spasticity), epilepsy, behavioral problems (hyperactivity, aggressiveness), and/or abnormal brain morphology, including arachnoid cyst, cerebral atrophy, mild ventriculomegaly, abnormal CNS myelination or corpus callosum agenesis.


A congenital cardiac malformation characterized by a communication between the atrial chambers of the heart.

Summary:
Epidemiology
Overall, openings between the atrial chambers account for about 6 to 8% of all congenitally malformed hearts. As a group, the prevalence at birth is between 6 to 9/10000; however, this is likely an underestimated due to the asymptomatic nature of the disease. The female-to-male ratio is 2-4:1.
Clinical description
There are four types of defects, named according to their position relative to the atrial septum. The ostium secundum defect is the most common type, accounting for three-quarters of all cases, located to the region of the oval fossa, most commonly due to a deficiency of the primary atrial septum (septum primum) but deficiency of the septum secundum (superior interatrial fold) may also contribute. The ostium primum defect, which accounts for one-sixth of defects, is in reality an atrioventricular septal defect, with shunting exclusively at atrial level. Only these two defects are true atrial septal defects. The sinus venosus defect (one-tenth of cases) is a hole outside the confines of the oval fossa, through which a caval vein and/or pulmonary vein(s) override the atrial septum or the septum secundum (superior interatrial fold) producing an interatrial or anomalous veno-atrial communication.The rarest defect, the coronary sinus defect, is a communication between the left atrium and the coronary sinus allowing interatrial communication through the orifice of the coronary sinus, and is due to absence or partial unroofing of the coronary sinus. Interatrial communications are most often asymptomatic in childhood but clinical manifestations can include: rapid breathing, shortness of breath, fatigue, sweating, palpitations, frequent respiratory infections, and poor growth. Symptoms often manifest by the age of 30 to 40 years. Adults with interatrial communications are at increased risk of developing pulmonary arterial hypertension, heart failure, arrhythmias, and stroke. About one third of affected children have an associated hereditary syndrome, such as Down's syndrome, Alagille syndrome, Holt-Oram syndrome, Ellis-van Creveld syndrome, or Noonan syndrome.
Etiology
Several susceptibility genes have been identified.
Diagnostic methods
The defect is most often suspected during a physical examination. Cardiac auscultation reveals a systolic outflow murmur. Echocardiography, chest X-ray and electrocardiogram, and cardiac catheterization may help the diagnosis, although the latter technique is now rarely required for diagnostic purposes.
Differential diagnosis
Differential diagnosis includes other congenital cardiac anomalies that result in left-to-right shunt at the atrial level, including partial atrioventricular septal defect and anomalous pulmonary venous return.
Antenatal diagnosis
A significant defect may be diagnosed during fetal life, although prenatal diagnosis is difficult as interatrial communication is an integral part of fetal circulation.
Genetic counseling
Most defects occur sporadically as a result of spontaneous genetic mutations, but hereditary forms have been reported. Familial secundum defects can be associated with mutations in transcription factors NKX2.5 (5q34), GATA4 (8p23.1), TBX6 (16p11.2), along with conduction disorders such as atrioventricular block.
Management and treatment
Closure of the defect is recommended if left-to-right shunt is important with right ventricular overload and dilatation. Transcatheter device closure is nowadays the treatment of choice for secundum defects beyond the infant period. For other types of interatrial communications, and in large secundum defects with deficient rims, open-heart surgery is indicated, and is complication-free in the majority of cases. Whatever the technique used, closure of the defect is rarely indicated before the age of 3 years. Large defects should be closed before the second decade of life.
Prognosis
Small-to-moderate defects may be asymptomatic and life expectancy is not reduced. In some children, small openings may close spontaneously (occurring in up to four-fifths of cases with small openings in the first 18 months of life). In some patients with large defects, Eisenmenger reaction can occur after the first decade of life.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Pr Lucile HOUYEL


A rare dendritic cell tumor characterized by a neoplasm composed of spindle to ovoid cells with phenotypic features similar to those of interdigitating dendritic cells. Solitary lymph node involvement is common, although extranodal localization (in particular skin and soft tissue) has also been reported. Patients usually present with an asymptomatic mass, sometimes with systemic symptoms such as fatigue, fever, and night sweats. Generalized lymphadenopathy, splenomegaly, or hepatomegaly may be seen in rare cases. The clinical course is generally aggressive.


Intermediate atrioventricular septal defect

A rare congenital non-syndromic heart malformation characterized by a common atrioventricular junction with a single atrioventricular valve ring, accompanied by an ostium primum type atrial septal defect and a small ventricular septal defect.


A rare genetic neonatal diabetes mellitus syndrome characterized by neonatal insulin-dependent diabetes mellitus, mild motor, speech or cognitive delay, and absence of epilepsy. Is it a less severe form of DEND syndrome.


Intermediate epidermolysis bullosa simplex with cardiomyopathy

A rare, inherited, epidermolysis bullosa characterized by aplasia cutis congenita on the extremities, leaving behind hypopigmentation and atrophy in a whirled pattern. Generalized blistering persists during childhood and heals with cutaneous and follicular atrophy, linear and stellate scars, and hypopigmentation. Skin fragility decreases with adulthood. Adult patients exhibit dyspigmentation and atrophy of the skin, scars, follicular atrophoderma, sparse body hair, progressive diffuse alopecia of the scalp, diffuse palmoplantar keratoderma, and nail changes. Dilative cardiomyopathy with heart failure complicates the disease course in young adulthood or later and may have lethal outcome. Ultra-structurally, intraepidermal splitting appears at the level of the basal keratinocytes, above the hemidesmosomes.


Intermediate generalized junctional epidermolysis bullosa

A form of junctional epidermolysis bullosa (JEB) characterized by generalized skin blistering, atrophic scarring, nail dystrophy or nail absence, and enamel hypoplasia, with extracutaneous involvement.

Summary:
Epidemiology
Prevalence of intermediate junctional epidermolysis bullosa (intermediate JEB) is unknown.
Clinical description
The condition is clinically apparent at birth. Skin blistering is generalized and healing can occur either with atrophic scars, sometimes accompanied by hypopigmentation or hyperpigmentation or, less commonly, with the formation of exuberant granulation tissue. Nail dystrophy or loss is a constant feature, and focal palmoplantar keratoderma can develop over time. Progressive and permanent hair loss is frequently present, affecting the scalp, eyelashes and eyebrows; pubic and axillary hair are scant or do not fully develop. Mucosal lesions mainly affect the oral and nasal cavity, although there is considerable individual variability. Ocular involvement has been reported in some patients and comprises corneal erosions and scars, and, rarely, ectropion. The teeth regularly show enamel hypoplasia, leading to severe caries. Chronic anemia of multifactorial etiology, although of varying severity, is frequent and may be associated with a growth delay.
Etiology
Intermediate JEB is caused by mutations in the COL17A1 (10q24.3), ITGB4 (17q25.1), LAMA3 (18q11.2), LAMB3 (1q32) and LAMC2 (1q25-q31) genes.
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by immunofluorescence mapping or transmission electron microscopy and genetic testing.
Differential diagnosis
The differential diagnosis includes other forms of EB. In the neonatal period, aplasia cutis congenita, herpes simplex infection, congenital erosive and vesicular dermatosis, epidermolytic ichthyosis, linear IgA bullous dermatosis, bullous pemphigoid, neonatal pemphigus and pemphigoid gestationis, bullous impetigo, and staphylococcal scalded skin syndrome may need to be considered.
Antenatal diagnosis
Antenatal diagnosis can be recommended in families with this subtype depending on the degree of severity.
Genetic counseling
The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Management is preventive: protective padding of the skin reduces blistering and careful wound care prevents secondary infection and reduces scarring. Oral hygiene is important for management of caries. A dietitian should evaluate nutritional requirements. Ocular, gastrointestinal, urinary and renal manifestations require specific treatment.
Prognosis
Although intermediate JEB is less severe than other forms of JEB, death can occur in infancy and childhood due to sepsis, failure to thrive and respiratory failure. Adult patients have an increased risk of developing squamous cell carcinomas in particular on the lower extremities, in areas of chronic blistering, long-standing erosions, or atrophic scarring.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Pr Cristina HAS | ERN-Skin*

                                * European Reference Network


Intermediate maple syrup urine disease (intermediate MSUD) is a milder form of MSUD (see this term) characterized by persistently raised branched-chain amino acids (BCAAs) and ketoacids, but fewer or no acute episodes of decompensation.

Summary:
Epidemiology
The estimated birth prevalence of MSUD is 1/ 150,000. Around 30% of cases are believed to be of the intermediate type.
Clinical description
Symptom onset of intermediate MSUD varies between the early months and the early years of childhood. Infants may have feeding problems, poor growth, maple syrup odor in urine and developmental delay. Older children usually present with learning difficulties. Like classic MSUD (see this term), catabolic stress can result in acute decompensation with anorexia, vomiting, ataxia (in infants/toddlers), cognitive impairment, sleep disturbances, hallucinations, hyperactivity, mood swings, acute dystonia, choreoathetosis (in adults), stupor, coma and cerebral edema, if untreated.
Etiology
MSUD is due to mutations in genes encoding 3 of the 4 subunits of the branched chain 2-ketoacid dehydrogenase (BCKAD) complex. The genes are BCKDHA (19q13.1-q13.2), encoding E1a, BCKDHB (6q14.1), encoding E1b, and DBT (1p31), encoding E2 respectively. Mutations lead to accumulation of BCAAs (especially leucine) and branched-chain alpha-ketoacids. In intermediate MSUD mutations in BCKDHB and DBT predominate. A mutation in the PPM1K gene (4q22.1) was found in one case.
Diagnostic methods
Intermediate MSUD can be diagnosed by tandem mass spectrometry newborn screening. Otherwise, plasma amino acid analysis is diagnostic. Plasma leucine levels are increased while isoleucine and valine levels may be normal or increased. Patients have 3-30% BCKAD activity so their levels of plasma BCAAs are not as high as those seen in classic MSUD (see this term). Molecular genetic testing can identify a disease causing mutation, equally confirming diagnosis.
Differential diagnosis
Differential diagnoses of the presenting symptoms include other inborn errors of intermediary metabolism such as NAGS deficiency, ornithine transcarbamylase deficiency, argininosuccinic aciduria (and other urea cycle defects), neonatal glycine encephalopathy, propionic acidemia, methylmalonic acidemia, and beta-ketothiolase deficiency (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation.
Genetic counseling
Intermediate MSUD is inherited autosomal recessively and genetic counseling is possible.
Management and treatment
Treatment of intermediate MSUD is similar to classic MSUD. Infants require high calorie BCAA-free formulas, dietary leucine restriction and close outpatient monitoring at a metabolic clinic. Management of acute decompensation requires aggressive enhancement of protein anabolism using glucose plus insulin, intravenous lipids, plasma amino acid monitoring, and isoleucine and valine supplements. Patients must adhere to a strict life-long diet to avoid episodes of acute decompensation. Special monitoring during pregnancy is vital.
Prognosis
With early diagnosis and appropriate therapy the prognosis is good, but because the disorder is mild, diagnostic delay is common and some neurological damage may be sustained.

                            Last update:
                            April 2014

                            - Expert reviewer(s):
                            Dr Bridget WILCKEN


Intermediate nemaline myopathy is a type of nemaline myopathy (NM; see this term) that shows features of typical NM (see this term) in neonates with a more severe progression.

Summary:
Epidemiology
The annual incidence of NM has been estimated at 1/50,000 live births, and intermediate NM might represent 20% of all cases.
Clinical description
Neonates with intermediate NM present with spontaneous anti-gravity movements and active respiratory muscles, but with a progressive generalized weakness which prevents achievement of gross motor milestones or leads to loss of ambulation and/or independent respiration by age 11 years. Children often develop joint contractures.
Etiology
The ACTA1 (1q42.13), NEB (2q22) or TPM3 (1q21.2) genes have been associated with intermediate NM.
Genetic counseling
The transmission pattern of the disease is autosomal recessive or dominant.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr Monique RYAN


A rare, genetic primary bone dysplasia with increased bone density characterized by susceptibility to fractures after minor trauma, anemia, and characteristic skeletal radiographic changes, such as sandwich vertebra, bone-within-bone appearance, Erlenmeyer-shaped femoral metaphysis, and mild osteosclerosis of the skull base. Dental anomalies and visual impairment secondary to optic nerve compression have been rarely described.


A rare ophthalmic disorder characterized by intraocular inflammation primarily localized to the vitreous and peripheral retina. It incorporates pars planitis, posterior cyclitis, and hyalitis. Patients present with painless floaters, decreased or blurred vision, less frequently with pain, redness, and photophobia. On examination, snow banking, vitreous snowballs, peripheral retinal vascular sheathing, vitreous cells, and vitreous haze can be seen. Complications include epiretinal membrane formation, cataract formation, cystoid macular edema, or band keratopathy, among others. The condition may be idiopathic or occur in the context of infectious or systemic diseases.


A rare rheumatologic disease characterized by recurrent self-remitting episodes of acute monoarticular arthritis, often with a fixed periodicity, typically affecting the knee or another large joint, which develops an effusion over 12 to 24 hours with only mild to moderate pain and minimal signs of inflammation. Attacks last three to five days and may parallel menses in females. Systemic symptoms are absent, and no joint damage occurs.


Intermittent maple syrup urine disease (intermittent MSUD) is a mild form of MSUD (see this term) where patients (when well) are asymptomatic with normal levels of branched-chain amino acids (BCAAs) but with catabolic stress are at risk of acute decompensation with ketoacidosis, which can lead to cerebral edema and coma if untreated.

Summary:
Epidemiology
MSUD has an estimated incidence of 1/150,000 live births. There is no data to suggest what number of patients has intermittent MSUD but it is probably underdiagnosed.
Clinical description
Unlike classic MSUD (see this term), patients with intermittent MSUD show normal growth and intellectual development during infancy and childhood. They may develop symptoms (mainly in childhood) with any catabolic stress (i.e. fasting, dehydration, fever, infections or pregnancy (in adults)). These precipitating factors can lead to a potentially fatal episode of acute decompensation with anorexia, nausea, vomiting, lethargy, ataxia (in infants/toddlers), cognitive impairment, sleep disturbances, hallucinations, hyperactivity, mood swings, acute dystonia, and choreoathetosis (in adults), that can progress to stupor, coma and cerebral edema. Intelligence and development are not usually affected by these episodes.
Etiology
MSUD is due to mutations in genes encoding 3 of the 4 subunits of the branched-chain 2-ketoacid dehydrogenase (BCKAD) complex. The genes are BCKDHA (19q13.1-q13.2), encoding E1a, BCKDHB (6q14.1), encoding E1b, and DBT (1p31), encoding E2 respectively. Mutations lead to an accumulation of BCAAs (especially leucine) and branched-chain alpha-ketoacids. In intermittent MSUD, mutations in DBT may predominate.
Diagnostic methods
Intermittent MSUD may be missed on tandem mass spectrometry newborn screening. BCAA levels are usually normal or only slightly elevated, except during times of physiological stress when the biochemical profile is similar to classic MSUD. Ketonuria and gas chromatography-mass spectrometry can also identify branched-chain alpha ketoacids (BCKAs) in the urine during decompensation only.
Differential diagnosis
Differential diagnoses of the presenting symptoms may include other inborn errors of intermediary metabolism such as NAGS deficiency, ornithine transcarbamylase deficiency, argininosuccinic aciduria (and other urea cycle defects), neonatal glycine encephalopathy, propionic acidemia and beta-ketothiolase deficiency (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation.
Genetic counseling
Inheritance is autosomal recessive and genetic counseling is possible.
Management and treatment
Patients with intermittent MSUD tolerate a normal intake of leucine and treatment is not necessary. However, they need regular review at a metabolic clinic and a management strategy to avoid acute decompensation including a high-energy, low-protein diet during illness. Management of acute decompensation requires aggressive enhancement of protein anabolism which may include using glucose plus insulin, intravenous lipids, plasma amino acid monitoring, and isoleucine and valine supplements.
Prognosis
The prognosis is good if metabolic control is maintained during times of stress and any episodes of acute decompensation are immediately treated.

                            Last update:
                            April 2014

                            - Expert reviewer(s):
                            Dr Bridget WILCKEN


Internal carotid artery (ICA) agenesis (uni or bilateral) is a developmental defect that may be asymptomatic or lead to cerebrovascular lesions. It is a rare malformation, with only around hundred cases reported in the literature. When symptoms are present, they are caused by cerebrovascular insufficiency, compression of the brain by vessels that dilate to compensate for the absence of the ICA, or the presence of an aneurysm. Associated intracranial aneurysms occur in 25 to 35% of patients and are often responsible for intracranial hemorrhage, which may present as the initial symptom. The absence of the ICA is the result of either agenesis or aplasia. The term agenesis is used when both the ICA and its bony canal are absent, whereas there is some evidence of carotid canals in cases of aplasia. The absence of the ICA can be detected by angiography or by computerised tomography.


A rare non-infectious, chronic and most often progressive disease of the urinary bladder. It is characterized by varying combinations and extent of pain, urinary frequency (pollakisuria), nocturia and urgency. Interstitial cystitis (IC) has a broad intersection with Bladder Pain Syndrome (BPS) and Overactive Bladder (OAB).

Summary:
Epidemiology
Prevalence of IC/BPS is approximately 1/200-2,000- for females and 1/2,450-12,500 for males. The prevalence of IC alone is less than 1/2,000. The estimated number of unreported cases might be much higher. Women are more affected than men (ratio 9:1).
Clinical description
IC is characterized by a permanent or intermittent unpleasant sensation (pain, pressure, bladder spasms) in the pelvic (or vulvar, suprapubic, pubic, vaginal, perineal, scrotal or urethral) region of more than 6 month duration, often with worsening during bladder filling. Limited bladder capacity is frequent but not a mandatory precondition. Frequency, nocturia and urgency are often associated with IC. Two types of IC can be distinguished: Hunner-Type and Non-Hunner-Type IC.
Etiology
The exact etiology of the disorder is unknown and might be multifactorial. Possible factors are urothelial alterations with an increased permeability of urine components, preceding infections (including history of bacterial cystitis), hormonal, vascular or neurological abnormalities, trauma, inflammation or autoimmune diseases. Other risk factors may include pelvic surgery, changes in microbiome, reduced microcirculation, histamine intolerance, dysfunction of the pelvic floor, endometriosis, genetic factors and psychological factors.
Diagnostic methods
IC is a diagnosis of exclusion. Diagnosis is based on the patient's history, questionnaires, pain protocol, bladder diary and physical examination including a pain mapping and urinalysis. Additional examinations include ultrasound, uroflowmetry, urethrocystoscopy, flow-electromyography and urodynamics, provocation tests (e.g. KCl test), hydrodistension of the bladder and bladder biopsy under anesthesia combined with a standardized counting for mast cells. A stool test may also helpful.
Differential diagnosis
Differential diagnoses include a long list of diseases of the musculoskeletal system and connective tissue, gastrointestinal diseases, gynecological diseases, neurological disorders, psychological disorders and urological diseases.
Management and treatment
Treatment is most often symptomatic, and ranges from non-invasive behavioral treatment to oral medication, complementary medicine, intravesical therapy (instillation), transurethral procedures, invasive / surgical interventions and rehabilitation measures. A phased approach is recommended and the therapy should be individualized. Cystectomy and urinary diversion is an ultima ratio, although with excellent results in pain control in patients with IC.
Prognosis
IC is a debilitating disease and extremely affects the quality of life including physical, psychological, domestic, social, sexual and occupational aspects. IC is a chronically-recurring or chronically-progressive disease. Most often IC results in a bladder with very low capacity, high frequency and intolerable pain.

                            Last update:
                            September 2020

                            - Expert reviewer(s):
                            Pr Thomas BSCHLEIPFER


Interstitial granulomatous dermatitis with arthritis is a rare rheumatologic disease characterized by the occurrence of inflammatory arthritis in association with large, erythematous, symmetrical cutaneous lesions (ranging from typical, but infrequent, cord-like lesions on the flanks to more common violaceous plaques on the trunk and limbs) featuring a typical histologic infiltrate mainly constituted of histiocytes.


Interstitial lung disease due to ABCA3 deficiency

A rare genetic respiratory disease characterized by a variable clinical outcome ranging from a fatal respiratory distress syndrome in the neonatal period to chronic interstitial lung disease developing in infancy or childhood with chronic cough, rapid breathing, shortness of breath and recurrent pulmonary infections. Clinical manifestations of respiratory failure include grunting, intercostal retractions, nasal flaring, cyanosis, and progressive dyspnea.


Interstitial lung disease due to SP-C deficiency

A rare genetic interstitial lung disease characterized by diffuse lung disease of variable phenotype ranging from severe respiratory insufficiency in infancy to asymptomatic adults, due to surfactant protein C deficiency. Typical presentation in infancy includes dyspnea, cough, wheezing, and gradual cyanosis, with or without failure to thrive. Radiological findings include diffuse ground-glass opacities in neonates, later interstitial thickening associated with lung hyperinflation, intraparenchymal/subpleural cysts, honeycombing, subpleural nodules, or bronchiectasis. Infiltrates and air leaks are frequent complications.


Interstitial lung disease-nephrotic syndrome-epidermolysis bullosa syndrome

A life-threatening multiorgan disorder which develops in the first months of life, presenting with respiratory distress and proteinuria in the nephrotic range, and leading to severe interstitial lung disease and renal failure. Some patients additionally display cutaneous alterations, ranging from blistering and skin erosions to an epidermolysis bullosa-like phenotype, with toe nail dystrophy and sparse hair.


Interventricular septum aneurysm is a rare, non-syndromic, congenital heart malformation characterized by the presence of a congenital aneurysm of the membranous portion of the interventricular septum. Patients may be asymptomatic or may present with ventricular or supraventricular tachycardia, fatigue, exertional dyspnea, palpitations, and cardiac murmur. Ventricular septal defects and conduction defects, such as first-degree atrio-ventricular block or incomplete right bundle branch block, may also be also associated.


A rare form of botulism, a rare acquired neuromuscular junction disease with descending flaccid paralysis caused by botulinum neurotoxins (BoNTs), and is due to intestinal colonization by Clostridium botulinum leading to toxin-mediated infection with toxemia. The disease affects infants (infant botulism) and very rarely adults (adult intestinal botulism).

Summary:
Epidemiology
Prevalence of intestinal botulism is unknown. So far, nearly 3,400 cases have been reported worldwide, mainly in infants (about 3,350 cases versus 20 cases in adults).
Clinical description
Clinical manifestations are similar to other forms of botulism, in particular those of foodborne botulism (see this term), except for the lack of gastrointestinal symptoms (nausea, vomiting and diarrhea).
Etiology
The disease is caused by botulinum neurotoxins (BoNTs), produced by C. botulinum type A,B,E, or very rarely by neurotoxigenic strains of C. baratii type F and C. butyricum type E, that can temporarily colonize the intestinal tract. Colonization in adults is generally associated with anatomical abnormalities of the gastrointestinal tract or alteration of protective endogenous microflora by broad-spectrum antibiotics following inflammatory intestinal disease or surgery. Colonization in infants is believed to occur because normal competitive microflora has not been fully established. After spore germination and toxinogenesis, the toxin is absorbed into the blood stream and distributed throughout the body, causing the typical manifestations of botulism.

                            Last update:
                            April 2011

                            - Expert reviewer(s):
                            Dr Lucia FENICIA


Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency is an extremely rare, autosomal recessive, gastroenterological disorder reported in three families so far that is characterized by meconium ileus without any further stigmata of cystic fibrosis (see this term) including pulmonary or pancreatic manifestations. Two of the reported patients developed chronic diarrhea in infancy. Homozygous mutations in the GUCY2C gene (12p12) leading to marked reduction or absence of enzymatic activity of guanylate cyclase 2C were found in the affected patients. The disease was reported to show partial penetrance.


Intractable diarrhea of infancy (IDI) is a heterogeneous syndrome that includes several diseases with different etiologies. Provisional classification of IDI, according to villous atrophy and based on immunohistological criteria, distinguishes two clearly different groups of IDI: 1) Immune-mediated: characterised by a mononuclear cell infiltration of the lamina propria and considered as being related to T cell activation. 2) The second histological pattern includes early onset severe intractable diarrhea histologically characterised by villous atrophy with low or without mononuclear cell infiltration of the lamina propria but specific histological abnormalities involving the epithelium.

Summary:
Clinical description
Based on recent advances in the genetics of autoimmune enteropathy as well as the pathophysiology and clinical presentation, autoimmune enteropathy can be classified into three different types: the classical form of autoimmune enteropathy, identical to the so-called immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX) syndrome (autoimmune enteropathy type 1); autoimmune enteropathy type 2 (without extra-intestinal manifestations) and autoimmune enteropathy type 3 (in girls). Microvillus inclusion disease (MVID) and Intestinal epithelial dysplasia (IED), also known as tufting enteropathy, are congenital enteropathies presenting with villous atrophy and are thought to be related to abnormal enterocytes. Another form of IDI that should be considered in a different way from the two other groups is so-called 'phenotypic diarrhoea'' or 'syndromatic diarrhoea''. This form of IDI presents with severe early onset diarrhea resisting bowel rest, non-specific villous atrophy and very characteristic extra-digestive (facial and hair dysmorphy) manifestations.
Diagnostic methods
Clinically, IDI may be easy to diagnose on the basis of the symptoms onset, clinical presentation and associated disorders. Histopathological analysis confirms the diagnosis.
Prognosis
Infants with IDI remain dependent on parenteralnutrition for months, years and, in most cases, forever because of the permanent intestinal failure associated with the high rate of digestive loss. As long-term parenteral nutrition is associated with complications and/or poor quality of life, alternative treatments, such as intestinal transplantation, have to be considered.

                            Last update:
                            March 2006

                            - Expert reviewer(s):
                            Pr Olivier GOULET


Intractable diarrhea-choanal atresia-eye anomalies syndrome is characterised by the association of intractable diarrhoea of infancy with choanal atresia. Short stature, a prominent and broad nasal bridge, micrognathia, single palmar creases, chronic corneal inflammation, cytopenia, and abnormal hair texture were also reported. So far, the syndrome has been described in three children from the same family. The absence of intellectual deficit and immune deficiency allow this syndrome to be distinguished from other forms of intractable diarrhoea of infancy described previously.


Intraductal papillary mucinous carcinoma of pancreas is a rare epithelial tumor of pancreas characterized by malignant, mucin-producing cystic mass, originating from the pancreatic ductal system, associated with local invasion and metastatic spread, composed of mucin-producing, columnar epithelial cells covering the dilated pancreatic ducts with a papillary structure. The presenting symptoms are non-specific and include abdominal pain, pancreatitis, steatorrhea, jaundice and diabetes. Many patients are asymptomatic at the time of diagnosis.


Intraductal tubulopapillary neoplasm of pancreas

A rare epithelial tumor of pancreas characterized by a solid, nodular mass growing within dilated pancreatic ducts, histologically composed of nodules of back-to-back tubular glands forming large cribriform structures, with high-grade dysplasia and ductal differentiation. There is no overt production of mucin. About half of the tumors occur in the head of the pancreas, one third involve the gland diffusely. Patients present with nonspecific symptoms including abdominal pain, vomiting, weight loss, steatorrhea, and diabetes mellitus, while obstructive jaundice is uncommon. This tumor type accounts for less than 1% of exocrine neoplasms and 3% of intraductal neoplasms of the pancreas.


Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder characterized by (i) pruritus with onset in the second or third trimester of pregnancy, (ii) elevated serum aminotransferases and bile acid levels, and (iii) spontaneous relief of signs and symptoms within two to three weeks after delivery.

Summary:
Epidemiology
ICP is observed in 0.4-1% of pregnancies in most regions of Central and Western Europe and in North America. In Chile and Bolivia, as well as Scandinavia and the Baltic states, roughly 5-15% and 1-2%, respectively, of pregnancies are associated with ICP.
Clinical description
Intrahepatic cholestasis of pregnancy increases the risk of preterm delivery (19-60%), meconium staining of amniotic fluid (27%), fetal bradycardia (14%), fetal distress (22-41%), and fetal loss (0.4-4.1%), particularly when associated with fasting serum bile acid levels >40 micromol/L.
Etiology
Genetic and hormonal factors, as well as environmental effects, may contribute to the pathogenesis of ICP.
Management and treatment
The hydrophilic bile acid, ursodeoxycholic acid (10-20 mg/kg/d), is today regarded as the first line treatment for intrahepatic cholestasis of pregnancy. Induction of delivery is recommended in the 38th week when lung maturity has been established.

                            Last update:
                            May 2007

                            - Expert reviewer(s):
                            Pr U.H.W. [Ulrich] BEUERS  - Pr Thomas PUSL


Intraneural perineurioma is a rare tumor of cranial and spinal nerves arising from peripheral nerve sheath and composed exclusively or predominantly of cells showing perineurial differentiation. It presents as a localized, tubular or fusiform enlargement of a nerve or nerve segment, usually in the extremities or the trunk, associated with a motor-predominant mononeuropathy including slow, painless, gradual loss of motor function in the involved nerve trunk with muscle weakness and atrophy and, rarely, sensory dysfunction. Cranial nerve involvement is rare.


Intraocular medulloepithelioma is a rare eye tumor characterized by a white, gray or yellow-colored cystic mass that arises from the primitive neuroectodermal, nonpigmented epithelium of the ciliary body, or occasionally from the optic nerve, optic disc, retina or iris. Typically it has a benign clinical course with good prognosis and generally presents with childhood onset of poor vision and pain, glaucoma, and/or cataract. Leukocoria, exotropia, exophthalmos, strabismus, epiphora, change in eye color, hyphema, and raised intraocular pressure are also remarkable manifestations.


Intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome

A rare genetic disease characterized by the presence of multiple café-au-lait macules and elevated rates of sister chromatid exchange demonstrated on cytogenetic testing. Pre- and postnatal growth deficiency with short stature, microcephaly, mild developmental delay, cardiomyopathy, and symptomatic gastro-esophageal reflux have also been described, while malar rash is typically absent.


Intrauterine growth restriction-short stature-early adult-onset diabetes syndrome

A rare genetic endocrine disease characterized by intrauterine growth restriction, failure of an adolescent growth spurt with proportional adult short stature, insulin resistance, and early adulthood-onset diabetes. Minimal subluxation of the fifth metacarpal-phalangeal joint has been reported, while metaphyseal dysplasia is absent. Testicular volume is low, but fertility is normal. There is no evidence of primary adrenal insufficiency.


Intravascular large B-cell lymphoma (IVLBCL) is a very rare form of diffuse large B-cell lymphoma (see this term) characterized by the selective growth of lymphoma cells within the lumina of small blood vessels (especially the capillaries) that most often presents with a wide range of clinical manifestations (as potentially any tissue can be involved), with patients from Western countries more frequently manifesting with neurological and cutaneous symptoms while patients from Asian countries more frequently displaying hepatosplenomegaly and thrombocytopenia. IVLBCL is characterized by an absence of lymphadenopathy, an aggressive clinical course and a poor prognosis.


Invasive infections due to vancomycin-resistant enterococci

A rare bacterial infectious disease characterized by invasive infection with vancomycin-resistant enterococci (VRE), typically after VRE colonization of the gastrointestinal tract or the skin in healthcare settings. Invasive infection most commonly occurs in immunocompromised individuals and patients with breaches in normal defensive barriers (such as intravascular lines or urinary catheters). Patients may develop urinary tract infection, bacteremia, and endocarditis, as well as infections of the abdomen, pelvis, biliary tract, and wounds. Less frequent infection sites include the bone, joints, and meninges, among others.


A form of gestational trophoblastic neoplasia similar to a hydatidiform mole but with deep invasion into the myometrium and histologically characterized by hyperplasia of trophoblasts, generalized cystic degeneration of chorionic villi and the presence of molar villi in the myometrium and/ or uterine blood vessels. Indicative signs include persistent unexplained metrorrhagia or secondary increase, stagnation, or non-normalization at 6 months of total serum chorionic gonadotropin (hCG) levels after evacuation of a hydatidiform mole. Metastases (in the lungs or vagina) may be observed.


Invasive non-typhoidal salmonellosis is a rare, bacterial, infectious disease caused by extraintestinal infection of non-typhoidal serotypes of  Salmonella enterica  in patients with underlying HIV infection, malaria or malignancy. It has a high mortality rate and patients typically present with fever, pallor and respiratory signs (cough, tachypnea, pneumonia). Gastrointestinal manifestations (diarrhea, vomit, abdominal pain) are not common. Occasionally, organ abscesses, septic shock and meningitis may be observed.


A rare vascular anomaly characterized by the association of capillary and venous malformations with hypotrophy or shortening of an affected limb due to alterations in bones, muscles, or subcutaneous tissues. In most cases, at least one of the findings is noted shortly after birth, while the other components become evident later in infancy.


Inverse Marcus-Gunn phenomenon is a rare congenital synkinesis where jaw opening by the pterygoid muscle (during eating or yawning) causes eyelid drooping from inhibition of the oculomotor nerve to the levator palpebrae superioris. Familial occurrence has been reported.