A rare mosaic syndrome characterized by the combination of two or more of the following: fibrous dysplasia of bone (FD), hyperpigmented macules, and hyperfunctioning endocrinopathies (precocious puberty, hyperthyroidism, growth hormone excess, endogenous Cushing syndrome).

Summary:
Epidemiology
It is a rare disease with an estimated prevalence of between 1/100,000 and 1/1,000,000.
Clinical description
FD can involve a single or multiple skeletal sites and can present with a limp, pain, pathologic fracture, or craniofacial asymmetry. Scoliosis is common and may be progressive. In addition to precocious puberty (vaginal bleeding or spotting and early development of breast tissue in girls, testicular and penile enlargement and precocious sexual behavior in boys), other hyperfunctioning endocrinopathies may occur including hyperthyroidism, growth hormone excess, Cushing syndrome, and hypophosphatemia due to renal phosphate loss. Hyperpigmented macules usually appear in the neonatal period.
Etiology
The disease results from somatic variants of the GNAS gene, specifically in the cAMP-regulating protein, Gs alpha. The extent of the disease is determined by the proliferation, migration and survival of the cell in which the mutation spontaneously occurred during embryonic development.
Diagnostic methods
Diagnosis of McCune-Albright syndrome (MAS) is usually established on clinical grounds, based on the presence of two or more characteristic features. The evaluation of patients with MAS should be guided by knowledge of the spectrum of tissues that may be involved, with specific testing for each. Genetic testing is possible, but is not routinely available.
Differential diagnosis
Differential diagnoses include neurofibromatosis, osteofibrous dysplasia, non-ossifying fibromas, idiopathic central precocious puberty, and ovarian neoplasm.
Management and treatment
Treatment is dictated by the tissues affected, and the extent to which they are affected. Some forms of surgical interventions may be indicated for treatment of craniofacial and skeletal abnormalities associated with FD (progressive visual disturbance, severe pain, severe disfigurement), as well as in the management of MAS-associated endocrinopathies and malignancies. Bisphosphonates may be helpful for treatment of bone pain. Strengthening exercises are recommended to help maintain the musculature around the FD bone and minimize the risk of fracture. Treatment of all endocrinopathies is required.
Prognosis
Morbidity is proportional to the number and extent of tissues involved. Longevity is generally not affected. MAS is rarely associated with malignancy. Malignant transformation of FD lesions occurs in probably less than 1% MAS patients.

                            Last update:
                            June 2024

                            - Expert reviewer(s):
                            Dr Alison BOYCE  - Dr Michael COLLINS


McDonough syndrome is a rare, multiple congenital anomalies/dysmorphic syndrome characterized by facial dysmorphsim (prominent superciliary arcs, synophrys, strabismus, large, anteverted ears, large nose, malocclusion of teeth), delayed psychomotor development, intellectual disability and congenital heart defects (e.g. pulmonic stenosis, patent ductus arteriosus, atrial septal defect). Additional features include thorax deformation (pectus excavatum/carinatum), kyphoscoliosis, diastasis recti and cryptorchidism. There have been no further descriptions in the literature since 1984.


A rare, genetic multiple congenital anomalies syndrome characterized by genitourinary malformations (hydrometrocolpos in females and in males, glanular hypospadias and prominent scrotal raphe) , postaxial polydactyly that may affect only one or several limbs, and to a lesser extent cardiac defects. Hydrometrocolpos is due to either a congenital obstruction, imperforate hymen or vaginal atressia, and causes a palpable mass and possibly hydronephrosis. Other anomalies occasionally reported include choanal atresia, pituitary dysplasia, esophageal atresia and distal tracheoesophageal fistula, Hirschsprung disease, vertebral anomalies, and hydrops fetalis. The disorder is allelic with Bardet-Biedl, and as some phenotypic overlap has been observed, patients should be reevaluated in later childhood for retinistis pigmentosas and other signs of Bardet-Biedl syndrome.


McLeod neuroacanthocytosis syndrome (MLS) is a form of neuroacanthocytosis (see this term) and is characterized clinically by a Huntington's disease-like phenotype with an involuntary hyperkinetic movement disorder, psychiatric manifestations and cognitive alterations, and biochemically by absence of the Kx antigen and by weak expression of the Kell antigens.

Summary:
Epidemiology
Prevalence and incidence are not known, but the disorder is very rare and a few hundred cases are suspected worldwide. MLS has been described in Europe, North and South America, and Japan without obvious clustering. The disease primarily affects males; female carriers rarely develop a neurological syndrome.
Clinical description
Onset of neurological symptoms is at 25-60 years of age and disease duration may be more than 30 years. About 1/3 of patients present with chorea indistinguishable from that observed in Huntington disease (see this term), and most patients will develop chorea during the course of the disease. Additional involuntary movements include facial dyskinesias, vocalizations and rarely feeding dystonia. Psychiatric manifestations including depression, schizophrenia-like psychosis and obsessive compulsive disorder (OCD) are frequent and may appear many years prior to the movement disorders. A subset of patients develops cognitive deficits, particularly in later disease stages. Generalized seizures and muscle weakness (rarely severe) and atrophy occur in about 1/2 of patients. MLS myopathy may predispose some to rhabdomyolysis, particular with neuroleptic medication use. Neuromuscular signs include sensorimotor axonal neuropathy, neurogenic muscle atrophy and variable additional myopathy. About 60% of patients develop cardiomyopathy manifesting with atrial fibrillation, malignant arrhythmias or dilated cardiomyopathy. Cardiac complications are a frequent cause of death. Some female heterozygote carriers show CNS manifestations related to MLS as well as corresponding neuropathological changes. MLS may be part of a ''contiguous gene syndrome'' on the X chromosome including chronic granulomatous disease, Duchenne muscular dystrophy or X-linked retinitis pigmentosa (see these terms).
Etiology
MLS is caused by mutations of the XK gene (Xp21.1) encoding the XK protein, which includes the Kx erythrocyte antigen. Most pathogenic mutations are nonsense mutations or deletions predicting an absent or shortened XK protein lacking the Kell protein binding site.
Diagnostic methods
Diagnosis may be challenging. CK levels are almost always elevated. The procedure of choice is determination of absent Kx antigen and reduced Kell antigens on erythrocytes in males, and fluorescence absorbent cell sorting with Kell antigens in female heterozygotes. Analysis of the XK gene revealing a mutation confirms the diagnosis.
Differential diagnosis
The differential diagnoses depend on the presenting symptoms and include chorea-acanthocytosis, Huntington disease, Huntington disease-like disorders, and Tourette's syndrome (see these terms).
Antenatal diagnosis
Routine methods for prenatal testing can be applied.
Genetic counseling
MLS is an X-linked disorder and genetic counseling is recommended. Affected males will pass on the mutant X chromosome to their daughters, whose sons will have a 1:2 risk of developing MLS and whose daughters will have a 1:2 risk of being carriers.
Management and treatment
So far, no curative or disease-modifying treatments are available and management is symptomatic. MLS patients and asymptomatic carriers of the McLeod blood group phenotype should undergo cardiologic evaluation due to serious cardiac complications.
Prognosis
MLS is relentlessly progressive and the prognosis is poor. Sudden death may be due to seizures, possibly autonomic dysfunction, and sudden cardiac death. There may be gradual generalized weakness with fatal aspiration pneumonia or systemic infections.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Hans JUNG


Meacham syndrome is a multiple malformation syndrome characterized by congenital diaphragmatic abnormalities, genital defects and cardiac malformations.

Summary:
Epidemiology
Less than 15 patients have been reported worldwide.
Clinical description
Ambiguous or female external genitalia are present in individuals with 46,XY karyotype. The genital abnormalities are variable and may include a true double vagina or septate vagina, absent uterus, abnormal male gonads in the presence of normal external female genitalia or male pseudohermaphroditism with abnormal internal female genitalia. Complex cyanotic congenital heart defects, (hypoplastic right lungs, anomalous pulmonary venous return and abnormalities of the diaphragm) are frequent. One patient with rhabdomyomatous dysplasia of the lungs has been reported.
Etiology
Mutations in the WT1 gene have been identified in some patients with Meacham syndrome. Mutations in the same gene have previously been detected in patients with Denys-Drash syndrome (see this term).
Diagnostic methods
Diagnosis is based on the clinical findings. The occurrence of a true double vagina should lead the clinician to careful pulmonary and cardiac evaluation.
Differential diagnosis
The main differential diagnosis comprises Denys-Drash syndrome, an allelic disorder with overlapping clinical features. Beckwith-Wiedemann, Simpson-Golabi-Behmel and Perlman syndromes should also be considered (see these terms).
Management and treatment
Management is supportive.
Prognosis
All patients reported to date died in early childhood.

                            Last update:
                            December 2008


A rare, lethal, genetic, multiple congenital anomaly disorder characterized by the triad of brain malformation (mainly occipital encephalocele), large polycystic kidneys, and polydactyly, as well as associated abnormalities that may include cleft lip/palate, cardiac and genital anomalies, central nervous system (CNS) malformations, liver fibrosis, and bone dysplasia.

Summary:
Epidemiology
Prevalence is estimated at 1/38,500 births in Europe. However, birth prevalence is higher in specific populations such as in Finland (1/9,000), Kuwaiti Bedouin populations (1/3,500), Gujarati Indians (1/1,300), and in Qatar (1/5,000). No gender predilection is reported.
Clinical description
Fetuses affected by Meckel syndrome (MKS) survive only a few days to a few weeks at the most, or die in utero. The main CNS features include occipital encephalocele, hydrocephalus, anencephaly, holoprosencephaly, as well as Dandy-Walker. Large polycystic kidneys with cystic dysplasia are a constant feature of Meckel syndrome. Hepatic dysgenesis and liver fibrosis are frequent. Polydactyly may affect all four extremities and is typically postaxial (80%) or very rarely preaxial. Affected individuals have pulmonary hypoplasia secondary to oligohydramnios. Cleft lip and palate, microphthalmia and micrognathia may be observed. Cardiac malformations may include atrial septal defect, aorta coarctation, patent arterial duct, and valvular pulmonary stenosis. Incomplete development of internal and external genitalia, and cryptorchidism in males are common.
Etiology
Defective ciliary biology underlies MKS. Mutations in many different cilia-related genes have been associated with this disorder, often in the context of consanguineous unions. Most of these genes are also responsible for Joubert syndrome, leading to the concept that MKS is the extreme lethal phenotype of Joubert syndrome.
Diagnostic methods
Diagnosis may be made on fetal ultrasonography showing occipital encephalocele and dysplastic kidneys. Two of the three major malformations or two other anomalies along with one classical feature are sufficient for diagnosis of MKS. Autopsy may also be required. The disorder is often detected before the 14th gestational week. Molecular genetic testing can be used to confirm the diagnosis or to guide genetic counseling.
Differential diagnosis
Differential diagnoses include trisomy 13, Bardet-Biedl syndrome, Hydrolethalus, and Smith-Lemli-Opitz Syndrome.
Antenatal diagnosis
Prenatal diagnosis by ultrasonography is possible starting from 12 weeks of pregnancy. Encephalocele, cystic kidneys and polydactyly may be detected.
Genetic counseling
MKS is inherited in an autosomal recessive manner. 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
No treatment is currently available for Meckel syndrome which has a constantly fatal outcome.
Prognosis
MKS is lethal in utero or in the very early neonatal period with pulmonary hypoplasia and kidney failure as the main causes of early demise.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Pr Tania ATTIE-BITACH | ITHACA*

                                * European Reference Network


Meconium aspiration syndrome is a pulmonary complication appearing in newborns with a meconium-stained amniotic fluid. Aspirated meconium can interfere with normal breathing by several mechanisms including airway obstruction, chemical irritation, infection and surfactant inactivation and induces more or less severe signs of respiratory distress at birth.


Medial condensing osteitis of the clavicle

A rare bone disease characterized by benign, usually unilateral, sclerosis of the inferomedial third of the clavicle. Patients present with localized swelling and persistent pain. Typical radiographic findings are expansion of the medial end of the clavicle with increased radio-density and signs of bone remodeling.


A rare median facial cleft characterized by median cleft of the lower lip (ranging in extent from a notch in the vermilion to a complete cleft involving the tongue, lower lip, and chin, and extending to the cervical region), median cleft of the mandible (ranging from notching to a complete cleft), and anomaly of the tongue including bifid tongue and tongue tie. Associated features in severe cases may include absent hyoid, thyroid cartilage, and manubrium sterni, as well as atrophic neck muscles.


Median cleft of the upper lip and maxilla

A rare median facial cleft characterized by a midline vertical cleft through the upper lip and premaxillary bone, which is highly variable in its extent and may also involve the nasal septum and central nervous system. Depending on the severity of the defect, associated manifestations include atrophy of midline structures, hypo-/hypertelorism, monophthalmia, proboscis, nasal deformity, median alveolar cleft, and short upper frenulum.


A rare familial facial anomaly characterized by a nodule beneath the vermilion border of the upper lip that tapered into the frenulum. The lesion is soft, easily compressible and asymptomatic. It can be wide (up to 8 mm) or flat and less prominent. Regression of the nodule by age has been reported. There have been no further descriptions in the literature since 1994.


Medich giant platelet syndrome (MGPS) is a platelet granule disorder characterized by thrombocytopenia with giant platelets resulting in easy bleeding.


Medium chain acyl-CoA dehydrogenase deficiency

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is an inborn error of mitochondrial fatty acid oxidation characterized by a rapidly progressive metabolic crisis, often presenting as hypoketotic hypoglycemia, lethargy, vomiting, seizures and coma, which can be fatal in the absence of emergency medical intervention.

Summary:
Epidemiology
The estimated birth prevalence of MCADD is thought to range from 1/4,900 to 1/27,000 in Caucasian populations and is highest in individuals of Northern European descent. The worldwide birth prevalence is 1/14,600.
Clinical description
MCADD usually presents 3 to 24 months after birth in previously healthy infants. However, neonatal presentations are well described as are those in adults, given sufficient metabolic stress (such as significant alcohol ingestion). Nevertheless, many affected individuals remain asymptomatic throughout life. Typically hypoketotic hypoglycemia, lethargy and vomiting are triggered by an infection, fasting or surgery. Some patients, however, can present with a progressive metabolic crisis despite ketosis and normal blood glucose. Rarely patients may present in crisis with ''paradoxically'' gross ketosis. During a crisis, a patient may manifest with lethargy, emesis, respiratory arrest, seizures, hepatomegaly and rapid progression to cardiac arrest unless emergency treatment is implemented. Potential brain injury occurring during these episodes can lead to an increased risk of long term neurological damage. Sudden unexplained death can sometimes be the first manifestation of this disease. Historically, about 25% of undiagnosed patients die during their first presentation of a crisis.
Etiology
MCADD is caused by mutations in the ACADM gene (1p31) which encodes the mitochondrial MCAD protein. The most prevalent mutation, c.985A>G, (K329E), p.(Lys329Glu), accounted for about 80% of clinical disease prior to newborn screening programs but many more individuals are now being identified with other ACADM mutations.
Diagnostic methods
Diagnosis is through the identification of a characteristic abnormal pattern in dried blood spots or plasma of acylcarnitines species (increased C6, C8 and increased ratio of C8/C10 with abnormal urine organic acid findings of C6 to C10 dicarboxylic acids, hexanoylglycine and suberylglycine). Final confirmation is by mutation analysis. MCADD is now included in newborn screening programs in many European countries such as the UK, Germany, the Netherlands, Portugal and Spain.
Differential diagnosis
Differential diagnosis includes other disorders of mitochondrial fatty acid oxidation including multiple acyl-CoA dehydrogenase deficiency (MADD) (see this term).
Genetic counseling
MCADD is inherited autosomal recessively. Genetic counseling is possible.
Management and treatment
Strict avoidance of fasting is the primary objective. Medium chain triglycerides should be avoided but no other special dietary restrictions are required. Guidelines are available for the safe interval time between feeds for infants and young children. The use of low dose carnitine supplementation in patients who develop a low blood carnitine status remains controversial. In symptomatic patients, simple carbohydrates are given by mouth (glucose tablets) or intravenously until blood glucose level is maintained at above 5 mmol/L. During intercurrent infections, an emergency regimen should be made available. Immediate medical attention is needed in case of decompensation. Artificial sweeteners should be avoided.
Prognosis
The prognosis is excellent in diagnosed patients who avoid fasting and who are managed appropriately during an intercurrent illness/ metabolic crisis.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Simon OLPIN


A rare disorder of copper metabolism characterized by intellectual deficit, enteropathy, sensorineural hearing loss, peripheral neuropathy, lamellar and erythrodermic ichthyosis, and keratodermia.


A rare renal tract malformation characterized by dilated malformation of the medullary collecting ducts (typically bilateral), and associated with stone formation, renal colic, hematuria, urinary tract infection, nephrocalcinosis, calcium nephrolithiasis, pyelonephritis, hypercalciuria and hypocitraturia. The disease is associated with abnormal distal tubular functions.

Summary:
Epidemiology
Prevalence of medullary sponge kidney (MSK) in the general population is unknown; rough estimations suggest a prevalence of 1/2,000-20,000. However, it is much higher, up to 20%, in recurrent renal calcium stone formers. MSK affects males and females equally.
Clinical description
The majority of patients with MSK are asymptomatic; diagnosis of symptomatic patients typically occurs between 30 to 50 years of age, though the range is wider. The major clinical manifestations are kidney stones, hematuria, and urinary tract infections. Clinical manifestations including hypercalciuria, impaired urine acidification, and hyperparathyroidism may contribute to decreased bone density, leading to osteopenia and osteoporosis that is observed in some MSK patients. Medullary ectasias vary between 1 to 7 mm in size and are frequently without stones. Stones are primarily composed of calcium phosphate and calcium oxalate, and typically recur every two years. Flank pain can occur in the presence or absence of stones, can be acute resembling renal colic. Chronic pain is rare, but can lead to significant disability. Hematuria can occur in the presence or absence of stones, can be microscopic or gross, singular or recurrent, and is typically painless unless clots lead to ureteral obstruction or it is associated with nephrolithiasis. Abnormal tubular functions observed include defective urinary concentrations, incomplete and overt distal tubular acidosis, and hypocitraturia. Occurrence in children is rare but typically manifests with severe bone-related consequences of distal renal tubular acidosis (failure to thrive, short stature and rickets-like symptoms). MSK may be associated with developmental anomalies and tumors, such as Wilms tumor, horseshoe kidney, contralateral congenital small kidney, Beckwith-Wiedemann syndrome, and congenital hemihypertrophy.
Etiology
Whilst no disease-causing gene mutations have been identified, MSK may be associated with GDNF variants. In addition, HNF1B variants are associated with a spectrum of kidney disorders and two family members with an MSK phenotype have been identified with HNF1B mutations.
Diagnostic methods
Urography was the cornerstone of MSK diagnosis, and reveals dilated papillary collecting ducts with collection of contrast medium appearing as striations or bouquets of flowers. These features can also be disclosed by multidetector computed tomography (CT) urography. MRI and Ultrasound do not have the required specificity to diagnose MSK.
Differential diagnosis
The differential diagnosis is essentially that of medullary nephrocalcinosis and other causes of multiple medullary cysts such as autosomal dominant interstitial kidney disease and autosomal dominant polycystic disease.
Genetic counseling
Typically, the disease is sporadic; however, family clustering of MSK has been observed and, in certain cases, is suggestive of autosomal dominant inheritance.
Management and treatment
Treatment with potassium citrate is effective in reducing calciuria and stone recurrence rate. A diet with a high intake of water, vegetables and fruit, and low in sodium and proteins, is recommended. Thiazides are suggested where calciuria does not improve. Whilst small stones can pass spontaneously, in recurring stone formers and selected symptomatic patients, pain can be controlled with laser papillotomy. Renal autotransplantation with pyelovesicostomy, a last resort in intractable, chronic painful stone disease, has also been reported in one MSK patient.
Prognosis
Long term prognosis is excellent.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Pr Giovanni GAMBARO


Medullary thyroid carcinoma (MTC) is developed from thyroid C cells that secrete calcitonin (CT).

Summary:
Epidemiology
MTC represents 5-10% of thyroid cancers with a 1-2% incidence in nodular thyroid diseases. Estimated prevalence in the general population is 1/14,300.
Diagnostic methods
Diagnosis is usually made in the presence of a solitary nodule often associated with nodal metastasis and confirmed by a high basal CT level which represents its biological marker. MTC may present as a sporadic form, and in about 30% of cases, as a familial form as a part of multiple endocrine neoplasia (see this term); a dominant inherited disease related to germline mutation of the protooncogene RET. Both biological (CT) and genetic (RET) markers allows optimal diagnosis and treatment of MTC; the former allowing screening and early diagnosis of MTC by routine CT measurements in nodular thyroid diseases that require adequate and complete surgery required to be performed. The former leads to the diagnosis of familial MTC and to the identification of at-risk subjects on whom early or prophylactic surgery may be performed.
Management and treatment
Treatment of MTC is based on complete surgical resection, including total thyroidectomy along with central and laterocervical nodal dissection. For locally advanced or metastatic MTC, complete cervical surgery is required and needs to be combined with other systemic treatments; as chemotherapy is not very efficient, radioimmunotherapy and RET target gene therapy (mainly tyrosine kinase inhibitors) appear as possible valuable therapeutic options for the future.
Prognosis
Ten-year survival is about 80% when patients are not surgically cured and reaches 95% when the biological marker CT is normalized after surgery.

                            Last update:
                            November 2007

                            - Expert reviewer(s):
                            Pr Bernard CONTE-DEVOLX  - Pr Patricia NICCOLI


Medulloblastoma with extensive nodularity (MBEN) is a histological variant of medulloblastoma (see this term), an embryonic malignancy, most often located in the inferior medullary velum and then growing into the fourth ventricle, and presenting in infants and young children with symptoms of increased intracranial pressure such as headache, listlessness, vomiting, diplopia and papilledema. It is often associated with Gorlin syndrome (see this term) and has a relatively good prognosis.


A rare embryonic tumor of the neuroepithelial tissue characterized clinically by increased intracranial pressure and cerebellar dysfunction, with the most common presenting symptoms being headache, vomiting, and ataxia. The disease can be classified according to histological (classic, anaplastic, large-cell, or desmoplatic medulloblastoma, or medulloblastoma with extensive nodularity) and molecular criteria (WNT-activated, sonic-hedgehog-activated, group 3, group 4).

Summary:
Epidemiology
Medulloblastoma (MB) is the most common malignant brain tumor in childhood. Annual incidence varies according to age a group, and is estimated in the USA at 0.47/100,000 in children (0-14 years of age), 0.11/100,000 in adolescents and young adults, 0.02/100,000 in adults (over 40 years of age). Males are more affected than females.
Clinical description
Age of disease onset is variable and can occur in patients ranging in age from the newborn period to adulthood (peak age at presentation is children 3-6 years, with only 25% of patients being between 15 and 44 years). The most common presenting symptoms are headache, vomiting, and ataxia. Additional features that may be observed include lethargy, motor or cranial nerve impairment, gaze palsy, visual impairment due to hydrocephalia, vertigo/hearing loss, behavioral changes/irritability, and extracranial pain (e.g. back pain in those with spinal metastases). Around 30% of pediatric cases present with metastases at diagnosis. Most metastases occur within the central nervous system by seeding via the cerebrospinal fluid (cranial or spinal), while spread to extracranial organs (e.g. bone marrow, liver, lungs) is very rare at diagnosis. In a minority of patients, MB is associated with Gorlin syndrome, familial adenomatous polyposis (FAP; the association of FAP and MB is referred to as the Turcot syndrome with polyposis) or with Li-Fraumeni Syndrome. Increased susceptibility to certain tumors (neuroblastoma), hematological malignancies (acute lymphoblastic leukemia, acute myeloid leukemia) or disorders caused by mutations in genes encoding components of the RAS signaling pathway (Noonan syndrome or neurofibromatosis-Noonan syndrome) have been reported in MB.
Etiology
To date, the exact etiology of MB is still unknown but genomic data has identified multiple candidate genes that contribute to the pathogenesis of different subgroups of MB. This includes inhibitors of the sonic hedgehog pathway SUFU (10q24.32), Ptch1 (9q22.32), the RNA helicase DDX3X (Xp11.3-p11.23), chromatin regulators KDM6A (Xp11.2) and N-CoR complex genes BCOR (Xp11.4), and the Parkinson's disease genes KMT2D (12q13.12), SMARCA4 (19p13.3), MYC (8q24.21), MYCN (2p24.3), and TP53 (17p13.1).
Diagnostic methods
MB occurs in the vermis and 20% occurs in the hemispheres of the cerebellum. WNT-activated MB may arise from the dorsal brainstem. Histologically, MB is characterized by small, round cells that stain blue with haematoxylin spectrum and appearance ranges from tumors with extensive nodularity to those with large cell/anaplastic features. Apart from classical MB, four histological variants of MB are recognized: anaplastic MB, large cell MB, MB with extensive nodularity, and desmoplastic/nodular MB. Four different molecular subgroups (WNT-activated, sonic-hedgehog-activated, group 3, group 4) have been identified.
Differential diagnosis
Differential diagnosis includes other brain tumors (ependymoma, glial tumor, atypical teratoid rhabdoid tumor; see these terms) and other causes of cerebellar alterations (infectious or cystic lesions, hemorrhages).
Genetic counseling
Genetic counseling is indicated in specific constellations, e.g. in sonic hedgehog-activated MB (Gorlin-syndrome, Li-Fraumeni-Syndrome, BRCA2), CTNNB1-negative WNT-activated MB (Turcot-syndrome).
Management and treatment
Initially, patients need to be checked for increased intracranial pressure, which if present, needs to be controlled either by medication (e.g. steroids) or by neurosurgical drainage (e.g. external drainage). The postoperative treatment depends on age, histological and molecular subgroup, and result of staging assessments (cranial and spinal MRI, assessment of lumbar cerebrospinal fluid if lumbar puncture is not contraindicated). In children older than 3-5 years, combinations of chemotherapy and craniospinal irradiation are applied. In younger children, brain sparing therapies avoiding irradiation can be administered in very specific constellations.
Prognosis
The overall survival rates are now 80% in standard risk patients, and 30-60 % in high-risk patients. Relapse occurs in nearly 75% of pediatric cases within 2 years.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Pr Stefan RUTKOWSKI


Meesmann corneal dystrophy (MECD) is a rare form of superficial corneal dystrophy characterized by distinct tiny bubble-like, round-to-oval punctate bilateral opacities in the central corneal epithelium, and to a lesser extent in the peripheral cornea, with little impact on vision.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is not known as a registry of affected cases does not exist. Numerous cases have been reported from Denmark, Germany, Japan, USA, Saudi Arabia and Poland.
Clinical description
Lesions develop during infancy. MECD often remains asymptomatic until middle age, when intermittent, mild ocular irritation, photophobia, transient blurred vision, and irregular astigmatism develop. The condition persists throughout life. In severe cases, subepithelial scarring produces a slight grayish central corneal opacification. Corneal sensitivity is normal.
Etiology
Meesmann corneal dystrophy is caused by a mutation in one of a pair of genes, KRT3 (12q13.13) or KRT12 (17q11-q1) that encode the two units of cytokeratin in the corneal epithelium. Stocker-Holt corneal dystrophy is a variant of MECD caused by a p. Arg19Leu amino acid change in cytokeratin 12.
Diagnostic methods
Light microscopy reveals intraepithelial cysts and the epithelium may be thickened and disorganized. Histopathologically, MECD is characterized by intraepithelial cysts at different levels in the corneal epithelium, which is irregular in thickness.
Differential diagnosis
Suspected cases of MECD should be differentiated from other disorders of the corneal epithelium, such as vapor spray keratitis, mild epithelial edema and the bleb pattern of epithelial basement membrane dystrophy. MECD and Lisch epithelial corneal dystrophy (LECD, see this term) have clinical similarities but are easily distinguished from one another by the different modes of inheritance, i.e. autosomal dominant versus X-linked recessive.
Genetic counseling
MECD has an autosomal dominant pattern of inheritance.
Management and treatment
Removal of the abnormal corneal epithelium has been used to treat MECD, but this approach is not curative as the dystrophy recurs in the regenerated epithelium.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


A rare, non-syndromic, posterior fossa malformation characterized by a cisterna magna that measures above 15 mm in length, 5 mm in height and 20 mm in width (or greater than 10 mm in fetuses) associated with a normal cerebellar vermis and absence of hydrocephalus. The majority of patients are asymptomatic; however, variable neurodevelopmental outcomes, including delayed speech and language development, motor development delay, visiospatial perception difficulties, and attention problems, has been observed in some patients.


Megaconial congenital muscular dystrophy

A rare, genetic, skeletal muscle disease characterized by an early-onset hypotonia, muscle weakness, global developmental delay with intellectual disability, and cardiomyopathy. Congenital structural heart defects and ichthyosiform cutaneous lesions have also been associated. Muscle biopsy shows characteristic enlarged mitochondria located at the periphery of muscle fibers.


Megacystic-megaureter syndrome is an urinary tract malformation characterized by the presence of a massive primary non-obstructive vesicoureteral reflux and a large capacity, smooth, thin walled bladder due to the continual recycling of refluxed urine. Recurrent urinary infections are commonly associated with this condition.


Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a rare congenital disease characterized by massive abdominal distension caused by a largely dilated non-obstructed urinary bladder (megacystis), microcolon and decreased or absent intestinal peristalsis.

Summary:
Epidemiology
MMIHS prevalence is unknown but the disease has been reported in 230 patients, of which 71% are females.
Clinical description
Enlarged and nonobstructed bladder is the first manifestation of MMIHS and can be detected prenatally. It results in abdominal distension, which is an early constant finding. Usual clinical presentation is similar to other neonatal intestinal obstructions: bile stained vomiting and failure to pass meconium. Patients show various visceral anomalies of the digestive tract including microcolon, malrotation of the gut, intestinal generalized hypo- or aperistalsis and short bowel. Along with the severe megacystis, malformations of the urinary tract with renal dysplasia (see this term), hydronephrosis, ureteral dilatation and hydroureter are frequently described. Undescended testis or bilateral streak gonads, cardiac anomalies, umbilical hernia or omphalocele have been reported in some cases.
Etiology
Etiology of MMIHS is unknown but various hypotheses have been proposed to describe the pathogenesis including genetic, neurogenic, myogenic and hormonal origin. The 15q11.2 region might be associated with MMIHS.
Diagnostic methods
Postnatally, MMIHS is mainly diagnosed by clinical presentation and supportive radiological and surgical findings. Histologically, vacuolar degeneration in the center of smooth muscle of the bowel and bladder has been described.
Differential diagnosis
This disorder should not be mistaken for a milder and autosomal dominant disorder, called chronic idiopathic intestinal pseudo-obstruction, in which megacystis is also present, or for prune belly syndrome (see these terms).
Antenatal diagnosis
Prenatal diagnosis of MMIHS is mostly based on fetal ultrasound, revealing enlarged urinary bladder and hydronephrosis. Recent reports have proposed prenatal magnetic resonance imaging (MRI) in combination with analysis of enzymatic changes to contribute to prenatal diagnosis of MMIHS. The enlarged bladder can be observed from the second trimester and polyhydramnios from the third.
Genetic counseling
MMIHS has been suggested to have an autosomal recessive inheritance pattern so genetic counseling remains difficult, to date.
Management and treatment
There is no curative treatment for MMIHS. Various surgical interventions including gastrostomy, jejunostomy and vesicostomy have been reported and have been generally unsuccessful in most patients. Several multivisceral transplantations have also been reported. In the majority of patients total parenteral nutrition is required.
Prognosis
Survival in MMIHS seems to have improved, thanks to more specialized care, innovations in parenteral nutrition, and introduction of multivisceral transplantation. However, prognosis and life expectancy of this generally fatal disease remains poor. Death is mainly caused by sepsis, malnutrition or multiple organ failure.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Prem PURI


Megakaryoblastic acute myeloid leukemia with t(1;22)(p13;q13) is a rare subtype of acute myeloid leukemia with recurrent cytogenetic abnormalities characterized by clonal proliferation of myeloid blasts with predominantly megakaryoblastic differentiation in the bone marrow and blood, often with extensive infiltration of the abdominal organs. It occurs typically in infants and usually presents with hepatosplenomegaly, anemia, thrombocytopenia and nonspecific symptoms related to ineffective hematopoiesis (fatigue, bleeding and bruising, recurrent infections). Myelofibrosis and fibrosis of other infiltrated organs is also characteristic of this disease.


Megalencephalic leukoencephalopathy with subcortical cysts

A form of leukodystrophy that is characterized by infantile-onset macrocephaly, often with mild neurologic signs at presentation (such as mild motor delay), which worsen with time, leading to poor ambulation, falls, ataxia, spasticity, increasing seizures and cognitive decline. Brain magnetic resonance imaging reveals diffusely abnormal and mildly swollen white matter as well as subcortical cysts in the anterior temporal and frontoparietal regions.


A rare developmental defect during embryogenesis that is characterized by growth dysregulation with overgrowth of the brain and multiple somatic tissues, with capillary skin malformations, megalencephaly (MEG) or hemimegalencephaly (HMEG), cortical brain abnormalities (in particular polymicrogyria), typical facial dysmorphisms, abnormalities of somatic growth with asymmetry of the body and brain, developmental delay and digital anomalies.

Summary:
Epidemiology
Over 200 patients have been reported without sex predominance.
Clinical description
Symptoms are usually recognizable at birth. Their severity varies widely among patients. Megalencephaly is a major clinical feature (MEG: occipitofrontal circumference [OFC] greater than or equal to 3 SD above the mean), which sometimes progresses to hydrocephaly, malformations of cortical development with polymicrogyria and Chiari malformation. Cutaneous capillary anomalies are often scattered over the limbs, palms, soles and trunk, are frequently pink/red and are aggravated by crying and emotions. Facial dysmorphism is observed with frontal bossing, full cheeks, prominent lips and nevus flammeus of the nose and/or philtrum and upper lip. There is a delay in speech and motor skills. Patients may present neurological symptoms, mainly neonatal hypotonia, and, less frequently, seizures. Additional clinical manifestations include prenatal overgrowth, limb asymmetry, joint laxity, soft skin and thick, ''doughy'' subcutaneous tissue, postaxial polydactyly and/or syndactyly of toes 2-3 or fingers 3-4. Some patients develop neoplasias (risk of tumor development estimated at 2-3%). There is a slight increased risk for congenital heart defects and/or cardiac rhythm abnormalities. Adult OFCs range from +2 to +10 SDs above the mean.
Etiology
Somatic mutations of the PIK3CA gene (3q26), with evidence of postzygotic mosaicism, were found in several patients. Two individuals had a de novo germline pathogenic variant in PIK3CA. The gene PIK3CA encodes the alpha catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase. PIK3CA mutations are found in several benign overgrowth syndromes, collectively known as PIK3CA-related overgrowth spectrum (PROS). The mutational spectrum in children with the disorder is broader than other PIK3CA-related overgrowth disorders.
Diagnostic methods
The disorder can be diagnosed based on clinical findings in individuals with classic features of MEG or HMEG (major finding 1) associated with neurologic findings of hypotonia, seizures, and mild to severe intellectual disability and characteristic capillary malformations (major finding 2) with focal or generalized somatic overgrowth.. Mosaic mutations of the PIK3CA gene were mainly identified with the advent of massively parallel or next-generation sequencing (NGS) methods. that facilitate detection of low-frequency variation. The level of mosaicism is often lowest in blood‐derived DNA, and higher in saliva and fibroblast‐derived DNA: multiple tissue samples should be tested, prioritizing samples other than blood.
Differential diagnosis
Differential diagnoses include Hemimegalencephaly (HMEG), Megalencephaly - polymicrogyria - post-axial polydactyly - hydrocephalus (MPPH), Klippel-Trénaunay syndrome (KTS), Beckwith-Wiedemann syndrome (BWS), PTEN-related overgrowth disorders.
Antenatal diagnosis
Findings of prenatal ultrasound include marked fetal overgrowth and progressive macrocephaly in the absence of maternal hyperglycemia or fetal hyperinsulinemia, ventriculomegaly, hydrocephalus, frontal bossing, polydactyly, limb asymmetry, polyhydramnios, hydrops fetalis and pleural effusions.
Genetic counseling
The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in PIK3CA would be expected to be the same as in the general population. However, low-level germline mosaicism may theoretically be present in a parent of a very rare child with a germline PIK3CA pathogenic variant.
Management and treatment
Management requires a multidisciplinary approach (involving pediatrician, neurologist, ophthalmologist, cardiologist, orthopedist, physiatrist, ENT, and dermatologist). Neurologic complications (obstructive hydrocephalus, increased intracranial pressure, cerebellar tonsillar ectopia or Chiari malformation; epilepsy in those with HMEG) may warrant neurosurgical intervention. Regular surveillance is recommended (brain MRI in the first 8 years of life, kidney ultrasound for Wilms tumor screening in the first 8 years of life). However, tumor risk in the disorder appears to be lower than in BWS.
Prognosis
Prognosis depends on the severity of symptoms. Early death, due to complex cardiac heart disease and arrhythmia, has been reported in rare occasions.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Livia GARAVELLI


A rare syndrome with a central nervous system malformation as a major feature characterized by macrocephaly, megalencephaly, bilateral perisylvian polymicrogyria, variable degrees of ventriculomegaly/hydrocephalus, developmental delay and intellectual disability, oromotor dysfunction, hypotonia, seizures, and dysmorphic facial features (such as frontal bossing, low-set ears, a flat nasal bridge, and high-arched palate). Postaxial polydactyly of one or more extremities is also common.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by overgrowth and macrocephaly with megalencephaly apparent at birth, global developmental delay, intellectual disability, and dysmorphic facial features (including frontal bossing, long face, sparse eyebrows, hypertelorism, downslanting palpebral fissures, and prognathism). Patients may exhibit tall stature with dolichostenomelia, arachnodactyly, kyphoscoliosis, and joint laxity, as well as neurologic manifestations, such as hypotonia, gait ataxia, or seizures. Brain imaging may show increased white matter volume, thick corpus callosum, or small cerebellum.


A rare central nervous system malformation characterized by an abnormally large brain, accompanied by abnormal head circumference measurements evident at birth or developing over the first years of life. The condition can be unilateral or bilateral and affects males more often than females. There is no typical pattern of symptoms, but mental retardation, seizures, and other neurologic abnormalities have been reported.


Megalocornea-intellectual disability syndrome is a rare intellectual disability syndrome most commonly characterized by megalocornea, congenital hypotonia, varying degrees of intellectual disability, psychomotor/developmental delay, seizures, and mild facial dysmorphism (including round face, frontal bossing, antimongoloid slant of the eyes, epicanthal folds, large low set ears, broad nasal base, anteverted nostrils, and long upper lip). Interfamilial and intrafamilial clinical variability has been reported.


MEGDEL syndrome is a rare, genetic, neurometabolic disorder characterized by neonatal hypoglycemia, features of sepsis that are not linked to infection, development of feeding problems, failure to thrive, transient liver dysfunction, and truncal hypotonia followed by dystonia and spasticity which results in psychomotor development arrest and/or regression. Progressive sensorineural deafness, intellectual disability and absent speech are also associated. Laboratory tests demonstrate 3-methylglutaconic aciduria and temporary elevated serum lactate and transaminases.


A rare X-linked syndromic intellectual disability characterized by mild to profound intellectual disability, microcephaly, growth delay, and hypogenitalism. Obesity, early-onset diabetes and epilepsy are more variably present.

Summary:
Epidemiology
To date, a total of 22 patients from 11 unrelated families, of all origins, have been reported in the literature with pathogenic variants in EIF2S3. Only male patients are affected while carrier females are asymptomatic.
Clinical description
The phenotype is heterogeneous ranging from a severe, complete phenotype, which is associated to a recurrent frameshift variant (p.(Ile465Serfs*4), to a less severe and/or incomplete phenotype associated with various missense variants. Patients with missense variants present with inconstant features including developmental delay (90%), growth retardation (83%), microcephaly (83%), and more variably epilepsy (33%), and obesity (33%). Endocrinopathy including low growth hormone level, hypopituitarism and hypogonadism was described in 66%. Although intellectual disability is common in patients with missense variants, its severity varied from mild to moderate or severe, while all patients with the frameshift variant shared severe to profound intellectual disability. Early-onset diabetes is a recurrent feature found in patients with the recurrent frameshift variant, while hypoglycaemia and glucose dysregulation are not constant in patients with EIF2S3 missense variant.
Etiology
MEHMO syndrome is caused by pathogenic variants in EIF2S3 (Xp22.11). The gene encodes the gamma subunit of the eukaryotic translation initiation factor-2, eIF2, essential for protein translation. Families with a recurrent frameshift variant p.(Ile465Serfs*4) in EIF2S3 exhibit a severe, full phenotype of MEHMO syndrome. The majority of patients with missense variants exhibit a less severe and/or incomplete phenotype.
Diagnostic methods
The diagnosis is usually found by next generation sequencing (e,g Whole Exome Sequencing).
Differential diagnosis
Differential diagnosis includes Wolcott-Rallison syndrome caused by pathogenic variants in EIF2AK3; primary microcephaly-mild intellectual disability-young-onset diabetes syndrome caused by TRMT10A or PPP1R15B; primary microcephaly-epilepsy-permanent neonatal diabetes syndrome caused by IER3IP1 pathogenic variants.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Transmission is X-linked recessive. Genetic counseling should be offered to at-risk couples (where the mother is a healthy carrier of a disease-causing variant) informing them that there is a 50% risk of having an affected male child at each pregnancy. Intrafamilial phenotypic variation is observed, most particularly concerning EIF2S3 missense variants.
Management and treatment
Multidisciplinary care is needed for this multisystemic disorder; initially including neonatal care, and then with regular pediatric, endocrinology and neuropediatric follow-up. Regular glycemic controls are suggested.
Prognosis
The prognosis depends on the severity of the syndrome. Patients with missense variants usually have a normal lifespan while severely affected patients (in particular with the recurrent frameshift variant p.(Ile465Serfs*4)) could present a poor life prognosis.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Dr Stéphanie MOORTGAT | ITHACA*

                                * European Reference Network


Meige disease is a frequent form of late-onset, primary lymphedema characterized by lower limb lymphedema typically developing during puberty.


Meigs syndrome is a rare neoplastic disease characterized by the clinical triad of benign ovarian tumor (typically, ovarian fibroma or fibroma-like tumor), hydrothorax and ascites, which resolve after tumor resection. Patients usually present with dyspnea, pelvic mass with or without a tender, distended abdomen and/or weight loss.


Melanoma and neural system tumor syndrome is an extremely rare tumor association characterized by dual predisposition to melanoma and neural system tumors (typically astrocytoma; see this term).

Summary:
Epidemiology
Prevalence and incidence rates are not known. Fewer than 20 affected families have been reported to date. Cases have been reported from France, Italy, the UK and the USA.
Clinical description
In reported families, affected individuals had cutaneous melanoma in association with dysplastic nevi, astrocytoma, benign or malignant peripheral nerve sheath tumor, neurofibroma, medulloblastoma, glioblastoma multiforme, ependymoma, glioma, and meningioma (see these terms). In some cases, melanoma was described first followed by nervous system tumors, and in other cases, melanoma was a secondary cancer.
Etiology
The etiology of this tumor association is unknown. Genetic mutations or germline deletions are thought to underlie this cancer susceptibility syndrome.
Genetic counseling
Male-to-male transmission was reported in one family but inheritance patterns are not clearly characterized. The increased risk appears to be found in both first- and second-degree relatives.

                            Last update:
                            March 2015

                            - Expert reviewer(s):
                            Dr Monica RODOLFO


A rare soft tissue tumor characterized by a slowly growing mass typically involving tendons and aponeuroses of the extremities, composed of polygonal or spindle-shaped cells with melanocytic differentiation. The tumor typically affects young adults, who often present with pain or tenderness at the tumor site. Prognosis is poor with high recurrence rates and frequent metastasis, especially to lymph nodes, lung, and bones.


A rare neurometabolic genetic disorder which is progressive and multisystemic due to mitochondrial dysfunction and that is characterized by encephalomyopathy, lactic acidosis, and stroke-like episodes.

Summary:
Epidemiology
Precise prevalence and incidence data are not available. Estimated prevalence has been reported about 0.2/100,000 in Japan. It is one of the most frequent mitochondrial disorders, which are estimated to affect 1/10,000 people. Males and females are affected equally.
Clinical description
MELAS is a multi-organ disease with protean manifestations. MELAS symptoms usually occur before 20 years, but can develop at any age. The hallmark feature is stroke-like episodes causing vomiting, headache, or epilepsy followed by loss of consciousness, frequently hemiparesis, hemianopia, and cortical blindness. Patients may have a history of developmental delay, short stature, learning disabilities before occurrence of stroke. Lactic acidosis is another systematic manifestation. Myopathy presents as hypotonia, exercise intolerance, and weakness. Other manifestations may include endocrinopathy (diabetes, mostly type 2 and occasionally type 1, hypo- or hyperthyroidism), polyneuropathy, cardiomyopathy, sensorineural hearing loss and intestinal pseudo-obstruction. Psychiatric manifestations include loss of appetite, depression, anxiety, psychosis, bipolar disorder, dementia, autism spectrum disorders, and rarely behavioral disturbances. Nephrotic syndrome is a rare manifestation. Dermatological involvement includes purpura, hirsutism, and erythema. The course is often progressive, with gradual cognitive decline, disability, and early demise.
Etiology
The exact pathogenesis has not been fully elucidated. Energy depletion due to mitochondrial dysfunction underlies the clinical manifestations. Among mutations in 19 mitochondrial genes so far identified , the 3243A>G mutation in the mitochondrial tRNA Leu(UUR) gene (MT-TL1) is most frequent (approximately 80%). These mutations lead to mitochondrial tRNA dysfunction, causing disturbances in mitochondrial protein synthesis.
Diagnostic methods
Diagnosis of MELAS is made based on a combination of the characteristic clinical features, laboratory findings indicative of mitochondrial dysfunction, and genetic testing. Diagnostic laboratory findings include demonstration of lactic acidosis, brain imaging during stroke not conforming to the vascular territory, muscle biopsy showing ragged red fibers, and respiratory chain analysis showing multiple partial defects. The diagnosis can be confirmed by molecular genetic testing. It is of note that the genetic test results alone cannot predict the diagnosis, because of variable phenotypes caused by the mutation (m.3243A-to-G), ranging from severe MELAS to diabetes, or deafness, or even asymptomatic.
Differential diagnosis
Various diseases causing juvenile-onset acute ischemic stroke need to be distinguished. In patients with migraine, epilepsy, or encephalitis MELAS should be ruled out. Further differential diagnoses are other mitochondrial disorders that share clinical manifestations with MELAS.
Antenatal diagnosis
Prenatal diagnosis, though possible, is difficult due to heterogeneity in the proportion of mutations between tissues.
Genetic counseling
MELAS is inherited in a mitochondrial manner, through maternal inheritance and rarely as de novo mutations. Genetic counseling is challenging due to heteroplasmy.
Management and treatment
There is currently no recommended treatment for MELAS syndrome. Agents that have been used albeit with insufficient evidence include arginine, taurine, citrulline, carnitine, creatine monohydrate, idebenone, dichloroacetate, coenzyme Q10, menadione, phylloquinone, ascorbic acid, riboflavin, and nicotinamide. Endocrine, cardiac, gastrointestinal, psychiatric, renal, and dermatological manifestations are managed with standard symptomatic measures. Progressive encephalomyopathy should be closely monitored.
Prognosis
MELAS progresses over years with accumulation of neurological deficits and exhibits high morbidity and mortality.

                            Last update:
                            July 2020

                            - Expert reviewer(s):
                            Pr Yoshihide SUNADA


Melhem-Fahl syndrome was described in two siblings born to consanguineous parents in 1985 and was characterized by the presence of 15 dorsal vertebrae and rib pairs. No other cases have been documented since the initial report.


A tropical infectious disease caused by the Gram-negative bacterium Burkholderia pseudomallei, which is present in soil and water in tropical countries. Melioidosis can present itself in many ways, including pneumonia, sepsis and abscess formation.

Summary:
Epidemiology
Melioidosis is present throughout the tropics and highly endemic in (Southeast) Asia and Australia. The disease is increasingly reported in African and South American countries. Melioidosis has a male predominance and may occur in any age group, but is more frequent between 40 and 60 years of age.
Clinical description
The incubation period varies from days to months or years. Melioidosis has a spectrum of clinical manifestations ranging from local skin infection to pneumonia, sepsis and abscess formation. Less frequent manifestations include involvement of the central nervous system or the musculoskeletal apparatus. Melioidosis presents as an acute disease in the majority of cases, characterized by respiratory infections and septicemia. It can also present as a chronic infection characterized by subacute tuberculosis-like lesions or non-healing skin infections.
Etiology
Melioidosis is caused by the Gram-negative bacterium Burkholderia pseudomallei, which is present in soil and water in tropical countries. Rice fields are associated with the presence of B. pseudomallei. The bacterium can enter the body via inoculation, inhalation or ingestion. Risk factors include diabetes, chronic kidney, lung and liver disease and alcohol abuse.
Diagnostic methods
The gold standard for diagnosis is culture and identification of B. pseudomallei from patient samples (of blood, sputum, urine and wounds). Ideally, suspected isolates are confirmed using PCR or sequencing methods. Currently available antibody tests, such as the indirect hemagglutination assay, are less reliable, but can provide information about exposure to the bacterium. Imaging is important to assess the extent of disease.
Differential diagnosis
Differential diagnosis includes tuberculosis, pneumonia, and other infectious diseases such as plague, typhoid fever and syphilis.
Management and treatment
Patients are treated with an initial intensive phase of antibiotics with ceftazidime or carbapenem (i.e. meropenem or imipenem) followed by a longer eradication phase with preferably cotrimoxazole.
Prognosis
The mortality varies and is dependent on available diagnostics and therapeutic options. The reported mortality is around 40% in low- and middle-income countries, while in Australia the mortality is almost 5%. Early recognition and adequate treatment are key. Relapses can occur.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                             J. [Jelmer] SAVELKOEL  - Pr W.J. [Joost] WIERSINGA


A rare orofacial granulomatosis characterized by the triad of recurrent or persistent orofacial edema (facial and lip edemas), fissured tongue, and relapsing, unilateral or bilateral peripheral facial nerve paralysis. Most cases present with partial symptoms. Typical age of onset is in childhood or adolescence. Histological examination shows non-caseating epithelioid cell granulomas and lymphedema.


Melnick-Needles syndrome (MNS) belongs to the otopalatodigital syndrome spectrum disorder and is associated with a short stature, facial dysmorphism, osseous abnormalities involving the majority of the axial and appendicular skeleton resulting in impaired speech and masticatory problems.

Summary:
Epidemiology
To date, less than 70 cases with MNS have been documented. MNS is a disorder essentially limited to females as it is lethal in males. Survivorship in males is possible due to mosaicism.
Clinical description
MNS is a congenital disorder characterized by a short stature, facial dysmorphism (small facies with prominent forehead, full cheeks, retrognathia, marked micrognathia), impaired speech, masticatory problems, and bowing of the arms and lower legs. Eye and ear abnormalities include bilateral exophthalmus, strabismus, blue sclera, conductive deafness and large pinna. Kyphoscoliosis is common. Mitral and tricuspid valve prolapse, bowel malrotation, hydronephrosis, and joint subluxation may be observed. Severe mandibular hypoplasia can cause upper airway restriction, obstructive sleep apnea syndrome and pneumonia and occasionally respiratory failure. Complete atrioventricular canal, prune belly syndrome and omphalocele have been reported in lethally affected males. Intelligence is normal. In females, the syndrome presents with bone dysplasia and facial dysmorphism. Males born to affected mothers show a lethal course of the disease in the embryonic or perinatal period.
Etiology
MNS is caused by gain of function mutations in the gene FLNA (Xq28) that encodes the actin-binding cytoskeletal protein filamin A. Several lines of evidence suggest that filamin participates in the remodeling of the cytoskeleton during development by integrating cell signaling events with subsequent alterations in cellular shape and motility. MNS is allelic with 4 other skeletal dysplasias (otopalatodigital syndrome type 1 and 2 (OPD1 and OPD2, respectively), terminal osseous dysplasia - pigmentary defects (TOD) and frontometaphyseal dysplasia (FMD).
Genetic counseling
MNS is inherited in an X-linked dominant manner. Male-to-male transmission has not been reported. The risk of transmitting the mutation in each pregnancy is 50%; males inheriting the mutation will be affected while females who inherit the mutation are less severely affected.

                            Last update:
                            May 2015

                            - Expert reviewer(s):
                            Pr Stephen ROBERTSON


Melorheostosis with osteopoikilosis is a rare sclerosing bone dysplasia, combining the clinical and radiological features of melorheostosis and osteopoikilosis (see these terms), that has been reported in some families with osteopoikilosis and that is characterized by a variable presentation of limb pain and deformities.

Summary:
Epidemiology
Less than 5 families have been reported in the literature to date.
Clinical description
As osteopoikilosis is a benign, usually asymptomatic condition, the clinical signs are primarily those of melorheostosis that can manifest with joint contractures, pain, stiffness, limited joint functions, limb-length discrepancy and deformity.
Etiology
The combination of melorheostosis with osteopoikilosis may be an unusual complication of familial osteopoikilosis. Osteopoikilosis is caused by a germline mutation in the LEMD3 gene (12q14). A germline mutation in the LEMD3 gene may predispose individuals with osteopoikilosis to develop melorheostosis. However, the exact pathogenesis is currently unknown.
Genetic counseling
Osteopoikilosis is inherited autosomal dominantly. There are no reports of parent to child transmission of melorheostosis. Genetic counseling is possible.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Pr Geert MORTIER


Melorheostosis is a rare connective tissue disorder characterized by a sclerosing bone dysplasia, usually limited to one side of the body (rarely bilateral), that manifests with pain, stiffness, joint contractures and deformities.

Summary:
Epidemiology
The estimated prevalence is of 1/1,100,000. More than 400 cases have been reported to date.
Clinical description
The disease usually presents in early childhood, and is frequently diagnosed before the age of 20, but can occur at any age. Patients can range from asymptomatic to those with joint contractures and/or chronic pain. The long bones of the extremities are most commonly affected and monostotic, polyostotic or monomelic presentations can occur. Usually, the initial manifestations are pain (from dull to sharp and penetrating), stiffness, limitation of joint movement or joint deformity. Pain is present in almost all cases and is usually aggravated by activity but it is rarely constant. Soft tissue fibrosis around the affected limb can also be noted. Other common associated manifestations include edema, hyperpigmented skin patches, circumscribed and linear scleroderma, vascular tumors and malformations. Limb shortening is rarely observed.
Etiology
Etiology of melorheostosis is unknown and it is considered a sporadic disease probably due to somatic mosaicism for a genetic defect. The pathology is essentially that of abnormal proliferation of compact haversian bone distorting the contour of bone periosteal and endosteal surfaces.
Diagnostic methods
Diagnosis is mainly based on conventional radiography. On plain radiographs, melorheostosis presents as linear lesions of increased bone density along the major axis (shafts or diaphyses) of the tubular bones. Lesions result in an increased thickness of the cortices and can expand to the external surface of the bones, giving the appearance of dripping wax along a candle. When there is polyostotic involvement, the linear lesions are typically continuous along the same side of the affected limb and ''jump'' across the joints. Soft tissue calcification and even ectopic ossification may be seen. Magnetic resonance imaging contributes to the assessment of soft tissue lesions. Radioisotope bone scanning can help distinguish melorheostosis from other bone lesions. Biopsy shows variable degrees of bone marrow fibrosis, along with markedly irregular bone with mixed areas of lamellar and woven bone. A mix of osteocartilagenous, fibrovascular, and adipose tissue is seen in the soft tissue masses.
Differential diagnosis
The main differential diagnoses include bone tumors generating dense bone such as osteosarcoma, as well as osteopathia striata, osteopoikilosis, myositis ossificans progressiva (see these terms) and osteoma. Rarely, in families with osteopoikilosis or Buschke-Ollendorf syndrome, patients with melorheostosis may be present (as seen in melorheostosis with osteopoikilosis) (see these terms).
Genetic counseling
Melorheostosis is a sporadic disorder. There are no reports of parent to child transmission. For a parent with isolated melorheostosis, the risk of having an affected child is very low.
Management and treatment
There is no curative treatment for melorheostosis. Management aims to relieve pain, correct deformity and restore movement of the affected limb(s). Bisphosphonates (pamidronate and etidronate) and most recently zoledronate have been shown to improve symptoms in some but not all patients (but further studies are needed). Physical therapy, serial casting, braces, manipulations, nerve blocks and sympathectomies are other conservative options. Surgical options include limb and tendon lengthening, fasciotomies, capsulotomies, osteotomies, excision of fibrous tissue and/or hyperostosis, contralateral epiphysiodesis, arthrodesis, callotasis and amputation. Surgical treatments are best performed after skeletal maturity is reached but deformities can recur.
Prognosis
Melorheostosis is not life-threatening but can greatly affect quality of life due to chronic pain that can worsen or reappear, even after surgery.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Pr Geert MORTIER


A rare, genetic, syndromic, sterol biosynthesis disorder affecting males characterized by skin manifestations, including collodion membrane, ichthyosis, and patchy hypopigmentary lesions, associated with severe neurological involvement (e.g. intellectual disability, delayed psychomotor development, seizures, hydrocephalus, cerebellar/corpus callosum hypoplasia, Dandy-Walker malformation, hypotonia) and craniofacial dysmorphism (large anterior fontanelle, telecanthus, hypertelorism, microphthalmia, prominent nasal bridge, low-set ears, micrognathia, cleft palate). 2,3 toe syndactyly, polydactyly, and kyphosis, as well as ophthalmic, cardiac and urogenital anomalies may also be associated.


Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR1 deficiency

Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete interferon gamma receptor 1 (IFN-gammaR1) deficiency is a genetic variant of MSMD (see this term) characterized by a complete deficiency in IFN-gammaR1, leading to impaired IFN-gamma immunity and, consequently, to severe and often fatal infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
Severe and often fatal BCG and EM infections begin in early childhood (before the age of 3) as a complete deficiency displays complete clinical penetrance in childhood. The most common pathogens include Mycobacterium fortuitum,  Mycobacterium chelonae, Mycobacterium smegmatis and Mycobacterium peregrinum. Infection is disseminated and can involve soft tissue, bone marrow, lungs, skin, bones and lymph nodes. Manifestations include fever, weight loss, hepatosplenomegaly, lymphadenopathies and lepromatous-like lesions. Salmonellosis has been reported in 5% of patients. Other infections caused by cytomegalovirus, Listeria monocytogenes and human herpes virus 8 have been reported in a single case.
Etiology
MSMD due to complete IFN-gammaR1 deficiency is caused by mutations in the  IFNGR1 gene on chromosome 6q23-q24. This gene encodes the IFN-gamma receptor ligand binding chain and a mutation leads to the halt of IFN-gammaR1 at the cell surface. More than 21 causal mutations have been identified to date, with most of them being homozygous. Two forms of clinically indistinguishable complete IFN-gammaR1 deficiency have been identified: with or without the expression of cell surface receptors.
Diagnostic methods
Diagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA, after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. High plasma concentrations of IFN-gamma suggest a complete IFN-gammaR deficiency. Leukocytes and fibroblasts from patients with this immunodeficiency do not respond to IFN-gamma in vitro. Histology of lymph nodes shows ill defined and poorly differentiated lepromatous-like multibacillary granulomas with few giant cells. Genetic testing reveals mutations in IFNGR1.
Differential diagnosis
Differential diagnoses include other genetic etiologies of MSMD, especially complete IFN-gammaR2 deficiency (see these terms). Chronic granulomatous disease, cystic fibrosis and severe combined immunodeficiency (see these terms) should also be excluded.
Antenatal diagnosis
As this variant is often fatal, antenatal diagnosis is offered to families with a known IFNGR1 mutation.
Genetic counseling
Transmission is autosomal recessive and genetic counseling is possible.
Management and treatment
The only curative option for MSMD due to AR complete IFN-gammaR1 deficiency is hematopoietic stem cell transplantation (HSCT). As there is a high risk for rejection with this procedure, treatment with IFN-gamma-depleted antibodies to lower pre-transplantation IFN-gamma levels will favor a more positive outcome. Due to a lack of specific receptors, IFN-gamma treatment is not indicated. BCG vaccination should be avoided in those with a known IFNGR1 mutation.
Prognosis
Prognosis is poor with most patients not living past 10 years of age.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Mendelian susceptibility to mycobacterial diseases due to complete IFNgammaR2 deficiency

Mendelian susceptibily to mycobacterial diseases (MSMD) due to complete interferon gamma receptor 2 (IFN-gammaR2) deficiency is a genetic variant of MSMD (see this term) characterized by a complete deficiency in IFN-gammaR2, leading to an undetectable response to IFN-gamma, and consequently, to severe and often fatal infections with bacillus Calmette-Guérin (BCG) and other environmental mycobacteria (EM).

Summary:
Epidemiology
The prevalence is unknown. Only ten children have been identified to date.
Clinical description
Severe and often fatal BCG and EM infections begin in early childhood (before the age of 3). The most common pathogens seen in patients include Mycobacterium fortuitum, Mycobacterium bovis BCG, Mycobacterium abscessus and Mycobacterium avium. Infections are disseminated and can involve soft tissue, bone marrow, lungs, skin, bones and lymph nodes. Infections manifest with fever, weight loss, hepatosplenomegaly and lymphadenopathies and can be fatal.
Etiology
This disease is caused by mutations in IFNGR2 on chromosome 21q22.1-22.2 which encodes the IFN-gamma receptor signal transducing chain, essential for IFN-gamma mediated immunity. Two clinically indistinguishable forms have been reportedly defined by the presence or absence of protein expression on the cell surface.
Diagnostic methods
Diagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA, after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. Leukocytes and fibroblasts from patients with this immunodeficiency do not respond to IFN-gamma in vitro. Genetic testing reveals mutations in IFNGR2.
Differential diagnosis
Differential diagnosis includes the other variants of MSMD, especially complete IFN-gammaR1 deficiency (see this term). Chronic granulomatous disease, cystic fibrosis and severe combined immunodeficiency (see these terms) should also be excluded.
Antenatal diagnosis
As this disease is often fatal, antenatal diagnosis is offered to families with a known IFNGR2 mutation.
Genetic counseling
MSMD due to complete IFN-gammaR2 deficiency is inherited autosomal recessively and genetic counseling is recommended.
Management and treatment
The only curative option for MSMD due to complete IFN-gammaR2 deficiency is hematopoietic stem cell transplantation (HSCT). Due to a lack of specific receptors, IFN-gamma treatment is not indicated. BCG vaccination should be avoided in those with a known IFNGR2 mutation.
Prognosis
Prognosis is poor with most patients not living past 10 years of age.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Mendelian susceptibility to mycobacterial diseases due to complete IL12B deficiency

Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete interleukin-12 subunit beta (IL12B) deficiency is a genetic variant of MSMD (see this term) characterized by mild bacillus Calmette-Guérin (BCG) infections and recurrent Salmonella infections.

Summary:
Epidemiology
The prevalence is unknown. Mutations have been found in 49 patients from 30 kindreds originating from India, Iran, Pakistan, Saudi Arabia and Tunisia.
Clinical description
The disease presents in early childhood. BCG is the most common infection encountered, usually after receiving the vaccination. Non-typhoidal Salmonella infections are also seen in half of all cases. A few other infections have been reported, including chronic mucocutaneous candidiasis (CMC), nocardiosis, and klebsiellosis. An incomplete clinical penetrance is observed in this immunodeficiency.
Etiology
MSMD due to complete IL12B deficiency is caused by homozygous mutations in the IL12B gene on chromosome 5q31.1-q33.1 which encodes for the IL-12p40 subunit. There are 9 different IL12B mutant alleles identified, including 2 small insertions, 3 small deletions, 2 splice site mutations, 1 large deletion and 1 nonsense mutation.
Diagnostic methods
Diagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. The patients lack detectable IL-12p70, IL-12p40 and produce low levels of IFN-gamma. Genetic testing reveals mutations in IL12B.
Differential diagnosis
Differential diagnoses include other genetic forms of MSMD, especially MSMD due to complete IL12RB1 deficiency (see this term).
Antenatal diagnosis
This immunodeficiency is not severe and antenatal diagnosis is not necessary.
Genetic counseling
MSMD due to complete IL12B deficiency is inherited in an autosomal recessive manner. Genetic counseling is possible for families where a IL12B mutation is known.
Management and treatment
BCG vaccination should be avoided in patients with this disease. Treatment involves prolonged antimicrobial therapy along with recombinant IFN-gamma to control infections, which is successful in most cases. Hematopoietic stem cell (HST) transplantation is not recommended.
Prognosis
Patients with this immunodeficiency usually have a good prognosis.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Mendelian susceptibility to mycobacterial diseases due to complete IL12RB1 deficiency

Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete interleukin-12 receptor subunit beta-1 (IL12RB1) deficiency is a genetic variant of MSMD (see this term) characterized by mild bacillus Calmette-Guérin (BCG) infections and recurrent Salmonella infections.

Summary:
Epidemiology
The prevalence is unknown. Over 140 cases have been reported in the world.
Clinical description
Disease onset usually occurs in patients before the age of 12 with the appearance of BCG disease, usually after receiving the vaccination. Over half of patients with this variant experience an additional infection with non-typhoidal Salmonella. Severe tuberculosis caused by Mycobacterium tuberculosis has been reported in several unrelated patients, providing the first documented evidence of a mendelian predisposition to tuberculosis. Other infections with Paracoccidiodes brasiliensis, Leishmania and Klebsiella have been reported in a single patient. Some patients also suffer from Candida infections. Most genetically affected siblings of index cases are asymptomatic, indicating low penetrance for case definition phenotypes.
Etiology
MSMD due to complete IL12RB1 deficiency is caused by mutations in the IL12RB1 gene (19p13.1) subunit that encodes for the IL-12R-beta1 chain. These mutations impair the IL-12/IL-23 pathway essential for production of IFN-beta and the resulting immunity against Salmonella and BCG infections. Two clinically indistinguishable forms have been reported defined by the presence or absence of protein expression on the cell surface.
Diagnostic methods
Diagnosis is made by laboratory analysis. In general, there is no expression of IL12RB1 at the surface of activated T-lymphocytes and NK cells. For the moment, only one mutation of IL12 RB1 leads to residual expression of the receptor on the cell surface. Low IFN-gamma levels are measured by ELISA after whole blood activation by BCG and BCG+IL-12. Genetic testing reveals mutations in IL12RB1. Impaired development of the Th17 cells is demonstrated in patients with this immunodeficiency.
Differential diagnosis
Other genetic etiologies of MSMD should be excluded.
Antenatal diagnosis
This immunodeficiency is not severe and antenatal diagnosis is not necessary.
Genetic counseling
MSMD due to complete IL12RB1 deficiency is inherited in an autosomal recessive manner so genetic counseling is possible.
Management and treatment
BCG vaccination should be avoided in those with a known mutation in the IL12RB1 gene. Treatment is usually attained from long term antimicrobial therapy combined with recombinant IFN-gamma. For those who have localized splenic/mesenteric lesions with poor drug penetration, surgical removal is indicated.
Prognosis
With proper treatment the prognosis is usually good with most patients reaching adulthood.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency

Mendelian susceptibility to mycobacterial diseases (MSMD) due to complete ISG15 deficiency is a genetic variant of MSMD (see this term) characterized by Bacille Calmette-Guérin (BCG) infections.

Summary:
Epidemiology
The prevalence is unknown. In 2012, three patients were reported from two unrelated kindreds from Turkey and Iran.
Clinical description
Patients are described to have BCG infections. Patients of 12 or 15 years of age were reported to have been infected in the past with many other viruses but with no unusually severe consequences reported.
Etiology
MSMD due to complete ISG15 deficiency is caused by mutations in the ISG15 gene (1p36.33), which encodes an IFN-alpha/beta inducible, ubiquitin-like intracellular protein. These mutations impair ISG15 secretion by leukocytes, a molecule which plays an essential role as an IFN-gamma-inducing secreted molecule needed for optimal antimycobacterial immunity.
Diagnostic methods
Diagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. Similarly to patients with an IL12RB1 deficiency, patients with an ISG15 deficiency produce small amounts of IFN-gamma whereas they produce normal amounts of IL12p40 and IL12p70. Genetic testing reveals mutations in ISG15.
Differential diagnosis
Other etiologies of MSMD, especially MSMD due to complete IL12RB1 deficiency (see this term), should be excluded.
Antenatal diagnosis
This immunodeficiency is not severe and antenatal diagnosis is not necessary.
Genetic counseling
MSMD due to complete ISG15 deficiency is inherited in an autosomal recessive manner and genetic counseling is possible.
Management and treatment
BCG vaccination should be avoided in those with a known ISG15 mutation. Treatment usually involves long term antimicrobial therapy combined with recombinant IFN-gamma.
Prognosis
With proper treatment the prognosis is presumed to be good.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Mendelian susceptibility to mycobacterial diseases due to partial IRF8 deficiency

Mendelian susceptibility to mycobacterial diseases (MSMD) due to partial IRF8 (interferon regulatory factor 8) deficiency is a rare genetic variant of MSMD (see this term) characterized by a selective susceptibility to relatively mild infections with bacillus Calmette-Guérin (BCG)..

Summary:
Epidemiology
The prevalence is unknown. Only 2 cases in the world have been described to date.
Clinical description
The first infections occur after vaccination with BCG and before the age of 2. They are relatively mild with manifestations of fever and lymphadenopathy. No other infectious diseases have been reported.
Etiology
MSMD due to a partial IRF8 deficiency is caused by heterozygous mutations in the IRF8 gene on chromosome 16q24.1 which encodes IRF8, a protein essential for the development of dendritic cells and the differentiation of macrophages and granulocytes. Mutations in the IRF8 gene impairs IL-12 secretion by monocytes and dendritic cells.
Genetic counseling
MSMD due to a partial IRF8 deficiency is inherited in an autosomal dominant manner so genetic counseling is possible.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency

Mendelian susceptibility to mycobacterial diseases (MSMD) due to partial STAT1 (signal transducer and activator of transcription 1) deficiency is a genetic variant of MSMD (see this term) characterized by a partial defect in the interferon (IFN)-gamma pathway, leading to mild mycobacterial infections.

Summary:
Epidemiology
The prevalence is unknown. In 2001, two patients from unrelated kindreds were described and they suffered only mild MSMD. Since 2001, up to six other kindreds have been described to have a partial dominant STAT1 deficiency associated with MSMD.
Clinical description
First infections occur after the age of 3, most commonly with weakly virulent Mycobacterium bovis BCG and Mycobacterium avium complex or with the more virulent Mycobacterium tuberculosis. Clinical penetrance is incomplete and some patients are asymptomatic while others have very mild clinical manifestations. None of the patients identified to date developed severe viral illness.
Etiology
MSMD due to partial STAT1 deficiency is due to heterozygous mutations in the STAT1 gene on chromosome 2q32.2-q32.3 encoding the signal transducer and activator of transcription 1. Two distinct forms have been described: one affecting phosphorylation and the other impairing DNA-binding activity.
Genetic counseling
Transmission is autosomal dominant and genetic counseling is possible.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare immunodeficiency syndrome, characterized by a narrow vulnerability to poorly virulent mycobacteria, such as bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria (EM), and defined by severe, recurrent infections, either disseminated or localized.

Summary:
Epidemiology
The prevalence is unknown.
Clinical description
MSMD due to autosomal recessive (AR) complete interferon gamma receptor 1 (IFN-gammaR1) and receptor 2 (IFN-gammaR2) deficiencies (see these terms), the most serious variants, develop in early childhood with first infections generally occurring around the age of 3. Serious, disseminated infections with BCG and EM are observed and can involve soft tissue, bone marrow, lungs, skin, bones and lymph nodes. Other infections with Salmonella spp., Listeria monocytogenes and viruses have been reported. MSMD due to partial IFN-gammaR1, partial IFN-gammaR2, complete IL-12R-beta1, complete IL12B, complete ISG15, partial STAT1 and partial IRF8 deficiencies and MSMD due to partial X-linked recessive (XR) mutations (see these terms) are usually less severe. They have minor symptoms and some occur after the age of 3 to adulthood. Patients are vulnerable to Mycobacterium tuberculosis. Severe diseases caused by non-typhoidal Salmonella species have been reported in half of patients, especially in those with IL-12R-beta1 or IL12B deficiencies.
Etiology
Only about half of patients with MSMD have an identified genetic etiology. Nine genes are known to be responsible for MSMD. Seven of them are inherited autosomally (IFNGR1, IFNGR2, STAT1, IL12B , IL12RB1 and more recently IRF8 and ISG15) and 2 are X-linked (IKBKG  and CYBB). MSMD is heterogeneous and thought to be mendelian based on the large number of consanguineous and/or multiplex kindred identified and/or X-linked heritance. The genetic defects impair IL-12 dependent IFN-gamma immunity. The high allelic heterogeneity results in 17 genetic disorders according to the mode of transmission, impact on function, association of a lack of protein expression or expression of an abnormal protein, and the specific function affected. Molecular and cellular mechanisms remain largely unknown.
Diagnostic methods
Diagnosis is made by laboratory analysis. IFN-gamma, IL-12p40 and IL-12p70 levels can be measured by ELISA, after whole blood activation by BCG, BCG+IL-12 and BCG+IFN-gamma. High plasma concentrations of IFN-gamma suggest a complete IFN-gammaR deficiency. Mutational analysis is necessary to identify the exact causative genes involved.
Differential diagnosis
Chronic granulomatous disease, cystic fibrosis and severe combined immunodeficiency should be excluded as well as complete defects in IRF8 or STAT1 and TyK2 (see these terms).
Antenatal diagnosis
Antenatal diagnosis can be offered to those families with the often fatal complete IFNGR deficiencies.
Genetic counseling
MSMD can be inherited in an AD, AR or X-linked manner. Genetic counseling is possible when a specific mutation is identified within a family.
Management and treatment
BCG vaccination should be avoided in those with MSMD. Patients with IL-12B, IL-12R-beta1 or ISG15 deficiencies and partial IFN-gammaR, IRF8 and STAT1 deficiencies respond well to antibiotic therapy and can also be treated with IFN-g therapy. Abdominal lymph node resection may be needed in some cases. Hematopoietic stem cell transplantation (HSCT) should be considered in those with complete IFN-gammaR1 and IFN-gammaR2 deficiencies but rates of rejection are high, probably due to high levels of IFN-gamma detected in the serum of these patients.
Prognosis
Prognosis depends on the specific mutation involved and the corresponding associated disorder. Some cases are fatal while others resolve with antibiotic therapy.

                            Last update:
                            February 2013

                            - Expert reviewer(s):
                            Dr Jacinta BUSTAMANTE  - Pr Jean-Laurent CASANOVA


A rare nervous system tumor characterized by a benign pigmented space-occupying lesion derived from leptomeningeal melanocytes. Symptoms typically show insidious onset and are related to the mass effect on adjacent tissues. Depending on the location of the tumor, they include focal neurological deficits, increased intracranial pressure, seizures, and spinal cord compression, among others. Although the tumor may behave aggressively, prognosis is good after complete surgical resection.


A rare, mostly benign, neoplastic disease characterized by a primary tumor of the meninges, usually located intracranially (~90%) but spinal meningiomas occur as well. Clinical symptoms relate to the location of the tumor and may include seizures, focal neurological deficits (sensory-motor or visual symptoms, cranial nerve dysfunction), vascular complications (occlusion of cerebral blood vessels, deep venous thrombosis, pulmonary embolism), chronically increased intracranial pressure neurocognitive impairment and/or loss of bladder/anus sphincter control.

Summary:
Epidemiology
In adults, intracranial meningiomas represent approximately 30% of central nervous system tumors. The male to female ratio is 1:3.5.
Clinical description
Whilst meningioma may appear at any age, it is predominantly diagnosed between the third and sixth decade of life. Meningiomas typically appear as oval or hemispheric lesions with broad dural attachment. They most frequently occur supratentorially at the calvaria or skull base meninges, along the falx and in the parafalcine location, but can also be found attached to the tentorium, in the cerebello-pontine angle, within the optic nerve sheath, intraventricularly, or in the spinal canal. Lesions are classified into grade I (benign, most frequent), II (atypical), III (malignant) based on local invasiveness, cellular features and mitotic activity. Osseous destruction is indicative of atypical or malignant meningioma. Hyperostosis of adjacent skull bone is highly suggestive of benign meningioma. There are 15 immunohistological subtypes; features are subtype dependent but typically include whorl formation, nuclear pseudo-inclusions, pseudo-syncytial growth, and strong somatostatin-receptor subtype 2 (SSTR2) and epithelial membrane antigen expression.
Etiology
The tumor most likely originates from arachnoid meningothelial cells. Several frequently mutated genes have been detected in meningiomas and include NF2, AKT1, SMO, PIK3CA, BAP1, TERT (promoter), SUFU, SMARCE1, and TRAF7.
Diagnostic methods
The radiological diagnosis is made using contrast-enhanced MRI. Contrast-enhanced CT may also be used and is valuable for the detection of calcification within the tumor, hyperostosis of adjacent bone, and intraosseous tumor growth, especially in skull-base meningiomas. PET-based imaging using SSTR ligands is a helpful additional diagnostic tool and can be used to discriminate the lesion from healthy tissue or other entities. If imaging strongly suggests meningioma, histological verification is not mandatory; however, exclusion of rare differential diagnoses such as metastasis is recommended. Moreover, current diagnostic methods are not able to predict tumor grade which may have therapeutic implications.
Differential diagnosis
The main differential diagnoses include other intracranial lesions, such as dural metastases, primary glial tumors that extend into the subarachnoid space, hematopoietic neoplasms (such as extra-axial non-Hodgkin lymphoma), pituitary neoplasms (e.g. adenomas or craniopharyngiomas), as well as inflammatory (rheumatoid arthritis, Wegener's granulomatosis, extra-axial neurosarcoidosis) and infectious diseases (tuberculosis, syphilitic gumma).
Genetic counseling
Genetic counseling should be considered for patients with multiple meningioma, particularly in combination with ependymoma or schwannoma (NF2-related), and multiple spinal clear-cell meningioma (SMARCE1-related).
Management and treatment
If treatment is required, surgery is the first option. Adjuvant therapies, mainly radiotherapy, may be required if location of the tumor is challenging, in case of significant residual disease or for grade III lesions. So far, there is no clear postoperative guideline for grade II meningiomas. Current systemic therapies have shown little or no response. Asymptomatic lesions (typically diagnosed incidentally) may be managed with observation and long-term follow-up with MRI until either symptoms develop, sustained growth occurs, or concerns of entrapment on sensitive structures arises.
Prognosis
Tumor grade and extent of resection (based on Simpson grading) are the most important predictors of progression-free survival. For completely resected grade I lesions, the risk of tumor recurrence is low. However, meningiomas may confer an aggressive clinical course with multiple recurrences and, infrequently, metastases to other organs. Of note, long-term sequelae (e.g. impairment of neurocognitive functioning and quality of life) following treatment have been reported.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Christine JUNGK  - Dr Felix SAHM


Meningococcal meningitis is an acute bacterial disease caused by Neisseria meningitides that presents usually, but not always, with a rash (non blanching petechial or purpuric rash), progressively developing signs of meningitis (fever, vomiting, headache, photophobia, and neck stiffness) and later leading to confusion, delirium and drowsiness. Neck stiffness and photophobia are often absent in infants and young children who may manifest nonspecific signs such as irritability, inconsolable crying, poor feeding, and a bulging fontanel. Meningococcal meningitis may also present as part of early or late onset sepsis in neonates. The disease is potentially fatal. Surviving patients may develop neurological sequelae that include sensorineural hearing loss, seizures, spasticity, attention deficits and intellectual disability.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by variable intellectual disability, developmental delay, autistic behavior, short stature, and microcephaly. Additional variable manifestations include feeding problems, vision and hearing impairments, recurrent upper airway infections, and epilepsy. Reported malformations are cryptorchidism and cerebral anomalies. Dysmorphic facial features include short and upslanted palpebral fissures, ptosis, telecanthus, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum.