Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, to stresses such as vigorous exercise and heat.

Summary:
Epidemiology
The incidence of MH reactions ranges from 1/5000 to 1/50,000-100,000 anesthesias. However, the genetic prevalence of the genetic abnormalities may be as great as 1/400 individuals. A significant male preponderance has been reported.
Clinical description
Clinical symptoms of MH are highly variable, ranging from self limiting courses with mild or moderate symptoms to fulminant MH crises. The classic signs of MH include marked hyperthermia, tachycardia, supraventricular and ventricular arrhythmia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, isolated masseter spasm or generalized muscle rigidity and rhabdomyolysis, all of which are related to a hypermetabolic response. In untreated patients, multiorgan failure (including acute renal failure) and circulatory collapse are the end-stage of the disease.
Etiology
In most cases, MH is caused by a defect in the ryanodine receptor. Over 400 variants have been identified in the ryanodine receptor gene (RYR1), located on chromosome 19q13.1, and at least 34 are causal for MH. The pathophysiologic changes of MH are due to an uncontrolled rise in myoplasmic calcium, which activates biochemical processes related to muscle activation. As a result of ATP depletion, muscle membrane integrity is compromised, leading to hyperkalemia and rhabdomyolysis. MH events are mainly triggered by volatile anesthetics and succinylcholine. Extremely rarely stresses such as exercise, emotion and heat may trigger a reaction.
Diagnostic methods
An early diagnostic clue is elevation of end-expired carbon dioxide. Arterial blood gas analyses reveal a combination of respiratory and metabolic acidosis with negative base excess, lactemia, hypercapnia, and hypoxemia. Diagnostic testing relies on assessing the in-vitro contracture response of biopsied muscle to halothane and caffeine. Other drugs such as ryanodine and 4-chloro-m-cresol have also been used but are not part of a standard protocol. A diagnosis of MH is given when contracture forces exceed the given threshold after exposure to these substances. Elucidation of the genetic changes has led to the introduction, on a limited basis so far, of genetic testing for susceptibility to MH. As the sensitivity of genetic testing increases, molecular genetics will be increasing useful for identifying those at risk.
Differential diagnosis
The differential diagnosis of a fulminant MH crisis includes sporadic pheochromocytoma, serotonin syndrome, neuroleptic malignant syndrome (see these terms), anaphylactic reaction, thyroid crisis and sepsis.
Genetic counseling
MH is inherited autosomal dominantly. Genetic counseling is possible in families with a known disease causing mutation.
Management and treatment
Dantrolene sodium is a specific antagonist of the pathophysiologic changes in MH and should be available wherever general anesthesia is administered. When MH is suspected, administration of triggering agents should be ceased immediately and anesthesia continued with intravenous propofol, opiods and/or sedatives. During an MH crisis, dantrolene should be administered at a dosage of 2.5 mg/kg, every 5-10 minutes until patient is stabilized. Volume resuscitation and administration of vasopressors might be needed to stabilize hemodynamics. Cooling (with cold intravenous fluids, topical ice or special cooling blankets) is essential as high temperatures exacerbate an established MH reaction.
Prognosis
The syndrome is likely to be fatal if untreated but thanks to the dramatic progress in understanding the clinical manifestations and pathophysiology of the syndrome, the mortality from MH has dropped from over 80%, thirty years ago, to less than 5% at present.

                            Last update:
                            February 2015

                            - Expert reviewer(s):
                             Teresa BULGER  - Dr Neil POLLOCK  - Dr Henry ROSENBERG  -  Anja SCHIEMANN  - Dr Kathryn STOWELL


A rare, aggressive, neoplastic disease characterized by the presence of a melanocyte tumor that develops in any mucosal membrane. Clinical manifestations vary depending on the site of occurrence.


Malignant migrating focal seizures of infancy

A rare epileptic and developmental encephalopathy characterized by seizure onset during the first months of life, focal seizures arising independently in both hemispheres, marked drug resistance, and severe, long-term cognitive disability.

Summary:
Epidemiology
The estimated prevalence of Epilepsy of infancy with migrating focal seizures (EIMFS) is approximately 1/900,000 children. Both sexes are equally affected.
Clinical description
Seizures start during the first 6 months of life, typically in the neonatal period. Seizures are initially infrequent and consist of focal motor, tonic or clonic seizures, showing in some patients as subtle seizures reported as behavioral arrest with minor motor signs, and prominent autonomic features. Seizure frequency rapidly increases and status epilepticus is common. At onset, focal seizures arise independently in both hemispheres and can migrate from one region to another. Seizures show a marked drug resistance. Neurological status progressively deteriorates with worsening seizures and leads to progressive hypotonia, loss of visual contact, and lack or regression of psychomotor achievements. Most patients develop microcephaly by 1 year of age.
Etiology
The genetic etiology is variable. 70% of children have an identified genetic etiology. Half of them present gain-of-function mutations affecting the KCNT1 gene, located on 9q34.4. In other cases, the genes involved may include SCN2A (2q24.3), KCNQ2 (20q13.33), PLCB1 (20p12.3), TBC1D24 (16p13.3),PIGA (Xp22.2), SCN1A (2q24.3), SLC25A22 (11p15.5), and SLC12A5 (20q13.12). The following genes have been reported in single cases: GABRA1, GABRB1, ATP1A3, CDKL5, and ITPA.
Diagnostic methods
Diagnosis is based on clinical and electroencephalographic (EEG) findings. The EEG background can be normal at onset; however, diffuse slowing of the background occurs with time. At onset, seizures may be subtle and video-EEG recordings are necessary to identify the seizures and the ictal EEG pattern. This is characterized by rhythmic theta discharges that affect different cortical regions consecutively in the same single seizure event giving the eponym ''migrating'' to EIMFS. Multifocal discharges appear with time in all cases. Rarely hypsarrhythmia is reported. Brain magnetic resonance imaging (MRI) is usually normal at onset and may show diffuse brain atrophy as the condition progresses. Delayed myelination with white matter hyperintensity on MRI and decreased N-acetyl aspartate on magnetic resonance spectroscopy are often reported early during the first months of the disease onset. Molecular genetic testing should be proposed in order to identify the causal pathogenic variant.
Differential diagnosis
Differential diagnosis includes other epileptic and developmental encephalopathies starting during the neonatal period, in particular when multifocal seizures and EEG abnormalities are present.
Antenatal diagnosis
Prenatal genetic diagnosis can be performed in families with a known mutation.
Genetic counseling
In the majority of patients, KCNT1 mutations arise de novo. In a few families with a known KCNT1 mutation, inheritance is autosomal dominant with variable penetrance and expressivity. Genetic counselling is highly recommended in all patients with known genetic etiology. According to the gene involved, the disorder may be autosomal dominant, autosomal recessive, or X-linked.
Management and treatment
Seizures are often difficult to treat and may continue into adulthood despite anti-seizures medications. Currently, there is no anti-seizures medication that has been proven to be more efficient to reduce seizure frequency and duration. Overtreatment should be avoided and follow-up by a reference center recommended.
Prognosis
Prognosis is poor with on-going drug resistant seizures, severe neurological disability, acquired microcephaly and reduced life expectancy, although a milder evolution has been reported in a few children. Some patients are also affected by severe gastrointestinal dysmotility and movement disorder.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Dr Giulia BARCIA | EpiCARE* - Dr Amy MC TAGUE  - Pr Rima NABBOUT | EpiCARE*

                                * European Reference Network


Malignant mixed Müllerian tumor of the ovary is a rare and very aggressive neoplasm presenting most commonly in postmenopausal women and is composed of adenocarcinomatous and sarcomatous elements and, depending on the types of these elements, can be classified as homologous or heterologous. It often has a poor prognosis.


Malignant non-dysgerminomatous germ cell tumor of ovary is a rare malignant germ cell tumor of ovary (see this term) arising from germ cells in the ovary, frequently unilateral at diagnosis, usually presenting during adolescence with pelvic mass, fever, vaginal bleeding and acute abdomen, with certain subtypes being occasionally associated with isosexual precocity, virilization, hyperthyroidism or carcinoid syndrome (see this term). Histologically they comprise the following: embryonal carcinoma, Yolk sac tumor, polyembryoma and mixed germ cell tumor.


Malignant peripheral nerve sheath tumor with perineurial differentiation is a rare soft tissue sarcoma composed predominantly of spindle-shaped neoplastic cells showing perineurial differentiation and displaying abundant cellular pleomorphism or anaplasia, frequent mitoses, tumor necrosis and high metastatic potential. It often presents as a soft, painless, solid mass in subcutaneous tissues of the trunk or limbs, but tumors have also been described in the facial area, mediastinum, retroperitoneum, pancreas, paravertebral column and the pelvic soft tissues. Frequent local recurrence and distant metastatic spread has been reported.


Malignant peripheral nerve sheath tumor (MPNST) is a rare and often aggressive soft tissue sarcoma occurring in a wide range of anatomical sites.

Summary:
Epidemiology
Exact prevalence and incidence are unknown. Incidence of MPNST in the general population has been reported to be 1/100,000. MPNSTs account for about 5 to 10% of all soft tissue sarcomas. The sex ratio is about equal. Incidence among neurofibromatosis type 1 patients (NF1; see this term) is reported to be approximately 5 to 10%.
Clinical description
The age of occurrence is highly variable but most cases are reported in adults (typically between 20 and 50 years of age). In most cases, tumors arise in major nerve trunks such as the sciatic nerve or in the brachial plexus and sacral plexus. They are highly variable in appearance and commonly present as a rapidly enlarging palpable mass that is sometimes painful, with associated neurologic deficits such as radicular pain, paresthesia, and motor weakness. Tumors are fusiform to globular in shape, usually well circumscribed, and can be white to yellow and soft or firm. They occur most commonly in the trunk, head, neck and proximal extremities. Very rare anatomical sites include the brain, breast, posterior mediastinum, bladder, adrenal gland and skin. Tumors are often aggressive and high-grade, with the tendency to recur or to metastasize. MPNSTs can occur sporadically or in patients with NF1. They occur either de novo or from a preexisting neurofibroma or rarely from a schwannoma.
Etiology
The etiology is unknown. Identified gene alterations include loss of the NF1 (17q11.2) and TP53 tumor suppressor gene (17p13.1). About 10% of tumors are associated with prior therapeutic or environmental radiation exposure.
Diagnostic methods
Histopathological examination is needed for definitive diagnosis. Biopsy usually reveals MPNST to be an infiltrative neoplasm with a varied range of cell morphologies (spindle, rounded or fusiform cells), with cellular fascicles which alternate with myxoid regions (marbled pattern). Diagnosis may be challenging because there are no specific immunohistochemical or molecular markers. Radiological imaging is used to determine the site and extension of the tumor.
Differential diagnosis
Other malignant neoplasms to include in the differential diagnosis include synovial sarcoma, fibrosarcoma, undifferentiated pleomorphic sarcoma, angiosarcoma (see these terms), melanoma, and myoepithelial tumors.
Management and treatment
Total surgical resection is the mainstay of treatment. If removal is not possible, excision combined with high-dose radiation therapy may be used. Local Radiotherapy may be beneficial, but appears to have little effect on long-term survival. Chemotherapy is generally not effective.
Prognosis
Prognosis is generally poor and depends on the size of the tumor and success of treatment. A less favorable prognosis is associated with large tumors, NF1-associated cases, and truncal localization. The recurrence rate is reported to be as high as 40% and approximately two thirds of cases metastasize (lungs and bone). Five-year survival rate is reported to be 26% to 60%, and 10-year survival to be around 45%.

                            Last update:
                            August 2014

                            - Expert reviewer(s):
                            Dr Khin THWAY


Malignant peritoneal mesothelioma is a primary peritoneal malignancy occurring in the lining cells (mesothelium) of the peritoneal cavity.

Summary:
Epidemiology
Peritoneal mesothelioma accounts for 10 to 30% of all malignant mesotheliomas. The annual incidence is approximately 1/500,000 in France but reaches 1/200,000 in some parts of Europe (Italy). Men are predominantly affected.
Clinical description
The tumors are usually diagnosed in late adulthood (median age: 55 years). Typical presenting features are abdominal distention, abdominal pain, presence of an abdominal mass, impaired general state, weight loss, and ascites. Dyspnea, coagulation disorders, edema of the lower limbs and intestinal occlusion may be observed.
Etiology
The relationship between peritoneal mesothelioma and asbestos exposure is unclear, especially in women, and has not been established unlike in malignant pleural mesothelioma. Other causes have been reported such as exposure to erionite, viral infection and vaccine products and/or genetic factors.
Diagnostic methods
Diagnosis is based on imaging techniques, such as ultrasound and chest-abdominal-pelvic computed tomography (CAP-CT). Diagnosis is confirmed histologically on tissue biopsy and by relevant immunostaining results (positive for calretinin and negative for carcinoembryonic antigen (CEA)), and should be performed by two experts.
Differential diagnosis
Differential diagnosis includes peritoneal carcinomatosis secondary to colorectal or gastric cancer and primary peritoneal carcinoma (see this term).
Management and treatment
Treatment strategies require a multidisciplinary approach and must be discussed by a panel of physicians in a specialized center. There are currently no validated recommendations on clinical management and no cytotoxic agents have been granted a European Marketing Authorization (MA) in this indication. Currently proposed treatment with curative intent involves a combination of cytoreductive surgery (visceral resections and peritonectomy procedures) with hyperthermic intraperitoneal chemotherapy (HIPEC) (off-label use) in specific patients (young, good general status, low tumor volume). Systemic chemotherapy (off-label use) is sometimes used in palliative treatment.
Prognosis
With palliative treatment (systemic chemotherapy), median survival does not reach 1 to 2 years. Following cytoreductive surgery and HIPEC, median survival of more than 50 months, and 5-year survival of more than 50% may be obtained.

                            Last update:
                            March 2011

                            - Expert reviewer(s):
                            Pr Olivier GLEHEN


Malignant Sertoli-Leydig cell tumor of the ovary

A rare malignant sex cord stromal tumor of ovary occuring typically in young women and characterized by manifestations of androgen excess (hirsutism, hair loss, amenorrhea, or oligomenorrhea), when functional.


Malignant sex cord stromal tumor of ovary

Malignant sex cord stromal tumor (SCST) of ovary is a rare ovarian cancer (see this term) arising from granulosa, theca, sertoli and leydig cells or stromal fibroblasts, occurring at any age and presenting with abdominal or pelvic mass, and characterized (with the exception of fibroma) by the production of sex steroids resulting in manifestations of hormone excess, with a relatively favorable prognosis.

Summary:
Epidemiology
Age related incidence rate was found to be 1 per 500,000 women. Sex cord stromal tumors constitute about 5% of ovarian malignancies.
Clinical description
Malignant SCST of ovary may occur at any age but usually occurs in child bearing or post menopausal age groups, presenting with manifestations of mass effect (abdominal pain or distention, gastrointestinal symptoms, or abdominal mass) and/or signs of sex hormone production (isosexual precocity including breast swelling and vaginal bleeding, primary or secondary amenorrhea, and/or virilization). Malignant SCST of ovary comprises the following 4 histological forms: gynandroblastoma; malignant granulosa cell tumor of ovary; malignant Sertoli-Leydig cell tumor of ovary; and malignant steroid cell tumor of ovary, not otherwise specified (see these terms).
Etiology
Mutations in the DICER1 (14q32.13) gene have been found to be a susceptibility factor for SCST, particularly in malignant Sertoli-Leydig cell tumor of ovary.
Diagnostic methods
Diagnosis is based on clinical features, particularly hormonal manifestations, and is supported by imaging (ultrasonogram, computed tomography) and tumor markers. Malignant granulosa cell tumor of ovary produces inhibin A and B which is helpful in diagnosis and follow-up. A FOXL2 mutation (3q23) has been found in most malignant granulosa cell tumors of the ovary, in adults. Chromosomal abnormalities have been recently detected among granulosa cell tumors and they include trisomy 12, monosomy 22 and chromosome 6 deletion. Diagnosis is confirmed by histological examination.
Differential diagnosis
Differential diagnoses include the more common malignant ovarian germ cell tumor of ovary, small cell carcinoma of the ovary (see this term) and ovarian metastasis of non-gonadal tumors. Malignant SCST of ovary is also found in association with enchondromatosis, Peutz Jeghers syndrome (see these terms) and Maffuci syndrome.
Management and treatment
Surgery is performed for staging, histological confirmation and debulking. Total abdominal hysterectomy and bilateral salphingo-oopherectomy is often the initial management. Fertility sparing surgery is offered to patients with localized disease. In the absence of significant infiltration, preservation of the uterus along with the contralateral tube and ovary is attempted in children. Adjuvant chemotherapy is given to patients with advanced tumors.
Prognosis
Hormonal symptoms lead to earlier diagnosis and hence a better prognosis in many malignant SCST tumors of ovary. Initial stage at diagnosis is the main prognostic factor. Histological type, presence of atypia and mitotic rate are other important prognostic factors. Stage, tumor size and presence of residual tumor after surgery influence the risk of recurrence

                            Last update:
                            October 2014

                            - Expert reviewer(s):
                            Pr Mojgan DEVOUASSOUX  - Pr Isabelle RAY-COQUARD


A rare ovarian germ cell tumor characterized by a unilateral large adnexal mass containing variable amounts of immature embryonal-type tissues (mostly in the form of neuroectodermal tubules and rosettes, sometimes with a component of cellular mitotically active glia), admixed with ectodermal and endodermal elements with varying degrees of maturation. Patients typically present in their first three decades of life with signs and symptoms related to mass effect. The tumor is often associated with the occurrence of innumerable miliary nodules of mature glia in the peritoneum (gliomatosis peritonei) and abdominal lymph nodes.


Malignant triton tumor (MTT) is a rare aggressive subtype of malignant peripheral nerve sheath tumor (MPNST; see this term) characterized histopathologically by focal rhabdomyoblastic differentiation.

Summary:
Epidemiology
Incidence of malignant triton tumors is not known. MTT accounts for about 5% of all MPNSTs. There appears to be an equal sex distribution.
Clinical description
Most cases are reported in adults (mean age of about 30 years) but patients of all ages have been described. It is estimated that between 40% and 70% of cases occur in patients with neurofibromatosis type 1 (see this term), with an earlier age of onset and predominantly in male subjects. The remaining cases are sporadic and occur at a later age. MTT generally arises from a peripheral nerve in the head, neck, extremities or trunk. Rare localizations include the brain, buttock, viscera, mediastinum and retroperitoneum. Exceedingly rare intracranial MTT, not associated with a cranial nerve, has been reported. MTT is defined histologically as a malignant peripheral nerve sheath tumor with additional rhabdomyoblastic differentiation. Prognosis is generally very poor since MTT is aggressive, with a poorer prognosis than classical MPNST, and is often difficult to completely resect. Local recurrence and distant metastases are common. 5-year survival for MTT is reported to be about 10-14%.
Etiology
The pathogenesis of MTTs has not been elucidated.

                            Last update:
                            August 2014

                            - Expert reviewer(s):
                            Dr Khin THWAY


Malonic aciduria is a metabolic disorder caused by deficiency of malonyl-CoA decarboxylase (MCD).

Summary:
Epidemiology
It is a very rare disorder that has been described in less than 20 patients.
Clinical description
This condition usually presents in early childhood and the manifestations are variable. The majority of patients are developmentally delayed with other features that include hypotonia, seizures, hypoglycaemia, metabolic acidosis, cardiomyopathy and diarrhoea.
Etiology
The disease is caused by mutations in the malonyl-CoA decarboxylase gene (MLYCD, chromosome 16q24) and is inherited as an autosomal recessive trait. The MCD enzyme is involved in the degradation of malonyl-CoA and it appears that inhibition of fatty acid synthesis as a result of malonyl-CoA accumulation is responsible for at least some of the clinical manifestations of the disorder.
Diagnostic methods
The diagnosis of malonic aciduria can be made by detecting elevated levels of organic acids (in particular malonic and methylmalonic acid) in the urine and high levels of malonylcarnitine in the blood. The diagnosis is confirmed by demonstrating reduced enzyme activity in cultured skin fibroblasts. Identification of the MLYCD gene mutation may also be useful for diagnosis and for genetic counselling.
Antenatal diagnosis
Screening of newborns may be possible through detection of elevated blood levels of malonylcarnitine using electrospray ionisation tandem mass spectrometry (ESI-MS/MS). Prenatal screening is theoretically possible through enzyme or DNA analysis of amniocytes or chorionic villus samples.
Management and treatment
The principle treatment is dietary, with patients being recommended to follow a low fat/high carbohydrate diet. Carnitine supplements may also be recommended.
Prognosis
The prognosis for patients is variable but the disease can be lethal in the neonatal period.

                            Last update:
                            December 2006

                            - Expert reviewer(s):
                            Pr Pascale DE LONLAY


A rare coronary artery congenital malformation characterized by displacement of one of the coronary arteries, originating closer to the aortic root or to the commissural area. The anomaly is considered to be asymptomatic, however, it may impose surgical difficulties during aortic root surgery.


MALT (mucosa-associated lymphoid tissue) lymphoma is a rare form of malignant non-Hodgkin lymphoma (see this term) that affects B cells and grows at the expense of lymphoid tissue associated with mucous membranes, but also occurs, more rarely, in lymph nodes.

Summary:
Epidemiology
It accounts for about 5% of non-Hodgkin lymphoma diagnosed annually. Annual incidence is estimated at about 1/313,000.
Clinical description
The disease mainly affects adults over 60 years of age (median age 65 years) with a slight female predominance. It is very rare in children. MALT lymphoma can develop in the gastrointestinal tract (especially in the stomach), lungs and glands (lacrimal, thyroid and breast). The main symptoms are nonspecific and include fatigue, fever, nausea, constipation, weight loss and anemia. Other symptoms depend on the affected organs: abdominal pain in cases with gastric involvement, recurrent respiratory infections in cases with pulmonary involvement and visual impairment in cases with lacrimal gland involvement. In general, patients do not have lymphadenopathy.
Etiology
In most cases, MALT lymphoma is secondary to autoimmune disease or chronic infection. There is a well-established link between chronic Helicobacter pylori infection and gastric MALT lymphoma. In 40% of cases of gastric lymphoma associated with H. pylori infection and in 53% of cases of MALT lymphoma not associated with H. pylori infection, MALT lymphoma is associated with a translocation t(11;18)(q21;q21) leading to the fusion of two genes, BIRC3 and MALT1, implicated in apoptosis regulation.
Diagnostic methods
Diagnosis is based on histology of the lesion, as in all lymphomas, a complete blood count and biochemical analysis. Endoscopic examination is required for gastrointestinal or pulmonary lymphoma. MRI and CT scanning are required to determine the stage of the disease. Bone marrow biopsy is also performed.
Differential diagnosis
Differential diagnoses include B cell lymphomas, diffuse large B cell lymphomas, all other non-Hodgkin lymphomas (see these terms), and infection with H. pylori.
Management and treatment
In cases with localized gastric involvement that are due to H. pylori, antibiotic therapy often results in regression of the lymphoma. In other cases, chemotherapy (chlorambucil, cyclophosphamide, or fludarabine) is required. Radiotherapy may be considered in cases of conjunctival lymphomas and in recurrent cases of localized forms, particularly gastric forms. Conjunctival MALT lymphoma is treated with interferon alpha-2a.
Prognosis
These lymphomas evolve slowly. When the lymphoma is isolated, the 10yr-survival rate after treatment is around 75%.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Vincent RIBRAG


Mammary-digital-nail syndrome is a syndromic limb malformation characterized by congenital onychodystrophy/anonychia, brachydactyly of the fifth finger, digitalization of the thumbs, with absence or hypoplasia of the distal phalanges of the hands and feet in association with juvenile hypertrophy of the breast with gigantomastia in peripubertal females.


MAN1B1-CDG is a form of congenital disorders of N-linked glycosylation characterized by intellectual disability, delayed motor development, hypotonia and truncal obesity. Additional features include slight facial dysmorphism (hypertelorism, downslanting palpebral fissures, large, low-set ears, hypoplastic nasolabial fold, thin upper lip), hypermobility of the joints and skin laxity. The disease is caused by mutations in the gene MAN1B1 (9q34.3).


Mandibular arteriovenous malformation is a rare vascular anomaly characterized by an abnormal connection of the arterial and venous vasculature, without capillary connections, in the mandibular area, commonly presenting with minor gingival bleeding, dental loosening, lower lip numbness, facial deformity and malocclusion. This usually high-flow vascular malformation may also present with potentially life-threatening, spontaneous, or tooth extraction-induced, hemorrhagic shock.


Mandibular hypoplasia-deafness-progeroid features-lipodystrophy syndrome

A rare, genetic, premature aging disease characterized by sensorineural deafness, generalized lack of subcutaneous fatty tissue (although with increased truncal deposition) noted from childhood, scleroderma, and facial dysmorphism which includes prominent eyes, a beaked nose, small mouth, crowded teeth and mandibular hypoplasia. Other associated features include growth delay, joint contractures, telangiectasia, hypogonadism (with lack of breast development in females), cryptorchidism, skeletal muscle atrophy, hypertriglyceridemia and diabetes mellitus/insulin resistance.


Mandibuloacral dysplasia (MAD) is a rare genetic bone disorder characterized by growth delay, postnatal development of craniofacial anomalies including mandibular hypoplasia, progressive acral osteolysis, mottled or patchy pigmentation, skin atrophy, and partial or generalized lipodystrophy.


Mandibulofacial dysostosis with alopecia

A rare mandibulofacial dysostosis characterized by the association with scalp alopecia and sparse eyebrows and eyelashes. Craniofacial dysmorphic features include zygomatic and mandibular dysplasia or hypoplasia, cleft palate, micrognathia, dental anomalies, auricular dysmorphism, and eyelid anomalies, among others. Patients may experience limited jaw mobility, glossoptosis, upper airway obstruction, and conductive hearing loss.


Mandibulofacial dysostosis-macroblepharon-macrostomia syndrome is a rare developmental defect during embryogenesis disorder characterized by macroblepharon, ectropion, and facial dysmorphism which includes severe hypertelorism, downslanting palpebral fissures, posteriorly rotated ears, broad nasal bridge, long and smooth philtrum, and macrostomia with thin upper lip vermilion border. Other features may include large fontanelles, prominent metopic ridge, thick eyebrows, mild synophrys, increased density of upper eyelashes, anterverted nares, abnormal dentition and capillary hemangioma.


A rare genetic, multiple congenital malformation syndrome characterized by malar and mandibular hypoplasia, microcephaly, ear malformations with associated conductive hearing loss, distinctive facial dysmorphism (with significantly overlap to Treacher Collins syndrome), developmental delay, and intellectual disability.

Summary:
Epidemiology
More than 100 cases have been reported to date in various ethnic groups.
Clinical description
Mandibulofacial dysostosis-microcephaly syndrome (MFDM) has a wide range of manifestations. Affected patients have malar and mandibular hypoplasia, sometimes with upper airway compromise at birth. Congenital or postnatal-onset microcephaly is found in 90 % of patients (rarely associated with epilepsy). Microcephaly is congenital in two thirds of patients and secondary (postnatal) in about one third. Patients also have preauricular skin tags, microtia or malformations of the pinna, auditory canal, and/or the middle ear (ossicles and semi-circular canals) causing hearing loss (HL) in more than 70 % of cases. HL is generally conductive (about 80 % of patients) and occasionally sensorineural or mixed. Esophageal atresia or tracheo-esophageal fistula is also found occasionally. MFDM also includes a distinctive facial appearance with prominent metopic ridge, up- or down-slanting palpebral fissures, prominent glabella, broad nasal bridge, bulbous nasal tip, and everted lower lip. Associated craniofacial malformations may include cleft palate, choanal atresia and facial asymmetry. Short stature is found in about 30 % of patients. Mild to severe developmental delay is very common and includes delayed walking and speech. Almost all affected individuals have intellectual disability that is mostly mild or moderate, and sometimes severe. Other major extracranial malformations may also be found and include congenital heart malformations (e.g. atrial and ventricular septal defects, tetralogy of Fallot, patent arterial duct, and aortic arch defects), cryptorchidism, clinodactyly, and thumb abnormalities.
Etiology
MFDM is caused by heterozygous, mostly de novo, mutations in the EFTUD2 gene (17q21.31), encoding 116 kDa U5 small nuclear ribonucleoprotein component. A range of deletions and rearrangements, as well as pathogenic missense, nonsense, splice, and frameshift mutations, have been identified.
Diagnostic methods
The diagnosis can be challenging but is generally based on the constellation of clinical manifestations and confirmed by molecular genetic testing revealing a mutation in the EFTUD2 gene.
Differential diagnosis
The differential diagnosis includes Treacher Collins, Nager and CHARGE syndromes and oculo-auriculo-vertebral spectrum.
Antenatal diagnosis
Prenatal testing for at-risk pregnancies is possible when the mutation has been identified in the family.
Genetic counseling
MFDM follows an autosomal dominant pattern of inheritance, although most mutations occur de novo. Genetic counseling should be offered to affected individuals, informing them of the 50% chance of offspring inheriting the disease-causing mutation and therefore being affected with the syndrome. The syndrome displays high penetrance but variable expressivity. Gonadal mosaicism has been reported.
Management and treatment
Intubation and/or tracheostomy may be required in some affected infants at birth. Craniofacial manifestations should be treated on a case-by-case basis and managed by a multidisciplinary team. Occupational, physical, and speech therapies should be provided, along with standard measures for hearing loss and possible cardiac defects.
Prognosis
The prognosis in MFDM is generally good. Life expectancy is normal in the absence of severe congenital anomalies. Feeding is a significant problem during infancy. The functional repercussions of the syndrome are highly variable with some patients being intellectually normal, some living semi-independently and employed, and some being nonverbal and in need of significant assistance.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Pr Dagmar WIECZOREK | ITHACA*

                                * European Reference Network


A rare disorder due to toxic effects characterized by a progressive, permanent affliction of the extrapyramidal system with the globus pallidus and striatum as primary targets of neurotoxic effects. Symptoms include headache, insomnia, memory loss, emotional instability, hyperreflexia, dystonia, tremor, speech disturbances, and gait abnormalities. Individual factors like age, gender, genetics, and pre-existing medical conditions appear to have a profound impact on manganese toxicity.


A form of filariasis, distributed throughout sub-Saharan Africa as well as in some locations of Central and South America and the Caribbean, caused by the parasitic worms Mansonella perstans and Mansonella ozzardi. The disease is often asymptomatic but may also cause fever, vertigo, myalgias, arthralgias and a sensation of coldness in the legs. Additional features include neuropsychiatric symptoms, skin rash, pruritus, nodules containing adult worms (in the conjunctiva or eyelids), lymphadenopathy, recurrent lymphedema in the limbs and face (resembling the Calabar swellings of loasis), severe abdominal pain and endocrine disturbances.


Mantle cell lymphoma is a rare form of malignant non-Hodgkin lymphoma (see this term) affecting B lymphocytes in the lymph nodes in a region called the ``mantle zone''.

Summary:
Epidemiology
It accounts for 2-10% of lymphomas. Prevalence is estimated at about 1/25,000.
Clinical description
Mantle cell lymphoma affects middle-aged adults, especially around 65 years (range 35-85 years) with males affected more than females (ratio M/F: 4:1). At diagnosis, most patients present with a disseminated form of the disease. Mantle cell lymphoma is often associated with generalized adenopathy (90% of cases), gastrointestinal disorders (60% of cases) and bone marrow involvement (55-80% of cases). Fever and impaired general condition (fatigue, loss of appetite and weight loss) may occur.
Etiology
Mantle cell lymphoma is caused by a chromosomal translocation t(11;14) (q13;q32), which juxtaposes the CCND1 gene to the gene encoding for heavy chain immunoglobulins, leading to abnormally high expression of cyclin D1, a cell cycle regulator, in the nucleus of lymphoma cells.
Diagnostic methods
Diagnosis is based on lymph node biopsy revealing the presence of tumor cells. Phenotypic immunohistochemical analysis as well as evidence of abnormal expression of cyclin D1 (or the translocation t(11;14) by FISH or conventional cytogenetics) is necessary to confirm the diagnosis. Analysis of the stage of the disease is done with imaging (ultrasound, CT scanning and MRI) as well as bone marrow analysis (biopsy). Endoscopic examination should be used to detect intestinal involvement.
Differential diagnosis
Differential diagnoses include follicular lymphoma (see this term) and other forms of lymphoma.
Management and treatment
Treatment of mantel cell lymphoma includes intensive chemotherapy combined with monoclonal antibodies. In younger patients, autologous stem cell transplantation is currently suggested. Torisel (chemotherapy) is a product that has received European market authorization as an orphan drug for refractory or relapsing disease. Rare localized forms of the disease may benefit from radiotherapy.
Prognosis
Few patients (30%) have a complete response to current treatments. The median overall survival time reported in the literature is 3-5 years.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Dr Vincent RIBRAG


A rare inherited disorder of branched-chain amino acid metabolism classically characterized by poor feeding, lethargy, vomiting and a maple syrup odor in the cerumen (and later in urine) noted soon after birth, followed by progressive encephalopathy and central respiratory failure if untreated. The four overlapping phenotypic subtypes are: classic, intermediate, intermittent and thiamine-responsive MSUD.

Summary:
Epidemiology
The estimated prevalence is around 1/150,000 live births, from published and unpublished newborn screening data.
Clinical description
Classic MSUD presents in the first days of life with poor feeding and drowsiness followed by a worsening encephalopathy with lethargy, intermittent apnea, stereotypic movements ("fencing" and ''bicycling") and opisthotonus. Coma and central respiratory failure supervene 7 to 10 days after birth. The only abnormality in biochemistry is ketosis. Intermediate MSUD clinically resembles classic MSUD but it can have a later onset and less severe symptoms. Intermittent MSUD patients are asymptomatic at birth but may suffer episodes of acute decompensation or develop neurological symptoms and developmental delay during childhood. Thiamin-responsive MSUD is clinically similar to intermediate MSUD with thiamin therapy improving dietary leucine tolerance.
Etiology
MSUD is due to mutations in the genes encoding subunits E1a, E1b, and E2 of the branched chain 2-ketoacid dehydrogenase (BCKAD) complex, involved in the second enzymatic step in the degradation of the branched chain amino acids (BCAAs): leucine, isoleucine and valine. BCKAD has four subunits: E1a, E1b, E2, and E3, which are encoded by the genes BCKDHA (19q13.1-q13.2), BCKDHB (6q14.1), DBT (1p31) and DLD (7q31-q32) respectively. Mutations in these genes lead to the accumulation of BCAAs (especially leucine) and their branched-chain alpha-ketoacids. Mutations in the E3 subunit gene (DLD) are not associated with MSUD but lead to pyruvate dehydrogenase E3 deficiency (see this term). A mutation in the PPM1K gene (4q22.1) has been reported in a single case of mild intermediate MSUD.
Genetic counseling
MSUD follows an autosomal recessive inheritance pattern and genetic counseling is possible.

                            Last update:
                            April 2014

                            - Expert reviewer(s):
                            Dr Bridget WILCKEN


Marburg acute multiple sclerosis is a rare variant of multiple sclerosis characterized by a rapidly progressive, aggressive form of multiple sclerosis with numerous large multifocal demyelinating lesions in deep white matter on cerebral MRI that usually leads to severe disability or death within weeks to months without remission. A relapsing form of multiple sclerosis is observed in surviving patients.


Marburg hemorrhagic fever (MHF), caused by Marburg virus, is a severe viral hemorrhagic disease characterized by initial fever and malaise followed by gastrointestinal symptoms, bleeding, shock, and multi-organ system failure.

Summary:
Epidemiology
MHF is endemic to Central Africa and is generally recognized in sporadic small outbreaks (<50 cases), although one large (>250 cases) nosocomial outbreak occurred in Angola in 2004-2005. Less than 500 cases have been reported to date.
Clinical description
After an incubation period of about 8 days (range 3-21 days), patients typically present with the abrupt onset of non-specific signs and symptoms including fever, malaise, headache, chest pain and myalgia/arthralgia, followed rapidly by gastrointestinal manifestations (vomiting, diarrhea, abdominal pain) and, in some cases, a maculopapular skin rash. Severe cases develop bleeding (sub-conjunctival hemorrhage, epistaxis, bleeding from the mouth and rectum, oozing from venipuncture sites), neurologic involvement (disorientation, convulsions, coma), shock and multi-organ system failure. Mild-to-moderate leukopenia and thrombocytopenia are often present and disseminated intravascular coagulation (DIC) commonly develops, best indicated by the presence of D-dimers.
Etiology
Over 25 different viruses cause viral hemorrhagic fever. Marburg virus is a member of the virus family Filoviridae, along with Ebola virus. Numerous strains have been identified, putatively with different degrees of lethality. Accumulating evidence implicates fruit bats as the Marburg virus reservoir, with primary human infection presumably from unwitting contact with bat excreta or saliva. Entry into caves and mines where fruit bats roost is a risk factor. Infection has also rarely occurred through contact with tissues of wild monkeys, presumably also infected through bat exposure. Human-to-human transmission occurs through direct contact with blood or bodily fluids of infected persons.
Diagnostic methods
Common diagnostic modalities include cell culture (restricted to biosafety level-4 laboratories), serologic testing by enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody (IFA), and reverse transcription polymerase chain reaction (RT-PCR). Because no commercial assays are presently available, these tests are typically performed only in a few specialized laboratories.
Differential diagnosis
MHF is difficult to distinguish from a host of other febrile illnesses, at least early in the course of disease. Other viral hemorrhagic fevers need to be excluded, especially Ebola hemorrhagic fever, as well as malaria, typhoid fever, leptospirosis, rickettsial infection, plague (see these terms), bacterial dysenteryand meningococcemia.
Management and treatment
Patients should be isolated and viral hemorrhagic fever precautions (face shields, surgical masks, double gloves, surgical gowns and aprons) should be used to prevent nosocomial transmission. As there is presently no antiviral drug available for MHF, treatment is supportive, following the guidelines for treatment of severe septicemia. Persons who have unprotected contact with someone with MHF should be monitored.
Prognosis
Case-fatality rates are typically over 80%, although it was only 22% in one outbreak in Europe stemming from imported monkeys. Shock, bleeding, neurological manifestations, high viremia, aspartate aminotransferase (AST) > 150 IU/L, and pregnancy confer a poor prognosis. Convalescence may last up to a year but survivors usually have no lasting sequelae.

                            Last update:
                            December 2012

                            - Expert reviewer(s):
                            Dr Daniel BAUSCH  -  Andrew BENNETT


A rare neurologic disease most prominently characterized by progressive demyelination and necrosis of the corpus callosum. It is in most cases associated with chronic alcoholism and malnutrition. Speed of onset and clinical presentation are very variable with a range of possible symptoms, including dementia, seizures, gait abnormalities, dysarthria, aphasia, athetosis, as well as stupor and coma.


A rare ophthalmic disorder characterized by congenital ptosis associated with pterygoid-levator synkinesis (also called jaw-winking).

Summary:
Epidemiology
The syndrome is responsible for 2-6% of congenital ptoses.
Clinical description
Severity of the ptosis and jaw-winking is highly variable. The ptosis is corrected by the opening of the mouth or lateral movements of the lower jaw. The synkinesis can be linked with Duane retraction syndrome and other various strabismus patterns. Amblyopia is also a frequent association. Anisometropia is occasionally reported.
Etiology
The etiology is still unclear and two main hypotheses have been proposed. The first hypothesis suggests the presence of an aberrant connection between the mandibular division of the trigeminal nerve and the oculomotor nerve, possibly provoked in utero. An ephaptic mechanism has been postulated: it would be a persistent phenomenon, determining a stereotyped, well reproducible, and stable movement. The second hypothesis proposes the unmasking of a primitive pathway, due to a neural misdirection in the brainstem, and an electric stimulus of the ipsilateral pterygoid nerve is known to determine a retraction of the upper eyelid in 20% of normal subjects.
Diagnostic methods
Diagnosis is made based on clinical presentation.
Differential diagnosis
Inverse Marcus Gunn phenomenon and Marin-Amat syndrome present as eyelid drooping on jaw opening. The first is a congenital condition in which the eyelid levator muscle is inhibited, while Marin-Amat syndrome occurs after facial paralysis and represents patients with a connection between the orbicularis oculi and not with levator muscle.
Genetic counseling
Marcus-Gunn syndrome is mainly sporadic, although familial cases with an irregular autosomal dominant inheritance have been reported.
Management and treatment
If only mild ptosis and mild jaw winking are present, no intervention is recommended. A moderate ptosis can be corrected with levator muscle advancement, but results in worsening of the aberrant movement. Candidates for this surgery are young adults with moderate ptosis that have learned how to minimize abnormal movements and can control mild synkinesis. Levator resection appears to be inadequate to correct severe ptosis (with high rates of ptosis recurrence) despite a good levator function and should not be performed. If there is severe ptosis and severe jaw-winking, levator excision associated with frontalis suspension or frontalis flap is the treatment of choice. Bilateral treatment yields more satisfactory cosmetic results. Unilateral treatment should be limited to patients with associated anomalies of the affected eye whom are reluctant to accept bilateral procedures.
Prognosis
Prognosis is usually good if an adequate treatment is planned. Occasionally, ptosis seems to improve with time, although there is no evidence that this really happens. A possibility is that, as time passes, the patient recognizes which movements are responsible for the synkinesis and learns how to control it.

                            Last update:
                            May 2024

                            - Expert reviewer(s):
                            Pr Francesco QUARANTA LEONI


A rare developmental defect during embryogenesis characterized by multiple joint contractures (arthrogryposis), a mask-like face with blepharophimosis, micrognathia, high-arched or cleft palate, low-set ears, decreased muscular bulk, kyphoscoliosis and arachnodactyly.

Summary:
Epidemiology
The prevalence is still unknown but to date between 30-50 cases have been described in the world literature.
Clinical description
The typical age of onset lies in the neonatal or infancy period and clinically Marden-Walker syndrome (MWS) is characterized by postnatal growth retardation and multiple joint contractures associated with restricted mobility of the joints. Facial dysmorphism includes a mask-like and asymmetric face along with blepharophimosis, low-set ears, high arched or cleft palate, micrognathia, short neck, and decreased muscular bulk. Other common features are kyphoscoliosis, pectus excavatum or carinatum, limited motor function in the shoulder, elbow and wrist joints and arachnodactyly and camptodactyly. Congenital talipes equinovarus, absent deep tendon reflexes and limbs with hypoplastic muscles are generally observed. Hypospadias with bilateral inguinal hernia may be observed. Minor cerebral malformations, cardiovascular or renal anomalies and intellectual deficit have also been described.
Etiology
The underlying pathological mechanism of MWS has not yet been clearly established, but it is assumed that it is a developmental disorder of the central nervous system. In two patients, pathological variants in PIEZO2 (18p11.22-p11.21) have been identified.
Diagnostic methods
The diagnosis of MWS is based on the minimal criteria (postnatal growth retardation, severe developmental retardation, multiple joint contractures, a 'mask-like' face with blepharophimosis, micrognathia, high-arched or cleft palate, low-set ears and (kyphoscoliosis). Magnetic resonance imaging (MRI) of the head and an echocardiography may reveal cerebral malformations and cardiovascular abnormalities respectively. Kyphosis is diagnosed using X-ray imaging.
Differential diagnosis
Differential diagnosis includes trisomy 13 and 18, Smith-Lemli-Opitz syndrome, Zellweger syndrome, spinal cord injury, amyoplasia congenita, infantile spinal muscular atrophy, Moebius syndrome, congenital hypomyelinating neuropathy, blepharophimosis-intellectual deficit syndromes, Van den Ende-Gupta syndrome, Freeman-Sheldon syndrome, Schwartz-Jampel syndrome (same clinical presentation but MWS lacks myotonia), infantile neuronal degeneration and focal infantile spinal muscular atrophy.
Antenatal diagnosis
Prenatal diagnosis of MWS in a fetus with a previously affected sibling may be achieved by finding intrauterine growth retardation and renal cystic disease. Moreover, arthrogryposis can be viewed antenatally on ultrasound from the second trimester onwards. Ultrasonographic examination may also indicate an oligohydramnios. The finding of the latter should encourage a more detailed ultrasonographic examination, as ankylosed joints can be detected in utero.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child.
Management and treatment
The treatment of MWS is symptomatic with multidisciplinary management. Conservative orthopedic treatment and physiotherapy are indicated.
Prognosis
Intellectual deficit observed in MWS remains severe but contracture is not progressive and decreases with advancing age and physiotherapy. The long term prognosis is limited in many patients due to complications e.g. skeletal deformities, lung infections and gastrointestinal problems.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Dr Gnanavelu INJETI  - Dr Amar TAKSANDE


Marfan syndrome is a systemic disease of connective tissue characterized by a variable combination of cardiovascular, musculo-skeletal, ophthalmic and pulmonary manifestations.

Summary:
Epidemiology
The prevalence is estimated at 1/5,000 and there is no difference between sexes.
Clinical description
Symptoms can appear at any age and vary greatly between individuals even within the same family. Cardiovascular involvement is characterized by 1) progressive dilation of the aorta accompanied by an increased risk of aortic dissection, which affects prognosis; the aortic dilation can result in a leaky aortic valve; and 2) mitral insufficiency, which can be complicated by arythmias, endocarditis or cardiac insufficiency. Skeletal involvement is often the first sign of the disease and can include dolichostenomelia (excessive length of extremities), large size, arachnodactyly, joint hypermobility, scoliotic deformations, acetabulum protrusion, thoracic deformity (pectus carinatum or pectus excavatum), dolichocephaly of the anteroposterior axis, micrognathism or malar hypoplasia. Ophthalmic involvement results in axile myopia, which can lead to retinal detachment and lens displacement (ectopia or luxation are characteristic signs). Ocular complications, particularly lens ectopia, can lead to blindness. Cutaneous signs (vergetures), a risk of pneumothorax and dural ectasia can also occur.
Etiology
In the vast majority of cases, Marfan syndrome is caused by mutations of the FBN1 gene (15q21), which codes for fibrilline-1, a protein essential for connective tissues. Frontier forms have been identified that are secondary to mutations in the TGFBR2 gene located on chromosome 3, which codes for a TGF-beta receptor.
Diagnostic methods
Diagnosis is based on clinical signs and family history. However, as a result of the widely variable clinical picture, the diagnosis can be difficult to establish. International diagnostic criteria (Ghent criteria) based on major and/or minor clinical signs have been established to aid diagnosis.
Differential diagnosis
Differential diagnoses include MASS syndrome, Shprintzen-Goldberg syndrome, mitral valve prolapse, Ehlers-Danlos syndrome and other diseases that present with aortic aneurysm such as Loeys-Dietz syndrome (see these terms).
Antenatal diagnosis
Prenatal genetic diagnosis is possible for families in which the causal mutation has been identified.
Genetic counseling
Transmission is autosomal dominant. An affected individual has a 50% risk of transmitting the mutation responsible for the disease. Some sporadic cases have been reported.
Management and treatment
Management should be multidisciplinary with consultations from different specialists including cardiologists, geneticists, rheumatologists, ophthalmologists, pediatricians and radiologists. Management should aim to limit aortic dilation (beta-blockers and a reduction in sport activities) and regularly monitor the aorta (annual echocardiograms) in order to allow the aortic root to be replaced before dissection occurs. Surgery can be offered for skeletal anomalies (vertebral column stabilization in the case of scoliosis or reparation of thoracic deformities) and ocular anomalies (laser treatment or replacement of a dislocated lens). Treatment is otherwise symptomatic.
Prognosis
Prognosis depends on the degree of aortic involvement. With regular follow-up and adequate management, patients now have a life expectancy close to that of the general population. Over the last 30 years that life expectancy has increased by 30 years.

                            Last update:
                            March 2010

                            - Expert reviewer(s):
                            Pr Guillaume JONDEAU


Marfanoid habitus-autosomal recessive intellectual disability syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by intellectual disability, psychomotor retardation, flat face and some features resembling Marfan syndrome, such as tall stature, dolichostenomelia, arm span larger than height, arachnodactyly of hands and feet, little subcutaneous fat, and muscle hypotonia. There have been no further descriptions in the literature since 1984.


Marfanoid habitus-inguinal hernia-advanced bone age syndrome

A rare developmental defect with connective tissue involvement disorder characterized by tall stature, inguinal hernia, facial dysmorphism (including a long, triangular face, prominent forehead, telecanthus, downslanting palpebral fissures, bilateral ptosis, everted lower eyelids, large ears, long nose, full, everted vermilions, narrow and high arched palate, dental crowding), and radiologic evidence of advanced bone age. Additional manifestations include hyperextensible joints, long digits, mild muscle weakness, myopia, and foot deformities (i.e. hallux valgus, talipes equinovarus).


A rare syndromic intestinal malformation characterized by the association of marfanoid features (including marfanoid habitus, severe myopia, retinal detachment, and mitral valve prolapse) with visceral diverticula (inguinal and/or femoral hernia and diverticula of the large and small bowel or urinary bladder). Some patients also had diaphragmatic eventration. There have been no further descriptions in the literature since 1996.


A rare autosomal dominant hair loss disorder characterized by the absence or scarcity of scalp hair, eyebrows, and eyelashes at birth; coarse and wiry hair during childhood; and progressive hair loss beginning around puberty.

Summary:
Epidemiology
Prevalence and incidence are unknown. To date, approximately 30 families and sporadic cases with a molecular diagnosis have been reported in the literature.
Clinical description
Affected individuals of both sexes are typically born with an absence or scarcity of scalp hair, eyelashes, and eyebrows. During early childhood the scalp hair becomes coarse and wiry. Loss of scalp hair begins around puberty in a pattern resembling that of androgenetic alopecia and progresses to almost total alopecia. Body, axillary, and pubic hair is sparse or absent as is beard hair in men and adolescent boys. No other ectodermal abnormalities are observed.
Etiology
The disorder is due to mutations in U2HR, an inhibitory upstream open reading frame of the HR gene located to 8p21.2, causing a gain of function of HR. Worldwide, about 20 different U2HR mutations have been identified in more than 30 affected families and sporadic cases. Recently, a missense mutation in EPS8L3, located on chromosome 1p13.2, was identified in a Chinese family; however, there are currently no other reports of this mutation.
Diagnostic methods
Diagnosis depends on clinical and microscopic examination and can be confirmed by mutational analysis of U2HR. Scanning electron microscopic study of the hair reveals irregular twisting, longitudinal ridging and cuticle peeling. Scalp biopsy shows a marked reduction in the number of follicles with follicular fibrosis. However, the small number of biopsies analyzed makes it difficult to obtain an objective impression.
Differential diagnosis
Differential diagnoses include hypotrichosis simplex, loose anagen syndrome, uncombable hair syndrome, ectodermal dysplasia syndromes, congenital atrichia, androgenetic alopecia and alopecia areata.
Genetic counseling
Transmission is autosomal dominant. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
No curative treatment exists.
Prognosis
Life expectancy is normal but quality of life can be reduced due to the psychological impact related to the hair phenotype.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Pr Regina BETZ


A rare autosomal recessive disorder characterized by cerebellar ataxia, early-onset bilateral cataracts, chronic myopathy; additional features are delayed motor development and variable intellectual disability, hypergonadotrophic hypogonadism and delayed puberty, and short stature.

Summary:
Epidemiology
Prevalence is not known, most likely in the 1-9/1,000,000 range. The estimated worldwide carrier frequency is 1:700, and in Finland it is 1:96. Disease onset occurs in infancy.
Clinical description
Hypotonia is usually present in early infancy, and muscle weakness is noticed during the first decade. Truncal ataxia, dysdiadochokinesia, nystagmus and dysarthria appear later. Cataracts can develop rapidly. Less constant features are skeletal deformities, somatic growth delay, and hypergonadotropic hypogonadism. Developmental milestones are often delayed and cognition varies from normal to severe intellectual disability. Cerebellar atrophy is observed on magnetic resonance imaging in all patients. Serum creatine kinase levels are usually only slightly or moderately elevated. Electromyography shows myopathic features. Electron microscopy of a muscle biopsy typically shows vacuolar myopathy and characteristic perinuclear membrane-like structures.
Etiology
Marinesco-Sjögren syndrome is caused by biallelic pathogenic variants in the SIL1 gene. Most of pathogenic variants are missense, but frameshift, nonsense and splice site variants have also been reported. SIL1 (nucleotide exchange factor SIL1) is present in the endoplasmic reticulum and plays a role as a co-chaperon in protein translocation into the endoplasmic reticulum, protein folding, control of degradation of misfolded proteins and response to cell stress. As a consequence, mutations in SIL1 lead to disturbance in proper folding of proteins and subsequently cell destruction.
Diagnostic methods
Diagnosis is based on typical clinical findings and/or biallelic pathogenic variants in the SIL1 gene. Ophthalmologic examination should be performed to detect cataract. Magnetic resonance imaging allows investigation of cerebellar atrophy particularly involving the vermis. Electron microscopy shows findings specific to Marinesco-Sjögren syndrome in muscle biopsy, while light microscopy does not.
Differential diagnosis
Differential diagnosis includes congenital cataracts-facial dysmorphism-neuropathy syndrome, congenital muscular dystrophy with cataracts and intellectual disability due to INPP5K gene variant, autosomal recessive spastic paraplegia type 46, autosomal recessive cerebellar ataxia with late-onset spasticity, ADan amyloidosis and dysequilibrium syndrome.
Antenatal diagnosis
Preimplantation or prenatal diagnosis are possible where the pathogenic variants have previously been identified in the index case and the parents.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variant). The risk of recurrence of having an affected child is 25% at each pregnancy.
Management and treatment
Treatment is symptomatic. Cataracts often require surgical removal to preserve vision. Hormonal replacement therapy may be needed if hypogonadism is present. Physical and occupational therapy are crucial.
Prognosis
Patients can survive to old age, with varying disability.

                            Last update:
                            December 2023

                            - Expert reviewer(s):
                            Dr Dídac CASAS-ALBA | ITHACA* - Pr Francesc PALAU | ITHACA*

                                * European Reference Network


A malformation syndrome that is characterized by facial dysmorphism, severe hypoplasia of the nasal bones and frontal sinuses, ocular involvement, early-onset hearing loss, skeletal and anhidrotic ectodermal anomalies and short stature with spondyloepiphyseal dysplasia and early-onset osteoarthritis.


A rare genetic multiple congenital anomalies syndrome characterized by abnormal bone maturation with skeletal anomalies, airway obstructions, failure to thrive, developmental delay, moderate to severe intellectual disability and characteristic facial features with macrocephaly, prominent forehead, shallow orbits, proptosis and blue sclerae.

Summary:
Epidemiology
Less than 60 cases have been reported in the literature to date.
Clinical description
Marshall-Smith syndrome was originally considered as an overgrowth condition based on advanced bone maturation. It is characterized by a dysostosis with skeletal anomalies including progressive kyphoscoliosis, postnatal failure to thrive in weight, short stature, and osteopenia with fractures. Wide bullet-shaped phalanges as well as large hands and feet are observed. Neonates and infants usually manifest with feeding difficulties and upper airway obstruction with respiratory distress due to glossoptosis, laryngomalacia and/or choanal stenosis. The majority of patients die in the neonatal period or early infancy from respiratory compromise. Respiratory infections are frequent. Patients surviving infancy also have developmental delay, moderate to severe intellectual disability and behavioral abnormalities such as anxiety and stereotyped movements. Brain MRI may show corpus callosum anomalies, macrogyria, pachygyria, delayed myelination, ventricular dilatation, hydrocephalus and periventricular leukomalacia. Characteristic facial features include high forehead, proptosis, blue sclerae, midface hypoplasia, short nose, depressed nasal bridge, anteverted nostrils and retrognathia. Vision impairment may occur as a result of optic nerve hypoplasia. Hypertrichosis, umbilical hernia, connective tissue, endocrine and cardiovascular anomalies may be associated. In a single case a concomitant Wilms tumor had developed, otherwise an increased risk of neoplasm development is not known.
Etiology
Marshall-Smith syndrome is cause by heterozygous de novo variants in the NFIX (Nuclear Factor I X; 19p13.13) gene. NFIX variants escape nonsense-mediated mRNA decay leading to abnormal proteins with an abnormal C-terminus (dominant-negative mechanism). The NFIX gene acts as the transcription factor in the nuclear factor I family, and is implicated in replication, signal transduction, and transcriptional processes, with, currently not fully elucidated mechanisms.
Diagnostic methods
The syndrome is clinically recognizable. The genetic diagnosis is established by identification of a heterozygous pathogenic variant in the NFIX gene. Most of the variants have been identified in exons 6-10 of the gene.
Differential diagnosis
The differential diagnoses for Marshall-Smith syndrome are Sotos syndrome, Malan overgrowth syndrome, Weaver syndrome, and bone fragility disorders. Radiological findings distinguish them based on skeletal findings.
Antenatal diagnosis
Prenatal diagnosis is possible if the disease-causing variant has been identified in the family. The recent implementation of prenatal whole exome sequencing could lead to molecular diagnostics during pregnancy.
Genetic counseling
Marshall-Smith syndrome is inherited in an autosomal dominant manner. All known pathogenic variants have occurred de novo, and in these cases the risk to sibs of the proband is very low due to a possible germinal mosaicism (<1%).
Management and treatment
Management of Marshall-Smith syndrome required a multidisciplinary approach with appropriate specialists. Patients need symptomatic treatment for airway obstruction, respiratory infections, and feeding difficulties, as well as specific management for bone fragility.
Prognosis
The prognosis is poor and most patients will die in the neonatal period or early infancy due to respiratory compromise. A few cases of prolonged survival have been reported in patients without respiratory complications.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Pr Valérie CORMIER-DAIRE  - Dr Valérie MALAN | ITHACA*

                                * European Reference Network


Martinique crinkled retinal pigment epitheliopathy

A rare, genetic retinal disease characterized by characteristic "dried-out soil" fundus pattern due to diffuse deep white lines in the macula, to the level of the retinal pigment epithelium, which is slightly elevated and rippled. Macular exudation may be associated, and Bruch's membrane may be affected too. Occasionally, peripheral nummular pigmentary changes may be observed, associated with blindness. The lesions enlarge with time, with a preferential macular extension and confluence. Complications may include polypoidal choroidal vasculopathy, choroidal neovascularization or atrophic fibrous macular scarring that can lead to reduced visual acuity over time.


A X-linked, clinical subtype of L1 syndrome, characterized by mild to moderate intellectual disability, delayed development of speech, hypotonia progressing to spasticity or spastic paraplegia, adducted thumbs, and mild to moderate distension of the cerebral ventricles.


A very rare malignant systemic mastocytosis (SM) characterized by a huge infiltration of bone marrow, and often of blood, by abnormal mast cells (MC) which frequently manifests with organ dysfunction (liver, spleen, peritoneum, bones, and marrow).

Summary:
Epidemiology
It is extremely rare (less than 1% of cases of SM).
Clinical description
Mast cell leukemia (MCL) is a hematological disease that may occur at any age and is characterized by a massive infiltration of bone marrow by abnormal mast cells (at least 20% MC on BM smears). In patients suffering from the classical variant of MCL, circulating MC are also found. However, in a substantial number of patients with MCL, the leukemic spread into the peripheral blood is less extensive or is even absent. When MCs comprise less than 10% of all circulating blood leukocytes, the disease is termed aleukemic MCL. In a majority of patients, cutaneous lesions are absent. In most patients with MCL, signs and symptoms of organ damage, so-called C Findings, are present, and qualify the disease as acute MCL (aMCL). Patients with aMCL have a very poor prognosis with a median survival of less than 6 months, due to multiple organ failures caused by massive infiltration by MCs and/or to anaphylactic shock. Presentation is with organ dysfunction related to mast cell invasion (C-findings) and the intense release of mediators resulting in syncope, recurrent flushing, diarrhea, pain and organomegaly. C-findings include bone marrow (BM) dysfunction, palpable hepatomegaly with impairment of liver function, ascites, and/or portal hypertension, skeletal involvement with large osteolytic lesions and/or pathological fractures, palpable splenomegaly with hypersplenism and malabsorption with ascites. However, a subvariant of MCL, termed chronic MCL (cMCL), is defined by at least 20% MCs on BM smears and absence of C-Findings. MC in BM smears of cMCL patients appear more mature than those in BM smears of aMCL patients. Patients with cMCL have longer median survival as compared to those with acute MCL. However, in patients with chronic MCL in whom one or more C-Findings develop, the diagnosis changes from chronic to acute MCL.
Etiology
In the few cases that have been studied, activating mutations of the gene KIT (D816V, D816Y, G820V), chromosome location 4q12, have been found in malignant mast cells, however, various chromosomal anomalies have also been noted.
Diagnostic methods
Diagnosis is based on the histological and cytological analysis of bone marrow samples. Cytological analysis reveals a proportion of bone marrow mast cells over 20%. In most cases of mast cell leukemia, bone marrow mast cells with an atypical appearance, immature with a bi or multi-lobed core or, sometimes, a blast-like morphological appearance. Abnormal mast cells are present in the blood in most cases, with a proportion greater than 10% of circulating white blood cells. Additional tests include measurement of serum tryptase (above 20 ng/mL, with values sometimes exceeding 1,000 ng/mL), searching for mutations of KIT and phenotyping bone marrow mast cells.
Differential diagnosis
Differential diagnoses include all other acute leukemias and rare cases of basophilic leukemia.
Management and treatment
Management includes chemotheraphy, with or without interferon alpha or cladribine. For MCL patients with rapid progression and those who are resistant against 2CdA or midostaurin, poly-chemotherapy (protocols otherwise used for high-risk AML) is usually recommended. In patients who are young and fit and have a suitable donor, stem cell transplantation (SCT) should be considered after successful debulking. The outcome after allogeneic SCT is better for those prepared with ablative conditioning compared with less-intensive (nonmyeloablative) conditioning. In cases with splenomegaly with hypersplenism, splenectomy is indicated. Hydroxyurea is a palliative treatment.
Prognosis
The prognosis in acute MCL is very poor and survival time is several months. In chronic MCL, the clinical course is unpredictable. Some of these patients have an indolent course for several months or even years. Other patients progress to acute MCL within a short time. In most cases reported so far, progression to acute MCL was seen.

                            Last update:
                            May 2020

                            - Expert reviewer(s):
                            Pr Michel AROCK


Mast cell sarcoma is a rare, neoplastic disease characterized by locally destructive sarcoma-like growth of a solitary mass, composed of atypical mast cells, and without systemic involvement. It can affect any organ and the symptoms depend on the location. Cells are medium to large, pleomorphic or epithelioid, with oval, bilobed or multilobulated nuclei, sometimes prominent multinucleated giant cells. The disease closely resembles other neoplasms and may share associated markers, however the tumor is positive for mast cell tryptase.


Maternal hyperthermia-induced birth defects

A rare maternal disease-related embryofetopathy characterized by variable developmental anomalies of the fetus due to teratogenic effect of elevated maternal body temperature (resulting from febrile illness or hot environment exposure). Reported developmental anomalies include neural tube defects (spina bifida, ecephalocele, anencephaly), cardiac defects (transposition of great vessels), urogenital defects (hypospadias), abdominal wall defects, cleft lip/palate, eye defects (cataract, coloboma) or various minor anomalies (e.g., bifid uvula, preauricular pit or tag). Consensus regarding cause-effect relationship has not been reached.


A rare disorder of phenylalanine (Phe) metabolism, an inborn error of amino acid metabolism, characterized by the development of microcephaly, growth retardation, congenital heart disease, facial dysmorphism and intellectual disability in non-phenylketonuric offspring of mothers with excess blood Phe concentrations.

Summary:
Epidemiology
The incidence of maternal phenylketonuria (PKU) in Europe is not known. Increased survival and improved health among females with treated PKU, thanks to neonatal screening, has increased the number of potential pregnancies with a risk of elevated maternal blood Phe.
Clinical description
Hyperphenylalaninemia is classified by blood Phe concentrations of more than 1,200 micromol/L (classic PKU) or less than 600 micromol/L (mild hyperphenylalaninemia), between 600 and 1,200 micromol/L as mild PKU. Maternal phenylketonuria syndrome has been shown to result in intrauterine and postnatal growth retardation with associated low birth weight, microcephaly, and intellectual disability in the offspring. Congenital heart malformation is also found and may include double-chambered right ventricle, tetralogy of Fallot, and ventricular septal defects. In severe cases, facial dysmorphism may also occur with various features reported including receding forehead, ptosis or fused eyes, strabismus, dysplastic ear helices, high palate, underdeveloped philtrum, anteverted nostrils, broad flat nasal bridge, deviated nasal septum, and micrognathia. Optimal maternal blood Phe concentrations should be strictly maintained throughout pregnancy to reduce the risk of these abnormalities. This can be achieved by minimal dietary Phe intake, along with tyrosine-enriched supplements. Studies have also shown that dietary treatment to control blood Phe concentrations can prevent the disorder if started before conception.
Etiology
Abnormally high maternal blood Phe concentrations underlie the clinical effects found in children with this disorder. PKU and hyperphenylalaninemia are caused by mutations in the PAH gene (12q22-q24.2).
Diagnostic methods
The diagnosis is based on clinical observation, blood Phe analysis and genetic test to evaluate the presence of the PAH variant.
Genetic counseling
Phenylketonuria is transmitted in an autosomal recessive manner. Children of affected parents will therefore mostly (75%) be heterozygous carriers or non-carriers of the defect.
Management and treatment
Maternal PKU is managed by a strict low-Phe diet (commonly ≤ 6 g/day natural protein is tolerated in the early stages of pregnancy but PHE amount is dependent on PKU severity), together with a Phe-free L-amino acid supplement and sufficient energy intake to ensure adequate maternal weight gain during pregnancy. The protein equivalent from amino acid and natural protein should supply ≥ 70 g/ day protein. Nausea and vomiting during the early phases of pregnancy is common and may lead to inadequate intake of amino acid and energy and subsequently unsatisfactory blood Phe control.
Prognosis
Prognosis is favorable if blood Phe concentrations are kept strictly below 360 micromol/L before and during the entire pregnancy.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Pr Nenad BLAU


Maternal riboflavin deficiency is a rare, genetic disorder of metabolite absorption or transport characterized by persistently decreased riboflavin serum levels due to a primary genetic defect in the mother and which leads to clinical and biochemical findings consistent with a secondary, life-threatening, transient multiple acyl-CoA dehydrogenase deficiency (MADD) in the newborn. The mother usually presents hyperemesis gravidarum in the absence of other features of riboflavin deficiency, such as skin lesions, jaundice, pruritus, sore mucous membranes, visual disturbances.


Maternal uniparental disomy of chromosome 1 is an uniparental disomy of maternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only mother is a carrier.


Maternal uniparental disomy of chromosome 13 is an uniparental disomy of maternal origin that most likely do not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only mother is a carrier.


Maternal uniparental disomy of chromosome 16 is a uniparental disomy of maternal origin which might be associated with intrauterine growth retardation and an elevated risk of congenital malformations. Healthy carriers have also been reported. In addition, cases of homozygosity for a recessive disease mutation for which the mother was a carrier have been described, and specific phenotype depends on the inherited disorder.


Maternal uniparental disomy of chromosome 2 is an uniparental disomy of maternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only mother is a carrier.


Maternal uniparental disomy of chromosome 20 (UPD 20) is a very rare chromosomal anomaly in which both copies of chromosome 20 are inherited from the mother. The main feature described is prenatal and postnatal growth retardation. Microcephaly, minor dysmorphic features and psychomotor developmental delay have been occasionally reported. Maternal UPD20 is most often ascertained by a mosaic trisomy 20 pregnancy.


Maternal uniparental disomy of chromosome 21

A uniparental disomy of maternal origin that does not seem to have an adverse impact on the phenotype of an individual. There is a possibility of homozygosity for a recessive disease mutation for which the mother is a carrier and specific phenotype depends on the inherited disorder.


Maternal uniparental disomy of chromosome 22 is a uniparental disomy of maternal origin that does not seem to have an adverse impact on the phenotype of an individual. There is a possibility of homozygosity for a recessive disease mutation for which the mother is a carrier and specific phenotype depends on the inherited disorder.


Maternal uniparental disomy of chromosome 4 is an uniparental disomy of maternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only mother is a carrier.


Maternal uniparental disomy of chromosome 6 is an uniparental disomy of maternal origin characterized by intrauterine growth retardation. Homozygosity for a recessive disease mutation for which only a mother is a carrier may lead to other phenotypes.


Maternal uniparental disomy of chromosome 9 is a uniparental disomy of maternal origin that most likely does not have any phenotypic expression except from cases of homozygosity for a recessive disease mutation for which only mother is a carrier.


Maternal uniparental disomy of chromosome X


A rare, genetic congenital malformation syndrome characterized by bilateral anopthalmia (or less commonly microphthalmia) in association with a variable combination of the following: pulmonary hypoplasia or agenesis, congenital diaphragmatic hernia or eventration, and variable cardiovascular defects (congenital heart defects and/or pulmonary artery atresia). Intellectual disability is noted in surviving patients. Other variable malformations affecting different organ systems, as well as facial dysmorphism, may be observed.


Maxillary arteriovenous malformation is a rare vascular anomaly characterized by an abnormal connection of the arterial and venous vasculature, without capillary connections, in the maxillofacial area, usually presenting with chronic, intermittent, and potentially life-threatening, hemorrhage. Association with infection, pain, pressure, pulsation, swelling, facial asymmetry, headache, ocular pain, tinnitus, otalgia, epistaxis, toothache and/or teeth mobility and compressibility into their sockets is possible, although it may also be asymptomatic.


A rare developmental anomaly characterized by midfacial hypoplasia affecting primarily the anterior part of the maxilla (premaxilla) and the nasal complex.

Summary:
Epidemiology
Maxillonasal dysplasia (also called Binder syndrome) occurs in less than 1/10,000 birth but is probably underdiagnosed.
Clinical description
Affected individuals have very specific facial features that are easy to recognize. The central face is underdeveloped (midfacial hypoplasia), with an abnormally flat reduced nose, small crescent-shaped nostrils and a very short columella. The nasomaxillary angle is increased because of the missing anterior nasal spine, giving a ''heel of axe'' appearance at the lip-columella junction. The philtrum of the upper lip may be bow shaped, but without convergence to columella, demonstrating the non-adhesion of the orbicularis muscle to the anterior nasal spine. The anterior maxilla is underdeveloped with frequent lateral incisors anomalies ranging from small dystrophies to a total absence. These dental particularities lead to anterior malocclusion (class III) whereas the posterior occlusion remains normal. Fingers anomalies (such as hypoplasia of distal phalanges) can be present when the malformation is associated to a chondrodysplasia punctata.
Etiology
The etiology and pathogenesis of maxillonasal dysplasia remains uncertain.
Diagnostic methods
Diagnosis is suspected on clinical presentation. The absence of anterior nasal spine on radiological exam is pathognomonic of Binder.
Differential diagnosis
Phenocopies of maxillonasal dysplasia have been described in children exposed in utero to phenytoin or to vitamin K deficiency, being induced either by drug (anticoagulants) or by biliary lithiasis. Some authors consider maxillonasal dysplasia as an allelic form of chondrodysplasia punctata. Others suggest that it does not represent a distinct disease entity or syndrome, but rather is a nonspecific abnormality of the nasomaxillary regions. Holoproencephaly and arhinencephaly are the two main differential diagnosis, but there is no brain anomaly or olfactory deficit in maxillonasal dysplasia.
Antenatal diagnosis
Maxillonasal dysplasia can be suspected during second semester routine ultrasound. Nasal hypoplasia, flat nasofrontal angle, and midface hypoplasia are specific indicators.
Management and treatment
Surgery is the main treatment of the syndrome when required. Since the degree of malformation varies significantly between patients, surgical correction must be tailored individually. It can consist in orthognathic surgery and nose reconstruction. Orthodontic treatments and prosthodontic rehabilitations can also be performed.
Prognosis
Facial prognosis depends on the degree of malformation. Maxillonasal dysplasia can have a negative impact on quality of life.

                            Last update:
                            April 2024

                            - Expert reviewer(s):
                            Pr Joël FERRI  - Dr Adeline KERBRAT


Mayer-Rokitansky-Küster-Hauser syndrome type 1

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome type 1, a form of MRKH syndrome (see this term), is an isolated form of congenital aplasia of the uterus and 2/3 of the vagina occurring in otherwise phenotypically normal females.

Summary:
Epidemiology
MRKH syndrome (including type 1 and type 2) has a worldwide prevalence of 1/4500 live female births. The rate of MRKH syndrome type 1 varies largely between different cohorts reported, therefore an accurate incidence of this type is not possible.
Clinical description
MRKH syndrome type 1 is most often diagnosed in adolescence as the first symptom is most commonly a primary amenorrhea in young women presenting with otherwise normal development of secondary sexual characteristics and normal external genitalia. Patients lack the uterus and the upper 2/3 of the vagina. Because of this, difficulties with sexual intercourse have been reported. Pelvic pain can be reported in those with uterine remnants. As the uterus is missing or not functional, women cannot bear children. However, the ovaries are normal and functional.
Etiology
The exact etiology of MRKH syndrome remains largely unknown. Initially, MRKH syndrome was considered to be of sporadic occurrence, suggesting the involvement of non-genetic or environmental factors. However, no link between an environmental cause and MRKH syndrome has ever been established. It is now clear that MRKH syndrome has a genetic origin, through increasing family descriptions and numerous genetic studies already completed. The latter have led to reveal several chromosomal abnormalities associated with the disease, such as small interstitial duplications in 1q21.1 and in Xpter-p22.32, or deletions in 4q34-qter, 8p23.1, 10p14, 16p11.2, 17q12, 22q11.21 and Xq21.31. These genomic rearrangements affect numerous genes. Putative candidate genes have been described, such as  HNF1B  (17q12), LHX1 (17q12), SHOX (Xp22.33 and Yp11.32), TBX6 (16p11.2), and ITIH5 (10p14). The phenotype-genotype correlations however, have not been established.
Genetic counseling
MRKH syndrome (type 1 or type 2) was thought to be purely sporadic but in familial cases it seems to be inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. Genetic counseling can be beneficial in these familial cases.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Dr Karine MORCEL


Mayer-Rokitansky-Küster-Hauser syndrome type 2

A form of Mayer-Rokitansky-Küster-Hauser syndrome, characterized by congenital aplasia of the uterus and upper two-thirds of the vagina that is associated with at least one other malformation such as renal, vertebral, or, less commonly, auditory and cardiac defects.

Summary:
Epidemiology
MRKH syndrome has an estimated worldwide incidence of 1/4500 live female births. The prevalence of MRKH syndrome type 2 is unknown.
Clinical description
MRKH syndrome type 2 is most often diagnosed in adolescence as the first symptom is most commonly a primary amenorrhea in young women presenting with otherwise normal development of secondary sexual characteristics and normal external genitalia. Patients lack the uterus and the upper 2/3 of the vagina. Because of this, difficulties with sexual intercourse have been reported. Pelvic pain can be reported in those with uterine remnants. As the uterus is missing or not functional, women cannot bear children but ovaries are normal and functional. Other associated malformations seen in MRKH type 2 include upper urinary tract malformations (40% of cases), unilateral renal agenesis (23-28%; see this term), ectopia of one or both kidneys (17%; see this term), renal hypoplasia (4%), horseshoe kidney and hydronephrosis. Skeletal abnormalities, mainly of the spine and less frequently in the face and limbs, are also reported. Spinal malformations encountered include scoliosis, isolated vertebral anomalies (asymmetric, fused or wedged vertebrae), isolated Klippel-Feil syndrome and/or Sprengel deformity (see these terms), rib malformation or agenesis, and spina bifida (see this term). Face and limb malformations are mainly brachymesophalangy, ectrodactyly, duplicated thumb, absent radius, atrio-digital dysplasia (Holt-Oram-like syndrome) and facial asymmetry. Hearing impairment, due to middle ear malformations or sensorineural defects, is seen in 10-25% of cases. Heart malformations are very rare but include valvular pulmonary stenosis, Tetralogy of Fallot (see these terms) Holt-Oram or velocardiofacial-like syndromes, aorto-pulmonary window or atrial septal defects.
Etiology
The exact etiology of MRKH syndrome remains largely unknown, even if the spectrum of malformation encountered suggests a developmental defect of the intermediate mesoderm during embryogenesis (by the end of the 4th week of fetal life), leading to an alteration of the blastema of the cervicothoracic somites and the pronephric ducts. Initially, MRKH syndrome was considered to be of sporadic occurrence, suggesting the involvement of non-genetic or environmental factors. However, no link between an environmental cause and MRKH syndrome has ever been established. It is now clear that MRKH syndrome has a genetic origin, through increasing family descriptions and numerous genetic studies already completed. The latter have led to reveal several chromosomal abnormalities associated with the disease, such as small interstitial duplications in 1q21.1 and in Xpter-p22.32, or deletions in 4q34-qter, 8p23.1, 10p14, 16p11.2, 17q12, 22q11.21 and Xq21.31. These genomic rearrangements affect numerous genes. Putative candidate genes have been described, such as HNF1B (17q12), LHX1 (17q12), SHOX (Xp22.33 and Yp11.32), TBX6 ( 16p11.2), and ITIH5 (10p14). The phenotype-genotype correlations however, cannot be established.
Genetic counseling
MRKH syndrome (type 1 or type 2) was thought to be purely sporadic but in familial cases it seems to be inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. Genetic counseling can be beneficial in these familial cases.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Dr Karine MORCEL


A rare spectrum of Mullerian duct anomalies characterized by congenital aplasia of the uterus and upper two-thirds of the vagina in otherwise phenotypically normal females. It can be classified as either Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome type 1 (corresponding to isolated utero-vaginal aplasia) or MRKH syndrome type 2 (utero-vaginal aplasia associated with other malformations).

Summary:
Epidemiology
MRKH syndrome has a worldwide incidence of 1/4500 live female births.
Clinical description
MRKH syndrome is most often diagnosed in adolescence as the first symptom is usually a primary amenorrhea in young women presenting otherwise with normal development of secondary sexual characteristics and normal external genitalia. MRKH syndrome type 1 and 2 patients lack the uterus and the upper 2/3 of the vagina leading to difficulties with sexual intercourse in some. Pelvic pain can be reported in those with uterine remnants. As the uterus is missing or not functional, women cannot bear children, but ovaries are normal and functional. Other associated malformations seen in MRKH type 2 include kidney abnormalities (40% of cases), skeletal abnormalities (20-25%), hearing impairment (10%), and, more rarely, heart defects.
Etiology
The exact etiology is largely unknown, even if the spectrum of malformations encountered suggests a developmental defect of the intermediate mesoderm during embryogenesis (by the end of the 4th week of fetal life), leading to an alteration of the blastema of the cervicothoracic somites and the pronephric ducts. It is now clear that MRKH syndrome has a genetic origin through increasing family descriptions and numerous genetic studies already completed. These latter have led to reveal several chromosomal abnormalities associated with the disease and several putative candidate genes have been described.
Diagnostic methods
The karyotype of MRKH patients is always 46, XX. Hormone levels are normal, showing normal and functional ovaries without hyperandrogenism. Transabdominal ultrasonography must be the first investigation in evaluating patients with suspected utero-vaginal aplasia. MRI can be performed to clearly visualize the malformation. A full check-up (renal ultrasonography, spine radiography, heart echography, audiogram) must be undertaken to search for any associated malformations.
Differential diagnosis
Differential diagnosis includes isolated vaginal atresia, which is found in various syndromes such as McKusick-Kaufman syndrome, androgen insensitivity syndrome, Mullerian aplasia and hyperandrogenism, and renal-genital-middle ear anomalies (see these terms).
Genetic counseling
MRKH syndrome was thought to be purely sporadic but familial cases seem to be inherited autosomal dominantly with incomplete penetrance and variable expressivity, and in these cases genetic counseling can be beneficial.
Management and treatment
The medical care of MRKH patients requires the coordinated efforts of pediatricians, gynecologists, surgeons, endocrinologists and psychologists. Treatment consisting in creating a neovagina must be offered to patients only when they are ready to start sexual activity and when emotionally mature (around 17-21 years). Frank's (nonsurgical) method requires the application of vaginal dilators on the vaginal dimple for at least 20 minutes/day for several months. If unsuccessful, various surgical procedures can be performed to create a neovagina. Clinical follow-up and regular intercourse are essential components to a successful outcome. Psychological support and counseling is strongly recommended for affected women and should provide patients with future fertility options (in vitro fertilization of one's own oocytes followed by surrogate pregnancy or adoption). For the associated malformations in MRKH type 2, specific medical care is directed toward the anomalies.
Prognosis
MRKH syndrome is not a life threatening disease. With treatment, sexual relationships are possible and fertility options are available.

                            Last update:
                            January 2015

                            - Expert reviewer(s):
                            Dr Karine MORCEL


Mazabraud syndrome is a rare primary bone dysplasia (see this term) characterized by the association of fibrous dysplasia with intramuscular myxomas. Fibrous dysplasia (usually polyostotic, sometimes monostotic) occurs during the growth period and can be asymptomatic or can present with pain, skeletal deformities or fractures while intramuscular myxoma, associated with polyostotic fibrous dysplasia (see this term) is usually multifocal, typically occuring in the vicinity of skeletal lesions, and presents in adulthood as a painless soft-tissue mass (most commonly in the thigh). Although it is a benign condition, local recurrences of myxomas after incomplete excision and malignant transformation of a fibrous dysplastic lesion into osteogenic sarcoma have been reported.