A rare, genetic, motor neuron disease characterized by slowly progressive, predominantly proximal, muscular weakness and atrophy which typically manifests with muscle cramps, fasciculations, decreased/absent deep tendon reflexes, hand tremor, and elevated serum creatine kinase at onset and later associates with reduced walking ability and impaired vibration sensation.

Summary:
Epidemiology
More than 97 patients have been described with Lower motor neuron syndrome with late-adult onset to date, all originating from Finland, where the point prevalence estimate rises to 1/8,000 in northern Karelia.
Clinical description
The main early signs generally present after 30 to 40 years of age, and usually include muscle cramps, fasciculations, decreased/absent deep tendon reflexes, elevated serum creatine kinase, and hand tremor. Disease progresses slowly and leads to muscular weakness and mild to moderate atrophy (predominantly affecting the proximal lower limbs, although occasional distal upper limb and abdominal involvement has also been reported). Impaired vibration sensation in the lower limbs may occur later in life, and some patients may develop mild dysphagia. Additional signs and symptoms include myalgia, and fatty degenerative replacement predominantly in the calves and hamstrings muscles. Respiratory functions are usually normal and there are no upper motor neuron signs.
Etiology
The disease is caused by a pathogenic mutation (p.G66V) in the CHCHD10 gene (22q11.2), encoding a mitochondrial, coiled-coil-helix-coiled-coil-helix protein of unknown function. CHCHD10 is involved in oxidative phosphorylation and possibly takes part in mitochondrial complex function (particularly complex IV), and in maintaining mitochondrial DNA. The exact pathogenic mechanism of this mutation remains poorly understood.
Diagnostic methods
Diagnosis is based on clinical and electromyographic evaluation showing prominent fasciculations and chronic denervation in all limbs and possibly in the trunk, as well as evidence of neurogenic changes on muscle biopsy. Diagnosis is confirmed by identification of a causative mutation on the CHCHD10 gene.
Differential diagnosis
The disorder must be differentiated from other neuromuscular diseases, including autosomal dominant adult-onset proximal spinal muscular atrophy and amyotrophic lateral sclerosis (ALS), due to significant genetic and/or clinical overlap.
Antenatal diagnosis
Antenatal diagnosis is possible in families with a known disease causing mutation.
Genetic counseling
The disease follows an autosomal dominant pattern of inheritance. Genetic counseling should be provided to affected families, informing them of the 50% risk of transmission in future pregnancies.
Management and treatment
Disease management is mainly symptomatic, as no specific treatment is available to date.
Prognosis
The disease has a relatively mild course, as most patients remain ambulatory for several decades after disease onset and present a normal life expectancy.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Dr Manu JOKELA


Lown-Ganong-Levine syndrome is an extremely rare conduction disorder characterized by a short PR interval (less than or equal to 120 ms) with normal QRS complex on electrocardiogram associated with the occurrence of episodes of atrial tachyarrythmias (e.g. atrial fibrillation, atrial tachycardia).


Lowry-MacLean syndrome is a very rare syndrome characterized by microcephaly, craniosynostosis, glaucoma, growth failure and visceral malformations.

Summary:
Epidemiology
Only three cases have been reported in the literature in three unrelated families.
Clinical description
Dysmorphic features include trigonocephaly, exotropia, cleft palate, beaked nose and low-set ears. All the affected patients have associated congenital visceral malformations including congenital heart defects, diaphragmatic hernia, genital or cerebral abnormalities.
Genetic counseling
The demonstration of congenital glaucoma, hallmark of the syndrome, in the father of an affected patient, supports autosomal dominant inheritance.
Prognosis
Prognosis is poor.

                            Last update:
                            January 2010


A rare disorder characterized by the association of epiphyseal dysplasia, short stature, microcephaly and, in the first reported cases, congenital nystagmus. So far, less than 10 cases have been described in the literature. Variable degrees of intellectual deficit have also been reported. Other occasional features include retinitis pigmentosa and coxa vara. Transmission appears to be autosomal recessive.


A rare primary bone dysplasia characterized by reduced bone mineral density (defined as a Z score below -2.0), vertebral compression fractures, and recurrent peripheral fractures caused by low-impact trauma, leading to bone pain and impaired mobility. Patients typically become symptomatic in childhood or adolescence.


The Lujan-Fryns syndrome or X-linked mental retardation (XLMR) with marfanoid habitus syndrome is a syndromic X-linked form of intellectual disability, associated with tall, marfanoid stature, distinct facial dysmorphism and behavioral problems.

Summary:
Epidemiology
The syndrome affects predominantly males. The prevalence in the general population is not known.
Clinical description
Patients present tall stature, long hyper-extensible fingers and toes, short halluces and long second toes. Patients have mild to moderate intellectual disability. Craniofacial features include long forehead, long narrow face, maxillary hypoplasia, small mandible, long nose with high and narrow nasal bridge, short and deep philtrum, thin upper lip and highly arched palate. The marfanoid stature becomes evident after puberty. In adulthood, patients are tall but height is in the normal range. A hypernasal voice and generalized hypotonia are often present. Secondary sexual development and testicular size are normal. Behavioral features include emotional instability, hyperactivity and shyness. Psychiatric disorders such as psychotic disturbances with hallucinatory visions and sounds, and schizophrenia can be present.
Etiology
The Lujan-Fryns syndrome is a developmental disorder of genetic origin. In the original Lujan family, a novel missense mutation in the mediator complex subunit 12, MED12 gene (Xq13) was found as the cause of Lujan-Fryns syndrome. Defects in this gene also cause FG syndrome (see this term). In some cases, mutations in the UPF3B gene (Xq25-q26) and in the ZDHHC9 gene (Xq26.1) have been reported in XLMR with marfanoid habitus.
Diagnostic methods
Diagnosis is based on the clinical manifestations and can be confirmed by the presence of the missense mutation in the MED12 gene. However, the frequency of the presence of a mutation in patients with the clinical diagnosis of Lujan-Fryns syndrome is not known.
Differential diagnosis
Differential diagnosis includes the fragile X syndrome (molecular analysis of the FMR-1 gene), Marfan syndrome (cardiac and ophthalmologic examination) (see these terms), and homocystinuria (biochemical analysis). Lujan-Fryns syndrome should be considered in the differential diagnosis of schizophrenia.
Antenatal diagnosis
There is currently no specific prenatal test for this condition. However, prenatal diagnosis for at-risk pregnancies first requires identification of the mutations in the family. Molecular analysis of the MED12 gene in chorionic villus samples is possible.
Genetic counseling
Genetic counseling, based on the X-linked mode of inheritance, should be offered to patients with a prior identified MED12 gene mutation.
Management and treatment
There is no specific treatment for this condition. Patients require specialized education and psychological follow-up. Psychiatric disorders (psychosis) should be diagnosed as early as possible.
Prognosis
Data on life expectancy are not available as most reports describe patients in adolescence and young adulthood. Special attention should be given to comorbidity and behavioral problems.

                            Last update:
                            January 2012

                            - Expert reviewer(s):
                            Pr Griet VAN BUGGENHOUT


Lujo hemorrhagic fever, caused by the Lujo virus (a newly discovered Old World arenavirus) is a zoonotic disease from Zambia, Africa, whose reservoir is unknown and is characterized by fever and hemorrhagic manifestations with an extremely high fatality rate of 80% (in the 5 reported cases to date) and a moderate to high level of nosocomial transmission.


A disorder defining by the association of Perineal hemangioma, External genitalia malformations, Lipomyelomeningocele, Vesicorenal abnormalities, Imperforate anus, and Skin tag. Eleven cases have been reported.


Lung agenesis-heart defect-thumb anomalies syndrome

A rare genetic disease characterized by the association of unilateral complete or partial lung agenesis, complex congenital cardiac anomalies such as atrial septal defect, total anomalous pulmonary venous return, or patent ductus arteriosus, and ipsilateral or bilateral thumb abnormalities. Presence of facial dysmorphism and other malformative features has also been reported.


Lung fibrosis-immunodeficiency-46,XX gonadal dysgenesis syndrome is characterised by immune deficiency, gonadal dysgenesis and fatal lung fibrosis. So far, it has been described in two sisters born to consanguineous parents. Both karyotypes were normal female (46,XX). No genetic anomalies could be identified by comparative genome hybridization analysis of their genomes or by analysis of genes known to be associated with these types of anomalies.


A rare form of chronic cutaneous lupus erythematosus characterized by recurrent, indurated, erythematous plaques and subcutaneous nodules with normal overlying epidermis, occurring predominantly on the face, upper arms, trunk, buttocks, and thighs. The lesions can ulcerate and lead to scarring. Histological findings include lobular lymphocytic panniculitis, hyaline fat necrosis, mucin deposition, and calcification. The condition may be associated with discoid or systemic lupus erythematosus.


A rare form of chronic cutaneous lupus erythematosus characterized by extreme photosensitivity with intermittent formation of erythematous, edematous, urticarial-like, smooth plaques on sun-exposed skin areas. The lesions heal without scarring. The course of the disease is benign, and development of systemic lupus erythematosus is infrequent. Most patients do not have lupus-related autoantibodies. Skin biopsy shows a perivascular and periadnexal lymphocytic infiltrate and increased dermal mucin deposition without involvement of the dermoepidermal junction.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by a variable phenotype including macrocephaly, postnatal overgrowth, advanced carpal ossification, obesity, speech delay, intellectual disability, autism spectrum disorders, and behavioral difficulties with aggressive outbursts, and variable facial dysmorphism. Seizures, structural abnormalities of the brain, as well as a variety of other manifestations such as recurrent otitis media, joint hypermobility, hirsutism, or naevi have also been reported.


Lyme disease (named after the towns in the USA where the disease was first identified) is a bacterial infection caused by Borrelia burgdorferi.

Summary:
Epidemiology
Incidence is variable and is estimated at 1-70/20,000 in Europe.
Clinical description
The clinical manifestations can be divided into three stages. Onset of the initial stage occurs between three days and one month after being bitten by an infected tick (generally the patient is aware of the bite) and is marked by erythema migrans, a characteristic cutaneous lesion that appears over time at various sites of the body. The second stage is characterized by dissemination to the central nervous system (resulting in facial paralysis, encephalitis etc.), joints, skin, heart and eye. The third (chronic) stage of the disease is characterized by joint, neurologic and cutaneous manifestations.
Etiology
The disease is transmitted to humans by bites from contaminated ticks (Ixodes) but rodents, birds and lizards are the main hosts.
Diagnostic methods
Diagnosis relies on recognition of the clinical picture during the initial stage of the disease, detection of  Borrelia burgdorferi through analysis of cultures, PCR and detection of  Borrelia burgdorferi DNA, or through elevations in antibody levels in patients in the second and third stages of the disease.
Prognosis
Treatment revolves around administration of antibiotics (amoxicillin and cyclines); with the treatment being more effective the earlier the antibiotics are administered. Prevention revolves around eradication of the ticks and on individuals taking protective measures against tick bites when visiting at-risk zones.

                            Last update:
                            April 2008

                            - Expert reviewer(s):
                            Dr Muriel CORNET  - Dr Elisabeth FERQUEL


A rare, multiple cystic lung disease characterized by progressive cystic destruction of the lung and lymphatic abnormalities, frequently associated with renal angiomyolipomas (AMLs).

Summary:
Epidemiology
Sporadic lymphangioleiomyomatosis (LAM) affects around 1/129 000 - 385 000 adult women in Europe. However, LAM may occur as a feature of tuberous sclerosis complex (TSC) and is present in up to 30-40% of adult TSC cases. Sporadic LAM affects almost exclusively females.
Clinical description
Defining manifestations of the disease are respiratory and include progressive dyspnea, pneumothorax and chylothorax. LAM may lead to chronic respiratory failure. A common extra-pulmonary manifestation is a high incidence of AMLs, mostly localized to the kidneys and usually asymptomatic (hemorrhage is rare). Chylous ascites, abdominal and thoracic lymphadenopathy and lymphangioleiomyomas (especially retroperitoneal) can be observed. Symptoms may worsen during pregnancy.
Etiology
Sporadic LAM is due to somatic mutations in the tuberous sclerosis genes TSC2 and/or TSC1, that encode the major signaling proteins tuberin and hamartin. Mutations result in excessive proliferation of LAM cells. In contrast, TSC is due to germline mutations.
Diagnostic methods
For a definite LAM diagnosis, a high resolution computed tomography (HRCT) scan shows typical lung cysts with diffuse distribution and may be associated together with one of the following: TSC; a lung biopsy showing cysts and abnormal immature smooth muscle-like cells (LAM cells); AMLs in the kidney; thoracic or abdominal chylous effusion; lymphangioleiomyoma; elevation of serum level of vascular endothelial growth factor D (VEGF-D) greater than 800 mg/L. The diagnosis of LAM is possible when only characteristic lung cysts are present.
Differential diagnosis
The two main differential diagnoses are adult pulmonary Langerhans cell histiocytosis and emphysema. Less frequent differential diagnoses include hypersensitivity pneumonitis, light chain-deposition disease, Birt-Hogg-Dubé syndrome and Sjögren syndrome.
Genetic counseling
Sporadic LAM is not inherited. In contrast, TSC may be inherited or result from de novo germline mutations of TSC1 or TSC2.
Management and treatment
LAM patients who develop respiratory symptoms should have periodic pulmonary function testing. Management of air flow obstruction is essential and a quarter of patients respond to inhaled bronchodilators. Patients should be informed of the risk of pneumothorax. Pleurodesis may be performed at first pneumothorax to prevent increased risk of recurrent pneumothorax. Surgical pleurodesis is often necessary for a recurrent pneumothorax or chylothorax. Single/bilateral lung transplantation is performed when other options have proven unsuccessful. The mTOR inhibitor sirolimus may be used in expert centers to stabilize or improve pulmonary function in cases with altered lung function (forced expiratory volume in one second [FEV1] < 70% of predicted value) or declining lung function (FEV1 decline > 90 mL/year). Asymptomatic AMLs < 4cm in diameter do not usually need to be treated but should be monitored. AMLs > 4 cm or with microaneurysms > 0.5 cm or bleeding risk should be treated by selective arterial embolization, sirolimus or everolimus therapy, or nephron sparing surgery. Estrogen therapy should be avoided.
Prognosis
Disease progression rate and severity is highly variable. The main predictor of prognosis is the rate of decline in pulmonary function.

                            Last update:
                            May 2022

                            - Expert reviewer(s):
                            Pr Vincent COTTIN | ERN-LUNG*

                                * European Reference Network


Lymphatic filariasis (LF) is a severe form of filariasis (see this term), caused by the parasitic worms Wuchereria bancrofti, Brugia malayi and Brugia timori, and the most common cause of acquired lymphedema worldwide. LF is endemic to tropical and subtropical regions. The vast majority of infected patients are asymptomatic but it can also cause a variety of clinical manifestations, including limb lymphedema, genital anomalies (hydrocele, chylocele), elephantiasis in later stages of the disease (frequently in the lower extremities), and tropical pulmonary eosinophilia (nocturnal paroxysmal cough and wheezing, weight loss, low-grade fever, adenopathy, and pronounced blood eosinophilia). Renal involvement (hematuria, proteinuria, nephritic syndrome, glomerulonephritis), and mono-arthritis of the knee or ankle joint have also been reported.


Lymphedema-atrial septal defects-facial changes syndrome is characterised by congenital lymphoedema of the lower limbs, atrial septal defect and a characteristic facies (a round face with a prominent forehead, a flat nasal bridge with a broad nasal tip, epicanthal folds, a thin upper lip and a cleft chin). It has been described in two brothers and a sister. Transmission appears to be autosomal recessive.


Lymphedema-cerebral arteriovenous anomaly-primary pulmonary hypertension syndrome

Lymphedema-cerebral arteriovenous anomaly syndrome is characterised by the variable association of a cerebrovascular malformation, foot lymphoedema and primary pulmonary hypertension. It has been described in a woman and four of her children. There have been no further descriptions in the literature since 1986.


A rare autosomal dominant syndromic lymphedema characterized by lower-limb lymphedema and varying degrees of abnormal growth of eyelashes from the orifices of the Meibomian glands (distichiasis), with occasional associated manifestations.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Lymphedema-distichiasis syndrome is characterized by primary lower limb lymphedema (with or without genital edema in males) usually starting in childhood or puberty (but in some cases later or, occasionally, at birth) and associated with distichiasis (extra eyelashes growing from the Meibomian gland orifices in the inner eyelid). Ptosis of the eyelid(s) is frequent. Other associated manifestations can include: heart abnormalities, cleft palate (with or without Pierre Robin sequence), renal malformations, varicose veins and extradural cysts. Distichiasis may lead to infection (styes), congenital ectropion, photophobia corneal abrasion or ulceration.
Etiology
The causative gene is FOXC2 (previously referred to as MFH1, located at 16q24.3), coding for transcription factor FOXC2.
Diagnostic methods
Diagnosis is suspected on clinical presentation with the presence of 'extra' eyelashes arising from the inner eyelid, ptosis and lower limb lymphedema; although the latter may not present until later in childhood or adolescence. The condition can usually be confirmed by genetic testing.
Differential diagnosis
The differential diagnosis includes other conditions presenting with late onset (i.e. not congenital) lymphedema of the lower limbs. This includes Meige disease, Noonan syndrome, Emberger syndrome (part of the GATA2 deficiency spectrum) and CELSR-related lymphedema.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member. The nuchal translucency, visible by sonograph, is often slightly increased (3mm to 4.5mm). The fetus may develop fetal hydrops in the second trimester. There may be congenital heart disease and or congenital renal malformations.
Genetic counseling
The disorder is autosomal dominant. Although the condition is usually inherited from an affected parent, some cases occur sporadically. 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
The standard treatment for the lower limb (and genital) lymphedema are made-to-measure compression garments with the option of intensive bandaging for moderate to severe swelling. Skin care is necessary to prevent infections. Every newly diagnosed patient should have a renal ultrasound and echocardiogram to exclude congenital malformations. They should also be examined for a cleft of the hard or soft palate. The distichiasis is often problematic, and they may require to be plucked or even electrolysis. If severe, they may require lamellar eyelid division and cryotherapy to the posterior lamella.
Prognosis
The severity may vary even within families. A normal life span is expected but there is a high mortality with the rare complication of fetal hydrops. Approximately 7% will have congenital heart disease but it is not usually severe. There is a high morbidity associated with recurrent cellulitis of the edematous limbs.

                            Last update:
                            June 2024

                            - Expert reviewer(s):
                            Dr Kristiana GORDON | VASCERN* - Pr Sahar MANSOUR | VASCERN*

                                * European Reference Network


Lymphedema-posterior choanal atresia syndrome

A rare genetic disease characterized by choanal atresia and early onset of lymphedema of the lower extremities. Additional reported features include facial dysmorphism (hypertelorism, broad forehead, smooth philtrum, unilateral low-set ear, and high-arched palate), hypoplastic nipples, and pectus excavatum.


Lymphoepithelial-like carcinoma is a rare, malignant epithelial tumor, composed of undifferentiated epithelial cells with dense lymphoid stroma, mimicking lymphoepithelioma. It often shows association with Epstein-Barr virus infection and can develop in various organs, such as the nasopharynx, stomach, skin, breast and lungs, among others. The presenting symptoms, as well as the radiologic features, are usually nonspecific and depend on the affected site and organ.


A rare idiopathic interstitial pneumonia characterized by a diffuse, dense, polyclonal lymphoid cell infiltration of the pulmonary interstitium and air spaces, with high prevalence in patients with immune dysregulation. Presenting symptoms are non-specific and include dyspnea and cough. The clinical course is highly variable, ranging from spontaneous resolution to progressive, fatal respiratory failure.


Lymphomatoid granulomatosis (LYG) is a very rare Epstein-Barr virus (EBV)-driven lymphoproliferative disease most commonly occurring in adults (in the fourth to sixth decade of life) and commonly affecting the lungs (with presentations varying from small bilateral pulmonary nodules to large necrotic and sometimes cavitating lesions), skin, central nervous system, and kidneys, but only very rarely affecting the lymph nodes and spleen. The symptoms associated with LYG depend on the site of disease involvement but mainly include cough, dyspnea or chest pain (in those with pulmonary involvement) and constitutional symptoms such as weight loss and fever.


Lymphomatoid papulosis (LyP) is a rare cutaneous condition characterized by chronic, recurrent, and self-regressing papulonodular skin eruptions. It belongs to the spectrum of primary cutaneous CD30+ lymphoproliferative disorders, along with primary cutaneous anaplastic large cell lymphoma (primary C-ALCL; see this term) with which it shares overlapping clinical and histopathologic features.

Summary:
Epidemiology
Exact prevalence is unknown.
Clinical description
LyP lesions develop at any age, more frequently during adulthood (mean age 45 years), as erythematous papules and nodules of less than 1.5-2 cm, grouped in clusters or disseminated throughout the body. Lesions may become necrotic in the center, show pigmentation and leave scarring. They spontaneously regress within 4 to 8 weeks but new lesions can occur at any time. Patients with LyP are at an increased risk of developing cutaneous or nodal lymphoid malignancies such as classic mycosis fungoides, ALCL, and Hodgkin lymphoma (see these terms).
Etiology
Etiology is unknown. In some reports, a correlation has been found between the use of immunosuppressive medication (e.g. anti-tumor necrosis factor (TNF) agents) for the treatment of chronic inflammatory diseases and the occurrence of LyP.
Diagnostic methods
Diagnosis is based on physical examination and medical history, and is confirmed by histopathologic and immunohistochemical evaluation of skin biopsies. Five histologic sub-types have been defined: type A (wedge-shaped mixed infiltrate with CD30+ tumor cells and inflammatory cells), type B (epidermotropic CD30+ T-cell infiltrate resembling MF), type C (sheets of CD30+ large atypical lymphoid cells), type D (CD30+ and CD8+ lymphocytes with cytotoxic TIA-1 staining resembling Berti's lymphoma), and type E (angiocentric and angiodestructive CD30+ T-cell infiltrate). In case of extracutaneous disease, no imagery techniques are recommended for LyP except pulmonary radiography.
Differential diagnosis
Differential diagnosis includes classical mycosis fungoides, primaryC-ALCL, diffuse large B cell lymphoma, Hodgkin lymphoma (see these terms), metastatic melanoma, and squamous cell carcinoma of the skin.
Management and treatment
Treatment includes use of topical steroids in the initial stages of the disease which, in cases with an increase in the number of lesions, is combined with or followed by phototherapy (psoralen-UVA light therapy [PUVA]) or oral low-dose methotrexate (MTX). Treatment does not guarantee total regression of lesions and relapses are common with the use of lower doses or the discontinuation of treatment. Interferon alfa-2a can be used as an alternative to MTX treatment.
Prognosis
Prognosis is good, with a normal life expectancy, even if the disease is chronic with recurring lesions and an increased risk of developing second lymphoid neoplasms (4-25% of patients). Complications due to long-term treatment may also appear and include a higher incidence of non-melanoma skin cancer (due to PUVA) or hepatic fibrosis (due to MTX).

                            Last update:
                            April 2014

                            - Expert reviewer(s):
                            Pr Martine BAGOT


Lymphoplasmacytic inflammatory pseudotumor of the liver

A subtype of inflammatory pseudotumor of the liver characterized by a benign, well-circumscribed tumor with diffuse lymphoplasmacytic infiltration with histological features of IgG4-related disease (numerous IgG4-positive plasma cells, prominent eosinophils, stromal fibrosis, fibroblastic proliferations and, frequently, obliterative phlebitis), and that is likely located around the hepatic hilum. Most often it is discovered as an incidental finding.


Lymphoplasmacytic lymphoma without IgM production

A rare B-cell non-Hodgkin lymphoma characterized by the presence of small B-lymphocytes, plasmacytoid lymphocytes, and plasma cells, and either non-secreting or secreting IgG or IgA paraproteins. The disease usually involves the bone marrow, sometimes also the spleen or lymph nodes. Patients typically present with symptoms related to anemia. Hyperviscosity, autoimmune phenomena, and B symptoms may also be observed. Mortality is higher as compared to Waldenström macroglobulinemia.


A rare form of hereditary nonpolyposis colon cancer (HNPCC) characterized by predisposition to a wide variety of cancers, including neoplasms of the digestive tract, urinary tract, endometrium, ovary, brain, and prostate, as well as sebaceous skin tumors. LS-associated tumors are typically characterized by the presence of microsatellite instability (MSI) and loss of expression of MMR proteins in tumor tissue.

Summary:
Epidemiology
The population prevalence of germline pathogenic variants in the MMR genes has been estimated at 1:279. Cancer type incidences vary with the affected gene, sex, and population. LS accounts for approximately 3% of colorectal (CRC) and endometrial cancers (EC).
Clinical description
LS-associated cancer usually occurs in adulthood, at earlier ages compared to the general population. CRC is the predominant LS-associated cancer; it has an increased risk of being synchronous or metachronous and is typically located in the proximal colon; symptoms include abdominal pain, iron deficiency or signs of colonic obstruction. EC is the most prevalent LS-associated cancer in women and manifests with pelvic pain and menorrhea. Other cancers include ovarian, stomach, hepatobiliary tract, pancreas, breast, small intestine, urinary tract, prostate, brain (mainly glioblastoma) and skin cancers (sebaceous adenomas/carcinomas/epitheliomas and keratoacanthomas). Muir-Torre and Turcot syndromes were terms used to describe patients with skin neoplasia, or with tumors of the colon and central nervous system, respectively.
Etiology
LS is caused by heterozygous pathogenic germline variants affecting DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2). Other variants involve C-terminal deletions of EPCAM leading to methylation of the adjacent MSH2 promoter in epithelial tissue. Rarely, LS is due to constitutional inactivation of MLH1 by epimutation.
Diagnostic methods
Amsterdam/revised Bethesda criteria fail to identify up to 50% of LS patients. MSI analysis and/or immunohistochemical analysis of MMR protein expression in CRC and EC is recommended for all patients. Universal or age-dependent somatic and/or germline genetic testing of these patients is undergoing evaluation. Cascade testing should follow the identification of an individual with a MMR pathogenic mutation.
Differential diagnosis
Differential diagnosis includes several forms of attenuated polyposis, particularly recessive tumor syndromes associated with germline biallelic pathogenic variants in MUTYH, NTHL1, MBD4, or MSH3, polymerase proofreading-related adenomatous polyposis, constitutional MMR deficiency, and other cancer predisposition syndromes such as PTEN hamartoma tumor or Li-Fraumeni syndrome. Unexplained cases might be classified as Lynch-like syndrome or familial CRC type X, depending on the status of the MMR system in the tumors.
Antenatal diagnosis
Prenatal and preimplantation genetic diagnoses are possible if a pathogenic variant has been identified in a parent.
Genetic counseling
LS follows an autosomal dominant mode of inheritance with incomplete penetrance. The inheritance pattern of MLH1 epimutations is variable, presumably reflecting their mechanistic basis. Genetic counseling should be offered to affected individuals and their relatives to inform them of the increased risk of cancer. Each child of an individual with LS has a 50% chance of inheriting the variant.
Management and treatment
Due to the high risk of synchronous or metachronous tumors, patients should be included in surveillance programs consisting of colonoscopy with removal of precancerous polyps, and transvaginal ultrasound examination and endometrial biopsy (with yearly education on EC and ovarian cancer) for women, every 1-2 years starting at the age of 20-25 years. Full colectomy should be considered in LS-CRC patients. Screening may start at an earlier age depending on family history. Aspirin decreases the risk of CRC. Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be proposed to women after childbearing age. Treatments supporting anti-tumoral immune response show great success against MSI-high tumors.
Prognosis
Early diagnosis and surveillance significantly reduce morbidity and mortality. LS-associated tumors tend to have a better prognosis at similar stage compared with microsatellite stable tumors.

                            Last update:
                            September 2023

                            - Expert reviewer(s):
                            Pr Stefan ARETZ | ERN GENTURIS* - Dr Marta PINEDA RÍU | ERN GENTURIS* - Dr Laura VALLE | ERN GENTURIS*

                                * European Reference Network


A rare disorder of amino acid absorption and transport characterized by a secondary urea cycle disorder with failure to thrive, hepatosplenomegaly, and a wide range of clinical manifestations including hematological (macrophagic activation syndrome or hemophagocytic lymphohistiocytosis, HLH), immune, digestive, renal, pulmonary and/or bones involvement.

Summary:
Epidemiology
Lysinuric protein intolerance (LPI) is mainly found in Japan and Finland where the prevalence is approximately 1/60,000. More than 200 cases have been reported in the literature.
Clinical description
The metabolic disturbance in LPI causes increased renal excretion and reduced absorption from intestine of dibasic amino acids and orotic aciduria. Patients affected by LPI may present with nausea and vomiting after protein ingestion, diarrhea, failure to thrive, hepatosplenomegaly, bone marrow abnormalities, osteopenia, episodes of hyperammoniaemic coma, altered immune response, autoimmune manifestations, cytopenias associated with macrophagic activation syndrome, chronic renal disease, and lung involvement (interstitial lung disease due to alveolar proteinosis).
Etiology
It is caused by defective dibasic amino acids transport at the basolateral membrane of epithelial cells in the kidney and intestine. LPI is caused by at least 69 affecting-function variants in the gene coding for solute carrier family 7A member 7 (SLC7A7) located at chromosome 14q11.2, with no clear genotype-phenotype correlation found so far.
Diagnostic methods
Diagnosis requires amino acid assays in plasma and urine where increased urinary excretion and low plasma concentration of lysine, arginine, and ornithine indicate positive diagnosis, but these signs may vary over time. Macrophagic activation syndrome is a constant finding, with hepatosplenomegaly, hyperferritinemia and elevated LDH. Identification of biallelic pathogenic variants (by single-gene testing or multigene panel depending on the clinical findings) can help confirm the diagnosis.
Differential diagnosis
The differential diagnoses include other causes of hyperammonemia, lysosomal storage diseases, other causes of macrophage activation syndrome, and some autoimmune disorders such as systemic lupus erythematosus.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
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 that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Acute hyperammonemic manifestations are treated by intravenous administration of nitrogen-scavenger drugs, dextrose infusion and/or extra-renal depuration following the usual guidelines for hyperammonemia management. Due to HLH, intravenous lipids should be avoided. Long term treatment revolves around protein-restricted diet (1-1.5 g/kg/day in children and 0.5-0.8 g/kg/day in adults) and supplement of citrulline (<100 mg/kg/day), and monitoring of biochemical markers. The complication of pulmonary alveolar proteinosis has been reported to be successfully treated by whole lung lavage.
Prognosis
Prognosis varies depending on early identification of the disease, hyperammonemia and pulmonary complications. Pulmonary involvement represents a major cause of impaired clinical course and fatal outcome. In adulthood, chronic kidney failure is common, and may require dialysis followed by renal transplantation. Long-term outcomes are also related to the unpredictable risk of occurrence of autoimmune and/or dysimmune manifestations, independent from the metabolic management.

                            Last update:
                            January 2024

                            - Expert reviewer(s):
                            Dr Juliette BOUCHEREAU | MetabERN* - Pr Manuel SCHIFF

                                * European Reference Network


A rare, progressive metabolic liver disease due to marked to complete lysosomal acid lipase deficiency and characterized by dyslipidemia and massive lipid accumulation leading to hepatomegaly and liver dysfunction, splenomegaly, accelerated atherosclerosis.

Summary:
Epidemiology
Based on allele frequency, worldwide birth prevalence is estimated at 1/177,000; however, birth prevalence is lower in populations with Finnish, Ashkenazi Jewish, and South or East Asian ancestry.
Clinical description
Presentation is along a clinical continuum with variable rates of progression and severity. The early-onset, rapidly progressive form, Wolman disease, presents in the neonatal or infantile period with non-specific symptoms of massive hepatosplenomegaly, liver failure, diarrhea/steatorrhea and vomiting, resulting in malabsorption, and cachexia. Adrenal calcifications occur in approximately half of infants. The later onset form, cholesteryl ester storage disease (CESD), presents between childhood and adulthood with a more variable clinical course that ranges from insidious to symptomatic. Progressive lysosomal lipid accumulation leads to the characteristic liver pathology and dysfunction (including hepatomegaly, liver fibrosis and/or cirrhosis, and elevated serum transaminases), dyslipidemia (elevated serum LDL-cholesterol and triglycerides, with normal to low HDL-cholesterol concentrations), premature atherosclerosis, splenomegaly and, eventually, end-stage liver failure. Secondary complications are variable and may include portal hypertension, ascites, cachexia, esophageal varices, gastrointestinal bleeding, coronary artery disease, aneurysm, stroke, anemia and thrombocytopenia. Approximately one-third of children experience severe gastrointestinal symptoms, including frequent diarrhoea, vomiting, abdominal pain, malabsorption and steatorrhoea.
Etiology
The disease is due to mutations in the gene LIPA (10q23.2-q23.3) encoding the enzyme lysosomal acid lipase (LAL). LAL hydrolyzes cholesteryl esters and triglycerides, and thus LAL deficiency results in gradual accumulation of these lipids in the liver, spleen, and other organs. The variable phenotype is due to the amount of residual LAL activity, less than 1% for Wolman disease and between 1-12% for CESD.
Diagnostic methods
The disease is suspected on clinical presentation of hepatomegaly, elevated transaminases, total cholesterol, low-density lipoprotein, and triglycerides, and low high-density lipoprotein. Liver biopsy shows microvesicular steatosis and/or fibrosis or cirrhosis. Immunostaining for lysosomal fat accumulation may facilitate diagnosis. Confirmation is by assessment of LAL activity on dry blood spot testing or in leukocytes and/or presence of a LIPA gene mutation.
Differential diagnosis
Differential diagnosis includes familial hypercholesterolemia, non-alcoholic fatty liver disease, cryptogenic cirrhosis, and combined hyperlipidemia, as well as other lysosomal storage disorders.
Antenatal diagnosis
Prenatal molecular genetic testing is possible in affected families.
Genetic counseling
The pattern of inheritance is autosomal recessive and genetic counseling is recommended. The sibling recurrence risk is 25%.
Management and treatment
Supportive measures include statins and cholestyramine to cholesterol, and liver transplant for end-stage liver failure. Patients should follow a diet low in cholesterol and triglycerides, and nutritional status should be monitored. Magnetic resonance imaging to assess liver and spleen volumes may be useful. Enzyme replacement therapy (ERT) with the enzyme sebelipase alfa (authorized in Europe and the US) is available; however, the long-term clinical efficacy is yet to be determined. In infants with severe disease, ERT improves 1-year survival rates. In patients with later-onset disease, ERT reduces alanine aminotransferase levels and liver fat content, and improves the lipid parameters. Anemia and thrombocytopenia should be treated with standard approaches.
Prognosis
In Wolman disease, patients rarely survive beyond infancy. In CESD, the prognosis and life expectancy is variable depending on the severity of the disease and timely diagnosis. The long-term prognosis with ERT is, as yet, unknown.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Dr Barbara BURTON


A rare lysosomal disease characterized by intermittent vomiting, hypotonia, lethargy, opisthotonos, and fatal outcome in early infancy, associated with deficient acid phosphatase in lysosomes. There have been no further descriptions in the literature since 1971.


A rare, genetic skeletal dysplasia marked by disproportionate short stature and the characteristic Madelung wrist deformity.

Summary:
Epidemiology
Prevalence of Léri-Weill dyschondrosteosis (LWD) is unknown.
Clinical description
The characteristics of mesomelic disproportion of the limbs and Madelung deformity may develop over time, presenting anywhere from birth to adolescence. The wrist deformity is bilateral and is characterized by shortened and bowed radii and ulnae leading to dorsal dislocation of the distal ulna and limited mobility of the wrist and elbow. Expression is variable but the clinical features are generally more severe in females. Male patients show an athletic body habitus due to muscular hypertrophy, without any underlying muscle disorder. Intelligence is normal.
Etiology
In around 70% of cases, LWD is caused by haploinsufficiency of the short stature homeobox (SHOX) gene, which maps to the pseudoautosomal region 1 (PAR1) of the sexual chromosomes (Xp22.33 and Yp11.32). Haploinsufficiency results from heterozygous mutations and deletions of SHOX, or of the enhancer regions located upstream and downstream of SHOX, in the PAR1. The molecular defect remains unknown in the remaining 30% of LWD cases. SHOX-associated LWD is part of a spectrum of disorders (ranging from the most severe Langer mesomelic dysplasia (LMD) to LWD to short stature, all associated with SHOX/PAR1 anomalies. The prevalence of SHOX/PAR1 mutations is estimated at 1/1000.
Diagnostic methods
Diagnosis of LWD may be suspected on the basis of the clinical and radiologic findings and can be confirmed by molecular analysis (preferably multiplex ligation-dependent probe amplification for PAR1 deletions and DNA sequencing for point mutations, small deletions and insertions of SHOX).
Differential diagnosis
Differential diagnoses should include the other SHOX-related haploinsufficiency disorders and related conditions such as Turner syndrome and distal monosomy Xp.
Antenatal diagnosis
Prenatal genetic testing is available; however, requests for testing for these disorders are uncommon but are more frequent for LMD. LWD may be suspected by ultrasound at 20 weeks of gestation on presentation of short limbs.
Genetic counseling
LWD is inherited in a pseudoautosomal dominant manner with each child of an affected individual having a 50% risk of inheriting the mutation. If both parents have LWD, the offspring will have a 50% risk of having LWD, a 25% risk of having LMD, and a 25% risk of having neither condition.
Management and treatment
Management should include regular surveillance with biannual height evaluations and annual wrist radiographs. Treatment options include administration of recombinant human growth hormone (rhGH) to improve final adult height; or concurrent use of rhGH and gonadotrophin-releasing hormone agonist (GnRHa) to prevent the blunted pubertal growth spurt caused by the presence of estrogen. Molecular genetic testing of at-risk family members ensures early treatment with rhGH therapy to improve growth. Wrist splints, supports and ergonomic devices may reduce wrist discomfort. In some cases, surgical intervention (physiolysis of the ulnar aspect of the distal radius and excision of the Vickers ligament) is required in mid-to-late childhood and may decrease pain and restore wrist function.
Prognosis
The quality of life is good for individuals with LWD. Pain may worsen with age due to arthritis in the joint. Individuals with LMD have problems associated with their severe short stature and severely shortened arms.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Karen HEATH


Machado-Joseph disease type 1 is a rare, usually severe subtype of Machado-Joseph disease (SCA3/MJD, see this term) characterized by the presence of marked pyramidal and extrapyramidal signs.

Summary:
Epidemiology
The prevalence of this form of MJD is not known. It accounts for 13% of all SCA3 cases.
Clinical description
Onset is generally early (mean of 24 years) and symptoms progress rapidly. MJD Type 1 patients generally present with cerebellar signs and external progressive ophthalmoplegia with variable degrees of pyramidal manifestations (spasticity, hyperreflexia). Patients also have extrapyramidal signs including dystonia.
Etiology
The disease is caused by CAG repeat expansion mutations in the ATXN3 gene (14q21). Patients with this subtype of SCA3 tend to have larger CAG expansions than those with other subtypes.
Genetic counseling
MJD follows an autosomal dominant pattern of inheritance.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Machado-Joseph disease type 2 is a subtype of Machado-Joseph disease (SCA3/MJD, see this term) with intermediate severity characterized by an intermediate age of onset, cerebellar ataxia and external progressive ophthalmoplegia, with variable pyramidal and extrapyramidal signs.

Summary:
Epidemiology
The prevalence of this form of MJD is not known. It is the most frequent form of SCA3 and accounts for 57% of all SCA3 cases.
Clinical description
Patients develop the disease in middle adulthood (mean age 40 years). If present, extrapyramidal and peripheral manifestations are mild. Some patients progress within 5 to 10 years to type 1 MJD (see this term) if significant extrapyramidal signs develop, or type 3 MJD (see this term) if significant peripheral signs appear.
Etiology
The disease is caused by CAG repeat expansion mutations in the ATXN3 gene (14q21).
Genetic counseling
MJD follows an autosomal dominant pattern of inheritance.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Machado-Joseph disease type 3 is a subtype of Machado-Joseph disease (SCA3/MJD, see this term) of milder severity characterized by late onset, slower progression, and peripheral amyotrophy.

Summary:
Epidemiology
The prevalence of this form of MJD is not known. It accounts for 30% of all SCA3 cases.
Clinical description
The mean age of onset is 46 years and signs include cerebellar ataxia and external progressive ophthalmoplegia along with peripheral amyotrophy, with or without mild pyramidal and extrapyramidal features.
Etiology
The disease is caused by CAG repeat expansion mutations in the ATXN3 gene (14q21).
Genetic counseling
MJD follows an autosomal dominant pattern of inheritance.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Dr Shinsuke FUJIOKA  - Dr Nathaniel WHALEY  - Dr Zbigniew WSZOLEK


Macrocephaly-developmental delay syndrome is a rare, intellectual disability syndrome characterized by macrocephaly, mild dysmorphic features (frontal bossing, long face, hooded eye lids with small, downslanting palpebral fissures, broad nasal bridge, and prominent chin), global neurodevelopmental delay, behavioral abnormalities (e.g. anxiety, stereotyped movements) and absence or generalized tonic-clonic seizures. Additional features reported in some patients include craniosynostosis, fifth finger clinodactyly, recurrent pneumonia, and hepatosplenomegaly.


A rare, genetic, neurological disease characterized by association of macrocephaly, dysmorphic facial features and psychomotor delay leading to intellectual disability and autism spectrum disorder. Facial dysmorphism may include frontal bossing, hypertelorism, midface hypoplasia, depressed nasal bridge, short nose, and long philtrum.


Macrocephaly-intellectual disability-left ventricular non compaction syndrome is a rare, genetic, syndromic intellectual disability characterized by motor and cognitive developmental delay with language impairment, macrocephaly, hypotonia, dysmorphic facial features (including long face, slanting palpebral fissures and prominent, flattened nose) and left ventricular noncompaction cardiomyopathy. Patients also present skeletal abnormalities (e.g. scoliosis, finger clinodactyly, pes planus), slender build and shy behavior. Strabismus and various neurological signs (including ataxia, tremor and hyperreflexia) may be associated, as well as epilepsy, autism and MRI findings showing a small cerebellum and abnormalities of the corpus callosum. A phenotypic variant with no cardiac involvement has been reported.


Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability, characterized by macrocephaly, intellectual disability, seizures, dysmorphic facial features (including tall forehead, downslanting palpebral fissures, hypertelorism, depressed nasal bridge, and macrostomia), megalencephaly, and small thorax. Other reported features are umbilical hernia, muscular hypotonia, global developmental delay, autistic behavior, and café-au-lait spots, among others.


A rare, syndromic intellectual disability characterized by macrocephaly, short stature, intellectual disability, variable degree of spastic paraplegia, central nervous system malformations (hydrocephalus, Dandy-Walker malformation), and dysmorphic features, such as high and broad forehead, midface hypoplasia, and small and broad hands and feet. There have been no further descriptions in the literature since 1993.


Macrocephaly-spastic paraplegia-dysmorphism syndrome is a rare syndrome of multiple congenital anomalies characterized by macrocephaly (of post-natal onset) with large anterior fontanelle, progressive complex spastic paraplegia, dysmorphic facial features (broad and high forehead, deeply set eyes, short philtrum with thin upper lip, large mouth and prominent incisors), seizures, and intellectual deficit of varying severity. Inheritance appears to be autosomal recessive.


A rare common cystic lymphatic malformation characterized by a benign cystic lesion composed of dilated lymphatic channels. Macrocystic lesions consist of cysts larger than 1 cm in diameter. They usually present at birth or during the first years of life and most often occur in the head and neck region but may affect any site. Symptoms depend on the location and extent of the lesion. Infection, trauma, or intracystic hemorrhage can lead to lesional expansion. Malignant transformation does not occur.


A rare non-syndromic limb overgrowth characterized by isolated congenital enlargement of some or all tissue elements of one or more digits of the hand, typically within a peripheral nerve territory, with the nerve itself being elongated, as well as increased in diameter. The index finger is most commonly affected. If two or more digits are involved, these are always adjacent. The enlargement may be progressive with disproportionate or static with proportionate growth and can be unilateral or bilateral. Patients may experience pain and reduced range of motion.


A rare non-syndromic limb overgrowth characterized by isolated congenital enlargement of some or all tissue elements of one or more digits of a foot. Enlargement may be progressive with disproportionate or static with proportionate growth and can be unilateral or bilateral. It typically occurs within a peripheral nerve territory, with the nerve itself being elongated, as well as increased in diameter.


A rare hemophagocytic syndrome characterized by excessive activation and proliferation of macrophages and T cells occurring in the context of a variety of diseases, including infections, neoplasms, rheumatic disorders, and leading to sudden onset of persistent fever, lymphadenopathy, and hepatosplenomegaly. Complications include profound depression of one or more blood cell lines with coagulopathy and pancytopenia, and impaired liver and renal function. Bone marrow examination reveals numerous well differentiated macrophages actively phagocytosing hematopoietic elements.


A rare acquired skeletal muscle disease characterized by infiltration of the epimysium, perimysium, and perifascicular endomysium by macrophages with crystal inclusions composed of aluminum salts at the site of a previous vaccination (most commonly the deltoid muscle). Muscle necrosis is typically absent. Patients may present with myalgias, arthralgias, muscle weakness, chronic fatigue, asthenia, fever, and cognitive dysfunction. Signs and symptoms usually develop slowly over several months.


Macrosomia-microphthalmia-cleft palate syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by early macrosomia, bilateral severe microphthalmia and a protuberant abdomen with hepatomegaly. Additional reported features include brachycephaly, large fontanelles, prominent forehead, upturned nose and median cleft palate. Cyanotic apneic spells and overwhelming infection lead to death within the first 6 months of life. There have been no further descriptions in the literature since 1989.


Macrostomia-preauricular tags-external ophthalmoplegia syndrome

A rare developmental defect during embryogenesis characterized by macrostomia or abnormal mouth contour, preauricular tags or pits, and uni- or bilateral ptosis due to external ophthalmoplegia. This syndrome belongs to the oculoauriculovertebral spectrum, a developmental disorder affecting the structures derived from the first and second branchial arches.


Macrothrombocytopenia with mitral valve insufficiency is a rare hemorrhagic disorder due to a platelet anomaly characterized by dysfunctional platelets of abnormally large size, moderate thrombocytopenia, prolonged bleeding time and mild bleeding diathesis (ecchymoses and epistaxis), associated with mitral valve insufficiency.


Macular amyloidosis (MA) is a rare chronic form of cutaneous amyloidosis (see this term), a skin disease characterized by the accumulation of amyloid deposits in the dermis, clinically characterized by pruritic hyperkeratotic gray-brown macules that give a rippled or reticulated pattern of pigmentation usually in the upper back and extensor sites of arms, forearms and legs, and histologically by the deposition of amyloid in the upper dermis and close to the basal cell layer of the epidermis. MA is commonly associated with other skin diseases, such as atopic dermatitis.


Macular coloboma-cleft palate-hallux valgus syndrome is characterised by the association of bilateral macular coloboma, cleft palate, and hallux valgus. It has been described in a brother and sister. Pelvic, limb and digital anomalies were also reported. Transmission is autosomal recessive.


Macular corneal dystrophy (MCD) is a rare, severe form of stromal corneal dystrophy (see this term) characterized by bilateral ill-defined cloudy regions within a hazy stroma, and eventually severe visual impairment.

Summary:
Epidemiology
Prevalence of this form of corneal dystrophy is not known. Cases of MCD have been identified worldwide. The condition is most prevalent in India, Saudi Arabia, Iceland and parts of the USA.
Clinical description
Whitish opacities in the cornea usually appear during adolescence but may develop in early infancy, or as late as the 6th decade of life. The non-transparent areas progressively merge as the entire corneal stroma becomes cloudy, causing severe visual impairment usually before the 5th decade. The bilateral corneal opacities progressively extend through the entire thickness of the central and peripheral corneal stroma. The corneal stroma is thinner than normal.
Etiology
Most cases of MCD are caused by mutations in the CHST6 gene (16q22) encoding a protein involved in the production of keratan sulfate, which plays a role in the maintenance of corneal transparency. More than 125 mutations in this gene have been identified to date.
Diagnostic methods
MCD is characterized histopathologically by intracytoplasmic accumulations of non-sulfated keratan sulfate within the keratocytes and corneal endothelium, sparing the corneal epithelium. MCD is classified as a corneal stromal dystrophy but also involves the Descemet membrane and the corneal endothelium.
Differential diagnosis
The clinical features of MCD are similar to the corneal involvement found in the systemic mucopolysaccharidoses, such as mucopolysaccharidosis type IH and IS and the mucolipidoses (see these terms).
Genetic counseling
An autosomal recessive mode of inheritance has been shown in most cases, but some cases are of unknown etiology.
Management and treatment
Since the condition affects the entire corneal stroma, Descemet membrane and corneal endothelium, lamellar keratoplasty does not excise all damaged tissue. Corneal transplantation may therefore be needed. Vision can be restored by corneal grafting but opacities may recur in the graft after many years.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Gordon KLINTWORTH


Maculopapular cutaneous mastocytosis (MCM) is a form of cutaneous mastocytosis (CM; see this term) characterized by the presence of multiple hyperpigmented macules, papules or nodules associated with abnormal accumulation of mast cells in the skin.

Summary:
Epidemiology
MCM is the most common form of CM (accounting for up to 90% of cases) but the prevalence in the general population is unknown. Incidence has been estimated at between 1/1000 and 1/125 births. This entity is most commonly reported among the Caucasian population and affects both sexes, although a slight male predominance (1.7-1.8:1) has been reported in cases with early onset.
Clinical description
The majority of patients present in infancy or childhood but onset may also occur in adulthood. As lesions vary in aspect, several subvariants have been described in the past (plaque form, typical form, telangiectatic form, and nodular form) but are all now grouped under the same entity. The plaque or papular form presents with orange/yellow papules or plaques often appearing during the first few months of life. Typical or classic forms have a more widespread, symmetrical distribution of round or oval red/brown macules. The telangiectatic form (telangiectasia macularis eruptiva perstans; TMEP) is a disputed entity described as a rare variant occurring in adults and characterized by the presence of red/brown telangiectatic macules. The nodular form is rare. In MCM, the size and number of lesions is variable, typically ranging in size from 1 mm to over 1 cm and in number from 10-1000 lesions. MCM may appear on all regions of the body but the trunk and extremities are most frequently involved. The palms and soles are usually spared. Darier's sign, dermographism and pruritus are additional features of MCM. Extensive mechanical manipulation and other factors that trigger mast cell degranulation (non-steroidal anti-inflammatory drugs, physical stimuli, emotional stress, insect venom and certain foods) may lead to systemic symptoms such as flushing, headache, dyspnea, wheezing, rhinorrhea, nausea, vomiting, diarrhea, and syncope.
Etiology
Mutations in the KIT gene (4q11-q12) have been identified in patients with MCM. However, this mutation is rare in the pediatric population and the etiology and pathogenesis of MCM in these cases remains to be determined. MCM generally occurs sporadically but rare familial cases have been reported.
Diagnostic methods
Diagnosis in children is based on the clinical appearance of the lesions and the positive Darier's sign. Occasionally (generally in cases with presentation after 5 years of age), a skin biopsy may be required for confirmation of the diagnosis. In adults, a bone marrow examination should be performed to exclude the diagnosis of SM.
Differential diagnosis
The diagnosis is usually straightforward but misdiagnosis as chronic urticaria or idiopathic anaphylaxis has been reported.
Management and treatment
Trigger factors should be avoided and symptomatic management includes administration of antihistamines, topical steroids and mast cell membrane stabilizers. PUVA or UVA1 therapy may also be used for adolescents or adults who do not respond to other forms of treatment.
Prognosis
The prognosis is good, especially for patients with childhood onset below the age of 5 years, with improvement (around 50% of cases) or complete resolution (30% of cases) of symptoms by adolescence. In contrast, spontaneous resolution is rare in patients with adult-onset forms of the disease and there is a higher risk of systemic involvement.

                            Last update:
                            June 2013

                            - Expert reviewer(s):
                            Pr A.P. [Arnold] ORANJE


Madras motor neuron disease (MMND) is characterized by weakness and atrophy of limbs, multiple lower cranial nerve palsies and sensorineural hearing loss.

Summary:
Epidemiology
Less than 200 cases have be reported to date, predominantly from Southern India. Isolated MMND cases have been reported from Thailand and Italy.
Clinical description
Onset occurs at a young age (often before the age of 15), with a slight male preponderance or equal sex distribution. Parental consanguinity has been reported in some cases. Main clinical features include thin habitus, wasting and weakness predominantly of the distal limb muscles, involvement of facial and bulbar muscles, and pyramidal dysfunction. Multiple cranial nerve palsies particularly involve the 7th, and the 9th to 12th cranial nerves. Hearing impairment was described in all patients. Optic atrophy is reported in some patients.
Etiology
The etiopathogenesis of MMND remains unknown. The majority of cases are sporadic. A few familial cases have been reported, but the mode of inheritance is yet to be determined. Inflammation and/or environmental factors may play a role in the etiology of MMND.
Diagnostic methods
Diagnosis is clinical and is supported by the association of benign focal atrophy of the extremities with hearing impairment. Neuroimaging studies may help to distinguish MMND from other motor neuron diseases.
Differential diagnosis
Differential diagnoses include amyotrophic lateral sclerosis, spinocerebellar ataxia syndromes, Brown-Vialetto-Van Laere syndrome, progressive muscular atrophy, post-polio progressive muscular atrophy, and spinal muscular atrophy (see these terms).
Management and treatment
Currently, there is no cure for MMND. Management should involve a multidisciplinary team (neurologists, physical therapists, occupational therapists, palliative care specialists, specialist nurses and psychologists) and should focus on the relief of symptoms. Symptomatic treatment and supportive care can help patients to maintain their daily living activities. Patients should be offered hearing aids.
Prognosis
The disease shows a slowly progressive but benign course. Most of the reported patients survived for over 30 years after the onset of the disease.

                            Last update:
                            April 2008

                            - Expert reviewer(s):
                            Dr Luciano MERLINI


A rare disorder characterized by multiple enchondromatosis associated with multiple (dark, irregularly shaped) hemangiomas. Less commonly, lymphangiomas are also reported.

Summary:
Epidemiology
About 250 cases worldwide have been reported in the literature so far. The disease affects both males and females.
Clinical description
Symptoms are present usually in childhood, but may occur at birth, during infancy or, rarely, at a later age. Vascular anomalies are diagnosed a median of 2 years after the enchondromas. Because of this, it may be misdiagnosed as Ollier disease. Moreover, fewer than 15% of patients with Maffuci syndrome are diagnosed with vascular anomalies before the age of 1 year. Enchondromas are commonly found in the bones of the hands and feet, as well as the femur, tibia, fibula, and pelvis, rarely the humerus, ribs, and skull. Lesions are asymmetrically distributed and may be uni- or bilateral. This asymmetric distribution may result in bones deformities which include asymmetrical growth, limb length inequality or angular deformity (genu varum or genu valgum). Functional impairment and deformities may cause fractures in some patients. Soft tissue, visceral, or cutaneous hemangiomas manifest as blue subcutaneous nodules. Rarely, lymphangiomas or phlebectasias may be found. Hemangiomas can be uni- or bilateral and are generally asymmetric with wide distribution and reported locations including the leptomeninges, eyes, pharynx, tongue, trachea, and intestines. The disease course tends to be slow, with bone and skin abnormalities resolving in the second or third decade of life. There is however a risk of malignant progression from enchondromas to chondrosarcoma in adulthood. Hemangiomas can also become malignant in about 8.5% of cases. Other reported malignancies include pancreatic and hepatic adenocarcinoma, mesenchymal ovarian tumors, as well as glioma, astrocytoma, and sarcomas.
Etiology
Somatic mutations in IDH1 (2q34) and IDH2 (15q26.1) have been identified in affected tissue (enchondromas or spindle cell hemangiomata) of most tested patients. No familial case has been reported.
Diagnostic methods
The diagnosis is based on the characteristic occurrence of enchondromas and hemangiomas. As in Ollier disease, diagnosis of enchondromas is based on clinical and conventional radiological evaluations. Enchondromas appear as radiolucent defects that originate in the metaphyses.
Differential diagnosis
Ollier disease is the main differential diagnosis.
Management and treatment
Management and treatment aim to relieve symptoms and are not indicated in asymptomatic patients. Regular examinations by an orthopedic surgeon and dermatologist to evaluate changes in the skin and bone lesions are mandatory. Annual monitoring of malignant transformation is recommended. No specific therapy exists to treat the disease. Surgery is at present the only option when complications occur.
Prognosis
Depending on the extent of skeletal involvement, Maffucci syndrome may result in severe deformities with functional and quality of life repercussions. Life span depends on malignant transformation but is otherwise normal. Prognosis is difficult assess because of wide clinical expression and variability, and low prevalence of the disease.

                            Last update:
                            May 2023

                            - Expert reviewer(s):
                            Dr Luca SANGIORGI | ERN BOND*

                                * European Reference Network


A rare Prader-Willi-like syndrome characterized by arthrogryposis, including contractures of the proximal and distal interphalangeal joints, and autism spectrum disorder due to MAGEL2 mutation. Overlapping phenotypes with Prader-Willi syndrome include hypotonia, feeding difficulties, weigth gain, developmental delay, intellectual disability and hypogonadism. Minority of patients manifest hyperphagia and morbid obesity in contrast to patients with Prader-Willi syndrome.


A rare autoinflammatory syndrome characterized by the presence of features of relapsing polychondritis and Behçet's disease in the same individual. This includes cartilage inflammation of the ears, nose, throat, and rib cage, as well as recurrent oral and genital ulcers, respectively. Patients may also present ocular involvement (in particular anterior uveitis or scleritis), arthritis, fever, colitis, thrombophlebitis, central nervous system vasculitis, or, in rare cases, arterial aneurysms. Symptoms of polychondritis occur secondary to those of Behçet's disease in the vast majority of cases.


Majeed syndrome is a rare genetic multisystemic disorder characterized by chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anemia, which may be accompanied by neutrophilic dermatosis.

Summary:
Epidemiology
The syndrome is extremely rare. Fourteen cases born into consanguineous families, from the Middle East, India and Spain have been reported.
Clinical description
Onset is generally within the first two years of life although it may present later in childhood (range 1 month to 8 years) as bone pain. Chronic recurrent multifocal osteomyelitis (CRMO) associated with Majeed syndrome is typically more severe than that of non-syndromic CRMO, and is more persistent, with short remissions and more frequent exacerbations. It can be associated with fever, joint pain, delayed bone age, growth failure, short adult stature, and development of flexion contractures. Patients also have a hypochromic, microcytic anemia with dyserythropoiesis present on 11 of 11 bone marrow biopsies. In half of the cases, the anemia is mild with the remainder requiring one or more transfusions for anemia. The inflammatory neutrophilic dermatosis Sweet syndrome has been reported in two patients with Majeed syndrome. Other reported manifestations include failure to thrive, hepatomegaly, neutropenia, and transient cholestatic jaundice. The course is chronic and the syndrome may have a significant impact on quality of life.
Etiology
Majeed syndrome is caused by a mutation in LPIN2 (18p11.31), which encodes phosphatidate phosphatase LPIN2 (Lipin-2), important in lipid metabolism. Recent studies have shown that Lipin-2 is a negative regulator of the NLRP3 inflammasome.
Diagnostic methods
The diagnosis is based on the typical clinical manifestations and on molecular genetic testing of the causative gene mutation. Osteomyelitis can be diagnosed on skeletal radiographs but may require magnetic resonance imaging (MRI). Bone, bone marrow and skin biopsies may also be needed.
Differential diagnosis
Differential diagnoses include Caffey disease, SAPHO syndrome, non-syndromic CRMO, deficiency of the interleukin-1 receptor antagonist (DIRA) and immune deficiency.
Antenatal diagnosis
Prenatal diagnosis is possible in affected families when a disease causing mutation has been identified.
Genetic counseling
Majeed syndrome follows an autosomal recessive pattern of inheritance. Genetic counseling can inform parents with an affected child of their 25 % risk of having an affected child at each pregnancy.
Management and treatment
Treatment is empiric. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main treatment options for non-syndromic CRMO, but are not likely to control bone inflammation in Majeed syndrome patients. Corticosteroids may also be used to control CRMO and inflammatory dermatosis, but have a multitude of side effects that limit their use for long term treatment. Methotrexate with or without pamidronate has been utilized in a few cases with mild to moderate improvement reported. TNF inhibitors were used in 2 children without significant benefit. IL-1 beta inhibition looks more promising with resolution of clinical symptoms, normalization of blood inflammatory markers and normalization of radiologic bone lesions in 4 of 4 patients treated.
Prognosis
The prognosis has generally been poor because of progressive bone and hematological manifestations, however, outcomes have improved with more aggressive treatments. There is limited information on long-term outcomes in patients treated with IL-1 beta inhibitors but short-term follow-up has shown sustained clinical response to this biologic class.

                            Last update:
                            August 2017

                            - Expert reviewer(s):
                            Dr Polly FERGUSON


Mal de débarquement (MdD) is a rare otorhinolaryngological disease characterized by a persistent sensation of motion such as rocking, swaying, tumbling and/or bobbing following a period of exposure to passive movement, usually an ocean cruise or other types of water, train, automobile or air travel and less commonly other movements (like sleeping on a waterbed). Onset may be spontaneous in some patients. Manifestations begin shortly after the stimulus, persist for 6 months to years and may be associated with anxiety, fatigue and impaired cognition. Symptoms are often accentuated when in an enclosed space or when attempting to be motionless (sitting, lying down or standing in a stationary position) and are relieved when in passive motion such as in a moving car, airplane or train.


A rare diffuse palmoplantar keratoderma characterized by symmetric palmoplantar hyperkeratosis that progressively extends to the dorsal surfaces of hands and feet (transgrediens). The disease can be associated to hyperhidrosis, lichenoid plaques and perioral erythema.

Summary:
Epidemiology
The estimated worldwide prevalence is 1:100,000. About 300 patients with a molecularly confirmed pathogenic variants are described in the literature. Most of these patients were from Mediterranean countries in Europe, North Africa, the Middle East, and South Asia.
Clinical description
Onset is in the first months of life. The first symptom is erythema on the palms and soles, rapidly followed by diffuse, yellowish hyperkeratosis. Keratoderma of the dorsal surface of the distal phalanges gradually extends (sometimes in a glove/stocking-like manner) to the dorsa of the hands and feet, affecting the wrists and ankles in the majority of cases. In most patients, transgressive keratoderma also affects the apparence of the ulnar forearms. Keratoderma on the palms and soles is usually surrounded by a red, erythrodermic scale. Hyperconvexity of the nails and conical terminal phalanges are constant features of the disease, mainly in adult patients. In older patients, contractures of the hands and fingers and sclerodactyly (whitish, conical, sclerodermiform phalanges) are common. Hyperhidrosis, pseudoainhum and brachydactyly can be observed in some patients. Other features include perioral erythema, lichenoid plaques on the knees and the elbows, and nail abnormalities.
Etiology
Mal de Meleda (MDM) is caused by biallelic mutations in the gene SLURP1 (chromosome 8q24). SLURP1 mediates keratinocyte apoptosis and down-regulates tumor necrosis factors-induced inflammation. The variants are mostly missense and nonsense mutations, or, to a lesser extent, splicing substitutions or small deletions. A case of large deletion was also described in the literature. Less than 30 different pathogenic variants with an allele frequency of less than 0,001 each are described in the databases.
Diagnostic methods
The diagnosis is based on the evaluation of clinical signs and confirmed by multiplex ligation-dependent probe amplification (MLPA), quantitative PCR or DNA sequencing (e.g. Sanger sequencing, NGS).
Differential diagnosis
Differential diagnosis includes diffuse palmoplantar keratodermas such as Papillon-Lefevre-Syndrome, Greither disease, epidermolytic palmoplantar keratoderma, non-epidermolytic palmoplantar keratoderma, and palmoplantar keratodermas, Nagashima type. It also includes mild forms of pachyonychia congenita, and Vohwinkel syndrome with ichthyosis.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
MDM is an autosomal recessive transmitted disease with full penetrance. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment recommendations include systemic retinoids, oral retinoid acid or oral acitretin (20 mg/day), topical antimicrobial and keratolytic therapy.
Prognosis
The progressive nature of the lesions in MDM can lead to severe functional handicap with reduced mobility of hands and feet.

                            Last update:
                            March 2023

                            - Expert reviewer(s):
                            Pr Judith FISCHER | ERN-Skin*

                                * European Reference Network


Malakoplakia is a chronic multisystem granulomatous inflammatory disease characterized by the presence of single or multiple soft plaques on various organs of the body.

Summary:
Epidemiology
Prevalence is unknown but more than 700 cases have been described in the literature.
Clinical description
Malakoplakia can occur in all ages, with a mean age at diagnosis of 50 years old and a female predominance. Pediatric cases are rare. It is most common in immunodeficient patients with a history of diabetes, transplantation, lymphoma, steroid therapy or alcoholism. In the majority of cases (60-80%), malakoplakia affects the urinary tract (bladder, kidney, and ureters) and cases of locoregional extension have been reported (retroperitoneal region and lymph nodes). Other organs can also be involved, with the gastrointestinal system (left colon, sigmoid, rectum, stomach) being the second most common site (15%). Other sites include the genital tract, skin, neck, tongue, lungs, and central nervous system. Patients are either asymptomatic or present with clinical symptoms that are non specific (fever, pain) and that vary depending on the organ involved. In case of urinary tract involvement, patients generally present with chronic urinary tract infections and symptoms such as urinary urgency, hesitancy, intermittent dysuria, hematuria, and proteinuria. In case of gastrointestinal involvement, patients can present with symptoms such as recurrent diarrhea, dyspepsia, abdominal pain, and hemorrhage. In case of malakoplakia of the female genital tract, patients usually present with vaginal bleeding. Cutaneous malakoplakia presents as papules or ulcerations on various locations (abdomen, face, perianal region) associated with rash and itching. Malakoplakia can also be associated with other granulomatous diseases such as sarcoidosis and tuberculosis, and with carcinomas (prostate and colorectal carcinomas).
Etiology
Malakoplakia seems to be due to an impaired response to bacterial infection. Macrophages and monocytes show a defective phagolysosomal activity: they phagocytose bacteria but are unable to digest them completely. Partially digested bacteria accumulate in the cytoplasm and lead to a granulomatous reaction of the immune cells. It has been suggested that the defective phagolysosomal activity could be due to a decrease in the concentration of intracellular cyclic guanosine monophosphate (cGMP).
Diagnostic methods
The diagnosis of malakoplakia is difficult due to the absence of specific clinical symptoms and no specific characterization in imaging. Diagnosis is based on endoscopy which reveals the presence of vascularized yellowish or white polypoid nodules or plaques. The diagnosis is confirmed by biopsy of the affected tissue. Histological examination reveals the presence of von Hansemann cells (histiocytes with small nuclei and granular acidophilic cytoplasm) with Michaelis-Gutmann bodies (periodic acid-Schiff and von Kossa positive calcific inclusions). This lesion is pathognomonic for malakoplakia. Michaelis-Gutmann bodies probably correspond to partially digested calcified bacterial inclusions.
Differential diagnosis
Depending on the organ involved, differential diagnoses include primary or metastatic malignancies, inflammatory diseases (sarcoidosis, Crohn's disease; see these terms), infections (tuberculosis, Whipple disease; see these terms), and cutaneous fungal infections.
Management and treatment
Treatment consists in antibiotherapy that uses intracellular molecules (fluoroquinolones, trimethroprim-sulfametoxazol). Currently, the duration of therapy is still not standardized. In pseudo-tumoral cases, surgical removal of the lesions is required.
Prognosis
Prognosis is usually good. However, recurrences and complications may occur over the years such as renal failure in case of urinary tract involvement.

                            Last update:
                            August 2011

                            - Expert reviewer(s):
                            Dr Maïté DAROUX


A rare multisystemic genetic disorder characterized by a characteristic facial features with macrocephaly, overgrowth in infancy, intellectual disability and behavioral problems including anxieties and aggressiveness.

Summary:
Epidemiology
Approximatively 80 patients have been reported in the literature to date.
Clinical description
Malan syndrome is an overgrowth disorder characterized by postnatal overgrowth (in infancy and childhood), developmental delay, moderate to severe intellectual disability and unusual behavior (i.e. anxieties, noise sensitivity, hetero/auto-aggressive behavior). It is worth noting that overgrowth is less marked in adulthood. The most characteristic facial features include macrocephaly, long, triangular face, prominent forehead, depressed nasal bridge, deeply set eyes, downslanting palpebral fissures, short nose with anteverted nares, small mouth with an everted lower lip and a prominent chin. Additional variable manifestations comprise musculoskeletal abnormalities with slender habitus, scoliosis and pectus excavatum as well as long hands. Visual problems are frequent, especially strabismus, myopia, hypermetropia, nystagmus and underdeveloped optic nerves. Structural brain imaging abnormalities (i.e. enlarged ventricles, hypoplasia of the corpus callosum, cortical dysplasia and periventricular nodular heterotopia) have also been reported. Some patients have seizures and/or electroencephalogram abnormalities. The increased prevalence of epilepsy in individuals with deletions of NFIX may be explained by the presence of a contiguous gene disorder.
Etiology
NFIX (Nuclear factor I X) haploinsufficiency is responsible for this syndrome and may be the result of heterozygous loss-of-function variants in the NFIX (Nuclear Factor I X (19p13.13) gene or 19p13 microdeletions encompassing the gene NFIX.
Diagnostic methods
Malan syndrome is a clinically recognizable overgrowth syndrome. The diagnosis is based on the major clinical findings including postnatal overgrowth, facial dysmorphism with macrocephaly, intellectual disability and behaviorally anxiety. The genetic diagnosis is established by identification of a heterozygous pathogenic variant in NFIX or a deletion encompassing this gene. Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and/or comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, genome sequencing).
Differential diagnosis
The differential diagnoses include Sotos syndrome, Weaver syndrome and Marfan or Marfan-like syndromes. In case of large 19p13 deletions, other clinical signs are reported corresponding to the 19p13.13 microdeletion syndrome.
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
Malan syndrome is inherited in an autosomal dominant manner. In the majority of cases, the pathogenic variants or deletions occur de novo. In this situation, the risk to sibs of the proband is very low due to a possible germinal mosaicism (<1%). In the rare familial cases, there is a 50% risk of transmitting the disease from an affected individual to offspring.
Management and treatment
Management of Malan syndrome requires a multidisciplinary approach with appropriate medical specialists for intellectual disability, seizures, musculoskeletal and ocular abnormalities. Special education training along with behavioral intervention therapy may also be required.
Prognosis
Malan syndrome has significant impact on quality of life.

                            Last update:
                            December 2020

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

                                * European Reference Network


A life-threatening parasitic disease caused by Plasmodium (P. ) parasites that are transmitted by Anophles mosquito bites to humans and is typically clinically characterized by attacks of fever, headache, chills and vomiting.


Male hypergonadotropic hypogonadism-intellectual disability-skeletal anomalies syndrome

This syndrome is characterized by hypergonadotropic hypogonadism, intellectual deficit, congenital skeletal anomalies involving the cervical spine and superior ribs, and diabetes mellitus.

Summary:
Epidemiology
It has been described in two brothers.
Clinical description
Testicular biopsy revealed germinal aplasia and complete seminiferous tubular fibrosis.

                            Last update:
                            May 2009


Male infertility due to globozoospermia is a male infertility due to sperm disorder characterized by the presence, in sperm, of a large majority of round-headed spermatozoa that lack the acrosome and have an aberrant nuclear membrane and midpiece defects. The acrosomeless spermatozoa is not able to penetrate the zona pellucida and thus fertilization failures, even with intracytoplasmic sperm injection, are frequent.


Male infertility due to large-headed multiflagellar polyploid spermatozoa

A rare male infertility due to a sperm disorder characterized by the presence, in sperm, of a very high percentage of spermatozoa with enlarged head, irregular head shape, multiple flagella, and abnormal midpiece and acrosome. It is generally associated with severe oligoasthenozoospermia and a high rate of sperm chromosomal abnormalities (polyploidy, aneuploidy).


Male infertility with azoospermia or oligozoospermia due to single gene mutation

A rare, genetic male infertility due to a sperm disorder characterized by the absence of a measurable amount of spermatozoa in the ejaculate (azoospermia), or a number of sperm in the ejaculate inferior to 15 million/mL (oligozoospermia), resulting from a mutation in a single gene known to cause azoo- or oligo-spermia. Sperm morphology may be normal.


Male infertility with teratozoospermia due to single gene mutation is a rare, genetic male infertility due to sperm disorder characterized by the presence of spermatozoa with abnormal morphology, such as macrozoospermia or globozoospermia, in over 85% of sperm, resulting from mutation in a single gene known to cause teratozoospermia. It is a heterogeneous group that includes a wide range of abnormal sperm phenotypes affecting, solely or simultaneously, head, neck, midpiece, and/or tail.


A rare condition characterized by the occurrence and/or diagnosis of a malignancy during pregnancy. The most frequently diagnosed neoplasms are gynecologic tumors, especially cervical cancer, followed by hematologic malignancies. Patient management should be carried out by a multidisciplinary team of specialists.


Malignant atrophic papulosis (MAP) is a rare, chronic, thrombo-obliterative vasculopathy characterized by papular skin lesions with central porcelain-white atrophy and a surrounding teleangiectatic rim. Systemic lesions may affect the gastrointestinal tract and the central nervous system (CNS) and are potentially lethal.

Summary:
Epidemiology
Less than 200 cases have been described in the literature.
Clinical description
MAP onset occurs in adults aged 20-50 with skin lesions that appear initially as small erythematous papules, predominantly on the trunk and the upper extremities. Over several days, the center of the lesions sinks and develops a characteristic morphology: 0.5-1 cm wide papules with an atrophic porcelain-white center and an erythematous, teleangiectatic rim. This condition is chronic and lesions persist over years, often throughout life. Face, scalp, palms of hands and soles of feet are rarely involved. In the systemic variant, which may develop simultaneously or even years after cutaneous symptoms, patients may present with multiple limited infarcts of the intestine, with abdominal pain, bleeding and diarrhea, and/or of the CNS, with cerebrovascular accidents (in rare cases, medullary). It may more rarely manifest as pericarditis or in other organs such as the lungs, presenting as pleuritis. Ocular involvement, which affects the eyelids, conjuctiva, retina, sclera and the choroid plexus, as well as the development of diplopia and ophthalmoplegia (as secondary side effects of the neurologic involvement), has also been described.
Etiology
The etiopathogenesis of the disease remains unknown. Hypotheses implicating vasculitis, coagulopathy or a primary dysfunction of endothelial cells have been proposed. Many patients have been reported to have defects in blood coagulation.
Diagnostic methods
Diagnosis is based primarily on the cutaneous clinical picture that is nearly pathognomonic. In early stages, histology of lesions may reveal a superficial and deep perivascular lymphocytic infiltration with distinct mucin deposition. Later a wedge-shaped connective tissue necrosis in the deep dermis, due to a thrombotic occlusion of the small arteries and sparse lymphocytes, occurs. More developed lesions show prominent changes in the dermoepidermal junction, with atrophy of the epidermis and an area of sclerosis in the papillary dermis.
Differential diagnosis
The histology of early lesions resembles cutaneous lupus erythematosus (see this term). More developed lesions can imitate lichen sclerosus (see this term).
Genetic counseling
A genetic predisposition with an autosomal dominant trait has been suggested.
Management and treatment
Therapeutic efforts with anticoagulants and compounds that facilitate blood perfusion, such as acetylosalicylic acid, pentoxifylline, dipyridamole, ticlodipine and heparin have achieved a partial regression of skin lesions in some individual cases. As all patients may potentially develop the systemic, life-threatening variant, an annual follow-up is mandatory. A clinical inspection of the skin should be combined with additional examinations including brain magnetic resonance tomography, gastroscopy, colonoscopy, X-ray of the chest and abdominal ultrasound, in order to assess the long-term prognosis. No effective treatment for the systemic manifestations has been established, however, subcutaneous treprostinil has been tested successfully in one case with intestinal and CNS manifestations.
Prognosis
Idiopathic, monosymptomatic, cutaneous presentations are benign, however, systemic manifestations can develop years after the occurrence of skin lesions. Systemic manifestations are progressive and may lead to serious complications: bowel perforation and peritonitis as well as thrombosis of the cerebral arteries or massive cerebral hemorrhage, meningitis, encephalitis, radiculopathy and myelitis which have been reported to be lethal in around 50% of patients within 2-3 years.

                            Last update:
                            April 2013

                            - Expert reviewer(s):
                            Pr Christos ZOUBOULIS


Malignant epithelial tumor of salivary glands

A rare neoplastic disease characterized by the presence of a tumor located in the parotid, sublingual, submandibular and/or minor salivary glands, which presents with a wide spectrum of clinical features depending on the location, size and type of salivary gland involved, ranging from clinically asymptomatic, slow-growing, painless mass(es), that may or may not be fixed to underlying skin or muscles, to rapidly growing mass(es) associated with pain, facial weakness/nerve palsy, otorrhoea, dysphagia, palatal/parapharyngeal fullness, nasal obstruction/bleeding, voice hoarseness/change, dyspnea, trismus, palate bone erosion, telangiectasia, mucosal/skin ulceration and/or cervical adenopathy.


Malignant germ cell tumor of ovary is a rare ovarian cancer arising from germ cells in the ovary, frequently unilateral at diagnosis which characteristically presents during adolescence with pelvic mass, fever, vaginal bleeding and acute abdomen.

Summary:
Epidemiology
The annual incidence is 1/200000 females in Europe. Ovarian germ-cell tumors represent 15-20% of all ovarian tumors, 3% of which are malignant.
Clinical description
Malignant germ cell tumor of ovary is almost always unilateral at diagnosis (except malignant dysgerminomatous germ cell tumor, which can be bilateral in 10 to 15% cases). It usually presents during adolescence with symptoms of abdominal pain, pelvic mass, fever and vaginal bleeding. In about 10% of tumors the mass may grow rapidly, resulting in acute abdomen due to capsular distension, necrosis, hemorrhage, rupture or torsion. Certain subtypes may occasionally be associated with isosexual precocity, dysgenetic gonads, virilization, hyperthyroidism or carcinoid syndrome. Malignant germ cell tumor of ovary comprises the following histological subtypes: malignant dysgerminomatous germ cell tumor (most frequent form), malignant non dysgerminomatous germ cell tumor (yolk sac tumor, embryonal carcinoma, mixed germ cell tumor), primary non-gestational choriocarcinoma of ovary and malignant teratoma of ovary.
Etiology
They are rapidly growing neoplasms that arise from germ cells in the ovary.
Diagnostic methods
Diagnosis relies on clinical findings, serum tumor markers and imaging. Imaging includes pelvic ultrasonography and computed tomography of abdomen and pelvis (if extra ovarian metastasis is suspected) and chest X-ray (to detect metastasis to lung and mediastinum). Dosage of human chorionic gonadotropin (hCG), lactate dehydrogenase (LDH) and alpha fetoprotein (alpha-FP) also contribute to the diagnosis, the prognosis and follow-up of the disease. 12 p isochromosome (i(12p)) and chromosome 12 over-representation are observed, in non teratomatous ovarian germ cell tumors while pure teratomas lack i(12p). Diagnosis is only confirmed histologically after laparotomy or laparoscopy.
Differential diagnosis
Differential diagnoses include the less common malignant ovarian sex cord-stromal tumor, small cell carcinomas of the ovary (see these terms) and ovarian involvement of non-gonadal tumors.
Management and treatment
Malignant germ cell tumor of ovary shows excellent sensitivity to platinum. Young women with tumor confined to a single ovary are treated with fertility sparing surgery (unilateral salphingo-oopherectomy with preservation of uterus and contralateral ovary), followed by careful surgical staging with appropriate adjuvant chemotherapy usually comprising of bleomycin, etoposide and cisplatin for stage I tumor (except pure dysgerminoma). In women with advanced disease, preservation of reproductive function is still possible particularly if the contralateral ovary is normal. Paclitaxel and ifosfamide can also be used in case of relapse or resistance to cisplatin.
Prognosis
When treated promptly and appropriately, these tumors have excellent prognosis with return of normal menstrual function and fertility rates and no increase in teratogenicity.

                            Last update:
                            September 2014

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


Malignant germ cell tumor of the cervix uteri is an extremely rare uterine neoplasm characterized by a usually polypoid, friable tumor deriving from primordial germ cells located in the uterine cervix. Presentation is non-specific and often includes abnormal vaginal bleeding and/or discharge, a cervical mass protruding from the vagina, abdominal and/or pelvic pain or, less commonly, difficulty passing stool and perianal pain. Various histological subtypes (incl. dysgerminoma, yolk sac tumor, choriocarcinoma and malignant teratoma) are reported.


Malignant germ cell tumor of the corpus uteri is an extremely rare uterine neoplasm characterized by a typically polypoid mass deriving from primordial germ cells localized in the endometrium. Presentation is non-specific and often includes abnormal vaginal bleeding and/or discharge, a mass protruding from the vagina, abdominal and/or pelvic pain or, less commonly, difficulty passing stool and perianal pain. The malignant teratoma and yolk sac tumor histological subtypes are the most common.


Malignant germ cell tumor of the vagina is an extremely rare, malignant, vulvovaginal neoplasm, deriving from primordial germ cells in the vagina, typically characterized by painless bloody vaginal discharge and a polypoid mass which protrudes from the vagina. Serum alpha-fetoprotein is usually elevated and rapid progression, local agression and early metastasis to liver and lungs is reported.


Malignant granulosa cell tumor of the ovary

A rare malignant sex cord stromal tumor of ovary arising from the granulosa cells of the ovary, which occurs in peri and post menopausal women, and that presents with abnormal vaginal bleeding, abdominal pain and distension. The tumor is frequently unilateral, estrogen secreting, and has a slow natural history and a tendency to relapse long after the initial diagnosis.