A group of rare lysosomal storage diseases characterized by progressive neurocognitive decline, loss of functional abilities and premature death. There are four etiological subtypes of mucopolysaccharidosis type 3 (MPS III, Sanfilippo syndrome) called Sanfilippo syndrome type A, B, C, and D. Each subtype is caused by deficiency of a particular enzyme involved in the degradation of heparan sulfate leading to substrate accumulation and cellular dysfunction.

Summary:
Epidemiology
The total number of patients with Sanfilippo syndrome is most likely underestimated due to delayed or missed diagnoses. The combined prevalence of Sanfilippo syndrome is estimated as 1:50,000 to 1:250,000 depending on the population studied. Sanfilippo syndrome type A is the most common subtype globally; however, the prevalence of subtypes can vary depending on the geographic region. Sanfilippo syndrome types C and D are much less common.
Clinical description
The age at onset, severity of symptoms and rate of disease progression vary greatly in Sanfilippo patients. The behavioral, cognitive, and physical findings present as a clinical spectrum from early-onset, rapidly progressive disease with death in late childhood and adolescence, to slower progressing forms that present in later childhood with survival into adulthood. After a period of normal development typical disease manifests between 1 and 4 years of age with mild global developmental or speech delay. Behavioral disturbances include but are not limited to hyperactivity, attention deficit, loss of impulse control, unawareness of dangerous situations, autistic-like behavior, hyperorality and unresponsiveness to discipline. Furthermore, patients frequently present with severe sleep disturbances. Physical manifestations are often less pronounced and might include musculoskeletal, respiratory, gastrointestinal, cardiovascular symptoms and hearing loss. In later stages of the disease patients show a decline in engagement with their environment, dementia, and progressive loss of motor function. Patients may develop seizures, dysphagia, and become fully bedridden.
Etiology
Deficiencies in one of the four enzymes required for heparan sulfate (HS) degradation are responsible for each of the subtypes: heparan-N-sulfatase for Sanfilippo syndrome type A (SGSH gene), alpha-N-acetylglucosaminidase for type B (NAGLU gene), alpha-glucosaminide N-acetyltransferase for type C (HGSNAT gene), and N-acetylglucosamine-6-sulfate sulfatase for type D (GNS gene). Numerous pathogenic variants have been identified in corresponding genes.
Diagnostic methods
In individuals with clinical features suggestive of Sanfilippo syndrome confirmation of diagnosis requires at least two biochemical or genetic tests. Diagnosis is based on detection of increased levels of HS in urine, demonstration of one of the four enzyme deficiencies and/or evidence of pathogenic or likely pathogenic variants in the corresponding genes. For types A and D, the measurement of the activity of another sulfatase is compulsory for exclusion of multiple sulfatase deficiency.
Differential diagnosis
Sanfilippo syndrome should be included in the differential diagnosis of children with behavioural disorders, attention deficit syndrome and autism spectrum disorders. Furthermore, other neuropathic types of mucopolysaccharidoses (e.g. neuropathic Hunter syndrome) do present with a similar phenotype.
Antenatal diagnosis
Antenatal diagnosis is possible where the pathogenic variants have previously been identified.
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
There is currently no approved disease-modifying therapy for patients with Sanflippo syndrome. However, disease-specific therapies are being studied within clinical trials including but not limited to enzyme replacement therapies accessing the central nervous system as well as in vivo and ex vivo gene therapies. Patient care requires a multidisciplinary team with experience in the management of Sanfilippo syndrome focusing on supportive interventions to maintain function, optimize ability, and maximize quality of life. Consensus guidelines for clinical care are available.
Prognosis
The prognosis is poor with death usually occurring within the second decade of life in severe cases (> 80% of cases). Patients with attenuated phenotypes have a more variable life span, in rare cases surviving into the seventh decade of life.

                            Last update:
                            June 2024

                            - Expert reviewer(s):
                            Dr Nicole MUSCHOL | MetabERN*

                                * European Reference Network


A rare lysosomal storage disease characterized by mild to severe spondylo-epiphyso-metaphyseal dysplasia, manifesting with disproportionate short stature (short neck and trunk), joint laxity, pectus carinatum, genum valgum, abnormal gait, tracheal narrowing, spinal abnormalities (kyphosis and scoliosis), respiratory impairment and valvular heart disease.

Summary:
Epidemiology
The prevalence at birth varies worldwide between 1/240,000 - 7,600,000, the median worldwide prevalence at birth is approximately 1/1,500,000.
Clinical description
Clinically, the two forms of MPS, IVA and IVB, have similar skeletal manifestations; however, MPS IVA has a more severe phenotype. MPS IVA is generally diagnosed during the second year of life. Progressive skeletal and joint deformities lead to impairment in walking and daily activities, and include platyspondyly, kyphosis, scoliosis, pectus carinatum, genu valgum, long bone deformities, and joint hyperlaxity (neck, hands, fingers, hips, knees). A rapidly progressive growth failure, with arrest at around 3-5 years of age in severe cases, results in short stature. Potential nervous complications are secondary to skeletal deformations. From the age of 2 to 5 years, hypoplasia of the odontoid vertebra combined with joint hyperlaxity leads to an instability at the level of the first two cervical vertebrae, with a risk of spinal cord compression. Facial dysmorphism includes prominent forehead, large mandible, and short neck. Respiratory impairment, with heavy restriction of lung capacity, susceptibility to pneumonia, and tracheal obstruction/narrowing, is often indicated by life-threatening sleep apnea, cor pulmonale or anesthetic complications. Extra-skeletal manifestations include hepatomegaly, valvulopathies, hearing loss, corneal clouding and dental hypoplasia. Intelligence is normal. Patients typically have low endurance, debilitating fatigue, and pain. Many patients become wheelchair-dependent in their second decade.
Etiology
The dysfunction and dysplasia is a result of body-wide accumulation of glycosaminoglycans (GAGs). MPS IVA is due to deficiency in the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS, 16q24.3) required for degradation of keratin sulfate (KS) and chondroitin 6-sulfate. MPS IVB is due to deficiency in beta-galactosidase (GLB1, 3p22.3) required for KS degradation.
Diagnostic methods
Preliminary investigations may include urinary analysis of GAGs; however, total urinary GAG level overlaps between MPS IV patients and age-matched controls. Urine KS and blood KS should be measured. Definitive diagnosis is by demonstration of enzymatic deficiency in plasma, serum, leukocytes or fibroblasts.
Differential diagnosis
Differential diagnosis includes MPS I, II, VI, and VII, spondyloepiphyseal dysplasia, Legg-Calve-Perthes disease, and GM1 gangliosidosis type 3 for MPS IVB.
Antenatal diagnosis
Where the genetic mutation has previously been identified in a family member, prenatal diagnosis is possible through molecular analysis or enzyme measurements in trophoblasts or amniocytes.
Genetic counseling
The pattern of inheritance is autosomal recessive in both forms and genetic counseling should be offered to affected families. The risk of disease transmission is 25% where both parents are unaffected carriers.
Management and treatment
The treatment remains symptomatic (prosthesis, surgery, neck consolidation by vertebral fusion, tracheal vascular reconstruction for near-fatal tracheal obstruction, walking aids or wheelchair). Non-invasive assessment of airway obstruction at an early stage is critical. General anesthesia may be problematic due to intubation difficulties. Imaging of the cervical spine is commonly required. Clinical therapies include hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT), both of which lead to the partial restoration of the clinical phenotype but are not reported to improve skeletal manifestations. ERT with elosulfase alfa is approved for MPS IVA and may be associated with increased endurance and pulmonary function, and reduced urinary excretion of KS. HSCT has been used on over 30 MPS IVA patients, however, further studies are required to evaluate therapeutic efficacy. In MPS IVB, management and treatment remains supportive and surgical.
Prognosis
The common causes of mortality are airway compromise and heart disease. Prognosis depends on disease severity and quality of care. Left untreated, MPS IVA patients do not generally survive beyond the third decade of life; with appropriate management, patients may survive beyond the age of 50 with some surviving over 70 years of age.

                            Last update:
                            August 2020

                            - Expert reviewer(s):
                            Pr Shunji TOMATSU


Mucopolysaccharidosis type 6 (MPS 6) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B (ASB) leading to the accumulation of dermatan sulfate.

Summary:
Epidemiology
Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births.
Clinical description
The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (GAG, generally >100 microgram/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 microgram/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS 6, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness.
Etiology
The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (ASB or N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation.
Diagnostic methods
Diagnosis generally requires evidence of clinical picture, ASB activity of less than 10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude mucosulfatidosis, see this term). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive.
Differential diagnosis
In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS 1, 2, 4A, 7), sialidosis and mucolipidosis (see these terms).
Management and treatment
Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme®), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile.
Prognosis
Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided.

                            Last update:
                            April 2010

                            - Expert reviewer(s):
                            Dr Paul HARMATZ  - Dr Helen NICELY  - Dr Sean TURBEVILLE  - Dr Vassili VALAYANNOPOULOS


A rare, genetic lysosomal storage disease characterized by accumulation of glycosaminoglycans in connective tissue which results in progressive multisystem involvement with severity ranging from mild to severe. The most consistent features include musculoskeletal involvement (particularly dysostosis multiplex, joint restriction, thorax abnormalities, and short stature), limited vocabulary, intellectual disability, coarse facies with a short neck, pulmonary involvement (predominantly decreased pulmonary function), corneal clouding, and cardiac valve disease.

Summary:
Epidemiology
The prevalence at birth is reported to range between 1/345,000 -5,000,000. However, the frequency of the disease may be underestimated as the most frequent presentation is the antenatal form, which remains underdiagnosed.
Clinical description
Signs are extremely variable: there are prenatal forms with non-immune hydrops fetalis, and severe neonatal forms with dysmorphism, hernias, hepatosplenomegaly, club feet, dysostosis, small stature and severe hypotonia and neurological involvement that ultimately lead to profound intellectual deficit in patients who survive. At the other end of the spectrum, there are very mild cases that are discovered during adolescence or adulthood following presentation with thoracic kyphosis.
Etiology
Mutations in the gene GUSB  (7q11.21) causes beta-D-glucuronidase deficiency, which leads to accumulation of several glycosaminoglycans (dermatan sulfate (DS), heparan sulfate (HS), and chondroitin sulfate (CS)) in lysosomes.
Diagnostic methods
Diagnosis is supported by x-ray evidence of dysostosis multiplex and detection of increased levels of urinary glycosaminoglycan (either CS alone or CS+HS+DS) excretion, although this sign may be absent in adult forms. Diagnosis is confirmed by demonstration of beta-D-glucuronidase deficiency in cultured leucocytes or fibroblasts. Pseudodeficient alleles make mild forms more difficult to identify and prenatal diagnosis difficult.
Differential diagnosis
Differential diagnosis includes other types of mucopolysaccharidosis (MPS) and oligosaccharidosis. The determination of enzymatic activity in leucocytes allows heterozygous individuals to be detected for the severe forms. When the two mutations have been identified in the index patient, the detection of heterozygous relatives can be performed accurately.
Antenatal diagnosis
Diagnosis is possible in forms with in utero presentation and may prevent recurrence of pregnancies leading to in utero death or late termination of the pregnancy. Prenatal diagnosis (by molecular analysis or measurement of enzyme activity in trophoblasts or amniocytes) can be offered to parents with an affected child. Parents should be made aware of the availability of enzyme replacement therapy (ERT).
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
ERT with recombinant human beta-glucuronidase has been approved in Europe and the USA for MPS type 7, and has shown improvement in walking, lung function and hepatosplenomegaly in clinical trials. Still, multidisciplinary management allows adapted symptomatic treatment, which is essential for improving the quality of life of the patients. In late-onset forms, treatment is mainly orthopedic. Bone marrow transplantation has been successful in three of five patients.
Prognosis
Prognosis is typically poor for antenatal forms, often leading to death in utero. Neonatal and childhood forms typically have a very limited life expectancy, whereas milder forms have a prolonged survival. Whilst ERT is now available, long term outcome data are not yet available on the ERT treated patients.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Dr William SLY


Mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders

A rare genetic disease characterized by early-onset respiratory difficulties and frequent respiratory infections, congenital heart defects, dysostosis multiplex, hepatosplenomegaly, renal involvement, hematopoietic abnormalities, facial dysmorphism (coarse facial features, large forehead, synophrys, long eyelashes, broad nasal bridge, macroglossia, short neck, and low hairline), and global developmental delay. Laboratory examination shows increased urinary excretion of glycosaminoglycans and increased plasma heparan sulfate, but no lysosomal enzyme deficiency. The disease is usually fatal in the first years of life.


A rare autoimmune bullous skin disease characterized clinically by blistering of the mucous membranes followed by scarring, and immunologically characterized by IgG, IgA and/or C3 deposits on the epidermal basement membrane. The disease principally involves the oral mucosa, but may also affect ocular, pharyngolaryngeal, genital, and esophageal mucous membranes.

Summary:
Epidemiology
Annual incidence was estimated to be 1/500,000 to 1/770,000 in Germany and France. A slight female predominance is reported.
Clinical description
The average age of onset is 60-70 years. The disease is rare in children. Mucous membrane pemphigoid is a chronic disease with periods of more rapid evolution. The disease manifests as fragile bullous lesions that give way to superficial erosions. The principle sites affected are the oral (80-90% of cases), ocular (50-70% of cases), pharyngolaryngeal (8-20% of cases), genital (15% of cases) and esophageal mucous membranes. Some forms affect only one mucosal membrane, in particular the buccal (erosive gingivitis) or ocular mucosae. An exclusively cutaneous form has also been observed in some cases. The ocular manifestations are initially inflammatory but then lead to retractile scarring of the conjunctive membrane, associated with corneal metaplasia resulting in vision loss.
Etiology
Whilst the etiology is unknown, several different antigens are implicated in the auto-antibody response including BPAg1, BPAg2, integrin subunits alpha-6/beta-4, laminin 5 and 6, and type VII collagen.
Diagnostic methods
Immunological studies reveal the presence of auto-antibodies against several antigens such as PB180, the alpha Laminin-5 subunit and the beta subunit of the integrin alpha-6 beta-4 complex. Histologically, the cutaneous or mucosal blisters are subepithelial, without evidence of acantholysis, and are indistinguishable from those of bullous pemphigoid. Diagnosis can be confirmed by direct (DIF) or indirect immunofluorescence analysis. Immunoelectron microscopy can differentiate bullous from cicatricial pemphigoid by the precise location of immune deposits along the basement membrane.
Differential diagnosis
Differential diagnosis includes the full range of autoimmune bullous disorders. Pemphigus vulgaris is differentiated by the DIF pattern with a labelling of the intercellular substance. Bullous pemphigoid is characterized by a predominant cutaneous involvement. Epidermolysis bullosa acquisita is a difficult to differentiate and relies on ELISA (enzyme-linked immunosorbent assay) anti collagene VII, a different localization of immune deposits along the basement membrane zone as imaged by immunoelectron microscopy, or DIF on salt separated skin. Oral erosive lichen planus and recurrent aphtosis do not show any immune deposits on DIF.
Management and treatment
Management should be multidisciplinary with close follow-up in specialized centers, in particular for the management of the ocular manifestations. The choice of therapeutic strategy (anti-inflammatory drugs, immunosuppressive therapy, intravenous immunoglobulins or local treatments) depends in the severity of the ocular disease.
Prognosis
The prognosis also revolves around the ocular manifestations, which may lead to blindness due to scarring of the conjunctive membrane and corneal metaplasia.

                            Last update:
                            June 2020

                            - Expert reviewer(s):
                            Pr Christophe BEDANE


A rare bone disease characterized by spontaneous adult-onset tarsal navicular osteonecrosis. Patients present with chronic mid- and hindfoot pain, swelling and tenderness over the dorsomedial aspect of the midfoot, flattening of the medial longitudinal arch, and pes planovarus. Radiographic findings include comma-shaped deformity due to collapse of the lateral part of the navicular bone and medial or dorsal protrusion of a portion or the entire bone. The condition may be bilateral or asymmetric and associated with pathological fractures.


Muenke syndrome is a syndromic craniosynostosis with significant phenotypic variability, usually characterized by coronal synostosis, midfacial retrusion, strabismus, hearing loss and developmental delay.

Summary:
Epidemiology
Birth prevalence is estimated at approximately 1/30,000, accounting for about 8% of all craniosynostoses and over 25% of cases with an identified genetic cause.
Clinical description
Muenke syndrome (MS) patients show a wide range of clinical findings, even within a single family. Most have coronal synostosis (more frequently bilateral), however, synostosis of other sutures, all sutures, macrocephaly without craniosynostosis, or a normal skull may be observed. Bilateral coronal synostosis usually results in brachycephaly (turribrachycephaly/cloverleaf skull are also possible) with temporal bossing and facial symmetry. Unilateral coronal synostosis results in plagiocephaly with facial asymmetry, frontal bossing, eyebrow elevation, anterior placement of the ear, and midface retrusion. Over 15% of mutation-positive individuals do not have premature fusion of the skull, but may or may not have other associated clinical findings. Craniofacial findings include: widely spaced eyes, ptosis or proptosis, strabismus, and high arched palate or cleft lip/palate. Over 70% of patients have some form of, usually mild, hearing loss (sensorineural being the most common, followed by conductive and mixed). Neurologic complications such as elevated intracranial pressure and hydrocephalus can occur, especially when two or more sutures are prematurely fused. Additional extracranial manifestations include: otitis media, brachydactyly, broad toes, broad thumbs, clinodactyly, developmental delay, intellectual disability (often mild), epilepsy, and/or increased risk for behavioral problems, including adaptive behavior.
Etiology
MS is due to a mutation in the FGFR3 gene (4p16.3), encoding fibroblast growth factor receptor 3, which is required for normal skeleton development.
Diagnostic methods
Molecular genetic testing identifying a p.Pro250Arg mutation in FGFR3 confirms diagnosis. Suture involvement and the presence of hydrocephalus can be visualized by radiography, 3D computed tomography, and MRI. Characteristic extracranial radiographic features include: fusion of the carpal and tarsal bones, short and broad (''thimble-like'') middle phalanges of the hands and feet, and epiphyseal coning.
Differential diagnosis
Differential diagnoses include other types of syndromic craniosynostosis such as Crouzon and Saethre-Chotzen syndromes and Pfeiffer syndrome type 1.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease-causing mutation. Prenatal ultrasound examination may be used as an adjunct to prenatal genetic testing.
Genetic counseling
Inheritance is autosomal dominant and genetic counseling can inform a parent with MS of their 50% risk of passing on the pathogenic variant to future offspring.
Management and treatment
Management of MS should be multidisciplinary. Patients should be tested for hearing loss and be subsequently monitored, even if initial evaluation is normal. Developmental and behavioral assessments, eye exams, speech therapy and/or special education should be evaluated on a case-by-case basis. Surgical management is offered based on craniosynostosis severity. Typically, an initial craniosynostosis repair (usually at 3-6 months of age), that consists of fronto-orbital advancement and cranial vault remodeling, is performed. A secondary (or tertiary) transcranial repair, with or without extracranial contouring, may be needed. Endoscopic strip craniectomy is a newer and less invasive procedure, usually performed before the age of 3 months.
Prognosis
The prognosis is variable. Good outcomes are observed if patients receive early surgical reconstruction (based on severity), as well as early and continued medical management of the neurologic, auditory, ocular, developmental and behavioral manifestations. Life-expectancy is normal.

                            Last update:
                            March 2017

                            - Expert reviewer(s):
                             Yonit. A ADDISSIE  - Dr Paul KRUSZKA  - Dr Maximilian MUENKE


A rare developmental defect during embryogenesis characterized by growth delay and multiorgan manifestations.

Summary:
Epidemiology
The exact prevalence is unknown. Worldwide, around 150 cases have been reported. Most cases described are from Finland where a birth prevalence of 1/37,000 has been reported.
Clinical description
Mulibrey nanism (MUL) manifests neonatally and during infancy. It is characterized by pre- and postnatal growth restriction, relative macrocephaly, thin extremities and typical craniofacial features (scaphocephaly, facial triangularity, broad forehead and low nasal bridge). Psychomotor development is mainly normal. Feeding difficulties are common in infants. Children are prone to respiratory problems. Characteristic features also include yellowish dots in the retinal mid peripheral region, a high-pitched voice and cutaneous naevi flammei. Radiologic findings include slender long bones with thick cortex, narrow medullary channel and fibrous dysplasia, J-shaped sella turcica and a small thoracic cage. A restrictive, perimyocardial heart disease is the most serious element of the disorder. Hepatomegaly and fatty liver are common. Insulin resistance is an important metabolic finding. More than 90% of the adults show abnormally high fasting insulin levels resulting in type 2 diabetes in half of the patients. Tumors have been detected in several internal organs. The most frequent malignant tumor is Wilms' tumor. Females are at high risk of developing ovarian fibrothecomas. Primary hypogonadism, both male and female, as well as infertility, are central clinical characteristics.
Etiology
MUL is caused by mutations in the TRIM37 gene (17q22) encoding the peroxisomal TRIM37 protein of unknown function. Worldwide, around 110 Finnish and 30 non-Finnish patients have a molecularly confirmed diagnosis. In Finland, one major founder mutation is seen in all patients with less than 10% of them being compound heterozygous combined with another mutation. Private mutations account for the non-Finnish cases. To date around 30 different disease associated mutations are known.
Diagnostic methods
The diagnosis relies on the clinical signs. Major and minor signs for clinical diagnosis have been established. Molecular diagnostics does confirm the diagnosis. Molecular genetic testing for the two most common mutations of the TRIM37 gene is available in Finland. However, sequencing of the whole TRIM37 gene is necessary particularly for non-Finnish patients. The TRIM37 gene is usually well covered by exome sequencing and targeted next-generation sequencing (NGS)-based panels.
Differential diagnosis
Differential diagnosis includes dysmorphic growth disorders with prenatal onset growth failure, namely Silver-Russell syndrome and 3M-syndrome.
Antenatal diagnosis
Prenatal molecular genetic testing is possible but is rational only in families known to be affected with the disease.
Genetic counseling
MUL is an autosomal recessive disorder. A genetic counseling should be offered to affected couples.
Management and treatment
Early recognition and management of feeding-, respiratory- or cardiac problems are of major importance. Regular cardiovascular follow-up is central, as well as assessment of growth and puberty. Abdominal ultrasound is well-grounded as the risk for tumors, namely Wilms' tumor, and organ abnormalities is elevated. From adolescence, the glucose metabolism should be monitored, and females need regular gynecological follow-up.
Prognosis
The severity of the heart disease is the main prognostic factor. The average survival is clearly shortened but a normal life span is not excluded.

                            Last update:
                            January 2019

                            - Expert reviewer(s):
                            Dr Marita LIPSANEN-NYMAN


Multicentric carpo-tarsal osteolysis with or without nephropathy

A very rare syndrome characterized by progressive loss of bone, usually the capsal and tarsal bones, resulting in deformity and disability, as well as chronic renal failure in many cases. The bone and renal disorders are sometimes associated with intellectual deficit and facial abnormalities.


A rare systemic or rheumatologic disease characterized by peripheral osteolysis (especially carpal and tarsal bones), interphalangeal joint erosions, subcutaneous fibrocollagenous nodules, facial dysmorphism, and a wide range of associated manifestations.

Summary:
Epidemiology
Multicentric osteolysis-nodulosis-arthropathy (MONA) spectrum prevalence and incidence of MONA are not known. Fewer than 50 cases have been reported worldwide. Cases have been reported from Saudi Arabia, Italy, Turkey, Algeria, Morocco, the United States, and Korea.
Clinical description
Onset is usually at preschool age (1-5 years) and the course of the disease is variable. Manifestations of the disorder include multiple peripheral osteolysis beginning at the carpal, tarsal, metacarpal/metatarsal-phalangeal and interphalangeal joints with subsequent generalization. The joint erosions lead to small hands and feet, arthropathy causing decreased range of motion, and progressive joint contractures. Some patients have been reported to have wide metacarpals and metatarsals, generalized osteoporosis of vertebrae, short stature, coarse face or facial dysmorphism (frontal bossing and hypertelorism), gum hypertrophy, corneal opacities, hyperpigmentation, hypertrichosis, and subcutaneous fibrocollagenous nodules. Associated cardiac malformations have been reported and included transposition of the great arteries, mitral valve prolapse, bicuspid aortic valve, and atrial and ventricular septal defects. Intrafamilial variability of manifestations is also found. Due to overlapping clinical features and the involvement of mutations in MMP2gene, Torg-Winchester syndrome and nodulosis-arthropathy-osteolysis (NAO) syndromes, that were originally reported separately, are now presumed to belong to the clinical spectrum of MONA (with other nomenclatures still being is use).
Etiology
MONA spectrum disorders are caused by mutations in the MMP2 gene (16q13-q21) or MMP14 gene (14q11-q12). The pathogenesis of the disorder remains unclear.
Diagnostic methods
The diagnosis is based on the clinical manifestations of the disease and can be confirmed by molecular genetic testing.
Differential diagnosis
The main differential diagnoses are juvenile idiopathic arthritis and multicentric carpotarsal osteolysis.
Genetic counseling
MONA spectrum disorders follow an autosomal recessive pattern on inheritance. Many cases are reported in children from consanguineous unions. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 25% risk of passing the mutation to offspring.
Management and treatment
There is no specific treatment for MONA spectrum. Management is primarily symptomatic. Some patients initially respond to non-steroidal anti-inflammatory drugs (NSAIDs).
Prognosis
The progressive joint destruction leads to significant disability; many patients are wheelchair bound. However, life expectancy does not appear to be significantly affected.

                            Last update:
                            November 2019

                            - Expert reviewer(s):
                            Dr Andreas ZANKL


A rare non-Langerhans cell histiocytosis characterized by the association of specific nodular skin lesions and destructive arthritis.

Summary:
Epidemiology
Prevalence is unknown but around 200 cases have been reported in the literature so far.
Clinical description
Onset is insidious, usually occurring at around 50 years of age. Multicentric reticulohistiocytosis (MRH) is a progressive disease, articular inflammation becomes more severe and, after periods of worsening and improving symptoms, incapacitating arthritis is a frequent feature. Multiple joints may be involved (mainly of the hands, wrists, shoulders, knees, hips and ankles). Joint symptoms oscillate and severe deforming arthritis, known as mutilating arthritis, is a prominent manifestation in between 11 and 45% of the cases, depending on the patient series. Similarly, cutaneous nodules appear and regress, with new eruptions developing over periods of many months, as the old ones become inactive, stabilize or disappear. The cutaneous nodules are either skin-colored or have a red/brown appearance and are usually asymptomatic. They are more frequent on the upper body, particularly the hands, and may also appear on mucosal surfaces. Internal organ involvement has also been reported. After a period of many years (usually 6 to 8), in the majority of cases, arthritis becomes quiescent and the mucocutaneous nodules stabilize or become smaller.
Etiology
The etiology is unknown. MRH is believed to reflect a peculiar type of reactive inflammatory response to unknown stimuli with involvement of macrophages and T lymphocytes. An underlying malignancy has been described in around a quarter of patients.
Diagnostic methods
Histopathological and immunohistochemical studies (revealing the characteristic reticulohistiocytic granulomas mainly composed of CD68 positive cells) are diagnostic in most cases. Radiologic examinations should be performed in all patients.
Differential diagnosis
The differential diagnosis should include leprosy, rheumatoid arthritis, xanthogranulomas, lymphomas, sarcoidosis, Urbach-Wiethe disease, Farber disease and dermatomyositis (see these terms).
Management and treatment
At present, no satisfactory treatment is available. Some chemotherapeutical schemes, particularly those involving alkylating agents and specific therapies targeted towards the tumor necrosis factor (TNF) or its receptors may lead to some improvement. Systemic steroids are usually of only limited benefit.
Prognosis
Patients with MRH usually undergo spontaneous remission within a variable period of 6 to 8 years, however, sequelae (esthetic sequelae associated with the skin lesions and deforming sequelae associated with the arthritis) are frequent after cure. Death can occur due to internal organ involvement or as a result of the underlying malignancy.

                            Last update:
                            February 2009

                            - Expert reviewer(s):
                            Dr Flavio LUZ  - Pr Marcia RAMOS-E-SILVA


A rare congenital anomaly of the kidney and urinary tract (CAKUT) in which one or both kidneys (unilateral or bilateral MCDK respectively) are large, distended by multiple cysts, and non-functional. Unilateral MCDK is typically asymptomatic if the other kidney is fully functional but may occasionally present with abdominal obstructive signs when the cysts become too large. Bilateral MCDK is considered a lethal entity and neonates present with features of the Potter sequence, severe pulmonary hypoplasia and severe renal failure, and generally die shortly after birth.


Multifocal atrial tachycardia is a rare supraventricular arrhythmia in neonates and young infants that is characterized by multiple P waves with varying P wave morphology and is usually asymptomatic.

Summary:
Epidemiology
It is a very rare condition occurring in around 1 per 150,000 live births.
Clinical description
'The disease mainly affects newborn infants (or those younger than 6 months of age) with a normal heart and no other underlying illness. Most infants are asymptomatic but some may show shortness of breath or respiratory distress. Less often, the disorder may occur in children with heart malformations (such as hypertrophic cardiomyopathy, tetralogy of Fallot, or atrioventricular canal defect; see these terms) or in those having recently undergone an open-heart surgery. Very rarely, multifocal atrial tachycardia can be associated with other clinical features and be part of a syndrome, such as in Costello syndrome where it is associated with growth retardation, coarse facies, intellectual disability, and skin anomalies (see this term).'
Etiology
The etiology is unknown.
Diagnostic methods
Diagnosis is made by surface electrocardiogram: atrial activity is polymorphic (at least 3 different morphologies of P waves with a discrete isoelectric baseline, and variable PP, RR, and PR intervals), rapid (atrial rates can increase up to 400 beats per minute), and irregular. Atrioventricular conduction is variable so that some P waves are not conducted. Rate-related QRS widening (aberrancy) is sometimes seen.
Differential diagnosis
Differential diagnosis includes most other types of tachycardia (e.g. nonsustained ventricular tachycardia, paroxysmal supraventricular tachycardia (PSVT)).
Management and treatment
If the ventricular rate is relatively normal and the infant is asymptomatic with normal heart function, no treatment may be necessary. Cardioversion is unsuccessful due to the fact that the arrhythmia is restarting all the time. A beta-blocker is probably the drug of choice, with an occasional patient with poor ventricular function needing treatment with amiodarone.
Prognosis
The natural history of multifocal atrial tachycardia is spontaneous resolution within weeks or months. In those who require drug treatment, medication can be withdrawn after that time. The long term outlook is good, with no late recurrence.

                            Last update:
                            November 2013

                            - Expert reviewer(s):
                            Dr Christopher WREN


Multifocal infantile hemangioma with extracutenous involvement

Diffuse neonatal hemangiomatosis is a rare vascular tumor from unknown origin characterized by multiple, progressive, rapidly growing cutaneous hemangiomas (e.g. in the scalp, face, trunk and extremities) associated with widespread visceral hemangiomas in the liver, lungs, gastrointestinal tract, brain, and meninges.


A rare lymphatic system anomaly characterized by multifocal congenital and progressive vascular lesions of the skin, gastrointestinal tract, and occasionally other anatomic sites, causing potentially life-threatening thrombocytopenic coagulopathy. Macroscopically, the lesions appear as round to oval, red-brown plaques, as large as a few centimeters in diameter. Histopathologically, they consist of dilated, thin-walled vessels with variable endothelial hyperplasia, positive for lymphatic endothelial cell markers, and resembling benign lymphangioendothelioma.


Multifocal motor neuropathy (MMN) is a rare acquired immune-mediatedneuropathy characterized clinically by a purely motor deficit with conduction block and asymmetric multifocal weakness, fasciculations, and cramping.


Multifocal pattern dystrophy simulating fundus flavimaculatus

A rare, patterned dystrophy of the retinal pigment epithelium characterized by multiple yellowish irregular flecks scattered or interconnected around the macula, simulating what is observed in Stargardt disease, and usually asymptomatic until adulthood when patients present with a slowly progressive loss of vision that often only becomes apparent in old age.


Multilocular cystic renal neoplasm of low malignant potential is a rare subtype of clear cell renal cell carcinoma with distinct pathological features of cysts lined by occasionally flattened cuboidal clear cells and septa containing aggregates of epithelial cells with clear cytoplasm, and excellent prognosis. The tumor usually presents as an asymptomatic, unilateral, solitary lesion, macroscopically consisting of numerous, fluid-filled, septated cysts of variable size. Rarely, the symptoms typically associated with renal tumors (flank pain, hematuria, palpable mass) may be present.


A rare benign renal tumor characterized by a typically unilateral, solitary, multiloculated cystic mass consisting of small, non-communicating cysts with flat, cuboidal, or hobnail epithelial lining, separated by fibrous septa which may have an ovarian stroma-like appearance or be paucicellular. The tumor is surrounded by a thick fibrous capsule and does not contain solid areas or necrosis. Patients may be asymptomatic or present with a palpable abdominal mass and/or abdominal or flank pain. Age distribution is bimodal, the typical age of onset being either below five or between 40 and 70 years of age.


A rare hereditary neuromuscular disorder characterized by multiple cores on muscle biopsy and clinical features of a congenital myopathy.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Marked clinical variability corresponds to genetic heterogeneity: the most instantly recognizable classic phenotype characterized by spinal rigidity, early scoliosis and respiratory impairment is due to recessive mutations in the selenoprotein N (SEPN1) gene, whereas recessive mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wider range of clinical features comprising external ophthalmoplegia, distal weakness and wasting or predominant hip girdle involvement resembling central core disease (CCD). In the latter forms, there may also be a histopathologic continuum with CCD caused by dominant RYR1 mutations, reflecting the common genetic background.
Etiology
The pathogenetic mechanisms of RYR1-related MmD are currently not well understood, but are likely to involve altered excitability and/or changes in calcium homeostasis. The presence of calcium-binding motifs within the selenoprotein N protein also suggests a possible role in calcium handling.
Diagnostic methods
The diagnosis of MmD is based on the presence of suggestive clinical features and multiple cores on muscle biopsy. Muscle MRI may aid genetic testing as distinct patterns of selective muscle involvement can be detected depending on the genetic background. Mutational analysis of the RYR1 or the SEPN1 gene may provide genetic confirmation of the diagnosis.
Management and treatment
Management is mainly supportive and has to address the risk of marked respiratory impairment in SEPN1-related MmD and the possibility of susceptibility to malignant hyperthermia in RYR1-related forms.
Prognosis
In the majority of patients, weakness is static or only slowly progressive, with the degree of respiratory impairment being the most important prognostic factor.

                            Last update:
                            July 2007

                            - Expert reviewer(s):
                            Dr Heinz JUNGBLUTH


Multinodular goiter-cystic kidney-polydactyly syndrome

Multinodular goiter - cystic kidney - polydactyly syndrome is a very rare syndrome characterized by the association of multinodular goiter, cystic renal disease and digital anomalies.

Summary:
Epidemiology
It has been described in two sibs and one unrelated child.
Clinical description
The two sibs had digitalized thumbs and preaxial polydactyly, the third child had normal thumbs and postaxial polydactyly. Goiter and/or digitalized thumbs and/or polydactyly were present in other members of families.
Genetic counseling
This syndrome seems to be transmitted as an autosomal dominant trait with variable expression and incomplete penetrance.

                            Last update:
                            October 2010


Multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome

A rare genetic lethal multiple congenital anomalies/dysmorphic syndrome characterized by severe hydranencephaly and renal dysplasia or agenesis. Pregnancy is complicated by oligo- or anhydramnios, leading to features of Potter sequence (including typical facies and microretrognathia, limb contractures, talipes equinovarus, and pulmonary hypoplasia) in the fetus. Affected fetuses either die in utero or shortly after birth. Histology of the brain shows widespread presence of multinucleated neurons and glial cells.


Multiple acyl-CoA dehydrogenase deficiency

Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid and amino acid oxidation and is a clinically heterogeneous disorder ranging from a severe neonatal presentation with metabolic acidosis, cardiomyopathy and liver disease, to a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness, and respiratory failure.

Summary:
Epidemiology
Birth prevalence is estimated at 1/200,000 but great variation is seen between countries/ethnicities.
Clinical description
Patients with MADD fall into 3 broad clinical phenotypes: 1) neonatal onset with congenital anomalies, 2) neonatal onset without anomalies, (together called MADD-severe (S); see this term) and 3) mild and/or late onset (MADD-mild (M); see this term). The first group of MADD-S patients are often premature presenting with severe non-ketotic hypoglycemia, hypotonia, hepatomegaly and severe metabolic acidosis within the first 24 hours of life. They usually have dysplastic kidneys with multiple cysts and may also have facial dysmorphism (low-set ears, high forehead, hypertelorism and hypoplastic midface), rocker-bottom feet and anomalies of external genitalia. Death usually occurs within the first week of life. The second group of patients usually present within the first 24-48 hours of life with hypotonia, tachypnea, hepatomegaly, metabolic acidosis and hypoketotic hypoglycemia. Most die during the first week(s) of life but some have survived for several months, usually dying with severe cardiomyopathy. MADD-M patients show a broad clinical spectrum of disease ranging from onset of intermittent episodes of vomiting, metabolic acidosis and hypoketotic hypoglycaemia (+/- cardiac involvement) during the first few months of life to adolescent/adult presentation with acute Reye-like illness with ketoacidosis and lipid storage myopathy. The latter subgroup often responds to pharmacological doses of riboflavin (rr-MADD).
Etiology
MADD is caused by mutations in the ETFA (15q23-q25), ETFB (19q13.3-q13.4) and ETFDH (4q32-q35) genes which encode the alpha and beta subunits of electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase. Dysfunction of either of these two flavoproteins leads to compromised fatty acid oxidation..
Diagnostic methods
Urinary organic acid analysis usually displays various combinations of increased dicarboxylic acids, glutaric acid, ethylmalonic acid, 2-hydroxyglutarate, and glycine conjugates. Blood acylcarnitines show increased C4-C18 species although patients may be severely carnitine depleted, which may limit the degree of these abnormalities. Fibroblast fatty acid oxidation flux and fibroblast acylcarnitine analysis following incubation with palmitic acid is usually abnormal. Final confirmation is by mutation analysis. Newborn screening programs are available in Austria, Belgium, Hungary, Iceland, Portugal and Spain.
Differential diagnosis
Differential diagnosis includes autosomal resessive polycystic kindney disease; carnitine palmitoyl transferase II deficiency, neonatal form; Zellweger syndrome and sterol biosynthesis disorders (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible when 2 pathogenic mutations have been identified in the family.
Genetic counseling
MADD is an autosomal recessive disorder and genetic counseling is available.
Management and treatment
Treatment for the more severe phenotypes involves restriction of both fat and protein and reliance on a high carbohydrate diet. Strict avoidance of fasting and of other precipitating stresses is essential. Emergency regimens should be available for any metabolic decompensation. Riboflavin supplementation of 100-400 mg/day is a very effective treatment for patients with rr-MADD as is CoQ10 supplementation in some. For moderately severe cases, 3-hydroxybutyrate has been used successfully, but further studies are still needed.
Prognosis
MADD-S is invariably fatal. Milder phenotypes have a more favorable prognosis.

                            Last update:
                            February 2014

                            - Expert reviewer(s):
                            Dr Simon OLPIN


Multiple benign circumferential skin creases on limbs

A rare genetic disease characterized by benign circumferential skin creases, mainly on the limbs, due to folding of excess skin. The creases often improve spontaneously in childhood. Patients also exhibit variable degrees of intellectual disability, short stature, cleft palate, and facial dysmorphism (including epicanthal folds, microphthalmia, broad nasal bridge, low-set, posteriorly rotated ears, and microstomia, among others). Variable additional features have been reported, such as seizures, infantile hypotonia, hearing impairment, strabismus, and urogenital anomalies. Brain imaging may show hypoplastic corpus callosum or mildly dilated ventricles.


A group of inborn errors of biotin metabolism characterized by reduced activities of biotin-dependent enzymes resulting in a wide spectrum of symptoms, including feeding difficulty, breathing difficulties, lethargy, seizures, skin rash, alopecia, and developmental delay. This group includes biotinidase deficiency and biotin holocarboxylase synthetase deficiency.


Multiple congenital anomalies-hypotonia-seizures syndrome type 2

A rare, genetic, lethal, neurometabolic malformation syndrome characterized by multiple, variable, congenital cardiac (systolic murmur, atrial septal defect), urinary (duplicated collecting system, vesicoureteral reflux) and central nervous system (thin corpus callosum, cerebellar hypoplasia) malformations associated with neonatal hypotonia, early-onset epileptic encephalopathy, and myoclonic seizures. Craniofacial dysmorphism (prominent occiput, enlarged fontanel, fused metopic suture, upslanted palpebral fissures, overfolded helix, depressed nasal bridge, anteverted nose, malar flattening, microstomy with downturned corners, Pierre-Robin sequence, high arched palate, short neck) and other manifestations (joint contractures, hyperreflexia, dysplastic nails, developmental delay) are also observed.


Multiple congenital anomalies-hypotonia-seizures syndrome

A rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by severe global developmental delay, hypotonia, and early-onset seizures, associated with multiple congenital anomalies, such as cardiac (e.g. patent foramen ovale, atrial septal defect, patent ductus arteriosus), genitourinary (i.e. hydrocele, renal collecting system dilatation, hydroureter, hydronephrosis, hypertrophic trabecular urinary bladder) and gastrointestinal abnormalities (including gastroesophageal reflux, anal stenosis, imperforate anus, ano-vestibular fistula), as well as facial dysmorphism which includes coarse facies, a prominent occiput, bitemporal narrowing, epicanthal folds, hypertelorism, nystagmus/strabismus/wandering eyes, low-set, large ears with auricle abnormalities, depressed nasal bridge, upturned nose, long philtrum, large, open mouth with thin lips, high-arched palate, and micro/retrognathia.


A rare inherited cancer syndrome, characterized by the development of multiple neuroendocrine tumors of the parathyroids, gastro-entero-pancreatic tract, and anterior pituitary gland, and less commonly the adrenal cortical gland, thymus and bronchi, with other non-endocrine tumors in some patients.

Summary:
Epidemiology
Prevalence of multiple endocrine neoplasia type 1 (MEN1) is estimated to range between 1/10,000-30,000. The sex ratio is equal.
Clinical description
Tumors can develop at any age with 95% of patients developing clinical symptoms by the 5th decade. Parathyroid tumors are the most common (95% of patients), followed by pancreatic islet tumors (40%) and anterior pituitary tumors (30%). Pancreatic neuroendocrine tumors include gastrinoma (50%), insulinoma (33%), glucagonoma (5%), vasoactive intestinal peptide (VIP)-oma, pancreatic polypeptide (PP)-oma and non-functioning tumors, and are associated with high levels of morbidity and mortality. Pituitary tumors include prolactinoma (66%), somatotrophinoma (25%), and ACTHomas (5%) and non-functioning adenomas (5%). The most common initial manifestation is primary hyperparathyroidism (PHPT; mean age onset in third decade of life), due to parathyroid hyperplasia and/or adenoma. PHPT can present with long periods of normal serum level of calcium (normocalcemic PHPT), that is often asymptomatic. When associated with hypercalcemia, and often also hypophosphatemia, PHPT can manifest clinical signs that may include nephrolithiasis, polyuria, polydipsia, constipation, fatigue, depression, confusion, anorexia, osteopenia and osteoporosis. Untreated PHPT can exacerbate over-secretion of gastrina from a concomitant gastrinoma and favor peptic ulcers. Gastrinomas lead to peptic ulcers in more than 50% of MEN 1 patients, and can be associated with Zollinger-Ellison syndrome.
Etiology
MEN1 is caused by germinal heterozygote inactivating mutations of the MEN1 gene (11q13) encoding the menin protein, a tumor suppressor.In many cases the genetic etiology remains unknown.
Diagnostic methods
MEN1 is clinically diagnosed in affected patients manifesting at least two of the main endocrine tumors (parathyroid, pituitary, and/or pancreatic) during their life. In these cases, the genetic testing is used and confirmed by the presence of a germinal mutation of the MEN1 gene.
Differential diagnosis
The differential diagnosis includes other types of MEN, mainly MEN2A and MEN4 (associated to the gene CDKN1B). Familial primary hyperparathyroidism should also be considered. Differential diagnosis with MEN4 is necessarily made by genetic testing.
Antenatal diagnosis
Prenatal diagnosis is possible, when one of the parent is carrier of a mutation of the MEN1.
Genetic counseling
MEN1 displays a high degree of penetrance; mutation carriers show up to 100% of disease penetrance after the age of 55. The inheritance pattern is autosomal dominant and genetic counseling should be provided to affected individuals and their families informing them that the risk of disease transmission is 50% from an individual with a pathogenic variant to their offspring.
Management and treatment
Annual life-long screening is recommended for all the carriers of a MEN1 mutations and individuals from affected families without an identified MEN1 mutations or who have not undergone the genetic test. Six-monthly screening is recommended for affected patients (CT, MRI, blood biochemistry). Treatment is prevalently by surgery based on approaches for each specific tumor. Some pharmacological therapies are available for treatment of hormone over-secretion and related symptoms; calcimimetic can be used to treat PHPT in patients in whom surgery had either failed or was contraindicated. Prior to surgery, bone anti-resorptive agents are used to reduce hypercalcemia and limit bone resorption. Dopamine agonists are used for prolactinoma. Somatostatin analogs for GH-secreting tumors and for controlling the secretory hyperfunction associated with carcinoid syndrome. Proton pump inhibitors or H2-receptor blockers reduce gastric acid output caused by gastrinomas.
Prognosis
Malignancy is the main risk patients (accounting for approximately 30% of deaths); however, untreated hormone over-secretion by functioning tumors can account for morbidity and mortality. Early diagnosis and treatment success are the main prognostic factors.

                            Last update:
                            April 2020

                            - Expert reviewer(s):
                            Pr Maria Luisa BRANDI  - Dr Francesca GIUSTI  - Dr Francesca MARINI


A rare multiple endocrine neoplasia (MEN) syndrome that is principally characterized by the association of medullary thyroid carcinoma (MTC) with other endocrine tumors. The variant MEN 2A is defined by MTC associated with pheochromocytoma and/or primary hyperparathyroidism (MEN2A); the variant MEN 2B is defined as an aggressive form of MTC in association with pheochromocytoma but without primary hyperparathyroidism.

Summary:
Epidemiology
The total prevalence of all variants of multiple endocrine neoplasia type 2 (MEN2) is approximately 1/35,000. MEN2A, accounts for 95% of MEN2 cases.
Clinical description
MEN2 can affect all age groups, with manifestations beginning in infancy to early childhood (MEN2B) or adulthood (MEN2A). Clinical manifestations are related to the tumors associated. MTC affects all forms of MEN2, is usually the first manifestation of the disease, and arises in the parafollicular cells of the thyroid. In MEN2A, MTC is associated in 50% of cases with pheochromocytoma (PCC) and in 20-30% with primary hyperparathyroidism (PHPT). PCC is almost always benign and is usually multicentric, bilateral, and confined to the adrenal gland. In classical MEN2A, PHPT is usually mild and between one to four parathyroid glands may be enlarged. MEN2A can also be associated with cutaneous lichen amyloidosis or Hirschsprung's disease (HD). In MEN2B, MTC often presents in infancy and is highly aggressive, metastasizing early to regional lymph nodes and beyond. Approximately 50% of patients with MEN2B develop PCC. They also have a unique physical appearance characterized by a typical facies (mucosal neuromas of the lips and tongue), ophthalmologic abnormalities (alacrima in infancy, thickened and everted eyelids, mild ptosis, and prominent corneal nerves), skeletal anomalies (marfanoid body habitus, narrow long facies, pes cavus, pectus excavatum, high-arched palate, scoliosis, hyperextensible joints and slipped capital femoral epiphyses), and a generalized ganglioneuromatosis throughout the aerodigestive tract.
Etiology
MEN2 is caused by a heterozygote germline activating mutation in the RET proto-oncogene (10q11.2), encoding a membrane tyrosine kinase receptor. The clinical subtypes depend on which functional domain the mutations affect.
Diagnostic methods
Clinical diagnosis involves identification of MTC, PCC, and eventually PHPT. MTC is diagnosed by ultrasound (US) of the neck and serum levels of calcitonic (Ctn) and carcinoembryonic antigen (CEA). Screening of PCC consists of measuring metanephrines and normetanephrines from either free plasma or a 24-hour urine test. Adrenal imaging with CT or MRI is indicated in patients with positive biochemical results. A positive genetic test of RET confirms the clinical diagnosis in affected patients.
Differential diagnosis
Differential diagnoses include MTC, Hirschsprung disease and familial medullary thyroid carcinoma (FMTC). FMTC is also associated with germline RET variants but patients only manifest MTC.
Antenatal diagnosis
Prenatal diagnosis is possible where the mutation has previously been identified in a family member.
Genetic counseling
MEN2 is an autosomal-dominant syndrome and individuals carrying the pathogenic variant have a 50% risk of transmitting the variant to each offspring, independent of sex. Approximately 75% of MEN2B cases are sporadic (with the RET mutation arising de novo), while 25% are familial.
Management and treatment
RET mutation predicts the clinical phenotype and guides treatment. As recommended by the American thyroid association, management and treatment is stratified according to risk of aggressive MTC: highest risk (HST); high risk (H); moderate risk (MOD). All patients require evaluation of serum Ctn every 6 months for the first year, then annually if serum Ctn remains normal or undetectable. Annual US of the neck is indicated for both H and HST categories. Total thyroidectomy (TTX) should be performed when the serum Ctn level becomes elevated in MOD, and at or before 5 years of age (based on serum Ctn levels) for H and HST risk groups. Life-long thyroid hormone supplementation is needed after thyroid removal. The tyrosine kinase inhibitors, vandetanib and cabozantinib, are approved (in the USA and Europe) for the treatment of patients with advanced progressive MTC. MEN2A patients in the H and MOD risk groups should be simultaneously screened for PHPT and PCC. Only visibly enlarged parathyroids should be resected.
Prognosis
The prognosis depends on the stage at which MTC is diagnosed and efficacy of initial surgical treatment. Early diagnosis and complete initial resection of tumors increases life expectancy.

                            Last update:
                            June 2021

                            - Expert reviewer(s):
                            Pr Maria Luisa BRANDI  - Dr Francesca GIUSTI  - Dr Francesca MARINI


A form of multiple endocrine neoplasia type 2 (MEN2) syndrome characterized by medullary thyroid carcinoma in association with pheochromocytoma (one or both adrenal glands can be affected) and/or primary hyperparathyroidism (caused by parathyroid adenoma). Onset is typically later than in MEN2B, before 35 years of age. Diarrhea is the most frequent systemic symptom. Patients can develop Hirschsprung disease and, less frequently, cutaneous lichen amyloidosis or excessive production of adrenocorticotropic hormone.


A rare form of multiple endocrine neoplasia type 2 (MEN2) syndrome characterized by aggressive medullary thyroid carcinoma in association with other endocrine tumors, notably pheochromocytoma (one or both adrenal glands can be affected). Onset is typically in infancy or childhood and patients often have a typical facies (mucosal neuromas of the lips and tongue, and bumpy lips), ophthalmologic abnormalities (alacrima in infancy, thickened and everted eyelids, mild ptosis, and prominent corneal nerves), skeletal anomalies (marfanoid body habitus, narrow long facies, pes cavus, pectus excavatum, high-arched palate, scoliosis, hyperextensible joints and slipped capital femoral epiphyses), and a generalized ganglioneuromatosis throughout the aerodigestive tract. Chronic constipation, abdominal distension, diarrhea, or megacolon at birth are often the initial manifestations.


Multiple endocrine neoplasia type 4 (MEN4) is a very rare form of MEN (see this term), an inherited cancer syndrome, characterized by parathyroid and anterior pituitary tumors, possibly associated with adrenal, renal, and reproductive organ tumors.

Summary:
Epidemiology
The prevalence of multiple endocrine neoplasia type 4 is unknown, but the syndrome is very rare. To date, 12 index cases have been reported. Prevalence is thought to be less than 1/million.
Clinical description
MEN4 is a recently described MEN-like syndrome similar to MEN1 (see this term). Age of onset of tumors is variable. Patients have been reported to develop parathyroid tumors from fourth decade of life and pituitary tumors from the third decade. Affected patients develop parathyroid tumor with associated primary hyperparathyroidism (81%) and anterior pituitary tumors (42%). In MEN4 patients, various types of pituitary adenoma have been reported: Cushing disease, somatotropic adenoma, prolactinoma, and non-functioning pituitary adenoma (see these terms). Cases of gastric and bronchial carcinoid tumor or Zollinger-Ellison syndrome (see this term) have also been reported. Other associated tumors include reproductive organ tumors, peripheral neuroendocrine tumor of cervix uteri (see this term), and adrenal or renal tumors.
Etiology
MEN4 is caused by heterozygous inactivating mutations in the CDKN1B gene (12p13.1-p12) encoding p27, a cyclin-dependent kinase inhibitor that acts as a negative regulator of cell cycle progression. In MEN4, unlike in MEN1, CDKN1B acts as a non-conventional oncosuppressor gene and no loss of heterozygosity has been reported. The exact MEN4 tumorigenesis molecular mechanisms remain to be elucidated but it is suspected that the mutated allele could be responsible for the reduction of p27 protein localized in the nucleus and, thus, able to exert its role of negative regulator of cell cycle progression and cell growth.
Genetic counseling
Most cases are the result of autosomal dominant inheritance. Some cases of sporadic de novo occurrence are however reported. Genetic counseling should be provided to affected individuals and their families.

                            Last update:
                            April 2015

                            - Expert reviewer(s):
                            Pr Maria Luisa BRANDI


Multiple endocrine neoplasia (MEN) is a group of rare inherited cancer syndromes characterized by the development of two or more endocrine gland tumors, sometimes with tumor development in other tissues or organs.

Summary:
Epidemiology
The overall prevalence and incidence of MEN are not known. The prevalence of MEN1 is estimated to be approximately 1/10,000 to 1/30,000, while the total prevalence of MEN2 variants is approximately 1/35,000. MEN4 is extremely rare. The incidence of MEN1 has been estimated from random postmortem studies to be 0.25%, and to be 1-18% in patients with primary hyperparathyroidism, 16 to 38% in patients with gastrinomas, and less than 3% in patients with pituitary tumors.
Clinical description
Multiple endocrine neoplasia syndromes can develop in patients of all ages: from infants to elderly patients over 70 years of age. Manifestations vary depending on the affected endocrine glands. There are three types of MEN (multiple endocrine neoplasia types 1, 2, and 4; see these terms) based on the underlying genetic abnormalities, the endocrine glands involved and the clinical manifestations. Each type includes a different combination of pituitary, pancreatic, parathyroid, medullary, thyroid, and adrenal tumors. MEN1 is characterized by parathyroid, pituitary gland, and pancreatic tumors. MEN2 is divided into two subtypes: MEN2A characterized by medullary thyroid carcinoma (see this term) in combination with pheochromocytoma (see this term) and primary mild hyperparathyroidism; and MEN2B (formerly MEN3), a rare form, involving medullary thyroid carcinoma, pheochromocytoma, mucosal ganglioneuromas and marfanoid habitus. MEN4 involves the development of parathyroid and anterior pituitary tumors.
Etiology
MEN1 is caused by inactivating mutations in the MEN1 gene (11q13), and in some patients by mutations in the cyclin-dependent kinase inhibitor genes (CDKN1A, CDKN2B, CDKN2C). MEN2A and MEN2B are due to activating mutations in the RET gene (10q11.2), and MEN4 to inactivating mutations in the CDKN1B gene (12p13.1-p12). Patients with MEN1-like phenotypes (primary hyperparathyroidism associated with various tumors and lesions of the pituitary gland, pancreas, and duodenum) have also been found to have inactivating germline heterozygote mutation in CDKN1B.
Genetic counseling
MEN follows an autosomal dominant pattern of inheritance and some sporadic cases are reported. First-degree relatives have a 50% risk of developing the disorder, making appropriate genetic counseling very important in affected families. Biochemical and genetic screening may be suggested to family members.

                            Last update:
                            April 2015

                            - Expert reviewer(s):
                            Pr Maria Luisa BRANDI


Multiple epiphyseal dysplasia due to collagen 9 anomaly is a rare primary bone dysplasia disorder characterized by normal or mild short stature, early-onset pain and/or stiffness of the joints (mainly affecting knees but also elbows, wrists, ankles and fingers, with relative sparing of the hips) and early degenerative joint disease. Other skeletal anomalies (incl. varus or valgus deformities, osteochondritis dissecans, abnormal carpal shape, free articular bodies) and mild myopathy have also been reported.


Multiple epiphyseal dysplasia type 1 (MED 1) is a form of multiple epiphyseal dysplasia that is characterized by normal or mild short stature, pain in the hips and/or knees, progressive deformity of extremities and early-onset osteoarthrosis. Specific features to MED 1 include a more pronounced involvement of hip joints and gait abnormality and a shorter adult height. MED1 is allelic to pseudoachondroplasia with which it shares clinical and radiological features. The disease follows an autosomal dominant mode of transmission.


Multiple epiphyseal dysplasia type 4 is a multiple epiphyseal dysplasia with a late-childhood onset, characterized by joint pain involving hips, knees, wrists, and fingers with occasional limitation of joint movements, deformity of hands, feet, and knees (club foot, clinodactyly, brachydactyly), scoliosis and slightly reduced adult height. Radiographs display flat epiphyses with early arthritis of the hip, and double-layered patella. Multiple epiphyseal dysplasia type 4 follows an autosomal recessive mode of transmission. The disease is allelic to diastrophic dwarfism, atelosteogenesis type 2 and achondrogenesis type 1B with whom it forms a clinical continuum.


Multiple epiphyseal dysplasia type 5 is a multiple epiphyseal dysplasia characterized by an early-onset of pain and stiffness (involving knee and hip), progressive deformity of the extremities and precocious osteoarthritis associated with delayed and irregular ossification of epiphyses. Features specific to multiple epiphyseal dysplasia, type 5 include normal stature and lesser incidence of gait abnormalities. Radiographs reveal epiphyseal and metaphyseal irregularities. Multiple epiphyseal dysplasia type 5 follows an autosomal dominant mode of transmission.


Multiple epiphyseal dysplasia, Lowry type is a rare primary bone dysplasia characterized by small, flat epiphyses (esp. the capital femoral epiphyses), rhizomelic shortening of limbs, cleft of secondary palate, micrognathia, mild joint contractures and facial dysmorphism (incl. mildly upward-slanting palpebral fissures, hypertelorism, broad nasal tip). Additionally reported features include scoliosis, genu valgum, mild pectus excavatum, platyspondyly, dislocated radial heads, brachydactyly, hypoplastic fibulae and talipes equinovarus.


Multiple epiphyseal dysplasia-macrocephaly-facial dysmorphism syndrome

A rare primary bone dysplasia characterized by the association of multiple epiphyseal dysplasia with macrocephaly and dysmorphic facial features (such as frontal bossing, hypertelorism, flat malar region, low-set ears, and short neck). Patients are of normal stature and present with joint swelling and genu valgum. Additional reported manifestations include clinodactyly, spindle-shaped fingers, and pectus excavatum.


Multiple epiphyseal dysplasia-miniepiphyses syndrome

Multiple epiphyseal dysplasia, with miniepiphyses is a rare primary bone dysplasia disorder characterized by strikingly small secondary ossification centers (mini-epiphyses) in all or only some joints, resulting in severe bone dysplasia of the proximal femoral heads. Short stature, increased lumbar lordosis, genua vara and generalized joint laxity have also been reported.


Multiple epiphyseal dysplasia-severe proximal femoral dysplasia syndrome

Multiple epiphyseal dysplasia, with severe proximal femoral dysplasia is a rare primary bone dysplasia characterized by severe, early-onset dysplasia of the proximal femurs, with almost complete absence of the secondary ossification centers and abnormal development of the femoral necks (short and broad with irregular metaphyses). It is associated with gait abnormality, mild short stature, arthralgia, joint stiffness with limited mobility of the hips and irregular acetabula, and hip and knee pain. Coxa vara and mild spinal changes are also associated.


A rare group of primary bone dysplasia disorders characterized by the association of epiphyseal anomalies of long bones causing joint pain early in life, recurrent osteochondritis and early arthrosis. This group contains an heterogeneous group of diseases with variable expression. Common reported clinical signs include waddling gait and pain at onset, and moderate short stature. Some forms are mainly limited to the femoral epiphyses, while several other syndromes are characterized by the association of multiple epiphyseal dysplasia with other clinical manifestations such as myopia, deafness and facial dysmorphism. Diagnosis relies on identification of the radiological features.


Multiple intestinal atresia is a rare form of intestinal atresia characterized by the presence of numerous atresic segments in the small bowel (duodenum) or large bowel and leading to symptoms of intestinal obstruction: vomiting, abdominal bloating and inability to pass meconium in newborns.


Multiple mitochondrial dysfunctions syndrome type 1

A rare mitochondrial disease characterized by failure to thrive, infantile encephalopathy, muscular hypotonia, global developmental delay and regression, pulmonary arterial hypertension, episodes of apnea and bradycardia, respiratory failure, hyperglycinemia, and lactic acidosis. Hypertrophic or dilated cardiomyopathy have also been reported. Brain imaging may show leukoencephalopathy involving variable regions. The disease is typically fatal in early infancy.


Multiple mitochondrial dysfunctions syndrome type 2

A rare mitochondrial disease characterized by infantile onset of severe regression after a period of normal development, epileptic encephalopathy, hypotonia, movement disorder, cardiomyopathy, hyperglycinemia, and lactic acidosis. Optic atrophy may also be present. Brain imaging findings are highly variable and include white matter abnormalities. The disease is typically fatal in infancy.


Multiple mitochondrial dysfunctions syndrome type 3

A rare neurometabolic disease, due to a lipoic acid biosynthesis defect, with a highly variable phenotype, typically characterized by early-onset acute or subacute developmental delay or regression frequently associated with feeding difficulties. Clinical severity is variable and may range from mild cases which present a later onset with slow neurological deterioration and general improvement over time to severe cases with clinical signs since birth and leading to early death. Associated manifestations include hypotonia, vision loss, respiratory failure, seizures, and intellectual disability. Brain magnetic resonance imaging frequently shows cavitating leukoencephalopathy with lesions in the periventricular/central white matter and parieto-occiîtal lobes.


Multiple mitochondrial dysfunctions syndrome type 4

A rare, severe, genetic, neurometabolic disease characterized by infantile-onset of progressive neurodevelopmental regression, optic atrophy with nystagmus and diffuse white matter disease. Affected individuals usually have central hypotonia that progresses to limb spasticity and hyperreflexia, eventually resulting in a vegetative state. Recurrent chest infections are frequently associated and seizures (usually generalized tonic-clonic) may occasionally be observed. Brain magnetic resonance imaging shows diffuse bilateral symmetric abnormalities in the cerebral periventricular white matter, with variable lesions in other areas but sparing the basal ganglia.


Multiple mitochondrial dysfunctions syndrome type 5

A rare mitochondrial disease characterized by early infantile onset of progressive neurological deterioration with seizures, spasticity, and lack of psychomotor development. Brain imaging shows severe leukodystrophy and abnormalities of neuronal migration. Lactic acidosis is common. The disease is usually fatal in early childhood.


Multiple mitochondrial dysfunctions syndrome type 6

A rare mitochondrial disease characterized by onset of episodic developmental regression in the first year of life, often in the setting of febrile illnesses, as well as hypotonia and seizures or refractory epileptic encephalopathy. Other observed features include ataxia, dystonia, or optic atrophy, among others. Patients do not achieve independent ambulation or meaningful speech. Brain imaging may show progressive cerebellar or diffuse atrophy and signal abnormalities of the basal ganglia. Serum lactate is often elevated.


Multiple mitochondrial dysfunctions syndrome describes a group of rare inborn errors of energy metabolism due to defects in mitochondrial [4Fe-4S] protein assembly. Patients present with a neonatal/infancy onset of metabolic lactic acidosis (that may be associated with hyperglycinemia and other abnormal metabolic testing results), muscular hypotonia, absence of psychomotor development or developmental regression, as well as abnormal neuroimaging findings (including leukodystrophy, brain developmental defects, white matter abnormalities, cerebral atrophy), and other variable clinical features (e.g., optic atrophy, cardiomyopathy, pulmonary hypertension, seizures, and dysmorphic features). Early fatal outcome is usual.


Multiple myeloma (MM) is a malignant tumor of plasma cell characterized by overproduction of abnormal plasma cells in the bone marrow and skeletal destruction. The clinical features are bone pain, renal impairment, immunodeficiency, anemia and presence of abnormal immunoglobulins (Ig).


A primary bone disorder characterized by development of two or more cartilage capped bony outgrowths (osteochondromas) at the surface of the bones.

Summary:
Epidemiology
Multiple osteochondromas (MO) prevalence is estimated at 1:50,000, and seems to be higher in males (male-to-female ratio 1.5:1).
Clinical description
Osteochondromas develop and increase in size in the first decade of life, and usually cease to grow when the growth plates close at puberty. They are pedunculated or sessile (broad base) and can vary widely in size. The number of osteochondromas may vary significantly within and between families, the mean number of locations is 15-18. The majority are asymptomatic and located in bones that develop from cartilage, especially the long bones of the extremities, predominantly around the knee. The facial bones are not affected. Bone lesions on flat bones, vertebrae, and the ribs are less common and the skull is usually not involved. Osteochondromas may cause pain, functional problems and deformities (especially of the forearm), which may provide reason for surgical removal. The most important complication is malignant transformation of osteochondroma towards secondary peripheral atypical cartilaginous tumor or chondrosarcoma, which is estimated to occur in 0.5-5% of cases.
Etiology
Germline mutations in the tumor suppressor genes, EXT1 (8q24.11) or EXT2 (11p11.2), are found in almost 90% of MO patients. The EXT genes encode glycosyltransferases, catalyzing heparan sulphate polymerization.
Diagnostic methods
The diagnosis is based on radiological and clinical documentation, supplemented with, if available, histological evaluation of the osteochondromas. Diagnostic criteria (WHO 2020) include radiological findings of at least two osteochondromas of the juxta-epiphyseal region of long bones, and a positive family history and/or a proven germline mutation in one of the EXT genes.
Differential diagnosis
MO should be distinguished from metachondromatosis, dysplasia epiphysealis hemimelica and Ollier disease.
Antenatal diagnosis
If the exact mutation is known antenatal diagnosis is technically possible.
Genetic counseling
MO is an autosomal dominant disorder and is genetically heterogeneous. Genetic counseling should be proposed to individuals having the disease-causing mutation informing them that there is 50% risk of passing the mutation to offspring.
Management and treatment
Management includes removal of osteochondromas when they are the cause of complaints. Removed osteochondromas should be examined for malignant transformation towards secondary peripheral atypical cartilaginous tumor or chondrosarcoma. Patients should be well instructed and regular follow-up for early detection of malignancy seems justified. For secondary peripheral chondrosarcoma, en-bloc resection of the lesion and its pseudocapsule with tumor-free margins should be performed, preferably in a bone tumor referral centre.
Prognosis
Osteochondromas are benign lesions and do not affect life expectancy.

                            Last update:
                            February 2021

                            - Expert reviewer(s):
                            Pr J.V.M.G. [Judith] BOVÉE


Multiple paragangliomas associated with polycythemia

A rare, endocrine disease characterized by early onset of polycythemia, and later occuring multiple parangliomas. Clinical presentation includes hypertension, headaches, fatigue, nausea, anxiety, and high concentration of red blood cells, leading to increased risk of stroke and pulmonary thromboembolism.


A group of rare genetic disorders characterized by the presence of joint contractures and multiple soft tissue webs (pterygia) across the neck and various joints, as well as typical facial appearance and a variety of other congenital anomalies. Both lethal (lethal and X-linked lethal multiple pterygium syndrome) and non-lethal (autosomal recessive and autosomal dominant multiple pterygium syndrome) forms occur.


Multiple pterygium-malignant hyperthermia syndrome

An extremely rare arthrogryposis syndrome, described in only two pairs of siblings from two unrelated families to date, and characterized by the association of arthrogryposis, congenital torticollis, dysmorphic facial features (i.e. asymmetry of the face, myopathic facial movements, ptosis, posteriorly rotated ears, cleft palate), progressive scoliosis and episodes of malignant hyperthermia. There have been no further descriptions in the literature since 1988.


Multiple sclerosis-ichthyosis-factor VIII deficiency syndrome is characterized by the association of multiple sclerosis with lamellar ichthyosis (see this term) and hematological anomalies (beta thalassemia minor and a quantitative deficit of factor VIII-von Willebrand complex). Other clinical manifestations may include eye involvement (optic atrophy, diplopia), neuromuscular involvement (ataxia, pyramidal syndrome, gait disturbance) and sensory disorder. There have been no further descriptions in the literature since 1992.


Multiple self-healing squamous epithelioma (also known as Ferguson-Smith disease (FSD)) is a rare inherited skin cancer syndrome characterized by the development of multiple locally invasive skin tumors resembling keratoacanthomas of the face and limbs which usually heal spontaneously after several months leaving pitted scars.

Summary:
Epidemiology
The prevalence is unknown but to date over 100 cases have been reported with several large affected families originating in western Scotland.
Clinical description
Tumors typically start as a reddish macule which becomes papular, enlarged and ulcerated. As the tumor involutes, a horny plug forms that falls out leaving a deep pit with irregular, over-hanging edges. Tumors have a predilection for sun-exposed areas, especially nose, ears and circumoral regions. Lesions on the limbs are often larger and leave flat scars. The trunk is seldom affected. Lifetime tumor numbers range from a few to over a hundred. The age of onset of a first tumor is very variable ranging from 8 to over 70 years (median 28 years). Histological assessment of these tumors reveals well differentiated squamous carcinomas. Treatment with radiotherapy must be avoided because more numerous, more invasive tumors arise in previously irradiated skin.
Etiology
FSD may be due to loss of function mutations in the gene TGFBR1 (9q22) which encodes a transmembrane serine/threonine kinase receptor involved in TGF-β signaling. Mutations in the gene TGFBR1 are also found in Loeys-Dietz syndrome (LDS; see this term) but the spectrum of TGFBR1 mutations differs and the mutations found in most FSD families have not been associated with a predisposition to aortic aneurysm or other developmental defects that occur in LDS. It has been suggested that FSD is an oligogenic trait. Inherited permissive variants at TGFBR1 and a second, as yet unidentified, linked locus on the long arm of chromosome 9 appear to be required for tumor development. 90% of TGFBR1 mutation carriers in affected families developed the condition by age 60. Palmar and plantar skin are not affected suggesting that the tumors arise from hair follicles.
Genetic counseling
Although FSD is likely to be an oligogenic trait, the condition is inherited in an autosomal dominant manner because the TGFBR1 mutations and predisposing variants at the second linked locus are usually inherited together in affected families.

                            Last update:
                            February 2015

                            - Expert reviewer(s):
                            Pr Malcolm FERGUSON-SMITH  - Dr David GOUDIE


A rare lysosomal disease characterized by a clinical phenotype that combines the features of different sulfatase deficiencies (whether lysosomal or not). Clinical manifestations can include developmental delay, progressive neurologic deterioration, hydrocephalus, hypotonia, coarse facial features, retinopathy, skeletal anomalies, hepatomegaly and ichthyosis to a variable degree. Multiple sulfatase deficiency (MSD) comprises severe to attenuated forms historically classified as neonatal (most severe form), infantile (most common form) or juvenile (rarest form).

Summary:
Epidemiology
The estimated prevalence is 1/500,000. So far, there are approximately 150 reported cases without apparent ethnological and sexual distribution.
Clinical description
This disease begins between birth and the juvenile period. Patients with an early neonatal form can present with intrauterine growth retardation and respiratory distress at birth. They may also have facial dysmorphism, skeletal abnormalities, splenomegaly, congenital heart defects, ichthyosis and muscle hypotonia. Failure to thrive is a common clinical sign inherent to the different clinical MSD presentations. The infantile form often presents with developmental delay preventing the child from reaching developmental milestones, mildly coarse facial features, ichthyosis, organomegaly, dysostosis multiplex, and ichthyosis of variable degree. Attenuated forms differ from severe forms in that the disease progresses more slowly and not all clinical signs need to be present. Patients often achieve independent ambulation and speech before neurocognitive decline begins. Retinopathy, gallbladder sludge, hydrocephalus, hypertrichosis, dysostosis multiplex, and neuropathy can occur at all stages and in every form of MSD.
Etiology
An autosomal recessive mutation in the SUMF1 gene on chromosome 3p26 causes MSD. The mutation alters the function of the sulfatase-activating enzyme FGE (Formylglycine-generating enzyme). There exist over 50 pathogenic mutations of SUMF1 most of which are missense mutations allowing residual FGE function towards sulfatase activation that result in reduced (to a variable degree) or completely absent activity sulfatases (lysosomal or not).
Diagnostic methods
Clinical manifestations associated with a detection of glycosaminoglycans and sulfatides in the urine is indicative of MSD. The diagnosis is confirmed if there is loss of activity of at least two sulfatases in leukocytes or if a genetic test reveals a pathogenic mutation in the SUMF1 gene.
Differential diagnosis
Differential diagnosis includes all single sulfatase deficiencies like metachromatic leukodystrophy (arylsulfatase A deficiency), Hunter syndrome, Maroteaux-Lamy syndrome, or Sanfilippo syndrome type A and D among others. X-linked ichthyosis, saposin B deficiency, mucolipidosis and other lysosomal diseases are additional differential diagnosis.
Antenatal diagnosis
Preimplantation and prenatal genetic testing can be performed if pathogenic SUMF1 variants have been identified in an affected family member.
Genetic counseling
The transmission is autosomal recessive. With each pregnancy, there is a 25% chance that the child will be affected and a 50% chance that the child will be a carrier.
Management and treatment
Currently, no specific treatment exists. A multidisciplinary approach is essential to increase quality of life and includes physiotherapy, skin treatment, neurological examinations, and monitoring of bone fragility, hearing, vision, gastrointestinal and respiratory disorders.
Prognosis
MSD has multiple clinical expressions and a prognosis can be hard to establish. However there exist different categories of MSD which may help evaluate its severity. The 50% survival rate has been estimated to be approximately 13 years. High motor function, achievement of speech, low number of clinical signs at a given age and high residual functionality of the FGE variant correlate with an attenuated course of MSD, and vice versa.

                            Last update:
                            December 2023

                            - Expert reviewer(s):
                            Dr Laura ADANG  - Dr Rebecca AHRENS-NICKLAS  - Dr Lars SCHLOTAWA


A rare subcutaneous tissue disease characterized by growth of symmetric non-encapsulated masses of adipose tissue mostly around the face and neck, with variable clinical repercussions (e.g. reduced neck mobility, compression of respiratory structures).

Summary:
Epidemiology
Multiple symmetric lipomatosis (MSL) primarily affects men and has a sex ratio of 15:1 to 30:1, depending on the region. The disorder may occur in all ethnic groups. Prevalence and incidence are not known but estimates are available for certain countries (e.g. prevalence for males in Italy 1/25,000). More than 300 cases have been reported.
Clinical description
MSL generally occurs in mid- to late-adulthood (30-60 years of age), but cases in childhood, adolescence and in elderly have also been reported. The course of the disease is characterized by rapid early development, followed by slow progressive growth of adipose deposits in and around the face, neck, occipital region, supraclavicular fossa, and shoulder areas. The thighs may be affected. Patients often initially present to medical attention for esthetic reasons and/or difficulties when dressing. Over time, neck muscles may become compressed, reducing the size of the trachea and esophagus with associated respiratory obstruction and obstructive sleep apnea. Patients also often have polyneuropathy, liver disease, and metabolic syndrome with abnormal glucose tolerance, and hyperlipidemia. Most affected patients are obese but some rare cases (10%) show a normal body weight. Malignant transformation into liposarcoma has been reported in very rare cases. MSL can also be associated with partial lipodystrophy and myopathy.
Etiology
The pathogenesis of MSL is not fully understood, but it may be related to defective noradrenergic regulation of mitochondria in brown fat. The disease is strongly associated with alcohol abuse (up to 90% of patients). Rare genetic forms have also been described, generally occurring earlier in a familial form. Disease-causing mutations have been reported in MFN2 (1p36.22) and LIPE (19q13.2) genes, encoding the mitofusin 2 and the hormone sensitive lipase, respectively.
Diagnostic methods
Diagnosis of MSL may be complicated because of confusion with obesity. Clinical findings showing a specific distribution of adipose tissue are diagnostic (specifically, sparing of the distal arms and legs), as is alcohol abuse. Nevertheless, a family history of MSL should be searched. Ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) can confirm the presence of symmetrical, non-encapsulated fat deposits. Biopsy of fatty masses can also be used to rule out liposarcoma. Dyslipidemia, insulin resistance and diabetes should also be investigated.
Differential diagnosis
Obesity and liposarcoma are the main differential diagnoses. Other disorders to consider include Cushing syndrome, familial partial lipodystrophy, especially Dunnigan syndrome related to LMNA gene mutations, familial angiolipomatosis, Prune belly syndrome and lymphoma.
Genetic counseling
A mitochondrial and autosomal recessive inheritance have been reported. MSL can also be transmitted following an autosomal dominant mode of inheritance.
Management and treatment
In some patients, treatment may not be required. When treatment is needed for esthetic reasons, or due to sleep apnea, aerodigestive tract compression, or severe pain, it generally involves surgery such as lipectomy, liposuction (or ultrasound-assisted liposuction). Cessation of alcohol intake is recommended but generally not associated with a decrease of lipomatosis. Weight loss may help in halting progression in some cases. The treatment of associated morbidities (diabetes, cirrhosis) is required. Screening for alcohol- (and often tobacco-) associated cancers is useful.
Prognosis
MSL is basically a benign condition but in some cases, there may be serious physical, cosmetic and psychological repercussions. Associated disorders may affect the prognosis. Alcoholism plays a greater role in morbidity and mortality than MSL itself.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Marie-Christine VANTYGHEM


Multiple synostoses syndrome (MSS) is a rare developmental bone disorder characterized by proximal symphalangism of the fingers and/or toes often associated with fusion of carpal and tarsal, humeroradial, and cervical spine joints.


Multiple system atrophy, cerebellar type (MSA-c) is a form of multiple system atrophy (MSA; see this term) with predominant cerebellar features (gait and limb ataxia, oculomotor dysfunction, and dysarthria).

Summary:
Epidemiology
MSA-c is observed predominantly in patients from Asia. A Japanese study reported a high percentage of patients (83.8%) exhibiting MSA-c features with only 16.2% of patients being categorized as MSA-parkinsonian type (MSA-p; see this term). In the Western Hemisphere, one third of all MSA patients have MSA-c. Genders are equally distributed.
Clinical description
The mean age of disease onset is 55 to 60 years. Gait ataxia is the most typical early symptom of MSA-c. Autonomic dysfunction (bladder dysfunction including early urinary incontinence, orthostatic hypotension, constipation, Raynaud syndrome) occurs early and is mandatory for the diagnosis of MSA-c. Additional features of MSA-c include dysphonia, dysphagia and other cerebellar features including limb ataxia and occulomotor dysfunction (sustained gaze-evoked nystagmus, positional down-beat nystagmus). All patients develop at least some parkinsonian signs (bradykinesia, rigidity, irregular jerky postural tremor) in the course of the disease. Pyramidal signs (generalized hyper-reflexia and, in some cases, positive Babinski sign) may be observed. Respiratory disturbances (sleep apnea, stridor and inspiratory sighs) and night time sleep disturbances, including rapid eye movement (REM) sleep behavior disorder (RBD) and periodic limb movements in sleep (PLMS), are frequently observed.
Etiology
The exact etiology of MSC-c is unknown while the presence of cytoplasmic aggregates of α-synuclein, primarily in the oligodendroglia, in combination with predominant neurodegeneration of the olivopontocerebellar structures are pathological hallmark features of MSA-c. Mutations in the COQ2 gene (4q21.23 ) (encoding an enzyme involved in the biosynthesis of coenzyme Q10) have been shown in multiplex families with MSA, while some variants were associated with an increased for sporadic MSA.
Genetic counseling
MSA-c occurs sporadically. However, some familial cases of MSA have been described.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Pr Wassilios MEISSNER