Monosomy 13q14 is a rare chromosomal anomaly syndrome, resulting from a partial deletion of the long arm of chromosome 13, characterized by developmental delay, variable degrees of intellectual disability, retinoblastoma and craniofacial dysmorphism (incl. micro/dolichocephaly, high and broad forehead, prominent eyebrows, thick, anteverted ear lobes, short nose with a broad nasal bridge and bulbous tip, prominent philtrum, large mouth with thin upper lip and thick, everted lower lip). Other features reported include high birth weight, macrocephaly, pinealoma, hepatomegaly, inguinal hernia and cryptorchidism.


Monosomy 13q34 is a rare chromosomal anomaly syndrome, resulting from the partial deletion of the long arm of chromosome 13, principally characterized by global developmental delay, mild intellectual disability, obesity and mild craniofacial dysmorphism (microcephaly, wide rectangular forehead, downslanting palpebral fissures, mild ptosis, prominent nose with long nasal bridge and broad tip, small chin). Other variable reported features include congenital heart defects, hand and foot anomalies (e.g. polydactyly) and agenesis of the corpus callosum.


Monosomy 18p refers to a chromosomal disorder resulting from the deletion of all or part of the short arm of chromosome 18.

Summary:
Epidemiology
The incidence is estimated to be about 1:50,000 live-born infants.
Clinical description
In the commonest form of the disorder, the dysmorphic syndrome is very moderate and non-specific. The main clinical features are short stature, round face with short philtrum, palpebral ptosis and large ears with detached pinnae. Intellectual deficiency is mild to moderate. A small subset of patients, about 10 to 15 percent of cases, present with severe brain/facial malformations evocative of holoprosencephaly spectrum disorders.
Etiology
In two-thirds of the cases, the 18p- syndrome is due to a mere terminal deletion occurring de novo. In the remaining cases the following are possible: a de novo translocation with loss of 18p, missegregation of a parental translocation or inversion, or a ring chr18. Parental transmission of the 18p- syndrome has been reported.
Diagnostic methods
Cytogenetic analysis is necessary to make a definite diagnosis.
Differential diagnosis
Differential diagnosis may include a wide number of syndromes with short stature and mild intellectual deficiency. In young children, deletion 18p syndrome may be vaguely evocative of either Turner syndrome or trisomy 21 (see these terms).
Antenatal diagnosis
Deletion 18p can be detected prenatally by amniocentesis or chorionic villus sampling and cytogenetic testing.
Genetic counseling
Recurrence risk for siblings is low for de novo deletions and translocations, but is significant if a parental rearrangement is present.
Management and treatment
No specific treatment exists but speech therapy and early educational programs may help to improve the performances of the children.
Prognosis
Except for the patients with severe brain malformations, the life expectancy does not seem significantly reduced.

                            Last update:
                            February 2008

                            - Expert reviewer(s):
                            Dr Catherine TURLEAU


A partial deletion of the long arm of chromosome 18 characterized by highly variable phenotype, most commonly including hypotonia, developmental delay, short stature, growth hormone deficiency, hearing loss and external ear anomalies, intellectual disability, palatal defects, dysmorphic facial features, skeletal anomalies (foot deformities, tapering fingers, scoliosis) and mood disorders.


A rare autosomal anomaly syndrome, with a highly variable phenotype, typically characterized by short length, joint abnormalities (e.g. dysplasia, hyperextensibility, contractures, dislocation), congenital cardiac defects, and craniofacial dysmorphism (incl. microcephaly, a high, prominent, narrow and/or hairy forehead, epicanthus, upward-slanting and/or small palpebral fissures, broad, high or depressed nasal bridge and malformed ears). Delayed motor development and intellectual disability is observed in patients not presenting early demise.


A rare developmental defect during embryogenesis, resulting from partial or total deletion of the short arm of chromosome 5, classically characterized by a high-pitched, monotone, cat-like cry (cri du chat) present since birth, associated with varying degrees of intellectual disability, developmental delay, microcephaly, and facial dysmorphism.

Summary:
Epidemiology
Monosomy 5p prevalence at birth ranges from 1/15,000 to 1/45,000, with females being slightly more affected than males.
Clinical description
Newborns typically exhibit low birthweight and microcephaly, as well as asphyxia cyanotic crises, and impaired suction. The disorder shows high phenotypic variability that evolves over time. Craniofacial dysmorphism includes microcephaly, round face, broad nasal bridge, hypertelorism, epicanthic folds, strabismus, downward-slanting palpebral fissures, low-set ears, down-turned corners of mouth, high-arched palate, microretrognathia, and malocclusion. Psychomotor delay and intellectual disability usually become evident in the first year of life and recurrent respiratory and intestinal infections may be observed during infancy. Pre- and postnatal growth delay, with weight more affected than height, is reported. With increasing age, the following features develop: hypotonia changes to hypertonia, face becomes long and narrow and supraorbital arch prominent, dental malocclusions arise, palpebral fissures tend to become horizontal, and premature grey hair appears.
Etiology
The disorder is due to a partial or total deletion of the short arm of chromosome 5, with the critical region located between 5p15.2 and 5p15.3. The deletion size may range from 0.5 to 40 Mb. Deletions may be terminal (most frequent), interstitial, or due to an unbalanced translocation. In approximately 80% of cases, the deletion is a de novo event.
Diagnostic methods
Diagnosis is suspected based on clinical characteristics, in particular the typical cry. Karyotype analysis can confirm the diagnosis. In doubtful cases, when there is conflict between the clinical suspicion and an apparently normal karyotype result, FISH analysis, quantitative PCR and/or CMA should be performed.
Differential diagnosis
Differential diagnosis includes Mowat-Wilson and Wolf-Hirschhorn syndromes, 1p36 monosomy, 17q21 microdeletion, and other chromosomal anomalies.
Antenatal diagnosis
Prenatal diagnosis is possible by ultrasonographic observation of structural abnormalities. Some cases present with cerebellar abnormalities. Chorionic villus sampling or amniocentesis, with karyotype, FISH or CMA analysis may reveal deletion of the critical region on chromosome 5p. However, in some cases, ultrasound can be normal. Noninvasive prenatal testing (NIPT) is currently commercially available in some countries and can be used as a screening method for some microdeletion syndromes, including Cri-du-chat syndrome. In families with an already known translocation involving 5p, preimplantation genetic testing for chromosomal structural rearrangement (PGT-SR) is possible.
Genetic counseling
Genetic counseling, including communication of risk of recurrence, family orientation, and anticipatory supervision for common complications, is possible for cases with a diagnosis of Cri-du-chat syndrome. Parents should be tested in order to rule out a balanced translocation. The recurrence risk for a de novo deletion is negligible.
Management and treatment
No specific treatment exists, however, rehabilitation, initiated early-on, has proven to be beneficial as it seems to improve prognosis and social adaptation. During the neonatal period, physical therapy should be started in the first week of life to help with any difficulty in swallowing and suction. Physical therapy, psychomotricity, and speech therapy are suggested for psychomotor and speech retardation. Patients often have sensorineural deafness; therefore, audiometric examinations should be routinely carried out. Malformations, including congenital heart disease and renal abnormalities, should be rule out as soon as the diagnosis is suspected. Periodic general check-up is recommended, including ENT, ophthalmological and dental assessments.
Prognosis
It is reported a 10% mortality, with 75 - 90% of the cases within the first year of life. The type, size, and location of the deletion greatly influence the severity and prognosis of the disease, with patients with larger deletions typically being more severe. Early diagnosis greatly influences prognosis as early detection allows for the prompt implementation of therapeutic measures, thus improving the outcome of physical and psychomotor development and helping with social adaptation.

                            Last update:
                            January 2020

                            - Expert reviewer(s):
                            Dr Kim CHONG  - Dr Rachel HONJO KAWAHIRA


Monosomy 9p is a rare chromosomal anomaly characterized by psychomotor developmental delay, facial dysmorphism (trigonocephaly, midface hypoplasia, upslanting palpebral fissures, dysplastic small ears, flat nasal bridge with anteverted nostrils and long philtrum, micrognathia, choanal atresia, short neck), single umbilical artery, omphalocele, inguinal or umbilical hernia, genital abnormalities (hypospadia, cryptorchidism), muscular hypotonia and scoliosis.


Interstitial 9q22.3 microdeletion is associated with a phenotype including macrocephaly, overgrowth and trigonocephaly. Psychomotor delay, hyperactivity and distinctive facial features were also observed. It has been described in two unrelated children.


A rare disorder of the anterior segment of the eye characterized by a unilateral or bilateral rapidly progressive, intractable, painful, ulcerative keratitis which initially affects the peripheral cornea and may spread circumferentially and then centrally. The destructive process involves stromal corneal tissue only, leaving the epithelium and endothelium largely unaffected. There is no involvement of the adjacent sclera. The condition can be complicated by glaucoma, cataract, and perforation.


A rare cranial malformation characterized by hyperostosis frontalis interna, variably associated with metabolic and endocrine disorders (such as obesity, diabetes mellitus, and hirsutism, among others). Compression by calvarial thickening may lead to cerebral atrophy and present with cognitive impairment, neuropsychiatric symptoms, headaches, and epilepsy. The condition predominantly affects women.


A rare genetic syndromic intellectual disability characterized by language delay and mild to moderate intellectual disability associated with truncal obesity, congenital nonprogressive retinal dystrophy with poor night vision and reduced visual acuity, and micropenis in males. Cataracts may occur in the second or third decade of life.


A congenital optic disc anomaly characterized by a funnel shaped excavation of the posterior fundus that incorporates the optic disc. Clinically, the optic disc malformation resembles the morning glory flower. Morning glory disc anomaly (MGDA) is usually unilateral and often results in a decrease in best-corrected visual acuity (BCVA). MGDA can be isolated or associated with other ocular or non-ocular anomalies.

Summary:
Epidemiology
The overall prevalence of MGDA is unknown, but it is estimated at 1/38,500 among subjects between 2 and 19 years old in Sweden. More than 100 cases have been reported in the medical literature. The disease is thought to be more common in women than in men.
Clinical description
MGDA often manifests early in childhood with strabismus of the affected eye. When the child is older and BCVA can be assessed, a substantial visual loss is noted (BCVA usually ranging between counting fingers and 20/200 in the affected eye). However, visual acuity is not always severely impaired, and can be close to normal. MGDA can be isolated or associated with other ocular anomalies in the same or contralateral eye (nystagmus, cataract, microphthalmia, glaucoma, coloboma of the crystalline lens, optic nerve drusen, aniridia, lid haemangioma, preretinal gliosis, peripheral retinal non-perfusion, serous retinal detachment, lenticonus, glioma or cyst of any optic pathway, acute retrobulbar optic neuritis, etc.). In younger patients, MGDA combined with persistent hyperplastic primary vitreous may indicate higher incidence of, and more severe associated complications. Associated facial dysmorphism (hypertelorism, dysplastic ears, cleft lip and palate, etc.), intracranial anomalies (basal encephalocele, other types of encephalocele, affected pituitary gland, corpus callosum agenesis, cerebral midline lipomas, etc.) and renal abnormalities (renal hypoplasia, chronic glomerulonephritis, hydronephrosis, etc.) have been reported, as well as several neurovascular and cardiac defects. MGDA can be associated with Moyamoya disease, PHACES syndrome, Aicardi syndrome, neurofibromatosis type 2, Arnold-Chiari malformation type I, CHARGE syndrome, Poland syndrome, among others. Bilateral cases are rare and might be correlated with a more severe systemic involvement.
Etiology
The exact etiology is not fully understood, but the syndrome is related to poor development of the posterior sclera and lamina cribrosa during gestation. The PAX6 gene could be linked to the anomaly.
Diagnostic methods
The diagnosis is based on clinical examination and relies on fundoscopy findings, showing an enlarged optic disc with peripapillary pigmentations, funnel shaped deep excavation, a radiating pattern of retinal blood vessels and a pale fluffy tuft of hyperplastic glial tissue overlying the optic disc. Optical coherence tomography, OCT may show a serous retinal detachment. Other MGDA-associated ocular anomalies, disorders elsewhere, e.g. cerebral malformations, systemic involvement and diseases, etc. should be ruled out.
Differential diagnosis
The differential diagnoses include optic disc colobomas, staphylomas and amblyopia.
Management and treatment
There is no curative treatment for the anomaly. However, associated amblyopia is usually treated by occlusion of the contralateral eye with good possibilities of some visual improvement. Strabismus can be corrected with surgery. Serous retinal detachment seems common, usually not requiring treatment but needing follow up. Vitrectomy with peripapillary photocoagulation and silicone oil tamponade may be required if a proliferative retinal detachment is associated with macular hole in children with MGDA. Associated somatic disorders/conditions, especially cranial malformations, cerebrovascular anomalies, cardiovascular anomalies, renal anomalies, endocrine and other systemic disease, etc. should be diagnosed and, if possible, treated accordingly.
Prognosis
The visual loss is usually non-progressive but MGDA increases the risk of serous retinal detachment (30% of patients in some studies). Other reported complications include choroidal neovascularization.

                            Last update:
                            January 2019

                            - Expert reviewer(s):
                            Dr Kristina TEÄR FAHNEHJELM


Morvan syndrome is a rare, life-threatening, acquired neurologic disease characterized by neuromyotonia, dysautonomia and encephalopathy with severe insomnia. Signs involving central (e.g. hallucinations, confusion, amnesia, myoclonus), autonomic (e.g. variations in blood pressure, hyperhidrosis) and peripheral (e.g. painful cramps, myokymia) hyperactivity, as well as systemic manifestations (such as weight loss, pruritus, fever), are reported. Thymoma is present in some cases.


Mosaic genome-wide paternal uniparental disomy

A rare chromosomal anomaly characterized by a combination of paternal uniparental and biparental cell lineages, leading to variable clinical presentation that predominantly includes features of Beckwith-Wiedemann syndrome and increased risk of various tumors. In addition, features of Angelman syndrome and transient neonatal diabetes might be expected.


A rare autosomal trisomy, characterized by reduced fetal movements and intrauterine growth retardation, low birth weight, and multiple congenital anomalies. The latter include, amongst others, facial dysmorphism (like hypertelorism, cleft lip/palate, micrognathia, low hairline, and small, low-set, and posteriorly rotated ears), head circumference below average, deformities of the hands (camptodactyly) and feet, marked hypertrichosis, and anomalies of the brain, heart, and lungs. Lethality appears to depend on the degree of mosaicism.


Mosaic trisomy 10 is a rare chromosomal anomaly syndrome, with a highly variable phenotype, principally characterized by growth delay, craniofacial dysmorphism (incl. prominent forehead, hypertelorism, upslanting palpebral fissures, blepharophimosis, low-set malformed large ears, high arched palate, cleft lip/palate, retrognathia) and cardiac, renal and skeletal (e.g. radial ray defects, scoliosis) malformations, with death usually ocurring neonatally or in early infancy. Other reported features include central nervous system and ear anomalies, as well as facial clefts and anal atresia.


Mosaic trisomy 12 is a rare chromosomal anomaly syndrome, with a highly variable phenotype, principally characterized by developmental or growth delay, short stature, craniofacial dysmorphism (e.g. turricephaly, tall forehead, downslanting palpebral fissures, posteriorly rotated and low set ears, narrow palate), congenital heart defects (e.g. atrial septal defect, patent ductus arteriosus), hypotonia, and pigmentary dysplasia. Scoliosis, hearing loss, facial/body asymmetry, and intellectual disability have also been reported.


Mosaic trisomy 14 is a rare chromosomal anomaly disorder, with a highly variable phenotype, principally characterized by growth and developmental delay, intellectual disability, body asymmetry/hypotonia, congenital heart defects, genitourinary abnormalities (cryptorchidism, micropenis, large clitoris, labial swelling), and abnormal skin hyperpigmentation. Patients usually present with craniofacial dysmorphism such as microcephaly, abnormal palpebral fissure, hypertelorism, ear abnormalities, broad nose, low-set ears, micro/retro-gnathia, and cleft or highly arched palate.


Mosaic trisomy 15 is a rare chromosomal anomaly syndrome principally characterized by intrauterine growth restriction, congenital cardiac anomalies (incl. ventricular and atrial septal defects, patent ductus arteriosus) and craniofacial dysmorphism (incl. hypertelorism, downslanting palpebral fissures, wide nasal bridge). Patients also present brain (e.g. hypoplastic cerebellum, ventricular asymmetry), renal (e.g. small dysplastic kidneys), and/or genital (undescended testis, small penis, hypoplastic labia majora) anomalies. Digital and skin pigmentation abnormalities have also been reported.


Mosaic trisomy 16 is a rare chromosomal anomaly syndrome with a highly variable phenotype ranging from minor anomalies with normal development to intrauterine growth retardation, abnormal skin pigmentation, craniofacial and body asymmetry, cardiac (e.g. ventricular septal defect) and genital (e.g. hypospadias, cryptorchidism) anomalies, scoliosis and hearing loss to neonatal death. Additional features observed include skeletal malformations (e.g. clino/polydactyly, talipes), mild facial dysmorphism, and developmental delay.


Mosaic trisomy 17 is a rare chromosomal anomaly syndrome, with a highly variable clinical presentation, mostly characterized by growth delay, intellectual disability, body asymmetry with leg length differentiation, scoliosis, and congenital heart anomalies (e.g. ventricular septal defect). Prenatal ultrasound findings include intrauterine growth retardation, nuchal thickening brain anomalies (e.g. cerebellar hypoplasia), pleural effusion and single umbilical artery. Patients with no associated malformations have also been reported.


Mosaic trisomy 2 is a rare chromosomal anomaly syndrome, with a highly variable phenotype, principally characterized by intrauterine growth restriction, growth and motor delay, craniofacial dysmorphism (e.g. microcephaly, hypertelorism, micro/anophthalmia, midface hypoplasia, cleft lip/palate), congenital heart and neural tube defects, as well as various skeletal (e.g. scoliosis, radioulnar hypoplasia, preaxial polydactyly) and gastrointestinal (e.g. intestinal malrotation, Hirschsprung disease) anomalies. Central nervous system malformations (including ventriculomegaly, thin corpus callosum, spina bifida) have also been reported.


Mosaic trisomy 20 is a rare chromosomal anomaly syndrome with a highly variable phenotype ranging from normal (in the majority of cases) to a mild, subtle phenotype principally characterized by spinal abnormalities (i.e. stenosis, vertebral fusion, and kyphosis), hypotonia, lifelong constipation, sloped shoulders, skin pigmentation abnormalities (i.e. linear and whorled nevoid hypermelanosis) and significant learning disabilities despite normal intelligence. More severe phenotypes, with patients presenting psychomotor and speech delay, mild facial dysmorphism, cardiac (i.e. ventricular septal defect, dysplastic tricuspid mitral valve) and renal anomalies (e.g. horseshoe kidneys), have also been reported.


Mosaic trisomy 22 is a rare chromosomal anomaly syndrome, with a highly variable phenotype, principally characterized by prenatal and postnatal growth delay, mild to severe intellectual disability, hemiatrophy, webbed neck, ocular and cutaneous pigmentary anomalies, craniofacial dysmorphic features (e.g. microcephaly, upslanted palpebral fissures, ptosis, ear malformations, flat nasal bridge, micrognathia) and cardiac abnormalities (including ventricular and atrial septal defect, pulmonary or aortic stenosis). Hearing loss and limb malformations (e.g. cubitus valgus, syn/brachydactyly), as well as renal and genital anomalies, have also been reported.


Mosaic trisomy 3 is a rare chromosomal anomaly syndrome with high phenotypic variability ranging from a mild phenotype presenting joint pain and laxity, mild facial dysmorphism (e.g. long facies, prominent eyes, dysplastic ears, downturned corners of the mouth, micrognathia) and no developmental delays to more severe phenotypes including short stature, intellectual disability, severe developmental delays, additional craniofacial dysmorphic features (e.g. brachycephaly, high forehead, flat midface, short neck) and hearing impairment, as well as skeletal (e.g. pectus excavatum, scoliosis), ocular (e.g. coloboma) and cardiac abnormalities.


Mosaic Trisomy 4 is a rare autosomal anomaly, due to the presence of an extra copy of chromosome 4 in a fraction of all cells, with a variable phenotype characterized by intrauterine growth retardation, low birth weight/length/OFC, mild intellectual deficit, congenital heart defects, hypertrophic cardiomyopathy, dysmorphic features (asymmetry of the face, eyebrow anomalies, low-set, posteriorally rotated, dysplastic ears, micro-/retrognathia), characteristic thumb abnormalities (aplasia, hypoplasia) and skin abnormalities (hypo/hyperpigmentation). Delayed puberty may be associated.


Mosaic trisomy 5 is a rare chromosomal anomaly syndrome with a variable phenotype ranging from clinically normal to patients presenting intrauterine growth retardation, congenital heart anomalies (mainly ventricular septal defect), multiple dysmorphic features (e.g. hypertelorism, prominent nasal bridge) and other congenital anomalies (incl. eventration of diaphragm, agenesis of corpus callosum, cloverleaf skull, clinodactyly, anteriorly placed anus). Psychomotor development may be normal in spite of low growth parameters being associated.


Mosaic trisomy 7 is a rare chromosomal anomaly syndrome, with a highly variable phenotype, mostly characterized by blaschkolinear skin pigmentary dysplasia, body asymmetry, enamel dysplasia, and developmental and growth delay. Intellectual disability, facial dysmorphism (e.g. frontal bossing, abnormal palpebral fissures, strabismus, abnormally shaped ears, and micrognathia), and genital anomalies (e.g. undescended testes) have also been observed. It has been reported to be associated with maternal uniparental disomy of chromosome 7, resulting in a Silver-Russell syndrome phenotype. Cases with no associated malformations have also been reported.


A rare autosomal anomaly defined by the presence of three copies of chromosome 8 in some cells of the body, and clinically characterized by facial dysmorphism, typically deep palmar and plantar creases, mild intellectual deficit and joint, urinary, cardiac and skeletal anomalies.

Summary:
Epidemiology
Historically, the birth prevalence was estimated between 1/25,000-50,000 but supporting epidemiological studies are lacking. Males are more frequently affected than females (sex-ratio 4:1).
Clinical description
Facial dysmorphic features are mild and include elongation of the skull (scaphocephaly), prominent forehead, hypertelorism, deeply set eyes (50%), bulbous upturned nose (60%), micrognathia (with everted lower lips), large dysplastic ears with prominent anthelices and large lobules. Additional features include: agenesis of the corpus callosum, highly arched or cleft palate (8%), short and broad neck, tall stature, elongated narrow chest, shoulders and pelvis. Urinary (hydronephrosis, ureteral reflux), and cardiac and large vessels abnormalities are frequent (40% and 25% respectively). Camptodactyly (70%), arthrogryposis of the joints (aggravating with time), deep palmar (in infants) and plantar furrows (75%), absent or hypoplastic patellae, vertebral malformations (65%: segmentation anomalies, costal anomalies, scoliosis), epilepsy, as well as corneal opacity and strabismus are also commonly observed. Most individuals present a mild-to-moderate intellectual disability (IQ between 50 and 75), with some patients having normal intelligence. Usually speech is more delayed than other developmental domains. There is no correlation between the percentage of trisomic cells and the severity of the intellectual disability.
Etiology
Mosaic trisomy 8 is the result of a post-zygotic event (error in chromosome segregation during mitosis in a fetus having a normal karyotype or due to spontaneous correction of trisomy 8). Complete trisomy 8 is due to an error in chromosome segregation during meiosis and often results in miscarriage during the first trimester. When, exceptionally, the fetus survives, it presents the same phenotype as mosaic trisomy. Patients with isochromosome 8p (tetrasomy of the short arm (p) of chromosome 8) have the same phenotype as patients with trisomy 8p.
Diagnostic methods
Diagnosis is based on karyotype analysis or on detection of copy number variation by microarray or whole exome sequencing. In the latter case confirmation by karyotyping is recommended.
Differential diagnosis
Differential diagnosis includes non-specific syndromic intellectual disability.
Antenatal diagnosis
Prenatal ultrasound abnormalities (hydronephrosis, corpus callosum agenesis and increased nuchal fold) are occasionally observed. On the other hand, when mosaic trisomy 8 is detected without ultrasound abnormalities, this should be interpreted with care since confined placental mosaicism frequently occurs. Prenatal diagnosis should be considered in cases where one of the parents has a mosaic trisomy 8.
Genetic counseling
The origin of the mosaic trisomy 8 is either post-zygotic non-disjunction, i.e. a mitotic error in the fetus, or meiotic non-disjunction resulting in a full trisomy 8 karyotype with subsequently trisomy rescue by mitotic loss of a chromosome 8. Almost all cases occur sporadically, but genetic counseling should be offered to parents and the individuals themselves.
Management and treatment
Management requires a multidisciplinary approach. In some cases, cardiac surgery may be proposed.
Prognosis
Mosaic trisomy 8 seems to predispose to Wilms tumors, myelodysplasias and myeloid leukemia. Some mosaic trisomy 8 patients have had children. In absence of serious malformations, life expectancy is normal.

                            Last update:
                            July 2021

                            - Expert reviewer(s):
                            Pr C.M.A. [Conny] VAN RAVENSWAAIJ-ARTS | ITHACA*

                                * European Reference Network


Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal anomaly characterized by multiple mosaic aneuploidies that leads to a variety of phenotypic abnormalities and cancer predisposition.

Summary:
Epidemiology
To date, 41 cases of MVA have been described in the literature.
Clinical description
The most common clinical features are growth retardation of prenatal onset, microcephaly, developmental delay, structural central nervous system and ophthalmological anomalies (e.g. cataract, corneal opacities, microphthalmia and glaucoma), and mild dysmorphic features, including triangular facies, micrognathia, and epicanthic folds. Additional features include oligohydramnios, ventricular dilatation, Dandy-Walker malformation, fetal ascites, and increased nuchal translucency. Cancer occurs in approximately 1/3 of individuals. Wilms tumor, rhabdomyosarcoma, acute lymphoblastic leukemia, and granulosa cell malignant tumor of the ovary (see these terms) all occur before the age of 5 years. In one individual, carcinoma of the ampulla of Vater and of the colon occurred in adulthood.
Etiology
MVA is due to defective cell division, leading to aberrant disjunction of chromosomes during mitosis. This results in a high proportion (>10%) of aneuploid cells. Mutations of the BUB1B and CEP57 genes have been identified in individuals with MVA. BUB1B encodes BUBR1, a key protein in the mitotic spindle checkpoint. CEP57 is a centrosomal protein involved in nucleating and stabilizing microtubules. Individuals with BUB1B mutations have a high incidence of cancer (approximately 75%). No individual with a CEP57 mutation has thus far been diagnosed with cancer.
Diagnostic methods
Diagnosis of MVA is based on cytogenetic analysis showing variable aneuploidy.
Differential diagnosis
Aneuploidy can be a feature of chromosomal instability syndromes including Roberts syndrome, ataxia telangiectasia, xeroderma pigmentosum, Bloom syndrome, Werner syndrome and Nijmegen breakage syndrome. Microcephaly with chromosome instability can occur in Fanconi anemia (see these terms).
Antenatal diagnosis
Prenatal karyotype can be undertaken by chorionic villus sampling or amniocentesis. This allows prenatal diagnosis of familial recurrence or investigation of abnormal sonographic findings consistent with MVA.
Genetic counseling
MVA is inherited in an autosomal recessive manner. The parents of an affected child are obligate carriers. Recurrence risk to siblings is 25%. Carrier testing for at-risk family members of individuals with biallelic BUB1B or CEP57 mutations is possible.
Management and treatment
Clinical management depends on the affected individual's specific needs (e.g.: growth hormone therapy for the treatment of growth failure). Cases with a cytogenetic confirmation of MVA syndrome and/or demonstrated BUB1B mutations should be offered Wilms tumor surveillance with renal ultrasonography every three to four months until five years.
Prognosis
Prognosis is related to the nature of the malformations and the risk of malignancy.

                            Last update:
                            May 2012

                            - Expert reviewer(s):
                            Dr Sandra HANKS  - Pr Nazneen RAHMAN  - Dr Katie SNAPE


A rare congenital respiratory disorder characterized by marked dilatation of the trachea and proximal bronchi that leads to impaired airway secretion clearance and recurrent lower respiratory tract infections.

Summary:
Epidemiology
Mounier-Kühn syndrome is a rare underdiagnosed condition of unknown prevalence. About 300 cases have been reported to date. The condition is more frequent in men.
Clinical description
The disorder may manifest at various ages but is usually diagnosed in young adults with recurrent bronchopulmonary infections (e.g. bronchitis, pneumonia), and tracheobronchial irritation of varying degrees of severity causing chronic dry or productive cough with purulent sputum production, dyspnea (occasionally on exertion) and hemoptysis. Progressive hoarseness has also been observed. Bronchial crackles and/or wheezing and finger clubbing are common. In mild cases, patients are asymptomatic or present only with chronic cough and have normal pulmonary function. In the rare severe cases, patients may suffer from pulmonary obstructive diseases such as bronchiectasis or bullous emphysema, and airflow obstruction that can lead to chronic respiratory failure.
Etiology
Mounier-Kühn syndrome results from the atrophy of elastic fibers in the trachea and main bronchi which lead to thinning of the smooth muscle layer and subsequent tracheobroncheal flaccidity, dilatation and collapse. The etiologic mechanism remains unknown. Irritants like cigarette smoke and air pollution could act as irritating factors. The disease is sometimes associated with connective tissue diseases such as Ehlers-Danlos syndrome, Marfan syndrome and cutis laxa and might have a genetic origin; however no gene mutation has been identified to date.
Diagnostic methods
Mounier-Kühn syndrome is diagnosed when the coronal and the sagittal diameters of the trachea, measured on plain chest radiography or computed tomography (CT), are greater than 25 mm and 27 mm, respectively in males, and greater than 21 mm and 23 mm in females. Fiberoptic bronchoscopy shows dilatation of the trachea and proximal bronchi, expiratory collapse in patients with tracheomalacia, and possible presence of diverticula on the posterior wall. Biopsies of bronchial and tracheal wall tissue show loss of elastic fibers but are usually unnecessary. Pulmonary function tests can be normal or show varying degrees of airflow obstruction and increased residual volume.
Differential diagnosis
Differential diagnosis includes lower respiratory tract infections like bronchitis and chronic obstructive pulmonary disease, ankylosing spondylitis, and Williams-Campbell syndrome.
Genetic counseling
The disease is sporadic in most cases, although several familial cases have been described.
Management and treatment
Treatment is symptomatic. Chest physiotherapy can be proposed to improve mucociliary clearance and antibiotics are administered for treatment of pulmonary infections. Some patients may benefit from non-invasive positive-pressure ventilation, also needed at night in severe cases. Insertion of a tracheal or tracheobronchial stent, with or without surgical tracheobronchoplasty, was shown to reduce airway collapsibility in some highly selected cases with tracheomalacia. Double lung transplantation has been successful in one case.
Prognosis
The impact of this condition on life expectancy has not been evaluated. Complications include respiratory infections, tracheomalacia, pulmonary obstructive diseases, pneumothorax, and exceptionally lung fibrosis that can lead to chronic respiratory failure.

                            Last update:
                            December 2019

                            - Expert reviewer(s):
                            Pr Vincent COTTIN  - Dr Mouhamad NASSER


A rare multiple congenital anomaly syndrome characterized by a distinct facial phenotype, intellectual disability, epilepsy, Hirschsprung disease (HSCR) and variable congenital malformations.

Summary:
Epidemiology
Prevalence is estimated at 1/50,000-70,000 live births. Over 300 patients have been reported so far. It seems probable that Mowat-Wilson syndrome (MWS) is underdiagnosed, particularly in patients without HSCR.
Clinical description
The typical characteristic facies of MWS includes a high forehead, frontal bossing, large eyebrows that are medially flaring and sparse in the middle part, hypertelorism, deepset but large eyes, large and uplifted ear lobes with a central depression, saddle nose with prominent rounded nasal tip, prominent columella, open mouth with M-shaped upper lip, and a prominent but narrow and triangular pointed chin. The facies becomes more pronounced with age. Associated HSCR causes constipation which frequently persists after surgery. Patients usually have moderate to severe intellectual disability. Speech is absent or limited to a few words, with onset at around 4 years. Seizures are common; all types of seizures (absence, generalized tonic-clonic seizures, myoclonic, and focal seizures) have been reported. Most subjects have a happy demeanor with frequent smiling and a sociable personality. Other associated congenital anomalies can include cerebral (agenesis of the corpus callosum), cardiac (patent ductus arteriosus, ventricular septal defect), respiratory (valvular pulmonary stenosis, pulmonary artery sling, with or without tracheal stenosis), genitourinary (hypospadias, cryptorchidism, vesicoureteral reflux and hydronephrosis), ocular (microphthalmia) and musculoskeletal (pes planus, calcaneovalgus). Asplenia is rare. Affected children tend to have a high pain threshold.
Etiology
MWS is caused by heterozygous variants in the zinc finger E-box-binding homeobox 2 gene, ZEB2 (2q22.3). To date, over 100 variants have been reported in patients with a typical phenotype; variants are usually whole/partial gene deletions or truncating mutations, suggesting that haploinsufficiency is the main pathological mechanism. Genotype-phenotype analysis shows that facial gestalt and delayed psychomotor development are constant clinical features, while the frequent and severe congenital malformations are variable. In a small number of patients, missense variants affecting a functional domain of the ZEB2 protein can lead to an atypical phenotype.
Diagnostic methods
Distinct facies is particularly important for the initial clinical diagnosis and provides the hallmark warranting ZEB2 mutational analysis in all cases, even in the absence of HSCR. Congenital malformations and seizures require early clinical investigations for which patients should be referred to the relevant specialists (including neonatologists and pediatricians).
Differential diagnosis
Differential diagnoses include Pitt-Hopkins, Goldberg-Shprintzen megacolon, Smith-Lemli-Opitz and Angelman syndromes.
Antenatal diagnosis
Prenatal diagnosis is available for subsequent pregnancies of parents with an affected child.
Genetic counseling
MWS is an autosomal dominant disorder; however, the majority of MWS cases reported are sporadic. Germinal mosaicism has been described and recurrence risk has been calculated at 2%.
Management and treatment
Congenital heart disease and HSCR disease may require early surgery during the first days or months of life. Seizures are common and require standard therapy. Genitourinary anomalies may require surgery in the first few years of life. Psychomotor development is delayed in all patients and thus, rehabilitation (physical therapy, psychomotor and speech therapy) should be started as soon as possible. Musculoskeletal anomalies may require orthopedic intervention.
Prognosis
Mortality and morbidity depend on the presence and severity of congenital anomalies. Patients have been reported to live into early adulthood but require assistance with activities of daily living.

                            Last update:
                            October 2020

                            - Expert reviewer(s):
                            Dr Stefano Giuseppe CARAFFI | ITHACA* - Dr Livia GARAVELLI | ITHACA*

                                * European Reference Network


Moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome

Moyamoya angiopathy - short stature - facial dysmorphism - hypergonadotropic hypogonadism is a very rare, hereditary, neurological, dysmorphic syndrome characterized by moyamoya disease, short stature of postnatal onset, and stereotyped facial dysmorphism.

Summary:
Epidemiology
The syndrome is extremely rare and has been reported in three unrelated families to date, with 10 affected individuals in several generations. These families are not from Japan or Asia, whereas in general the incidence of moyamoya disease (see this term) is highest in Japan and other Asian countries, in comparison with other parts of the world.
Clinical description
Affected patients are all male (X-linked inheritance) and have moyamoya angiopathy (progressive stenosis of the terminal portion of the intracranial internal carotid arteries), short stature, hypergonadotropic hypogonadism, and other variable manifestations including stroke, hypertension, dilated cardiomyopathy (see this term), premature coronary heart disease, premature hair graying, azoospermia, and early bilateral acquired cataract. Moyamoya angiopathy causes cerebral infarcts or hemorrhage and acute neurological symptoms. Facial dysmorphism is characterized by hypertelorism, flared nares, long philtrum, and mild ptosis. Carrier females are not affected.
Etiology
The genetic cause appears to involve Xq28 deletions removing MTCP1/CMC4and BRCC3 (Xq28) .The specific pathophysiological mechanisms underlying this disorder remain obscure, but appear to involve alteration in DNA repair.
Genetic counseling
Reported cases are suggestive of a hereditary syndrome with an X-linked recessive pattern of inheritance.

                            Last update:
                            April 2015

                            - Expert reviewer(s):
                            Dr Karin KLIJN


Moyamoya disease with early-onset achalasia is an exceedingly rare autosomal recessive neurological disorder reported only in a few families so far. It is characterized by the association of early onset achalasia (manifesting in infancy) with severe intracranial angiopathy that is consistent with moyamoya angiopathy in most cases (moyamoya disease; see this term). Other variable associated manifestations include hypertension, Raynaud phenomenon, and livedo reticularis.


Moyamoya disease (MMD) is a rare intracranial arteriopathy involving progressive stenosis of the cerebral vasculature located at the base of the brain causing transient ischemic attacks or strokes.

Summary:
Epidemiology
The incidence of MMD is highest in Asian populations but MMD occurs in many other ethnic groups. The incidence ranges from 1/280,000 to 1/89,000 in Japan and China to1/1,100,000 in the US. The prevalence in Japan is estimated to be 1/30,000-1/9,500.
Clinical description
There are two peak incidence ages: young children (5-9 years) and adults (mid-40s). Involvement is usually bilateral but unilateral cases are reported. Disease manifestations are highly variable. Some affected individuals remain asymptomatic, some develop transient attacks, and others severe neurologic deficits as a result of infarcts or hemorrhage. Hemorrhage occurs less often in children. Other manifestations include headache, dizziness, seizures, and chorea. Some patients present intellectual disability. The course is also highly variable but generally progressive. The term MMD is used when there is no cause and Moyamoya syndrome (MMS) when the disease is associated with other diseases (sickle cell anemia, neurofibromatosis; see these terms).
Etiology
The etiology of MMD is not currently known but is thought to be multifactorial with genetic determinants playing a role. In Japan, about 15% of patients have a family history. Mutations in the RNF213(17q25.3) gene have been found in some patients but their pathogenic role remains unclear. The intracranial vasculopathy associated with smooth muscle actin alpha 2 (ACTA2) (10q23.31) mutations has been referred to as MMS, but it has distinctive angiographic features, including dilatation of proximal ICAs, an abnormally straight course of intracranial arteries, and absence of typical moyamoya collateral vessels.
Diagnostic methods
The diagnosis of MMD may be difficult because it is rare and because of the non-characteristic signs and symptoms. Diagnosis is suspected on the basis of the clinical presentation and imaging findings. Cerebral angiography is the standard confirmatory diagnostic method. Moyamoya disease involves in particular the supraclinoid internal carotid arteries and their proximal branches. The term moyamoya means "puff of smoke" in Japanese, in reference to the appearance of abnormal vascular collateral networks on angiography that develop adjacent to the stenotic vessels. Magnetic resonance angiography (MRA) can also be used.
Differential diagnosis
MMD may develop in an isolated manner but can also be associated with other diseases when it is known as MMS: typical angiographic MMDfeatures associated with other diseases, e.g. sickle cell anemia, Down syndrome, neurofibromatosis type 1 (see these terms) and many others.
Genetic counseling
Autosomal dominant inheritance with incomplete penetrance has been described in affected Japanese families. Other suggested patterns include autosomal-recessive, X-linked-recessive, or multifactorial inheritance.
Management and treatment
No specific treatment to stop progression or reverse the intracranial arteriopathy is available for MMD. Drug therapy is mainly used to counter disease complications such as stroke and transient ischemic attacks, to alleviate symptoms, and to prevent cognitive deterioration. Physical, occupational and speech therapy may be needed after attacks. Surgical revascularization procedures to restore blood flow to the brain involving direct, indirect or combined techniques have also been used and appear to reduce the risk ofischemic stroke and possibly cognitive dysfunction. The indication and timing of surgery remains controversial.
Prognosis
Early detection and appropriate treatment improve the long-term outcome. The prognosis depends on disease severity. Mortality rates are estimated at about 5% for adults and 2% for children. The main cause of death is hemorrhage.

                            Last update:
                            April 2015

                            - Expert reviewer(s):
                            Dr Karin KLIJN


A rare, genetic, epilepsy syndrome characterized by congenital alopecia, early-onset epilepsy, intellectual disability and speech delay. Large stature, delayed bone development and abnormal electroencephalogram have also been associated.


A rare disorder of multiple-pathway glycosylation characterised by psychomotor delay, seizures, failure to thrive, cardiomyopathy, and ichthyosis-like cutaneous anomalies.


MPI-CDG is a form of congenital disorders of N-linked glycosylation, characterized by cyclic vomiting, profound hypoglycemia, failure to thrive, liver fibrosis, gastrointestinal complications (protein-losing enteropathy with hypoalbuminaemia, life-threatening intestinal bleeding of diffuse origin), and thrombotic events (protein C and S deficiency, low anti-thrombine III levels), whereas neurological development and cognitive capacity is usually normal. The clinical course is variable even within families. The disease is caused by loss of function of the gene MPI (15q24.1).


MRCS syndrome is a rare, genetic retinal dystrophy disorder characterized by bilateral microcornea, rod-cone dystrophy, cataracts and posterior staphyloma, in the absence of other systemic features. Night blindness is typically the presenting manifestation and nystagmus, strabismus, astigmatism and angle closure glaucoma may be associated findings. Progressive visual acuity deterioration, due to pulverulent-like cataracts, results in poor vision ranging from no light perception to 20/400.


MT-ATP6-related mitochondrial spastic paraplegia

A rare complex hereditary spastic paraplegia characterized by adulthood-onset of slowly progressive, bilateral, mainly lower limb spasticity and distal weakness associated with lower limb pain, hyperreflexia, and reduced vibration sense. Axonal neuropathy is frequently observed on electromyography and nerve conduction examination.


MTHFS-related developmental delay-microcephaly-short stature-epilepsy syndrome

A rare, genetic, neurometabolic disease characterized by microcephaly, short stature, epilepsy, cerebral hypomyelination, severe global developmental delay, and progressive spasticity. Macrocytic anemia and hyperthermia have also been reported in association. Brain imaging reveals delayed myelination with minimal progression over time, mild cerebellar atrophy and/or thin corpus callosum.


A type of HCD characterized by the production of incomplete monoclonal mu-heavy chains without associated light chains. The clinical presentation resembles that of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Summary:
Epidemiology
The prevalence is unknown but the disease is extremely rare. Only about 35 cases have been reported in the world literature.
Clinical description
The age at diagnosis is usually between 50 and 60 years. The most common presenting symptoms are those of a lymphoproliferative malignancy although peripheral lymphadenopathy is less common than in CLL. Lytic bone lesions and osteoporosis have been reported in a few cases.
Etiology
The cause of mu-HCD is unknown.
Diagnostic methods
The diagnosis of mu-HCD is made by documentation of the abnormal heavy chain by immunofixation of serum and urine. Unlike alpha- and gamma-HCD, some patients with mu-HCD have increased free light chain secretion (Bence Jones proteinuria). Examination of the bone-marrow shows an increase in lymphocytes, plasma cells, or plasmacytoid lymphocytes.
Differential diagnosis
The differential diagnosis of mu-HCD includes all lymphoplasma-cell proliferative disorders. Without a suspicion for the disease, mu-HCD is difficult to diagnose. The finding of Bence Jones proteinuria in a patient with a lymphoproliferative disorder and vacuolated plasma cells in the bone marrow deserves further investigation for possible mu-HCD.
Management and treatment
There is no specific treatment for mu-HCD. If mu-HCD protein is found in the serum of an asymptomatic patient this should be followed closely for the development of a symptomatic lymphoplasma-cell proliferative disorder. Treatment of symptomatic patients with mu-HCD is similar to that employed in patients with CLL (eg, glucocorticoids, alkylating agents).
Prognosis
The disease course and prognosis seen in mu-HCD is highly variable. The median survival from time of diagnosis is 24 months and ranges from < 1 month to 11 years.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Pr Robert KYLE  - Dr Dietlind WAHNER-ROEDLER


MUC1-related autosomal dominant tubulointerstitial kidney disease

A rare autosomal dominant tubulointerstitial kidney (ADTKD) disease due to MUC1 mutations characterized clinically by a bland urinalysis (absence of blood or protein in the urine), and chronic kidney disease leading to end-stage kidney disease (ESKD) between 20 and 80 years.

Summary:
Epidemiology
Whilst prevalence data is limited, prevalence is estimated at 1/1,400,000 in the USA and 1/250,000 in Ireland. The disease has equal prevalence among all studied racial groups and genders.
Clinical description
Chronic kidney disease usually is first evident in the early twenties. Patients will have slowly progressive loss of kidney function, between 1 and 3 ml/min/1.73m2/year. The mean age of ESKD is approximately 45 years of age, although this varies widely from 20 to over 70 years of age, even among family members with the same mutation. The reason for this variation in age of ESKD is unclear.
Etiology
ADTKD-MUC1 is caused by frameshift mutations in the MUC1 gene, all of which result in the creation of the same frameshift protein. The most common mutation (responsible for approximately 95% of cases) is a cytosine duplication within a tract of seven cytosines. The protein deposits in the endoplasmic reticulum Golgi intermediate compartment (ERGIC) where it leads to cellular stress, early cell death, and progressive kidney failure.
Diagnostic methods
Diagnosis should be considered in families where a parent and child have chronic kidney disease, and urinalysis reveals no blood and little or no protein. De novo mutations may arise and are difficult to identify. Patients should first undergo multi-gene panel testing or whole exome sequencing for other mutations that cause ADTKD and then undergo specialized genetic testing for the MUC1 cytosine duplication, which is causative in 95% of cases of ADTKD-MUC1. This specific test is available in certain laboratories in Europe (see Orphanet Diagnostic Tests) and the USA. Multigene panels, whole exome, and whole genome sequencing do not detect this duplication. If negative, other causative mutations can be identified immunohistochemically in a research setting.
Differential diagnosis
ADTKD-UMOD is clinically very similar, distinguished only by the higher prevalence of gout. Most other conditions have other associated symptoms, but when these symptoms are less severe or not clinically noted, ADTKD-MUC1 should be considered. These include kidney disease related to DNAJB11, IFT140, or HNF1B, and, in rare cases, Alagille syndrome.
Antenatal diagnosis
Due to the difficulty in genetic testing for MUC1 variants, antenatal diagnosis is not currently available in the USA but is available in Europe.
Genetic counseling
The disorder is autosomal dominant. Counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. Genetic testing in childhood is not advised as patients are asymptomatic and may not have symptoms of CKD for more than two decades. Relatives should be informed of their risk of ADTKD-MUC1, as the disease is often misdiagnosed, and reaching out to family members can prevent the need for kidney biopsy or inappropriate treatment.
Management and treatment
There are currently no specific therapies available. Sodium glucose-2 transport inhibitors (SGLT2 inhibitors) are indicated in chronic kidney disease and may be helpful in ADTKD. Patients with ADTKD-MUC1 are excellent transplant candidates, as the disease does not recur in the transplanted kidney and most patients do not have other comorbid conditions. The goal should be transplant without ever needing dialysis. Family members should be screened for the familial MUC1 mutation to see if they can donate. Major advances are occurring in kidney disease management, with placement of pig kidneys, CRISPR technology to treat genetic disorders, and advances in immunosuppression-free kidney transplantation.
Prognosis
Patients usually develop end-stage kidney disease at a mean age of 45 years, but there is wide inter- and intra-familial variation. Some family members may go on dialysis in their twenties, while other family members may not start dialysis until past 70 years of age. Survival post-transplant is comparable to the general ESKD transplant population.

                            Last update:
                            June 2022

                            - Expert reviewer(s):
                            Pr Anthony BLEYER  - Pr Stanislav KMOCH


Mucinous adenocarcinoma of ovary is a rare, malignant epithelial tumor of the ovary characterized, macroscopically, by a large, usually unilateral tumor with smooth surface and evenly distributed cystic and solid areas and, histologically, by a complex papillary growth pattern with microscopic cystic glands and necrotic debris. Patients often present with pelvic pain and pressure, abdominal mass or gastrointestinal problems such as early satiety or bloating.


Mucinous adenocarcinoma of the appendix is a very rare, slow growing, well-differentiated epithelial neoplasm of the appendix characterized by abundant mucin production. Clinically, it presents as acute appendicitis (with abdominal pain, fever, leukocytosis) or as pseudomyxoma peritonei (wide-spread presence of mucin within the peritoneal cavity), however some patients may be completely asymptomatic at the time of diagnosis. In many cases, a second gastrointestinal malignancy is present.


Mucinous cystadenocarcinoma of the pancreas

A rare, epithelial tumor of the pancreas characterized, histologically, by columnar, mucin-producing epithelium associated with ovarian-type subepithelial stroma, which does not communicate with the pancreatic ductal system, most frequently localized to the body or tail of the pancreas. Clinically, small tumors (<3 cm) are usually asymptomatic, while large tumors typically present obstructive jaundice, a palpable abdominal mass, and may associate portal hypertension, hemobilia and diabetes mellitus.


Mucinous tubular and spindle cell renal carcinoma is a rare subtype of renal cell carcinoma characterized, histologically, by tubular architecture and sheets of spindle cells embedded in a mucinous/myxoid stroma and, macroscopically, by a solid, generally well-circumscribed, partially encapsulated tumor of variable size, with a homogenously colored, bulging cut surface, occassionally containing areas of hemorrhage or necrosis, usually located in the cortex. Patients can present abdominal/flank pain, adbominal mass and/or hematuria, however most are asymptomatic and tumor is discovered incidentally. Indolent behavior is frequent and association with nephrolithiasis and end-stage kidney disease has been noted.


Muckle-Wells syndrome (MWS) is an intermediate form of cryopyrin-associated periodic syndrome (CAPS; see this term) and is characterized by recurrent fever (with malaise and chills), recurrent urticaria-like skin rash, sensorineural deafness, general signs of inflammation (eye redness, headaches, arthralgia/myalgia) and potentially life-threatening secondary amyloidosis (AA type).

Summary:
Epidemiology
The prevalence of MWS is unknown. However a French survey through genetic laboratories has reported 135 cases and estimated CAPS prevalence at 1/360,000.
Clinical description
MWS onset is variable but patients usually present within the first few years of life with recurrent peak of fever (max of 39-40°C, starting generally in the evening (circadian pattern) and lasting a few hours, with a variable recurrence during a week. Intense general malaise and chills occur at the same time and lead to severe disability. Non-pruriginous urticarial rash (diffuse, erythematous, edematous plaques on a background of generalized, faintly erythematous patches) is a key feature of CAPS and is generally present with marked intensification during acute episodes. Progressive, high frequency, sensorineural deafness due at least in part to chronic inflammation of the cochlea begins in childhood (generally after the age of 10 years) resulting in complete deafness. Myalgia, arthralgias and distal edema are very common. With age, patients develop eythematous band over the hands as well as digital clubbing. Additional features include severe chronic fatigue, recurrent headaches, cognitive impairment, ocular involvement (conjunctivitis, uveitis, episcleritis), oral aphthosis, lymphadenopathy, thoracic and abdominal pain. Cold, fatigue, stress, or exercise are universal triggers of acute inflammation however acute attacks may appear unprovoked. Secondary amyloidosisis (see this term), revealed by persistent proteinuria, is a prominent feature affecting 25% of patients and can result in chronic renal insufficiency. Severe MWS cases, (MWS/CINCA) may display chronic meningitis, papillar edema with progressive optic atrophy. Failure to thrive and male sterility are common.
Etiology
MWS is due to dominant mutation in the NLRP3 (1q44) gene which encodes cryopyrin. This defect results in the gain of function of cryopyrin that ultimately leads to the increased secretion of the proinflammatory cytokine interleukin (IL)-1 beta and and dysregulated inflammation. Mutations in this gene may also cause two additional phenotypes of CAPS: familial cold urticaria (FCAS) and CINCA syndrome (see these terms), Patients carrying identical amino acid substitution may present with distinctly different clinical subtypes, suggesting that additional genetic and/or environmental modifying factors are important in disease expression. Somatic NLRP3 mosaicism could explain 30-60% of patients with negative conventional genetic testing. Some patients with a classical phenotype of MWS, FCAS or CINCA syndrome may not have mutations in NLRP3.
Genetic counseling
Transmission is autosomal dominant with variable expression within a family and from one family to another.

                            Last update:
                            July 2014

                            - Expert reviewer(s):
                            Pr Isabelle KONE-PAUT


Mucocutaneous venous malformations (VMCMs) are hereditary vascular malformations characterized by the presence of small, multifocal, bluish-purple venous lesions involving the skin and mucosa.

Summary:
Epidemiology
Prevalence is unknown but around 20 families have been identified so far.
Clinical description
The multifocal venous lesions are usually small (< 2cm in diameter), and are present at birth. They are soft and usually compressible and undergo proportionate growth with age. There is significant clinical variation with respect to the size, location and number of lesions, even between affected individuals from the same family. Classically, one individual in a given family has a large lesion. Small lesions are usually asymptomatic, whereas larger lesions can cause pain and invade subcutaneous muscle. New lesions appear with time. Patients with VMCMs have normal mental and physical development.
Etiology
VMCMs are associated with amino acid substitutions (R849W and Y897S) in the tyrosine-protein kinase endothelial cell receptor (TEK/TIE2; 9p21). Approximately 90% of individuals who have a mutation in the TEK gene develop mucocutaneous venous malformations by 20 years of age; conversely, approximately 10% of individuals with a TEK mutation are clinically unaffected.
Diagnostic methods
Diagnosis is based on clinical evaluation of the cutaneous lesions. Doppler ultrasound examination can be used to confirm slow blood flow, and MRI can be used to confirm the venous component and extent of the lesions. Ultrasound examination reveals saccular compressible venous-like cavities. Molecular genetic testing for confirmation of the diagnosis is available on a research basis.
Differential diagnosis
The differential diagnosis should include glomuvenous malformations (GVMs, which are deeper purple in color than VMCMs, painful on palpation, and more superficial than venous malformations; see this term) and Blue rubber bleb nevus syndrome (characterized by the association of cutaneous and mucosal venous-like lesions with gastrointestinal lesions; see this term).
Antenatal diagnosis
Prenatal diagnosis is feasible for affected families in which the disease-causing mutation has been identified, but is not widely available.
Genetic counseling
VMCMs are transmitted in an autosomal dominant manner with incomplete penetrance. Paradominant inheritance (presence of a germline mutation and a somatic mutation) appears to be involved in disease expression and may explain the variability in clinical phenotype. Genetic counseling should be provided for affected families, informing patients of a 50% risk of inheriting the disease-causing mutation and of the variability in clinical expression. There is no anticipation in reported families.
Management and treatment
The principle treatment approach is sclerotherapy, alone or in combination with plastic and reconstructive surgery depending on the size and location of the lesions. Ethanol (96%) for injection is the most commonly used sclerosing agent and obtained EU orphan drug designation in April 2005 for the treatment of congenital venous malformations. When D-dimers are elevated, indicating activation of coagulation, low-molecular-weight heparin can be used to treat the associated pain. Female patients should avoid using oral contraceptives with high estrogen levels.
Prognosis
The prognosis for patients is good, malignant transformation has not been reported and the life expectancy for patients is not reduced.

                            Last update:
                            January 2009

                            - Expert reviewer(s):
                            Pr Laurence BOON  - Pr Miikka VIKKULA


A rare, severe form of mucolipidosis characterized by growth retardation, skeletal abnormalities (dysostosis multiplex, craniosynostosis, contractures of the joints and osteopenia), facial dysmorphism, stiff skin, obstructive airway, cardiomegaly and severe global developmental delay.

Summary:
Epidemiology
Mucolipidosis type II (MLII) and type III (MLIII) represent a continuum of clinical severity and reported data is either combined or reported separately; in all instances the data is over 10 years old. The combined birth prevalence is estimated between 1/ 37,000-455,000 worldwide, whereas the reported birth prevalence for MLII is estimated between 1/123,000-2,000,000 in Europe. A founder effect has been reported in Saguenay-Lac-St-Jean region of Quebec where birth prevalence is estimated at 1/6,000.
Clinical description
MLII patients present prenatally (hydrops fetalis), directly after birth or within the first months of live with dysmorphic features, cardiac involvement, respiratory symptoms, dysostosis multiplex, severe growth abnormalities, transient neonatal hyperparathyroidism inducing rickets-like bone disease (not always present), clubfeet, hypotonia and global developmental delay; all symptoms gradually worsen over time. Facial dysmorphism includes a flat face, shallow orbits with proptotic eyes (due to craniosynostosis), depressed nasal bridge, prominent mouth and gingival hypertrophy. Coarsening of facial features is progressive. Spinal cord compression develops over time. Postnatal growth (both length and weight) usually stops in the second year of life and contractures develop in all joints. Most patients never walk. Cardiac involvement most commonly includes the thickening and insufficiency of the mitral or aortic valves. Breathing is noisy due to the progressive narrowing of airways, mucosal thickening and stiffening of all connective tissues which, along with cardiac involvement, leads to cardiorespiratory insufficiency.
Etiology
MLII is due to mutations in the GNPTAB gene (12q23.3), encoding the alpha and beta subunits of the N-acetylglucosamine phosphotransferase complex. Mutations in this gene lead to a failure of mannose-6-phosphate (MP6) synthesis, the marker on the oligomannosyl type glycan side chains of lysosomal enzymes, which targets the enzymes to the lysosomes. Without the MP6 signal, the enzymes are missorted into the extracellular space, leading to accumulation of the enzymes in the tissues.
Diagnostic methods
Diagnosis is based on clinical/radiographic examination as well as detection of elevated plasma lysosomal enzyme or decreased lysosomal enzyme activity. Radiographs reveal increasing osteopenia and dysostosis multiplex (diaphyseal widening and shortening of tubular bones, anterior-inferior hook configuration of first and/or second lumbar vertebra, and relatively long pubic and ischial bones). Lysosomal hydrolase levels in plasma and other body fluids are 5-20 times higher than normal. Molecular mutation screening of the GNPTAB gene confirms diagnosis.
Differential diagnosis
Differential diagnoses include Hurler syndrome, the infantile form of galactosialidosis, sialidosis type 2, infantile form of free sialic acid storage disease, and hypocalcemic rickets. Pacman dysplasia is in many instances the prenatal expression of MLII.
Antenatal diagnosis
Antenatal diagnosis is possible in chorionic villi by molecular testing.
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 no cure for MLII and treatment is supportive. Interactive programs to stimulate cognitive development, as well as ''low-impact'' therapies (such as aqua therapy) and occupational and/or speech therapy may be beneficial. Attention should be given to overfeeding, which should be avoided. Gingivectomy may be considered in those with severe mouth pain and infections. Respiratory support and assisted ventilation may be necessary in some cases. Infants and toddlers should have regular follow-ups (every 3 months) to monitor cardiac and pulmonary functioning, and afterwards every year throughout early childhood.
Prognosis
The prognosis is poor with a fatal outcome (most commonly due to cardiorespiratory insufficiency) most often occurring in early childhood.

                            Last update:
                            October 2021

                            - Expert reviewer(s):
                            Dr E. [Esmee] OUSSOREN | MetabERN*

                                * European Reference Network


Mucolipidosis III alpha/beta (MLIII alpha/beta) is a lysosomal disorder characterized by progressive slowing of the growth rate from early childhood, stiffness and pain in joints, gradual coarsening of facial features, moderate developmental delay and mild intellectual disability in most patients.

Summary:
Epidemiology
Prevalence has been estimated at 1/53,000 live births in Portugal and 1/1, 250,000 live births in the Netherlands.
Clinical description
Infants appear normal at birth. Onset is gradual and usually observed at around the age of 3 years with slowing of growth rate and apparent shoulder, hip and knee contractures. Dysmorphic facial features (full cheeks, depressed nasal bridge, prominent mouth and inconsistently mild gingival hypertrophy) are mild but coarsen with age. Otitis media is common in the young. Functional changes in hard and soft connective tissues result in a slowly progressive reduction in the range of motion in the shoulders, hips and knees. Gradual hardening of the cardiac valves, from childhood onwards, ultimately leads to cardiac insufficiency. Gait slows in childhood, becoming increasingly painful due to severe hip disease. Bone pain, even at rest, results from osteoporosis and osteolytic bone lesions. Moderate claw-like flexion deformity of the fingers and carpal tunnel syndrome are common complications. Bronchitis/bronchopneumonia is frequent in childhood and gradual restrictive lung disease becomes life-threatening in older patients. Mild intellectual disability has been reported in most patients. Death is often due to treatment-refractory cardiopulmonary failure.
Etiology
ML III alpha/beta is due to mutations in the GNPTABgene (12q23.3), encoding the inactive alpha/beta precursor protein that generates the catalytically active alpha and beta subunits of N-acetylglucosamine-1-phosphotransferase (GNPT). The gamma subunit is encoded by the GNPTG gene (16p13.3) and mutations in this gene cause the milder MLIII gamma (see this term). In MLIII alpha/beta, at least one of the two mutations is hypomorphic, which results in the later onset and a less severe phenotype than ML II.
Diagnostic methods
Diagnosis is based on clinical and radiographic observations at the time of onset and is confirmed initially by assays of several lysosomal enzymes in plasma demonstrating increased activity (up to 10-fold) of almost all lysosomal hydrolases. In cultured fibroblasts, the activity of the same lysosomal enzymes is significantly decreased but not totally absent. Mutation screening of the GNPTAB gene provides the most formal and useful confirmation of the diagnosis.
Differential diagnosis
Differential diagnoses include MLIII gamma; mucopolysaccharidosis type 1, 2, 4B, 6, and 7; free sialic acid storage disease, infantile form; multiple sulfatase deficiency; multiple epiphyseal dysplasia; progressive pseudorheumatoid arthropathy of childhood; chondrodysplasia punctata; and rheumatoid arthritis (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible in families with a patient with known disease-causing mutant genotype.
Genetic counseling
ML III alpha/beta is inherited autosomal recessively and genetic counseling is offered accordingly.
Management and treatment
There is no cure for ML III alpha/beta and treatment is purely supportive. Myringotomy and tube placement may be recommended to those with recurrent otitis media. Low-impact physical therapy and tendon release procedures (for carpal tunnel features) can provide some relief. Analgesics and IV bisphosphonate can treat bone pain. Young children should be examined biannually. After the age of 6, yearly visits may suffice, but cardiac valve status must be monitored. Cognitive stimulation is of paramount importance in children with only minor intellectual disability. Careful weighing of risk and benefit is required when considering surgery.
Prognosis
Prognosis is generally poor, with the morbidity of late complications adversely affecting quality of life and limiting life expectancy. Occasionally patients may survive into mid-adulthood.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Jules LEROY


Mucolipidosis type III gamma (ML 3 gamma) is a very rare lysosomal disease, that has most often been observed in the Middle East, characterized by a progressive slowing of the growth rate in early childhood; stiffness and pain in shoulders, hips, and finger joints; a gradual, mild coarsening of facial features; and by a slower progression, milder clinical course and longer life expectancy than that seen in mucolipidosis type II and mucolipidosis type III alpha/beta. Cognitive function is normal or only slightly impaired and retinitis pigmentosa has been reported in a few patients. Many survive into early adulthood, but ultimately succumb to cardiorespiratory insufficiency.


A rare lysosomal disease characterized by dysmorphic features and skeletal changes, restricted joint mobility, short stature, and hand deformities (such as claw hands, stiffness of hands, carpal tunnel syndrome, inability to make fists). Most patients have normal intellectual capacity and the clinical progression is less rapid than that of mucolipidosis type II (MLII).

Summary:
Epidemiology
MLII and mucolipidosis type III (MLIII) represent a spectrum of severity. The estimated combined prevalence at birth of MLII and MLIII is estimated between 1/ 37,000-455,000 worldwide. Whilst data is limited on MLIII, the prevalence at birth has been estimated at 1/1,250,000 in the Netherlands.
Clinical description
In MLIII, symptom onset is often in the first two decades of life and patients typically present with progressive hand deformities and restricted range of joint motion. For these symptoms, patients will often consult specialists such as rheumatologists and orthopedic or plastic surgeons. Progressive hip dysplasia may cause bone pain and leads to waddling gait. Other musculoskeletal problems like dysostosis multiplex, short stature, osteopenia, osteoarthritis, spinal cord compression and carpal tunnel syndrome are common in MLIII. Mild corneal clouding, cardiac valvular disease, mild coarsening of facial features, and mild intellectual disability are also possible.
Etiology
There are two subtypes, the MLIII alpha/beta subtype due to pathogenic variants in GNPTAB (12q23.3) and the milder MLIII gamma subtype with pathogenic variants in GNPTG (16p13.3). These two genes encode for the activity of the enzyme N-acetylglucosamine-1-phosphotransferase, which is decreased in MLIII. This enzyme catalyzes the first step of the formation of mannose 6-phosphate (M6P) on specific lysosomal soluble hydrolases. MP6 is an essential targeting signal for the transport to the lysosomes and without this, the enzymes are missorted into the extracellular space and are not broken down within the lysosomes. This all leads to accumulation of the enzymes in connective tissues, cartilage, bones, ligaments, and other tissues.
Diagnostic methods
Diagnostic procedures include clinical/radiographical examination as well measurement of the activity of several lysosomal enzymes in plasma and/or fibroblasts, where these enzymes are elevated in plasma and decreased in fibroblasts. Radiographs reveal increasing osteopenia and dysostosis multiplex. In addition, GlcNAc-1-phophotransferase activity can be measured in fibroblasts. Finally, molecular analysis of GNPTAB (MLII and III α, β) or GNPTG (MLIII γ) can be performed.
Differential diagnosis
Differential diagnosis includes the different types of mucopolysaccharidosis and alpha-mannosidosis.
Antenatal diagnosis
Antenatal diagnosis is possible in chorionic villi by molecular testing.
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 are currently no curative or disease-modifying treatments available for MLIII. Musculoskeletal problems often requires surgical (orthopedic or plastic) interventions at a young age or pain and or/ anti-inflammatory medications. Bisphosphonate treatment in MLIII patients can decrease pain, increase bone density and improve mobility. However, long-term treatment with bisphosphonates is not to be recommended as this can induce femoral fractures.
Prognosis
The MLIII α/ β subtype has a broad phenotypic range, from severely affected patients that die in childhood to milder affected patients displaying primarily skeletal symptoms, who survive into adulthood. Osteoarthritis is rapidly progressive in all patients (due to dysostosis multiplex and osteopenia) and results in cartilage destruction and bone lesions. All patients clinically suffer from bone and joint pain which has a great impact on the quality of life.

                            Last update:
                            October 2021

                            - Expert reviewer(s):
                            Dr E. [Esmee] OUSSOREN | MetabERN*

                                * European Reference Network


A rare lysosomal storage disease characterized clinically by severe global development delay due to neuronal dysmyelination, hypotonia which gradually progresses to spasticity during childhood, speech deficits, progressive visual impairment (due to corneal clouding, retinal degeneration and optic atrophy), achlorhydria, with increased gastrin secretion and iron deficiency anemia, and kidney disease and failure, all in the absence of dysmorphic features.

Summary:
Epidemiology
Mucolipidosis type IV (MLIV) is rare in the general population but is more prevalent among Ashkenazi Jews, among whom the prevalence at birth is 1/40 000.
Clinical description
The clinical spectrum of MLIV can range from severe to mild. MLIV patients typically have severe cognitive impairment, ocular abnormalities and achlorhydria with iron deficiency anemia. The most common presentation is of severe global developmental delay by the end of the first year of life and a progressive visual impairment during the first decade of life secondary to bilateral corneal opacities and retinal degeneration and resulting in blindness by adolescence. Development is usually limited to few or no words and poor hand use, and most patients do not achieve independent walking. Neurologic deficits (dys-/anarthria, slow chewing, eating and swallowing, spastic di- or quadriplegia, and hyperreflexive hypotonia) usually remain static during the first three decades of life, but in up to 15% neurologic deterioration may be observed. Brain MRI typically shows hypoplasia of the corpus callosum, signal abnormalities in the white matter, increased ferritin deposition in the thalamus and basal ganglia and (later in life) atrophy of the cerebellum. Progressive renal failure develops in the third decade of life. Strabismus and iron deficiency are present in about 50% of the patients. Milder manifestations or disproportionate affection of one of the organ systems may be observed. All of the MLIV patients have (asymptomatic) constitutive achlorhydria.
Etiology
MLIV is caused by biallelic mutations in the MCOLN1 (19p13.2) gene coding for mucolipin-1 protein, a nonselective cation channel which is distributed in the membranes of late endosomes and lysosomes in all tissues, with the highest expression in brain, kidney, liver, spleen, and heart. The exact pathophysiological mechanism is unknown, but is hypothesized that abnormal flux of calcium is probably the most important, resulting in disruption in sorting and/or transport of late endosomes/lysosomes. Two variants, c.406-2A>G and 6.4 kb del, account for 95% of pathogenic variants in individuals of Ashkenazi Jewish heritage.
Diagnostic methods
MLIV is suspected in the individuals with typical clinical findings and elevated plasma gastrin levels or polymorphic lysosomal inclusions in skin or conjunctival biopsy. Identification of biallelic pathogenic variants in MCOLN1 (19p13.2) confirms the diagnosis. Periodic Acid-Schiff staining of conjunctival cells reveals autofluorescent amorphous inclusions. Urine mucopolysaccharides, oligosaccharides and plasma lysosomal hydrolase assays are normal.
Differential diagnosis
Corneal clouding may initially lead to suspicion of mucolipidoses and mucopolysaccharidoses but MLIV is distinguished by absence of dysmorphism. The developmental profile is different to GM1 gangliosidosis.
Antenatal diagnosis
Prenatal diagnosis is done by molecular testing.
Genetic counseling
MLIV is transmitted as an autosomal recessive trait. Parents of an affected child bear a 25% risk of disease recurrence among the future offspring.
Management and treatment
No specific treatment exists, and management is symptomatic and targeted towards the visual manifestations and the neurological problems (cognitive delay, spasticity and speech deficit). Physical therapy with special focus on spasticity and ataxia can improve motor function. A speech therapist can advise patients with swallowing problems. Iron supplementation is used to treat iron deficiency. Cataract or strabismus surgery is often necessary.
Prognosis
Compared to other mucolipidoses (I and II), MLIV patients have a prolonged survival.

                            Last update:
                            October 2021

                            - Expert reviewer(s):
                            Dr E. [Esmee] OUSSOREN | MetabERN*

                                * European Reference Network


Mucopolysaccharidosis type 1 (MPS 1) is a rare lysosomal storage disease belonging to the group of mucopolysaccharidoses. There are three variants, differing widely in their severity, with Hurler syndrome being the most severe, Scheie syndrome the mildest and Hurler-Scheie syndrome giving an intermediate phenotype.

Summary:
Epidemiology
Prevalence is estimated at 1/100,000, with Hurler syndrome accounting for 57% of cases, Hurler-Scheie syndrome accounting for 23% of cases and Scheie syndrome accounting for 20% of cases.
Clinical description
In the severe form (Hurler syndrome or MPS I-H; see this term) skeletal deformities and a delay in motor and intellectual development are the leading symptoms. Onset occurs 6-8 months after birth. Other manifestations include corneal clouding, organomegaly, heart disease, short stature, hernias, facial dysmorphism and hirsutism. Radiological examination of the skeleton reveals the characteristic pattern of dysostosis multiplex. Hydrocephaly can occur after the age of two. Patients with the adult-onset form (Scheie syndrome or MPS I-S; see this term) are of almost normal height and do not show intellectual deficiency. Typical symptoms are stiff joints, corneal opacities, carpal tunnel syndrome and mild skeletal changes. Aortic valve disease can be present. Compression of the cervical spinal cord, caused by glycosaminoglycan infiltration of the dura, may lead to spastic paresis if not corrected by neurosurgical intervention. Patients with the intermediate form (Hurler-Scheie syndrome or MPS I-H/S; see this term) have normal or almost normal intelligence, but exhibit various degrees of physical impairment.
Etiology
The different phenotypes are caused by allelic mutations in the alpha-L-iduronidase (IDUA) gene (localized to 4p16.3). The mutations result in complete deficiency of the enzyme in Hurler syndrome or partial function in Scheie syndrome, leading to lysosomal accumulation of dermatan sulfate (DS) and heparan sulfate (HS).
Diagnostic methods
Early diagnosis is difficult as the first clinical signs are not specific (hernias, respiratory infections, etc.) but it is very important to allow early treatment. Biological diagnosis relies on detection of increased urinary excretion of DS and HS and the demonstration of the enzymatic deficiency (in plasma, leucocytes, fibroblasts, trophoblastic cells or amniocytes).
Differential diagnosis
Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; see this term) resembles mucopolysaccharidosis type I in many aspects, MPS VI patients, however, never have intellectual impairment. Mucopolysaccharidosis type II (see this term), an X-linked recessive disorder in which severe joint contractures are a characteristic symptom, also has many features in common with mucopolysaccharidosis type I.
Antenatal diagnosis
Antenatal diagnosis can be performed by enzyme assay or molecular genetics in families where the mutation has been identified.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling is recommended.
Management and treatment
The genotype should be established at diagnosis in all patients as this may aid in determining the therapeutic approach. Symptomatic treatment should be proposed by a multidisciplinary team. Hematopoietic stem cell transplantation has been shown to be useful in some patients. Treatment with the enzyme substitute (laronidase) obtained EU marketing authorization as an orphan drug in 2003. All patients including those who have not received a transplant or whose graft has failed may benefit significantly from enzyme replacement therapy (ERT). Given as weekly infusions, it leads to improvement of lung function and joint mobility.
Prognosis
Early treatment slows progression of the disease. However, it is not effective against neurological lesions. Life expectancy is normal or only slightly affected in Scheie syndrome, but is reduced in Hurler syndrome, with death occurring before adolescence due to serious cardiovascular and respiratory complications.

                            Last update:
                            October 2011

                            - Expert reviewer(s):
                            Pr Michael BECK


Mucopolysaccharidosis type 2, attenuated form (MPS2att), the less severe form of MPS2 (see this term), leads to a massive accumulation of glycosaminoglycans and a wide variety of symptoms including distinctive facies, short stature, cardiorespiratory and skeletal findings. It is differentiated from mucopolysaccharidosis type 2, severe form (see this term) by the absence of cognitive decline.

Summary:
Epidemiology
Prevalence of MPS2 at birth in Europe is 1/166,000. The minority of these cases present with the attenuated form.
Clinical description
MPS2att is clinically heterogeneous and its rate of progression is highly variable. Patients appear healthy at birth, with subtle initial symptoms appearing between 18 months and 4 years of age or even later, in particular umbilical or inguinal hernia. A distinctive facies (thickening of lips and nostrils, enlarged and protruding tongue), forms slowly and may first be observed at 2-4 years of age (often not evident until late). Swelling of the upper respiratory tract may be responsible for frequent infections, in particular otitis media; excessive snoring and sleep apnea; a distinctive hoarse voice and progressive loss of hearing. During early childhood growth is stunted and patients have a short stature with dysostosis multiplex and stiff joints that may make movement painful, hip dysplasia may also occur. Phalangeal joints are universally contracted resulting in claw-like hands; carpal tunnel syndrome is common. Spastic paresis due to spinal cord compression at the cranio-cervical region may also occur. Pressure exerted on the optic nerve may lead to loss of vision and retinal degeneration has also been reported in some cases. MPS2att patients, in general, have no cognitive impairments.
Etiology
MPS2 results from iduronate-2-sulfatase (I2S) deficiency, which leads to lysosomal accumulation of two specific mucopolysaccharides, dermatan sulfate and heparan sulfate. MPS2att, is typically associated with missense mutations of the causative gene IDS (Xq28), e.g.: c.1122C>T. In 12 cases of affected girls, skewed X inactivation led to MPS2.
Genetic counseling
MPS2 is the only MPS transmitted as an X-linked recessive trait; female carriers transmit the disorder to 50% of their sons.
Management and treatment
Extensive palliative care is required, patients must be regularly evaluated by echocardiogram, respiratory function, hearing tests, eye exams, nerve conduction velocity tests, cranial and cervical MRI with or without lumbar puncture to assess cerebrospinal fluid pressure. Hernia repair, tonsillectomy and adenoidectomy may be required. Cardiac valve or hip replacement and carpal tunnel release may be necessary in MPS2att patients over time; patients should be considered for weekly intravenous enzyme replacement therapy with idursulfase (Elaprase) as early as possible.
Prognosis
In general, if patients have no evidence of cognitive involvement by about 5 years of age, it is most likely that they will develop only the attenuated form of MPS2. Prognosis is highly variable. In most attenuated cases patients live into adulthood and require limited palliative care, however, it is impossible to predict outcomes due to the great variability of disease progression from patient to patient, even when siblings carry an identical mutation.

                            Last update:
                            September 2013

                            - Expert reviewer(s):
                            Dr Barbara BURTON


Mucopolysaccharidosis type 2, severe form

Mucopolysaccharidosis type 2 (MPS2, see this term), severe form (MPS2S), is associated with a massive accumulation of glycosaminoglycans and a wide variety of symptoms including a rapidly progressive cognitive decline; it is most often fatal in the second or third decade.

Summary:
Epidemiology
Prevalence of MPS2 at birth in Europe is 1/166,000, the severe form accounts for at least two-thirds of all cases.
Clinical description
MPS2S presents with the spectrum of symptoms observed in all MSP2 (see this term) cases, often with an earlier presentation. MPS2S patients have a decrease in growth rate in early to mid-childhood, along with respiratory difficulties and a thickening of lips and nostrils as well as an enlarged and protruding tongue (distinctive facies), which may become evident between 2-4 years of age. Psychomotor milestones are delayed, and regression often occurs. Between the ages of 2-6 years patients begin to exhibit aggressive behavior and hyperactivity, often lacking any sense of danger as they follow a course of progressive cognitive decline. Vision may be affected, and progressive hearing loss occurs in most cases. Myocardial thickening and cardiac valve dysfunction are common. Approximately 60-80 % of patients with MPS2 have the severe form of the disease with neurological implications.
Etiology
MPS2 results from iduronate-2-sulfatase (I2S) deficiency, which leads to lysosomal accumulation of two specific mucopolysaccharides, dermatan sulfate and heparan sulfate. MPS2S appears to be associated with a complete absence of functional enzyme due to nonsense mutations or complete gene deletions or rearrangements. In most cases, however, prognosis cannot be established by genotype alone.
Diagnostic methods
Diagnosis is based on detection of increased levels of DS and HS in the urine and confirmed by the demonstration of the enzyme deficiency in the serum, leukocytes or fibroblasts, or in dried blood spot samples. Enzymatic activity of another sulfatase should also be assessed. Genetic testing is possible; sequencing must include the entire IDS gene including its promoter region.
Management and treatment
Regular evaluation of patients should be followed by palliative care as is necessary. Cranial shunting to relieve hydrocephalus is often required. Weekly intravenous infusion with recombinant enzyme preparations has been shown to help with somatic symptoms. Intrathecal administration of enzyme replacement therapy holds promise to treat neurological aspects of MSP2; testing of such treatments is ongoing.
Prognosis
Prognosis is poor. MPS2S is most often fatal within the second or third decade of life, due to obstructive airway disease, infection, or cardiac failure due to valve dysfunction, pulmonary hypertension or cardiomyopathy.

                            Last update:
                            September 2013

                            - Expert reviewer(s):
                            Dr Barbara BURTON


A lysosomal storage disease with multisystemic involvement leading to a massive accumulation of glycosaminoglycans and a wide variety of symptoms including distinctive coarse facial features, short stature, cardio-respiratory involvement and skeletal abnormalities. It manifests as a continuum varying from a severe form with neurodegeneration to an attenuated form without neuronal involvement.

Summary:
Epidemiology
Mucopolysaccharidosis type 2 (MPS2) prevalence at birth in Europe is 1/166,000. It is an X-linked recessive disorder; very rare cases of female presentation have been reported.
Clinical description
MPS2 patients appear healthy at birth, with initial symptoms appearing between 18 months and 4 years of age. Macrocephaly develops during infancy and infants initially grow at normal or above average rates. Initial manifestations include: frequent respiratory tract infections (in particular otitis media); umbilical and inguinal hernia; intractable diarrhea; hepatosplenomegaly; and skin lesions resembling an orange peel (on the shoulder, back and thighs). A distinctive facies with thickening of lips and nostrils as well as an enlarged and protruding tongue forms slowly and may become evident between 2-4 years of age, later in attenuated cases. Progression varies from a severe form (MPS2, severe form) with early psychomotor regression to an attenuated form (MPS2, attenuated form) which manifests without cognitive involvement.
Etiology
MPS2 results from iduronate-2-sulfatase (I2S) deficiency, which leads lysosomal accumulation of two specific mucopolysaccharides, dermatan sulfate (DS) and heparan sulfate (HS). The causative gene, IDS, is located on Xq28, approximately 320 mutations have been reported to cause MPS2.
Diagnostic methods
Diagnosis is based on clinical signs followed by the detection of increased levels of DS and HS in the urine and confirmed by the demonstration of the enzyme deficiency in the serum, leukocytes or fibroblasts, or in dried blood spot samples. Enzymatic activity of another sulfatase should also be assessed. Genetic testing requires searching for exonic or whole-gene deletions, for point mutations in IDS and its promoter region, and for recombination with the nearby pseudogene IDS2.
Differential diagnosis
Differential diagnoses include mucopolysaccharidosis type 1, 6, 7; sialidosis type 2; mucolipidosis type 2 and 3; and multiple sulfatase deficiency.
Antenatal diagnosis
Prenatal diagnosis by measuring IDS activity or by mutation analysis in chorionic villi or amniocytes is only performed for male fetuses.
Genetic counseling
Women at risk of being a carrier should undergo genetic testing as MPS2 is X-linked recessive. Female carriers transmit the disorder to 50% of their sons; only 12 cases of affected girls have been described due to skewed X-inactivation.
Management and treatment
All patients should be considered for weekly intravenous enzyme replacement therapy (ERT) which has been shown to alleviate somatic symptoms. Cranial shunting should be performed to relieve cases of hydrocephalus. Hernia repair, tonsillectomy and adenoidectomy (to liberate the upper respiratory tract) and in some cases positive pressure ventilation or tracheostomy may be required. Cardiac valve or hip replacement and carpal tunnel release may be necessary over time. Extensive palliative care is required, patients must be regularly evaluated by echocardiogram, respiratory function, full radiologic examination to identify dysostosis multiplex, cranial and cervical MRI with or without lumbar puncture to assess cerebrospinal fluid pressure, hearing tests, eye exams and nerve conduction velocity tests.
Prognosis
Prognosis is highly variable. In the severe form (60-80% of cases) life expectancy is markedly reduced, death generally occurring before the age of 25 often as a result of cardio-respiratory complications. In the attenuated form, patients may survive into adulthood, sometimes even beyond the age of 60, and intellectual deficits are most often absent in these cases.

                            Last update:
                            June 2019

                            - Expert reviewer(s):
                            Dr Barbara BURTON