A rare congenital disorder of copper metabolism with severe multisystemic manifestations that are primarily characterized by progressive neurodegeneration and marked connective tissue anomalies. A pathognomonic feature is the typical sparse, abnormal steely hair.

Summary:
Epidemiology
Prevalence at birth is estimated at 1/300,000 and 1/360,000 in Europe and Japan, respectivley. In Australia, the birth prevalence is much higher (1/50,000-100,000), likely due to a founder effect. The disorder is X-linked and thus primarily affects males.
Clinical description
Menkes disease (MD) manifests in the neonatal period. Most patients are born at term with appropriate birth measurements. Cephalohematomas and spontaneous fractures are occasionally observed at birth. In the early neonatal period, patients may present with prolonged jaundice, hypothermia, hypoglycemia and feeding difficulties. Pectus excavatum and umbilical and inguinal hernias have also been reported. Unusual sparse and dull scalp hair is often the initial observation at the age of 1-2 months. Characteristically, the hair appears hypopigmented/depigmented, resembles steel wool and is friable, especially in the areas of the scalp subjected to friction. Additional symptoms are failure to thrive, poor eating, vomiting, and diarrhea. The appearance of pale skin, frontal or occipital bossing, micrognathia and pudgy cheeks may be observed. Patients develop gradual motor dysfunction and seizures. Muscular hypotonia in early life is replaced later-on by spasticity and weakness of the extremities. The clinical course is usually severe. Variable forms exist with occipital horn syndrome (OHS) being the mildest recognized form, which further presents with prominent bony exostoses and bladder diverticula.
Etiology
MD is caused by pathogenic variants in ATP7A (Xq21.1) encoding a membrane bound copper-transport protein (Cu2+-transporting ATPase-alpha polypeptide). To date, about 300 different variants in this gene have been reported. There is no obvious correlation between the variants and the clinical course.
Diagnostic methods
Initial diagnosis is based on clinical features (typical hair changes associated with hypotonia and delayed neuromotor development) and supported by demonstration of reduced levels of serum copper and ceruloplasmin. However, in the neonatal period these markers should be interpreted with caution, as their levels are also low in healthy newborns. In this period, plasma catecholamine analysis (ratio of DOPA to dihydroxyphenylglycol), indicative of dopamine beta-hydroxylase deficiency, may be used as a diagnostic test when the clinical diagnosis suggests MD. Although not specific, other laboratory investigations are useful to complete the clinical work up, these include light microscopy (for hair), radiological imaging (for generalized osteoporosis, metaphyseal flaring and spurs in the long bones, diaphyseal periosteal reaction and thickening, and Wormian bones in the cranial sutures), and arteriography (arterial tortuosity, especially of the intracranial arteries). Definitive diagnosis is based on molecular genetic testing.
Differential diagnosis
Differential diagnosis includes Ehlers-Danlos syndrome, Marfan syndrome, cutis laxa syndromes, mitochondrial disorders, osteogenesis imperfecta and child abuse.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member and the preferred situation is to determine the carrier status of the mother prior to pregnancy and prenatal diagnosis.
Genetic counseling
Transmission is X-linked recessive. Genetic counseling should be offered to couples where the mother is a carrier of a pathogenic variant, informing them that the risk for a male fetus to be affected is 50% at each pregnancy. In rare cases, a female fetus may be affected (manifesting heterozygote) and this possibility should also be considered during genetic counselling. Similarly, germ-line mosaicism has been described and, although probably infrequent, it should also be discussed when counselling non-carrier mothers of singleton cases.
Management and treatment
Treatment is mainly symptomatic. Early parenteral copper-histidine supplementation may modify disease progression and some symptoms by providing extra copper to tissue and to copper-dependent enzymes. Oral administration of copper is ineffective as it is trapped in the intestines.
Prognosis
Prognosis is poor and patients usually die in early childhood. However, careful medical care, and possibly copper administration, may extend life span.

                            Last update:
                            December 2020

                            - Expert reviewer(s):
                            Pr Bert CALLEWAERT | ERN-Skin* - Pr Zeynep TÜMER | ITHACA*

                                * European Reference Network


Menstrual cycle-dependent periodic fever

A rare anomaly of puberty or/and menstrual cycle characterized by recurrent fevers (higher than 38 degrees Celsius) associated with the luteal phase of the menstrual cycle in women.


A rare genetic neurological disorder characterized by childhood-onset dystonia with distinctive MRI changes in the basal ganglia, and optic atrophy developing either immediately or within a few years after the appearance of dystonia. Additional symptoms include chorea and other movement disorders, dysarthria, or nystagmus, among others. Motor disability progresses gradually, while cognitive function is relatively spared.


Mercury poisoning is caused mainly through ingestion or inhalation of any of the 3 forms of mercury, elemental, organic, and inorganic. Exposure to elemental mercury affects the pulmonary (inhalation of mercury vapors causes coughing, chills, fever, shortness of breath), dermatological (mild swelling, vesiculation, scaling, irritation, urticaria, erythema and allergic contact dermatitis accompanied by pain), and peripheral and central nervous (CNS) systems (depression, paranoia, extreme irritability, hallucinations, inability to concentrate, memory loss, hands, head, lips, tongue, jaw and eyelids tremors, weight loss, perpetually low body temperature, drowsiness, headaches, insomnia, fatigue). Exposure to inorganic mercury generally causes development of a metallic taste, local oropharyngeal pain, nausea, vomiting, bloody diarrhea, colic abdominal pain, renal dysfunction and, neurologic abnormalities; while that to organic mercury can lead to delayed neurotoxicity.


A rare mitochondrial oxidative phosphorylation disorder characterized by myoclonic seizures, ataxia, generalized epilepsy, muscle weakness and ragged red fibers in the muscle biopsy.

Summary:
Epidemiology
The prevalence in the general population of Europe ranges between 1/256,000-67,000 in the adult population, and the birth prevalence is reported at 1/202,000 in Sweden.
Clinical description
Patients usually present during adolescence or early adulthood with myoclonic epilepsy, sometimes with neurosensory deafness, optic atrophy, short stature or peripheral neuropathy. A few cases have been associated with lipomatosis, cardiomyopathy, pigmentary retinopathy, ophthalmoparesis and/or pyramidal signs. The disease is progressive with worsening of the epilepsy and onset of additional symptoms including ataxia, deafness, muscle weakness, and dementia. Magnetic resonance imaging of the brain may show cortical atrophy, cerebellar atrophy, basal ganglia calcifications and leucodystrophy. Clinical manifestations may vary greatly between patients from the same family and between families.
Etiology
MERRF syndrome is caused by mutations in the mitochondrial DNA. Over 80% of individuals with MERRF syndrome carry the m.8344A>G mutation in the lysine transfer RNA (tRNA Lys) gene (MTTK). Other mutations have been found in other transfer RNA genes or in the MTND5 gene. They may be associated with MERRF/MELAS overlap syndrome, in which affected individuals also suffer from stroke-like episodes.
Diagnostic methods
The diagnosis of MERRF syndrome relies on the demonstration of abnormal lactate accumulation in blood or, more often, in the cerebrospinal fluid or MRI brain spectroscopy, and on the muscle biopsy, which reveals the presence of cytochrome c oxidase negative muscle fibers and ragged red fibers. Biochemical analysis of muscle often shows cytochrome c oxidase deficiency or combined respiratory chain defect. Genetic testing usually shows heteroplasmic (coexistence of the mutant form with a residual population of wild type mitochondrial DNA) variant in the mitochondrial DNA. The proportion of the mutation may differ considerably between tissues. However, in MERRF syndrome, this proportion is most often very high (above 90%) in every tissue and the mutation may therefore be easily investigated in blood.
Differential diagnosis
The differential diagnosis comprises other syndromes characterized by progressive myoclonic epilepsy and ataxia including Unverricht-Lundborg disease, Lafora disease, neuronal ceroid lipofuscinosis, and sialidosis.
Antenatal diagnosis
The possibility of heterogeneous proportions of the mutation between tissues theoretically hampers prenatal diagnosis.
Genetic counseling
The heteroplasmy makes genetic counseling very arduous in MERRF syndrome. Mitochondrial DNA mutations are transmitted through maternal inheritance. An affected man cannot transmit the disease. The mutation will be transmitted along the maternal lineage but its proportion is unpredictable. Although higher proportions of the mutation in the blood of the mother result in a higher risk of having a child with severe phenotype, there are many examples of extreme segregation of the mutation from mother to child, which prevent efficient genetic counseling at an individual level.
Management and treatment
As with other mitochondrial encephalomyopathies, there is no specific treatment for MERRF syndrome. Seizures can be treated with conventional anticonvulsant therapies but valporic acid should be avoided (mainly if the cause of the mitochondrial epilepsy is a patnogenic variant in POLG gene) or administered with care. In the absence of proper clinical trials, it is difficult to evaluate the effect of proposed supportive treatment such as coenzyme Q10 and its analogue idebenone, carnitine, etc.
Prognosis
The prognosis for patients with MERRF syndrome is globally poor because of the progressive nature of the disease. However, the severity varies greatly and some patients, mainly those with non-cerebral presenting symptoms, may have a prolonged survival with relatively little handicap.

                            Last update:
                            January 2023

                            - Expert reviewer(s):
                            Pr Michelangelo MANCUSO | EURO-NMD*

                                * European Reference Network


Mesial temporal lobe epilepsy with hippocampal sclerosis is a rare epilepsy syndrome defined by seizures originating in limbic areas of the mesial temporal lobe, particularly in the hippocampus, amygdala, and in the parahippocampal gyrus and its connections, and hippocampal sclerosis, usually unilateral or assymetric. It is frequently associated with an initial precipitating event, such as febrile seizures, hypoxia, intracranial infection or head trauma, most often occurring in the first five years of life, followed by a latent period without seizures. Typical seizures consist of a characteristic aura that is frequently a rising epigastric sensation associated with emotional disturbances, illusions, and autonomic symptoms (widened pupils, palpitations), progressive impairment of consciousness, oro-alimentary automatisms (lip smacking, chewing, licking, tooth grinding), behavioral arrest, head deviation, dystonic postures, hand and verbal automatisms. Seizures are followed by postictal dysfunction. Initially, seizures are easily controlled with antiepileptic drugs, later they frequently become refractory and associated with progressive behavioral changes and memory deficits.


Mesoaxial synostotic syndactyly with phalangeal reduction

A rare non-syndromic syndactyly characterized by mesoaxial reduction of fingers, complete syndactyly of the 3rd and 4th fingers with synostoses of the corresponding metacarpals and associated single phalanges, malformed thumbs, and hypoplasia and clinodactyly of the 5th finger. Preaxial webbing of toes with terminal phalangeal hypoplasia of all toes has been reported in association.


A rare, congenital non-syndromic heart malformation characterized by an atypical location of the heart in a central position in the thorax, with the apex in the midline of the thorax. Atria are usually situs solitus, whereas ventricles may be situs inversus. Various congenital heart anomalies and visceral situs inversus have also been associated.


A rare syndromic osteochondrodysplasia characterized by progressive mesomelia and bony fusions in the extremities, distinctive facial gestalt, and soft palate anomalies.

Summary:
Epidemiology
To date, less than 10 patients have been reported.
Clinical description
In contrast to other mesomelic dysplasias, Mesomelia-synostoses syndrome (MSS) has a slowly progressive clinical course, at least until skeletal growth ceases. Symmetric acral synostoses and extra-skeletal involvement are distinguishing features. Craniofacial phenotype includes downslanted palpebral fissures, eyelid ptosis, telecanthus, soft palate hypoplasia and absent or hypoplastic uvula with hypernasal speech, and tall and mildly retruded chin. Skeletal anomalies comprise short stature, progressive non-inflammatory movement restriction of large and small joints, mesomelic bowing and shortening in upper and lower limbs, congenital or postnatal joint deformities (clino- and camptodactyly of fingers and toes, ulnar deviation of the wrists, radial head subluxation, genu valgum, pes equinus), and apparent postaxial brachydactyly of fingers and toes with sparing of the first two rays. MSS patients may present with complex congenital heart defects, congenital hydronephrosis, short umbilical cord and redundant skin on the umbilical stump, myopia, short sublingual frenulum and progressive hearing loss. Cognitive development is normal. Radiological anomalies include shortening of metacarpals and metatarsals II-III to V, synostoses between the bases of these bones or between metacarpals and metatarsals II to V and adjacent carpal/tarsal bones, partial fusion of carpal and tarsal bones, and mild medial bowing of distal femur.
Etiology
Non-recurrent deletions of two contiguous genes in 8q13.2q13.3, SULF1 and SLCO5A1, ranging in size from 582 to 738 Kb, have been found in six patients. Monoallelic expression of SULF1 without microdeletion has been reported in one patient. The exact mechanism that causes MSS is currently unclear, but it is likely that other genetic or epigenetic alterations besides the haploinsufficiency of one of the two genes contribute to the MSS phenotype.
Diagnostic methods
Diagnosis is based upon clinical and radiological findings. Copy-number losses involving SULF1 and SLCO5A1 may be detected by molecular analyses (e.g. genomic arrays).
Differential diagnosis
Radiologically, Kantaputra type mesomelic dysplasia shows very similar acral anomalies. Other rare mesomelic dysplasias (e.g. Langer or Fryns type mesomelic dysplasia) are not associated with synostoses. Syndromes with synostoses (e.g. Nievergelt syndrome, multiple synostoses or proximal symphalangism syndromes, Osebold-Remondini syndrome) show different patterns of associated anomalies.
Antenatal diagnosis
Both invasive prenatal diagnosis or preimplantation genetic diagnosis of 8q13 microdeletion are available for at-risk couples. Fetal ultrasound may reveal hypoplastic radii and ulnae, brachydactyly, unusual gaps between fingers or toes, clubfoot, micrognathia, and congenital heart defect or hydronephrosis, if present.
Genetic counseling
MSS is transmitted as an autosomal dominant trait. When a parent is affected, recurrence risk is 50%.
Management and treatment
Early diagnosis allows for more effective care: the progressive nature of skeletal and joint involvement deserves regular follow-up and treatment by orthopedic and rehabilitation specialists. Cardiac surgery or surgical correction of palatal anomalies and speech therapy may be needed.
Prognosis
Life expectancy is unknown, but clinical manifestations appear to remain stable in adulthood.

                            Last update:
                            December 2021

                            - Expert reviewer(s):
                            Pr Andrea DARDIS | MetabERN* - Dr Alessandro SPINELLI | MetabERN*

                                * European Reference Network


Mesomelic dwarfism, Reinhardt-Pfeiffer type

A rare disorder characterized by disproportionate short stature from birth with dysplasia of the ulna and fibula.

Summary:
Epidemiology
Prevalence is unknown but only a few families have been described in the literature so far.
Clinical description
Curvatures of the forearm, radial head luxation, and tibial anomalies have also been described.
Etiology
The syndrome is transmitted in an autosomal dominant manner and cases of this dysplasia have been described in families with Langer mesomelic dwarfism and Léri-Weill dyschondrosteosis (see these terms) leading to the suggestion that this dysplasia, type Reinhardt-Pfeiffer may also be associated with haploinsufficiency of the short stature homeobox (SHOX; Xp22.33 and Yp11.32) gene or anomalies of the downstream pseudoautosomal region 1 (PAR1) where SHOX enhancer elements are located.

                            Last update:
                            October 2009

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Mesomelic dwarfism-cleft palate-camptodactyly syndrome

A rare syndrome characterised by mesomelic shortening and bowing of the limbs, camptodactyly, skin dimpling and cleft palate with retrognathia and mandibular hypoplasia. It has been described in a brother and sister born to consanguineous parents. Transmission is autosomal recessive.


Mesomelic dysplasia Kantaputra type (MDK) is a rare skeletal disease characterized by symmetric shortening of the middle segments of limbs and short stature.

Summary:
Epidemiology
It has been described in five families.
Clinical description
In the upper limbs, the ulnae are very short, and the radii are bowed. The distal humerus has a dumbbell shape. The hands show progressive flexion contractures of the proximal interphalangeal joints. In the lower limbs, feet are fixed in plantar flexion so that the patients walk on their toetips. The prominent distal fibula on the ventral aspect is common and considered a hallmark. Fibula, talus and calcaneus are small and fibulo-calcaneal synostosis is a characteristic feature. Carpal and tarsal synostoses are observed in some individuals. All affected patients have normal craniofacial features and intelligence.
Etiology
Using microarray-based comparative genomic hybridization (array-CGH), two microduplications have been identified on chromosome 2 (2q31.1-q31.2), separated by a segment of normal copy number. The more centromeric duplication encompasses the HOXD cluster and it is proposed that duplications cause dysregulation of HOXD gene expression.
Genetic counseling
In all families, the condition is transmitted as an autosomal dominant trait.

                            Last update:
                            November 2010


A rare primary bone dysplasia characterized by severe mesomelic shortness particularly of the lower limbs with distinctive triangular or rhomboid-shaped tibiae and fibulae, accompanied by bony protuberances and skin dimples. Additional manifestations include radioulnar synostosis, dislocation of the radial head, abnormalities of the hands (such as oligosyndactyly or fusiform-shaped fingers) and feet (pes equinovarus, synostoses of tarsals/metatarsals and phalanges), and dysmorphic facial features.


Mesomelic dysplasia, Savarirayan type is characterised by severely hypoplastic and triangular-shaped tibiae, and absence of the fibulae. So far, two sporadic cases have been described. Moderate mesomelia of the upper limbs, proximal widening of the ulnas, pelvic anomalies and marked bilateral glenoid hypoplasia were also reported.


Metabolic myopathy due to lactate transporter defect is a rare metabolic myopathy characterized by muscle cramping and/or stiffness after exercise (especially during heat exposure), post-exertional rhabdomyolysis and myoglobinuria, and elevation of serum creatine kinase.


Metachondromatosis (MC) is a rare disorder characterized by the presence of both multiple enchondromas and osteochondroma-like lesions.

Summary:
Epidemiology
The prevalence is unknown and fewer than 40 cases have been reported.
Clinical description
The first signs of MC occur during the first decade of life. Most frequently, osteochondromas occur in the hands and feet, predominantly in digits and toes, and enchondromas involve the iliac crests and metaphyses of long bones. Osteochondromas are small and point towards the adjacent growth plate. MC does not lead to shortening or bowing of the long bones, joint deformity, or subluxation. The lesions spontaneously decrease in size or regress.
Etiology
Loss-of-function mutations, including deletions, non-sense mutations and splice sites mutations, of the PTPN11 gene (12q24) have been linked to MC in several families.
Diagnostic methods
Diagnosis is based on clinical signs, radiographic findings and familial history. The radiographic features are osteochondromas at the metaphyses of the short tubular bones (hands and feet) pointing towards the joints and coexisting with enchondromas.
Differential diagnosis
The differential diagnosis should include hereditary multiple osteochondromas (MO; see this term) in which the long bones are predominantly affected and the lesions point away from the joint/growth plate and may result in shortening or deformity of the affected bones. Other diseases to be considered include the non-hereditary conditions Ollier disease and Maffucci syndrome (in which multiple enchondromas are found in the medulla of the bone and are predominantly unilateral), and dysplasia epiphysealis hemimelica (DEH; characterized by a cartilaginous overgrowth mainly located in the lower extremities on one side of the body) (see these terms).
Antenatal diagnosis
Antenatal diagnosis is technically feasible.
Genetic counseling
MC has an autosomal dominant mode of inheritance. Genetic counseling may be proposed to the patients and their families.
Management and treatment
For severe malalignment of the fingers/toes, surgical intervention can be considered to remove osteochondromas.
Prognosis
No malignant transformation has been reported so far. Clinical course is unpredictable as there may be simultaneous growth of some of the lesions and regression of others. Nerve paralysis or vascular complications (avascular necrosis of the femoral head; see this term) may occur.

                            Last update:
                            May 2011

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


Metachromatic leukodystrophy, adult form

A subtype of Metachromatic leukodystrophy characterized by progressive psychomotor regression with an insidious onset after the age of 16 years, most often beginning with intellectual and behavioral changes, such as memory deficits or emotional instability. The clinical picture is dominated by gradual cognitive, later also motor, decline, taking a protracted course with periods of waxing and waning. Decerebration and death occur within decades after disease onset.


Metachromatic leukodystrophy, juvenile form

A subtype of Metachromatic leukodystrophy characterized by progressive psychomotor regression with an onset between 30 months and 16 years of age, often beginning with behavioral abnormalities or deterioration of school performance. Further manifestations are ataxia, gait disturbances, reduced deep tendon reflexes, spasticity, seizures, paralysis, dementia, and loss of speech, vision, and hearing, eventually resulting in complete loss of motor and cognitive skills, and decerebration. The rate of deterioration is variable with possible survival up to the third decade of life.


Metachromatic leukodystrophy, late infantile form

A subtype of Metachromatic leukodystrophy characterized by rapidly progressive psychomotor regression with an onset before 30 months of age after a period of apparently normal development. Manifestations developing during the course of the disease are impaired feeding and swallowing due to pseudobulbar palsies, seizures, painful spasms, muscle weakness, ataxia, paralysis, dementia, and loss of speech, vision, and hearing, quickly resulting in complete loss of motor and cognitive skills, and decerebration. Death occurs within the first decade of life.


A rare lysosomal disease characterized by accumulation of sulfatides in the central and peripheral nervous system due to deficiency of the enzyme arylsulfatase A, leading to demyelination. Three clinical subtypes can be distinguished based on the age of onset: late infantile, juvenile, and adult. Lead symptoms are deterioration in motor or cognitive function or behavioral problems, depending on the subtype, all eventually culminating in a decerebrated state and death after a highly variable disease course and duration. Mode of inheritance is autosomal recessive.


A rare form of metaphyseal dysplasia characterized by short stature, rhizomelic micromelia and a mild varus deformity of the legs evident from the first months of life, that is associated with radiological features of severe metaphyseal changes (irregularities, widening and marginal blurring) in long bones, most prominent in proximal femurs, and generalized osteopenia, and that usually spontaneously resolves by the age of three years. Severe autosomal dominant and milder recessive variants have been observed.


Metaphyseal chondrodysplasia, Jansen type

A rare autosomal dominant skeletal dysplasia characterized by short-limbed short stature (due to severe metaphyseal changes that are often discovered in childhood by imaging), waddling gait, bowed legs, contracture deformities of the joints, short hands with clubbed fingers, clinodactyly, prominent upper face and small mandible, as well as chronic parathyroid hormone-independent hypercalcemia, hypercalciuria, and mild hypophosphatemia.


Metaphyseal chondrodysplasia, Kaitila type is a rare multiple metaphyseal dysplasia disease characterized by disproportionate short stature, short limbs and digits, tracheobronchial malacia and progressive thoracolumbar scoliosis. Radiographic imaging shows progression from marked metaphyseal dysplasia of tubular bones in childhood to short and broad bones with mild dysplasia of the joints in adulthood. There have been no further descriptions in the literature since 1982.


Metaphyseal chondrodysplasia, Rosenberg type

Ulna metaphyseal dysplasia syndrome is a rare primary bone dysplasia characterized by dysplasia of the distal ulnar metaphyses, as well as metacarpal/metatarsal dysplasia and metaphyseal changes resembling enchondromata. Patients usually present bony swelling of the wrists with or without pain (knees and ankles may also be affected). Other variably associated features include platyspondyly, skeletal development delay, short stature and coxa valga.


Metaphyseal chondrodysplasia, Schmid type

Schmid metaphyseal chondrodysplasia is a rare disorder characterized by moderately short stature with short limbs, coxa vara, bowlegs and an abnormal gait.

Summary:
Epidemiology
Prevalence is unknown.
Etiology
The disorder is caused by mutations in the COL10A1 (6q21-q22) gene encoding the collagen alpha-1(X) chain.
Diagnostic methods
The condition is usually diagnosed during the second or third year of life. Diagnosis relies on detection of the metaphyseal lesions at radiography.
Differential diagnosis
Hypochondroplasia (see this term) and sequelae from rickets are the principle differential diagnoses. Other metaphyseal dysplasias (such as cartilage-hair hypoplasia or Jansen type metaphyseal chondrodysplasia; see these terms) can be excluded as they are associated with very short stature and other features.
Antenatal diagnosis
Prenatal diagnosis should not be proposed for this disease.
Genetic counseling
Schmid metaphyseal chondrodysplasia is transmitted in an autosomal dominant manner. Genetic counseling may be recommended with a 50% risk of recurrence.
Management and treatment
Orthopedic correction is the only possible treatment.

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Metaphyseal chondrodysplasia, Spahr type

A rare, genetic, primary bone dysplasia disease characterized by usually moderate, postnatal short stature, progressive genu vara deformity, a waddling gait, and radiological signs of metaphyseal dysplasia (i.e. irregular, sclerotic and widened metaphyses), in the absence of biochemical abnormalities suggestive of rickets disease. Intermittent knee pain, lordosis, and delayed motor development may also occasionally be associated.


Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria is an extremely rare genetic disorder characterized by the unique association of enchondromatosis with D-2 hydroxyglutaric aciduria (see these terms). Clinical features include enchondromatosis (with short stature, severe metaphyseal dysplasia and mild vertebral involvement), elevated levels of urinary 2-hydroxyglutaric acid and mild developmental delay.


Metaphyseal dysostosis-intellectual disability-conductive deafness syndrome is characterised by metaphyseal dysplasia, short-limb dwarfism, mild intellectual deficit and conductive hearing loss, associated with repeated episodes of otitis media in childhood. It has been described in three brothers born to consanguineous Sicilian parents. Variable manifestations included hyperopia and strabismus. The mode of inheritance is autosomal recessive.


Metaphyseal dysplasia, Braun-Tinschert type is characterised by metapyhseal undermodeling with broadening of the long bones and femora with an 'Erlenmeyer flask'' appearance, expansion and bowing of the radii with severe varus deformity and flat exostoses of the long bones at the metadiaphyseal junctions.

Summary:
Epidemiology
It has been described in four German families originating from the same town in Bohemia and in a 7-year-old Japanese girl.
Differential diagnosis
Erlenmeyer flask deformity is also a prominent feature of the autosomal recessive Pyle type of metaphyseal dysplasia (see this term). The two conditions can be distinguished by the mode of inheritance and by the presence of the marked varus deformity of the distal part of the radii in Braun-Tinschert metaphyseal dysplasia.
Genetic counseling
Transmission of metaphyseal dysplasia, Braun-Tinschert type is autosomal dominant.

                            Last update:
                            June 2007


Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome is characterized by metaphyseal dysplasia associated with short stature and facial dysmorphism (a beaked nose, short philtrum, thin lips, maxillary hypoplasia, dystrophic yellowish teeth) and acral anomalies (short fifth metacarpals and/or short middle phalanges of fingers two and five). It has been described in several members spanning four generations of a French-Canadian family. The syndrome is likely to be transmitted as an autosomal dominant trait.


Metaplastic carcinoma of the breast is a rare, aggressive subtype of invasive breast carcinoma characterized by rapid growth, relatively large tumor size and a tendency to metastasize to distant organs, particularly the lungs, with relatively less frequent involvement of the axillary lymph nodes. Histologically, the tumor shows high-grade cellularity and heterologous differentiation, including chondroid, osseous, pleomorphic/sarcomatoid, spindled, and squamous elements. Patients usually present with a fast-growing, large, well-circumscribed, mobile lump in the breast, which can become painful and involve the chest wall and the skin, leading to ulceration.


Metatropic dysplasia (MTD) is a rare spondyloepimetaphyseal dysplasia characterized by a long trunk and short limbs in infancy followed by severe and progressive kyphoscoliosis causing a reversal in proportions during childhood (short trunk and long limbs) and a final short stature in adulthood.

Summary:
Epidemiology
The prevalence is unknown. Approximately 81 cases have been reported in the literature to date.
Clinical description
The phenotypic spectrum of MTD is variable with severe cases being lethal in utero, or shortly after birth, and others having only milder skeletal changes. Infants present at birth with a long trunk and short limbs. Craniofacial abnormalities can also be noted and include a prominent forehead, midface hypoplasia, and a squared-off jaw. Some are born with an elongation of the coccyx and rarely reported additional findings include sensorineural hearing loss. Rapidly progressive kyphoscoliosis appears during childhood and a reversal in proportions is seen with a shortening of the trunk and relatively long extremities. Kyphoscoliosis can lead to thorax deformities and to a decrease in pulmonary function and respiratory distress that can be fatal. The small joints are usually hypermobile while contractures of the large joints are not uncommon and are usually progressive. Severe kyphoscoliosis and possible atlantoaxial instability can lead to myelopathy. Adults reach an average height of 107-135 cm. Intelligence is normal.
Etiology
MTD is due to mutations in the transient receptor potential vanilloid 4 (TRPV4) gene (12q24.1) encoding a polymodal Ca2+ permeable cation channel found in a variety of tissues. Mutations in this gene cause an increase in calcium in the chondrocytes and consequently disrupted endochondral ossification and the clinical manifestations of MTD.
Diagnostic methods
Diagnosis is based on clinical and radiological findings. Radiological findings include short diaphyses with wide metaphyses, marked platyspondyly, precocious calcification of hyoid and cricoid cartilage, halberd shaped pelvis, severe hypoplasia of the anterior part of the first cervical vertebrae and squared-off, irregular calcaneal bones. Radiological manifestations change at different ages. Molecular genetic testing can identify a mutation in the TRPV4 gene, confirming diagnosis.
Differential diagnosis
Differential diagnoses include mucopolysaccharidosis type IV and other types of spondylometaphyseal dysplasia, in particular spondylometaphyseal dysplasia, Kozlowski type (see these terms), an allelic disorder that shows important overlap with mild MD cases.
Antenatal diagnosis
Prenatal diagnosis is possible through genetic testing and prenatal assessment (with a 3D computed tomography scan or ultrasound) and should be offered when a mutation in the family is known.
Genetic counseling
MTD is inherited autosomal dominantly and genetic counseling is possible. Parents with MTD have a 50% risk of passing the disease on to their offspring. Many cases occur de novo, but in families with no history of the disease, germline mosaicism cannot be excluded.
Management and treatment
Treatment is targeted at possibly avoiding the progression of skeletal deformity and maintaining pulmonary function. Standard practice includes bracing until skeletal maturity is reached. A conservative approach is usually preferred, but surgical procedures (i.e. corrective spine surgery with posterior fusion) can be successful in some cases in halting deformity. Preoperative evaluation of pulmonary function is mandatory before any invasive procedure is considered. Regular follow-up should monitor for any breathing difficulties or signs of myelopathy. A tracheostomy and long-term ventilatory support may be necessary in severe cases.
Prognosis
The prognosis varies on the severity of the disease. Life expectancy is not usually affected unless there are respiratory complications.

                            Last update:
                            January 2014

                            - Expert reviewer(s):
                            Dr Elena ANDREUCCI


Methanol poisoning is a rare poisoning resulting in elevated anion gap metabolic acidosis, due to the alcohol dehydrogenase (ADH)-mediated production of formic acid (which is poisonous to the central nervous system), and characterized by dizziness, nausea, vomiting, confusion, metabolic acidosis, visual disturbances (which if left untreated can lead to blindness), coma, and death (due to respiratory failure).


A teratogenic embryofetopathy that results from maternal exposition to methimazole (MMI; or the parent compound carbimazole) in the first trimester of pregnancy. MMI is an antithyroid thionamide drug used for the treatment of Graves' disease. In the infant, MMI may result in choanal atresia, esophageal atresia, omphalocele, omphalomesenteric duct anomalies, congenital heart disease (such as ventricular septal defect), renal system malformations and aplasia cutis. Additional features that may be observed include facial dysmorphism (short upslanting palpebral fissures, a broad nasal bridge with a small nose and a broad forehead) and athelia/hypothelia.


Methionine adenosyltransferase I/III deficiency

A rare inborn error of metabolism characterized by persistently elevated serum methionine levels. Half of patients reported with MAT I/III deficiency, notably those with hypermethioninemia below 800 µM, have no CNS abnormalities and are clinically asymptomatic. However, individuals with higher levels might show evidence of central nervous system abnormalities, most notably hypo- or demyelination on brain MRI, as well as developmental delay and intellectual disability. Bad breath or a strong smell of urine and sweat may be noted in some patients.


A rare intoxication characterized by acute renal tubular toxicity due to crystallization of methotrexate in the renal tubular lumen (which in turn leads to impaired methotrexate clearance and further deterioration of renal function and exacerbation of non-renal adverse events), myelosuppression with pancytopenia, gastrointestinal mucositis, maculopapular skin rash, chemical conjunctivitis, hepatotoxicity (reversible chemical hepatitis and hyperbilirubinemia), pulmonary toxicity, and, in severe cases, multiorgan failure. Central nervous system involvement, including headaches, seizures, and stroke-like symptoms, may also be observed.


Methotrexate-associated lymphoproliferative disorders are rare immunodeficiency-associated lymphoproliferative diseases characterized by lymphoid proliferation or lymphomas (large B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, reactive lymphadenitis and a polymorphic post-transplant lymphoproliferative disorder) that develop in patients with different autoimmune diseases treated with methotrexate. Swelling is the predominant manifestation of the disease and regression after methotrexate withdrawal is observed in a significant proportion of patients.


Methylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency is a rare inborn error of metabolism disease characterized by mild to moderate, persistent elevation of methylmalonic acid in plasma, urine and cerebrospinal fluid. Clinical presentation may include acute metabolic decompensation with metabolic acidosis (presenting with vomiting, dehydration, confusion, hallucinations), nonspecific neurological symptoms, or may also be asymptomatic.


Methylmalonic acidemia with homocystinuria type cblF

cblF type methylmalonic acidemia with homocystinuria is a form of methylmalonic acidemia with homocystinuria (see this term), an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures.

Summary:
Epidemiology
To date, 15 cases have been reported.
Clinical description
cblF type methylmalonic acidemia with homocystinuria has a variable age of onset (from birth to 11 years of age) and manifestations also vary and can include development delay, feeding difficulties, signs of megaloblastic anemia (pallor, fatigue, anorexia), hypotonia, stomatitis and skin rashes.
Etiology
The disorder is caused by mutations in the LMBRD1 gene (6q13) and is transmitted in an autosomal recessive manner.

                            Last update:
                            March 2012

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


Methylmalonic acidemia with homocystinuria, type cblC

cblC type methylmalonic acidemia with homocystinuria is a form of methylmalonic acidemia with homocystinuria (see this term), an inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures.

Summary:
Epidemiology
To date, over 500 cases of cblC have been reported, making it the most frequent type of methylmalonic acidemia with homocystinuria.
Clinical description
The disease typically presents with failure to thrive, acute neurological deterioration, intellectual deficit, lethargy, seizures, microcephaly, a salt-and-pepper retinopathy, and signs of megaloblastic anemia (pallor, fatigue, anorexia). Severe brain abnormalities including hydrocephalus, white matter abnormalities, cerebral atrophy, and unusual basal ganglia lesions are common. Onset of the disorder can be early (infantile) or late (juvenile or adult), with the late-onset form characterized by ataxia, dementia and psychosis.
Etiology
cblC type methylmalonic acidemia with homocystinuria is caused by mutations in the MMACHC gene (1p36.3) and is transmitted in an autosomal recessive manner.

                            Last update:
                            March 2012

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


Methylmalonic acidemia with homocystinuria, type cblD

cblD type methylmalonic acidemia with homocystinuria is a form of methylmalonic acidemia with homocystinuria (see this term), an inborn error of vitamin B12 (cobalamin) metabolism characterized by variable biochemical, neurological and hematological manifestations.

Summary:
Epidemiology
To date, 17 cases of cblD have been reported (6 classic cblD, 5 cblDv1 and 6 cblDv2).
Clinical description
Three different presentations have been described: the classic form with combined methylmalonic aciduria and homocystinuria; cblD variant 1 (cblDv1) with isolated homocystinuria; and cblD variant 2 (cblDv2) with isolated methylmalonic aciduria. Clinical presentation is extremely variable. The disorder can present from early infancy to late childhood. Presenting signs are variable depending on which aspect(s) of cobalamin metabolism are affected and can include developmental delay, severe learning difficulties, seizures, movement and gait abnormalities, behavioral problems and signs of megaloblastic anemia (pallor, fatigue, anorexia).
Etiology
The causal gene for cblD is MMADHC (2q23.2) and the disorder is transmitted in an autosomal recessive manner.

                            Last update:
                            March 2012

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


Methylmalonic acidemia with homocystinuria

A rare inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures. There are four complementation classes of cobalamin defects (cblC, cblD, cblF and cblJ) that are responsible for methylmalonic acidemia - homocystinuria (methylmalonic acidemia - homocystinuria cblC, cblD cblF and cblJ).

Summary:
Epidemiology
Annual incidence in the USA, based on the California newborn screening program, has been estimated at 1/67,000 (for the cblC form). cblC is the most frequent type (over 550 cases). To date, rare cases of cblD (6 cases), cblF (15 cases) and cblJ (3 cases) have been reported.
Clinical description
Onset of the disorder can be between early infancy to adulthood. Patients with methylmalonic acidemia with homocystinuria of all types can present with developmental delay, signs of megaloblastic anemia (pallor, fatigue, and anorexia), lethargy and seizures. In addition, patients with cblC present with acute neurological deterioration, retinal deterioration, microcephaly and severe brain abnormalities including hydrocephalus, white matter abnormalities and unusual basal ganglia lesions. Patients with cblD present with severe learning difficulties, behavioral problems and movement and gait abnormalities and patients with cblF and cblJ present with feeding difficulties, hypotonia, stomatitis, mild facial dysmorphism, cardiac malformations, and skin rashes. Patients who become symptomatic beyond infancy may present with ataxia, dementia or psychosis.
Etiology
Methylmalonic acidemia - homocystinuria is caused by anomalies in the synthesis of both adenosylcobalamin (AdoCbl) and of methylcobalamin (MeCbl) resulting from genetic defects in the cbl complementation classes C, D, F and J. CblC is caused by mutations in the MMACHC gene (1p36.3), cblD by mutations in the MMADHC gene (2q23.2), cblF by mutations in the LMBRD1 gene (6q13) and cblJ by mutations in the ABCD4 gene.
Diagnostic methods
Measurement of organic acids and amino acids, in particular evidence of increased total plasma homocysteine (tHcy), is suggestive of the disease. Diagnosis is confirmed by complementation analysis of cultured patient fibroblasts or by identification of mutations in the MMACHC, MMADHC, LMBRD1 or ABCD4 genes.
Differential diagnosis
Differential diagnoses include acquired vitamin B12 deficiency, vitamin B12-responsive methylmalonic aciduria, and homocystinuria without methylmalonic aciduria (see these terms). The combination of methylmalonic aciduria, homocystinuria and normal serum cobalamin concentrations is required to distinguish patients.
Antenatal diagnosis
Antenatal diagnosis is possible by measurement of methylmalonate and homocysteine in amniotic fluid and maternal urine at mid-trimester and by studies of cobalamin metabolism in cultured amniotic fluid cells. Molecular diagnosis is possible when the affected gene and the mutation(s) segregating in the family are known. Prenatal therapy (treating the mother with hydroxycobalamin during pregnancy) has been reported in two cases with apparent success.
Genetic counseling
All four forms of the disorder are transmitted in an autosomal recessive manner. Genetic counseling should be provided to affected families.
Management and treatment
Patients are treated with intramuscular injections of hydroxycobalamin, oral betaine, and folic acid. Good metabolic control and correction of hematologic problems can sometimes be achieved with this treatment but most patients continue to have signs of motor and language delay, intellectual deficit and abnormal ophthalmologic findings. Early diagnosis and treatment are important.
Prognosis
Prognosis is better in patients with later-onset disease.

                            Last update:
                            May 2013

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


Methylmalonic acidemia without homocystinuria

Methylmalonic acidemia is an inborn error of vitamin B12 metabolism characterized by gastrointestinal and neurometabolic manifestations resulting from decreased function of the mitochondrial enzyme methylmalonyl-CoA mutase.

Summary:
Epidemiology
Prevalence of methylmalonic acidemia has been estimated at 1/48,000 to 1/61,000 in North America, and at 1/26,000 in China (these values may include patients with methylmalonic acidemia with homocystinuria; see this term).
Clinical description
Clinical signs include lethargy, failure to thrive, recurrent vomiting, dehydration, respiratory distress, and muscle hypotonia, as well as developmental delay, intellectual deficit, hepatomegaly and coma. Long-term consequences of the disorder include neurological damage due to metabolic stroke affecting the brain stem, and end stage renal failure. The disease can either be responsive or unresponsive to treatment with vitamin B12 (vitamin B12-responsive or unresponsive methylmalonic acidemia; see these terms). Patients with mut0 or cblB tend to be more severely affected than patients with cblA, cblDv2 or mut-.
Etiology
Vitamin B12-responsive methylmalonic acidemia is caused by defects in the synthesis of adenosylcobalamin (AdoCbl) that result from genetic defects in cobalamin metabolism (cblA, cblB or cblD variant 2 [cblDv2]). Vitamin B12-unresponsive methylmalonic acidemia is caused by complete (mut0) or partial (mut-) deficiency in the activity of the mitochondrial enzyme methylmalonyl-CoA mutase. cblA is caused by mutations in the MMAA gene (4q31.1-2), cblB by mutations in the MMAB gene (12q24.1), cblDv2 by mutations in the MMADHC gene (2q23.2), and mut0 and mut- by mutations in the MUT gene (6p21), and all are transmitted in an autosomal recessive manner. The previously reported cblH disorder is now known to be cblDv2.

                            Last update:
                            March 2012

                            - Expert reviewer(s):
                            Dr David ROSENBLATT  - Dr David WATKINS


Methylmalonic aciduria due to transcobalamin receptor defect is a rare metabolite absorption and transport disorder characterized by a moderate increase of methylmalonic acid (MMA) in the blood and urine due to decreased cellular uptake of cobalamin resulting from decreased transcobalamin receptor function. Patients are usually asymptomatic however, screening reveals increased C3-acylcarnitine and MMA in plasma. Serum homocysteine levels may vary from normal to moderately elevated and retinal vascular occlusive disease, resulting in severe visual loss, has been reported.


A rare inborn error of metabolism characterized by a spectrum of presentation ranging from hyperimmunoglobulinemia D with periodic fever (HIDS) to mevalonic aciduria.

Summary:
Epidemiology
Some 300 cases of mevalonate kinase deficiency (MKD) have been reported worldwide. Many cases are probably not diagnosed, implying that prevalence may be higher than expected. Males and females are affected equally.
Clinical description
All patients suffer from recurrent inflammatory episodes with fever, pain, diarrhea, skin eruptions, and headache. Patients with the more severe phenotype, mevalonic aciduria (MVA), can also exhibit developmental, neurological and ophthalmological involvement. MKD develops antenatally, during infancy, or in childhood and covers a clinical spectrum ranging from a relatively mild periodic fever disorder to a lethal metabolic disease. There are two types of MKD depending on the severity of the clinical manifestations: Hyperimmunoglobinemia D syndrome (HIDS) with periodic episodes of fever lasting 3 to 7 days, and MVA which includes dysmorphic features, failure to thrive, developmental delay, progressive ataxia, psychomotor delay, progressive ocular manifestations, short stature, and myopathy later in life.
Etiology
MKD is caused by mutations in the MVK gene (12q24), which encodes mevalonate kinase involved in cholesterol and isoprenoid production. The exact pathogenesis is currently unclear. Enzyme deficiency results in impaired cholesterol biosynthesis and increased production of inflammatory mediators. The residual enzyme activity is correlated with the severity of the manifestations with HIDS patients having a residual activity between 1.8% and 28%, while MVA patients have enzyme activities below 0.5%. However, overlap between both phenotypes may occur. No clear genotype-phenotype correlations have been identified.
Genetic counseling
MKD follows an autosomal recessive pattern of inheritance.

                            Last update:
                            February 2016

                            - Expert reviewer(s):
                            Dr Joost FRENKEL  - Dr Jerold JEYARATNAM


A rare, severe form of mevalonate kinase deficiency (MKD) characterized by dysmorphic features, failure to thrive, psychomotor delay, ocular involvement, hypotonia, progressive ataxia, myopathy, and recurrent inflammatory episodes.

Summary:
Epidemiology
The exact prevalence and incidence of MVA are not known. Fewer than 50 patients have been reported to date. A small proportion of patients with MKD have mevalonic aciduria (MVA), while most cases correspond to the milder phenotype known as Hyperimmunoglobinemia D with periodic fever (HIDS).
Clinical description
Onset of MVA is usually during infancy and in some severe cases antenatally. The clinical presentation is variable with cases of severe disease with significantly reduced life expectancy to milder cases with no effect on life expectancy. Infants may be born with shortened limbs and dysmorphic features (dolichocephaly, microcephaly, frontal bossing, a triangular-shaped face, down-slanting eyelids, and dysplastic or low-set ears. Affected patients may also present with marked failure to thrive, and recurrent episodes of fever (that may be fatal in infancy) possibly accompanied by hepatosplenomegaly, lymphadenopathy, abdominal pain, vomiting, diarrhea, arthralgia, myalgia, mouth ulcers, and skin eruptions. During childhood, patients may show failure to thrive, developmental delay and progressive ataxia; in later childhood or adolescence they may develop progressive ocular disorders such as uveitis, blue sclera, retinitis pigmentosa, or cataracts. Short stature and myopathy are reported in older patients.
Etiology
MVA is caused by mutations in the MVK gene (12q24). MVK encodes mevalonate kinase, which is involved in cholesterol and isoprenoid production. In patients with the severe form of MKD, enzyme deficiency is nearly complete causing the severe manifestations of the disorder. Severity usually depends on the degree of residual enzyme activity.
Genetic counseling
MKD follows an autosomal recessive pattern of inheritance. Genetic counseling should be proposed to affected families.
Management and treatment
Inflammatory attacks can often be controlled with interleukin-1 blocking agents such as canakinumab or anakinra. Severely affected patients have been seen to improve significantly upon allogeneic hematopoietic stem cell transplantation.

                            Last update:
                            February 2016

                            - Expert reviewer(s):
                            Dr Joost FRENKEL  - Dr Jerold JEYARATNAM


A rare form of disorder of protein N-glycosylation characterized by facial dysmorphism (large, posteriorly rotated ears with prominent antihelices, convex nasal ridge, open mouth, large and crowded teeth), stereotypic hand movements, seizures, and varying degrees of developmental delay. A bleeding tendency is also observed and this results from diminished platelet aggregation. The disease is caused by loss-of-function mutations in the gene MGAT2 (14q21).


Micro syndrome is an autosomal recessive disorder caracterised by ocular and neurodevelopmental defects and by microgenitalia. It presents with severe intellectual disability, microcephaly, congenital cataract, microcornea, microphthalmia, agenesis/hypoplasia of the corpus callosum, and hypogenitalism.

Summary:
Epidemiology
Since its initial description, 26 cases of Micro syndrome have been reported in the literature.
Clinical description
With exception of the ophthalmologic features, the clinical and dysmorphic findings are either unapparent or subtle in the early postnatal period.
Etiology
Mutations in RAB3GAP, a gene showing linkage to a region of homozygosity at 2q21.3, have been identified in some families. The RAB3GAP gene encodes a member of the Rab3 protein family, which is involved in regulated exocytosis of neurotransmitters and hormones. It has been suggested that the hypogenitalism is hypothalamic in origin, and that the ocular and neurodevelopmental defects result from abnormal neurotransmitter vesicular transport and exocytosis.
Diagnostic methods
Ocular findings are the most reliable diagnostic signs of Micro syndrome, especially during infancy. Pathognomonic ophthalmologic findings include microphthalmia, microcornea, cataract, atonic pupils, mild optic atrophy, and severe cortical vision impairment.
Differential diagnosis
Micro syndrome should be considered in any infant with congenital cataract.
Management and treatment
There is no specific treatment for Micro syndrome and the management is symptomatic. The conventional approach used for congenital cataract should be recommended.

                            Last update:
                            January 2006

                            - Expert reviewer(s):
                            Dr Pinar AGRAS  - Dr Murat DERBENT


Microbrachycephaly-ptosis-cleft lip syndrome is characterised by the association of intellectual deficit, microbrachycephaly, hypotelorism, palpebral ptosis, a thin/long face, cleft lip, and anomalies of the lumbar vertebra, sacrum and pelvis. It has been described in two Brazilian sisters. Transmission appears to be autosomal recessive.


Microcephalic cortical malformations-short stature due to RTTN deficiency

A rare, genetic, neurodevelopmental disorder with primordial microcephaly characterized by primary microcephaly, moderate to severe intellectual disability, and global developmental delay. Variable brain malformations are common ranging from simplified gyration, to cortical malformations such as pachygyria, polymicrogyria, reduced sulcation and midline defects. Craniofacial dysmorphism (e.g. sloping forehead, high and broad nasal bridge) are related to the primary microcephaly. Short stature is frequently observed, and may be severe.

Summary:
Epidemiology
To date, approximately 30 cases with identified RTTN mutations have been reported in the scientific and medical literature. Males and females are equally affected.
Clinical description
Presentation can be in utero or at birth with congenital microcephaly. Cortical malformations are common with a broad spectrum ranging from polymicrogyria-like dysgyric cortex to severe congenital microcephaly with large interhemispheric cysts. The cortical malformation is often predominant in frontal regions, suggesting elective underdevelopment of frontal lobes. The neurological problems include severe cognitive, motor and speech delay and only rarely seizures. The clinical severity correlates with the extension of the migration disorder and with the extent of microcephaly. Variable congenital anomalies occur, including eye anomalies (microphthalmia, abnormal orbitae, ankyloblepharon, optic hypoplasia), pituitary failure (growth and endocrine anomalies), urogenital malformations (cryptorchidism, micropenis, double uterus), kidney defect (agenesis, ectopy, pyelocaliectasis), skeletal anomalies (kyphoscoliosis, hip dysplasia), and heart defects. Short stature is variable and can be severe.
Etiology
Germline biallelic variants in RTTN (18q22.2) are responsible for the disease.
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by genetic testing: exome sequencing or panel-based exome sequencing.
Differential diagnosis
Differential diagnosis is of other causes of autosomal-recessive non-syndromic primary microcephaly with primary dwarfism or short stature.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
The pattern of inheritance is autosomal recessive; genetic counseling is recommended for at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Supportive care includes physical therapy to manage the complications of spasticity, occupational therapy, and speech therapy based on individual needs. Nutritional needs commonly require nasogastric tube feeding, followed eventually by gastrostomy tube placement. Seizures are treated with antiepileptic drugs based on the specific seizure type.
Prognosis
The prognosis of these severe neurodevelopmental diseases is poor, with multiple disabilities and the subsequent complications (respiratory, nutritional, orthopedic) in almost all cases. For patients with severe cortical malformations (lissencephalies, polymicrogyria-like cortical dysplasia), it is usually appropriate to discuss the level of care to be provided in the event of a severe intercurrent illness. No data are available on the quality of life or life expectancy of patients with RTTN mutations.

                            Last update:
                            March 2021

                            - Expert reviewer(s):
                            Pr Nadia BAHI-BUISSON | ITHACA*

                                * European Reference Network


Microcephalic osteodysplastic dysplasia, Saul-Wilson type is a skeletal dysplasia characterized by a distinct facial phenotype, short stature, brachydactyly, clubfoot deformities, cataracts, and microcephaly. It has been described in four patients. Facial features include frontal bossing with a depression over the metopic suture, a narrow nasal root with a beaked nose, and midfacial hypoplasia with prominent eyes. Characteristic radiographic findings are observed (irregularities of the vertebral bodies, hypoplasia of the odontoid process, short phalanges, coning several epiphyses etc.).


A rare bone disease and a form of microcephalic primordial dwarfism characterized by severe pre- and postnatal growth retardation, with marked microcephaly in proportion to body size, skeletal dysplasia, abnormal dentition, insulin resistance, and increased risk for cerebrovascular disease.

Summary:
Epidemiology
Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) is one of the most common forms of microcephalic primordial dwarfism (MPD) and accounts for more than 150 cases worldwide.
Clinical description
MOPDII is congenital, with a perinatal and infancy onset. It is characterized by severe pre- and postnatal growth retardation, with proportionate severe microcephaly, skeletal dysplasia, abnormal dentition, an increased risk for cerebrovascular disease (aneurysms and Moya Moya disease in 19%-52% of cases) and insulin resistance. Intrauterine growth restriction (IUGR) is common. The average length, weight, and head occipitofrontal circumference (OFC) at birth are respectively 7.0, 3.9, and 4.6 SDs below the population mean (after correcting for gestational age <37 weeks). Head growth appears to stop by 18 months of age giving rise to the appearance of progressive microcephaly. At maturity, the average height, weight, and OFC are respectively 10.3, 14.3, and 8.5 SDs below the population mean. Skeletal dysplasia with progressive scoliosis, radial head dislocation and coxa vara may be seen. Distinct craniofacial features include prominent, small pinnae with attached lobes; small, dysplastic and poorly rooted, opalescent dentition and sparse hair. Further hallmarks of MOPD II include high-pitched nasal voice, areas of hypo- and hyperpigmentation (with café-au-lait spots), poikiloderma, acanthosis nigricans, and truncal obesity in adolescence and adulthood. A disorder initially named primordial short stature-microdontia-opalescent and rootless teeth was originally and mistakenly reported to have distinct MOPD, but it is now recognized to be the same entity as MOPD II.
Etiology
MOPD II is caused by mutations in PCNT (21q22.3), encoding pericentrin, which anchors a wide range of centrosomal proteins and protein complexes during cell division. Disruption of pericentrin is thought to cause mitotic spindle defects, and impaired cell proliferation. A role in ATR DNA damage dependent signaling has also been proposed.
Diagnostic methods
Diagnosis relies on clinical features, radiographic examinations of bone age that usually show disharmonic maturation of centers and a retarded bone age. Diagnosis is confirmed by genetic screening of PCNT. Some individuals have elevated platelet counts.
Differential diagnosis
Differential diagnosis includes Meier-Gorlin syndrome, LIG4 syndrome, XRCC4 deficiency, Seckel syndrome, MOPD types I and III, SHORT syndrome, Schimke immuno-osseous dysplasia, and Dubowitz syndrome.
Antenatal diagnosis
Pregnancies with affected children are often complicated by the observation of IUGR. Early age of delivery is noted. C-sections may be performed at earlier ages due to the IUGR. Prenatal diagnosis is possible if the causative mutation(s) in PCNT have been identified in the carrier parents.
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
Management is mainly symptomatic. Screening for CNS vascular abnormalities with brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) is recommended at diagnosis and every 12 to 18 months. Yearly screening for signs of insulin resistance including a lipid profile should be performed (beginning at grade school age), as well as monitoring for anemia, platelet counts, and hip and spine anomalies.
Prognosis
Life expectancy is generally decreased, but individuals live into their 30s. Many complications arise, but most can be handled by adapting modern medical techniques to the diminutive size. Vascular anomalies are a common complication. They may involve neurovasculature in childhood, and renal and coronary arteries in adulthood, the latter of which may be life-threatening.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Dr Michael BOBER  -  Angela DUKER


Microcephalic osteodysplastic primordial dwarfism types I and III

A rare, severe, primary bone dysplasia characterized by intrauterine and postnatal growth retardation, microcephaly, facial dysmorphism, skeletal dysplasia, low-birth weight and brain anomalies.

Summary:
Epidemiology
Less than 60 cases have been described in the literature so far.
Clinical description
The facial dysmorphism is characterized by a round face, metopic ridge, small anterior fontanelle, a sloping forehead, prominent occiput, protruding eyes, prominent nose, small dysplastic ears and micrognathia. The neck is short. Sparse hair and eyebrows, and dry skin are frequently observed. Skeletal anomalies include short limbs, brachydactyly, flexion contractures markedly delayed epiphyseal ossification and, more variably, dislocation of the hips and elbows. The most frequent neurological manifestations are intellectual deficit and seizures, and reported brain anomalies include brain hypoplasia, lissencephaly or pachygyria, hypoplastic frontal lobes, arachnoid cysts, agenesis of the corpus callosum or and mild cerebellar vermis hypoplasia. Cardiac anomalies and retinal dystrophy are more variably reported.
Etiology
Caused by bi-allelic mutations of RNU4ATAC (2q14.2), a gene encoding a small nuclear RNA involved in minor (U12) splicing. Mutations in the same gene also cause Roifman syndrome in which there are many overlapping features but Roifman is distinguished by immunodeficiency.
Diagnostic methods
Diagnosis is made on the basis of the clinical and radiological phenotype including marked growth retardation and microcephaly, severe brain anomalies and common radiological bone features including delayed epiphyseal ossification, short and bowed tubular bones, enlarged metaphyses, elongated clavicles, mild platyspondyly, cleft vertebral arches, short fingers and toes and small iliac wings.
Differential diagnosis
The differential diagnosis should include MOPD type 2 and other syndromes associated with primordial dwarfism, such as Seckel syndrome and microcephalic primordial dwarfism due to RTTN deficiency.
Antenatal diagnosis
Prenatal diagnosis, by ultrasonography showing brain anomalies, IUGR and short distal limb at around 20 weeks of gestation, has been reported in affected families.
Genetic counseling
MOPD type I/III is transmitted as an autosomal recessive trait. Genetic counseling should be offered to at risk families (where each parent is an unaffected carrier) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is supportive only. Particular attention should be provided to growth and psychomotor development. Medical care and management should be provided according to malformations and intellectual deficiency. Great attention should be paid to apparently mild medical events (fever, drowsiness), especially in the first three years of life.
Prognosis
The prognosis is poor with most of the reported patients dying either in utero or unexpectedly as a result of a fever or an apparently mild medical event within the first 3 years of life. Several RNU4ATAC mutations appear to be compatible with prolonged survival, sometimes until adulthood.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Patrick EDERY | ITHACA* - Dr Audrey PUTOUX

                                * European Reference Network


Microcephalic primordial dwarfism due to ZNF335 deficiency is characterized by severe antenatal microencephaly, simplified gyration, agenesis of the corpus callosum, absence of basal ganglia (very rare), pontocerebellar atrophy and involvement of the white matter with secondary cerebral atrophy. Congenital cataract, choanal atresia, multiple arthrogryposis and spastic tetraparesis can occur.


Microcephalic primordial dwarfism, Dauber type is a rare, genetic developmental defect during embryogenesis characterized by severe pre- and postnatal growth retardation, severe microcephaly, severe developmental delay and intelletual disability, severe adult short stature and facial dysmorphism (incl. hypotelorism, small ears, prominent nose). Other reported features include skeletal anomalies (Madelung deformity, clinodactyly, mild lumbar scoliosis, bilateral hip dysplasia) and seizures. Absence of thelarche and menarche is also associated.


Microcephalic primordial dwarfism, Montreal type

A rare, genetic multiple congenital anomalies/dysmorphic syndrome characterized by severe short stature and craniofacial dysmorphism (microcephaly, narrow face with flat cheeks, ptosis, prominent nose with a convex ridge, low-set ears with small or absent lobes, high-arched/cleft palate, micrognathia), associated with premature graying and loss of scalp hair, redundant, dry and wrinkled skin of the palms, premature senility and varying degrees of intellectual disability. Cryptorchidism and skeletal anomalies may also be observed. There have been no further descriptions in the literature since 1970.


Microcephalic primordial dwarfism, Toriello type

A rare disorder characterised by growth retardation with prenatal onset, cataracts, microcephaly, intellectual deficit, immune deficiency, delayed ossification and enamel hypoplasia. It has been described in two siblings. Transmission is autosomal recessive.


Microcephalic primordial dwarfism-insulin resistance syndrome

A rare genetic disease characterized by severe pre- and postnatal growth failure with short stature and microcephaly, facial dysmorphism (including a small jaw and prominent midface), severe insulin resistance, fatty liver, and hypertriglyceridemia developing in childhood, and primary gonadal failure. Mild global learning difficulties and acanthosis nigricans have also been reported.


Microcephaly - albinism - digital anomalies syndrome is a very rare syndrome associating microcephaly, micrognathia, oculocutaneous albinism, hypoplasia of the distal phalanx of fingers and agenesia of the distal end of the right big toe.

Summary:
Epidemiology
It has been described in two sibs.
Clinical description
Both brother and sister had psychomotor retardation and died in the course of a respiratory infection.
Genetic counseling
The reported cases suggest that the condition is hereditary, and is transmitted as an autosomal recessive trait.

                            Last update:
                            October 2010


Microcephaly-brachydactyly-kyphoscoliosis syndrome is characterized by profound intellectual deficit in association with microcephaly, short stature, brachydactyly type D, a flattened occiput, downslanting palpebral fissures, low-set large ears, a broad prominent nose and kyphoscoliosis. It has been described in three sisters. The disorder is likely to be transmitted as an autosomal recessive trait.


Microcephaly-brain defect-spasticity-hypernatremia syndrome is a rare congenital genetic syndrome with a central nervous system malformation as a major feature characterized by microcephaly, hypertonia, developmental delay and cognitive impairment, swallowing difficulty, hypernatremia, and hypoplasia of the frontal parts and fusion of the lateral ventricles on brain MRI. There have been no further descriptions in the literature since 1986.


Microcephaly-capillary malformation syndrome is a rare, genetic vascular anomaly characterized by severe congenital microcephaly, poor somatic growth, diffuse multiple capillary malformations on the skin, intractable epilepsy, profound global developmental delay, spastic quadriparesis and hypoplastic distal phalanges.


Microcephaly-cardiac defect-lung malsegmentation syndrome

Microcephaly - cardiac defect - lung malsegmentation syndrome is a very rare syndrome characterized by the combination of microcephaly, heart defects, renal hypoplasia, lung segmentation defects and cleft palate.

Summary:
Epidemiology
It has been described in three female sibs (including a fetus).
Clinical description
Dysmorphic features were not characteristic.
Genetic counseling
The condition seems to be hereditary, and transmitted as an autosomal recessive trait.
Prognosis
Prognosis is poor and all infants died in infancy.

                            Last update:
                            July 2010


Microcephaly-cardiomyopathy syndrome is characterised by severe intellectual deficit, microcephaly and dilated cardiomyopathy. Hand and foot anomalies have also been reported. The syndrome has been described in three individuals. Transmission is autosomal recessive.


Microcephaly-cerebellar hypoplasia-cardiac conduction defect syndrome is a rare, genetic congenital anomalies/dysmorphic syndrome characterized by growth failure, global developmental delay, profound intellectual disability, autistic behaviors, acquired second-degree heart block with bradycardia and vasomotor instability. Hands and feet present with long fusiform fingers, campto-clinodactyly and crowded toes while craniofacial dysmorphism includes microcephaly, broad forehead, thin eyebrows, upslanting palpebral fissures, large ears with prominent antihelix, prominent nose, long philtrum, thin upper lip vermillion and prominent lower lip. Neurological signs include hypotonia, brisk reflexes, dystonic-like movements and truncal ataxia and imaging shows cerebellar hypoplasia and simplified gyral pattern.


Microcephaly-cervical spine fusion anomalies syndrome is characterized by microcephaly, facial dysmorphism (beaked nose, low-set ears, downslanting palpebral fissures, micrognathia), mild intellectual deficit, short stature, and cervical spine fusion anomalies producing spinal cord compression. It has been described in two brothers born to consanguineous parents. Transmission is likely to be autosomal recessive.


Microcephaly-cleft palate-abnormal retinal pigmentation syndrome is a rare orofacial clefting syndrome characterized by microcephaly, cleft of the secondary palate and other variable abnormalities, including abnormal retinal pigmentation, facial dysmorphism with hypotelorism and maxillary hypoplasia. Goiter, camptodactyly, abnormal dermatoglyphics and mild intellectual disability may also be associated. There have been no further descriptions in the literature since 1983.


Microcephaly-complex motor and sensory axonal neuropathy syndrome is an extremely rare subtype of hereditary motor and sensory neuropathy characterized by severe, rapidly-progressing, distal, symmetric polyneuropathy and microcephaly (which can be evident in utero) with intact cognition. Clinically it presents with delayed motor development, hypotonia, absent or reduced deep tendon reflexes, progressive muscle wasting and weakness and scoliosis.


Microcephaly-congenital cataract-psoriasiform dermatitis syndrome

A rare sterol biosynthesis disorder characterized by microcephaly, bilateral congenital cataract, mild developmental delay, growth delay with short stature, psoriasiform dermatitis of variable severity, and immune dysregulation. Behavioral disorder, joint contractures, and arthralgia have also been described.


Microcephaly-corpus callosum and cerebellar vermis hypoplasia-facial dysmorphism-intellectual disability syndrom

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by global developmental delay and moderate to severe intellectual disability, as well as variable other manifestations, such as macro- or microcephaly, epilepsy, hypotonia, behavioral problems, stereotypic movements, and facial dysmorphism (including arched eyebrows, long palpebral fissures, prominent nasal bridge, upturned nose, dysplastic ears, and broad mouth), among others. Brain imaging may show cerebellar anomalies, hypoplastic corpus callosum, enlarged ventricles, polymicrogyria, or white matter abnormalities.


Microcephaly-corpus callosum hypoplasia-intellectual disability-facial dysmorphism syndrome

A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by variable degrees of developmental delay and intellectual disability with poor or absent speech, hypotonia, hypoplastic or absent corpus callosum, and facial dysmorphism (such as long face, frontal bossing, hypertelorism, downslanting palpebral fissures, and tented upper lip). Additional reported features include microcephaly, seizures, gait ataxia, scoliosis, and syndactyly of fingers, among others.


Microcephaly-deafness-intellectual disability syndrome is characterised by microcephaly, deafness, intellectual deficit and facial dysmorphism (facial asymmetry, prominent glabella, low-set and cup-shaped ears, protruding lower lip, micrognathia). It has been described in a mother and her son. The mode of inheritance is probably autosomal dominant.


Microcephaly-facial dysmorphism-ocular anomalies-multiple congenital anomalies syndrome

A rare genetic disease characterized by a highly variable phenotype comprising ocular anomalies (congenital glaucoma, myopia, retinal detachment, and/or Axenfeld-Rieger anomaly), congenital hypothyroidism, hearing loss, microcephaly, dental defects, kidney anomalies, cerebrovascular anomalies, and distal limb anomalies. Dysmorphic facial features may include square face with prominent jaw, broad flat nasal bridge, short philtrum, and prominent ears.


Microcephaly-facio-cardio-skeletal syndrome, Hadziselimovic type is a rare syndrome with cardiac malformations (see this term), characterized by prenatal-onset growth retardation (low birth weight and short stature), hypotonia, developmental delay and intellectual disability associated with microcephaly and craniofacial (low anterior hairline, hypotelorism, thick lips with carp-shaped mouth, high-arched palate, low-set ears), cardiac (conotruncal heart malformations such as tetralogy of Fallot; see these terms) and skeletal (hypoplastic thumbs and first metacarpals) abnormalities.


A rare intellectual disability syndrome characterized by intellectual deficit, marfanoid habitus, microcephaly, and glomerulonephritis. There have been no further reports since 1992.


Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome

A rare genetic disease characterized by microcephaly, global developmental delay, intellectual disability, abnormal muscle tone, and sensorineural hearing impairment. Additional variable manifestations include epilepsy, cortical visual impairment, gastrointestinal disturbances, growth restriction, scoliosis, as well as immunodeficiency and thrombocytopenia. Brain imaging may show cerebral atrophy, thin corpus callosum, and hypomyelination.


Microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) is a rare autosomal dominant condition characterized by variable expression of microcephaly, ocular disorders including chorioretinopathy, congenital lymphedema of the lower limbs, and mild to moderate intellectual disability.

Summary:
Epidemiology
The exact prevalence of MCLID is not known but the disorder is thought to be rare. Approximately 50 families with clinical features of the syndrome have been described to date with mutations in the KIF11 gene reported in 25 families worldwide. Males and females appear to be affected equally.
Clinical description
MCLID presents with variable expression of the main clinical features (microcephaly, chorioretinopathy, lymphedema and intellectual disability). The microcephaly is primary, and the severity is variable even within families. Mild to moderate learning difficulties are common. A characteristic facial phenotype including upslanting palpebral fissures, broad nose with rounded tip, anteverted nares, long philtrum with thin upper lip, and prominent chin and ears is well recognized. The ocular features include choroidal atrophy and non-progressive dysplasia. Hypermetropic astigmatism, myopic astigmatism, retinal folds, and microphthalmia are also observed. Lymphedema when present, is generally congenital, bilateral and confined to the dorsa of the feet, and resembles the lymphedema seen in Milroy disease (see this term). Congenital heart defects and epilepsy may be rare features of the syndrome.
Etiology
There is likely to be genetic heterogeneity. However, a significant proportion of cases are caused by mutations in the kinesin family member 11 (KIF11) gene (10q24.1). KIF11 encodes EG5, a homotetramer kinesin motor, likely to be important for the development and maintenance of retinal and lymphatic structures. Individuals with pathogenic mutations in KIF11 have been reported without clinical features of the syndrome demonstrating reduced penetrance.
Genetic counseling
Inheritance is autosomal dominant with variable expression and reduced penetrance.

                            Last update:
                            June 2014

                            - Expert reviewer(s):
                            Dr Gabriela JONES  - Pr Sahar MANSOUR  - Dr Pia OSTERGAARD


Microcephaly-microcornea syndrome, Seemanova type is characterised by microcephaly and brachycephaly, eye anomalies (microphthalmia, microcornea, congenital cataract), hypogenitalism, severe intellectual deficit, growth retardation and progressive spasticity. It has been described in two patients (a male and his sister's son). Both patients also presented with facial dysmorphism, including upslanting palpebral fissures, epicanthal folds, highly arched palate, microstomia, and retrognathia. This syndrome is transmitted as an X-linked trait.


A rare genetic multiple congenital anomalies/dysmorphic syndrome characterized by severe intrauterine growth retardation, profound microcephaly, dysmorphic craniofacial features (such as craniosynostosis and distinctive facial appearance with short palpebral fissures, broad and beaked nose, microstomia, micrognathia, low-set ears, and short neck), and variable malformations of the limbs, especially the arms. Cardiac, gastrointestinal, and genitourinary anomalies have also been reported. Brain imaging shows gray and white matter abnormalities and hypoplastic or absent corpus callosum. The disease is commonly fatal in the fetal to neonatal period due to respiratory failure.


Microcephaly-polymicrogyria-corpus callosum agenesis syndrome is a rare, genetic, central nervous system malformation syndrome characterized by marked prenatal-onset microcephaly, severe motor delay with hypotonia, bilateral polymicrogyria, corpus callosum agenesis, ventricular dilation, small cerebellum and early lethality.


Microcephaly-seizures-intellectual disability-heart disease syndrome

A rare, multiple congenital anomalies/dysmorphic syndrome characterized by microcephaly, intellectual disability, seizures, and congenital heart defects (e.g. atrial/ventricular septal defect, hypoplastic aortic arch with persistent ductus arteriosus). Additional manifestations include mild hypothyroidism, skeletal abnormalities, micropenis, delayed psychomotor development, dysmorphic facial features (including epicanthus, depressed nasal bridge, prominent antitragus), and pulmonary vascular occlusive disease. There have been no further descriptions in the literature since 1989.


Microcephaly-short stature-intellectual disability-facial dysmorphism syndrome is a rare genetic malformation syndrome with short stature characterized by postnatal microcephaly, failure to thrive and short stature, global developmental delay and intellectual disability, hypotonia, dysmorphic features (short nose, depressed nasal bridge, low set ears, short neck, clinodactyly and cutaneous syndactyly of T2-3 at birth and broad forehead, midface retrusion, epicanthal folds, laterally sparse eyebrows, short nose, long philtrum, widely spaced teeth, micrognathia and coarsening of facial features later in life). Other associated features include postnatal transient generalized edema, myopia, strabismus, hypothyroidism.


Microcephaly-short stature-limb abnormalities syndrome

A rare genetic multiple congenital anomalies syndrome characterized by severe microcephaly, intrauterine growth retardation, short stature and variable limb anomalies such as radial ray defects, short limbs, absent/hypoplastic patellae, syndactyly, brachydactyly and hypoplastic carpal or metacarpal bones. Craniofacial dysmorphism is characterized by long and broad nose, microstomia and micrognathia. Intellectual disability is mild when present. Cases with extremely severe phenotype with very short limbs and poor lung development are perinatally lethal.


Microcephaly-thin corpus callosum-intellectual disability syndrome

A rare, genetic, syndromic intellectual disability disease characterized by progressive postnatal microcephaly and global developmental delay, as well as moderate to profound intellectual disability, difficulty or inability to walk, pyramidal signs (including spasticity, hyperreflexia and extensor plantar response) and thin corpus callosum revealed by brain imaging. Ophthalmologic signs (including nystagmus, strabismus and abnormal retinal pigmentation), foot deformity and genital anomalies may also be associated.


Microcornea-glaucoma-absent frontal sinuses syndrome

A rare developmental defect during embryogenesis syndrome characterized by the association of microcornea, glaucoma and frontal sinus hypoplasia. Thick palmar skin and torus palatinus have also been reported. There have been no further descriptions in the literature since 1995.


Microcornea-myopic chorioretinal atrophy-telecanthus syndrome

A rare syndromic chorioretinal dystrophy characterized by childhood onset of mild to severe myopia with microcornea and chorioretinal atrophy, typically associated with telecanthus and posteriorly rotated ears. Other variable features include early-onset cataracts, ectopia lentis, ecotpia pupilae and retinal detachment.


Microcornea-posterior megalolenticonus-persistent fetal vasculature-coloboma syndrome

A rare developmental defect of the eye characterized by bilateral microcornea, posterior megalolenticonus, persistent fetal vasculature (extending from the posterior pole of the lens to the optic disc) and posterior chorioretinal coloboma.


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


A rare benign ovarian stromal tumor characterized by a stromal neoplasm with variable microcystic morphology, low mitotic activity, and diffuse nuclear beta-catenin and cyclin D1 immunoreactivity, while inhibin and calretinin are not expressed. Patients most commonly present with symptoms of a unilateral pelvic mass. Hormonal manifestations are usually absent. The tumor may be associated with familial adenomatous polyposis.


Microcytic anemia with liver iron overload

A congenital hypochromic microcytic anemia with progressive liver iron overload paradoxically associated with normal to moderately elevated serum ferritin levels has been described in three unrelated patients.

Summary:
Etiology
This syndrome is due to mutations in  DMT1 which codes for a transporter mediating the uptake of iron from the intestinal lumen in cytosol of duodenal enterocytes.
Management and treatment
Anemia poorly responds to oral iron treatment.

                            Last update:
                            October 2006


Familial and de novo recurrent Xp11.22-p11.23 microduplication has been recently identified in males and females.

Summary:
Epidemiology
To date, twelve patients have been described.
Clinical description
All patients show moderate to severe intellectual deficit and speech delay. Seizures, early puberty and lower-extremity anomalies, including pes planus or cavus, 5th toe hypoplasia, and syndactyly, are common. A peculiar electroencephalographic (EEG) pattern characterized by rolandic-like spikes and/or continuous spike wave during slow sleep (CSWS) exists in childhood.
Etiology
The microduplication was identified by microarray-based comparative genomic hybridization (aCGH). Most affected females show preferential activation of the duplicated X chromosome. Duplications are mediated by nonallelic homologous recombination (NAHR) or Alu-mediated recombination.

                            Last update:
                            February 2010

                            - Expert reviewer(s):
                            Dr Nicole MORICHON-DELVALLEZ


A benign form of holoprosencephaly characterized by midline defects without the typical HPE defect in brain cleavage and which can variably manifest with microcephaly, hypotelorism, midline cleft lip and/or flat nose, choanal stenosis, pyriform sinus stenosis, coloboma as well as a single median maxillary incisor.


Microgastria-limb reduction defect syndrome

A rare multiple congenital anomalies syndrome characterized by congenital microgastria and a uni- or bilateral limb reduction defect, that can include absent or hypoplastic thumbs, radius, ulna and/or amelia. Association with other variable abnormalities, including intestinal malrotation, asplenia, dysplastic kidneys, hypoplastic lungs, dysplastic corpus collosum, and abnormal genitalia, has been reported.


Micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome

A rare multiple congenital anomalies/dysmorphic syndrome with intellectual disability characterized by mild global developmental delay, intellectual disability or learning difficulties, behavioral problems (like autistic, hyperactive, or aggressive behavior), variable dysmorphic craniofacial features, and abnormalities of the fingers (brachydactyly, tapering fingers, prominent interphalangeal joints). Additional manifestations are highly variable and include recurrent infections and skeletal anomalies, among others.


Microlissencephaly-micromelia syndrome is a syndrome of abnormal cortical development, characterized by severe prenatal polyhydramnios, postnatal microcephaly, lissencephaly, upper limb micromelia, dysmorphic facies (coarse face, hypertrichosis, and short nose with long philtrum), intractable seizures, and early death. Hypoparathyroidism was noted in one case.


Microlissencephaly describes a heterogenous group of a rare cortical malformations characterized by lissencephaly in combination with severe congenital microcephaly, presenting with spasticity, severe developmental delay, and seizures and with survival varying from days to years.


Microphthalmia with brain and digit anomalies is characterised by anophthalmia or microphthalmia, retinal dystrophy, and/or myopia, associated in some cases with cerebral anomalies. It has been described in two families. Polydactyly may also be present. Linkage analysis allowed identification of mutations in the  BMP4 gene, which has already been shown to play a role in eye development.


A rare developmental disorder characterized by bilateral microphthalmia or anophthalmia, synostosis, syndactyly, oligodactyly and/or polydactyly.

Summary:
Epidemiology
The prevalence is unknown but more than 35 cases have been reported to date, mainly from consanguineous parents.
Clinical description
The disease presents at birth with unilateral, or more often, bilateral anophthalmia or microphthalmia and numerous limb anomalies (including synostosis, syndactyly, oligodactyly, polydactyly and long bone hypoplasia). Typically patients have clinical anophthalmia/severe microphthalmia with little/no vision. The most common limb anomalies are synostosis of the fourth and fifth metacarpals, a short 5th finger and only 4 toes bilaterally. Developmental milestones (such as responsive smile) are often delayed and most patients have moderate to severe intellectual deficiencies. Facial features can include flattened midface, sparse eyelashes, short palpebral fissures, high palate and cleft lip. Renal (horseshoe kidney), venous and vertebral anomalies have also been reported in rare cases. Early postnatal/perinatal death has occurred in several cases.
Etiology
The majority of cases are caused by mutations in the SPARC-related modular calcium binding protein 1 SMOC1 gene (14q24.1) which may be involved in the regulation of bone morphogenetic proteins. The existence of other causative genes is possible but they have not yet been discovered. The FNBP4 gene (11q12.1) was identified in a case with a phenotype similar to OAS but further studies are necessary to conclude if it is indeed causative of OAS.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical findings. Computed tomography (CT) scans and magnetic resonance imaging (MRI) can also be helpful in identifying the presence or absence of the globe, optic nerve and extra ocular muscles. Identifying a mutation in the SMOC1 gene confirms diagnosis.
Differential diagnosis
Differential diagnoses include isolated cryptophthalmia and other forms of syndromic microphthalmia such as microphthalmia, Lenz type, oculofaciocardiodental syndrome and anophthalmia/microphthalmia-esophageal atresia (see these terms).
Antenatal diagnosis
Prenatal testing via CVS or amniocentesis is possible if the causative mutation in a family has been identified. Ultrasound can also be utilized to identify the limb anomalies associated with OAS.
Genetic counseling
The disease is inherited autosomal recessively so genetic counseling is possible in affected families and can help in informing parents of the recurrence risk of OAS in subsequent pregnancies. If both parents are carriers there is a 25% risk with each pregnancy of having an affected child.
Management and treatment
There is no cure for OAS. Treatment for anophthalmia/microphthalmia may be discussed with an oculoplastic surgeon and ocularist. For anophthalmia, expansion of the eyelids, socket and orbital bones is recommended as soon as possible after birth and is done via conformer therapy by an ocularist or by oculoplastic surgery using hydrogel socket expanders followed by orbital implants or dermis-fat grafts. This can help patients with achieving a more typical appearance by preventing facial deformity. Those with some vision (if the microphthalmia is not severe) may benefit from visual aids. Some limb abnormalities may also be surgically corrected to help the patient gain mobility or function, therefore orthopedic evaluation is necessary. All individuals with OAS should receive evaluation by a vision teacher and special education may be necessary.
Prognosis
Little is known about the prognosis given the rarity but quality of life is usually affected due to intellectual disability, visual impairment and limb anomalies.

                            Last update:
                            December 2013

                            - Expert reviewer(s):
                             Tanya BARDAKJIAN  - Dr Adele SCHNEIDER


Microphthalmia with linear skin defects syndrome

A rare X-linked, syndromic eye disorder characterized by ocular defects (microphthalmia, orbital cysts, corneal opacities) and linear skin dysplasia of the neck, head, and chin. Additional findings may include agenesis of corpus callosum, sclerocornea, chorioretinal abnormalities, hydrocephalus, seizures, intellectual deficit, and nail dystrophy.


A rare X-linked inherited form of syndromic microphthalmia characterized by unilateral or bilateral microphthalmia (and/or clinical anophthalmia) with or without coloboma in addition to a range of extraocular manifestations such as microcephaly, malformed ears, dental abnormalities (i.e. irregular shape of incisors), skeletal anomalies (duplicated thumbs, syndactyly, clinodactyly, camptodactyly), urogenital anomalies (hypospadias, cryptorchidism, renal dysgenesis, hydroureter) and mild to severe intellectual disability. It is allelic to two disorders: oculofaciocardiodental syndrome and premature aging appearance-developmental delay-cardiac arrhythmia syndrome.


Microphthalmia-ankyloblepharon-intellectual disability syndrome is characterized by microphthalmia, ankyloblepharon and intellectual deficit. It has been described in seven male patients from two generations of a Northern Ireland family. The causative gene is localized to the Xq27-q28 region. The syndrome is transmitted as an X-linked recessive trait.