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Microcephaly-Capillary Malformation Syndrome

Synonym: MIC-CAP Syndrome

, MSc, MD, FRCPC, , MD, FAAP, FACMG, , BSc, and , PhD, MD, FRCPC, FCCMG.

Author Information

Initial Posting: .

Summary

Clinical characteristics.

The microcephaly-capillary malformation (MIC-CAP) syndrome is characterized by microcephaly, generalized cutaneous capillary malformations (ranging from a few to hundreds of oval/circular macules or patches varying in size from 1-2 mm to several cm), hypoplastic distal phalanges of the hands and/or feet, intractable epilepsy, and profound developmental delay.

Seizures, which can include focal, tonic, complex partial, and infantile spasms, seem to stabilize after the first two years of life. Myoclonus of the limbs and eyelids is common; other abnormal movements (dyskinetic, choreiform) may be seen. Minimal developmental progress is made after birth. To date the diagnosis has been confirmed in 12 affected individuals (including 2 sibs).

Diagnosis/testing.

MIC-CAP syndrome is suspected based on clinical and neuroimaging studies (simplified gyral pattern with increased extra-axial space and progressive cerebral atrophy). The diagnosis is confirmed by the presence of biallelic pathogenic variants in STAMBP, encoding STAM-binding protein (STAMBP). In the 11 families with a molecularly confirmed diagnosis identified to date, compound heterozygous pathogenic variants have been identified in nine, homozygous pathogenic variants resulting from parental consanguinity in one, and uniparental disomy (UPD) in one.

Management.

Treatment of manifestations: As for all children with profound developmental disability, infants and children with MIC-CAP syndrome require stimulation and recreation. Central hypotonia and peripheral hypertonia require care by physicians and therapists specializing in physical habilitation, including proper seating and bracing to maintain posture and prevent contractures. Seizures require management by an experienced pediatric neurology team; frequently multiple anticonvulsant medications are required for adequate seizure control. Standard care for other medical issues (e.g., enteral feeding team to optimize nutrition and weight gain).

Surveillance: Regular follow up with a child neurologist for seizure management and a complex care/palliative care team or experienced pediatrician to monitor for complications associated with severe neurologic impairment. Periodic reevaluation with a clinical geneticist for current information/recommendations for MIC-CAP syndrome

Agents/circumstances to avoid: Valproic acid may or may not be associated with adverse effects.

Genetic counseling.

MIC-CAP syndrome results from biallelic STAMBP pathogenic variants, most often from inheriting one pathogenic variant from each parent (autosomal recessive inheritance) and rarely from uniparental isodisomy. Risks to family members depend on the genetic mechanism.

  • Autosomal recessive inheritance: At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Uniparental disomy: The risk to sibs of a proband to be affected is unknown, but likely very low (<1%).

For both modes of inheritance, carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.

Diagnosis

No formal diagnostic criteria exist for the microcephaly-capillary malformation (MIC-CAP) syndrome. Because only 12 molecularly confirmed cases have been reported to date, the full range of phenotypic features is not yet completely understood.

MIC-CAP syndrome should be suspected in individuals with the following clinical and neuroimaging features:

  • Congenital microcephaly. Occipito-frontal head circumference (OFC) less than two standard deviations (SD) below the mean for sex, gestational age, and ethnicity at birth. OFC may be as small as 8 SD below the mean
  • Multiple generalized cutaneous capillary malformations present at birth and distributed over the scalp, torso, buttocks, limbs, and genitalia. The number ranges from a few to hundreds; size ranges from one to two millimeters to several centimeters. They are pink or red, blanchable, roughly oval or circular macules or patches.
  • Hypoplastic distal phalanges and nails of the hands and/or feet. Fingers (particularly 2, 3, and 4) may be tapered with hypoplastic nails. Toes (especially 3 and 4) may be hypoplastic with unusual implantation.
  • Neonatal onset of intractable epilepsy
  • Simplified gyral pattern with increased extra-axial space and progressive cerebral atrophy on brain imaging

MIC-CAP syndrome is confirmed in individuals with biallelic pathogenic variants in STAMBP. To date all individuals with clinical findings typical of MIC-CAP syndrome known to the authors have had biallelic pathogenic variants in STAMBP. In the 11 families with a molecularly confirmed diagnosis, compound heterozygous pathogenic variants have been identified in nine, homozygous pathogenic variants due to parental consanguinity in one, and uniparental disomy (UPD) in one [McDonell et al 2013; Author, unpublished data].

The two approaches to molecular genetic testing are:

  • Single-gene testing beginning with sequence analysis of STAMBP. Uniparental disomy testing of probands with one pathogenic variant detected may be clinically appropriate.
  • A multigene panel that includes STAMBP, if available. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Microcephaly-Capillary Malformation Syndrome

Gene 1Test MethodVariant Detection Frequency by Test Method 2
STAMBPSequence analysis 3See footnote 4
Uniparental disomy (UPD) 5
Deletion/duplication analysis 6None reported to date
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

The ability of the test method used to detect a variant that is present in the indicated gene

3.

Sequence analysis can detect variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

In 11 families with a molecularly confirmed diagnosis identified to date, ten had biallelic pathogenic variants and one had UPD.

5.

Various methods (e.g., SNP analysis, quantitative PCR, MLPA, massively-parallel sequencing) can detect UPD. Testing may require parental blood specimens.

6.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Clinical Characteristics

Clinical Description

The defining clinical characteristics of the microcephaly-capillary malformation (MIC-CAP) syndrome are typically present at birth. The most consistent clinical features reported to date are congenital microcephaly and congenital generalized cutaneous capillary malformations, early-onset intractable epilepsy, and profound developmental delay [Carter et al 2011, Isidor et al 2011, Mirzaa et al 2011, McDonell et al 2013]. Given the small number of affected individuals reported to date (12 individuals from 11 families), the natural history is not yet completely understood.

Microcephaly. Microcephaly is typically present at birth; head growth decelerates during the first several months of life. Occipito-frontal head circumference (OFC) as small as 8 SD below the mean has been reported.

Generalized cutaneous capillary malformations. Growth of capillary malformations (which are present at birth) is commensurate with growth of the rest of the body. They may fade somewhat with age.

Histologic examination shows dilated small-caliber vessels in the papillary dermis, consistent with capillary malformations [Carter et al 2011, Mirzaa et al 2012].

Seizures. Onset may be in utero to the early neonatal period. Seizures are usually observed on the first day of life. Seizures are frequent (dozens to hundreds per day) in the first two years of life and have occurred in all reported individuals.

Multiple seizure types including focal, tonic, complex partial, and infantile spasms are possible. Electroencephalogram (EEG) shows diffuse epileptiform activity with frequent multifocal spikes, abnormally slow background activity, and/or burst suppression pattern.

Seizures have been intractable to anticonvulsant therapy and ketogenic diet in most individuals. After the first two years of life, the seizures seem to stabilize to some degree and fewer medications may be required to keep seizures under reasonable control.

Profound neurologic impairment. Minimal developmental progress is made after birth. Most individuals do not attain head control or independent sitting due to spastic quadriparesis with severe central hypotonia. Cognitive development is poor, likely due to the underlying brain abnormality and intractable epilepsy.

Individuals are not visually responsive and those tested have cortical visual impairment.

Most have normal hearing by brain stem auditory evoked potential testing and respond to voice and music.

The majority of individuals require gastrostomy tube feeding because of poor swallowing mechanism, poor control of oral secretions, and/or aspiration with recurrent pneumonia (11/12). A few have required tracheostomy for recurrent apnea and/or to manage secretions (3/12).

One individual with molecularly proven MIC-CAP syndrome has only moderate developmental delays (see Genotype-Phenotype Correlations).

Distal limb anomalies. Hands and feet may have hypoplastic or absent distal phalanges and nails; fingers (particularly 2, 3, and 4) may be tapered and toes may have unusual implantation. Dorsa of the hands and feet may have non-pitting edema. Hands may have single or unusual palmar creases and fifth finger clinodactyly.

Other findings can include: cutaneous syndactyly, sandal gap, and deep-set and/or small, narrow nails.

Facial dysmorphism. Features include sloping forehead, low anterior hairline, round face, hypertelorism, epicanthus, long palpebral fissures, ptosis, short nose with upturned tip, low-set and posteriorly rotated ears with fleshy lobules, high arched palate, downturned corners of mouth, and micrognathia.

Some may have an abnormal hair pattern in a "Mohawk" distribution (sparse laterally and longer along sagittal suture), and/or abnormal or multiple hair whorls.

Myoclonus of limbs and eyelids is frequently reported (7/10 reported individuals) and tends to persist with age.

Other abnormal movements may be seen (dyskinetic, choreiform).

Other features may include:

  • Large anterior fontanelle at birth
  • Small size for gestational age (birth weight and length 2-4 SD below mean) (5/10 individuals)
  • Postnatal growth deficiency and short stature (5/10 individuals)
  • Optic atrophy, roving eye movements, exotropia
  • Sensorineural hearing impairment (1 individual)
  • Cerebellar angiomata (1 individual)
  • Cleft palate (1 individual)
  • Facial asymmetry due to bony deficiency of maxilla (1 individual)
  • Adrenal insufficiency (1 individual)
  • Hypoplastic scrotum and small testes
  • Kidney malformations (duplicated collecting system in 1 individual; unilateral dysplastic kidney in 1 individual) and vesicoureteral reflux
  • Structural cardiac defects such as ASD, VSD, PDA, PFO, mild right ventricular hypertrophy (each reported in 1 individual)
  • Umbilical or inguinal hernia (2 sibs)

Life span is unknown, but shortened due to severe neurologic impairments. The oldest living individual known is nine years old at last assessment. At least three children have died in infancy. The cause of death in one 12-month-old male was thought to be septic shock following acute pancreatitis, possibly secondary to valproate therapy [Carter et al 2011].

Brain imaging typically shows obvious microcephaly with a simplified gyral pattern (reduced number of gyri and shallow sulci) and mild to moderately enlarged extra-axial spaces. This pattern is severe and diffuse (rather than predominantly frontal as in primary autosomal recessive microcephaly).

Progressive cortical atrophy with relative sparing of the cerebellum has been noted as early as the second year of life in some individuals.

Cortical myelination may be reduced or abnormal.

Other common neuroimaging findings include hippocampal hypoplasia, thinning of the corpus callosum, and hypoplasia of the optic nerves and/or optic chiasm.

Neuropathology. In one individual who died at age 12 months, brain autopsy showed a very small brain (weight approximately equivalent to a newborn brain) with disproportionately small cerebral hemispheres compared to the cerebellum, diffuse cortical atrophy, thin corpus callosum, and white matter loss in the centrum semiovale and hippocampi. The descending pathways were hypoplastic with small cerebral peduncles and pyramids. There was widespread gliosis of optic nerves and tracts, lateral geniculate nuclei, visual cortex, and subcortical white matter [Carter et al 2011].

Genotype-Phenotype Correlations

One affected individual had a milder phenotype with moderate developmental delay and a less severe form of epilepsy [Isidor et al 2011]. At birth her head circumference was within the normal range (-1.8 SD); at her last evaluation at age five years, head circumference was -2.5 SD. She is able to walk independently and can speak in short phrases. She has approximately 30 capillary malformations of the skin and characteristic hypoplastic fingers and toes. Sequencing of STAMBP showed a homozygous noncoding intronic pathogenic variant (c.1005+358A>G) which activated a cryptic splice site leading to leaky splicing of the full-length transcript. She had a three-fold reduction in STAMBP transcript expression; STAMBP protein expression was markedly reduced but not absent [McDonell et al 2013].

Thus, the effect of pathogenic variant(s) on STAMBP likely influences the severity of clinical presentation, with complete absence of protein production leading to the most severe phenotypes.

Prevalence

Prevalence is unknown. To date 12 affected individuals (including 2 sibs) from 11 families worldwide have had the diagnosis confirmed by molecular genetic testing.

Most reported individuals are of European descent; the two reported sibs are African American, and one individual is of Polynesian descent.

Differential Diagnosis

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) caused by mutation in RASA1. RASA1-related disorders are characterized by the presence of multiple, small (1-2 cm in diameter) capillary malformations mostly localized on the face and limbs. About 30% of affected individuals also have associated arteriovenous malformations (AVMs) and/or arterio-venous fistulas (AFVs), fast-flow vascular anomalies that typically arise in the skin, muscle, bone, spine, and brain; life-threatening complications of these lesions can include bleeding, congestive heart failure, and/or neurologic consequences.

Unlike MIC-CAP syndrome, individuals with a RASA-1 pathogenic variant are not microcephalic and do not have intractable epilepsy or neurologic impairment.

Inheritance is autosomal dominant.

Primary autosomal recessive microcephaly is characterized by congenital microcephaly with simplified gyral pattern but without other major brain or somatic malformations. The classic form is characterized by occipito-frontal head circumference (OFC) less than 2 SD below the mean for sex, age, and ethnicity at birth and at least -3 SD after age six months; mild to severe cognitive impairment without major motor delay; absence of neurologic signs except mild seizures or hyperkinesia; normal facies except for a narrow, sloping forehead that often accompanies reduced cranial size; absence of malformations in other organ systems; and normal growth except for mildly short stature (up to -3 SD below the mean). Biallelic pathogenic variants in several genes have been identified as causes of primary microcephaly, the most common of which is ASPM.

MIC-CAP syndrome is distinguished from primary autosomal recessive microcephaly by the presence of capillary malformations, intractable epilepsy, severe neurologic impairment, and distal limb anomalies.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with microcephaly-capillary malformation (MIC-CAP) syndrome, the following evaluations are recommended:

  • Developmental assessment to determine the types of services and therapies needed (e.g., physiotherapy, occupational therapy, communication assistance)
  • Pediatric neurology evaluation
  • Ophthalmology evaluation to assess for functional vision, strabismus, refractive errors, and optic atrophy
  • Swallowing/feeding evaluation to assess for dysphagia and aspiration and determine need for enteral feeding
  • Baseline audiology evaluation
  • Baseline echocardiogram and abdominal ultrasound examination
  • Pediatric palliative care consultation and psychosocial support for family
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Development. As for all children with profound developmental disability, infants and children with MIC-CAP syndrome require stimulation and recreation. Given that most have poor vision, regular tactile and auditory stimulation are recommended.

Physical habilitation. Central hypotonia and peripheral hypertonia require care by physicians and therapists specializing in physical habilitation. If the child is non-ambulatory, proper seating and bracing is required to maintain posture and prevent contractures.

Neurologic. Seizure management during infancy requires an experienced pediatric neurology team to manage medically refractory epilepsy. Multiple anticonvulsant medications are frequently required for adequate seizure control. A few individuals have responded favorably to ketogenic diet or corticosteroids.

Other. Standard care for other medical issues (e.g., enteral feeding team to optimize nutrition and weight gain)

Surveillance

Appropriate surveillance includes the following:

  • Regular follow up with a child neurologist for seizure management
  • Regular follow up with a complex care/palliative care team or experienced pediatrician to monitor for complications associated with severe neurologic impairment (e.g., aspiration, constipation, contractures, pressure sores)
  • Periodic reevaluation with a clinical geneticist to review the most current information and recommendations for individuals with MIC-CAP syndrome

Agents/Circumstances to Avoid

Valproic acid. One individual with MIC-CAP syndrome died from complications of pancreatitis after starting valproic acid for seizures [Carter et al 2011]. However, several other individuals with MIC-CAP syndrome have been treated with valproic acid without adverse effects. Therefore, it is unclear whether or not an association exists between MIC-CAP syndrome and adverse outcomes with valproic acid therapy. The benefits of use of valproic acid for seizure management in some patients may outweigh the potential risk for serious complications.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Microcephaly-capillary malformation (MIC-CAP) syndrome results from the presence of biallelic STAMBP pathogenic variants, most often one inherited from each parent (autosomal recessive inheritance); rarely, two copies of a STAMBP pathogenic variant result from uniparental isodisomy.

Risks to family members depend on the genetic mechanism.

Risk to Family Members – Autosomal Recessive

Parents of a proband

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Risk to Family Members – Uniparental Isodisomy

Parents of a proband. One parent is heterozygous for the pathogenic variant present in the homozygous state in the proband.

Sibs of a proband

  • The risk to each sib of a proband of being affected is unknown, but likely very low (<1%).
  • The risk to each sib of a proband of being a carrier is 50%.

Risks Independent of Genetic Mechanism

Offspring of a proband. No individuals with MIC-CAP syndrome have reproduced.

Other family members. Each sib of a confirmed carrier is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the STAMBP pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MIC-CAP are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for Microcephaly-Capillary Malformation Syndrome have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Microcephaly-Capillary Malformation Syndrome: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
STAMBP2p13​.1STAM-binding proteinSTAMBPSTAMBP

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Microcephaly-Capillary Malformation Syndrome (View All in OMIM)

606247STAM-BINDING PROTEIN; STAMBP
614261MICROCEPHALY-CAPILLARY MALFORMATION SYNDROME; MICCAP

Molecular Genetic Pathogenesis

Gene structure. STAMBP spans 38 kb. Three STAMBP transcripts have been identified; they comprise ten (NM_213622.2; NM_201647.2) or eleven exons (NM_006463.4) and all encode the same protein isoform of 424 amino acids. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic variants identified to date have been missense, nonsense, or small nucleotide deletions. Intronic pathogenic variants resulting in splice site variants have also been noted. (At least 1 intronic pathogenic variant was identified in 3 families.) Several of these pathogenic variants lead to the generation of out-of-frame transcripts and premature termination codons.

Identified pathogenic variants have mostly been unique to each family; however recurrent pathogenic variants have been noted (p.Arg424Ter [c.1270C>T], p.Phe100Tyr [c.299T>A], and p.Arg38Cys [c.112C>T]), suggestive of mutational hot spots (NP_006454.1 and NM_006463.4; Table 2 and Table 3 [pdf]).

In the 11 families with a molecularly confirmed diagnosis identified to date, compound heterozygous pathogenic variants have been identified in nine, homozygous pathogenic variants due to parental consanguinity in one, and uniparental disomy (UPD) in one [McDonell et al 2013; Author, unpublished data].

Table 2.

STAMBP Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequence
c.112C>Tp.Arg38CysNM_006463​.4
c.299T>Ap.Phe100Tyr
c.1270C>Tp.Arg424Ter
c.1005+358A>GN/A

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. STAMBP encodes a 424-amino acid JAMM-family de-ubiquinating enzyme containing a microtubule-interacting and transport domain [Tsang et al 2006, Sierra et al 2010], SH3 binding motif [Kato et al 2000], JAMM (JAB1/MPN/MOV34) motif [McCullough et al 2006], nuclear localization signal [Tanaka et al 1999], and a distal ubiquitin recognition site [Davies et al 2011].

STAMBP is recruited to the endosomal sorting complexes required for transport (ESCRTs), a group of distinct macromolecule assemblies that mediate the sorting and trafficking of ubiquitinated proteins from endosomes to lysosomes [Tanaka et al 1999, Agromayor & Martin-Serrano 2006, McCullough et al 2006, Kyuuma et al 2007]. Thus, STAMBP has a role in the active regulation of receptor-mediated signaling enabling protein homeostasis and processes such as autophagy.

Abnormal gene product. Pathogenic variants in individuals with MIC-CAP syndrome have been associated with either reduced or absent STAMBP protein [McDonell et al 2013].

Investigations to date suggest that ubiquitin-conjugated protein aggregation may play a role in inducing progressive apoptosis in persons with MIC-CAP syndrome [McDonell et al 2013].

Investigation of the RAS-MAPK and PI3K-AKT-mTOR signal transduction pathways in cell lines from individuals with MIC-CAP syndrome showed activated and insensitive signaling that may contribute to the characteristic vasculature seen in affected individuals [McDonell et al 2013].

Stambp-deficient mice are indistinguishable from wild-type mice at birth. They exhibit postnatal growth retardation and brain atrophy, and die between postnatal days 19 and 23. Histopathologic analysis of brain sections detected a significant loss of neurons and apoptotic cells in the CA1 subfield of the hippocampus. Brain atrophy was accompanied by complete loss of the CA1 neurons in the hippocampus and marked atrophy of the cerebral cortex [Ishii et al 2001].

References

Literature Cited

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  • Carter MT, Geraghty MT, De La Cruz L, Reichard RR, Boccuto L, Schwartz CE, Clericuzio CL. A new syndrome with multiple capillary malformations, intractable seizures, and brain and limb anomalies. Am J Med Genet. 2011;155A:301–6. [PubMed: 21271646]
  • Davies CW, Paul LN, Kim M, Das C. Structural and thermodynamic comparison of the catalytic domain of AMSH and AMSH-LP: Nearly identical fold but different stability. J Mol Biol. 2011;413:416–29. [PMC free article: PMC3321355] [PubMed: 21888914]
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  • Kato M, Miyazawa K, Kitamura N. A deubiquitinating enzyme UBPY interacts with the Src homology 3 domain of Hrs-binding protein via a novel binding motif PX(V/I)(D/N)RXXKP. J Biol Chem. 2000;275:37481–7. [PubMed: 10982817]
  • Kyuuma M, Kikuchi K, Kojima K, Sugawara Y, Sato M, Mano N, Goto J, Takeshita T, Yamamoto A, Sugamura K, Tanaka N. AMSH, an ESCRT-III associated enzyme, deubiquitinates cargo on MVB/late endosomes. Cell Struct Funct. 2007;31:159–72. [PubMed: 17159328]
  • McCullough J, Row PE, Lorenzo O, Doherty M, Beynon R, Clague MJ, Urbé S. Activation of the endosome-associated ubiquitin isopeptidase AMSH by STAM, a component of the multivesicular body-sorting machinery. Curr Biol. 2006;16:160–5. [PubMed: 16431367]
  • McDonell LM, Mirzaa GM, Alcantara D, Schwartzentruber J, Carter MT, Lee LJ, Clericuzio CL, Graham JM Jr, Morris-Rosendahl DJ, Polster T, Acsadi G, Townshend S, Williams S, Halbert A, Isidor B, David A, Smyser CD, Paciorkowski AR, Willing M, Woulfe J, Das S, Beaulieu CL, Marcadier J., FORGE Canada Consortium. Geraghty MT, Frey BJ, Majewski J, Bulman DE, Dobyns WB, O'Driscoll M, Boycott KM. Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome. Nature Genet. 2013;45:556–62. [PMC free article: PMC4000253] [PubMed: 23542699]
  • Mirzaa GM, Conway RL, Gripp KW, Lerman-Sagie T, Siegel DH, deVries LS, Lev D, Kramer N, Hopkins E, Graham JM Jr, Dobyns WB. Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am J Med Genet A. 2012 Feb;158A:269–91. [PubMed: 22228622]
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  • Tsang HTH, Connell JW, Brown SE, Thompson A, Reid E, Sanderson CM. A systematic analysis of human CHMP protein interactions: Additional MIT domain-containing proteins bind to multiple components of the human ESCRT III complex. Genomics. 2006;88:333–46. [PubMed: 16730941]

Chapter Notes

Author Notes

Dr Melissa Carter continues to collect clinical information about MIC-CAP syndrome. Through Dr. Carter, families affected by MIC-CAP syndrome may connect with some of the families who made this research possible. Contact melissa.carter@sickkids.ca.

Dr Ghayda Mirzaa studies the developmental basis of developmental brain disorders, with a particular focus on disorders of abnormal brain size, at Seattle Children’s Research Institute.

Dr Kym Boycott’s research is focused on elucidating the molecular pathogenesis of rare inherited diseases using next-generation sequencing approaches. She leads two nation-wide collaborative Canadian initiatives studying more than 500 rare disorders. For further information please visit: www.care4rare.ca.

Acknowledgments

We thank the patients, their families, and our collaborators for their valuable contribution to research regarding this syndrome.

Revision History

  • 12 December 2013 (me) Review posted live
  • 17 July 2013 (mtc) Original submission
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Bookshelf ID: NBK174452PMID: 24354023

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Tests in GTR by Gene

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