Clinical characteristics.

The defining clinical characteristics of the microcephaly-capillary malformation (MIC-CAP) syndrome are typically present at birth: microcephaly and generalized cutaneous capillary malformations (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, early-onset intractable epilepsy, and profound developmental delay. Seizures, which can be focal, tonic, and complex partial and can include infantile spasms, appear to stabilize after age two years. Myoclonus of the limbs and eyelids is common; other abnormal movements (dyskinetic, choreiform) may be seen. To date, the diagnosis has been confirmed in 18 individuals from 15 families.

Diagnosis/testing.

The diagnosis of MIC-CAP syndrome is established in a proband with suggestive findings and biallelic pathogenic variants in STAMBP identified by molecular genetic testing.

Management.

Treatment of manifestations: Supportive care by multidisciplinary specialists including a medical geneticist, neurologist, developmental pediatrician, and feeding specialist is recommended. Central hypotonia and peripheral hypertonia require attention to proper seating and bracing to maintain posture and prevent contractures. Seizures require management by an experienced pediatric neurology team, as multiple anticonvulsant medications are frequently required for adequate seizure control. A feeding tube is essential to optimize nutrition and weight gain while reducing the risk of aspiration.

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.

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

Genetic counseling.

MIC-CAP syndrome is an autosomal recessive disorder caused by biallelic STAMBP pathogenic variants. Typically, one pathogenic variant is inherited from each parent; however, in some instances both pathogenic variants are inherited from one parent (uniparental isodisomy).

• If both parents are known to be heterozygous for a STAMBP pathogenic variant, each sib of an affected individual has at conception 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.
• If the proband has MIC-CAP syndrome as the result of uniparental isodisomy, only one parent is heterozygous for a STAMBP pathogenic variant, and if neither parent has a chromosome rearrangement, each sib of an affected individual has at conception a 50% chance of being an asymptomatic carrier and an approximately 50% chance of being unaffected and not a carrier. The risk to sibs of a proband of being affected is unknown but is presumed to be less than 1%.

Once the STAMBP pathogenic variants have been identified in an affected family member (or – if the proband has MIC-CAP as the result of uniparental isodisomy – identification of the one familial STAMBP pathogenic variant), carrier testing for at-risk family members, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

MIC-CAP syndrome should be suspected in individuals with the following clinical and neuroimaging findings and family history.

Clinical findings

• Congenital microcephaly. Occipitofrontal head circumference at birth is more than two standard deviations (SD) below the mean for sex, gestational age, and ethnicity, and may be as small as −8 SD.
• Multiple generalized cutaneous capillary malformations (pink or red, blanchable, roughly oval or circular macules or patches) 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 [McDonell et al 2013] (full text; see Figure 1).
• Neonatal-onset intractable epilepsy
• 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. 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 [McDonell et al 2013] (full text; see Figure 1).
• Facial dysmorphism includes 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 [McDonell et al 2013].
• 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.

Imaging findings

• Simplified gyral pattern (reduced number of gyri and shallow sulci) with increased extra-axial space and progressive cerebral atrophy is seen on brain imaging.
• Cortical myelination may be reduced or abnormal.
• Other common neuroimaging findings include hippocampal hypoplasia, thinning of the corpus callosum, hypoplasia of the optic nerves and/or optic chiasm and other malformations of cortical development.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of MIC-CAP syndrome is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in STAMBP identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic STAMBP variants of uncertain significance (or identification of one known STAMBP pathogenic variant and one STAMBP variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with microcephaly and/or seizures may be more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The defining clinical characteristics of the microcephaly-capillary malformation (MIC-CAP) syndrome are typically present at birth: microcephaly and 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 (18 individuals from 15 families), the natural history is not yet completely understood.

Microcephaly is present at birth in most cases, with occipitofrontal head circumference ranging from 0 to 8 SD below the mean. Head growth generally decelerates during the first several months of life.

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 or appear within the first days to months after birth. Seizures are most often 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 described include focal, tonic, and complex partial, as well as infantile spasms. Electroencephalogram shows diffuse epileptiform activity with frequent multifocal spikes, abnormally slow background activity, and/or burst suppression pattern.

In most individuals, seizures are refractory to anticonvulsant therapy and ketogenic diet. After age two years, the seizures may stabilize to some degree and fewer medications may be required to keep seizures under reasonable control.

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

Individuals are often not visually responsive; those tested have cortical visual impairment and/or optic atrophy.

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

The majority require gastrostomy tube feeding because of poor swallowing mechanism, poor control of oral secretions, and/or aspiration with recurrent pneumonia. A few (3/18) have required tracheostomy for recurrent apnea and/or to manage secretions.

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

Abnormal movements

• Myoclonus of limbs and eyelids is common (8/18 reported individuals) and tends to persist with age.
• Dyskinetic and choreiform movements may also be seen in some individuals.

Vision impairment

• Optic atrophy (10/18 reported individuals)
• Cortical vision impairment, roving eye movements, and nystagmus (reported in a few individuals)

Other features

• Large anterior fontanelle at birth
• Small size for gestational age (birth weight and length 2-4 SD below mean)
• Postnatal growth deficiency and short stature
• 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 (1 individual)
• 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, and mild right ventricular hypertrophy (each reported in 1 individual)
• Umbilical or inguinal hernia (2 sibs)

Life span is unknown but shortened because of severe neurologic impairments. The oldest living individual known was 12 years old at last assessment. At least three children have died in infancy. The cause of death in one male age 12 months was thought to be septic shock following acute pancreatitis, possibly secondary to valproate therapy [Carter et al 2011]. The cause of death in others has not been reported.

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

The effect of pathogenic variant(s) on the protein STAMBP likely influences the severity of the MIC-CAP syndrome phenotype, with complete absence of protein production leading to the most severe phenotypes.

One affected female 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. She has a homozygous noncoding intronic pathogenic variant (c.1005+358A>G) that activated a cryptic splice site leading to leaky splicing of the full-length transcript. She had a threefold reduction in STAMBP transcript expression; STAMBP protein expression was markedly reduced but not absent [McDonell et al 2013].

Prevalence

Prevalence is unknown. To date 18 affected individuals (including 3 sets of sibs) from 15 families worldwide have molecularly confirmed MIC-CAP syndrome.

Most reported individuals are of European descent; individuals from other ethnic backgrounds (African, Arab, Asian, and Polynesian) have also been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with microcephaly-capillary malformation (MIC-CAP) syndrome, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care provided by multidisciplinary specialists including a medical geneticist, neurologist, feeding team, and developmental pediatrician is recommended.

Surveillance

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 EU Clinical Trials Register 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.

Mode of Inheritance

Microcephaly-capillary malformation (MIC-CAP) syndrome is an autosomal recessive disorder caused by biallelic STAMBP pathogenic variants. Typically, the proband has inherited one STAMBP pathogenic variant from each parent. Alternatively, the proband has MIC-CAP syndrome as the result of uniparental isodisomy for chromosome 2 (i.e., 2 copies of chromosome 2, with the STAMBP pathogenic variant inherited from 1 parent and no copy of chromosome 2 inherited from the other parent).

Risk to Family Members

Parents of a proband

• In most families, both parents of an affected child are carriers (i.e., heterozygotes) for a STAMBP pathogenic variant.
• Less commonly, only one parent is heterozygous for a STAMBP pathogenic variant and the child has MIC-CAP syndrome as the result of uniparental isodisomy and consequent homozygosity for the STAMBP pathogenic variant from the carrier parent [McDonell et al 2013].
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if both are heterozygous for a STAMBP pathogenic variant. If carrier testing detects the pathogenic variant in only one parent:
  • And the child appears to have homozygous STAMBP pathogenic variants, possible explanations include a large deletion on one allele (if not previously tested for) and uniparental isodisomy for chromosome 2 [McDonell et al 2013];
  • And the child has compound heterozygous STAMBP pathogenic variants, the child may theoretically have one inherited pathogenic variant and one de novo pathogenic variant (de novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017]).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a STAMBP pathogenic variant, each sib of an affected individual has at conception 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.
• If the proband has MIC-CAP syndrome as the result of uniparental isodisomy, only one parent is heterozygous for a STAMBP pathogenic variant, and neither parent has a chromosome rearrangement, each sib of an affected individual has at conception a 50% chance of being an asymptomatic carrier and an approximately 50% chance of being unaffected and not a carrier; the risk to sibs of a proband of being affected is unknown but is presumed to be less than 1%.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with MIC-CAP syndrome are not known to reproduce.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is heterozygous for a STAMBP pathogenic variant, the parent's family members are at risk of being carriers.

Carrier Detection

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

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

STAMBP encodes the deubiquitinating isopeptidase STAM-binding protein (STAMBP). It belongs to the JAMM (JAB1/MPN/MOV34) family of deubiquitinating enzymes that regulate ubiquitin signaling through polymeric ubiquitin chain disassembly and through target-protein ubiquitin removal. STAMBP also interacts with GRB2, a component of the interconnected RAS-MAPK and PI3K-AKT-mTOR transduction pathways [Tanaka et al 1999, McCullough et al 2006, Tsang et al 2006, Sierra et al 2010, Davies et al 2011].

Observations of patient-derived cell lines suggest that ubiquitin-conjugated protein aggregation and ensuing progressive apoptosis as a potential mechanism for microcephaly. In addition, interrogation of several endpoints in the RAS-MAPK and PI3K-AKT-mTOR pathways has shown elevated and insensitive signal transduction in patient-derived cell lines. The constitutive activation of these two interconnected pathways as a result of impaired STAMBP function is believed to play a role in the vascular malformations and developmental characteristics typical of MIC-CAP syndrome [McDonell et al 2013].

Mechanism of disease causation. To the authors' knowledge, all patient-derived cell lines with STAMBP pathogenic variants have demonstrated either reduced or absent STAMBP expression compared to wild type controls [McDonell et al 2013].

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. Email: [email protected].

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 nationwide collaborative Canadian initiatives studying more than 1,000 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

• 18 March 2021 (bp) Comprehensive update posted live
• 12 December 2013 (me) Review posted live
• 17 July 2013 (mtc) Original submission

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