Microcephaly-Capillary Malformation Syndrome

Excerpt

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).

1. 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.

2. 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.