Microcephaly-Capillary Malformation-Syndrome

Extremely rare, sporadically occurring microcephalic capillary malformation syndrome (MIC-CAP), the symptoms of which are typically already present at birth. In addition to microcephaly, isolated or multiple disseminated, patchy cutaneous capillary malformations are found on the skin.

So far, the diagnosis has been confirmed in 18 people from 15 families.

Mutation in the STAMBP gene (The STAMBP gene codes for a zinc metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains (McCullough J et al. 2004). The zinc protease plays a role in signal transduction for cell growth and MYC induction mediated by IL-2 and GM-CSF (Tanaka N et al. 1999). Enhances BMP (bone morphogenetic protein) signaling by antagonizing the inhibitory effect of SMAD6 and SMAD7 (Itoh F et al. 2001). The enzyme is involved in the negative regulation of the PI3K-AKT-mTOR and RAS-MAP signaling pathways (Itoh F et al. (2001).

The skin findings are variable and range from a few red homogeneous patches (see Fig.) to numerous, disseminated patches ranging in size from 1-2 cm to several cm. Skin ulcerations or phlebectasias are absent. The name Carter-Mirza patches has been proposed for these bright red patches, which are rather elongated in shape and lack an anemic halo.

Hypoplastic distal phalanges of the hands and/or feet are also found.

Neurology: Early onset intractable epilepsy and profound developmental delay. The seizures, which may be focal, tonic and complex partial seizures and may include infantile spasms, appear to stabilize after the second year of life.

Myoclonus of the limbs and eyelids is common; other abnormal movements (dyskinetic, choreiform) may be observed.

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

Genetic counseling: MIC-CAP syndrome is an autosomal recessive disorder caused by biallelic STAMBP pathogenic variants. Usually one pathogenic variant is inherited from each parent; however, in some cases both pathogenic variants are inherited from one parent (uniparental isodisomy). If both parents are known to be heterozygous for a pathogenic STAMBP variant, each sibling of an affected individual at conception has a 25 percent chance of being affected, a 50 percent chance of being an asymptomatic carrier, and a 25 percent chance of being unaffected and not a carrier.

Treatment of manifestations: Supportive care by multidisciplinary specialists is recommended, including a medical geneticist, neurologist, developmental pediatrician and nutritionist. For central hypotonia and peripheral hypertension, care should be taken to ensure correct sitting posture and support to maintain posture and avoid contractures. Seizures require treatment by an experienced pediatric neurology team, as multiple anticonvulsant medications are often required for adequate seizure control. A feeding tube is essential to optimize nutrition and weight gain while reducing the risk of aspiration.

Defects of the brain and heart lead to the early death of children.

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

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