Contributed equally
To the best of our knowledge, the present study reported the case of the first Chinese patient with microcephaly-capillary malformation (MIC-CAP) syndrome caused by a novel compound heterozygous mutation in the STAMBP gene, which encodes STAM binding protein. The present study also provides a review of relevant previously published studies. A boy with MIC-CAP syndrome with developmental delay, intractable epilepsy and prominent dyskinesia was examined. A pathogenic mutation was identified by whole-exome sequencing, and the protein structure and function affected by this mutation were predicted using bioinformatics analysis. Finally, the clinical features of 16 other cases reported in previous studies were reviewed and compared. A novel compound heterozygous mutation of the
Mutations in the STAM binding protein (STAMBP) gene cause microcephaly-capillary malformation (MIC-CAP) syndrome (OMIM, 614261; ORPHA, 294016), which was described as a novel syndrome several years ago (
To the best of our knowledge, the present study reported the case of the first Chinese patient with MIC-CAP syndrome caused by a novel compound heterozygous
Ethical approval for the present study was obtained from the Institutional Review Board, Children's Hospital of Chongqing Medical University (permit no. 2018-64). Informed consent was obtained from the parents of the patient.
The case described in the present study is that of a boy born after 40 weeks and 5 days of gestation, G2P1 (second pregnancy and first successful birth of the mother), to nonconsanguineous Chinese parents (father, 23 years old; mother, 22 years old). The boy was born through normal delivery, with a birth weight of 3,600 g. The birth length and head circumference were not known.
The patient was admitted (June 2018) to the Department of Neurology, Children's Hospital of Chongqing Medical University at the age of 1 year and 5 months. A routine examination of general health and neurological evaluations were carried out. Magnetic resonance imaging (MRI), electroencephalography and metabolic screening were performed according to the manufacturer's protocols. All the available clinical characteristics of the patient along with the aforementioned auxiliary examination results are summarized in the present study.
Peripheral blood samples (5 ml) from the proband and the parents were collected into graded negative pressure vacuum EDTA anticoagulant tubes. All sample preparation, whole-exome sequencing and Sanger sequencing were performed by Beijing Mygenostics Co, Ltd. Several online databases containing data from different ethnic groups were used as following; dbSNP (
The prediction of mutations was assessed using software, including PolyPhen_2_Predict, PolyPhen_2 (
The PubMed (
The child developed early-onset epilepsy after 3 months, with a generalized tonic-clonic seizure, which progressed to clusters of infantile spasms (2–10 clusters/day) 1 month later. The patient was treated successively with levetiracetam (40–50 mg/kg/day), topiramate (6–7 mg/kg/day), valproic acid (30 mg/kg/day) and corticosteroids at the outpatient clinic. The spasms decreased and became myoclonic, but the epilepsy remained refractory.
The patient was admitted to the neurologic ward after 1 year and 2 months. The patient had drooping mouth corners, a short nose and neck, and sporadic, multiple, small capillary malformations (
The patient was on a ketogenic diet during the inpatient stay and received immunoglobulin intravenously as a result of recurrent pneumonia, 22 days later, he was discharged. During the follow-up, the seizures were still not well controlled, although the ketogenic diet ratio was modified from 2:1 to 4:1 (4 g fat/l g combined protein, carbohydrate). After 1 month, the patient received vigabatrin (60 mg/kg/day) and the seizures reduced by 80% a week later. Unfortunately, the patient suddenly succumbed 3 weeks later; no definitive causes were found as no autopsy was performed.
The MRI scans showed slightly dilated lateral ventricles and increased extra-axial spaces. Interictal electroencephalography showed hypsarrhythmia and slow wave background with bioccipital spike-slow wave during waking (
Exome sequencing revealed intronic (c.1119-1G>T) and exonic mutations in the proband and their parents, which was confirmed via Sanger sequencing (
The clinical features and pathogenic variants of 16 previously reported cases of MIC-CAP are summarized in
So far as we know, the present study presented the first case of a Chinese patient affected by refractory epilepsy, microcephaly, severe developmental delay and diffuse cutaneous capillary malformations. These four symptoms were also observed in all of the patients studied in previous reports (100%) (
A novel compound heterozygous co-segregating mutation in
To date, only 16 cases (11 male and 5 female) from 13 families in 8 ethnic groups have been reported, with 18 different
In conclusion, to the best of our knowledge, the present study reported the first case of a Chinese patient with refractory epilepsy as an initial symptom of MIC-CAP. Additionally, novel pathogenic compound heterozygosity of the
Not applicable.
The present study was supported in part by a grant from the Children's Hospital of Chongqing Medical University for Special Project on Difficult and Rare Diseases (grant no. HJYN2013-4).
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
FW, YD, YW and MZ conceived and designed the study, and analyzed the data; JW, MC, XL, PY, SL and LJ collected the clinical information; JC and LY performed the EEG analysis; FW, YD and MZ prepared the manuscript. All authors read and approved the final manuscript.
Ethical approval for the present study was obtained from the Institutional Review Board, Children's Hospital of Chongqing Medical University (grant no. 2018-64).
Informed consent was obtained from the parents of the patient.
The authors declare that they have no competing interests.
Case presentation. Sporadic multiple small capillary malformations (black arrows) found on the (A) forehead and (B) upper back. At the age of 12 months, interictal electroencephalogram revealed hypsarrhythmia (C), and slow wave background with bioccipital spike slow wave (D) during waking.
Pedigreeof the family. (A) Sanger sequencing showing a novel
Thermocycling conditions for Sanger sequencing.
Step | Temperature (°C) | Time | Cycle |
---|---|---|---|
1 | 95 | 10 min | 1 |
2 | 94 | 30 sec | 3 |
64 | 30 sec | ||
72 | 45 sec | ||
3 | 94 | 30 sec | 5 |
62 | 30 sec | ||
72 | 45 sec | ||
4 | 94 | 30 sec | 10 |
60 | 30 sec | ||
72 | 45 sec | ||
5 | 94 | 30 sec | 17 |
58 | 30 sec | ||
72 | 45 sec | ||
6 | 72 | 5 min | 1 |
7 | 4 | Holds |
Summary of the patient and 16 previously reported MIC-CAP cases caused by STAMBP mutations.
Patients | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 |
---|---|---|---|---|---|---|---|---|---|
Basic characteristics | |||||||||
Reference | This study | McDonell |
|||||||
Gender | M | F | M | M | M | M | F | M | F |
Age | 1 year 3 months | 2 years | 9 months | 12 months | 2 years | 22 days | 5 years 4 months | 2 months | 28 months |
Ethnicity | Chinese | African-American | ED | European | European | European | European | European | |
GA, BW (weeks, SD or g) | 40+5, 3,600 | 39, −1.5 | 39, −1.5 | 36+5, −1.5 | 36, −2 | 37, −2 | Term, +1.8 | 36, −1.5 | 37+2, −4 |
Symptoms and signs | |||||||||
Microcephaly | + | + | + | + | + | + | + | + | + |
Capillary malformations | + | + | + | + | + | + | + | + | + |
Dysmorphic appearance |
+1,4 | +3 | +3 | − | +3 | +3 | +3 | +3 | +3 |
IE (age of onset) | +(3 months) | +(NA) | +(NA) | +(NA) | +(NA) | +(NA) | +(NA) | +(NA) | + |
Infantile spasms | + | + | − | + | − | − | − | − | NA |
Myoclonus | + | − | + | + | + | − | − | + | + |
Developmental delay | + | + | + | + | + | + | + | + | + |
Spastic quadriparesis | + | + | + | + | + | + | − | − | + |
Optic atrophy | NA | + | + | + | + | + | NA | NA | + |
Dyskinesia | + | NA | NA | NA | NA | NA | NA | NA | NA |
Auxiliary examination | |||||||||
Neuroimaging features |
+ |
+ |
+ |
+ |
+ |
+ |
− | + |
+ |
EEG anomalies | + | Presumed+ |
Presumed + | Presumed + | Presumed + | Presumed + | Presumed + | Presumed + | Presumed + |
Basic characteristics | |||||||||
Reference | McDonell |
Faqeih |
Naseer |
Hori |
Demikova |
||||
Gender | F | M | M | M | M | M | M | F | 5 F/12 M |
Age | 8 months | 15 months | 8 years 6 months | 5 years | NA | NA | 2 years | 6 months | |
Ethnicity | Polynesian | ED | Arabic | Egyptian | Japanese | Russia | 9 | ||
GA, BW (weeks, SD or g) | 37+6, −1.5 | 35, −1.5 | Term. 2,600 | NA, 2,800 | NA | NA | 37, 2,680 | 30, 2,250 | |
Symptoms and signs | |||||||||
Microcephaly | + | + | + | + | + | + | + | + | 17 (100%) |
CM | + | + | + | + | + | + | + | + | 17 (100%) |
Dysmorphic appearance | +3 | +3 | +1,2 | +1,2,3 | +1,2,3 | +1,2,3 | +1,2,4 | +1,4 | 17 (100%) |
IE (age of onset) | + | + | +(7 months) | +(7 months) | +(Infancy) | +(Infancy) | +(7 months) | +(2 months) | 17 (100%) |
Infantile spasms | + | + | NA | NA | NA | NA | + | + | 7 (41.2%) |
Myoclonus | NA | + | NA | NA | NA | NA | NA | + | 8 (47.1%) |
Developmental delay | + | + | + | + | + | + | + | + | 17 (100%) |
Spastic quadriparesis | + | + | + | + | NA | NA | − | + | 12 (70.1%) |
Optic atrophy | − | − | + | + | + | + | − | NA | 10 (58.8%) |
Dyskinesia | + | NA | NA | NA | NA | NA | NA | NA | 2 (11.2%) |
Auxiliary examination | |||||||||
Neuroimaging features | + |
+ |
+ |
+ |
+ |
+ |
+ |
+ |
16 (94.1%) |
EEG anomalies | Presumed + | Presumed + | + | + | + | + | + | + | 17 (100%) |
P2 and P3, P12 and P13, and P14 and P15 were siblings. P12 and P13, and P14 and P15 were born to parents from consanguineous marriage.
Dysmorphic appearance: 1widely spaced eyes; 2long palpebral fissures; 3underdeveloped distal phalanges; 4downturned mouth.
Neuroimaging features:
simplified gyral pattern
cerebral atrophy/increased extra-axial space
hippocampal hypoplasia.
Presumed +: These cases had intractable epilepsy but without detailed EEG data. BW, birth weight; CM, capillary malformations; EEG, electroencephalography; ED, European descent; GA, gestational age; IE, intractable epilepsy, NA, not available.