PMC3319791_01
a: Photographs of our patient at 3 months of age showing dysmorphic facial features, sloped shoulders and joint limitation. To the right note the syndactyly and contractures of hands and feet bilaterally (LH - left hand; RH - right hand; LF - left foot; RF - right foot). b: Photographs of our patient at 4 years of age showing myopathic facies, downslanting palpebral fissures, and same hand and foot anomalies as previous.
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F1
Lips were thin and there was micrognathia (Fig 1). Both hands were clenched with contractures involving the metacarpophalangeal and interphalangeal joints of digits 2-5 with all held in ulnar deviation and both thumbs were adducted (Fig 1). There was partial syndactyly of the 2nd-3rd toes bilaterally and syndactyly of the 1st-2nd toes on the right (Fig 1).
Standard 12-lead ECG recorded at 2 days of age showing rightward QRS axis deviation, incomplete right bundle branch block, and striking QT interval prolongation with a raw measurement of 464ms rate-corrected to 640ms using Bazett's formula. There is a subtle T-wave alternans most apparent in leads I and II.
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F2
The baby developed episodes of hypoglycemia, hypocalcemia, seizures and arrhythmia with self-limited episodes of polymorphic ventricular tachycardia, 2:1 AV block and marked ventricular repolarization delay (prolonged QTC) with striking QT interval prolongation with a raw measurement of 464ms rate - corrected to 640ms using Bazett's formula at two days of life (Fig 2).
Patient's CT scan and MRA: (a) CNS and craniofacial montage: CT 3D reconstruction at 4 days of age reveals markedly enlarged sutures and anterior fontanel for gestational age. (b) MRA at 9 days of age demonstrates incidental dominant right anterior cerebral artery and bilaterally patent middle cerebral arteries. (c) Axial T2W image and DWI (d) at 9 days of age reveal subacute left hemispheric stroke with persistence of diffusion restriction (arrow).
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F3
Magnetic resonance imaging of the brain demonstrated acute infarction involving the left cerebral hemisphere, but no other vascular or structural abnormality (Fig 3).
Radiographs of the hands (a,b) demonstrate bilateral ulnar deviation, adduction of the thumbs and unilateral soft tissue syndactyly of digits 4 and 5 (arrow). Pelvic AP radiograph (c) reveals shallow steep acetabuli and femoral head dislocation. Lateral foot radiograph (d) demonstrates vertical talus and pes planus deformity.
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F4
X-rays of the upper extremities showed ulnar deviation of the 2nd through 5th digits on both hands and syndactyly of the 4-5th fingers (Fig 4). X-rays of the feet showed vertical talus and horizontal calcanei (Fig 4).
Sequencing of the CACNA1C gene identified a novel mutation c.4418C>G in exon 36, predicting an amino acid substitution of a glycine for an alanine at codon 1473 (p.Ala1473Gly). The same analysis done on both parents did not identify the mutation in either of them.
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F5
Sequencing of the CACNA1C gene done a few years later when it became available, identified a novel mutation c.4418C>G in exon 38, predicting an amino acid substitution of a glycine for an alanine at codon 1473 (p.Ala1473Gly) (Fig 5).Assessments of the pathogenicity of the p.Ala1473Glu mutation was performed on two sites, PolyPhen-2 and SIFT (http://genetics.bwh.harvard.edu/pph2/ and http://sift.jcvi.org/).