Tests for autoantibodies including antinuclear antibody and anti-dsDNA (a subgroup of antinuclear antibody) were all negative. Prothrombotic investigations revealed a protein C activity of 124% (range: 70–130), protein S activity of 117% (range: 60–130), and antithrombin III activity of 139% (range: 80–120). Tests for antiphospholipid antibodies and lupus anticoagulant were negative. Hereditary prothrombotic risk factors including factor V G1691A, prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR C677T and MTHFR A1298C) and plasminogen activator inhibitor-1 (PAI-1) were analyzed. PAI-1 4G/4G genotype and homozygous MTHFR A1298C polymorphism were found positive. Echocardiographic examination of the patient was normal. Whereas HLA-B27 was negative, HLA-B51 was positive, pathergy reaction after needle-prick was negative.
Vancomycin and cefotaxime were initiated with the diagnosis of meningitis, despite normal CSF findings, as she was treated with ceftriaxone in the primary healthcare center before LP. Fever and nuchal rigidity persisted. Low-molecular-weight heparin (enoxaparin) (1 mg/kg/dose, twice daily) treatment was started after MRI, and all clinical findings including fever improved. As a consequence, antimicrobial treatments were stopped, the dose of enoxaparin was adjusted, and 1-month follow-up was uneventful.
The clinical findings of the present case in addition to the other cases that were reported previously are summarized in Table 1.
The combination of partial distal aphalangia, duplication of metatarsal IV, microcephaly and borderline intelligence is a very rare syndromic condition, with a suspected autosomal dominant or recessive pattern of inheritance (Martínez-Frías et al., 1995; Di Rocco, 2002; Utine et al., 2009). The present patient is the fourth patient with this very rare condition. The presence of parental consanguinity once again supports the autosomal recessive inheritance.
Partial distal aphalangia and duplication metatarsal IV was suspected clinically, based on the limb findings, microcephaly and borderline intelligence. A thrombotic process was not reported previously with this clinical synopsis. Accompanying clinical aspects are worth reporting, as the condition is yet not elucidated in molecular etiology. This patient presented with the signs and symptoms of meningitis, and massive cerebral sinovenous thrombosis (CSVT) was seen during clinical workup. Similarly, other additional clinical findings including neonatal hepatitis, short stature, megaureter, and scoliosis were previously reported in association with this genetic condition (Table 1); however, it is less likely that there is an association with the synopsis. In contrast, although there are many genetic conditions with oligodactyly and syndactyly, a combination with duplication metatarsal IV, microcephaly and borderline intelligence renders the present condition rather unique.
Massive CSVT in the pediatric age group is a rare condition with an incidence between 0.4 and 0.7 per 100 000 children per year. The etiology and pathophysiology of CSVT in the pediatric population is still poorly understood, and the role of thrombophilic risk factors remains to be elucidated. CSVT in children is a multifactorial disease that, in the majority of cases, results from a combination of prothrombotic risk factors and/or the underlying clinical condition (Kenet et al., 2010). Trauma, infections (sinusitis, mastoiditis, meningitis, and the other conditions affecting the head and neck area), collagen vascular disorders, hemoglobinopathies, and metabolic and inflammatory bowel diseases have been suggested as potential risk factors for CSVT (Menascu et al., 2011). In the present patient, the diagnosis of meningitis was not confirmed with CSF examination. In addition, fever persisted despite antimicrobial treatment, which only disappeared after initiation of thrombolytic therapy. Accordingly, meningitis was ruled out and was not considered a risk factor for CSVT.
The underlying tendency for massive thrombophilia was investigated by a thrombosis panel in the patient. PAI-1 is the major inhibitor of fibrinolysis; however, there is still considerable controversy regarding whether the 4G/4G polymorphism of the PAI-1 gene is a risk factor for myocardial infarction or deep venous thrombosis. Ozyurek et al. (2007) evaluated the significance of FVG1691A, PTG20210A, MTHFR C677T, and PAI 4G/5G genotype in the development of cerebral thrombosis in 113 Turkish children and compared the results with healthy individuals. The prevalence of the 4G/4G genotype was not statistically significant between the patient group and the control group. The PAI-1 4G/4G genotype in our patient was not considered an underlying cause for such massive thrombosis. Coexistent homozygous MTHFR 1298 polymorphism and PAI-1 4G/4G genotype may be associated with an increased risk of developing CSVT in this patient.
No association has been reported previously between this genetic condition and thrombosis. However, we consider this patient worth reporting, not only for being supportive for the possible autosomal recessive mode of inheritance but also for the incidental co-occurrence with massive cerebral thrombosis, as this may lead to a better clinical delineation of the condition when future patients are described.
Conflicts of interest
There are no conflicts of interest.
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Utine GE, Alanay Y, Aktaş D, Alikaşifoğlu M, Boduroğlu K. (2009). Partial distal aphalangia, duplication of metatarsal IV, microcephaly and borderline intelligence: a third patient suggesting autosomal recessive inheritance. Am J Med Genet A 149A:1317–1318.