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Partial distal aphalangia, duplication of metatarsal IV, microcephaly, and borderline intelligence: a fourth patient with parental consanguinity and additional feature of massive cerebral thrombosis

Ozsurekci, Yasemina; Komurluoglu, Aycab; Aytac, Selinc; Oguz, Kader K.d; Utine, Edae; Ceyhan, Mehmeta

doi: 10.1097/MCD.0000000000000057
Short Case Reports

aPediatric Infectious Diseases Unit

bDepartment of Pediatrics

cPediatric Hematology Unit

dDepartment of Radiology

ePediatric Genetics Unit, Hacettepe University Faculty of Medicine, Ankara, Turkey

Correspondence to Yasemin Ozsurekci, MD, Pediatric Infectious Diseases Unit, Hacettepe University Faculty of Medicine, Sıhhıye, Ankara 06100, Turkey Tel: +90 312 3051166; fax: +90 312 3108241; e-mails: and

Received December 20, 2013

Accepted September 3, 2014

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List of key features

  • Partial distal aphalangia
  • Duplication of metatarsal IV
  • Microcephaly
  • Borderline intelligence
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The combination of partial distal aphalangia, duplication of metatarsal IV, microcephaly and borderline intelligence (OMIM %600384) has been reported previously in three families (Martínez-Frías et al., 1995; Di Rocco, 2002; Utine et al., 2009). The cardinal features of the condition comprise these four findings and are additionally accompanied by oligodactyly, nail and digit hypoplasia, syndactyly, and clinodactyly. Individual patients have been also reported to have short stature, scoliosis, megaureters, and hemorrhagic disease of the newborn as a complication of neonatal hepatitis.

Herein we report the case of a female patient with this rare condition who was born to a consanguineous couple, thereby supporting the putative autosomal recessive nature of the condition. She was referred to the Pediatric Infectious Diseases Unit with suspected meningitis and was diagnosed with massive sinovenous thrombosis during clinical evaluation, which was not previously reported as an accompanying feature of this genetic disorder.

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Case report

A 12-year-old female patient was referred to the Hacettepe University, Pediatric Infectious Diseases Unit with fever, headache, and nausea lasting for 4 days. She was diagnosed with meningitis without performing lumbar puncture (LP) and was treated with ceftriaxone for 4 days in a primary healthcare center. The patient was the second child of a consanguineous couple. She was born at term with a birth weight of 3200 g by uncomplicated vaginal delivery.

On physical examination on the day of admission to our hospital, the child was awake and oriented, responded to verbal stimuli, and had normally reacting isochoric pupils. Neurological examination was normal with preserved muscular strength; however, she had terminal nuchal rigidity. Ophthalmologic examination revealed papilledema with no signs of iritis nor uveitis. Her height was 150 cm (3rd–10th centiles), weight was 35 kg (third centile), and head circumference was 51 cm (third centile). Distal phalanges of fingers two to five were hypoplastic, the fifth digits being most severely affected, and no distal phalanx was present on the left (Fig. 1). She had five toes on the left and four on the right with partial cutaneous syndactyly. Radiographs showed duplication of the metatarsal IV on the right. The third toe on the left had only a single hypoplastic phalanx, whereas toes two, four, and five on the left and toes three to five on the right lacked distal phalanges (Fig. 2). Her IQ was calculated as 75. Family history revealed that she had an unaffected brother and unaffected parents, but three deceased paternal uncles reportedly had similar abnormalities of the hands and feet.

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Initial laboratory tests revealed a hemoglobin level of 12.8 g/dl (range: 11.7–15.5), a platelet count of 278×10−9/l (range: 150–388×10−9), and a leukocyte count of 9.2×10−9/l (range: 4.1–11.2×10−9/l). Her peripheral smear examination was normal. C-reactive protein was 1.24 mg/dl (range: 0–0.8) and erythrocyte sedimentation rate was 22 mm/h (normal<20). Blood urea nitrogen was 18 mg/dl, creatinine was 0.42 mg/dl, and electrolytes were normal. Urinalysis was negative for protein and blood; microscopic examination revealed no cellular elements or casts. The remaining biochemical laboratory test results were normal. Cytology of cerebrospinal fluid (CSF) after LP was normal. Bacterioscopy of CSF by Gram stain indicated no bacterial microbiota.

Brain MRI was performed on the day of admission to the hospital because of clinical unresponsiveness to previous antibacterial treatment and papilledema. Brain MRI revealed widespread thrombosis in dural venous sinuses, as suggested by lack of signal void, bright T1 signal, and ‘empty sinus’ appearance due to nonenhancing clot following intravenous gadolinium-based contrast material administration. The right sigmoid and transverse sinuses, superior sagittal sinus down to the sinus confluensum, straight sinus, internal cerebral veins, and vein of Galen were involved. Focal areas of T2 hyperintensity were observed in the right frontal white matter and splenium of the corpus callosum and bilateral medial thalami and caudate nuclei (Fig. 3). These lesions resolved greatly, leaving minor signal alterations at follow-up MRI obtained 5 days later (Fig. 4).

Fig. 3

Fig. 3

Fig. 4

Fig. 4

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.

Table 1

Table 1

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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.

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Conflicts of interest

There are no conflicts of interest.

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