von Voss-Cherstvoy syndrome with transient thrombocytopenia and normal psychomotor development

INTRODUCTION

DK-phocomelia (MIM 223340) is the term introduced by Cherstvoy et al. [1980] to describe a syndrome of phocomelia of upper limbs, encephalocele, variable brain anomalies, urogenital abnormalities, and thrombocytopenia. Though still used, the designation of this condition as DK-phocomelia is inadequate since upper limb involvement may be limited to radial anomalies. The pathogenesis and cause of this syndrome are unknown. All reported cases have been sporadic and both sexes have been affected. Parental consanguinity reported by Lubinsky et al. [1994] suggests an autosomal recessive pattern of inheritance. All previously reported cases of von Voss-Cherstvoy syndrome have had apparently normal chromosomes except for that described by Bamforth and Lin [1997] with mosaicism for a deletion of 13q12 in fibroblasts.

Here, we describe a patient with von Voss-Cherstvoy syndrome associated with transient thrombocytopenia and normal psychomotor development.

CLINICAL REPORT

The propositus, a 15-month-old patient, is the only child of non-consanguineous, healthy parents. Mother and father are African-American and 17 years old at the birth of the child. Family history was unremarkable. There was no exposure to alcohol, drugs, and other teratogens, or history of infectious illness and maternal diabetes during the pregnancy. The patient was born at 38 weeks of gestation and weighed 2,135 g (below the 5th centile), measured 45 cm (10th–25th centile), and had a cranial circumference (OFC) of 34 cm (50th–75th centile). The Apgar scores were 9 at 1 min and 9 at 5 min. He had a left parieto occipital meningoencephalocele, defects of upper limbs, and ambiguous genitalia, i.e., severe micropenis, flat scrotum, and testes within the inguinal canals.

In the first days of life, the infant underwent meningoncephalocele repair. Before the operation, brain magnetic resonance imaging (MRI) showed a left parieto-occipital meningoencephalocele measuring 2.5 cm with a small portion of brain herniating through the defect. Histopathologic findings showed stratified squamous epithelium and an underlying dermis containing numerous, interlacing lymphovascular channels in a background of endothelial and glial tissues consistent with small lymphangioma. No neural tissue was identified within the specimen analyzed. During the first weeks of life, thrombocytopenia was also noted. Platelet count on the first day of life was 47,000/mm³, 60,000/mm³ at 7 days, and 122,000/mm³ at 13 days. The platelet count increased to 321,000/mm³ at 20 days and has stayed within the normal range in all subsequent determinations. Hemoglobin and hematocrit values were normal throughout.

Skeletal survey at birth showed thin skull bones with a “beaten silver” appearance, absence of radii with short and bowed ulnae, and flexion deformities at the elbows and wrists. The first metacarpals and thumbs were present (Fig. 1). There was no evidence of gross spinal anomaly nor were there abnormalities of the lower limbs. Chest radiograph was normal.

Ultrasonography of the abdomen did not show any abnormalities; kidneys were normal. A small midline structure posterior to the bladder was consistent with a rudimentary uterus or müllerian remnant. No ovaries were seen and the testes were detected in the inguinal canals.

An HCG stimulation test showed normal production of testosterone and a normal testosterone/dihydrotestosterone ratio. The antimüllerian hormone level was 49 ng/ml (normal values 48–83.2 ng/ml). Levels of adrenal hormones, including androstenedione, 17-hydroxy-progesterone, and cortisol, were normal. Plasma sterol profile determined by GC/MS because of a suspected disorder of cholesterol biosynthesis, such as Smith–Lemli–Opitz syndrome, did not demonstrate any abnormalities. Chromosomes were normal (46,XY). Results of breakage studies using diepoxide butane (DEB) were normal. Because of a previously reported von Voss-Cherstvoy syndrome patient with somatic mosaicism for del(13q) [Bamforth and Lin, 1997], fibroblasts were studied with normal results.

After consultation with the urology, endocrinology, psychology, and genetics services, it was recommended that sex assignment be female. However, the family decided to raise the infant as male.

At the last examination at 15 months (Fig. 2), the patient had a normal growth and normal psychomotor development. His length was 75.6 cm (5th–10th centile), weight 9,940 g (10th–25th centile), and OFC 49 cm (75th–90th centile). He had head control at 6 months and sat independently at 7 months. At 15 months, he pulled himself up to stand, climbed over objects, and walked without support. He could speak 4–5 words. MRI of the brain performed at 13 months of age showed polygyria with abnormal ventricular system, multiple serpiginous vessels within the extra-axial spaces in the middle cranial fossa, and an elongated, immature corpus callosum. The pituitary was normal (Fig. 3). Results of audiometry were normal. Acoustic emittance measures indicated middle ear disorder in both ears.

DISCUSSION

Our patient's findings suggest the diagnosis of von Voss-Cherstvoy syndrome, a disorder included in the group of syndromes with radial ray and hematologic abnormalities. In all cases reported so far, the severe deficiency affects only the upper limbs and the range of deficiency varies from radial agenesis and phocomelia to virtual amelia [Urioste et al., 1994]. This clinical variability is in accordance with the wide range of severity observed in genetic and teratogenic limb deficiency syndromes [Temtamy and McKusick, 1978].

The differential diagnosis of von Voss-Cherstvoy syndrome includes Fanconi syndrome (MIM 227650), TAR syndrome (MIM 274000), and Roberts syndrome (MIM 268300). von Voss-Cherstvoy syndrome is not a chromosomal breakage syndrome. In our patient, results of chromosomal breakage studies were normal. There is considerable clinical overlap between von Voss-Cherstvoy syndrome and TAR syndrome since both conditions are associated with limb defect and thrombocytopenia. The presence of thumbs despite absent radii is a characteristic of TAR syndrome [Hall, 1987]. This finding was also present in our patient and in other von Voss-Cherstvoy syndrome patients [Cherstvoy et al., 1980; Bird et al., 1994; Lubinsky et al., 1994; Bamforth and Lin, 1997]. In contrast with von Voss-Cherstvoy, lower limbs are affected in about 50% of cases of TAR syndrome [Greenhalgh et al., 2002] and no brain malformations or sexual differentiation defects have been reported. Similar to previous reports [Cherstvoy et al., 1980; Lubinsky et al., 1994; Urioste et al., 1994], our patient presents with a defect of the corpus callosum. While a nonspecific finding, this appears to be a common finding in this syndrome. Moreover, although it has rarely been reported in TAR syndrome [Gorlin, cited by Cohen and Lemire, 1982], the presence of meningoencephalocele is the most discriminating finding between the two conditions.

Our patient also had some findings of Roberts syndrome. This is an autosomal recessive condition characterized by marked limb defects, cleft lip, and palate, prenatal growth retardation, urogenital and cardiac abnormalities [Van Den Berg and Francke, 1993]. However, the presence of meningoencephalocele, the absence of facial clefts, and the lack of involvement of the lower limbs makes this diagnosis unlikely.

Among the patients with von Voss-Cherstvoy syndrome reported so far our patient is interesting since his phenotype is the less severe and gradually improved with time and he presented with only transient neonatal thrombocytopenia, normal growth, and psychomotor development, and no evidence of kidney malformations. A comparison between our case and the patients reported in the literature is shown in Table I.

The association of defects in hematopoiesis and limb formation suggests the possible involvement of the homeobox (HOX) family of genes, which are expressed in both cell lineages [Thorsteinsdottir et al., 1997; Goodman, 2002]. Interestingly, one member of this gene family, HOXA11 is mutated in a syndrome including thrombocytopenia and radio-ulnar synostosis [Thompson and Nguyen, 2000].