Brain & Development 26 (2004) 209–212 www.elsevier.com/locate/braindev
Case report
Another case of cerebro-facio-thoracic dysplasia (Pascual-Castroviejo syndrome) Miguel Rufo-Camposa,*, Pilar Riveros-Huckstadta, Germa´n RodrI´guez-Criadob, RocI´o Herna´ndez-Sotoa a
Paediatric Neurology Department, Hospital Infantil Universitario Virgen Del Rocio, Avda Manuel Siurot s/n, 41013, Seville, Spain b Dysmorphology Unit, Hospital Infantil Universitario Virgen Del Rocio, Avda Manuel Siurot s/n, 41013, Seville, Spain Received 25 February 2003; received in revised form 2 July 2003; accepted 2 July 2003
Abstract We report another case of cerebro-facio-thoracic dysplasia (Pascual-Castroviejo syndrome) characterized by mental retardation and characteristic facies: narrow forehead, synophris, hypertelorism, broad nasal bridge, long philtrum, micrognathia, triangular-shaped mouth and low posterior hairline, and also brachycephaly, calcified clinoid ligaments, and upper rib deformities. Although the severity of mental retardation within the syndrome varies, the reported case shows not only a severe degree, but also cerebral malformations not reported in any of the previous cases of cerebro-facio-thoracic syndrome. These include cortical – subcortical atrophy with hypoplasia of the corpus callosum, and of the cerebellar vermis. We also discuss the inheritance pattern and differential diagnosis, comparing this phenotype to other similar dysmorphic syndromes. q 2003 Elsevier B.V. All rights reserved. Keywords: Cerebro-facio-thoracic dysplasia; Pascual–Castroviejo syndrome
1. Introduction In 1975, Pascual-Castroviejo et al. reported, in three unrelated children (two females and a male), a new syndrome named ‘cerebro-facio-thoracic dysplasia’ [1]. This syndrome was characterized by mental retardation, typical facies (narrow forehead, synophris, hypertelorism, broad nasal bridge, long philtrum, micrognathia, triangularshaped mouth and low posterior hairline) brachycephaly, calcified clinoid ligaments, and upper rib deformities. Two of the three families investigated were consanguineous, suggesting autosomal recessive inheritance. Later on, Philip et al. [2] reported two siblings born to healthy consanguineous parents presenting with dysmorphic features, complex vertebral and rib abnormalities and mental retardation. Both children showed an affable character in spite of the evident signs of mental retardation. They considered this family to be another case of cerebro-thoracic dysplasia. In 1996, and under the name of cerebro-facio-thoracic syndrome, Guion-Almeida * Corresponding author. Fax: þ 34-955012921. E-mail address:
[email protected] (M. Rufo-Campos). 0387-7604/$ - see front matter q 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0387-7604(03)00133-5
et al. reported another case with the same features as previously described [3]. We report a case with cerebro-facio-thoracic dysplasia features, looking at the inheritance pattern, possibly as autosomal recessive, and describe cerebral malformations including hypoplasia of the lower cerebellar hemispheres and vermis.
2. Case report A male infant was born at 40 weeks gestation to a mentally retarded 18-year-old mother who became pregnant after being raped twice by her paternal uncle. He was born by uncomplicated spontaneous vaginal delivery and had intrauterine growth retardation with a low birth weight of 2450 g (2.36 S.D. below the mean). The head circumference was 32 cm (2 S.D. below the mean) and chest circumference was 31 cm (1.83 S.D. below the mean). Length was 45 cm (2.69 S.D. below the mean). Apgar score was 10 at 5 min. Shortly after birth, the infant developed mild respiratory distress and remained in hospital for 9 days; during this period he underwent a cranial ultrasound scan which
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showed a large cisterna magnum with asymmetrical lateral ventricles. At 1 month of age, he underwent surgery for pyloric stenosis and bilateral inguinal hernias. When he was 7 months old, he was first admitted to our unit with a first episode of unresponsiveness, generalized hypertonia, and fixed gaze with eyes rolling up, over 5 –10 min, which subsided after rectal diazepam was given. These episodes recurred twice while in hospital. On examination his weight was 6550 g (1.76 S.D. below the mean), head circumference was 43.0 cm (1.1 S.D. below the mean), and length 63 cm (1.76 S.D. below the mean). He also showed dysmorphic features: hypertelorism, broad short nose, synophrys, narrow forehead, large low-set ears, flat facies, short neck with low hair line, flat occiput, broad thumbs, microcephaly, abnormal dermatoglyphics and thoracic asymmetry with a narrow thorax, but without raised scapulae. Other findings included abdominal recti muscle diastasis and dorsolumbar scoliosis. On neurological examination he showed generalized mild hypotonia, poor head control, reduced motility, and pronation of both arms with overlapping of the fingers; primitive reflexes, such as grasping, were present but there was no parachute response, nor did he reach for objects. Maturity assessment was estimated at 3– 4 months of age. The remainder of his systemic physical examination was normal. Investigations, including urinalysis, complete blood count, biochemistry, thyroid function tests were all normal. TORCH, HIV and hepatitis screen were negative. EEG and visual and auditory evoked potentials were normal; chromosomal study showed a 46 XY male karyotype. An abdominal ultrasound scan was normal. Skeletal survey disclosed thoracolumbar hemivertebrae as well as wedged vertebrae in the lower cervical and thoracic regions with bifid ribs and bony bridges joining the posterior arches in some (Fig. 1). Long bones were rough and short (femur 11.3 cm, tibia 9 cm, fibula 8.1 cm, humerus 9.2 cm, ulna 8.2 cm, and radius 7 cm.) Cranial CT scan showed cortical – subcortical atrophy with hypoplasia of the cerebellar vermis. MRI (Fig. 2A,B) in T1 revealed moderately dilated ventricles, small frontal lobes, a deep Sylvian fissure, reduced hippocampal volume and hypoplasia of the corpus callosum. In lower projections we could appreciate the hypoplastic cerebellar hemispheres and vermis with an enlarged subarachnoid space. Follow-up of this patient continues in our Outpatient Paediatric Neurology Clinic. Assessment during his last visit, at age 8 years (Fig. 3), showed diminished responses to stimuli, with affable behavior, severe developmental delay, dorsolumbar scoliosis and moderate hypotonia that prevented him from standing, along with the dysmorphic features previously described. The trend of his somatic growth was normal.
Fig. 1. Roentgenogram of chest showing wedged thoracic and lower cervical vertebrae with bifid ribs and bony bridges joining the posterior arches in some segments.
3. Discussion It is well known that the most common variant of spondylocostal dysostosis is the autosomal recessive trait, though there is great variability within the inheritance pattern even within the same family [4]. The costovertebral malformations found in this syndrome are frequently associated with midline defects affecting facies and other organs [5], rendering the clinical diagnosis difficult to establish. The patient described here presented particular characteristics such as consanguinity, mental retardation, dysmorphic features and costovertebral abnormalities, similar to those described by Pascual-Castroviejo et al. [1]. In comparing our patient with previously described cases (Table 1) we found the same costovertebral abnormalities including bifid ribs, hemivertebrae and a peculiar form of costal synostosis with bony bridges joining the posterior arches in some ribs. Dysmorphic features include epicanthus, hypertelorism, narrow forehead, broad nasal bridge, short neck, low-set ears, low hairline, marked micrognathia, broad short nose, synophrys, and flat facies. Frequently, these patients also have intracranial defects; in the case discussed here, we found a cortical –subcortical atrophy, reduced hippocampal volume and hypoplasia of
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Fig. 3. Current appearance of the patient. Dysmorphic features, synophris, hypertelorism, low hairline, short neck, moderate hypotonia, severe mental retardation and dorsolumbar scoliosis.
the corpus callosum and cerebellar vermis. Mental retardation is uniformly present in these patients, though the severity varies; usually they exhibit a pleasant and affectionate affect. Less frequent manifestations reported include inguinal and umbilical hernia, (our patient presented abdominal recti muscle diastasis). Macrocephaly has been reported by Pascual-Castroviejo [1] in one case, and in two cases described by Philip [2]; our patient did not have this feature. Interclinoid ligament calcification has been described in only two cases. When considering differential diagnosis we must consider other syndromes presenting with vertebral malformations, such as the Cornelia de Lange syndrome, which despite a similar facial appearance and mental retardation does not present thoracic bony abnormalities or micrognathia; nevertheless, this syndrome also may be associated with limb malformations. Because of the facial appearance (prominent forehead, hypertelorism and some degree of micrognathia) Coffin R Fig. 2. (a,b) Coronal and sagittal MRI views of the brain show corticalsubcortical atrophy, reduced hippocampal volume, hypoplastic cerebellar vermis, moderately dilated lateral ventricles, small frontal lobes, deep Sylvian fissure and hypoplastic corpus callosum.
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Table 1 Seven reported cases of cerebrofaciothoracic dysplasia Guio´n-Almeida
Present report
þ þ þ
þ þ ?
2
þ þ þ
? ? ?
2 ? ?
2 þ þ
þ þ þ þ
2 þ þ þ
2 þ þ þ
2 þ þ þ
2 þ þ þ
þ þ þ þ þ þ
þ þ þ þ þ 2
þ 2 þ þ þ þ
þ 2 þ þ ? 2
þ þ þ 2 ? þ
þ þ þ þ þ þ
þ þ þ
þ þ þ
þ þ þ
þ 2 2
þ 2 2
þ þ 2
þ þ 2
? ? 2
þ 2 2
2 þ 2
þ 2 2
þ þ 2
þ 2 2
2 þ þ
Clinical features
Pascual-Castroviejo
Philip
High birth weight Consanguinity Polyhydramnios Postnatal growth deficiency Affable behavior Mental retardation Morphological Epicanthus Hypertelorism Broad short nose Short neck Low-set, posteriorly angulated ears Synophrys Flat face Low hairline Narrow forehead Inguinal hernia Skeletal Costovertebral anomalies Narrow thorax Raised scapulae Central nervous system Anomaly septum pellucidum Hypoplasia corpus callosum Hypoplasia cerebellar vermis
2 þ 2
þ þ 2
þ þ 2
þ þ þ
2 þ þ
2 þ þ
2 þ þ
þ þ þ þ
þ þ þ þ
þ þ þ þ þ 2
syndrome must also be considered; these patients also present with vertebral abnormalities leading to kyphosis, although no rib malformations have been described and facial dysmorphic features are more prominent [6,7]. Similar dysmorphic features have been described in Robinow syndrome [8], although many features are discordant, such as the normal genitalia, mental retardation and lack of limb bony abnormalities in Pascual-Castroviejo syndrome. More recently, Moerman et al. described a new syndrome [9] with spondylocostal anomalies, macrocephaly, intracranial malformations such as hydrocephalus and agenesis of the corpus callosum, congenital heart and renal defects and short stature. The severity of malformations makes this condition lethal and patients do not survive very long. The information obtained through the few cases of cerebro-facio-thoracic syndrome described so far, suggest that most likely this is a hereditary condition transmitted as an autosomal recessive trait. With current imaging technology, antenatal diagnosis is possible, the most practical being careful ultrasonographic monitoring in search of common manifestations such as cerebral malformations (macrocephaly, abnormalities of the septum pellucidum and corpus callosum), ribs and thoracic vertebral malformations.
2
References [1] Pascual Castroviejo I, Santolaya JM, Lopez Martin V, Rodriguez-Costa T, Tendero A, Mulas F. Cerebro-facio-thoracic dysplasia: report of three cases. Dev Med Child Neurol 1975;17:343–51. [2] Philip N, Guala A, Moncla A, Monlouis M, Ayme´ S, Giraud F. Cerebro-facio-thoracic dysplasia: a new family. J Med Genet 1992;29: 497– 9. [3] Guion-Almeida ML, Richieri-Costa A, Saavedra D, Cohen Jr MM. Cerebro-facio-thoracic syndrome. Am J Med Genet 1996;61:152 –3. [4] Ayme´ S, Preus M. Spondylocostal/spondylothoracic dysostosis: the clinical basis for prognosticating and genetic counseling. Am J Med Genet 1986;24:599–606. [5] Casamassima AC, Casson MC, Nance WE, Kodreff M, Caldwell R, Kelly T, et al. Spondylocostal dysostosis associated with anal and urogenital anomalies in a Mennonite sibship. Am J Med Genet 1981;8: 117– 27. [6] Coffin GS, Siris E, Wegienka LC. Mental retardation with osteocartilagenous anomalies. Am J Dis Child 1966;112:205–13. [7] Procopis PG, Turner B. Mental retardation, abnormal fingers and skeletal anomalies: Coffin’s syndrome. Am J Dis Child 1972;124: 258– 61. [8] Teebi A. Autosomal recessive Robinow syndrome. Am J Med Genet 1980;35:64–8. [9] Moerman P, Vanderberghe K, Fryns JP, Haspelagh M, Lauweryns JM. A new lethal chondrodysplasia with spondylocostal dysostosis multiple internal anomalies and Dandy-Walker cyst. Clin Genet 1985;27: 160– 4.
