Corpus Callosum, Agenesis Of, With Facial Anomalies And Robin Sequence

Description

Toriello-Carey syndrome is a multiple congenital anomaly disorder with variable systemic manifestations, most commonly including mental retardation, agenesis of the corpus callosum, postnatal growth delay, cardiac defects, usually septal defects, distal limb defects, and urogenital anomalies in affected males. Patients have facial dysmorphic features, micrognathia, including full cheeks, hypertelorism, flattened nasal bridge, anteverted nares, and short neck. Not all features are found in all patients and some patients may have additional features such as anal anomalies or hernias (summary by Toriello et al., 2003).

In a review of the Toriello-Carey syndrome, Toriello et al. (2016) stated that while corpus callosum abnormalities and micrognathia with highly arched or cleft palate are seen in most patients, other manifestations are widely variable. They noted that etiologic heterogeneity has been observed in reported patients, with at least 20% of patients having chromosome anomalies, and that no good candidate genes have been identified by exome sequencing. The authors commented that this condition might not be a unitary diagnostic entity. They recommended chromosome microarray for any child suspected of having the condition, followed by standard of care by genetic testing.

Clinical Features

Toriello and Carey (1988) described findings in 4 children, 3 of them sibs, who appeared to have a previously undescribed multiple congenital anomaly (MCA) syndrome. The manifestations included agenesis of the corpus callosum, telecanthus, short palpebral fissures, small nose with anteverted nares, Pierre Robin sequence, abnormally shaped ears, redundant neck skin, laryngeal anomalies, cardiac defect, short hands, and hypotonia. The affected sibship consisted of a girl and apparently monozygotic twin boys who died in the immediate neonatal period. Lacombe et al. (1992) described a single case born of nonconsanguineous parents and proposed the designation Toriello-Carey syndrome.

Chinen et al. (1999) described 2 Japanese sisters, born of consanguineous parents, with Toriello-Carey syndrome and a phenotype as severe as that reported in male cases. The younger sister died suddenly at age 4 months.

Ohta et al. (1999) described endocardial fibroelastosis in a patient with Toriello-Carey syndrome.

Aftimos and McGaughran (2001) described a female patient who had additional findings including an anteriorly placed anus. She had a severe, complicated congenital heart disease and died in the neonatal period, which argued against the possibility that this is an X-linked disorder with more severe manifestations in males.

Wegner and Hersh (2001) reported a male infant with clinical manifestations consistent with Toriello-Carey syndrome and summarized the findings in this and 11 previously reported cases.

Barisic et al. (2003) reported a brother and sister with Toriello-Carey syndrome who were born after pregnancies complicated by oligohydramnios and died at 8 days and 6 months of life, respectively. Both had pre- and postnatal growth retardation, a ventricular septal defect, and pulmonary stenosis. Previously unreported features seen in 1 or both sibs included hirsutism, entropion, intestinal malrotation, synostosis of the metacarpal bones, and pachygyria.

Kataoka et al. (2003) reported a Japanese boy with Toriello-Carey syndrome with some additional features. At 30 weeks' gestation, prenatal ultrasonography showed hydrocephalus, intrauterine growth retardation, and polyhydramnios. At birth, the infant showed micrognathia, telecanthus, a small nose with depressed nasal root, low-set ears, cleft palate, hypoplastic nails, and bilateral cryptorchidism. MRI showed agenesis of the corpus callosum and cerebellar hypoplasia. Chest radiograph showed 13 pairs of ribs, and echocardiogram showed an atrial septal defect. The child exhibited severe respiratory failure at birth, and examination showed mild bronchomalacia. He also had episodic abdominal distention, vomiting, and malrotation of the gut without stenosis or mechanical obstruction. He died at day 413 from respiratory failure. Postmortem examination showed lung immaturity with extramedullary hematopoiesis. In addition, there were patchy defects of the intestinal longitudinal muscle with myogenic degeneration of smooth muscle cells; intestinal neural plexuses were intact.

Toriello et al. (2003) reviewed approximately 20 published cases of Toriello-Carey syndrome and 25 unpublished cases. They concluded that although there is not as striking a facial gestalt as there is in some conditions, there was enough consistency to suggest a characteristic facies of Toriello-Carey syndrome, as was documented by several photographs. They concluded that the disorder is probably autosomal recessive. Among 24 reported sibs, 7 were similarly affected. One child was the product of an incestuous relationship. A brother and sister in the report by Toriello et al. (2003) (their Figs. 2 and 3) were later found by Basel-Vanagaite et al. (2014) (their patients 4 and 5) to have Kaufman oculocerebrofacial syndrome (244450).

Uras et al. (2009) reported a newborn with Toriello-Carey syndrome, born of consanguineous parents. The patient had significant respiratory distress and hypotonia at birth, requiring intubation. He had a small head, posteriorly sloped forehead, open anterior fontanel, short nose with depressed nasal bridge, telecanthus, small palpebral fissures, malformed ears, thin lips, and microretrognathia. The scrotum was hypoplastic, and the testes were not palpable. Brain imaging showed hypoplasia of the corpus callosum and mild dilation of the lateral ventricles. Heart anomalies included an atrial septal defect and patent ductus arteriosus. Auditory brainstem testing indicated hearing loss.

Yokoo et al. (2013) reported a Japanese boy with features characteristic of Toriello-Carey syndrome and severe congenital tracheal stenosis. The infant had short, downslanting palpebral fissures, small nose with anteverted nares, a high palate, micrognathia, cryptorchidism, and low-set ears. Magnetic resonance imaging of the brain showed agenesis of the corpus callosum, and an echocardiography showed double-outlet right ventricle, infundibular pulmonary stenosis, and a ventricular septal defect. The infant developed severe respiratory distress immediately after birth, and cervical computed tomography on day 1 of life showed severe tracheal stenosis. A tracheostomy was performed on day 2 of life. Surgical repair was not performed because of the infant's congenital heart disease. The tracheal tube size was progressively increased to mechanically dilate his trachea. Ventilatory support was successfully withdrawn on day 57, and the child was last observed to be doing well with a tracheostomy at age 18 months. Yokoo et al. (2013) noted that surgical tracheal plasty was avoided because of the progressive tracheal dilatation used to treat their patient.

Inheritance

Although Czarnecki et al. (1996) reviewed 10 reported cases, including 2 of their own, and suggested that an X-linked gene or sex-influenced gene might be involved in Toriello-Carey syndrome, the reports of Chinen et al. (1999) and Uras et al. (2009) supported autosomal recessive inheritance as proposed in the original report.

The report of a severely affected female by Aftimos and McGaughran (2001) argued against X-linked recessive inheritance.

In a review, Toriello et al. (2003) concluded that the transmission pattern in this disorder is most likely autosomal recessive.

Cytogenetics

McGoey et al. (2010) reported 2 sibs, a girl and a boy, with features suggestive of Toriello-Carey syndrome associated with a microduplication of chromosome 3q29 and microdeletion of 6p25 resulting from an unbalanced segregation of a paternally-inherited balanced reciprocal translocation, t(3;6)(q29;p25.1). The 16-year-old girl presented at age 3 months with hydrocephalus and dysmorphic features, including frontal bossing, hypertelorism, flattened nasal bridge, downslanting palpebral fissures, upturned nose with anteverted nares, small mouth, short neck, widely spaced nipples, and tapering digits. Brain MRI showed hypoplastic corpus callosum and periventricular demyelinization. She had significantly delayed developmental milestones, with walking achieved at age 5 years and poor speech. Her brother had similar facial and brain MRI features, as well as atrial septal defect, kyphoscoliosis, small penis, and high-arched palate. He was mentally retarded and developed obsessive-compulsive skin picking (dermatillomania). Both patients also had bilateral conductive hearing loss. Whole genome array analysis demonstrated that both patients had an interstitial 3.8-Mb duplication of 3q29 and a 5.7-Mb terminal deletion of 6p25. The father, who carried the balanced translocation, had a learning disability and seizures as an adolescent. McGoey et al. (2010) reviewed the literature on chromosomal abnormalities in Toriello-Carey syndrome and noted that there are no consistent findings in the distribution of chromosomal defects reported. However, nearly 25% of cases suspected to have the disorder based on clinical features have been found to harbor chromosomal aberrations. McGoey et al. (2010) concluded that the diagnosis of Toriello-Carey syndrome should be reserved for patients with previously characterized clinical manifestations and normal genetic studies that should include microarray analysis.