DiGeorge Syndrome with Sacral Myelomeningocele and Epilepsy.

DiGeorge syndrome (DGS) is the most common microdeletion syndrome. The phenotype of DGS is highly variable involving facial, velopharyngeal, cardiac, immunologic, endocrinal, and neuropsychiatric abnormalities. Although neural tube defects (NTDs) have not been described as components of DGS in standard pediatric textbooks, there have been a few case reports of DGS with NTDs. Furthermore, in patients with DGS, seizures can occur due to hypocalcemia or cortical dysgenesis. Few cases of epilepsy have been reported with NTDs without a cortical defect. Here, we report a case of an infant with DGS with a sacral myelomeningocele inherited from the mother. The infant developed epilepsy without hypocalcemia or cortical dysgenesis which is considered related to the sacral myelomeningocele.

INTRODUCTION

DiGeorge syndrome (DGS) is a common genetic syndrome that usually presents in early childhood with immune deficiency, cardiovascular malformation, velopharyngeal insufficiency, hypocalcemia, and developmental delay. The majority of cases occur de novo; however, familial presentations have been reported in 10% of the cases.[1]

A cardiovascular anomaly is one of the most common manifestations of DGS (occurring in >70% of patients). Conotruncal cardiac defects are usually considered as a clue for the diagnosis. DGS in the absence of cardiovascular malformations may be underestimated.[23]

Patients with DGS can develop hypocalcemia-induced seizure due to parathyroid hypoplasia. Neural tube defects (NTDs) are caused by failure of neurulation, including a disturbance in the adhesion processes at the neurula stage. NTDs are the most common congenital malformations affecting the brain and spinal cord. Multifactorial etiologies, including both genetic and environmental factors, are responsible for the observed defects. NTDs have been reported as a risk factor for epilepsy. There are few reports regarding NTDs in children with DGS.[45] Spina bifida has been reported as a risk factor for epilepsy, but the cause and incidence of epilepsy are controversial.[6]

Here, we report DGS with a sacral myelomeningocele and epilepsy without hypocalcemia. Epilepsy is considered related to the sacral myelomeningocele, interestingly without cortical dysgenesis.

CASE REPORT

A 9-month-old female infant was initially admitted to our hospital due to acute bronchiolitis. In her history, she was born with a sacral myelomeningocele and had undergone surgery for this condition at the age of 1 week, but a ventriculoperitoneal shunt was not required. The patient was the first child of unrelated Turkish parents. She was born at term after an uneventful gestational delivery. She also had no history of repeated infections, cardiac anomalies, or seizures. A physical examination demonstrated a weight and head circumference of 6 kg (3rd percentile) and 40 cm (3rd percentile), respectively, and her height was 68 cm (50th percentile). She showed atypical facial features, hypertelorism, short philtrum, micrognathia, low set ears, fish-like mouth, and a wide nasal bridge. A neurological examination revealed hypotonia, with no movement in the bilateral lower limbs, and a surgical scar was found surrounding the region of the repaired myelomeningocele. Her cardiac examination was normal. Laboratory investigations including a thyroid function test, parathyroid hormone levels, and other routine hematology and biochemical parameters were within normal limits. In the chest X-ray, the thymus could not be identified. The echocardiogram was unremarkable. There were no renal anomalies on clinical or ultrasound examinations. Peripheral lymphocyte subsets revealed a mild T-cell deficiency with CD3 (28%), CD4 (21.5%), CD8 (10.5%), CD 19 (38%), and normal levels of immunoglobulins. Her mother’s facial features appeared mildly dysmorphic. She had mild mental retardation with learning disabilities, a nasal voice, and hypothyroidism. She had no history of seizures or repeated infections. Her serum calcium, parathyroid hormone levels and echocardiography were normal. In view of the facial dysmorphism in both the patient and her mother and the presence of a T-cell deficiency, we suspected DGS. Both the patient’s and mother’s chromosomal examinations with fluorescence in situ hybridization analysis showed a chromosome 22q11.2 deletion. On the basis of these results, we accepted the diagnosis of DGS. At the age of 1 year, the patient experienced a clonic seizure while calcium concentration was normal. An electroencephalogram and brain magnetic resonance imaging were within normal limits. The seizure repeated a second time after 1 month while serum calcium concentrations were normal limits. Antiepileptic medications controlled the seizure.

DISCUSSION

DGS is caused by hemizygous microdeletions on chromosome 22q11. Most cases occur sporadically although vertical transmission has been documented. Particularly affected are the heart and great vessels, the endocrine glands of the neck, the face, the soft palate, and cognitive development. Maternal inheritance of a 22q11 microdeletion has been reported as a risk factor for the tetralogy of Fallot. However, our patient did not present with this condition. Although endocrinopathies are common in patients, out patient’s thyroid hormones and parathyroid hormone levels were within normal limits.[23]

The association between conotruncal heart defects and sacral meningoceles was first described by Kousseff in 1984. Nickel et al. reported on three cases with chromosome 22q11 deletion syndrome who had NTDs. Therefore, these authors suggested that genetic studies should be performed to detect chromosome 22q11.2 deletions in children with NTDs and congenital heart defects. Alternatively, the same authors in another study with 295 spina bifida patients reported that 22q11 deletions are a rare cause of NTDs.[45] Factors affecting the prevalence of epileptic seizures in children with spina bifida accompany shunt requirements and other abnormalities of the central nervous system. While the prevalence of epileptic seizures ranges from 14.7% to 29% in shunted patients, it ranges from 2% to 8% in nonshunted patients.[6] Yoshida et al. have reported that 75 patients with spina bifida epilepsy developed epileptic seizures in 12% of the cases, all of whom had ventriculoperitoneal shunts for hydrocephalus. Epilepsy correlates with cerebral abnormalities in patients with NTDs.[7] The current case presented with extracardiac manifestations with both NTDs and mother’s facial dysmorphia serving as clues for the diagnosis. We recommend that children with NTDs with or without cardiac anomalies be evaluated for DGS. It should be kept in mind that seizures can occur without hypocalcemia in patient with DGS. Our patient developed epilepsy without a cortical defect or history of a shunt. This condition, being multifactorial, should be considered with the presentation of epilepsy in patients with NTDs. All parents of children affected by 22q11.2 deletions may benefit from genetic testing for this deletion because of the recurrence risk in future pregnancies. Early intervention services are beneficial for children with DGS; these interventions may include physical therapy, occupational therapy, and speech therapy.

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Conflicts of interest

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