Holoprosencephaly spectrum among Egyptian patients: clinical and cytogenetic study.

We report 24 patients with holoprosencephaly (HPE) spectrum screened for Del 7q36 and subtelomere 13q. They were divided according to the type of HPE into: 6 alobar, 15 semilobar, 1 lobar and 2 middle interhemispheric variant (MIH). All patients presented with global developmental delay. Microcephaly was in 83.3% and midfacial developmental defects were in the form of; cyclopia, arrhinia and agnathia in 2 patients (8.3%), premaxillary agenesis in 2 patients (8.3%), cleft lip and palate in 7 patients (29.2%), hypotelorism in 8 patients (33.3%) and hypertelorism in 9 patients (37.5%). The neurological deficits were as follows: abnormal tone and spasticity were present in all of them with exceptional of a single patient with MIH who presented with hypotonia and was able to walk independently at the age of 3 years, athetoid and/or dystonic movements of limbs in 22 patients, seizures in twelve patients (50%) and abnormal EEG in 15 patients (62.5%). Poor temperature regulation was found in 50% of patients and diabetes insipidus was documented in 3 patients (12.5%). The MRI showed complete or partial fusion of basal ganglia and thalami in 21 patients (87.5%) and 19 patients (79.2%) respectively, fused mesencephalon in 8 patients (33.3%), incomplete separation of mesencephalon from diencephalon in 4 patients (16.7%), dorsal cyst in 10 patients (41.7%), abnormal gyral pattern anteriorly in 15 patients (62.5%), anterior located sylvian fissures in 22 patients (99.7%), complete or partial agenesis of the corpus callosum (ACC) in all patients and Dandy-Walker malformation (DWM) in three patients (12.5%). A small occipital cephalocele was detected clinically and radiological as atretic type in MIH patient. Karyotype analysis demonstrated 47, XY+13 in a patient with alobar holoprosencephaly, 46, XY,t(12;13) (q13q24.1;q14q33) in a semilobar case associated with DWM, 46, XY, del(13)(q34) in one semilobar case and three cases had del 7q36 using FISH technique in two semilobar cases and one lobar case. Conclusion: This study highlights the clinical spectrum in patients with HPE and report a case of HPE and DWM associated with t(12;13). Neuroimaging delineated the pathogenesis underlying developmental defects in HPE. Accurate molecular diagnosis is crucial for further understanding of the pathogenesis of HPE.

Prenatal magnetic resonance imaging diagnosis of molar tooth sign at 17 to 18 weeks of gestation in two fetuses at risk for Joubert syndrome and related cerebellar disorders.

We report on the prenatal MRI diagnosis of Joubert syndrome and related cerebellar disorders (JSRD) in 2 unrelated fetuses at 17-18 weeks of gestation who were referred to us with history of siblings with JSRD and additional renal affection in the second case. Ultrasonography (US) showed non-specific cranial findings in both fetuses such as prominent cisterna magna and ventricular system as well as bilateral renal enlargement in the first case. MRI identified the molar tooth sign (MTS) and suggested a JSRD affection in both fetuses. The final suggested diagnosis for both cases was Joubert syndrome with intrafamilial variability in renal expression. This report describes the earliest prenatal detection of MTS. We include a discussion of the differential diagnosis of renal affection in conjunction with MTS and review the previously reported cases with prenatal MRI detection of MTS. The report emphasizes the role of MRI in the early specific prenatal diagnosis of JSRD through the recognition of MTS.

Role of MR imaging in prenatal diagnosis of pregnancies at risk for Joubert syndrome and related cerebellar disorders.

BACKGROUND AND PURPOSE: JSRD are rare autosomal recessive brain malformations. We hypothesized that MR imaging can assess fetuses at risk for JSRD and might influence their diagnoses. MATERIALS AND METHODS: We prospectively performed cranial MR imaging for 12 fetuses (mean GA, 23 weeks; SD, 3.7) at 25% recurrence risk for JSRD. We correlated prenatal MR imaging findings with postnatal MR imaging and clinical outcome. Retrospectively, we compared posterior fossa measurements of the cases with those of 24 age-matched fetuses with proved normal brain MR imaging. Institutional review board approval and consents were obtained. Statistical methods included a t test and ANCOVA tests. RESULTS: Fetal MR imaging correctly diagnosed 3 cases at 22, 28, and 29 weeks of gestation as JSRD, and 9 cases as normal. In JSRD-affected fetuses, prenatal MR imaging detected narrow pontomesencephalic junction (isthmus) with deepening of the interpeduncular fossa and thick horizontally placed superior cerebellar peduncles (MTS), deformed anteriorly convex floor of the fourth ventricle, and midline cerebellar cleft in place of the hypoplastic vermis. Measurements on axial fetal MR imaging at pontomesencephalic junction, ratio of AP diameters of interpeduncular fossa to midbrain/isthmus, and ratio of the AP to transverse diameters of the fourth ventricle were significantly higher in JSRD-affected fetuses than in nonaffected cases and the control group. CONCLUSIONS: MR imaging can diagnose JSRD in at-risk pregnancies by detecting posterior fossa signs. Measurements at the pontomesencephalic junction may enhance fetal MR imaging accuracy in diagnosing JSRD.

The molar tooth sign: a new Joubert syndrome and related cerebellar disorders classification system tested in Egyptian families.

Joubert syndrome and related cerebellar disorders (JSRD) are a group of recessive congenital ataxia conditions usually showing neonatal hypotonia, dysregulated breathing rhythms, oculomotor apraxia, and mental retardation. The pathognomonic finding in JSRD is the unique molar tooth sign (MTS) on brain imaging. There is a tremendously broad spectrum of signs and symptoms mainly including kidney, retina, and liver disease, along with polydactyly and facial dysmorphisms. Here we propose a new diagnostic classification within JSRD that includes four major subtypes. To test this classification, we performed a systematic recruitment and genetic evaluation from a single referral center in Egypt. Thirteen families were identified, four showed evidence of linkage to one of the four known genetic loci, three showed novel AHI1 mutations, and nine were excluded from known loci. Each family could be classified into one of the four subtypes. This classification may thus be useful in the evaluation of patients with JSRD.