Dual white matter pathology in fetal holoprosencephaly featuring concurrent malformative and destructive features: A case series.

Holoprosencephaly (HPE) is a classic brain malformation involving defective forebrain induction and patterning. Cases of HPE bearing white matter abnormalities have not been well documented, with only rare cases exhibiting hypoxic-ischemic damage. However, neuroradiologic studies of HPE using diffusion tensor imaging have suggested the presence of white matter architectural disarray. Described in this case series are the clinicopathologic features of 8 fetuses with HPE who underwent autopsy at BC Children's Hospital. All 8 cases exhibited subacute to chronic, periventricular leukomalacia (PVL)-like white matter pathology, with 7 of 8 cases also demonstrating aberrant white matter tracts, one of which manifested as a discreet bundle crossing the midline within the ventral aspects of the fused deep gray nuclei. In 6 of these 7 cases, the PVL-like pathology resided within this aberrant white matter tract. Original workup, alongside an additional HPE-focused next-generation sequencing panel identified a likely etiologic cause for the HPE in 4 cases, with an additional 2 cases exhibiting a variant of unknown significance in genes previously suggested to be involved in HPE. Despite our in-depth clinicopathologic and molecular review, no unifying etiology was definitively identified among our series of fetal HPE bearing this unusual pattern of white matter pathology.

Effects of GLP1 receptor analogues in obesity with neurodevelopmental disorder: case report of a patient with holoprosencephaly.

Holoprosencephaly is an anomaly in the division of the prosencephalon into cerebral hemispheres during the second month of gestation. Patients can present with early-onset obesity favoured by the cognitive impairment. We present a case of a 24 year-old woman with holoprosencephaly and class III obesity who was treated by 2.4 mg/week SEMAGLUTIDE. Her body weight decreased from 115.3 to 94.3 kg after one-year (18% of total body weight loss). In addition, she presented a marked reduction in self- and hetero-aggressive behaviour when exposed to the sight of food. The treatment was well tolerated, with the exception of a few vomiting when eating palatable food too quickly. GLP1-RAs may be interesting for obesity treatment in the context of neurodevelopmental disorders. They appear to reduce compulsive eating and aggressive behaviour, particularly in relation to exposure to food, and lead to weight loss similar to that seen in people without neurodevelopmental disorders.

Cranial vault reduction cranioplasty for severe macrocephaly due to holoprosencephaly and subdural hygroma: a case report.

BACKGROUND: Severe macrocephaly can still be found in developing countries. This condition is usually caused by neglected hydrocephalus and can cause a lot of morbidities. Cranial vault reconstruction cranioplasty is the main treatment option for severe macrocephaly. Holoprosencephaly is often seen with features of microcephaly. Hydrocephalus should be considered as the main cause in HPE patients with features of macrocephaly. In this report, we present a rare case of cranial vault reduction cranioplasty procedure in patient with severe macrocephaly due to holoprosencephaly and subdural hygroma. CASE DESCRIPTION: A 4-year-10-month-old Indonesian boy was admitted with head enlargement since birth. He had a history of VP shunt placement when he was 3 months old. But the condition was neglected. Preoperative head CT showed massive bilateral subdural hygroma that compressed brain parenchyma caudally. From the craniometric calculation, the occipital frontal circumference was 70.5 cm with prominent vertex expansion, the distance between nasion to inion was 11.91 cm and the vertical height was 25.59 cm. The preoperative cranial volume was 24.611 cc. The patient underwent subdural hygroma evacuation and cranial vault reduction cranioplasty. The postoperative cranial volume was 10.468 cc. CONCLUSION: Subdural hygroma can be a rare cause of severe macrocephaly in holoprosencephaly patients. Cranial vault reduction cranioplasty and subdural hygroma evacuation is still the main treatment option. Our procedure successfully reduces significant cranial volume (57.46% volume reduction).

Sinus pericranii associated with syntelencephaly: a case report.

BACKGROUND: Sinus pericranii is a rare cranial venous malformation resulting in a subcutaneous mass due to abnormal communication between intracranial and subperiosteal/interperiosteal veins. To date, to the best of our knowledge, there are no reports of sinus pericranii associated with syntelencephaly, a subtype of lobar holoprosencephaly. We herein report a case of sinus pericranii associated with syntelencephaly. This report can provide us better understanding of the etiology of sinus pericranii, the potential risks, and the treatment options for these patients. CASE PRESENTATION: A 2-year-4-month old female patient who received the diagnosis of syntelencephaly as a neonate presented with a subcutaneous mass in the parietal region. The mass was soft, nonpulsatile, 3 × 2 cm in size, and showed enlargement in the lying position. Color cranial Doppler ultrasound, head magnetic resonance imaging (MRI), and cerebral angiography revealed a dilated vessel passing through the parietal bone and forming a communication between the superior sagittal sinus and scalp veins. Based on these findings, sinus pericranii was diagnosed. The head MRI also showed coronal craniosynostosis, a tight posterior fossa. At age 2 years and 7 months, the patient underwent a transection of the sinus pericranii and the mass resolved without any complications or recurrences for more than 2.5 years to date. CONCLUSION: Sinus pericranii is a rare cranial and venous malformation sometimes accompanied by brain malformations or craniosynostosis that may become more apparent as the brain and skull develop. Since this condition can be complicated by intracranial hemorrhage and sinus thrombosis, early detection is necessary to determine the treatment options. Physicians should be alert to the possibility of this condition if they observe a soft cranial mass that appears to decrease in size in the sitting position and bulge in the lying position.

Congenital complete arhinia with alobar holoprosencephaly.

Congenital arhinia is a life-threatening, rare craniofacial disorder, which, when not identified and managed early can cause severe respiratory distress at birth due to upper airway obstruction. Since neonates are obligate nasal breathers, simultaneous sucking and breathing requirement in neonates with arhinia leads to respiratory distress. Inspiration and expiration through the oral passage alone may result in thoracic retraction, thereby further exacerbating respiratory distress. We report a rare case of congenital complete arhinia with alobar holoprosencephaly in a 9-month-old. With no family history of congenital malformations, maternal risk factors and uneventful pregnancy, a term female neonate was delivered vaginally without immediate post-delivery respiratory distress. Examination revealed microcephaly, absent fontanelles, fused cranial sutures and bilateral microphthalmia. Breathing was spontaneous, with no immediate signs of respiratory distress. An additional diagnosis of alobar holoprosencephaly was made after a head computed tomography (CT) scan was done. Management included the initial stabilisation phase of supplemental oxygen and an orogastric tube for feeding. The baby did not require both tracheostomy and gastrostomy tubes, as she was not in severe respiratory distress requiring a tracheostomy tube nor having difficulties feeding with the orogastric tube.

Case report: a novel mutation in ZIC2 in an infant with microcephaly, holoprosencephaly, and arachnoid cyst.

RATIONALE: Holoprosencephaly (HPE) is a severe congenital brain malformation resulting from failed or incomplete forebrain division in early pregnancy. PATIENT CONCERNS: In this study, we reported a 9-month old infant girl with mild microcephaly, semilobor HPE, and arachnoid cyst. DIAGNOSES: Potential genetic defects were screened directly using trio-case whole exome sequencing (WES) rather than traditional karyotype, microarray, and Sanger sequencing of select genes. OUTCOMES: A previous unpublished de novo missense mutation (c.1069C >G, p.H357D) in the 3rd zinc finger domain (ZFD3) of the ZIC2 gene was identified in the affected individual, but not in the parents. Sanger sequencing using specific primers verified the mutation. Extensive bioinformatics analysis confirmed the pathogenicity of this extremely rare mutation. Phenotype-genotype analysis revealed significant correlation between the 3rd zinc-finger domain with semilobor HPE. LESSONS: These findings expanded the spectrum of the ZIC2 gene mutations and associated clinical manifestations, which is the first identification of a mutated ZIC2 gene in a Han infant girl with mild microcephaly, semilobor HPE, and arachnoid cyst.

The solitary median maxillary central incisor (SMMCI) syndrome: Associations, prenatal diagnosis, and outcomes.

Solitary median maxillary central incisor (SMMCI) syndrome is a complex disorder consisting of multiple, developmental defects involving midline structures of the head, which includes the cranial bones, the maxilla, and its container dentition (specifically the central incisor tooth germ), together with other midline structures of the body. SMMCI may appear as an isolated trait or in association with other midline developmental anomalies. We describe the case of a patient with SMMCI. He presented with a solitary median maxillary incisor, short stature, corpus callosum anomalies and a microform of holoprosencephaly (HPE), diabetes insipidus, and neurodevelopmental delay. The diagnosis was performed postnatally based on clinical features, radiological imaging, and a comprehensive genetic study. SMMCI can be diagnosed during the prenatal or neonatal periods or during infancy. Evaluation of the superior maxillary bone is important for prenatal diagnosis. Direct evaluation through bidimensional ultrasound or the use of multiplanar ultrasound or tridimensional reconstruction should be performed in cases of brain or face malformations. Early diagnosis can contribute to improved prenatal assessment and postnatal management.

Reverse Distraction for Treatment of Hydrocephalic Macrocephaly in Late Childhood.

Macrocephaly diminishes quality of life for children whose head size inhibits independent mobility and appropriate interaction with caregivers. Cranial reduction is a method of addressing these issues, historically with a high morbidity due most commonly to bleeding and shunt complications. The authors present a 9-year-old girl with holoprosencephaly and severe macrocephaly from progressive hydrocephalus who underwent cranial reduction via reverse distraction osteogenesis, a method to slowly reduce the skull volume. The patient underwent circumferential occipital temporoparietal frontal craniotomy with placement of 4 cranial distractors, followed approximately 1 month later by removal of the distractors and cranioplasty with resorbable fixation devices. The patient demonstrated significant postoperative improvement in head control and interaction in school activities. This is the oldest patient with macrocephaly treated with reverse distraction in the literature to date. The slow contraction of the cranial vault with limited bony surgery at the time of initial reduction provides an additional safety margin, and should be considered in older children presenting with profound macrocephaly.

First-Trimester Diagnosis of Agnathia-Otocephaly Complex: A Series of 4 Cases and Review of the Literature.

First-trimester ultrasound findings in 4 fetuses with agnathia-otocephaly complex are described. In addition, information from 3 cases reported in the literature was also reviewed, for a total of 7 cases analyzed. All 7 fetuses presented with agnathia and 6 with ventrocaudal displacement of the ears (melotia/synotia). Four fetuses had holoprosencephaly. In 6 cases, the parents opted for termination of pregnancy. The remaining case resulted in premature delivery at 26 weeks due to severe polyhydramnios and early neonatal death. This report highlights the important role of ultrasound in the identification of agnathia-otocephaly complex in the first trimester of pregnancy.

Alobar holoprosencephaly associated with a rare chromosomal abnormality: Case report and literature review.

RATIONALE: Holoprosencephaly is a structural malformation of the brain that results from the complete or incomplete noncleavage of the forebrain of the embryo into 2 hemispheres. We report a severe case of alobar holoprosencephaly diagnosed at 38 weeks, associated with cebocephaly, microcephaly, and craniosynostosis. PATIENT CONCERN: The main knowledge added by this case is the late ultrasound diagnosis and chromosomal analysis that revealed a very rare abnormality (45X/46,XX/47,XX) with mosaicism at chromosome 18. DIAGNOSES: Investigation of the mother revealed nothing remarkable from clinical point of view and on laboratory tests. Ultrasonography identified a fetal biometry appropriate for gestational age, except for the head biometry and abdominal circumference, that were appropriate for less than the fifth percentile. Microcephaly, a large midline monoventricle, absent midlinestructures, cleft lip, cebocephaly (hypotelorism, single-nostril nose), ethmocephaly (hypotelorism, interorbital proboscis) and craniosynostosis, were also present. Fetal magnetic resonance imaging of fetus revealed an absent midline structure, a central monoventricle, abnormal corpus calosum, and abnormal gyri. INTERVENTIONS: A cesarean section at 38 weeks was indicated for fetal bradycardia and a female baby was delivered, with Apgar score 6, weight 2290g. After birth, the diagnosis of the fetus confirmed holoprosencephaly with facial anomalies and demonstrated repeated tonic-clonic seizure, severe respiratory failure, cyanosis, decreased muscle tone, palor, and apnea. Laboratory examination of the newborn revealed acidosis and a prolonged of prothrombin time. The neonate was treated for severe respiratory distress syndrome, with immediate intubation and resuscitation. Vitamin K, fresh frozen plasma, and antibiotics were also administered. OUTCOMES: After delivery, exitus of the fetus occurred at 3 days and 18hours due to massive pulmonary hemorrhage. LESSONS: We described a case of alobar holoprosencephaly diagnosed at 38 weeks of gestation and associated with a rare chromosomal abnormality (45X/46,XX/47,XX) with mosaicism at chromosome 18. Emotional implications could have been less severe if the patient underwent regular ultrasonography allowing a diagnosis in the first or early second trimester.

Management Strategies for Hydrocephalus in Alobar Holoprosencephaly: A Case Report and Discussion.

Holoprosencephaly is a rare congenital malformation resulting from an impaired midline division of the prosencephalon into distinct cerebral hemispheres. Hydrocephalus is a frequent problem among the few survivors with alobar holoprosencephaly (aHPE), its most severe form. The literature about neurosurgical management of hydrocephalus in this condition is limited and dispersed, and there are still some points that need to be resolved. We report the case of a newborn with aHPE, hydrocephalus, and central diabetes insipidus. We delineate the complexity of the management of these patients and emphasize the benefits of using an initial programmable shunt valve. Further discussion about management strategies includes reviewing previous reports and the benefits of shunting for hypothalamic osmoreceptor function.

Detailed qualitative analysis of honeybush tea (Cyclopia spp.) volatiles by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry and relation with sensory data.

The volatile composition of honeybush (Cyclopia) species was studied by comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOF-MS). Headspace-solid phase micro-extraction (HS-SPME) was used to extract the volatile compounds from tea infusions prepared from the three species C. genistoides, C. maculata and C. subternata. A total of 287 compounds were identified, 101 of which were confirmed using reference standards, while the remainder were tentatively identified using mass spectral and retention index (RI) data. The identification power of TOF-MS enabled the tentative identification of 147 compounds for the first time in honeybush tea. The majority of the compounds identified were common to all three Cyclopia species, although there were differences in their relative abundances, and some compounds were unique to each of the species. In C. genistoides, C. maculata and C. subternata 265, 257 and 238 compounds were identified, respectively. Noteworthy was the tentative identification of cinnamaldehyde in particular C. maculata samples, which points to the likely contribution of this compound to their distinct sensory profiles. This study emphasises the complexity of honeybush tea volatile composition and confirms the power of GC×GC combined with TOF-MS for the analysis of such complex samples.

Human germline hedgehog pathway mutations predispose to fatty liver.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease. Activation of hedgehog (Hh) signaling has been implicated in the progression of NAFLD and proposed as a therapeutic target; however, the effects of Hh signaling inhibition have not been studied in humans with germline mutations that affect this pathway. METHODS: Patients with holoprosencephaly (HPE), a disorder associated with germline mutations disrupting Sonic hedgehog (SHH) signaling, were clinically evaluated for NAFLD. A combined mouse model of Hh signaling attenuation (Gli2 heterozygous null: Gli2+/-) and diet-induced NAFLD was used to examine aspects of NAFLD and hepatic gene expression profiles, including molecular markers of hepatic fibrosis and inflammation. RESULTS: Patients with HPE had a higher prevalence of liver steatosis compared to the general population, independent of obesity. Exposure of Gli2+/- mice to fatty liver-inducing diets resulted in increased liver steatosis compared to wild-type mice. Similar to humans, this effect was independent of obesity in the mutant mice and was associated with decreased expression of pro-fibrotic and pro-inflammatory genes, and increased expression of PPARγ, a potent anti-fibrogenic and anti-inflammatory regulator. Interestingly, tumor suppressors p53 and p16INK4 were found to be downregulated in the Gli2+/- mice exposed to a high-fat diet. CONCLUSIONS: Our results indicate that germline mutations disrupting Hh signaling promotes liver steatosis, independent of obesity, with reduced fibrosis. While Hh signaling inhibition has been associated with a better NAFLD prognosis, further studies are required to evaluate the long-term effects of mutations affecting this pathway. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is characterized by excess fat deposition in the liver predominantly due to high calorie intake and a sedentary lifestyle. NAFLD progression is usually accompanied by activation of the Sonic hedgehog (SHH) pathway leading to fibrous buildup (scar tissue) and inflammation of the liver tissue. For the first time patients with holoprosencephaly, a disease caused by SHH signaling mutations, are shown to have increased liver steatosis independent of obesity. This observation was recapitulated in a mouse model of attenuated SHH signaling that also showed increased liver steatosis but with decreased fibrosis and inflammation. While SHH inhibition is associated with a good NAFLD prognosis, this increase in liver fat accumulation in the context of SHH signaling inhibition must be studied prospectively to evaluate its long-term effects, especially in individuals with Western-type dietary habits.

[Alobar holoprosencephaly associated with diabetes insipidus and hypothyroidism in a 10-month old infant]. / Holoprosencéphalie alobaire avec diabète insipide et hypothyroïdie chez un nourrisson de 10 mois.

Holoprosencephaly (HPE) is a serious brain malformation due to a failure of medial forebrain cleavage. This is an abnormality which is more often associated with craniofacial malformations, psychomotor development delay, diabetes insipidus and variable endocrine disorders. It is due to different causes including chromosomal abnormalities (trisomy 13, 18)and polymalformative syndromes (CHARGE Syndrome). Diagnosis is based on brain imaging. A few rare cases have been described in the literature. We here report the case of alobar HPE in a 10-month old infant. Diagnosis was based on cerebral CT scan performed due to delayed psychomotor development and in the absence of visible malformations. Endocrine assessment allowed to detect central diabetes insipidus and central hypothyroidism, probably of hypothalamic origin.