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.

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.

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.

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.

Primary Abbe Flap for Median Cleft Lip Deformity: New Trends on an Old Concept.

OBJECTIVE: The authors present our experience using primary Abbe flaps for median cleft lip. METHODS: The records of 9 patients who underwent primary Abbe flaps were reviewed for indications, operative details, and complications. Flap design is discussed, including the "W" method to facilitate columellar reconstruction. Maxillomandibular fixation was not used. RESULTS: From 2004 to 2015, 9 patients with median cleft lip received primary Abbe flaps. Mean age was 10.2 ± 6.2 months. Lobar holoprosencephaly was confirmed by imaging in 5 of the 9 patients. Operative time averaged 70 ± 22 minutes. Flap division was performed at a mean of 3.6 ± 0.9 weeks. Patients were followed for a mean of 45 ± 49 months. No flaps were lost to vascular compromise and no dehiscences or infections were noted after initial repair. Five patients required prolonged intubation ranging from 4 to 7 days and 3 required transition to gastric feedings postoperatively. One patient with holoprosencephaly expired for reasons independent of surgery. Four patients have undergone 5 lip revisions to date. CONCLUSIONS: Patients with holoprosencephaly-spectrum disorder and median cleft lip have more favorable prognoses today. The Abbe flap may be safely and advantageously used for the primary repair of median cleft lip with extreme prolabial tissue deficiency.

Subcortical heterotopia appearing as huge midline mass in the newborn brain.

INTRODUCTION: We report the case of a 2-year-old boy who showed a huge midline mass in the brain at prenatal assessment. CASE REPORT: After birth, magnetic resonance imaging (MRI) revealed a conglomerate mass with an infolded microgyrus at the midline, which was suspected as a midline brain-in-brain malformation. MRI also showed incomplete cleavage of his frontal cortex and thalamus, consistent with lobar holoprosencephaly. The patient underwent an incisional biopsy of the mass on the second day of life. The mass consisted of normal central nervous tissue with gray and white matter, representing a heterotopic brain. The malformation was considered to be a subcortical heterotopia. With maturity, focal signal changes and decreased cerebral perfusion became clear on brain imaging, suggesting secondary glial degeneration. Coincident with these MRI abnormalities, the child developed psychomotor retardation and severe epilepsy focused on the side of the intracranial mass.

Lip Repair Surgery for Bilateral Cleft Lip and Palate in a Patient Diagnosed with Trisomy 13 and Holoprosencephaly.

We report a case of lip repair surgery performed for bilateral cleft lip and palate in a patient diagnosed with trisomy 13 and holoprosencephaly. At the age of 2 years and 7 months, the surgery was performed using a modified De Hann design under general anesthesia. The operation was completed in 1 h and 21 min without large fluctuations in the child's general condition. The precise measurement of the intraoperative design was omitted, and the operation was completed using minimal skin sutures. It is possible to perform less-invasive and short surgical procedures after careful consideration during the preoperative planning. Considering the recent improvements in the life expectancy of patients with trisomy 13, we conclude that surgical treatments for non-life threatening malformations such as cleft lip and palate should be performed for such patients.

ECLAMC: 41 años de vigilancia de la holoprosencefalia en Chile. Período 1972-2012 / Frequency of holoprosencephaly in Chile

Background: Holoprosencephaly is a structural anomaly of the brain that consists in a defect of the prosencephalon development that leads to face and neurological defects of variable intensity. Aim: To estimate holoprosencephaly prevalence at birth. Patients and Methods: All cases of holoprosencephaly, born alive or stillbirths, registered in the 15 Chilean Hospitals of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) between 1972 and 2012, were studied. Craniofacial and other anomalies found in newborns affected by holoprosencephaly are described. Results: Fifty five cases of holoprosencephaly (58% males) were found among the 798.222 registered births (rendering a prevalence at birth of 0.69 per 10.000 newborns). The most common cranial defect was medial cleft lip with cleft palate (27.3%), bilateral cleft lip (11%) or both (38.2%), cyclopia (14%), single nostril (10.9%) and proboscis (9.1%). Eleven percent cases had a trisomy 13. A slight increase in prevalence over time was observed. Conclusions: Holoprosencephaly has a low frequency in Chile and is associated to trisomy 13. The increase in prevalence could be explained by a better prenatal diagnosis (ultrasonography).

Limitación/adecuación del esfuerzo terapéutico en pediatría / Limitation/adequacy of therapeutic effort in pediatrics

En niños con condiciones de salud que amenazan sus vidas, el trayecto de la enfermedad puede llevar, en ocasiones, a que los profesionales de la salud y las familias se pregunten si continuar los tratamientos representa la mejor opción para el niño. A veces, limitar o suspender las medidas de soporte vital resulta más apropiado, especialmente si el tratamiento sólo preserva la existencia biológica o si el objetivo global del cuidado ha cambiado a “solamente mantener el confort”. Se presenta el caso de un niño portador de encefalopatía crónica en etapa terminal, en el cual se implementaron medidas de adecuación del esfuerzo terapéutico con el objetivo de permitir una muerte digna. Se describe el proceso de toma de decisiones conjunta con los padres, la forma de registro médico y las principales medidas de cuidado al final de la vida.

Sometimes, the disease trajectory in children with life threatening conditions can lead health professionals and families to wonder whether continuing treatment is the best option for the child. Occasionally, limiting or discontinuing life support measures is advisable, especially if treatment only preserves biological existence or the overall goal of care has shifted to just “maintaining comfort”. The study presents the case of a child with chronic encephalopathy in terminal stadium, for whom measures of therapeutic adequacy were implemented with the aim of allowing a quite death. The shared decision-making process, the medical record document and the main measures of care at end of life are described.

Early two-stage repair of clefts in holoprosencephaly.

UNLABELLED: Holoprosencephaly (HPE) presents with a spectrum of severity, but in its totality is the most common malformation of the embryonic forebrain occurring 1 in 10,000 to 1 in 20,000 live births. Due to the poor prognosis, treatment of mid-face clefts in HPE patients have classically been addressed in a delayed fashion after 1-year of age. Improvements in the ability to manage medical complications associated with HPE along with an increased understanding and lower mortality rates in less severe forms have challenged these previous practiced routines. Accompanied by advances in understanding of HPE and identification of genes responsible for sporadic forms, we are able to better guide timing of surgical intervention. We present a patient with lobar HPE and a type IV facial deformity treated with early repair of the median facial cleft. We believe this treatment strategy was safe, given her relatively good prognosis. We propose that patients with HPE displaying less severe neural non-cleavage may be good candidates for earlier two-stage intervention. SUMMARY: The historically poor prognosis of patients with holoprosencephaly (HPE) has led to midline facial clefts have being addressed in a delayed fashion after 1-year of age. Improvements in the ability to manage medical complications associated with HPE and lower mortality rates in less severe forms have challenged these previous practiced routines. Additionally, the identification of genes responsible for sporadic forms of HPE can better guide timing of surgical intervention and improve developmental outcomes. We present a patient with lobar HPE and a type IV facial deformity treated with an early two-stage repair of the median facial cleft. We propose patients with HPE displaying less severe neural non-cleavage may be good candidates for earlier intervention.

Holoprosencephaly with cerebellar vermis hypoplasia in 13q deletion syndrome: Critical region for cerebellar dysgenesis within 13q32.2q34.

We describe two unrelated patients with terminal deletions in the long arm of chromosome 13 showing brain malformation consisting of holoprosencephaly and cerebellar vermis hypoplasia. Array comparative genomic hybridization analysis revealed a pure terminal deletion of 13q31.3q34 in one patient and a mosaic ring chromosome with 13q32.2q34 deletion in the other. Mutations in ZIC2, located within region 13q32, cause holoprosencephaly, whereas the 13q32.2q32.3 region is associated with cerebellar vermis hypoplasia (Dandy-Walker syndrome). The rare concurrence of these major brain malformations in our patients provides further evidence that 13q32.2q32.3 deletion, harboring ZIC2 and ZIC5, leads to cerebellar dysgenesis.

A novel association of an uncommon pigmentation pattern: coexistence of cutis tricolor with intracranial teratoma and holoprosencephaly.

Cutis tricolor was first described in a 17-year-old male patient by Happle et al. as a rare coexistence of circumscribed hyperpigmentation and hypopigmentation close to each other on a background of normally pigmented skin. Cutis tricolor has been reported as an isolated cutaneous finding or in various associations. To the best of our knowledge, cutis tricolor in association with teratoma and holoprosencephaly has not been reported in the literature. Herein, we report a male patient who presented with a teratoma and a combination of whorl-like hypopigmentation together with hyperpigmented patches adjacent to each other on intermediately pigmented skin. This case report supports the view that cutis tricolor may be a marker of an underlying neurological abnormality.

[Solitary median maxillary central incisor syndrome]. / Het solitaire mediane maxillaire centrale incisief-syndroom.

Solitary Median Maxillary Central Incisor syndrome is a rare condition (prevalence 1:50,000), with the characteristic dental feature of a solitary central incisor in the maxilla, positioned exactly in the midline. This single incisor is symmetrical and can be present in the deciduous as well as in the permanent dentition. The syndrome can occur as a mild form of the broad holoprosencephaly-spectrum, but can also be associated with other characteristics. The etiology is still largely unknown, but the syndrome is probably based especially on genetic causes. Early recognition of the syndrome is of great importance for establishing the diagnosis, for additional investigation, for possible treatment of associated anomalies and for the correct advice concerning the risk of inheritance of severe congenital birth defects, related to holoprosencephaly. Dentists and orthodontists can play an important role in this regard and should therefore be able to recognise the clinical features of this condition and know how to refer a patient for further diagnostic counselling.

Second trimester ultrasound markers of fetal aneuploidy.

Although it is widely accepted that the best time to screen for chromosomal abnormalities is the first trimester, ultrasound evaluation of the fetus in the second trimester has also been shown to be useful for this purpose. A multitude of markers of varying strength has been developed over the past 30 years. In addition, the optimal time to diagnose fetal anomalies with confidence is also the mid second trimester. Therefore, performance of obstetrical ultrasound at this point in gestation continues to be an important component of prenatal care.

Developmental disorders of the dentition: an update.

Dental anomalies are common congenital malformations that can occur either as isolated findings or as part of a syndrome. This review focuses on genetic causes of abnormal tooth development and the implications of these abnormalities for clinical care. As an introduction, we describe general insights into the genetics of tooth development obtained from mouse and zebrafish models. This is followed by a discussion of isolated as well as syndromic tooth agenesis, including Van der Woude syndrome (VWS), ectodermal dysplasias (EDs), oral-facial-digital (OFD) syndrome type I, Rieger syndrome, holoprosencephaly, and tooth anomalies associated with cleft lip and palate. Next, we review delayed formation and eruption of teeth, as well as abnormalities in tooth size, shape, and form. Finally, isolated and syndromic causes of supernumerary teeth are considered, including cleidocranial dysplasia and Gardner syndrome.

Is fetal cerebral MRI worthwhile in antenatally diagnosed isolated cleft lip with or without palate?

OBJECTIVE: This study aims to evaluate the use of fetal brain magnetic resonance imaging (MRI) following an antenatal sonographic diagnosis of isolated cleft lip with or without cleft palate (CL/P). METHOD: This was a retrospective study of 92 fetuses antenatally diagnosed with isolated CL/P on screening ultrasound. All patients underwent expert diagnostic antenatal ultrasound, fetal brain MRI, and karyotype analysis. RESULTS: Five cases were excluded from the study as associated abnormalities were detected on expert ultrasound: corpus callosum agenesis (n = 1), retrognathism (n = 3), and ectrodactyly (n = 1). Fetal MRI diagnosed unsuspected midline cerebral abnormalities in four out of the 87 remaining cases (4.6%): vermis agenesis (n = 1), isolated arhinencephaly (n = 2), and suspicion of pituitary abnormality (n = 1). All karyotype analyses were normal. CONCLUSION: In CL/P, the incidence of associated cerebral abnormalities overlooked on ultrasound is 4.6%. Careful evaluation of midline structures by expert ultrasound in CL/P is necessary and may be sufficient. MRI can be useful if the US examination is limited or in case of family history. However, the choice to proceed to fetal MRI may vary from institution to institution.

Clinical profile and etiologies of children with central diabetes insipidus: a single-center experience from Turkey.

AIM: The aim of this study is to evaluate the clinical, anthropometric, hormonal, and radiological characteristics of children with central diabetes insipidus (DI). METHODS: Case records of 34 children (22 boys and 12 girls) with documented central DI referred to the Pediatric Endocrinology and Adolescent Clinic of Dokuz Eylul University Faculty of Medicine were reviewed. The mean age at diagnosis was 6.4 +/- 5.6 years (range, 0.08-16 years). All patients underwent anterior pituitary function assessment and magnetic resonance imaging of pituitary at diagnosis. The median duration of follow-up was 7.9 +/- 4.5 years. RESULTS: The etiology of central DI was organic in 22 (64.7%) patients, trauma in 2 (5.9%) patients, and idiopathic in 10 (29.4%) patients. Organic causes consisted of craniopharyngioma in 7 patients, Langerhans cell histiocytosis in 4 patients, germinoma in 4 patients, holoprosencephaly in 3 patients, astrocytoma in 1 patient, cavernous hemangioma in 1 patient, Rathke's cleft cyst in 1 patient, and autoimmune polyendocrinopathy in 1 patient. Anterior pituitary hormone deficiencies were documented in 18 (53%) patients. Organic central DI group had a greater prevalence of anterior pituitary hormone deficiency when compared with the idiopathic group (66% and 10%, respectively; p = 0.007). The final height of patients with organic etiology were significantly lower than the idiopathic group (155 and 178, cm respectively; p = 0.021). CONCLUSIONS: Etiological diagnosis is possible in a significant proportion (70.6%) of children with central DI. Findings of this study suggest that accompanying anterior pituitary hormone deficiencies and short stature may be considered as indicators of organic etiology.