Genetic Study in a Cohort of Children With ROHHAD Syndrome

Introduction: Rapid-onset obesity, hypoventilation, hypothalamic dysfunction and autonomic dysregulation (ROHHAD) is a rare syndrome beginning at 3-6 years of age with approximately 150 cases described. Additional features include eye abnormalities, neurobehavioral dysfunction and paraneoplastic tumors. The etiology of the complex phenotype remains unknown. Methods: This study aims to investigate the genetic landscape of this complex phenotype by whole exome sequencing (WES) and copy number variation (CNV) analysis. We recruited 33 families (27 trios, 1 duo and 5 singletons) with a proband with ROHHAD syndrome (Ize-Ludlow 2007, Pediatrics). WES of 89 individuals was performed at the Center for Mendelian Genomics, Broad Institute. The Illumina platform with a mean coverage of ~100X (> 90% targets 20x) and Infinium Global Screening Array BeadChip 24v1.0 were used. Results: This report includes 28 probands (female = 18, 64%) with rapid onset obesity (100%), hypoventilation (88%), hypothalamic dysfunction (69%), eye disorders (62%) and neurobehavioral abnormalities (76%). Neuroendocrine tumor, ganglioneuroblastoma, was present in 38% (n=13). No unifying causative single gene or CNV was identified, but a number of sequence variants are prioritized. ARNT2, which encodes for a helix-loop-helix transcription factor, plays a role in the development of the hypothalamic-pituitary axis, postnatal brain growth, and visual and renal function. The de novo monoallelic missense variant was found in a 14-year old white girl (BMIz +3.25) with extreme obesity and a neurobehavioral phenotype. OCRL1, a multi-domain protein involved in cytoskeleton-plasma membrane adhesion, endosomal trafficking and in primary cilium assembly. Mutations in this gene have also been known to cause Lowe syndrome. A hemizygous X-linked frameshift variant in a 5-year old white boy with extreme obesity (BMIz +5.48), central hypoventilation neurobehavioral dysfunction and ganglioneuroblastoma. A monoallelic missense variant in NSD1, a transcriptional intermediary factor acting as a histone methyltransferase, was identified in a 8-year old Hispanic girl with severe obesity (BMIz +2.91), neurobehavioral disorder, pituitary and eye dysfunction and ganglioneuroblastoma. NSD1 is known to cause Sotos and Beckwith-Wiedemann. Compound heterozygous variants in KIF7, a key component of the Hedgehog signaling pathway, were identified in a 14-year old white girl with severe obesity (BMIz +3.00), autistic behavior, pituitary dysfunction and central hypoventilation. This gene is known to cause autosomal recessive hydrolethalis and acroscallosal syndromes with mutations also noted in Bardet-Biedl, Meckel and Joubert syndromes. Conclusion: While no unifying genetic cause has been identified in ROHHAD syndrome, it is possible that the phenotype represents a collection of complex genetic syndromes.

Vitrectomy for Tractional Retinal Detachment Due to Combined Hamartoma of the Retina and Retinal Pigment Epithelium

Purpose: We discuss a peripheral combined hamartoma of the retina and retinal pigment epithelium (CHRRPE) with a macula-involving TRD that was repaired by vitrectomy surgery. Methods: A case report is presented. Results: A 15-year-old white girl with no significant medical or ocular history presented to the retina clinic with a 1-month history of progressive loss of inferior visual field in the right eye. A large, elevated CHRRPE was found in the superior midperipheral retina. On involvement of the macula, urgent vitrectomy surgery with peeling of the cortical vitreous membrane to the margins of the hamartoma was performed. Eighteen months later, vision had returned to 20/16 and the retina, relieved of traction, continued to reattach with trace remaining cystic changes at the fovea on optical coherence tomography. Conclusions: Physicians should consider vitrectomy surgery with membrane peeling of the cortical vitreous for TRD due to CHRRPE.

“Problem Children” and “Children with Problems”: Discipline and Innocence in a Gentrifying Elementary School

This article examines the ways Hazel, a white girl entering kindergarten, became known as a child with a problem rather than a problem child in her gentrifying school. Building on a year of classroom observations and interviews with students, school staff, and parents, author Alexandra Freidus identifies the role of racialized discourses related to disposition, medicalization, family, and community in shaping Hazel’s reputation and contrasts Hazel’s reputation with that of Marquise, a Black boy in her class. Hazel’s and Marquise’s storylines teach us that to fully understand and address the differences in how Black and white children are disciplined, we need to look closely at the allowances and affordances we make for some students, as well as how we disproportionately punish others. By examining the ways educators in a gentrifying school construct white innocence and Black culpability, this study illustrates the relational nature of the “school discipline gap” and helps us understand how and why some children are disproportionately subject to surveillance and exclusion and others are not.

“Problem Children” and “Children with Problems”: Discipline and Innocence in a Gentrifying Elementary School

This article examines the ways Hazel, a white girl entering kindergarten, became known as a child with a problem rather than a problem child in her gentrifying school. Building on a year of classroom observations and interviews with students, school staff, and parents, author Alexandra Freidus identifies the role of racialized discourses related to disposition, medicalization, and family and community in shaping Hazel’s reputation and contrasts Hazel’s reputation with that of Marquise, a Black boy in her class. Hazel’s and Marquise’s storylines teach us that to fully understand and address the differences in how Black and white children are disciplined, we need to look closely at the allowances and affordances we make for some students, as well as how we disproportionately punish others. By examining the ways educators in a gentrifying school construct white innocence and Black culpability, this study illustrates the relational nature of the “school discipline gap” and helps us understand how and why some children are disproportionately subject to surveillance and exclusion when others are not.

Not a white girl and speaking English with slang: Negotiating Hmong American identities in Minneapolis-St. Paul, Minnesota, USA

This paper analyzes metalinguistic comments of two young Hmong Americans in the Minneapolis-St Paul area regarding their identity negotiation using tactics of intersubjectivity (Bucholtz & Hall 2004a, 2004b, 2005), the notion of brought-along identity (Williams 2008) and Zhang's (2017) sociohistorical perspectives in analyzing linguistic variation. Two Hmong American individuals were selected from over 60 Hmong American interviewees because their vowel production is nearly identical to each other and that of the local white youth. Although their almost identical vowel production is viewed as their acculturation to the local white majority norm in the first- and second-wave variationist sociolinguistic perspective (Eckert 2012), their speech's characterization reveals a range of potential meanings (Eckert 2008) to index nuanced and unique positions in their local community. The young woman is ambivalent about her speech being characterized as “not having an accent” and claims that she is “not a white girl”. The teenage boy discusses his speech as “Hmonglish” and “English with slang” but carefully distances himself from quintessential African American English. While their characterization of their speech is distinct from each other, their tactics are strikingly similar. Through highlighting and downplaying differences and similarities to a locally salient way of speaking that indexes whiteness or blackness, the two Hmong Americans carve out their own complex identities of race, ethnicity, gender, and class in a local setting.