Hirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500-5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbing the normal migration, proliferation, differentiation, and/or survival of the enteric neural crest cells as well as impaired interaction with the enteric progenitor cell niche. Early linkage analyses in Mendelian and syndromic forms of HSCR uncovered variants with large effects in major HSCR genes including RET, EDNRB, and their interacting partners in the same biological pathways. With the advances in genome-wide genotyping and next-generation sequencing technologies, there has been a remarkable progress in understanding of the genetic basis of HSCR in the past few years, with common and rare variants with small to moderate effects being uncovered. The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. This review summarizes the roadmap of genetic discoveries of HSCR from the earlier family-based linkage analyses to the recent population-based genome-wide analyses coupled with functional genomics, and how these discoveries facilitated our understanding of the genetic architecture of this complex disease and provide the foundation of clinical translation for precision and stratified medicine.

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The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications.

Congenital Central Hypoventilation Syndrome (CCHS), also referred with the expression "Ondine's Curse", is a rare genetic life-long disease resulting from the mutation of PHOX2B gene on chromosome 4p12.3. CCHS represents an autonomic nervous system disorder; its more fearsome manifestation is central hypoventilation, due to a deficient response of chemoreceptors to hypercapnia and hypoxia. Several associated symptoms can occur, such as pupillary anomalies, arrhythmias, reduced heart rate variability, esophageal dysmotility, and structural comorbidities (Hirschsprung's Disease or neural crest tumours). CCHS typical onset is during the neonatal period, but cases of delayed diagnosis have been reported; moreover, both sporadic or familial cases can occur. In preterm newborns, asphyxia and typical prematurity-related findings may overlap CCHS clinical manifestations and make it harder to formulate a correct diagnosis. The early recognition of CCHS allows appropriate management, useful to reduce immediate and long- term consequences.

Neonatal Congenital Central Hypoventilation Syndrome: Why We Should not Sleep on it. Literature Review of Forty-two Neonatal Onset Cases.

Central Congenital Hypoventilation Syndrome (CCHS) is a rare diagnosis that presents with various forms of autonomic dysfunction. The disease is characterized by reduced chemoreflexes and severe hypoventilation during sleep. Several case reports have noted that patients with CCHS have been found to suffer from hypoglycemic episodes, which frequently present as a seizure. In this report, we will review previous case presentations to alert the physicians about this association with hypoglycemic episodes. Early treatment and monitoring of hypoglycemia will prevent further complications for these populations.

Central Congenital Hypoventilation Syndrome associated with hypoglycemia and seizure

The neural crest is an important transient structure that develops during embryogenesis in vertebrates. Neural crest cells are multipotent progenitor cells that migrate and develop into a diverse range of cells and tissues throughout the body. Although neural crest cells originate from the ectoderm, they can differentiate into mesodermal-type or endodermal-type cells and tissues. Some of these tissues include the peripheral, autonomic, and enteric nervous systems; chromaffin cells of the adrenal medulla; smooth muscles of the intracranial blood vessels; melanocytes of the skin; cartilage and bones of the face; and parafollicular cells of the thyroid gland. Neurocristopathies are a group of diseases caused by the abnormal generation, migration, or differentiation of neural crest cells. They often involve multiple organ systems in a single person, are often familial, and can be associated with the development of neoplasms. As understanding of the neural crest has advanced, many seemingly disparate diseases, such Treacher Collins syndrome, 22q11.2 deletion syndrome, Hirschsprung disease, neuroblastoma, neurocutaneous melanocytosis, and neurofibromatosis, have come to be recognized as neurocristopathies. Neurocristopathies can be divided into three main categories: dysgenetic malformations, neoplasms, and combined dysgenetic and neoplastic syndromes. In this article, neural crest development, as well as several associated dysgenetic, neoplastic, and combined neurocristopathies, are reviewed. Neurocristopathies often have clinical manifestations in multiple organ systems, and radiologists are positioned to have significant roles in the initial diagnosis of these disorders, evaluation of subclinical associated lesions, creation of treatment plans, and patient follow-up. Online supplemental material is available for this article. ©RSNA, 2019.

https://pubs.rsna.org/doi/pdf/10.1148/rg.2019190086

Neurocristopathies: Enigmatic Appearances of Neural Crest Cell-derived Abnormalities.

Background Congenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant disorder caused by pathogenic variants in paired-like homeobox 2B (PHOX2B) gene. Characteristics of neonatal-onset CCHS cases have not been well assessed. The aim of this study is to expand current knowledge of clinical and genetic features of neonates with CCHS and provide data on the genotype-phenotype correlation. Methods We made a retrospective analysis of 14 neonates carrying PHOX2B pathogenic variants from 2014 to 2019 and we reviewed previously published neonatal-onset cases. Clinical and genetic data were analyzed. Moreover, genotype-phenotype correlation analysis was performed. Results We identified a total of 60 neonatal-onset CCHS cases (35 males and 25 females) including 14 novel cases from our local cohort. Nearly 20% (18.2%) of the patients were born prematurely. Nearly half (46.2%) of the patients had abnormal family history. Polyhydramnios was observed in 21.3% (10/47) of the patients. About 90% of the patients manifested symptoms of hypoventilation in the first week of life. Fourteen patients (23.3%) were classified as mild-CCHS and the rest were severe-CCHS. Gastrointestinal manifestations were observed in 71.7% of the patients. Approximately twofold more males than females were affected by Hirschprung disease (HSCR)/variant HSCR (75.8% vs. 35%, P=0.003). Neural crest tumor occurred in 9.1% (4/44) patients. Half patients had polyalanine repeat expansion mutations (PARMs) in PHOX2B (seven with 25 PARM, nine with 26 PARM, twelve with 27 PARM, one with 28 PARM and one with 31 PARM) and the other half patients had 23 distinct non-polyalanine repeat expansion mutations (NPARMs) with one novel pathogenic variant (c.684dup). The prevalence of HSCR and mild-CCHS among patients with NPARMs was significantly greater than that of the patients with PARMs. Conclusions This report provides a large cohort of neonatal-onset CCHS cases. The results indicate that severe hypoventilation and HSCR are frequently observed in this group. NPARMs accounted for half of the cohort with some genotypes tend to be associated with mild phenotype. Molecular testing in neonates with suspicion of CCHS and genetic counseling for CCHS families are highly recommended.

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Congenital central hypoventilation syndrome in neonates: report of fourteen new cases and a review of the literature

Resumo Objetivo Relatar caso de neonato com episodios de apneias recorrentes, diagnosticado com sindrome de hipoventilacao central congenita (SHCC) associada a doenca de Hirschsprung (DH), o que configurou sindrome de Haddad. Descricao do caso Terceiro filho de casal nao consanguineo, nascido a termo, parto normal sem intercorrencias, peso e comprimento adequados para idade gestacional. Logo apos o nascimento apresentou bradipneia, bradicardia e cianose, foi submetido a intubacao orotraqueal e iniciada antibioticoterapia empirica devido a suspeita de sepse neonatal precoce. Durante internacao em UTI neonatal evoluiu com dificuldade de extubacao devido a episodios de dessaturacao durante sono e vigilia. Apresentou quadros recorrentes de hipoglicemia, hiperglicemia, acidose metabolica, distensao abdominal, leucocitose, aumento de proteina C reativa, com hemoculturas negativas e suspeita de erro inato do metabolismo. Aos dois meses foi diagnosticada doenca de Hirschsprung de segmento longo, foi submetido a resseccao do segmento e colostomia a Hartmann. Feita pesquisa genetica por reacao em cadeia da polimerase para pesquisa de SHCC, que evidenciou alelo mutado do gene PHOX2B e confirmou o diagnostico. Comentarios Trata‐se de doenca genetica rara, de heranca autossomica dominante, causada por mutacao no gene PHOX2B , localizado na banda cromossomica 4p12, que resulta em disfuncao do sistema nervoso autonomo. A SHCC tambem pode cursar com doenca de Hirschsprung e tumores derivados da crista neural. Ha correlacao entre fenotipo e genotipo, alem de grande variabilidade fenotipica intrafamiliar. No periodo neonatal pode simular quadros de sepse e erros inatos do metabolismo.

http://www.scielo.br/pdf/rpp/v34n3/0103-0582-rpp-34-03-0374.pdf

Síndrome de hipoventilação central congênita associada à doença de Hirschsprung: relato de caso e revisão de literatura

Objective To report the case of a newborn with recurrent episodes of apnea, diagnosed with Congenital Central hypoventilation syndrome (CCHS) associated with Hirschsprung's disease (HD), configuring Haddad syndrome. Case description Third child born at full-term to a non-consanguineous couple through normal delivery without complications, with appropriate weight and length for gestational age. Soon after birth he started to show bradypnea, bradycardia and cyanosis, being submitted to tracheal intubation and started empiric antibiotic therapy for suspected early neonatal sepsis. During hospitalization in the NICU, he showed difficulty to undergo extubation due to episodes of desaturation during sleep and wakefulness. He had recurrent episodes of hypoglycemia, hyperglycemia, metabolic acidosis, abdominal distension, leukocytosis, increase in C-reactive protein levels, with negative blood cultures and suspected inborn error of metabolism. At 2 months of age he was diagnosed with long-segment Hirschsprung's disease and was submitted to segment resection and colostomy through Hartmann's procedure. A genetic research was performed by polymerase chain reaction for CCHS screening, which showed the mutated allele of PHOX2B gene, confirming the diagnosis. Comments This is a rare genetic, autosomal dominant disease, caused by mutation in PHOX2B gene, located in chromosome band 4p12, which results in autonomic nervous system dysfunction. CCHS can also occur with Hirschsprung's disease and tumors derived from the neural crest. There is a correlation between phenotype and genotype, as well as high intrafamilial phenotypic variability. In the neonatal period it can simulate cases of sepsis and inborn errors of metabolism.

https://repositorio.unb.br/bitstream/10482/30184/2/ARTIGO_SindromeHipoventilacaoCentral.pdf

Evely Mirella Santos França

Papers

Síndrome de hipoventilação central congênita associada à doença de Hirschsprung: relato de caso e revisão de literatura

Congenital central hypoventilation syndrome associated with Hirschsprung's Disease: case report and literature review