Mutations in MYO1H cause a recessive form of central hypoventilation with autonomic dysfunction.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare life-threatening disorder of respiratory and autonomic regulation. It is classically caused by dominant mutations in the transcription factor PHOX2B. The objective of the present study was to identify the molecular cause of a recessive form of central hypoventilation with autonomic dysfunction. METHODS: Here, we used homozygosity mapping and whole-genome sequencing in a consanguineous family with CCHS in combination with functional analyses in CRISPR/Cas9 engineered mice. RESULTS: We report on a consanguineous family with three affected children, all tested PHOX2B mutation negative, presenting with alveolar hypoventilation and symptoms of autonomic dysregulation. Whole-genome sequencing revealed a homozygous frameshift mutation in exon 25 of the MYO1H gene (c.2524_2524delA) segregating with the phenotype in the family. MYO1H encodes for the unconventional myosin IH, which is thought to function as a motor protein in intracellular transport and vesicle trafficking. We show that Myo1h is broadly expressed in the mouse lower medulla, including the CO2-sensitive Phox2b+ retrotrapezoid neurons. To test the pathogenicity of the variant, we engineered two Myo1h mutant mouse strains: the first strain (Myo1h*) resembling the human mutation and the second being a full knock-out (Myo1hFS ). Whole-body plethysmography studies in Myo1h* newborns with the re-engineered human mutation revealed hypoventilation and a blunted response to CO2, recapitulating the breathing phenotype observed in the kindred. CONCLUSIONS: Our results identify MYO1H as an important gene in CO2 sensitivity and respiratory control and as the cause of a rare recessive form of congenital central hypoventilation.

Congenital Cases of Concomitant Harlequin and Horner Syndromes.

We report three pediatric cases of concomitant congenital Horner and Harlequin syndromes. This association suggests a lesion at the superior cervical ganglion or just inferior. Often, no underlying lesion is documented.

Congenital Harlequin syndrome as an isolated phenomenon: A case report and review of the literature.

UNLABELLED: Harlequin syndrome (HS) is a rare autonomic disorder due to a hemifacial cutaneous sympathetic denervation. It is characterized by unilateral diminished sweating and flushing of the face even though after heat or prolonged exercise. It is typically acquired. Congenital cases only represent a 6% of all individuals with HS. All congenital HS cases reported so far showed a concomitant Horner syndrome, probably due to a stellate ganglion involvement. HS represents an uncommon autonomic disorder due to a hemifacial cutaneous sympathetic denervation. It is clinically characterized by a dramatic alteration in facial appearance: ipsilateral denervated pale and dry half from the other intact red and moist half. CONCLUSION: We present, to the best of our knowledge, the first case of a patient with a congenital HS as an isolated phenomenon.

A patient with PMP22-related hereditary neuropathy and DBH-gene-related dysautonomia.

Recurrent focal neuropathy with liability to pressure palsies is a relatively frequent autosomal-dominant demyelinating neuropathy linked to peripheral myelin protein 22 (PMP22) gene deletions. The combination of PMP22 gene mutations with other genetic variants is known to cause a more severe phenotype than expected. We present the case of a patient with severe orthostatic hypotension since 12 years of age, who inherited a PMP22 gene deletion from his father. Genetic double trouble was suspected because of selective sympathetic autonomic disturbances. Through exome-sequencing analysis, we identified two novel mutations in the dopamine beta hydroxylase gene. Moreover, with interactome analysis, we excluded a further influence on the origin of the disease by variants in other genes. This case increases the number of unique patients presenting with dopamine-ß-hydroxylase deficiency and of cases with genetically proven double trouble. Finding the right, complete diagnosis is crucial to obtain adequate medical care and appropriate genetic counseling.

A practical guide for the diagnosis of primary enteric nervous system disorders.

OBJECTIVE: Primary gastrointestinal neuropathies are a heterogeneous group of enteric nervous system (ENS) disorders that continue to cause difficulties in diagnosis and histological interpretation. Recently, an international working group published guidelines for histological techniques and reporting, along with a classification of gastrointestinal neuromuscular pathology. The aim of this article was to review and summarize the key issues for pediatric gastroenterologists on the diagnostic workup of congenital ENS disorders. In addition, we provide further commentary on the continuing controversies in the field. RESULTS: Although the diagnostic criteria for Hirschsprung disease are well established, those for other forms of dysganglionosis remain ill-defined. Appropriate tissue sampling, handling, and expert interpretation are crucial to maximize diagnostic accuracy and reduce interobserver variability. The absence of validated age-related normal values for neuronal density, along with the lack of correlation between clinical and histological findings, result in significant diagnostic uncertainties while diagnosing quantitative aberrations such as hypoganglionosis or ultrashort Hirschsprung disease. Intestinal neuronal dysplasia remains a histological description of unclear significance. CONCLUSIONS: The evaluation of cellular quantitative or qualitative abnormalities of the ENS for clinical diagnosis remains complex. Such analysis should be carried out in laboratories that have the necessary expertise and access to their own validated reference values.

Congenital central hypoventilation syndrome and the PHOX2B gene: a model of respiratory and autonomic dysregulation.

The paired-like homeobox 2B gene (PHOX2B) is the disease-defining gene for congenital central hypoventilation syndrome (CCHS). Individuals with CCHS typically present in the newborn period with alveolar hypoventilation during sleep and often during wakefulness, altered respiratory control including reduced or absent ventilatory responses to hypercarbia and hypoxemia, and autonomic nervous system (ANS) dysregulation; however, a subset of individuals present well into adulthood. Thermoregulation is altered and perception of shortness of breath is absent, but voluntary breathing is retained. Structural and functional magnetic resonance imaging (MRI) and limited post-mortem studies in subjects with CCHS reveal abnormalities in both forebrain and brainstem. MRI changes appear in the hypothalamus (responsible for thermal drive to breathing), posterior thalamus and midbrain (mediating O(2) and oscillatory motor patterns), caudal raphé and locus coeruleus (regulating serotonergic and noradrenergic systems), the lateral medulla, parabrachial pons, and cerebellum (coordinating chemoreceptor and somatic afferent activity with breathing), and insular and cingulate cortices (mediating shortness of breath perception). Structural and functional alterations in these sites may result from PHOX2B mutations or be secondary to hypoxia/perfusion alterations from suboptimal management/compliance. The study of CCHS, with collaboration between physician-scientists and basic scientists, offers a rare opportunity to investigate control of breathing within the complex physiological network of the ANS.

Congenital central hypoventilation syndrome: neurocognitive functioning in school age children.

OBJECTIVE: Examine indices of neurocognitive functioning in children with PHOX2B mutation-confirmed neonatal onset congenital central hypoventilation syndrome (CCHS) and relate them to indices of PHOX2B genotype, demographics, and disease severity. METHODS: Subjects were 20 patients with PHOX2B mutation-confirmed CCHS diagnosed as neonates who had undergone neurocognitive assessment in the course of clinical care at the Rush Children's Hospital CCHS Center between 1990 and 2006. Neurocognitive variables of interest included Full Scale IQ (FSIQ) and Wechsler-derived marker indices (subtests) of verbal comprehension (Vocabulary), visuoperceptual reasoning (Block Design), working memory (Digit Span), and clerical/processing speed (Coding). RESULTS: Single sample t-tests revealed participants' general intelligence index (FSIQ; mean 84.9, SD 23.6) to be lower than the general population, though the range of FSIQ observed was broad. Visuoperceptual reasoning and clerical/visuographic speed marker indices were similarly depressed. These deficits were related to special education participation but not to PHOX2B genotype status or other demographic and clinical risk factors. CONCLUSIONS: PHOX2B mutation-confirmed CCHS confers risk for adverse neurocognitive outcome, though the range of functioning observed raises questions about factors that may contribute to neurocognitive variability. Visuoperceptual reasoning and clerical/visuographic speed appear particularly vulnerable. PHOX2B genotype and disease severity indicators were unrelated to neurocognitive indices, possibly due to our modest sample. Future research should employ comprehensive neurocognitive assessment emphasizing visuoperceptual ability, mental speed, attention, and information processing efficiency. Increased recognition and expedited diagnosis with PHOX2B testing should allow larger studies of the relationship between neurocognitive functioning, PHOX2B genotype/mutation, and disease severity and management.

A nonverbal learning disability in a case of central hypoventilation syndrome without a PHOX2B gene mutation.

This study examines the neuropsychological profile of a boy with congenital central hypoventilation syndrome (CCHS) without a paired-like homeobox gene (PHOX2B) mutation. CCHS is a rare disorder of autonomic nervous system development characterized by an impaired ventilatory response to hypercarbia and hypoxemia. Mild intellectual deficits are common but a specific cognitive profile is not established in CCHS. We describe a nonverbal learning disorder as a CCHS endophenotype and recommend that detailed neuropsychological testing be performed on all individuals with CCHS. Defining the psycho-educational needs in CCHS may avert compounding the emotional and medical stresses of this already debilitating disorder.

International Classification of Functioning, Disability and Health in children with congenital central hypoventilation syndrome.

PURPOSE: The main aim of this study is to examine the functioning of children with congenital central hypoventilation syndrome (CCHS), a rare disorder of respiratory control associated with physiological and anatomical manifestations of a generalised autonomic nervous system dysfunction, using WHO's International Classification of Functioning, Disability and Health, Children and Youth version (ICF-CY). METHOD: The data of 26 children, (F = 17) aged 1.5-17.5 years, were collected. Data were analysed in the following four age groups: <3, 3-6, 7-12 and 13-18 years, using only the ICF-CY questionnaires' cross-age items. RESULTS: In the body functions, component breathing and paying attention were common problems for four age groups. In the activity and participation component, all children, except adolescents, showed problems with language. Furthermore, problems in social interaction were evident for all age ranges, except the youngest. Finally, in the environmental factors component, parents reported limitations concerning the natural environment and human-made changes to the environment that were common to all ages. CONCLUSIONS: The study supports the usefulness of supplementing diagnostic classifications with functional classifications to obtain complete information on health-related conditions in children with CCHS.

Abnormal sympathetic nervous system development and physiological dysautonomia in Egr3-deficient mice.

Sympathetic nervous system development depends upon many factors that mediate neuron migration, differentiation and survival. Target tissue-derived nerve growth factor (NGF) signaling-induced gene expression is required for survival, differentiation and target tissue innervation of post-migratory sympathetic neurons. However, the transcriptional regulatory mechanisms mediated by NGF signaling are very poorly defined. Here, we identify Egr3, a member of the early growth response (Egr) family of transcriptional regulators, as having an important role in sympathetic nervous system development. Egr3 is regulated by NGF signaling and it is expressed in sympathetic neurons during development when they depend upon NGF for survival and target tissue innervation. Egr3-deficient mice have severe sympathetic target tissue innervation abnormalities and profound physiological dysautonomia. Unlike NGF, which is essential for sympathetic neuron survival and for axon branching within target tissues, Egr3 is required for normal terminal axon extension and branching, but not for neuron survival. The results indicate that Egr3 is a novel NGF signaling effector that regulates sympathetic neuron gene expression required for normal target tissue innervation and function. Egr3-deficient mice have a phenotype that is remarkably similar to humans with sympathetic nervous system disease, raising the possibility that it may have a role in some forms of human dysautonomia, most of which have no known cause.

Anesthetic implications of undiagnosed late onset central hypoventilation syndrome in a child: from elective tonsillectomy to tracheostomy.

Late onset central hypoventilation syndrome is a neurological disorder that can present with postoperative respiratory complications and delayed emergence in children after anesthesia. We present a child who had unanticipated respiratory complications following an elective tonsillectomy who eventually required a tracheostomy and long-term ventilatory support.

Alphafoetoprotein and acetylcholinesterase in amniotic fluid as a factor suggesting fetal skin and nerve lesions in a case of congenital varicella syndrome.

BACKGROUND: Prenatal care of pregnant women exposed to varicella skin rash during the first half of pregnancy remains a frequent concern in countries that do not have access to systematic vaccination. The frequency of maternofetal transmission is low. Ultrasound is the usual tool for prenatal survey of exposed fetuses. But many anomalies due to VZV infection are not accessible to ultrasound alone. CASE REPORT: We review a case in which the diagnosis of fetal infection suspected due to transient fetal bowel hyperechogenicity was confirmed in amniotic fluid by molecular biology (PCR). RESULTS: An unusual elevation of alphafoetoprotein in maternal blood and in amniotic fluid was associated with inguinal skin, muscular and nerve destruction. CONCLUSION: In fetuses diagnosed with in utero varicella infection, in addition to a precise diagnosis and follow-up, we suggest that elevated AFP levels in maternal blood and amniotic fluid together with the presence of acetylcholinesterase in amniotic fluid may be related to lesion of fetal skin and nerves.

Epidemiologic survey of 196 patients with congenital central hypoventilation syndrome.

This study examined the cross-sectional medical and social characteristics of children diagnosed with congenital central hypoventilation syndrome (CCHS). A detailed questionnaire was mailed to all families with a child with CCHS who are affiliated with a family network or support group. The questionnaire response rate was >75% (n=196). Mean age was 10.22 years +/- 6.6 years (SD) (range, 0.4-38 years), with a 1:1 sex ratio. Multisystem involvement was almost universal among the cohort, with Hirschsprung's disease (HD) present in 16.3%; 61.7% of the children had a tracheotomy, but 14.3% were never tracheotomized, with 77 subjects (39.3%) not having a tracheostomy tube at time of survey. Respiratory support approaches varied but clearly reflected the trend towards earlier and more widespread transition to noninvasive ventilatory modalities. Significant developmental problems were noted, but attendance in regular classes occurred in the majority. Significant deficiencies in routine periodic evaluation and management were reported. In addition, the presence of CCHS was associated with a significant financial and psychosocial burden to the families. In conclusion, a comprehensive survey of 196 CCHS children and their families revealed a cross-sectional picture of substantial medical and psychosocial complexities associated with this disorder, and pointed out substantial inadequacies in routine preventive care that appear to impose stress on the families. The emerging trend of earlier transition to noninvasive ventilatory support warrants future studies. Implementation of recommended guidelines for diagnosis and multidisciplinary follow-up of CCHS should ultimately ameliorate the long-term outcome of this lifelong condition.

Molecular genetics of colorectal motility disorders.

In the last years, several genes have been identified which are involved in the development and differentiation of the enteric nervous system (ENS). Among the congenital intestinal innervation disorders described (aganglionosis, hypoganglionosis, heterotopic ganglia, intestinal neuronal dysplasia), up to now Hirschsprung's disease (HSCR) has been linked to mutational defects in these genes. GDNF and its co-receptor RET are the genes with the most mitogene potency on precursor cells of the ENS. The endothelin system (EDNRB/EDN3) also plays a key role in the development of the ENS by preventing its premature differentiation. Our own studies could show that, whereas a homozygous mutation of EDNRB causes long-segment HSCR, a heterozygous EDNRB deficiency leads to alterations of the ENS resembling the histopathology observed in intestinal neuronal dysplasia. Modern molecular genetic technologies combined with a subtle phenotypic assessment of the ENS will allow investigators to identify other genes within the complex signalling cascade required for the formation of the ENS. The recognition that intestinal innervation disorders are, at least in part, a multigenetic disease should provide support for consequent genetic screening in these patients.

[Clinico-psychopathological aspects of borderline mental disorders in infancy]. / Kliniko-psikhopatologicheskie aspekty pogranichnykh psikhicheskikh rasstroistv v mladenchestve.

The authors summarize the data obtained during a comprehensive examination of 200 children of the first year of life with borderline mental disorders. Abnormalities of vegetative and instinctive regulation, psychomotor and affective disorders which are, as a rule, of the borderline nature, occupy the leading position in the structure of the above-indicated disorders. The latter ones are associated frequently enough with different types of development retardation and neurological deviations from normal. The signs of differentiating between these disorders and analogous ones within the framework of endogenous mental pathology are depicted. The role is demonstrated of etiological factors (perinatal encephalopathy, constitutional, psychosocial, disturbances of the mother-child system). The studies attest to the basic demonstrability of psychopathological abnormalities and to their great diversity in infants.

Congenital dopamine-beta-hydroxylase deficiency. A novel orthostatic syndrome.

A woman was referred with severe orthostatic hypotension at the age of 21. Ptosis, skeletal muscle hypotonia, and recurrent hypoglycaemia had been noticed in early childhood. There was noradrenergic denervation and adrenomedullary failure but baroreflex afferents, cholinergic innervation, and adrenocortical function were intact. Noradrenaline and adrenaline were undetectable in plasma, urine, and cerebrospinal fluid (CSF), but dopamine was 7-fold to 12-fold normal in plasma, 4-fold normal in urine, and 20-fold normal in CSF. Measurements of catecholamine metabolites showed further evidence for impairment of noradrenaline and adrenaline biosynthesis due to deficient dopamine-beta-hydroxylation. Dopamine-beta-hydroxylase was undetectable in plasma and CSF. Physiological and pharmacological stimuli of sympathetic neurotransmitter release caused increases in plasma dopamine rather than plasma noradrenaline.

Congenital dysautonomia with secretory diarrhea.

A 1-year-old boy was evaluated because of failure-to-thrive and persistent diarrhea. His illness was characterized by autonomic dysfunction sharing some features of both familial dysautonomia and congenital sensory neuropathy with anhidrosis, but was consistent with neither diagnosis. The gastrointestinal tract was involved: esophageal motility was abnormal and moderate secretory diarrhea was present. This report documents an unusual case of congenital autonomic dysfunction with secretory diarrhea.

Sleep apnea studies in an infant with congenital primary hypoventilation ("Ondine's curse").

Recurrent apneic episodes were typically associated with sleep, not wakefulness, in an infant with congenital primary hypoventilation ("Ondine's Curse"). Quiet sleep (SLQ) was shown to constitute a higher risk condition than active sleep (SLA) at the ages she was recorded polygraphically (2-4 months old). This infant's respiratory disorder was complicated by recurrent pneumonia, seizures and deficient growth which resulted in death at the age of eight months. Necropsy revealed bronchopulmonary dysplastic fibrosis and cor pulmonale. Neuropathologic examination failed to reveal pathologic changes in the brainstem.