A novel missense mutation in the PHOX2B gene is associated with late onset central hypoventilation syndrome

We report the case of a 15-month-old male suffering from Late Onset Congenital Central Hypoventilation Syndrome and recto-sigmoid Hirschsprung's disease, an association that has not been reported thus far. Nevertheless, our patient showed a missense mutation of the PHOX2B gene already known in isolated late onset central hypoventilation, resulting in a substitution of the Ala140 residue with a Glu residue (p.A140E). The present association of LO-CHS and HSCR in a patient harboring a rare and atypical PHOX2B mutation allows to refine the mutational spectrum of this disease and suggests individualized ventilatory care along with specific surgical and oncological approaches.     

PHOX2B gene mutation in a patient with late-onset central hypoventilation

Congenital central hypoventilation syndrome, which is related to abnormal autonomic control of breathing and typically manifests at birth, was recently associated with PHOX2B gene mutations. In contrast, central hypoventilation with later onset constitutes a poorly defined group of unknown etiology. Here, we report on the identification of a de novo heterozygous PHOX2B mutation in a patient with central hypoventilation manifesting in childhood. This finding suggests that some of these cases may be genetically determined and allelic to congenital central hypoventilation syndrome.     

Diagnostic practices and disease surveillance in Canadian children with congenital central hypoventilation syndrome

OBJECTIVE:

To assess the diagnostic and surveillance practices of Canadian pediatric subspecialists for children with congenital central hypoventilation syndrome (CCHS).

METHODS:

The present analysis was a prospective cross-sectional study. A web-based survey was sent to 303 pediatric subspecialists in Canada: 85 pediatric respirologists, 77 pediatric neurologists and 141 neonatologists. The survey included 36 questions about the current diagnostic and surveillance management of pediatric CCHS. Differences in responses among respirologists, neurologists and neonatologists were evaluated for each question, where feasible, and responses were compared with the 2010 American Thoracic Society (ATS) Clinical Policy Statement for CCHS.

RESULTS:

A total of 83 (27%) participants responded to the survey; the highest survey response rate (40%) was from respirologists. For the diagnosis of CCHS, 25% of respondents did not order genetic testing, either alone or with another test, to make a diagnosis of CCHS. The criteria and tests recommended by the ATS to make a diagnosis of CCHS – genetic testing, diagnosis of exclusion, polysomnogram and plus or minus a hypercapnic challenge – were ordered by 23 (43%) of the 54 respondents. Although polysomnograms were ordered for more than 90% of children with CCHS, only 37% of respirologists aimed for a carbon dioxide range of 35 mmHg to 40 mmHg during polysomnogram titrations.

CONCLUSIONS:

The results demonstrate variability in the diagnostic and surveillance practices of pediatric subspecialists in children with CCHS across Canada. The present study provides an initial needs assessment and demonstrated that there are significant deviations in practice from the 2010 ATS guidelines.     

Congenital central hypoventilation syndrome associated with Hirschsprung's disease and neuroblastoma: Case of multiple neurocristopathies

We report on a male infant with the rare combined occurrence of congenital central hypoventilation syndrome (CCHS or Ondine's curse), Hirschsprung's disease (HD), and neuroblastoma. Current therapeutical options leave no doubt that children with isolated forms of CCHS, HD, or neuroblastoma must be treated, but management decisions and the ethical dilemma become more difficult with the presence of multiple neurocristopathies. Our patient was dependent on mechanical ventilation and total parenteral nutrition, when a neuroblastoma was diagnosed at age 5 months. We initiated an attempt at curative chemotherapy. The tumor failed to respond to recommended chemotherapeutic regimens, and the patient died at 11 months of age. We emphasize the importance of screening CCHS patients for associated illnesses such as neuroblastoma and ganglioneuroblastoma at time of diagnosis. Pediatr Pulmonol. 2002; 33:71–76. © 2002 Wiley‐Liss, Inc.     

Supraglottic foreign body in a woman with Down's syndrome and congenital heart disease: A case report

Rationale:An impacted foreign body (FB) in the larynx of an adult is a rare but potentially life-threatening occurrence. Patients with Down''s syndrome (DS) are vulnerable to airway FB. However, the anesthesia for FB removal can be challenging. This report describes a case in which a FB was impacted between the vestibular folds in an adult with DS, congenital heart disease, and a difficult airway.Patient concerns:A 41-year-old woman swallowed a piece of sharp-tipped wooden skewer presented with a sudden onset of aphonia, dysphagia, and an acute sore throat without respiratory difficulty. The patient had DS, congenital heart disease, pulmonary arterial hypertension, and severe obstructive sleep apnea–hypopnea syndrome. The airway evaluation indicated that ventilation and intubation would be difficult due to retrognathia, macroglossia, adenotonsillar hypertrophy, and Mallampati''s classification III.Diagnosis:The clinical symptoms and laboratory examination confirmed FB penetrated between the vestibular folds.Interventions:After careful multidisciplinary preoperative assessment and preparation, the FB was removed successfully by direct laryngoscopy under moderate sedation and spontaneous ventilation, with the application of 1% lidocaine as topical anesthesia.Outcomes:The laryngeal FB was removed successfully without any complications. And the patient was discharged home the next day.Lessons:This case report shows the importance of anesthetic depth for laryngeal FB removal. The use of moderate sedation (allowing spontaneous ventilation) and adequate analgesia combined with local anesthesia enabled the patient to withstand the stress of direct laryngoscopy. Appropriate assessment, careful preparation, and multidisciplinary collaboration yielded the smooth removal of a laryngeal FB in an adult with DS.     

Secondary amyloidosis causing nephrotic syndrome in a patient with non‐Hodgkin's lymphoma: quite a rare diagnosis

Secondary amyloidosis is usually a complication of chronic inflammation. Amyloidosis cases during the course of non‐Hodgkin's lymphoma (NHL) are usually of AL‐type, only one NHL patient with secondary amyloidosis has been reported. Our 79‐year‐old male patient visited us with multiple lymphadenopathies, and he was diagnosed with nodal marginal zone B‐cell lymphoma. After four cycles of combined chemotherapy; his urea, creatinine levels started to increase and he developed nephrotic‐range proteinuria. His rectal biopsy demonstrated amyloid deposition in submucosal vessel walls. The patient has been under hemodialysis for 10 months and his lymphoma is still in partial remission. We presented this case because it is the second NHL patient who developed secondary amyloidosis during his disease course.     

Clinical assessment and FGFR2 mutation analysis in a Chinese family with Crouzon syndrome: A case report

Rationale:Crouzon syndrome is an autosomal dominant genetic disorder caused by mutations in fibroblast growth factor receptor 2 (FGFR2) and one of the most common types of craniosynostosis. Here we report the detection of FGFR2 mutation and its related clinical findings in 2 patients with Crouzon syndrome from a Chinese family.Patient concerns:We report a case of a 28-year-old male patient presented with the chief complaint of gradually blurring of his eyes over the last 6 months before visiting our clinics. History revealed low visual acuity in his right eye since childhood. Physical examination showed that both the patient and his mother have the appearance of craniofacial dysostosis, mandibular prognathism, ocular proptosis, short superior lip, scoliosis, and thoracic deformity.Diagnosis:Auxiliary examinations lead to the diagnosis of Crouzon syndrome with binocular optic atrophy, myelinated retina nerve fibers, and ametropia in both eyes, and amblyopia in the right eye of the male patient. The molecular genetic analysis confirmed the diagnosis by detecting a heterozygous pathogenic mutation c.1026C > G (C342W) in exon 10 of FGFR2 in both the patient and his mother, but not in any of the unaffected family members.Interventions and outcomes:None.Lessons:Our study confirms the presence of optic nerve atrophy in patients with Crouzon syndrome carrying FGFR2 C342W mutations and indicates that MRI and funduscopy should be performed to examine the optic nerve changes for patients with Crouzon syndrome.     

Surfactant deficiency syndrome in an infant with a C‐terminal frame shift in ABCA3: A case report

Deficiency in ATP binding cassette A3 (ABCA3) causes neonatal respiratory distress, hypoxemic respiratory failure, and interstitial lung disease. ABCA3 transports phospholipids into the lamellar bodies of type II alveolar cells, a critical step in alveolar surfactant production. We report a term infant with ABCA3 surfactant deficiency syndrome with the E292V (c.875A>T; p.Glu292Val) mutation in trans with a novel C‐terminal frame shift mutation (c.4938delC; p.Met1647fs). This mutation removes the final 58 amino acids and substitutes 33 incorrect amino acids. The frame shift spares membrane spanning and nucleotide binding domains, but disrupts a highly conserved C‐terminal domain, which includes sequence motifs necessary for the function of human paralogs ABCA1, ABCA4, and the bacterial homolog DrrA. This observation suggests the C‐terminal domain is also required for normal function of ABCA3.

     

Ketogenic diet rescues cognition in ApoE4+ patient with mild Alzheimer's disease: A case study

It has been established that there is a correlation between Alzheimer's disease and apolipoprotein E, specifically the ApoE4 genetic variant. However, the correlation between Apoe4, insulin resistance and metabolic syndrome (MetS) pathologies still remains elusive. As apolipoprotein E has many important physiological functions, individuals with the ApoE4 allele variant, also known as the Alzheimer's disease gene, are primarily at a greater risk for physiological consequences, specifically cognitive impairment (Chan et al., 2016). In this case study, a 71-year old female, heterozygous for ApoE4 with a family history of Alzheimer's Disease (AD) and the dual diagnosis of mild AD/metabolic syndrome (MetS) was placed on a 10-week nutrition protocol purposed at raising plasma ketones through carbohyrdrate restricted, high fat ketogenic diet (KD), time- restricted eating and physical/cognitive exercise. Primary biomarkers for MetS were measured pre/mid-/post intervention. The MoCA (Montreal Cognitive Assessment) was administered pre/post intervention by a licensed clinical therapist. The results were statistically significant. The HOMA-IR decreased by 75% from 13.9 to 3.48. Triglycerides decreased by 50% from 170mg/dL to 85mg/dL. VLDL dropped by 50% from 34mg/dL to 17mg/dL, and HgA1c decreased from 5.7% to 4.9%. The baseline MoCA score was 21/30; post treatment score was 28/30. The significant results in both MetS biomarkers and the MoCA score suggest that a ketogenic diet may serve to rescue cognition in patients with mild AD. The results of this case study are particularly compelling for ApoE4 positive (ApoE4+) subjects as ketogenic protocols extend hope and promise for AD prevention.