Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Gastrointestinal Sensory Neuropathy and Dysmotility in Fabry Disease: Presentations and Effect on Patient's Quality of Life.

INTRODUCTION: Fabry disease is a rare multisystemic lysosomal disease resulting in variable manifestations of the gastrointestinal (GI), neurologic, cardiac, and renal systems. Whether GI manifestations are a result of gut dysmotility is undetermined. We aimed to explore GI manifestations in depth and their effect on patients with Fabry disease and to characterize gut motility. METHODS: We recruited adult patients with Fabry disease reporting GI manifestations. All patients answered a battery of questionnaires covering symptom severity, GI-specific quality of life, and effects of work/productivity and underwent a wireless motility capsule test to measure pan-gut motility. RESULTS: In 48 patients with Fabry disease, abnormal bowel habits and abdominal pain were the most common symptoms. Bloating, nausea, vomiting, and reflux were also prevalent. Neurologic manifestations were found in 95.8% of patients, along with their GI manifestations. Dysmotility was found in less than 35% of wireless motility capsule tests. Colon transit time was associated with constipation severity and Bristol Stool Scale. Several GI symptoms were associated with reduced quality of life, anxiety, and work/productivity, but not Fabry severity score. DISCUSSION: This is the largest study of GI manifestations in patients with Fabry disease that characterizes gut motility. We found little association between GI manifestations and motility indices, suggesting that visceral hypersensitivity may be a major driver of symptoms. GI symptoms affect different aspects of patients' lives, yet are not always well-discussed or optimally managed in Fabry disease. Disease severity scores when used for therapeutic decision making do not often include GI symptoms or their impact.

History of trying exclusion diets and association with avoidant/restrictive food intake disorder in neurogastroenterology patients: A retrospective chart review.

BACKGROUND: Exclusion diets for gastrointestinal symptom management have been hypothesized to be a risk factor for avoidant/restrictive food intake disorder (ARFID; a non-body image-based eating disorder). In a retrospective study of pediatric and adult neurogastroenterology patients, we aimed to (1) identify the prevalence and characteristics of an exclusion diet history and (2) evaluate if an exclusion diet history was concurrently associated with the presence of ARFID symptoms. METHODS: We conducted a chart review of 539 consecutive referrals (ages 6-90, 69% female) to adult (n = 410; January-December 2016) and pediatric (n = 129; January 2016-December 2018) neurogastroenterology clinics. Masked coders (n = 4) retrospectively applied DSM-5 criteria for ARFID and a separate coder assessed documentation of exclusion diet history. We excluded patients with no documentation of diet in the chart (n = 35) or who were not orally fed (n = 9). RESULTS: Of 495 patients included, 194 (39%) had an exclusion diet history, and 118 (24%) had symptoms of ARFID. Of reported diets, dairy-free was the most frequent (45%), followed by gluten-free (36%). Where documented, exclusion diets were self-initiated by patients/parents in 66% of cases, and recommended by gastroenterology providers in 30%. Exclusion diet history was significantly associated with the presence of ARFID symptoms (OR = 3.12[95% CI 1.92-5.14], p < 0.001). CONCLUSIONS: History of following an exclusion diet was common and was most often patient-initiated among pediatric and adult neurogastroenterology patients. As patients with self-reported exclusion diet history were over three times as likely to have ARFID symptoms, providers should be cognizant of this potential association when considering dietary interventions.

Upper Esophageal Sphincter Dysfunction in Children with Type 1 Laryngeal Cleft after Failed Primary Cleft Repair.

Changes in pharyngeal and upper-esophageal-sphincter (UES) motor dynamics contribute to swallowing dysfunction. Children with type 1 laryngeal clefts can present with swallowing dysfunction and associated symptoms which may persist even after the initial endoscopic intervention. This study sought to characterize pharyngeal and esophageal motor function in children with type 1 laryngeal clefts who had persistent presenting symptoms after their initial therapeutic intervention. We retrospectively analyzed high-resolution esophageal manometry studies of children ≤ 18 years old with type 1 laryngeal clefts who had an esophageal manometry study performed for persistent symptoms after an initial repair. A total of 16 children were found to have significantly increased UES resting pressure, UES pre- and post-swallow maximum pressures, and duration of UES contraction during swallows in comparison to nine age-matched controls of children without pharyngeal anatomical abnormalities. There was no difference between UES residual pressures or pharyngeal dynamics between the two groups. UES resting and residual pressures did not correlate with VFFS in penetration and aspiration scores of children with type 1 laryngeal clefts status post repair. Our study is the first to identify specific changes in UES motor function in patients with type 1 laryngeal cleft post initial repair.

A Child Psychiatry Perspective on Encopresis.

Fecal incontinence, known as encopresis, is the repetitive, intentional or unintentional passage of stool in inappropriate places in children who are developmentally four years old or older. Incontinence can have a chronic course and is associated with emotional distress and a substantial negative impact on quality of life. We review how a medical and behavioral health multidisciplinary approach provides the optimal clinical care for this condition, and we discuss how the unique skill set of the child psychiatrist may address the complex family dynamics and psychiatric comorbidities which may be preventing remission from this condition. Identifying and understanding these factors is essential in developing a comprehensive and effective treatment plan.

Prevalence and Characteristics of Avoidant/Restrictive Food Intake Disorder in Pediatric Neurogastroenterology Patients.

ABSTRACT: Recent reports document avoidant/restrictive food intake disorder (ARFID) symptoms among 13-40% of adults presenting to neurogastroenterology clinics, but ARFID in pediatrics is understudied. We conducted a retrospective review of charts from 129 consecutive referrals (ages 6-18 years; 57% female) for pediatric neurogastroenterology examination, from January 2016 through December 2018. Eleven cases (8%) met the full criteria for ARFID by the Diagnostic and Statistical Manual of Mental Disorders, 5th edition and 19 cases (15%) had clinically significant avoidant/ restrictive eating behaviors with insufficient information for a definitive ARFID diagnosis. Of patients with ARFID symptoms (n = 30), 20 (67%) cited fear of gastrointestinal symptoms as motivation for their avoidant/ restrictive eating. Compared to patients without ARFID symptoms, patients with ARFID symptoms were older (P  < .001), more likely to be female (51% vs 79%, P  = 0.014), and more frequently presented with eating/weight-related complaints (15% vs 33%, P  = 0.026). This pilot retrospective study showed ARFID symptoms present in 23% of pediatric neurogastroenterology patients; further research is needed to understand risk and maintenance factors of ARFID in the neurogastroenterology setting.

Modified external approach to the pediatric cricopharyngeal myotomy: A case series.

OBJECTIVE: To assess the success of a modified approach to external pediatric cricopharyngeal myotomy in children with inappropriate upper esophageal sphincter relaxation as determined by video fluoroscopic swallow study (VFSS) and pediatric manometry findings. METHODS: This is a case series in which hospital records of all patients who underwent a modified external approach to pediatric cricopharyngeal myotomy 2017 to 2019 were reviewed at a single institution. The primary outcome measure was post-operative diet and presence of aspiration/penetration on post-operative VFSS. RESULTS: A total of 7 patients underwent modified external approach to pediatric cricopharyngeal myotomy. The average age of the child at the time of surgery was 5.6 (±3.7) years. The average duration (SD) of surgery was 90 (±30) minutes and no complications were observed. 6 of 7 patients (86%) demonstrated an improvement in swallow function after the procedure. The single child who did not was suffering from a posterior fossa tumor which was resected and radiated, which likely made their dysphagia multi-factorial. Although no pediatric normative data exists for upper esophageal sphincter pressure, we observed an average decrease in UES residual pressure of 8.5 (±15.1) mmHg and an average decrease in mean UES pressure of 21.2 (±35.1) mmHg. CONCLUSIONS: The modified external approach to the pediatric cricopharyngeal myotomy appears to be a safe and efficient procedure with no apparent complications to date. However, further longitudinal data is needed to formally evaluate the efficacy of this procedure when treating pediatric cricopharyngeal achalasia.

Benefit of Pelvic Floor Physical Therapy in Pediatric Patients with Dyssynergic Defecation Constipation.

OBJECTIVES: Chronic constipation is a common childhood problem and often caused or worsened by abnormal dynamics of defecation. The aim of this study was to assess the benefit of pelvic floor physical therapy (PFPT), a novel treatment in pediatrics for the treatment of chronic constipation with dyssynergic defecation. METHODS: This was a retrospective study of 69 children seen at a pediatric neurogastroenterology program of a large tertiary referral center for chronic constipation and dyssynergic defecation, determined by anorectal manometry and balloon expulsion testing. We compared the clinical outcome of patients who underwent PFPT (n = 49) to control patients (n = 20) whom received only medical treatment (laxatives/stool softeners). Additionally, characteristics of the treatment group were analyzed in relation to therapeutic response. RESULTS: Thirty-seven (76%) of the patients who received physical therapy had improvement in constipation symptoms, compared to 5 (25%) of the patients on conservative treatment (p < 0.01). Additionally, patients who received pelvic physical therapy had fewer hospitalizations for cleanouts (4 vs. 25%, p = 0.01) and -colonic surgery than those that were treated with medical therapy exclusively (0 vs. 10%, p = 0.03). Among the patients who received physical therapy, those that suffered from anxiety and/or low muscle tone had a higher response rate (100%). There were no adverse effects from the intervention. CONCLUSION: The new field of pediatric PFPT is a safe and effective intervention for children with dyssynergic defecation causing or contributing to chronic constipation, particularly in children whose comorbidities include anxiety and low -muscle tone.

Botulinum toxin injection for childhood constipation is safe and can be effective regardless of anal sphincter dynamics.

BACKGROUND: Childhood constipation is common. Previously, internal anal sphincterotomy has been used for hypertensive/non-relaxing sphincters; however, recent benefit has been shown with Botulinum Toxin (BT) injections. The aim is to investigate BT, including response duration, symptom association and effectiveness in relation to sphincter dynamics. METHODS: Retrospective study of 164 children receiving sphincter BT for severe constipation unresponsive to medication management. Charts reviewed for symptoms, anorectal manometry (ARM) findings and response defined by decreased pain or increased defecation. Patients were grouped: normal sphincter pressure (≤50 mmHg), elevated (>50 mmHg), normal and abnormal rectoanal inhibitory reflex (RAIR). RESULTS: There were 142 analyzed and 124 completed ARMs; 98 (70%) had positive response with 57% lasting greater than 6 months. 36 had normal sphincter pressure with 24 (69%) responding. 88 had elevated pressure with 60 (68%) responding (p=0.87). 90 normal RAIRs with 64 (71%) responding. 34 abnormal RAIRs with 22 (64%) responding (p=0.41). With logistic regression, fecal incontinence prior to BT was a predictor of poor response (p= 0.02). The most common side effect was fecal incontinence typically resolving within week with equal frequency regardless of sphincter dynamics. CONCLUSIONS: BT is effective for children with chronic constipation. Patients with fecal incontinence are less likely to respond. More than half had prolonged beneficial response. Those with normal and abnormal sphincter dynamics had similar responses and without differences in side effects. Therefore, injection may be considered in patients with intractable constipation unresponsive to medication, regardless of anal sphincter dynamics. LEVEL OF EVIDENCE: Level III (Treatment Study: Retrospective comparative study).

Modified approach for pediatric external cricopharyngeal myotomy.

Pediatric cricopharyngeal achalasia is an uncommon but important cause of oropharyngeal dysphagia. Failure of upper esophageal sphincter relaxation is the currently understood pathophysiology. Therapies include balloon dilation, botulinum toxin injection, and endoscopic or open cricopharyngeal myotomy (CPM). Open CPM is usually performed at the posterior midline of the cricopharyngeus and can be a risky procedure given concern for esophageal perforation and damage to the recurrent laryngeal nerve. Here, we present a novel modified technique for open CPM using a superficial anterolateral transection approach in the case of a young male with refractory cricopharyngeal achalasia.

Treatment of Functional Abdominal Pain With Antidepressants: Benefits, Adverse Effects, and the Gastroenterologist's Role.

OBJECTIVES: Pediatric functional abdominal pain is often treated with tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). The aim is investigating antidepressant use for treatment efficacy, correlation of response to psychiatric factors, and impact of adverse effects in regard to physicians' prescribing patterns. METHODS: Retrospective review (2005-2013) children (5-21 years old) with functional abdominal pain treated with SSRI or TCA. Of the 531 cases with functional abdominal pain, 192 initiated SSRIs or TCAs while followed by gastroenterology. Charts reviewed for symptoms, adverse effects, and response: decreased pain or increased daily functioning. RESULTS: Sixty-three of 84 (75%) SSRI patients improved, 56 of 92 (61%) TCA patients improved (P = 0.03). Logistic regression controlling for psychiatric factors: SSRI remained significant over TCA (P = 0.04). Thirty-two of 67 (48%) patients with constipation received TCAs and 26 of 45 (58%) patients with diarrhea received SSRIs (P = 0.64). Three SSRI patients reported gastrointestinal effects, all diarrheal-type symptoms, and 2 TCA patients reported gastrointestinal effects, both constipation, in all it led to discontinuation. Thirteen (29%) of diarrheal-type patients reported adverse effects causing discontinuation as compared to 7 (8%) in the constipation group (P = .01). Twenty-one (25%) SSRI patients reported adverse effects with 5 (6%) mood disturbances. Twenty (22%) TCA patients reported adverse effects, 13 (14%) with mood disturbances (P = .07). Overall, 12 (14%) SSRI patients discontinued medication due to adverse effects, whereas 16 (17%) TCA patients (P = 0.24) did. CONCLUSIONS: Patients had significantly greater response to SSRIs than TCAs, remaining significant after controlling for psychiatric factors. Little significance is given to patient's associated gastrointestinal symptoms, frequently resulting in adverse effects and termination of medication.

Understanding the gastrointestinal manifestations of Fabry disease: promoting prompt diagnosis.

Fabry disease is a rare X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement such as diarrhea, abdominal pain, early satiety and nausea. The gastrointestinal symptoms of Fabry disease are thought to be due to neuropathic and myopathic changes leading to symptoms of dysmotility that are encountered in many other disorders. The gastrointestinal symptoms can often be one of the presenting signs of the disease in childhood, but can be misdiagnosed by gastroenterologists for many years due to their nonspecific presentation. As the chief treatment for Fabry is enzyme-replacement therapy that has been shown to stabilize and possibly reverse disease course, recognition of these symptoms and early diagnosis in an attempt to prevent progression with treatment, is critical.

Characterizing non-OCD anxiety disorders in psychiatrically referred children and adolescents.

BACKGROUND: To characterize childhood and adolescent anxiety disorders in a psychiatric clinic. METHODS: Subjects were 1375 youth referred to a pediatric psychopharmacology program at a major academic center from 1991-2002. DSM-III-R diagnoses were obtained by Schedule for Affective Disorders and Schizophrenia for School-Age Children. RESULTS: Of 1375 referred youth, 794 had at least one non-obsessive-compulsive anxiety disorder, and 581 psychiatric comparison subjects had at least one disruptive behavior disorder and no anxiety disorders. There were 367 (46%) youth with one anxiety disorder, 224 (28%) with two disorders. Most prevalent were separation anxiety (49%), and overanxious disorder (47%). Mean ages of onset ranged from simple phobia (4.1) to panic disorder (8.5). Risk analyses revealed anxiety disorders significantly increased risk for anxiety and mood disorders. CONCLUSIONS: The full complement of anxiety disorders occurs in youth.