Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States.

Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care.

Long-term safety and efficacy of pegunigalsidase alfa: A multicenter 6-year study in adult patients with Fabry disease.

PURPOSE: Fabry disease (FD) is a rare lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding α-galactosidase (α-Gal)-A. We evaluated long-term safety/efficacy of pegunigalsidase alfa, a novel PEGylated α-Gal-A enzyme replacement therapy (ERT) now approved for FD. METHODS: In a phase-1/2 dose-ranging study, 15 ERT-naive adults with FD completed 12 months of pegunigalsidase alfa and enrolled in this 60-month open-label extension of 1 mg/kg pegunigalsidase alfa infusions every 2 weeks. RESULTS: Fifteen patients enrolled (8 males; 7 females); 10 completed ≥48 months (60 months total treatment), and 2 completed 60 months (72 months total treatment). During treatment, most treatment-emergent adverse events were mild/moderate in severity and all infusion-related reactions were mild/moderate in severity. Four patients were transiently positive for anti-pegunigalsidase alfa IgG. Patients showed continuous reduction in plasma lyso-Gb3 concentrations with mean (standard error) reduction of 76.1 [25.1] ng/mL from baseline to month 24. At 60 months, the estimated glomerular filtration rate slope was comparable to that observed in patients treated with other ERTs. Cardiac function assessments revealed stability; no cardiac fibrosis was observed. CONCLUSION: In this first long-term assessment of pegunigalsidase alfa administration in patients with FD, we found favorable safety/efficacy. Our data suggest long-term continuous benefits of pegunigalsidase alfa treatment in adults with FD.

Polygenic Infantile Juvenile Polyposis Syndrome Managed With Sirolimus and Endoscopic Polypectomy.

In the following clinical case of infantile juvenile polyposis syndrome (JPS), administration of a pharmacologic agent sirolimus was associated with reduced disease burden without need for bowel resection. The positive impact included improvement in protein-losing enteropathy, decreased intestinal blood loss, and improved weight gain. In addition, the number of polyps resected per unit time and frequency of upper and lower endoscopic evaluation needed dropped after initiation of sirolimus. This case report describes a positive clinical outcome and discusses the use of sirolimus with aggressive polypectomy as a potential treatment for the rare disease entity of polygenic infantile JPS. Through this case, we aim to emphasize that while administration of this drug may mitigate many sequelae of infantile JPS, it does not appear to eliminate the need for aggressive polypectomy.

Presacral neuroendocrine tumors associated with the Currarino syndrome.

Currarino syndrome (CS) is an autosomal dominant syndrome caused by mutations in MNX1 and characterized by anorectal abnormalities, partial sacral agenesis, and presacral masses. The presacral masses are typically benign; however, malignant degeneration can occur, and presacral neuroendocrine tumors (NETs) have been reported in six cases. We report three individuals from two families affected by CS in which multiple individuals developed presacral NETs. The first family, 491, had six members with features of CS, including two siblings who presented with presacral, Grade 2 NETs, one of which had metastasized to bone and lymph nodes. A germline c.874C>T (p.Arg292Trp) mutation was found in a highly conserved region of MNX1 in three affected members who underwent sequencing. A second somatic variant/deletion in MNX1 was not detected in either patient's tumor. In the second family, 342, the proband presented with an incidentally discovered presacral NET. The proband's father had previously undergone resection of a presacral NET, and so genetic testing was performed, which did not reveal an MNX1 mutation or copy number variants. The lack of a second, somatic mutation in the tumors from family 491 argues against MNX1 acting as a tumor suppressor, and the absence of a germline MNX1 mutation in family 342 suggests that other genetic and anatomic factors contribute to the development of presacral NETs. These cases highlight the variable presentation of CS, and the potential for malignancy in these patients.

Genetic analysis of CHARGE syndrome identifies overlapping molecular biology.

PURPOSE: CHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome. METHODS: We performed whole-exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome. RESULTS: Pathogenic variants in CHD7 were present in 15 of 28 individuals (53.6%), whereas 4 (14.3%) individuals had pathogenic variants in other genes (RERE, KMT2D, EP300, or PUF60). A variant of uncertain clinical significance in KDM6A was identified in one (3.5%) individual. The remaining eight (28.6%) individuals were not found to have pathogenic variants by WES. CONCLUSION: These results demonstrate that the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes. Additionally, they implicate a shared molecular pathology that disrupts epigenetic regulation of multiple-organ development.

Breast fibroadenomas in the pediatric population: common and uncommon sonographic findings.

BACKGROUND: Sonography is usually requested to evaluate palpable pediatric breast lumps, and solid masses are almost always fibroadenomas. Lack of familiarity with the findings of fibroadenomas can lead to diagnostic uncertainty and sometimes unnecessary biopsy and excision. We sought to review the spectrum of sonographic findings in our cases of pathology proven pediatric fibroadenomas. OBJECTIVE: The purpose of this retrospective study was to describe the sonographic appearances of pathologically proven pediatric breast fibroadenomas. MATERIALS AND METHODS: A query of the Department of Radiology database at our institution was performed for all patients younger than 19 years who underwent breast US from January 2001 to June 2009. A total of 332 patients were identified: 282 girls (85%) and 50 boys (15%). Ninety-one girls and no boys had a solid breast mass based on US findings. Forty-three children had a total of 49 pathologically proven breast masses with the diagnoses of fibroadenoma (44), hamartoma (1), non-Hodgkin lymphoma (1), tubular adenoma (1), pseudoangiomatous stromal hyperplasia (1) and lactation changes (1). Reviews of medical records, histological results and sonographic examinations of all pathology-proven fibroadenomas were performed. US findings were characterized according to location, multiplicity, size, shape, echogenicity and homogeneity, definition of margins, posterior acoustic features and Doppler vascularity. RESULTS: The vast majority of solid breast masses in girls are histologically benign. Fibroadenomas accounted for 91% of the pathologically proven solid breast masses. Common findings on US imaging are an oval shape, hypoechoic echo pattern, posterior acoustic enhancement and internal Doppler signal. Lobulations were found in 57% of the masses. Less common findings are absent internal vascular flow and complex echo pattern, while isoechoic echo pattern, posterior shadowing and angular margins are rare or unusual. CONCLUSION: Fibroadenomas represent the most common solid mass in the breasts of girls. Sonographic appearances are usually characteristic and do not significantly differ from those found in adults. The radiologist must be aware of common and uncommon sonographic appearances of fibroadenomas in the pediatric age group and should be cautious when recommending histological confirmation based on imaging findings, as breast malignancy is extremely rare.