Fabry disease in infancy and early childhood: a systematic literature review.

PURPOSE: Fabry disease is a pan-ethnic, progressive, X-linked genetic disorder that commonly presents in childhood and is caused by deficient activity of the lysosomal enzyme alpha-galactosidaseA (α-gal A). Symptoms of Fabry disease in the pediatric population are well described for patients over five years of age; however, data are limited for infancy and early childhood. The purpose of this article is to delineate the age of detection for specific Fabry symptoms in early childhood. METHODS: A systematic retrospective analysis of PubMed indexed, peer-reviewed publications and case reports in the pediatric Fabry population was performed to review symptoms in patients reported before 5 years of age. RESULTS: The most frequently reported symptom in all age groups under 5 years was acroparesthesias/neuropathic pain, reported in 9 children, ranging in age from 2.0-4.0 years. Also notable is the frequency of gastrointestinal issues reported in 6 children aged 1.0-4.1 years of age. CONCLUSION: This article finds clear evidence that symptoms can occur in early childhood, before age 5 years. Given early presenting symptoms and the ability to monitor these disease hallmarks, a timely referral to a medical geneticist or other specialty clinician experienced in managing children with Fabry disease is strongly indicated.

Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions.

BACKGROUND: X linked intellectual disability (XLID) is common, with an estimated prevalence of 1/1000. The expanded use of array comparative genomic hybridisation (CGH) has led to the identification of several XLID-associated copy-number variants. METHODS: Array CGH analysis was performed using chromosomal microarray with ∼105 000 oligonucleotides covering the entire genome. Confirmatory fluorescence in situ hybridisation analyses were subsequently performed. Chromosome X-inactivation (XCI) was assessed using methylation-sensitive restriction enzyme digestion followed by PCR amplification. RESULTS: A novel ∼0.5 Mb duplication in Xq28 was identified in four cognitively impaired males who share behavioural abnormalities (hyperactivity and aggressiveness) and characteristic facial features (high forehead, upper eyelid fullness, broad nasal bridge and thick lower lip). These duplications were inherited from mothers with skewed XCI and are mediated by nonallelic homologous recombination between the low-copy repeat regions int22h-1 and int22h-2, which, in addition to int22h-3, are also responsible for inversions disrupting the factor VIII gene in haemophilia A. In addition, we have identified a reciprocal deletion in a girl and her mother, both of whom exhibit normal cognition and completely skewed XCI. The mother also had two spontaneous abortions. CONCLUSIONS: The phenotypic similarities among subjects with int22h-1/int22h-2-mediated Xq28 duplications suggest that such duplications are responsible for a novel XLID syndrome. The reciprocal deletion may not be associated with a clinical phenotype in carrier females due to skewed XCI, but may be lethal for males in utero. Advancements in array CGH technology have enabled the identification of such small, clinically relevant copy-number variants.

A novel missense mutation in the MEN1 gene in a patient with multiple endocrine neoplasia type 1.

OBJECTIVE: To describe a novel germline missense mutation in exon 2 of the MEN1 gene identified in a man with multiple endocrine neoplasia type 1 (MEN 1). METHODS: We describe the patient's clinical, laboratory, and genetic data, and we review the relevant literature. RESULTS: A 41-year-old man with a history of primary hyperparathyroidism and left lower parathyroidectomy presented with nausea, vomiting, and hematemesis. Laboratory data revealed an elevated gastrin level. Computed tomography of the abdomen demonstrated a 3.5-cm mass in the head of pancreas. A functional study with a somatostatin receptor scan showed increased uptake in the region of the pancreatic mass. The patient's symptoms promptly improved after the Whipple procedure, although he was also noted to have a markedly elevated calcium concentration along with inappropriately elevated parathyroid hormone levels. Sestamibi scan identified a hyperfunctioning right upper parathyroid gland. His calcium level normalized after parathyroidectomy, and results from pituitary hormone studies were all normal. Genetic testing of the MEN1 gene identified a novel mutation: Arg52Gly. The Arg52Gly mutation replaces the normal arginine residue (CGC) with a glycine residue (GGC) at position 52 of the resultant menin protein. This mutation was present in family members from 3 generations. CONCLUSIONS: We report a novel disease-causing germline missense mutation in exon 2 of the MEN1 gene in a patient with MEN 1. Nonconservative replacement of arginine, a small, neutral amino acid, with glycine, a bulky positively charged amino acid, could potentially have a deleterious effect on the menin protein.

Diffusion-weighted and dynamic contrast-enhanced imaging as markers of clinical behavior in children with optic pathway glioma.

BACKGROUND: Optic pathway gliomas (OPGs) are common pediatric brain tumors that pose significant clinical challenges with regard to predicting which tumors are likely to become symptomatic and require treatment. These tumors can arise sporadically or in the context of the inherited cancer predisposition syndrome neurofibromatosis type 1 (NF1). Few studies have suggested biological or imaging markers that predict the clinical course of this disease. OBJECTIVE: In this cross-sectional study, we hypothesized that the clinical behavior of OPGs in children can be differentiated by diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI. MATERIALS AND METHODS: A total of 27 children with OPG were studied using DW and DCE MRI protocols. Diffusivity and permeability were calculated and correlated with the clinical behavior the OPG. RESULTS: Mean diffusivity values of 1.39 microm2/ms and mean permeability values of 2.10 ml/min per 100 cm3 of tissue were measured. Clinically aggressive OPGs had significantly higher mean permeability values (P = 0.05) than clinically stable tumors. In addition, there was a strong correlation between clinical aggressiveness and the absence of NF1 (P < 0.01). CONCLUSION: These results suggest that DCE MRI might be a useful biomarker for clinically aggressive OPG, which should be confirmed in larger prospective longitudinal studies.