Pamela Arn

Mutations in the TGF-β Repressor SKI Cause Shprintzen-Goldberg Syndrome with Aortic Aneurysm

Elevated transforming growth factor (TGF)-β signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-β signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-β in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-β activity. Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-β signaling cascades and higher expression of TGF-β–responsive genes relative to control cells. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in humans with SGS. These data support the conclusions that increased TGF-β signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm.

Hepatocellular carcinoma in glycogen storage disease type Ia: a case series.

SummaryWe present a series of 8 patients (6 males, 2 females) with hepatocellular carcinoma (HCC) and glycogen storage disease type Ia (GSD Ia). In this group, the age at which treatment was initiated ranged from birth to 39 years (mean 9.9 years). All patients but one were noncompliant with treatment. Hepatic masses were first detected at an age range of 13–45 years (mean 28.1 years). Age at diagnosis of HCC ranged from 19 to 49 years (mean 36.9 years). Duration between the diagnosis of liver adenomas and the diagnosis of HCC ranged from 0 to 28 years (mean 8.8 years, SD=11.5). Two patients had positive hepatitis serologies (one hepatitis B, one hepatitis C). α-Fetoprotein (AFP) was normal in 6 of the 8 patients. Carcinoembryonic antigen (CEA) was normal in the 5 patients in which it was measured. Current guidelines recommend abdominal ultrasonography with AFP and CEA levels every 3 months once patients develop hepatic lesions. Abdominal CT or MRI is advised when the lesions are large or poorly defined or are growing larger. We question the reliability of AFP and CEA as markers for HCC in GSD Ia. Aggressive interventional management of masses with rapid growth or poorly defined margins may be necessary to prevent the development of HCC in this patient population.

Glycogen Storage Disease Type III diagnosis and management guidelines

Purpose: Glycogen storage disease type III is a rare disease of variable clinical severity affecting primarily the liver, heart, and skeletal muscle. It is caused by deficient activity of glycogen debranching enzyme, which is a key enzyme in glycogen degradation. Glycogen storage disease type III manifests a wide clinical spectrum. Individuals with glycogen storage disease type III present with hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation. Those with type IIIa have symptoms related to liver disease and progressive muscle (cardiac and skeletal) involvement that varies in age of onset, rate of disease progression, and severity. Those with type IIIb primarily have symptoms related to liver disease. This guideline for the management of glycogen storage disease type III was developed as an educational resource for health care providers to facilitate prompt and accurate diagnosis and appropriate management of patients.Methods: An international group of experts in various aspects of glycogen storage disease type III met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management.Results: This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (cardiovascular, gastrointestinal/nutrition, hepatic, musculoskeletal, and neuromuscular) involved in glycogen storage disease type III. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic transplantation, and prenatal diagnosis, are addressed.Conclusions: A guideline that will facilitate the accurate diagnosis and appropriate management of individuals with glycogen storage disease type III was developed. This guideline will help health care providers recognize patients with all forms of glycogen storage disease type III, expedite diagnosis, and minimize stress and negative sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.

Clinical and Mutational Spectrum of Neurofibromatosis Type 1–like Syndrome

CONTEXT Autosomal dominant inactivating sprouty-related EVH1 domain-containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with café au lait macules (CALMs), axillary freckling, and macrocephaly. The extent of the clinical spectrum of this new disorder needs further delineation. OBJECTIVE To determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1-like syndrome (NFLS) in a large cohort of patients. DESIGN, SETTING, AND PARTICIPANTS In a cross-sectional study, 23 unrelated probands carrying a SPRED1 mutation identified through clinical testing participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1318 unrelated anonymous samples collected in 2003-2007 from patients with a broad range of signs typically found in neurofibromatosis type 1 (NF1) but no detectable NF1 germline mutation underwent SPRED1 mutation analysis. MAIN OUTCOME MEASURES Comparison of aggregated clinical features in patients with or without a SPRED1 or NF1 mutation. Functional assays were used to evaluate the pathogenicity of missense mutations. RESULTS Among 42 SPRED1-positive individuals from the clinical cohort, 20 (48%; 95% confidence interval [CI], 32%-64%) fulfilled National Institutes of Health (NIH) NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. None of the 42 SPRED1-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas. In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 27 pathogenic mutations in 34 probands and 7 probable nonpathogenic missense mutations in 9 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73%; 95% CI, 63%-80%) had an NF1 mutation and 18 (19%; 95% CI, 12%-29%) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS. CONCLUSIONS A high SPRED1 mutation detection rate was found in NF1 mutation-negative families with an autosomal dominant phenotype of CALMs with or without freckling and no other NF1 features. Among individuals in this study, NFLS was not associated with the peripheral and central nervous system tumors seen in NF1.

Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics.

Disclaimer: This guideline is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this guideline is completely voluntary and does not necessarily ensure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this guideline. Clinicians also are advised to take notice of the date this guideline was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Purpose:Glycogen storage disease type I (GSD I) is a rare disease of variable clinical severity that primarily affects the liver and kidney. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib), resulting in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa. Patients with GSD I have a wide spectrum of clinical manifestations, including hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation. Individuals with GSD type Ia typically have symptoms related to hypoglycemia in infancy when the interval between feedings is extended to 3–4 hours. Other manifestations of the disease vary in age of onset, rate of disease progression, and severity. In addition, patients with type Ib have neutropenia, impaired neutrophil function, and inflammatory bowel disease. This guideline for the management of GSD I was developed as an educational resource for health-care providers to facilitate prompt, accurate diagnosis and appropriate management of patients.Methods:A national group of experts in various aspects of GSD I met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management.Results:This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (hepatic, kidney, gastrointestinal/nutrition, hematologic, cardiovascular, reproductive) involved in GSD I. Conditions to consider in the differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic and renal transplantation, and prenatal diagnosis, are also addressed.Conclusion:A guideline that facilitates accurate diagnosis and optimal management of patients with GSD I was developed. This guideline helps health-care providers recognize patients with all forms of GSD I, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It also helps to identify gaps in scientific knowledge that exist today and suggests future studies.Genet Med 16 11.

Surgical management of children and young adults with marfan syndrome and pectus excavatum

Significant chest wall deformities occur in two thirds of children with Marfan syndrome (MS). The symptoms, physical findings, and surgical outcome of 11 patients with MS and severe pectus excavatum who required operative repair were reviewed. The diagnosis of MS was made before the pectus repair in six patients, at the time of evaluation of pectus in two patients, and after the repair in three patients. Symptoms included dyspnea upon exertion, tachypnea, and chest pain. Physical findings included aortic root enlargement or valvular disease, mitral valve disease, ligamentous disease, congestive heart failure, and ocular disease. All patients had severe pectus deformities with a narrow anteroposterior diameter in the midline, as well as a broad chest defect that extended bilaterally to the midclavicular line. The heart was shifted into the left side of the chest in all patients. A Ravitch-type pectus repair with a stainless steel substernal strut was used in eight patients, with one patient suffering a late recurrence; in three patients no strut was used, and all three had recurrence. There were no postoperative complications. In the postoperative follow-up of seven patients, symptomatic improvement of cardiopulmonary performance was noted. Four of the patients required subsequent open heart surgery, including replacement of the aortic valve in one patient, and composite grafts of the ascending aorta in three patients. Postoperative cardiac arrest was the only major open heart complication. All four patients recovered and did well after surgery, showing significant cardiac and pulmonary functional improvement.(ABSTRACT TRUNCATED AT 250 WORDS)

SRVX, a sex reversing locus in Xp21.2→p22.11

Duplication within Xp21 causes female or intersexual development in human embryos with an XY chromosome complement. We have mapped the responsible gene, SRVX (sex reversal X), in XY-sex-reversed maternal half siblings who had inherited the duplication from their mother. The limited size of the duplication in our cases, relative to its extent in other similar cases, allows assignment of the SRVX locus to Xp21.2→p22.11. We infer that SRVX is part of a pathway of sex-determining genes that includes SRY and SRA1, the latter recently assigned to chromosome 17q. If mutation of SRA1 or SRVX can reverse the sex of the XY fetus, this would explain why mutation within SRY is found only sporadically in women with XY gonadal dysgenesis.

The natural history of MPS I: global perspectives from the MPS I Registry

Purpose:In this study, we aimed to describe the natural history of mucopolysaccharidosis I.Methods:Data from 1,046 patients who enrolled in the MPS I Registry as of August 2013 were available for descriptive analysis. Only data from untreated patients and data prior to treatment for patients who received treatment were considered. Age at symptom onset, diagnosis, and treatment initiation were examined by geographic region and phenotype (from most to least severe: Hurler, Hurler–Scheie, and Scheie). For each symptom, frequency and age at onset were examined.Results:Natural history data were available for 987 patients. Most patients were from Europe (45.5%), followed by North America (34.8%), Latin America (17.3%), and Asia Pacific (2.4%). Phenotype distribution was 60.9% for Hurler, 23.0% for Hurler–Scheie, and 12.9% for Scheie (3.2% undetermined) syndromes. Median age at symptom onset for Hurler, Hurler–Scheie, and Scheie syndromes was 6 months, 1.5 years, and 5.3 years, respectively; median age at treatment initiation was 1.5 years, 8.0 years, and 16.9 years, respectively. Coarse facial features and corneal clouding were among the most common symptoms in all three phenotypes.Conclusion:A delay between symptom onset and treatment exists, especially in patients with attenuated mucopolysaccharidosis I. A better understanding of disease manifestations may help facilitate prompt diagnosis and treatment and improve patient outcomes.Genet Med 16 10, 759–765.

Characterization of Surgical Procedures in Patients with Mucopolysaccharidosis Type I: Findings from the MPS I Registry

OBJECTIVE To clarify the extent and chronology of surgical burden in relation to symptom onset and diagnosis in patients with mucopolysaccharidosis I (MPS I) as reported in the MPS I Registry, an international observational database. STUDY DESIGN Analysis of surgical data from 544 patients enrolled in the MPS I Registry. Among all patients with at least 1 reported surgery, the number and frequency of procedures, and age at procedure, diagnosis, and symptom onset were collected overall, by patient, and by reported phenotype (Hurler, Hurler-Scheie, Scheie). RESULTS Overall and by phenotype, approximately 75% of patients in the MPS I Registry reported at least 1 surgery. The most common were myringotomies and related procedures, hernia repair, adenoidectomy/tonsillectomy, and carpal-tunnel release. Median age at first surgery was <5 years. A median of 3 to 4 surgeries was reported per patient. By age 1.5, 4, and 10 years, respectively, 22%, 44%, and 54% of patients reported > or = 2 surgeries. At least 1 surgery preceded diagnosis in 36%, 46%, and 63% of patients with Hurler, Hurler-Scheie, and Scheie, respectively. CONCLUSIONS Pediatricians and pediatric surgeons need to be aware of the surgical burden of MPS I and be alert to its presenting signs and symptoms in children scheduled for surgery.

Hyperphenylalaninemia with high levels of 7-biopterin is associated with mutations in the PCBD gene encoding the bifunctional protein pterin-4a-carbinolamine dehydratase and transcriptional coactivator (DCoH)

Pterin-4a-carbinolamine dehydratase (PCD) is required for efficient tetrahydrobiopterin regeneration after phenylalanine hydroxylase activity. This catalytic function was proposed to be specifically defective in newborns with a mild form of hyperphenylalaninemia (HPA) and persistent high urinary levels of primapterin (7-biopterin). A second regulatory task of the same protein is DCoH, a coactivation of transcription by hepatocyte nuclear factor 1alpha (HNF-1alpha), a function that is apparently not impaired in these HPA individuals. It has been shown elsewhere that the human PCD/DCoH bifunctional protein is encoded by a single 4-exon-containing gene, PCBD, located on chromosome 10q22. We have now examined the PCBD gene for mutations at the genomic level in six such HPA patients from four different families. By the use of new intron-specific primers, we detected, in all six patients, single, homozygous nucleotide alterations, in exon 4, that were inherited from their parents. These homozygous alterations predicted mutant PCD/DCoH with a single amino acid exchange, in two cases (alleles T78I), or premature stop codons, in the other four patients (alleles E86X and Q97X). Recombinant expression in Escherichia coli revealed that the mutant proteins-T78I, E86X, and Q97X-are almost entirely in the insoluble fraction, in contrast to wild type, which is expressed as a soluble protein. These data support the proposal that HPA in combination with urinary primapterin may be due to autosomal recessive inheritance of mutations in the PCBD gene specifically affecting the dehydratase activity.