Paraganglioma of the Vagina Associated With Germline SDHB Mutation: Report of a Case With Review of the Literature.

Paragangliomas are rare neuroendocrine neoplasms in the vagina, and their molecular pathogenesis has not been documented. We report a case of vaginal paraganglioma in a 15-yr-old adolescent girl who presented with irregular heavy menses and anemic symptoms. Examination under anesthesia revealed a polypoid mass of 3 cm size in the left anterior vaginal wall, which was resected piecemeal. Histology showed a circumscribed nodular tumor with typical nested morphology of paraganglioma and no significant nuclear atypia. Immunohistochemically the tumor cells were diffusely positive for synaptophysin and chromogranin while being negative for cytokeratin, accompanied by S100-positive sustentacular cells. SDHB immunohistochemistry demonstrated the absence of cytoplasmic staining in the tumor cells with preserved staining in sustentacular cells, raising the possibility of a germline mutation in the genes encoding subunits of succinate dehydrogenase. Sanger sequencing for all the exons and exon-flanking intronic regions of the SDHB gene revealed no mutation, but further investigation with multiplex ligation-dependent probe amplification identified a heterozygous deletion of exon 1 of the SDHB gene in the patient and her mother, confirming the diagnosis of SDHB-related hereditary paraganglioma-pheochromocytoma syndrome. The patient had no evidence of disease upon imaging surveillance and follow-up for 56 mo. A review of the published cases of vaginal paraganglioma seems to suggest a relatively young age of presentation, commonly encountered as incidental findings in asymptomatic patients or presenting with abnormal vaginal bleeding. The association between vaginal paraganglioma and germline SDHB mutation has not been reported. We believe this case illustrates the clinical significance of SDHB immunohistochemistry and genetic testing for this rare vaginal neoplasm.

A systematic review of familial Alzheimer's disease: Differences in presentation of clinical features among three mutated genes and potential ethnic differences.

There are great diversities of clinical phenotypes among the various familial Alzheimer's disease (FAD) families. We aimed to systematically review all the previously reported cases of FAD and to perform comparisons between Asian and white patients. In this regard, we collected individual-level data from 658 pedigrees. We found that patients with presenilin 1 (PSEN1) mutations had the earliest age of onset (AOO; 43.3 ± 8.6 years, p < 0.001) and were more commonly affected by seizures, spastic paraparesis, myoclonus, and cerebellar signs (p < 0.001, p < 0.001, p = 0.003, and p = 0.002, respectively). Patients with PSEN2 mutations have a delayed AOO with longest disease duration and presented more frequently with disorientation (p = 0.03). Patients with amyloid precursor protein (APP) mutations presented more frequently with aggression (p = 0.02) and those with APP duplication presented more frequently with apraxia (p = 0.03). PSEN1 mutations before codon 200 had an earlier AOO than those having mutations after codon 200 (41.4 ± 8.0 years vs. 44.7 ± 8.7 years, p < 0.001). Because 42.9% of the mutations reported are novel, the mutation spectrum and clinical features in Asian FAD families could be different from that of whites. Asian patients with PSEN1 mutations presented more frequently with disorientation (p = 0.02) and personality change (p = 0.01) but less frequently with atypical clinical features. Asian patients with APP mutations presented less frequently with aphasia (p = 0.02). Thus, clinical features could be modified by underlying mutations, and Asian FAD patients may have different clinical features when compared with whites.

Diagnosis of 5α-reductase 2 deficiency: is measurement of dihydrotestosterone essential?

BACKGROUND: 5α-Reductase 2 deficiency (5ARD) is a known cause of 46,XY disorders of sex development (DSD). Traditionally, the diagnosis relies on dihydrotestosterone (DHT) measurement, but the results are often equivocal, potentially leading to misdiagnosis. We reviewed alternative approaches for diagnosis of 5ARD. METHODS: We conducted a retrospective review of the results of urinary steroid profiling (USP) by GC-MS and mutational analysis of SRD5A2 [steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)] by PCR and direct DNA sequencing of all 46,XY DSD patients referred to our laboratory with biochemical and/or genetic findings compatible with 5ARD. We also performed a literature review on the laboratory findings of all 5ARD cases reported in the past 10 years. RESULTS: Of 16 patients diagnosed with 5ARD between January 2003 and July 2012, 15 underwent USP, and all showed characteristically low 5α- to 5ß-reduced steroid metabolite ratios. Four patients had DHT measured, but 2 did not reach the diagnostic cutoff. In all 12 patients who underwent genetic analysis, 2 mutations of the SRD5A2 gene were detected to confirm the diagnosis. Twenty-four publications involving 149 patients with 5ARD were published in the review period. Fewer than half of these patients had DHT tested. Nearly 95% of them had the diagnosis confirmed genetically. CONCLUSIONS: 5ARD can be confidently diagnosed by USP at 3 months postnatally and confirmed by mutational analysis of SRD5A2. Interpretation of DHT results may be problematic and is not essential in the diagnosis of 5ARD. We propose new diagnostic algorithms for 46,XY DSD.

A recurrent de novo DYNC1H1 tail domain mutation causes spinal muscular atrophy with lower extremity predominance, learning difficulties and mild brain abnormality.

We describe four unrelated patients with the same de novo heterozygous missense mutation c.751C>T in the DYNC1H1 gene. We found a high phenotype-genotype correlation with all four patients having early childhood-onset predominant lower limb muscle weakness and wasting which was slowly progressing and later-onset mild upper extremities proximal weakness. All four patients presented minor cognitive dysfunction with learning difficulty and developmental behavioural comorbidities with mild abnormalities in the brain MRI. The leg muscle MRI findings are highly consistent in DYN1CH1-related spinal muscular atrophy with lower limb predominance (SMALED) with relative sparing of biceps femoris and semitendinosus, and hypertrophy of adductor longus in the thighs; and sparing the anterior and medial muscles in the calves. This report provides important clinical evidence indicating the de novo heterozygous missense mutation c.751C>T in the DYNC1H1 gene is pathogenic causing SMALED. Muscle MRI is more specific than muscle biopsy in the diagnosis of SMALED.

Spinal Muscular Atrophy With Respiratory Distress Type 1-A Child With Atypical Presentation.

The authors report a child with spinal muscular atrophy with respiratory distress type 1 (SMARD1). She presented atypically with hypothyroidism and heart failure due to septal defects that required early heart surgery and microcephaly in association with cerebral atrophy and thin corpus collosum. The subsequent asymmetrical onset of diaphragmatic paralysis, persistent hypotonia, and generalized muscle weakness led to the suspicion of spinal muscular atrophy with respiratory distress type 1. Sanger sequencing confirmed a compound heterozygous mutation in the Immunoglobulin Mu Binding Protein 2 (IGHMBP2) gene, with a known mutation c.2362C > T (p.Arg788*) and a novel frameshift mutation c.2048delG (p.Gly683A1afs*50). Serial nerve conduction study and electromyography confirmed progressive sensorimotor polyneuropathy and neuronopathy. In summary, this case report describes a child with spinal muscular atrophy with respiratory distress type 1 also with congenital cardiac disease and endocrine dysfunction, expanding the phenotypic spectrum of this condition. A high index of suspicion is needed in diagnosing this rare condition to guide the management and genetic counseling.

Significance of Size of Persistent/Recurrent Central Nodal Disease on Surgical Morbidity and Response to Therapy in Reoperative Neck Dissection for Papillary Thyroid Carcinoma.

BACKGROUND: To balance the risk of disease progression, morbidity, and efficacy of reoperative central neck dissection (RCND) in papillary thyroid carcinoma, the latest clinical guidelines recommend early surgery over surveillance when the largest diseased node is >8 mm in its smallest dimension. However, the evidence remains scarce. To determine an appropriate size for first-time RCND, the relationship between size of largest diseased central node, morbidity, and response-to-therapy following RCND was examined. METHODS: A total of 130 patients who underwent RCND following initial surgery for persistent/recurrent nodal disease were reviewed. Patients with largest diseased central node measured preoperatively by ultrasonography were included. Eligible patients were categorized into three groups: largest central node <10 mm (group I), 10-15 mm (group II), and >15 mm (group III). Surgical morbidity and response to therapy at one year after RCND were compared between groups. To evaluate biochemical response, patients with structural incompleteness were excluded. RESULTS: Group III not only had significantly more high-risk tumors (by American Thyroid Association risk stratification) at initial therapy (64.5% vs. 44.4%, respectively; p = 0.038), but this group also a higher risk of extranodal extension (35.5% vs. 16.0%; p = 0.055), recurrent laryngeal nerve involvement (19.4% vs. 0.0%; p < 0.001), incomplete surgical resection (48.4% vs. 7.4%; p < 0.001), new-onset vocal cord paresis (16.7% vs. 2.5%; p = 0.017), overall surgical morbidity (22.6% vs. 7.4%; p = 0.021), and biochemical incompleteness (80.6% vs. 67.9%; p = 0.004) than groups I and II combined did. However, overall morbidity did not differ between groups I and II (5.7% vs. 8.7%; p = 0.694). After adjusting for American Thyroid Association risk stratification, only the size of the largest diseased central node ≥15 mm (odds ratio = 7.256 [confidence interval 1.302-40.434], p = 0.001) was an independent risk factor for biochemical incompleteness following RCND. CONCLUSIONS: Patients with larger diseased central node(s) had a significantly higher risk of local invasion, surgical morbidity, and biochemical incompleteness. Relative to nodal size <10 mm, size >15 mm in the largest disease central node was an independent risk factor for incomplete biochemical response, while nodal size 10-15 mm was not. These findings imply that the recommended threshold of 8 mm might be too stringent and could be raised to 15 mm without increasing the surgical morbidity from RCND.

Novel presenilin 1 mutation (p.F386I) in a Chinese family with early-onset Alzheimer's disease.

Autosomal dominant familial Alzheimer's disease accounts for 0.5% of all Alzheimer's disease. A familial Alzheimer's disease Chinese family, with 7 affected family members, underwent PSEN1 screening in 3 affected family members. A heterozygous novel missense mutation in the PSEN1 gene c.1156T>A, altering phenylalanine to isoleucine at codon 386, was identified. Because the change occurred in conserved domains of this gene and cosegregated with affected family members, this change may have a mutagenic and probably pathogenic effect.

A novel nonsense mutation in the LPL gene in a Chinese neonate with hypertriglyceridemia.

BACKGROUND: Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive disorder characterized by hypertriglyceridemia. The genetic defect lies in a mutation of the LPL gene. METHODS: A Chinese neonate with non-consanguineous parents was incidentally found to have hypertriglyceridemia. Mutation in her LPL gene was screened by using polymerase chain reaction and direct DNA sequencing. RESULTS: Homozygous missense mutations (L252V) were detected in the LPL gene of the patient. A novel nonsense mutation (C27X) was also identified. CONCLUSION: Our finding supports L252V mutation in the LPL gene is a common mutation in Chinese with familial hyperchylomicronemia syndrome. DNA-based diagnosis in this syndrome is definitive. It saves the need for heparin-infusion test, which carries the risk of hemorrhage, and the measurement of LPL activity, which is tedious and is not widely available.

Novel missense mutation in the CASR gene in a Chinese family with familial hypocalciuric hypercalcemia.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder characterized by asymptomatic and non-progressive hypercalcemia resulting from loss-of-function mutations of the CASR (calcium-sensing receptor) gene located on chromosome 3, or from mutations in two mapped but unidentified genes located on chromosome 19. METHODS: We report a middle-aged woman incidentally found to have FHH. To determine the molecular basis of FHH in this Chinese family, we performed direct DNA sequencing of the CASR gene of the proband. RESULTS: We found that the proband is heterozygous for a novel missense mutation P798T, confirming the diagnosis of FHH. Family screening showed that all of the offspring with biochemical features of FHH have the P798T mutation. The mutation, P798T, is located in the third intracellular loop of the CASR, possibly affecting the downstream calcium sensing pathway and therefore inactivating the receptor function. CONCLUSIONS: The molecular basis of FHH in a Chinese family was established. The developed mutation detection assay provides a reliable method for identifying FHH carriers.

Analysis of inborn errors of metabolism: disease spectrum for expanded newborn screening in Hong Kong.

BACKGROUND: Data of classical inborn errors of metabolism (IEM) of amino acids, organic acids and fatty acid oxidation are largely lacking in Hong Kong, where mass spectrometry-based expanded newborn screening for IEM has not been initiated. The current study aimed to evaluate the approximate incidence, spectrum and other characteristics of classical IEM in Hong Kong, which would be important in developing an expanded newborn screening program for the local area. METHODS: The laboratory records of plasma amino acids, plasma acylcarnitines and urine organic acids analyses from year 2005 to 2009 inclusive in three regional chemical pathology laboratories providing biochemical and genetic diagnostic services for IEM were retrospectively reviewed. RESULTS: Among the cohort, 43 patients were diagnosed of IEM, including 30 cases (69%) of amino acidemias (predominantly citrin deficiency, hyperphenylalaninemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency and tyrosinemia type I), 5 cases (12%) of organic acidemias (predominantly holocarboxylase synthetase deficiency) and 8 cases (19%) of fatty acid oxidation defects (predominantly carnitine-acylcarnitine translocase deficiency). The incidence of classical IEM in Hong Kong was roughly estimated to be at least 1 case per 4122 lives births, or 0.243 cases per 1000 live births. This incidence is similar to those reported worldwide, including the mainland of China. The estimated incidence of hyperphenylalaninemia was 1 in 29 542 live births. CONCLUSIONS: Our data indicate that it is indisputable for the introduction of expanded newborn screening program in Hong Kong. Since Hong Kong is a metropolitan city, a comprehensive expanded newborn screening program and referral system should be available to serve the neonates born in the area.