Achara Sathienkijkanchai

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.

Amniotic Constriction Band: A Multidisciplinary Assessment of Etiology and Clinical Presentation

Amniotic constriction band , first described in 1832 by Montgomery1, is one term used to describe a wide range of associated congenital anomalies, including anular constrictions of multiple extremities, oligodactyly, acrosyndactyly, talipes equinovarus, cleft lip and cleft palate, and hemangiomas. Additional, less common clinical manifestations include complete absence of the limb, short umbilical cord, craniofacial disruptions, neural tube defects, cranial defects, scoliosis, and body-wall defects, such as gastroschisis and extrathoracic heart. Some of these manifestations are uncommonly noted at birth because they result in spontaneous abortion2-5. The prevalence of amniotic constriction band is approximately one in 1200 to one in 15,000 live births6,7. The prevalence rate for male infants has been reported to be 0.91 and, for female infants, 1.44. These defects are reported to occur 1.76 times more frequently among African-Americans as compared with Caucasians6. Evidence of familial involvement is extremely rare. Although temporal and geographic clustering has been reported, this phenomenon is not well understood8. The variability of presentation between patients, the unusual nature of this constellation of findings, and the lack of a consensus on etiology are all reflected in the fact that thirty-four different names have been used to describe this entity in the literature9. Most of the descriptive terminology used to describe this entity relates to the extremity manifestations; the central manifestations affecting the face and body have not typically been considered for nomenclature. The various names include amnion rupture sequence, aberrant tissue band syndrome, ADAM (amniotic deformity, adhesions, mutilations) complex2, constriction band syndrome, constriction ring syndrome, amnion disruption sequence, and Streeter dysplasia, among others9. The use of the word “syndrome” is controversial because there are no classic, consistently present and defining features of amniotic …

Clinical and molecular findings in Thai patients with isolated methylmalonic acidemia

Isolated methylmalonic acidemia (MMA) is a genetically heterogeneous organic acid disorder caused by either deficiency of the enzyme methylmalonyl-CoA mutase (MCM), or a defect in the biosynthesis of its cofactor, adenosyl-cobalamin (AdoCbl). Herein, we report and review the genotypes and phenotypes of 14 Thai patients with isolated MMA. Between 1997 and 2011, we identified 6 mut patients, 2 cblA patients, and 6 cblB patients. The mut and cblB patients had relatively severe phenotypes compared to relatively mild phenotypes of the cblA patients. The MUT and MMAB genotypes were also correlated to the severity of the phenotypes. Three mutations in the MUT gene: c.788G>T (p.G263V), c.809_812dupGGGC (p.D272Gfs*2), and c.1426C>T (p.Q476*); one mutation in the MMAA gene: c.292A>G (p.R98G); and three mutations in the MMAB gene: c.682delG (p.A228Pfs*2), c.435delC (p.F145Lfs*69), and c.585-1G>A, have not been previously reported. RT-PCR analysis of a common intron 6 polymorphism (c.520-159C>T) of the MMAB gene revealed that it correlates to deep intronic exonization leading to premature termination of the open reading frame. This could decrease the ATP:cobalamin adenosyltransferase (ATR) activity resulting in abnormal phenotypes if found in a compound heterozygous state with a null mutation. We confirm the genotype-phenotype correlation of isolated MMA in the study population, and identified a new molecular basis of the cblB disorder.

Phenotypic and mutation spectrums of Thai patients with isovaleric acidemia

Background:  Isovaleric acidemia (IVA) is an autosomal recessive disorder caused by deficiency of isovaleryl‐CoA dehydrogenase (IVD). Clinical features include vomiting, lethargy, metabolic acidosis, and “sweaty feet” odor. The pathognomonic metabolite, isovalerylglycine, is detected on urine organic acid analysis. Clinical diagnosis of IVA can be confirmed on mutation analysis of the IVD gene.

Carnitine–acylcarnitine translocase deficiency: Two neonatal cases with common splicing mutation and in vitro bezafibrate response

BACKGROUND Mitochondrial fatty acid oxidation (FAO) disorders are among the causes of acute encephalopathy- or myopathy-like illness. Carnitine-acylcarnitine translocase (CACT) deficiency is a rare FAO disorder, which represent an energy production insufficiency during prolonged fasting, febrile illness, or increased muscular activity. CACT deficiency is caused by mutations of the SLC25A20 gene. Most patients developed severe metabolic decompensation in the neonatal period and died in infancy despite aggressive treatment. PATIENTS AND METHODS We herein report the clinical findings of two unrelated cases of CACT deficiency with mutation confirmation, and in vitro bezafibrate responses using in vitro probe acylcarnitine (IVP) assay. Patients 1 and 2 are products of nonconsanguineous parents. Both patients developed cardiac arrest at day 3 of life but survived the initial events. Their blood chemistry revealed hypoglycemia and metabolic acidosis. The acylcarnitine profiles in both patients demonstrated increased long-chain acylcarnitines, suggesting CACT or carnitine palmitoyltransferase-2 (CPT2) deficiency. RESULTS The mutation analysis identified homozygous IVS2-10T>G in the SLC25A20 gene in both patients, confirming the diagnosis of CACT deficiency. The IVP assay revealed increased C16, C16:1, but decreased C2 with improvement by bezafibrate in the cultured fibroblasts. The short-term clinical trial of bezafibrate in Patient 1 did not show clinical improvement, and died after starting the trial for 6 months. CONCLUSION This splicing mutation has been identified in other Asian populations indicating a possible founder effect. IVP assay of cultured fibroblasts could determine a response to bezafibrate treatment. A long-term clinical trial of more enrolled patients is required for evaluation of this therapy.

Amino acid disorders detected by quantitative amino acid HPLC analysis in Thailand: An eight-year experience

BACKGROUND Amino acid disorders are a major group of inborn errors of metabolism (IEM) with variable clinical presentations. This study was aimed to provide the data of amino acid disorders detected in high-risk Thai patients referred to our metabolic lab from all over the country. METHODS From 2001 to 2009, we analyzed amino acids by HPLC in 1214 plasma and cerebrospinal fluid specimens. These specimens were obtained from patients with clinical suspicion of IEM or with positive newborn screening. The clinical data of the patients with confirmed diagnoses of amino acid disorders were also analyzed. RESULTS Fifty-eight patients were diagnosed with amino acid disorders, including 20 cases (34.5%) with maple syrup urine disease, 13 (22.4%) with phenylketonuria and hyperphenylalaninemia, 13 (22.4%) with nonketotic hyperglycinemia, 9 (15.5%) with urea cycle defects, 2 (3.4%) with classical homocystinuria, and 1 (1.7%) with ornithine aminotransferase deficiency. There was considerable delay in diagnoses which led to poor outcomes in most patients. CONCLUSION The prevalence of amino acid disorders in Thailand is distinct from other countries. This will guide the selection of the prevalent IEM for the future expansion of newborn screening program in this country.

Overlapping phenotype of wolf-hirschhorn and beckwith-wiedemann syndromes in a girl with der(4)t(4; 1 1)(pter;pter)

We report on an 8‐month‐old girl with a novel unbalanced chromosomal rearrangement, consisting of a terminal deletion of 4p and a paternal duplication of terminal 11p. Each of these is associated with the well‐known clinical phenotypes of Wolf–Hirschhorn syndrome (WHS) and Beckwith–Wiedemann syndrome (BWS), respectively. She presented for clinical evaluation of dysmorphic facial features, developmental delay, atrial septal defect (ASD), and left hydronephrosis. High‐resolution cytogenetic analysis revealed a normal female karyotype, but subtelomeric fluorescence in situ hybridization (FISH) analysis revealed a der(4)t(4;11)(pter;pter). Both FISH and microarray CGH studies clearly demonstrated that the WHS critical regions 1 and 2 were deleted, and that the BWS imprinted domains (ID) 1 and 2 were duplicated on the der(4). Parental chromosome analysis revealed that the father carried a cryptic balanced t(4;11)(pter;pter). As expected, our patient manifests findings of both WHS (a growth retardation syndrome) and BWS (an overgrowth syndrome). We compare her unique phenotypic features with those that have been reported for both syndromes.

Clinical characteristics and mutation analysis of propionic acidemia in Thailand

BackgroundPropionic acidemia (PA) is caused by a deficiency of propionyl CoA carboxylase. A characteristic urine organic acid profile includes 3-hydroxypropionate, methylcitrate, tiglylglycine, and propionylglycine. The diagnosis of PA is confirmed by detection of mutations in the PCCA or PCCB genes. We herein report the clinical and molecular findings of four Thai patients with PA.MethodsClinical findings of four Thai patients with PA were retrospectively reviewed. Urine organic acids were analyzed by gas chromatography-mass spectrometry. PCR-sequencing analyses of encoding exons and intron/exon boundaries of the PCCA and PCCB genes were performed.ResultsAll patients had neonatal onset of PA. One patient died of cardiomyopathy, and another one of pneumonia and metabolic decompensation. The remainder experienced significant neurocognitive impairment. Mutation analysis of the PCCA gene identified homozygous c.1284+1G>A in patient 1, c.230G>A (p.R77Q) and c.1855C>T (p.R619X) in patient 2, homozygous c.2125T>C (p.S709P) in patient 3, and only one mutant allele, c.231+1G>T in patient 4. No PCCB mutation was identified. Four mutations including c.230G>A, c.231+1G>T, c.1855C>T, and c.2125T>C have not been reported previously.ConclusionsThe clinical and molecular study of these Thai patients provided additional knowledge of the genotype and phenotype characteristics of PA. The results of the study suggested that PCCA mutations in Asian populations were distinct from those of other populations.

Isolated facial hemihyperplasia: manifestation of Beckwith-Wiedemann syndrome.

Abstract Facial asymmetry is a common finding in infants and can be the result of a number of distinctive conditions such as hemifacial microsomia, overgrowth syndromes, a soft tissue tumor, and a vascular malformation. However, overgrowth syndromes such as Beckwith-Wiedemann syndrome (BWS) typically manifest more extensive involvement; it rarely presents as isolated facial overgrowth. Here, we present a 7-year-old boy who presented with facial asymmetry. He was found to have isolated facial hemihyperplasia, involving his right cheek and teeth. No abnormalities were seen in the rest of his examination. The diagnosis of BWS was considered and was confirmed by detection of a methylation abnormality in H19 (DMR1). This case demonstrates that BWS should be considered, even with isolated facial involvement. This is important, as affected patients are predisposed to certain malignancies, especially in the first 5 to 8 years of life. Therefore, specialized surveillance is recommended as the part of management.

A genetic model for cloacal exstrophy, the extreme cloacal malformation

Cloacal exstrophy (CE) or vesicointestinal fissure is an uncommon but well known anomaly that represents the extreme cloacal malformation. It is most often seen as an isolated anomaly, or as part of the OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects). Limb anomalies are also seen with CE. Unlike the OEIS complex, limb anomalies occur as independent malformations. Here, we present two cases of CE with limb anomalies that are consistent with the phenotype seen in Disorganization (Ds), an unusual human malformation syndrome. From reviewing the mouse model, it may be that the Ds gene is a candidate for isolated CE as well.