Hyaline Fibromatosis Syndrome: Early Outcomes Following Major Craniofacial Mass Excision.

Hyaline fibromatosis syndrome (HFS) is a rare congenital disorder characterized by abnormal hyaline deposition within soft tissues. Hyaline fibromatosis syndrome manifests in 2 distinct forms: (1) infantile systemic hyalinosis and (2) juvenile hyaline fibromatosis. Infantile systemic hyalinosis, the more severe form, typically emerges in early childhood with extensive systemic involvement. In contrast, juvenile HFS is less severe, allowing patients to survive into adulthood. Common clinical manifestations include thickened skin, hyperpigmented patches, gingival hypertrophy, skin nodules, and progressive severe joint contractures, leading to significant morbidity and potential mortality. This case report describes a 7-year-old child who was diagnosed with HFS and presented with a very large, ulcerated, rapidly expanding craniofacial mass. The patient underwent successful treatment involving a multidisciplinary medical team and strategic surgical intervention, achieving favorable postoperative outcomes.

Metopic and Sagittal Craniosynostosis in Williams Syndrome.

Craniosynostosis has been previously reported in patients with Williams syndrome. Due to the associated significant cardiovascular anomalies, with an attendant increased risk of death under anaesthesia, most patients have been managed conservatively. Here we report the multidisciplinary approach in a 12-month-old female infant with Williams syndrome who has metopic and sagittal craniosynostosis. The child successfully underwent calvarial remodelling procedures, with the clinical outcome demonstrating dramatically improved global development after surgery.

Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients.

BACKGROUND: Gaucher disease (GD) is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010-2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before. RESULTS: There were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 variants including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2+1G>A, IVS6-1G>C, IVS7+1G>C, IVS9-3C>G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2+1G>A, Rec1a, and IVS6-1G>C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa. CONCLUSIONS: Neuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD.

Resolution of Primary Immune Defect in 22q11.2 Deletion Syndrome.

PURPOSE: Patients with 22q11.2 deletion syndrome have a variable decrease in immunological parameters, especially regarding T cell counts. The aim of this study was to investigate immunological change over time and factors associated with immunological recovery among patients with 22q11.2 deletion syndrome. METHODS: Patients with 22q11.2 deletion syndrome diagnosed by fluorescence in situ hybridization (FISH) were studied. Immunological parameters were evaluated every 6 months until patients returned to normal. Infection and vaccination histories were recorded and analyzed, and Kaplan-Meier survival curves were plotted to describe resolution of immunodeficiency. RESULTS: Forty-nine patients with an age range of 4 to 222 months were included. Twenty-five (51%) patients were female. In hypocalcemia, the odds ratio for CD4 lymphopenia was 17.03 (95%CI 1.82-159.23; p value = 0.01). Thirty patients (61.2%) exhibited decreased CD4+ T cell numbers, which returned to normal level in 18 (60%) patients. Median age of CD4+ T cell resolution was 2.5 years. T cell functions were abnormal in three patients. T cell functions returned to normal in all patients at a median age of 1.1 years. Six patients (13.5%) had abnormal serum immunoglobulin levels, with levels improving in four patients at 1.4 years of age. The most common infection was pneumonia (69.4%). BCG vaccination was administered in 47 of 49 patients at birth. Among 32 patients who had T cell defect, one patient developed BCGitis and one developed disseminated BCG. CONCLUSION: Immunodeficiencies identified among patients with 22q11.2 deletion syndrome were T cell defect (65.3%) and decreased immunoglobulin levels (12.2%). Median age of CD4 resolution was 2.5 years.

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.

Clinical characteristics and mutation analysis of propionic acidemia in Thailand.

BACKGROUND: Propionic 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. METHODS: Clinical 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. RESULTS: All 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. CONCLUSIONS: The 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.

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.

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.

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. METHODS: The cases of five unrelated Thai patients with IVA, identified on urine organic acid analysis, are described. Mutation analysis of the IVD gene was performed using polymerase chain reaction sequencing of the entire coding regions. RESULTS: Four out of the five IVA patients had an acute neonatal form. The hematologic abnormalities were common and thus could be presenting symptoms in the absence of metabolic acidosis. As for the neurological outcome, only one patient had normal intelligence. Mutation analysis of the IVD gene identified the mutations c.457-3_2CA>GG, c.1199A>G (p.Y371C), c.281C>G (p.A65G), c.358G>A (p.G91R), and c.827T>C (p.L247P). The poor outcome in most patients might be explained by the delayed diagnosis and initial unavailability of the metabolic formulas and medications in Thailand. The c.457-3_2CA>GG mutation was identified in all of the present patients. This suggests that it is the most common mutation in the Thai population. Therefore, it could be a founder mutation in Thai subjects. One of the present Thai IVA patients also had the p.Y371C mutation, which is common in Han Chinese subjects. In addition, two novel mutations, p.A65G and p.L247P, were identified. CONCLUSION: The present study provides additional knowledge on the genotype-phenotype of IVA, suggesting that IVD mutations in Asian populations are distinct from these in Western populations.

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.

Isolated facial hemihyperplasia: manifestation of Beckwith-Wiedemann syndrome.

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.

Overlapping phenotype of Wolf-Hirschhorn and Beckwith-Wiedemann syndromes in a girl with der(4)t(4;11)(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.

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.

Fetal warfarin syndrome.

Fetuses exposed to Warfarin in the first trimester of pregnancy have an increased risk of embryopathy which consists of nasal hypoplasia and stippled epiphyses, known as fetal warfarin syndrome or warfarin embryopathy. We herein report a first case of an infant with fetal warfarin syndrome in Thailand. The patient was an offspring of a 34-year-old mother with history of SLE and arterial embolism for several years. She had an unplanned pregnancy while taking warfarin. The patient developed difficulty breathing in the first few hours after birth from severe nasal hypoplasia. He also had short limbs, brachydactyly, nail hypoplasia, and calcifications in the epiphyseal regions of humeri, femora and vertebrae radiographically. The patient eventually died from respiratory failure at 6 months of age.

Neural tube defects at Siriraj Hospital, Bangkok, Thailand--10 years review (1990-1999).

OBJECTIVES: Neural tube defects (NTDs), (including anencephaly, meningomyelocele and encephalocele), are among the most common birth defects, with high associated mortality and morbidity. NTDs occur in 1-5 per 1,000 births, with marked geographic and ethnic variations. However, there are few data concerning the incidence, associated anomalies, treatment and outcome of NTDs in Thailand. The objective of this study is to analyze data on NTD cases from 1990-1999 at Siriraj Hospital, a hospital with 18,000-20,000 deliveries annually. MATERIAL AND METHOD: A retrospective chart review of patients with NTDs who were born at or referred to Siriraj Hospital 1990-1999 was performed. RESULTS: During the 10 year period we examined, there were 115 patients with NTDs treated in the Department of Pediatrics as well as in other Departments at Siriraj Hospital. The incidence of NTD is 0.67 per 1,000 births. The sex distribution was equal among NTD cases, 55 (48%) females, 59 (51%) males and one (1%) unidentified sex. Isolated NTDs accounted for 105 (91%) cases, and 10 (8.7%) had at least 1 other structural anomaly such as cleft lip/palate, imperforate anus, amniotic band sequence, or ambiguous genitalia. Among all NTD cases, there were 55 (48%) with myelomeningocele, 45 (39%) with anencephaly, and 14 (12%) with encephalocele. Seventeen (15%) cases died; among these, 7 (41% of deaths) died in utero, 8 (47% of deaths) died in the early neonatal period, and 2 (12%) died after 1 year of age. Regarding treatment, 95 surgical corrections, 47 excisions and repairs, 45 excisions and VP shunts, 1 laminectomy and 2 club feet corrections were performed. CONCLUSIONS: In this hospital-based study of 115 patients with NTD, we found an incidence of 0.67/1000 births; however, as this was a hospital-based study, the community incidence is likely higher. Most cases were isolated NTDs, and almost half of NTDs were meningomyelocele. There was a high rate of mortality. Further studies are warranted to better elucidate the health burden from NTDs in Thailand. Public health interventions aimed at increasing the periconceptional consumption of folic acid should be implemented or enhanced to reduce the incidence of NTDs in Thailand.