Kabuki syndrome with midgut malrotation and hyperinsulinemic hypoglycemia: A rare co‐occurrence from Thailand

Kabuki syndrome (KS) is a rare heterogeneous phenotypic genetic syndrome, characterized by hypotonia, developmental delay and/or intellectual disability with typical facial features. It is challenging to diagnose KS in newborn and young infant. We report a Thai girl who presented with two rare co‐occurrence phenotypes, hyperinsulinemic hypoglycemia and midgut malrotation. She had not have distinctive facial dysmorphism during neonatal period. At 4 months of age, she had poor weight gain with some facial features suggestive KS. Singleton whole exome sequencing (WES) was carried out followed by Sanger sequencing of the supposed variant. The result indicated a novel de novo heterozygous KMT2D mutation, c.15364A>T (p.Lys5122*), confirming KS. Our patient revealed rare clinical manifestations from the diverse population and address the benefit of WES in establishing early diagnosis of KS before typical facial gestalt exhibited, which allows timely and appropriate management to maximize developmental achievement.     

Case report of a Thai male cystic fibrosis patinet with the 1898+ 1G-->T splicing mutation in the CFTR gene: a review of East Asian cases. Mutations in brief no. 196. Online

Cystic fibrosis (CF) is the most common fatal autosomal recessive multisystem disorder, which occurs mainly in European-derived populations. The incidence of CF varies between 1 in 2000 to 3000 live-births in various ethnic groups. The disease is rare in East Asians. Here we report a 9 year old Thai male patient, who was diagnosed to have CF based on recurrent pneumonia, a slow weight gain, pancreatic insufficiency and repeatedly elevated sweat chloride levels by two different methods. A comprehensive genetic analysis showed the splicing mutation, 1898+ 1G-->T, which was apparently of maternal origin. Literature search found 39 documented cases of CF patients in East Asians. CFTR (MIM# 602421) genotyping was performed in 14 patients including our patient and in 9 of them a CF allele was identified. The findings seem to indicate that the splicing mutations, 1898+ 1G-->T and 1898+ 5G-->T are more common in East Asian CF patients.     

Nonketotic hyperglycinemia in two siblings with neonatal seizures

Seizures are a common problem in neonates. Differential diagnoses include infection, trauma, hypoxia and congenital metabolic disorders. Among these, congenital metabolic disorder is less familiar to general pediatricians. We report two patients with nonketotic hyperglycinemia (NKH), a rare and lethal congenital metabolic disease. Transient hyperammonemia and transient hypouricemia, uncommon features found in NKH, were detected in one patient. High doses of sodium benzoate and dextromethorphan failed to modify the clinical course. Neuropathology denoted characteristic diffuse vacuolization and changes in reactive and gliotic astrocytes. The clinical course, biochemical findings, diagnostic approaches and diagnostic tests are discussed in detail. Recent modalities of treatment are reviewed. Because of its rarity and rapidly progressive course, it maybe underdiagnosed resulting in death before being recognized. Awareness of the possibility of congenital metabolic disorder in early neonatal catastrophe will increase the diagnostic rate.     

Mutations of the slow muscle alpha-tropomyosin gene,TPM3, are a rare cause of nemaline myopathy

The alpha-tropomyosin-3 (TPM3) gene was screened in 40 unrelated patients with nemaline myopathy (NM). A single compound heterozygous patient was identified carrying one mutation that converts the stop codon to a serine and a second splicing mutation that is predicted to prevent inclusion of skeletal muscle exon IX. TPM3 mutations are a rare cause of NM, probably accounting for less than 3% of cases. The severity of cases with TPM3 mutations may vary from severe infantile to late childhood onset, slowly progressive forms.     

Rib defects in patterns of multiple malformations: a retrospective review and phenotypic analysis of 47 cases

Rib anomalies may occur in isolation, as well as in association with abnormalities of vertebral segmentation and multi-system malformations. Specific entities include the VACTERL and MURCS associations, spondylocostal dysostosis, and spondylothoracic dysostosis. The relative significance of rib anomalies in other lesser known syndromes and associations remains unclear. To document the diagnoses and related defects in patients with rib anomalies as part of broader pattern of anomalies, we retrospectively identified 47 cases from a hospital population, and evaluated specific costal findings and associated birth defects. In our study, fusion was the most common pattern of rib anomaly (72%), followed by bifid (28%) and hypoplastic ribs (26%). Unrecognized patterns of multiple congenital anomalies (MCA) and VACTERL association were the commonest specific diagnoses with a frequency of 30 and 28%, respectively. An associated vertebral defect was found in 72% of the patients. Of those with no vertebral anomaly, the combinations of "rib and cardiac defects alone" and "rib and renal defects alone" were seen in one-third of the patients (4/13). Both the occurrence and type of rib anomaly were helpful in defining certain syndromes and enhanced the likelihood of identifying related malformations.     

CT and US findings of a rare case of amoebic liver abscess rupturing into the pericardial cavity

A rare case of amoebic liver abscess that ruptured into the pericardial cavity is reported. This is the first case in the world in which CT scan and ultrasonography were performed in conjunction with each other in demonstrating the fistulous tract. CT scan, ultrasonographic and echocardiographic findings were described in detail. Pericardectomy with surgical drainage and supportive measures led to complete recovery after 37 days of hospitalization.     

Pericardial effusion in primary systemic carnitine deficiency

Summary A patient with pericardial effusion and a complicated presentation of primary systemic carnitine deficiency (PSCD) is described. This is the first case of PSCD reported to have pericardial effusion. Compound heterozygosity for two mutations in the SLC22A5 gene, T440M and F23del, and four SLC22A5 polymorphisms (c.IVS3+6A>G, c.−77G>A, c.−78C>T, and p.S95S) were identified in the patient. Electronic supplementary material Supplementary material is available for this article at     

Comprehensive and long-term outcomes of enzyme replacement therapy followed by stem cell transplantation in children with Gaucher disease type 1 and 3

Background

Gaucher disease (GD) is a lysosomal storage disorder, characterized by hepatosplenomegaly, pancytopenia, bone diseases, with or without neurological symptoms. Plasma glucosylsphingosine (lyso-Gb1), a highly sensitive and specific biomarker for GD, has been used for diagnosis and monitoring the response to treatment. Enzyme replacement therapy (ERT) is an effective treatment for the non-neurologic symptoms of GD. Neuronopathic GD (type 2 and 3) accounts for 60%–70% of the Asian affected population.

Methods

We explored combination therapy of ERT followed by hematopoietic stem cell transplantation (HSCT) and its long-term outcomes in patients with GD type 3 (GD3).

Results

Four patients with GD3 and one with GD type 1 (GD1) underwent HSCT. The types of donor were one matched-related, one matched-unrelated, and three haploidentical. The age at disease onset was 6–18 months and the age at HSCT was 3.8–15 years in the patients with GD3. The latest age at follow-up was 8–22 years, with a post-HSCT duration of 3–14 years. All patients had successful HSCT. Chronic graft-versus-host disease occurred in one patient. The enzyme activities were normalized at 2 weeks post HSCT. Lyso-Gb1 concentrations became lower than the pathological value. All of the patients are still alive and physically independent. Most of them (4/5) returned to school. None of the patients with GD3 had seizures or additional neurological symptoms after HSCT, but showed varying degrees of cognitive impairment.

Conclusions

ERT followed by HSCT could be considered as an alternative treatment for patients with GD3 who have a high risk of fatal neurological progression.     

Molecular characterization of type 3 (neuronopathic) Gaucher disease in Thai patients

Gaucher disease is an autosomal recessive lysosomal storage disorder due to deficiency of the lysosomal enzyme glucocerebrosidase. Three clinical phenotypes, type 1, nonneuronopathic; and types 2 and 3, acute and subacute neuronopathic are recognized. The incidence of Gaucher disease in the Thai population is unknown, but likely under-diagnosed. We performed molecular analysis in four patients, from three sibships, with type 3 Gaucher disease. Four mutant glucocerebrosidase (GBA) alleles were identified including two novel splice site mutations, IVS6-1G>C and IVS9-3C>G; both are predicted to result in truncated protein products, p.F255fsX256, and p.K464fsX487 and p.S463fsX480, respectively. One patient, homozygous for the L444P point mutation, had a "Norbottnian-like" phenotype, with more severe visceral involvement, kyphosis, barreled chest, and no neurological involvement other than supranuclear gaze palsy. These molecular studies of neuronopathic Gaucher disease will provide additional genotype-phenotype correlation particularly in non-Caucasian population.