Yoon-Myung Kim

Endocrine dysfunctions in children with Williams-Beuren syndrome.

Purpose Williams-Beuren syndrome (WBS) is caused by a hemizygous microdeletion of chromosome 7q11.23 and is characterized by global cognitive impairment, dysmorphic facial features, and supravalvular aortic stenosis. Endocrine dysfunctions have been reported in patients with WBS. This study was performed to investigate the frequency, clinical features, and outcomes of endocrine dysfunctions in children with WBS. Methods One hundred two patients were included. The diagnosis was confirmed by chromosome analysis and fluorescent in situ hybridization. Medical charts were reviewed retrospectively to analyze endocrine dysfunctions such as short stature, precocious puberty, thyroid dysfunctions, and hypocalcemia. Results The age at diagnosis was 3.7±4.4 years (one month to 19 years). Height- and weight-standard deviation score (SDS) were –1.1±1.1 and –1.4±1.4 at presentation, respectively. Short stature was found in 26 patients (28.3%) among those older than 2 years. Body mass index-SDS increased as the patients grew older (P<0.001). Two males and one female (2.9%) were diagnosed with central precocious puberty. Nine patients (8.8%) were diagnosed with primary hypothyroidism at age 4.0±4.3 years (one month to 12.1 years); their serum thyroid stimulating hormone and free T4 levels were 15.2±5.4 µU/mL and 1.2±0.2 ng/dL, respectively. Hypercalcemia was observed in 12 out of 55 patients under age 3 (22%) at the age of 14.3±6.6 months (7 to 28 months) with a mean serum calcium level of 13.1±2.1 mg/dL. Conclusion Endocrine dysfunctions are not uncommon causes of morbidity in patients with WBS. The severity and outcomes of their endocrine manifestations were heterogeneous. Long-term follow-up is needed to predict the prognosis of endocrine features.

MPV17 mutations in patients with hepatocerebral mitochondrial DNA depletion syndrome.

MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (MDS) is a very rare condition, and only a few cases have been reported in East Asian countries. Here, we describe four Korean children affected by hepatocerebral MDS. The DGUOK, POLG1, and MPV17 genes were analyzed, and all patients had MPV17 mutations.

Characteristic dysmorphic features in congenital disorders of glycosylation type IIb

Over 100 types of congenital disorders of glycosylation (CDG) have been reported and the number is rapidly increasing. However, each type is very rare and is problematic to diagnose. Mannosyl-oligosaccharide glucosidase (MOGS)-CDG (CDG type IIb) is an extremely rare CDG that has only been reported in three patients from two unrelated families. Using targeted exome sequencing, we identified another patient affected by this condition. This patient had increased serum trisialotransferrin levels. Importantly, a review of the features of all four patients revealed the recognizable clinical hallmarks of MOGS-CDG. The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency.

Rare Frequency of Mutations in Pituitary Transcription Factor Genes in Combined Pituitary Hormone or Isolated Growth Hormone Deficiencies in Korea

Purpose Congenital hypopituitarism is caused by mutations in pituitary transcription factors involved in the development of the hypothalamic-pituitary axis. Mutation frequencies of genes involved in congenital hypopituitarism are extremely low and vary substantially between ethnicities. This study was undertaken to compare the clinical, endocrinological, and radiological features of patients with an isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD). Materials and Methods This study included 27 patients with sporadic IGHD and CPHD. A mutation analysis of the POU1F1, PROP1, LHX3, LHX4, and HESX1 genes was performed using genomic DNA from peripheral blood leukocytes. Results IGHD and CPHD were observed in 4 and 23 patients, respectively. Mean age at diagnosis was 8.28±7.25 years for IGHD and 13.48±10.46 years for CPHD (p=0.37). Serum insulin-like growth factor-1 and peak growth hormone (GH) levels following GH stimulation tests were significantly lower in patients with CPHD than in those with IGHD (p<0.05). Sellar MRI findings revealed structural abnormalities in 3 patients with IGHD (75%) and 21 patients with CPHD (91.3%) (p=0.62). A mutation analysis identified homozygous p.R109Q mutations in HESX1 in a patient with CPHD. Patients with CPHD had more severe GHD than those with IGHD. Conclusion The frequency of defects in the genes encoding pituitary transcription factors was extremely low in Korean patients with congenital hypopituitarism. Environmental factors and the impact of other causative genes may contribute to this clinical phenotype.

Life-threatening bleeding from gastric mucosal angiokeratomas during anticoagulation: A case report of Fabry disease

Rationale: Angiokeratomas are the earliest manifestation of Fabry disease (FD), and the extent of their appearance is related to disease severity. Angiokeratomas are mostly found on cutaneous regions. Patient concerns, diagnoses, interventions, and outcomes: Here we report an FD patient with widespread gastrointestinal angiokeratomas who developed life-threatening bleeding following anticoagulation for atrial fibrillation. Lessons: Careful observation for gastrointestinal bleeding is warranted for patients on anticoagulation with extensive cutaneous angiokeratomas. Furthermore, our experience suggests that surveillance is needed to assess the prevalence and extent of gastrointestinal angiokeratomas in patients with FD.

Severe form of neuroblastoma amplified sequence deficiency in an infant with recurrent acute liver failure

Neuroblastoma amplified sequence (NBAS) deficiency (MIM 616483) is a rare genetic condition with variable phenotype, ranging from isolated acute liver failure (ALF) to short stature, optic nerve atrophy, and Pelger–Hu€et anomaly (SOPH syndrome). Importantly, there are recognizable phenotype patterns in NBAS deficiency: relapsing ALF with febrile episodes, growth delay, facial dysmorphism such as hypotelorism, and optic nerve atrophy. Skeletal dysplasia, immunologic deficiency, cardiac and renal impairment, and cognitive deficit may also occur. We report on a new, very severe phenotype caused by NBAS deficiency and two novel NBAS mutations. Informed consent was given by the patient’s parents. This study was approved by the institutional review board of the Asan Medical Center (IRB No., 2018-0242). The patient was the fourth child of non-consanguineous Korean parents. The first child was normal, the second pregnancy resulted in spontaneous abortion, and the third child died of ALF at age 9 months, and was presumed to have NBAS deficiency. The present prenatal history was remarkable for intrauterine left humerus fracture. The patient was born after 36 weeks of gestation (height, 39 cm [<3rd percentile]; weight, 1.86 kg [<3rd percentile]). Dysmorphic features were noted, including a large anterior fontanelle, flat face, hypotelorism, bulbous nose, low-set ears, funnel chest, and marked hypotonia. Total bilirubin and direct bilirubin were initially elevated but resolved within 1 week with concurrent but transient elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). At age 5 months, the patient was hospitalized for lethargy preceded by 1 day of fever and vomiting, and was transferred to the present hospital for ALF. Neither hepatomegaly nor splenomegaly was noted. AST and ALT were elevated up to 3,253 and 3,419 IU/L, respectively. Total and direct bilirubin were 2.8 and 2.0 mg/dL, respectively. Prothrombin time–international normalized ratio was 4.28, and activated partial thromboplastin time was 42.9 s. Liver function normalized with i.v. glucose infusion after 4 days. Tests for congenital infection were all negative. Liver biopsy at age 6 months indicated diffuse clear cell change of hepatocytes and microvesicular steatosis (Fig. 1a–c). Brain magnetic resonance imaging showed corpus callosum thinning and dysmorphic lateral ventricles with enlarged frontal horns (Fig. 1d). The patient had similar episodes of fever-triggered ALF at ages 6, 7, and 12 months. Given these recurrent episodes of ALF with facial dysmorphism, as well as the severe delay in growth and development, extensive investigations were done, including analysis of plasma amino acids, plasma acylcarnitines, urine organic acids, and mitochondrial genome sequencing in leukocytes, which was unremarkable. Skeletal survey indicated brachycephaly, generalized osteopenia, thin ribs, coliosis, bowed left humerus, and thumb contractures (Fig. 1e,f). At age 12 months, whole exome sequencing was done in the genomic DNA from peripheral leukocytes. We assessed the candidate genes associated with inherited liver disease, Correspondence: Beom Hee Lee, MD PhD, Department of Pediatrics, Asan Medical Center Children’s Hospital, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea. Email: bhlee@amc.seoul.kr Received 4 August 2017; revised 23 October 2017; accepted 1 December 2017. doi: 10.1111/ped.13476

Long-term endocrine effects and trends in body mass index changes in patients with childhood-onset brain tumors

As survival rates have improved owing to advances in management strategies for pediatric brain tumors, long-term complications such as endocrine dysfunction, have emerged as a major issue. This study investigated the long-term endocrine effects of childhood-onset brain tumors in a large number of patients. This study included 151 patients with brain tumors diagnosed between January 1995 and December 2016. The following data were retrospectively reviewed: tumor location, tumor histology, endocrine abnormalities, hypothalamic involvement on brain imaging, treatment modalities, and trends in body mass index. The mean age at diagnosis of patients with sellar/suprasellar (SE/SUP-SE) tumors and supra/infratentorial (ST/IT) tumors was 9.9 ± 4.5 and 6.5 ± 4.2 years, respectively. In patient with prepubertal age at diagnosis, height standard deviation score was lower in patients with SE/SUP-SE tumors at diagnosis (P = 0.031), which was lower in patients with ST/IT tumors at the final visit (P < 0.001). The prevalence of combined pituitary hormone deficiencies was higher among patients with SE/SUP-SE tumors than in those with ST/IT tumors (81.7 vs. 36.1%, P < 0.001). Among 98 non-obese patients with SE/SUP-SE tumors, 36.7% developed obesity. The prevalence of combined pituitary hormone deficiencies and obesity was higher in patients with SE/SUP-SE tumors than in those with tumors in other locations; growth impairment was more severe in patients with ST/IT tumors.

Low prevalence of argininosuccinate lyase deficiency among inherited urea cycle disorders in Korea

Argininosuccinic aciduria (ASA), which is considered to be the second most common urea cycle disorder (UCD), is caused by an argininosuccinate lyase deficiency and is biochemically characterized by elevation of argininosuccinic acid and arginine deficiency. In addition to hyperammonemia, other characteristic features of ASA include hepatic fibrosis, hypertension, neurocognitive deficiencies, and trichorrhexis nodosa. Herein, we retrospectively reviewed the clinical findings, biochemical profiles, and genotypic characteristics of five Korean patients with ASA, who showed typical phenotypes and biochemical findings of the disease. Molecular analysis of these patients revealed six novel ASL mutations. Next, we investigated the prevalence of all types of UCDs in Korea. Of note, over a two decade periods, ASA was only detected in 6.3% of patients with a UCD, which made it the fourth most common UCD in Korea. In comparison with Caucasians, in whom ASA is the second most common UCD, ASA is comparatively rare in East Asian populations, including Japanese and Koreans. These findings suggest the possibility of geographic variation in UCDs among ethnic groups.

Biochemical and molecular analyses of infantile sialic acid storage disease in a patient with nonimmune hydrops fetalis

Nonimmune hydrops fetalis is the most severe clinical manifestation of lysosomal storage diseases (LSDs). Around 14 different LSDs have been accounted for as 1-15% of the cause of nonimmune hydrops fetalis. We report a Korean infant affected by an extremely rare but severe form of sialic acid storage disease. The patient presented with nonimmune hydrops fetalis, dysmorphic facial features, hepatosplenomegaly, and dysostosis multiplex and died at 39 days of age due to persistent pulmonary hypertension. LSD was suspected based on the presence of diffuse vacuolation of syncytiotrophoblast, villous stromal cells, and intermediate trophoblast in placental biopsy. Increased excretion of urinary free sialic acid was detected by liquid chromatography-tandem mass spectrometry. The patient was compound heterozygous of the c.908G>A (p.Trp303Ter) and the splicing mutation c.1259+5G>T (IVS9+5 G>T) in the SLC17A5 gene.

Hepatopulmonary syndrome caused by hypothalamic obesity and nonalcoholic fatty liver disease after surgery for craniopharyngioma: a case report

Hypothalamic obesity is often complicated in patients with craniopharyngioma due to hypothalamic damage by the tumor itself, treatment modalities, and associated multiple pituitary hormone deficiency. Hypothalamic obesity causes secondary diseases such as nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus (DM). We report a 19-year-old female who was diagnosed with craniopharyngioma, developed hypothalamic obesity after tumor resection, and progressed to hepatopulmonary syndrome. She manifested NAFLD 1 year after tumor resection. Two years later, the craniopharyngioma recurred, and she underwent a second resection. Three years after her second operation, she was diagnosed with type 2 DM, after which she did not visit the outpatient clinic for 2 years and then suddenly reappeared with a weight loss of 25.8 kg that had occurred over 21 months. One month later, she presented to the Emergency Department with dyspnea. Laboratory findings revealed liver dysfunction and hypoxia with increased alveolar artery oxygen gradient. Liver biopsy showed portal hypertension and micronodular cirrhosis. Echocardiography and a lung perfusion scan demonstrated a right to left shunt. She was finally diagnosed with hepatopulmonary syndrome and is currently awaiting a donor for liver transplantation. Patients surviving craniopharyngioma need to be followed up carefully to detect signs of hypothalamic obesity and monitored for the development of other comorbidities such as DM, NAFLD, and hepatopulmonary syndrome.